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Chronic Rejection of Cardiac Allografts is Associated with Increased Lymphatic Flow and Cellular Trafficking [Original Research Article]


Background—Cardiac transplantation is an excellent treatment for end-stage heart disease. However, rejection of the donor graft, particularly by chronic rejection leading to cardiac allograft vasculopathy, remains a major cause of graft loss. The lymphatic system plays a crucial role in the alloimmune response, facilitating trafficking of antigen presenting cells (APCs) to draining lymph nodes (dLN). The encounter of APCs with T lymphocytes in secondary lymphoid organs is essential for the initiation of alloimmunity. Donor lymphatic vessels are not anastomosed to that of the recipient during transplantation. The pathophysiology of lymphatic disruption is unknown and whether this disruption enhances or hinders the alloimmune responses is unclear. Although histological analysis of lymphatic vessels in donor grafts can yield information on the structure of the lymphatics, the function, however, following cardiac transplantation is poorly understood. Methods—Using Single photon emission computed tomography/CT (SPECT/CT) lymphoscintigraphy, we quantified the lymphatic flow index (LFI) following heterotrophic cardiac transplantation in a murine model of chronic rejection.Results—Ten weeks following transplantation of a minor antigen (HY) gender-mismatched heart graft, the LFI was significantly increased compared with gender-matched controls. Furthermore, the enhanced LFI correlated with an increase in donor cells in the mediastinal dLN; increased lymphatic vessel area; and graft infiltration of CD4+, CD8+ T-cells and CD68+ macrophages. Conclusions—Chronic rejection results in increased lymphatic flow from the donor graft to dLNs, which may be a factor in promoting cellular trafficking, alloimmunity, and cardiac allograft vasculopathy.

Derivation and Validation of a Novel Right-Sided Heart Failure Model After Implantation of Continuous Flow Left Ventricular Assist Devices:The EUROMACS (European Registry for Patients with Mechanical Circulatory Support) Right-Sided Heart Failure Risk Score [Original Research Article]


Background—The aim of the study was to derive and validate a novel risk score for early right-sided heart failure (RHF) after left ventricular assist device implantation.Methods—The European Registry for Patients with Mechanical irculatory Support (EUROMACS) was used to identify adult patients undergoing continuous-flow left ventricular assist device implantation with mainstream devices. Eligible patients (n=2988) were randomly divided into derivation (n=2000) and validation (n=988) cohorts. The primary outcome was early (<30 days) severe postoperative RHF, defined as receiving short- or long-term rightsided circulatory support, continuous inotropic support for ≥14 days, or nitric oxide ventilation for ≥48 hours. The secondary outcome was all-cause mortality and length of stay in the intensive care unit. Covariates found to be associated with RHF (exploratory univariate P<0.10) were entered into a multivariable logistic regression model. A risk score was then generated using the relative magnitude of the exponential regression model coefficients of independent predictors at the last step after checking for collinearity, likelihood ratio test, c index, and clinical weight at each step.Results—A 9.5-point risk score incorporating 5 variables (Interagency Registry for Mechanically Assisted Circulatory Support class, use of multiple inotropes, severe right ventricular dysfunction on echocardiography, ratio of right trial/ pulmonary capillary wedge pressure, hemoglobin) was created. The mean scores in the derivation and validation cohorts were 2.7±1.9 and 2.6±2.0, respectively (P=0.32). RHF in the derivation cohort occurred in 433 patients (21.7%) after left ventricular assist device implantation and was associated with a lower 1-year (53% versus 71%; P<0.001) and 2-year (45% versus 58%; P<0.001) survival compared with patients without RHF. RHF risk ranged from 11% (low risk score 0-2) to 43.1% (high risk score >4; P<0.0001). Median intensive care unit stay was 7 days (interquartile range, 4-15 days) versus 24 days (interquartile range, 14-38 days) in patients without versus with RHF, respectively (P<0.001). The c index of the composite score was 0.70 in the derivation and 0.67 in the validation cohort. The EUROMACS-RHF risk score outperformed (P<0.0001) previously published scores and known individual echocardiographic and hemodynamic markers of RHF.Conclusions—This novel EUROMACS-RHF risk score outperformed currently known risk scores and clinical predictors of early postoperative RHF. This novel score may be useful for tailored risk-based clinical assessment and management of patients with advanced HF evaluated for ventricular assist device therapy.

When VAD Things Happen to Good People [Editorial]


In his book, When Bad Things Happen to Good People, Harold Kushner explores explanations for human pain and suffering. He notes that while many of the afflictions of the human condition are beyond our understanding, none of us are exempt from the common experience. Despite the original publication of this thesis more than 35 years ago, Kushner's musings draw parallels to the patient experience with mechanically assisted circulation. The underlying mechanism and management of several morbid and mortal left ventricular assist device (LVAD) complications are beyond contemporary understanding but are sufficiently frequent to be considered common. The paper by Soliman in this issue of Circulation adds clarity to the question about why VAD things happen to good people by defining pre-operative risk factors that predispose patients to the development of right heart failure following implantation of a left-sided mechanical blood pump.

Exercise-Induced Changes in Glucose Metabolism Promote Physiologic Cardiac Growth [Original Research Article]


Background—Exercise promotes metabolic remodeling in the heart, which is associated with physiologic cardiac growth; however, it is not known whether or how physical activity-induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiologic cardiac growth. Methods—We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2) affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart.Results—Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, upon exercise adaptation and recovery there was an increase in myocardial phosphofructokinase activity and glycolysis. Cardiac-specific expression of a kinase-deficient PFK2 transgene (GlycoLo mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of GlycoLo mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient PFK2 in the heart (GlycoHi mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiologic cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose-fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling. Conclusions—Exercise-induced decreases in glycolytic activity stimulate physiologic cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.

Integrated Non-invasive Physiological Assessment of Coronary Circulatory Function and Impact on Cardiovascular Mortality in Patients with Stable Coronary Artery Disease [Original Research Article]


Background—It is suggested that the integration of maximal myocardial blood flow (MBF) and coronary flow reserve (CFR), termed coronary flow capacity, allows comprehensive evaluation of patients with known or suspected stable coronary artery disease. As management decisions are predicated on clinical risk, we sought to determine the independent and integrated value of maximal MBF and CFR for predicting cardiovascular death.Methods—MBF and CFR were quantified in 4,029 consecutive patients (median age 66 years, 50.5% women) referred for rest/stress myocardial perfusion positron emission tomography scans from January 2006 to December 2013. The primary outcome was cardiovascular mortality. Maximal MBF<1.8 ml×g-1×min-1 and CFR<2 were considered impaired. Four patient groups were identified based on the concordant or discordant impairment of maximal MBF or CFR. Association of maximal MBF and CFR with cardiovascular death was assessed using Cox and Poisson regression analyses.Results—A total of 392 (9.7%) cardiovascular deaths occurred over a median follow-up of 5.6 years. CFR was a stronger predictor of cardiovascular mortality than maximal MBF beyond traditional cardiovascular risk factors, left ventricular ejection fraction, myocardial scar and ischemia, rate-pressure-product, type of radiotracer or stress agent used, and revascularization post-scan (adjusted Hazard Ratio, HR [95% Confidence-Interval, CI]: 1.79 [1.38-2.31], p<0.001 per unit decrease in CFR after adjustment for maximal MBF and clinical covariates, and 1.03 [0.84-1.27], p=0.8 per unit decrease in maximal MBF after adjustment for CFR and clinical covariates). In univariable analyses, patients with concordant impairment of CFR and maximal MBF had high cardiovascular mortality of 3.3% (95% CI: 2.9-3.7%) per year. Patients with impaired CFR but preserved maximal MBF had an intermediate cardiovascular mortality of 1.7% (95% CI: 1.3-2.1%) per year; these patients were predominantly women (70%). Patients with preserved CFR but impaired maximal MBF had low cardiovascular mortality of 0.9% (95% CI: 0.6-1.6%) per year. Patients with concordantly preserved CFR and maximal MBF had the lowest cardiovascular mortality of 0.4% (95% CI: 0.3-0.6%) per year. In multivariable analysis, the cardiovascular mortality risk gradient across the four concordant or discordant categories was independently driven by impaired CFR irrespective of impairment in maximal MBF.Conclusions—CFR is a stronger predictor of cardiovascular mortality than maximal MBF. Concordant and discordant categories based on integrating CFR and maximal MBF identify unique prognostic phenotypes of patients with known or suspected coronary artery disease.

Conscious Sedation versus General Anesthesia for Transcatheter Aortic Valve Replacement: Insights from the NCDR(R) STS/ACC TVT Registry [Original Research Article]


Background—Conscious sedation is used during transcatheter aortic valve replacement (TAVR) with limited evidence as to the safety and efficacy of this practice.Methods—The NCDR STS/ACC TVT Registry was used to characterize the anesthesia choice and clinical outcomes of all U.S. patients undergoing elective percutaneous transfemoral TAVR between April 1, 2014 and June 30, 2015. Raw and inverse probability of treatment weighted (IPTW) analyses were performed to compare general anesthesia patients with conscious sedation patients on an intention-to-treat basis for the primary outcome of in-hospital mortality, and secondary outcomes including 30-day mortality, in-hospital and 30-day death/stroke, procedural success, ICU and hospital length-of-stay, and rates of discharge to home. Post-hoc falsification endpoint analyses were performed to evaluate for residual confounding. Results—Conscious sedation was used in 1,737/10,997 (15.8%) cases with a significant trend of increasing usage over the time period studied (p for trend <0.001). In raw analyses, intraprocedural success with conscious sedation and general anesthesia was similar (98.2% versus 98.5%, p=.31). The conscious sedation group was less likely to suffer in-hospital (1.6% vs. 2.5%, p=0.03) and 30-day death (2.9% vs. 4.1%, p = 0.03). Conversion from conscious sedation to general anesthesia was noted in 102/1737 (5.9%) of conscious sedation cases. After IPTW adjustment for 51 covariates, conscious sedation was associated with lower procedural success (97.9% vs. 98.6%, p<0.001) and a reduced rate of mortality at the in-hospital (1.5% vs. 2.4%, p<0.001) and 30-day (2.3% vs. 4.0%, p<0.001) timepoints. Conscious sedation was associated with reductions in procedural inotrope requirement, ICU and hospital length of stay (6.0 vs. 6.5 days, p < 0.001), and combined 30-day death/stroke rates (4.8% vs. 6.4%, p <0.001). Falsification endpoint analyses of vascular complications, bleeding, and new pacemaker/defibrillator implantation demonstrated no significant differences between groups after adjustment. Conclusions—In U.S. practice, conscious sedation is associated with briefer length of stay and lower in-hospital and 30-day mortality compared to TAVR with general anesthesia in both unadjusted and adjusted analyses. These results suggest the safety of conscious sedation in this population, though comparative effectiveness analyses using observational data cannot definitively establish the superiority of one technique over another.

Empagliflozin and Clinical Outcomes in Patients with Type 2 Diabetes, Established Cardiovascular Disease and Chronic Kidney Disease [Original Research Article]


Background—Empagliflozin, a sodium glucose cotransporter 2 inhibitor, reduced cardiovascular morbidity and mortality in patients with type 2 diabetes and established cardiovascular disease in the EMPA-REG OUTCOME® trial. Urinary glucose excretion with empagliflozin decreases with declining renal function, resulting in less potency for glucose lowering in patients with kidney disease. We investigated the effects of empagliflozin on clinical outcomes in patients with type 2 diabetes, established cardiovascular disease and chronic kidney disease.Methods—Patients with type 2 diabetes, established cardiovascular disease and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2 at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. We analyzed cardiovascular death, hospitalization for heart failure, all-cause hospitalization and all-cause mortality in patients with prevalent kidney disease (defined as eGFR <60 mL/min/1.73m2 and/or urine albumin-creatinine ratio [UACR] >300 mg/g) at baseline. Additional analyses were performed in subgroups by baseline eGFR (<45, 45 to <60, 60 to <90, ≥90 mL/min/1.73m2) and baseline UACR (>300, 30 to ≤300, <30 mg/g).Results—Of 7020 patients treated, 2250 patients had prevalent kidney disease at baseline, of whom 67% had a diagnosis of type 2 diabetes for >10 years, 58% were receiving insulin and 84% were taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers. In patients with prevalent kidney disease at baseline, empagliflozin reduced the risk of cardiovascular death by 29% compared with placebo (hazard ratio [HR] 0.71 [95% CI 0.52, 0.98]), the risk of all-cause mortality by 24% (HR 0.76 [95% CI 0.59, 0.99]), the risk of hospitalization for heart failure by 39% (HR 0.61 [95% CI 0.42, 0.87]) and the risk of all-cause hospitalization by 19% (HR 0.81 [95% CI 0.72, 0.92]). Effects of empagliflozin on these outcomes were consistent across categories of eGFR and of UACR at baseline and across the two doses studied. The adverse event profile of empagliflozin in patients with eGFR <60 mL/min/1.73m2 was consistent with the overall trial population.Conclusions—Empagliflozin improved clinical outcomes and reduced mortality in vulnerable patients with type 2 diabetes, established cardiovascular disease and chronic kidney disease.Clinical Trial Registration—URL: Unique identifier: NCT01131676.

Antiarrhythmic Drugs for Non-Shockable-Turned-Shockable Out-of-Hospital Cardiac Arrest: The Amiodarone, Lidocaine or Placebo Study (ALPS) [Original Research Article]


Background—Out-of-hospital cardiac arrest (OHCA) commonly presents with non-shockable rhythms (asystole and pulseless electrical activity (PEA)). Whether antiarrhythmic drugs are safe and effective when these evolve to shockable rhythms (ventricular fibrillation/pulseless ventricular tachycardia (VF/VT)) during resuscitation is not known. Methods—Adults with non-traumatic OHCA, vascular access and VF/VT anytime after ≥1 shock(s) were prospectively randomized, double-blind, to receive amiodarone, lidocaine or placebo by paramedics. Patients presenting with initial shock-refractory VF/VT were previously reported. The current study was a pre-specified analysis in a separate cohort who initially presented with non-shockable OHCA and were randomized upon subsequently developing shock-refractory VF/VT. The primary outcome was survival to hospital discharge; secondary outcomes included discharge functional status and adverse drug-related effects. Results—Of 37,889 patients with OHCA, 3,026 with initial VF/VT and 1,063 with initial non-shockable-turned-shockable rhythms were treatment-eligible, randomized and received their assigned drug. Baseline characteristics among non-shockable-turned-shockable patients were balanced across treatment arms except that placebo recipients included fewer men and were less likely to receive bystander-CPR. Active-drug recipients in this cohort required fewer shocks, supplemental doses of their assigned drug and ancillary antiarrhythmic drugs than placebo-recipients (p<0.05). In all, 16 (4.1%) amiodarone, 11 (3.1%) lidocaine and 6 (1.9%) placebo-treated patients survived to hospital discharge (p=0.24). There was no significant interaction of treatment assignment and discharge survival with the initiating OHCA rhythm (asystole, PEA, or VF/VT); survival in each of these categories was consistently higher with active-drugs, though the trends were not statistically significant. Adjusted absolute differences (95% confidence interval) in survival from non-shockable-turned-shockable arrhythmias with amiodarone vs placebo were 2.3% (-0.3, 4.8), p=0.08 and for lidocaine vs placebo 1.2% (-1.1, 3.6), p=0.30. Over one-half of these survivors were functionally independent or required minimal assistance. Drug-related adverse effects were infrequent. Conclusions—Outcome from non-shockable-turned-shockable OHCA is poor, but not invariably fatal. Though not statistically significant, point estimates for survival were greater after amiodarone or lidocaine than placebo, without increased risk of adverse effects or disability, and consistent with previously observed favorable trends from treatment of initial shock-refractory VF/VT with these drugs. Together the findings may signal a clinical benefit that invites further investigation. Clinical Trial Registration—URL: Unique Identifier: NCT01401647

Clinical Profile and Consequences of Atrial Fibrillation in Hypertrophic Cardiomyopathy [Original Research Article]


Background—Atrial fibrillation (AF), the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM), is capable of producing symptoms that impact quality of life and is associated with risk for embolic stroke. However, the influence of AF on clinical course and outcome in HCM remains incompletely resolved. Methods—Records were accessed of 1558 consecutive patients followed at the Tufts Medical Center Hypertrophic Cardiomyopathy Institute for 4.8 ± 3.4 years, from 2004 to 2014.Results—Of the 1558 HCM patients, 304 (20%) had episodes of AF, of which 226 (74%) were confined to symptomatic paroxysmal AF (PAF; average 5 ± 5; range 1 to > 20), while 78 (26%) developed permanent AF, preceded by 7 ± 6 PAF episodes. At last evaluation, 277 patients (91%) are alive at 62 ± 13 years of age, including 89% in NYHA class I or II. There was no difference in outcome measures for AF patients and age and gender matched HCM patients without AF. Four percent of AF patients died of HCM-related causes (n=11) with annual mortality 0.7 %; mortality directly attributable to AF (thromboembolism without prophylactic anticoagulation) was 0.1 %/year (n=2 patients). Patients were treated with antiarrhythmic drugs (most commonly amiodarone [n=103] or sotalol [n=78]), and with AF catheter ablation (n=49) or Maze procedure at surgical myectomy (n=72). Freedom from AF recurrence at 1 year was 44% for ablation patients and 75% with Maze (p<0.001). Embolic events were less common with anticoagulation prophylaxis (4/233; 2%) than without (9/66; 14%) (p<0.001). Conclusions—Transient symptomatic episodes of AF, although relatively uncommon in HCM, are unpredictable in frequency and timing, amenable to effective contemporary treatments, and infrequently progress to permanent AF. AF is not a major contributor to heart failure morbidity, nor a cause of arrhythmic sudden death, and when treated is associated with low-disease-related mortality, no different than for patients without AF. AF is an uncommon primary cause of death in HCM virtually limited to embolic stroke, supporting a low threshold for initiating anticoagulation therapy.

The J-curve in Patients Randomly Assigned to Different Systolic Blood Pressure Targets - an Experimental Approach to an Observational Paradigm [Original Research Article]


Background—Low systolic blood pressure (SBP) values are associated with an increased risk of cardiovascular events, giving rise to the so called J-curve phenomenon. We assessed the association between on-treatment SBP levels, cardiovascular events and all-cause mortality in patients randomized to different SBP targets.Methods—Data from two large randomized trials that randomly allocated hypertensive patients at high-risk for cardiovascular disease to intensive (SBP<120 mmHg) or conventional treatment (SBP<140 mmHg) were pooled and harmonized for outcomes and follow-up duration. Using natural cubic splines, the hazard ratio for all-cause mortality and cardiovascular events was plotted against the mean on-treatment systolic blood pressure per treatment group. Results—The pooled data consisted of 194,875 on-treatment SBP measurements in 13,946 (98.9%) patients. During a median follow-up of 3.3 years, cardiovascular events occurred in 1014 patients (7.3%) and 502 patients died (3.7%). For both blood pressure targets, an identical shape of the J-curve was present with a nadir for cardiovascular events and all-cause mortality just below the SBP target. Patients in the lowest SBP stratum were older, had a higher BMI, smoked more often and had a higher frequency of diabetes and cardiovascular events.Conclusions—Low on-treatment SBP levels are associated with increased cardiovascular events and all-cause mortality. This association is independent of the attained blood pressure level because the J-curve aligns with the SBP target. Our results suggest that the benefit or risk associated with intensive blood pressure lowering treatment can only be established via randomized clinical trials. Clinical Trial Registration—URL: Unique Identifiers: NCT01206062 and NCT00000620

Binding of FUNDC1 with Inositol 1,4,5-Trisphosphate Receptor in Mitochondria-Associated Endoplasmic Reticulum (ER) Membranes Maintains Mitochondrial Dynamics and Function in Hearts In Vivo [Original Research Article]


Background—FUN14 domain containing 1 (FUNDC1) is a highly conserved outer mitochondrial membrane protein. The aim of this study is to examine if FUNDC1 modulates the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondrial morphology, and function in cardiomyocytes and in intact hearts. Methods—The impacts of FUNDC1 on MAMs formation and cardiac functions were studied in mouse neonatal cardiomyocytes, in mice with cardiomyocyte-specific Fundc1 gene knockout (Fundc1f/Y/CreαMyHC+/−), and in the cardiac tissues of the patients with heart failure. Results—In mouse neonatal cardiomyocytes and intact hearts, FUNDC1 was localized in MAMs by binding to ER-resided inositol 1,4,5-trisphosphate type 2 receptor (IP3R2). Fundc1 ablation disrupted MAMs, reduced the levels of IP3R2 and Ca2+ in both mitochondria and cytosol whereas overexpression of Fundc1 increased the levels of IP3R2 and Ca2+ in both mitochondria and cytosol. Consistently, Fundc1 ablation increased Ca2+ levels in ER whereas Fundc1 overexpression lowered ER Ca2+ levels. Further, Fundc1 ablation in cardiomyocytes elongated mitochondria, and compromised mitochondrial functions. Mechanistically, we found that Fundc1 ablation-induced reduction of intracellular Ca2+ levels suppressed mitochondrial fission 1 protein (Fis1) expression and mitochondrial fission by reducing the binding of the cAMP response element binding protein (CREB) in the Fis1 promoter. Fundc1f/Y/CreαMyHC+/− mice but not their littermate control mice (Fundc1wt/Y/CreαMyHC+/−) exhibited cardiac dysfunction. The ligation of the left ventricle artery of Fundc1f/Y/CreαMyHC+/− mice caused more severe cardiac dysfunction than those in sham-treated Fundc1f/Y/CreαMyHC+/− mice. Finally, we found that the FUNDC1/MAMs/CREB/Fis1 signaling axis was significantly suppressed in the patients with heart failure.Conclusions—We conclude that FUNDC1 binds to IP3R2 to modulate ER Ca2+ release into mitochondria and cytosol and that a disruption of FUNDC1 and IP3R2 interaction lowers the levels of Ca2+ in mitochondria and cytosol, both of which instigate aberrant mitochondrial fission, mitochondrial dysfunction, cardiac dysfunction, and heart failure.

Interhospital Transfer Prior to Thrombectomy is Associated with Delayed Treatment and Worse Outcome in the STRATIS Registry [Original Research Article]


Background—Endovascular treatment with mechanical thrombectomy (MT) is beneficial for acute stroke patients suffering a large vessel occlusion, though treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared to direct presentation.Methods—STRATIS was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke due to anterior-circulation large vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without IV-tPA, and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0-2) at 90 days. We assessed 1) real-world time metrics of stroke care delivery, 2) outcome differences between direct and transfer patients undergoing MT, and 3) the potential impact of local hospital bypass.Results—A total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct vs. 311.5 minutes for transfer patients (p<0.001). Clinical outcomes were better in the direct group with 60.0% (299/498) achieving functional independence, compared to 52.2% (213/408) in the transfer group (odds ratio 1.38, 95%CI 1.06-1.79; p=0.02). Likewise, excellent outcome (modified Rankin Score 0-1) was achieved in 47.4% (236/498) of direct patients vs. 38.0% (155/408) of transfer patients (odds ratio 1.47, 95%CI 1.13-1.92; p=0.005). Mortality did not differ between the two groups (15.1% for direct, 13.7% for transfer; p=0.55). IV-tPA did not impact outcomes. Hypothetical bypass modeling for all transferred patients suggested that IV-tPA would be delayed by 12 minutes but MT would be performed 91 minutes sooner if patients were routed directly to endovascular-capable centers. If bypass is limited to a 20-mile radius from onset, then IV-tPA would be delayed by 7 minutes and MT performed 94 minutes earlier. Conclusions—In this large, real-world study, interhospital transfer was associated with significant treatment delays and lower chance of good outcome. Strategies to facilitate more rapid identification of large vessel occlusion and direct routing to endovascular-capable centers for severe stroke patients may improve outcomes.Clinical Trial Registration—URL: Unique identifier: NCT02239640

Identification of miR-124 as a Major Regulator of Enhanced Endothelial Cell Glycolysis in Pulmonary Arterial Hypertension via PTBP1 and PKM2 [Original Research Article]


Background—Pulmonary arterial hypertension (PAH) is characterized by abnormal growth and enhanced glycolysis of pulmonary artery endothelial cells (PAECs). However, the mechanisms underlying alterations in energy production have not been identified. Methods—Here, we examined the miRNA and proteomic profiles of blood outgrowth endothelial cells (BOECs) from patients with heritable PAH (HPAH) due to mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene and patients with idiopathic PAH (IPAH) to determine mechanisms underlying abnormal endothelial glycolysis. We hypothesized that in BOECs from PAH patients, the downregulation of miR-124, determined using a tiered systems biology approach, is responsible for increased expression of the splicing factor polypyrimidine-tract-binding protein (PTBP1), resulting in alternative splicing of pyruvate kinase muscle isoforms 1 and 2 (PKM1 and 2) and consequently, increased PKM2 expression. We questioned whether this alternative regulation plays a critical role in the hyperglycolytic phenotype of PAH endothelial cells.Results—HPAH and IPAH BOECs recapitulated the metabolic abnormalities observed in PAECs from IPAH patients, confirming a switch from oxidative phosphorylation to aerobic glycolysis. Overexpression of miR-124, or siRNA silencing of PTPB1, restored normal proliferation and glycolysis in HPAH BOECs, corrected the dysregulation of glycolytic genes and lactate production, and partially restored mitochondrial respiration. BMPR2 knockdown in control BOECs reduced expression of miR-124, increased PTPB1, and enhanced glycolysis. Moreover, we observed reduced miR-124, increased PTPB1 and PKM2 expression and significant dysregulation of glycolytic genes in the rat SUGEN-hypoxia model of severe PAH, characterized by reduced BMPR2 expression and endothelial hyperproliferation, supporting the relevance of this mechanism in vivo.Conclusions—Pulmonary vascular and circulating progenitor endothelial cells isolated from patients with PAH demonstrate downregulation of miR-124 leading to the metabolic and proliferative abnormalities in PAH ECs via PTPB1 and PKM1/PKM2. Therefore, the manipulation of this miRNA, or its targets, could represent a novel therapeutic approach for the treatment of PAH.

The Metabolic and Proliferative State of Vascular Adventitial Fibroblasts in Pulmonary Hypertension is Regulated through a MiR-124/PTBP1/PKM Axis [Original Research Article]


Background—An emerging "metabolic theory" of pulmonary hypertension (PH) suggests that cellular and mitochondrial metabolic dysfunction underlies the pathology of this disease. We and others have previously demonstrated the existence of hyper-proliferative, apoptosis-resistant, pro-inflammatory adventitial fibroblasts from human and bovine hypertensive pulmonary arterial walls (PH-Fibs) exhibit constitutive reprogramming of glycolytic and mitochondrial metabolism, accompanied by an increased ratio of glucose catabolism through glycolysis versus the TCA cycle. However, the mechanisms responsible for these metabolic alterations in PH-Fibs remain unknown. We hypothesized that, in PH-Fibs, miR-124 regulates polypyrimidine tract binding protein 1 (PTBP1) expression to control alternative splicing of pyruvate kinase muscle isoforms 1 and 2 (PKM1 and PKM2) resulting in an increased PKM2/PKM1 ratio which promotes glycolysis and proliferation even in aerobic environments. Methods—Pulmonary adventitial fibroblasts were isolated from calves and humans with severe PH (PH-Fibs) and from normal subjects (CO-Fibs). PTBP1 gene knockdown was achieved via PTBP1-siRNA, restoration of miR-124 was performed with miR-124 mimic. TEPP-46 and Shikonin were utilized to manipulate PKM2 glycolytic function. HDACi were used to treat cells. Metabolic products were determined by Mass spectrometry-based metabolomics analyses (UHPLC-MS), and mitochondrial function was analyzed by confocal microscopy and spectrofluorometry.Results—We detected an increased PKM2/PKM1 ratio in PH-Fibs compared to CO-Fibs. PKM2 inhibition reversed the glycolytic status of PH-Fibs, decreased their cell proliferation and attenuated macrophage IL-1β expression. Further, normalizing the PKM2/PKM1 ratio in PH-Fibs by miR-124 overexpression or PTBP1 knockdown reversed the glycolytic phenotype (decreased the production of glycolytic intermediates and byproducts, i.e. lactate), rescued mitochondrial reprogramming and decreased cell proliferation. Pharmacological manipulation of PKM2 activity with TEPP-46 and Shikonin, or treatment with histone deacetylase inhibitors (HDACi), produced similar results.Conclusions—In PH, miR-124, through the alternative splicing factor PTBP1, regulates the PKM2/PKM1 ratio, the overall metabolic, proliferative and inflammatory state of cells. This PH phenotype can be rescued with interventions at various levels of the metabolic cascade. These findings suggest a more integrated view of vascular cell metabolism, which may open unique therapeutic prospects in targeting the dynamic glycolytic and mitochondrial interactions and between mesenchymal inflammatory cells in PH.

Latent Rheumatic Heart Disease: Identifying the Children at Highest Risk of Unfavorable Outcome [Original Research Article]


Background—Screening echocardiography (echo) has emerged as a potentially powerful tool for early diagnosis of rheumatic heart disease (RHD). The utility of screening echo hinges on the rate of RHD progression and the ability of penicillin prophylaxis to improve outcome. We report the longitudinal outcomes of a cohort of children with latent RHD and identify risk factors for unfavorable outcomes.Methods—This was a prospective natural history study conducted under the Ugandan RHD registry. Children with latent RHD and ≥1 year of follow-up were included. All echos were re-reviewed by experts (2012 WHF criteria) for inclusion and evidence of change. Bi- and multi- variable logistic regression, Kaplan-Meier analysis, as well as Cox proportional hazard models were developed to search for risk factors for unfavorable outcome and compare progression-free survival between those treated and not treated with penicillin. Propensity and other matching methods with sensitivity analysis were implemented for the evaluation of the penicillin effect.Results—Blinded review confirmed 227 cases of latent RHD: 164 borderline and 63 definite (42 mild, 21 moderate/severe). Median age at diagnosis was 12 years and median follow-up was 2.3 years (IQR 2.0-2.9). Penicillin prophylaxis was prescribed in 49.3% with overall adherence of 84.7%. Of children with moderate/severe definite RHD, 47.6% had echo progression (including 2 deaths), and 9.5% echo regression. Children with mild definite and borderline RHD showed 26% and 9.8% echo progression and 45.2% and 46.3% echo improvement respectively. Of those with mild definite RHD or borderline RHD, more advanced disease category, younger age, and morphological mitral valve features were risk factors for an unfavorable outcome.Conclusions—Latent RHD is a heterogeneous diagnosis with variable disease outcomes. Children with moderate to severe latent RHD have poor outcomes. Children with both borderline and mild definite RHD are at substantial risk of progression. While long-term outcome remains unclear, the initial change in latent RHD may be evident during the first 1-2 years following diagnosis. Natural history data is inherently limited and a randomized clinical trial is needed to definitively determine the impact of penicillin prophylaxis on the trajectory of latent RHD.

Prevention of Stroke with the Addition of Ezetimibe to Statin Therapy in Patients with Acute Coronary Syndrome in IMPROVE-IT [Original Research Article]


Background—Patients who experience an acute coronary syndrome (ACS) are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after ACS. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT, with a focus on patients with a stroke prior to randomization.Methods—Post-ACS patients were randomized to placebo/simvastatin or ezetimibe/simvastatin and followed for a median of 6 years. Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the endpoints of stroke of any etiology, stroke subtypes, and the primary trial endpoint at 7 years. Results—Of 18,144 patients, 641 (3.5%) experienced at least one stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes, MI, and renal dysfunction. There was a non-significant reduction in the first event of stroke of any etiology (4.2% vs 4.8%; HR 0.86, 0.73-1.00; p=0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% vs 4.1%; HR 0.79, 0.67-0.94; p=0.008) and a non-significant increase in hemorrhagic stroke (0.8% vs 0.6%; HR 1.38, 0.93-2.04; p=0.11). Evaluating total events, including the first stroke and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR 0.83, 0.70-0.98; p=0.029) and ischemic stroke (HR 0.76, 0.63-0.91; p=0.003). Patients who had experienced a stroke prior to randomization were at higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% vs 18.8%; NNT=12; HR 0.60, 0.38-0.95; p=0.030) and 7.6% for ischemic stroke (8.7% vs 16.3%; NNT=13; HR 0.52, 0.31-0.86; p=0.011) with ezetimibe added to simvastatin therapy. Conclusions—The addition of ezetimibe to simvastatin in patients stabilized after ACS reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke.Clinical Trial Registration—URL: Unique Identifier: NCT00202878

Meta-Analysis of Death and Myocardial Infarction in the DEFINE-FLAIR and iFR-SWEDEHEART Trials [Research Letter]


In patients with coronary heart disease, revascularization can improve symptoms and in certain high-risk subgroups may improve prognosis. Coronary angiography provides anatomical information and the physiological significance of a stenosis can be determined using fractional flow reserve (FFR). Decisions on the need for and mode of revascularization can be optimized using FFR, however this involves administering adenosine to induce hyperemia. Generally, this test is well tolerated, but in some healthcare systems adenosine is either not licensed, unavailable, or expensive, limiting the use of FFR-guided management.

Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib [Original Research Article]


Background—Early detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE, a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15,067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days due to significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine: 1) whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and 2) whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial using proteomics.Methods—A nested case-control analysis of paired plasma samples, at baseline and at 3-months, was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls, 1:1. Main outcomes were: 1) a survey of 1,129 proteins for discovery of biological pathways altered by torcetrapib, 2) a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure or death. Results—Plasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the two treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared to the atorvastatin only arm by +1.08% (p=0.0004). Thirty-seven proteins changed in the direction of increased risk out of 49 proteins previously associated with cardiovascular and mortality risk.Conclusions—Heretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients.Clinical Trial Registration—URL: Unique Identifier: NCT00134264.

High-Sensitivity Cardiac Troponin and the Risk Stratification of Patients with Renal Impairment Presenting with Suspected Acute Coronary Syndrome [Original Research Article]


Background—High-sensitivity cardiac troponin testing may improve the risk-stratification and diagnosis of myocardial infarction, but concentrations can be challenging to interpret in patients with renal impairment and the effectiveness of testing in this group is uncertain.Methods—In a prospective multi-center study of consecutive patients with suspected acute coronary syndrome, we evaluated the performance of high-sensitivity cardiac troponin I in those with and without renal impairment (estimated glomerular filtration rate <60mL/min/1.73m2). The negative predictive value (NPV) and sensitivity of troponin concentrations below the risk stratification threshold (5ng/L) at presentation were reported for a primary outcome of index type 1 myocardial infarction, or type 1 myocardial infarction or cardiac death at 30 days. The positive predictive value (PPV) and specificity at the 99th centile diagnostic threshold (16ng/L in women, 34ng/L in men) was determined for index type 1 myocardial infarction. Subsequent type 1 myocardial infarction and cardiac death were reported at 1 year.Results—Of 4,726 patients identified, 904 (19%) had renal impairment. Troponin concentrations <5ng/L at presentation identified 17% of patients with renal impairment as low-risk for the primary outcome (NPV 98.4%, 95% confidence interval [CI] 96.0-99.7%; sensitivity 98.9%, 95%CI 97.5-99.9%), compared to 56% without renal impairment (P<0.001) with similar performance (NPV 99.7%, 95%CI 99.4-99.9%; sensitivity 98.4%, 95%CI 97.2-99.4%). The PPV and specificity at the 99th centile were lower in patients with renal impairment at 50.0% (95%CI 45.2-54.8%) and 70.9% (95%CI 67.5-74.2%) respectively, compared to 62.4% (95%CI 58.8-65.9%) and 92.1% (95%CI 91.2-93.0%) in those without. At 1 year, patients with troponin concentrations >99th centile and renal impairment were at greater risk of subsequent myocardial infarction or cardiac death than those with normal renal function (24% vs. 10%, adjusted hazard ratio 2.19, 95%CI 1.54-3.11).Conclusions—In suspected acute coronary syndrome, high-sensitivity cardiac troponin identified fewer patients with renal impairment as low-risk and more as high-risk, but with lower specificity for type 1 myocardial infarction. Irrespective of diagnosis, patients with renal impairment and elevated cardiac troponin concentrations had two-fold greater risk of a major cardiac event compared to those with normal renal function, and should be considered for further investigation and treatment.Clinical Trial Registration—URL: Unique Identifier: NCT01852123

Tryptophan-Derived 3-Hydroxyanthranilic Acid Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice In Vivo [Original Research Article]


Background—Abnormal amino acid metabolism is associated with vascular disease. However, the causative link between dysregulated tryptophan metabolism and abdominal aortic aneurysm (AAA) is unknown. Methods—Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. Mice with deficiencies in both apolipoprotein e (Apoe) and IDO (Apoe-/-/IDO-/-) were generated by cross-breeding IDO-/- mice with Apoe-/- mice. Results—The acute infusion of angiotensin II (AngII) markedly increased the incidence of AAA in Apoe-/- mice, but not in Apoe-/-/IDO-/- mice, which presented decreased elastic lamina degradation and aortic expansion. These features were not altered by the reconstitution of bone marrow cells from IDO+/+ mice. Moreover, AngII infusion instigated interferon (IFN)-γ, which induced the expression of IDO and kynureninase (KNU) and increased 3-hydroxyanthranilic acid (3-HAA) levels in the plasma and aortas of Apoe-/- mice, but not in IDO-/- mice. Both IDO and KNU controlled the production of 3-HAA in vascular smooth muscle cells. 3-HAA upregulated MMP2 via transcription factor nuclear factor-kappa B (NF-κB). Furthermore, KNU knockdown in mice restrained 3-HAA, matrix metallopeptidase (MMP)2, and resultant AAA formation by AngII infusion. Intra-peritoneal injections of 3-HAA into Apoe-/- and Apoe-/-/IDO-/- mice for 6 weeks increased the expression and activity of MMP2 in aortas without affecting metabolic parameters. Finally, human AAA samples had stronger staining with the antibodies against 3-HAA, IDO, and KNU than those in adjacent nonaneurysmal aortic sections of human AAA samples. Conclusions—These data define a previously undescribed causative role for 3-HAA, which is a product of tryptophan metabolism, in AAA formation. Furthermore, these findings suggest that 3-HAA reduction may be a new target for treating cardiovascular diseases.

CTRP9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways [Original Research Article]


Background—Cell therapy remains the most promising approach against ischemic heart injury. However, the poor survival of engrafted stem cells in the ischemic environment limits their therapeutic efficacy for cardiac repair post myocardial infarction (MI). C1q/tumor necrosis factor-related protein-9 (CTRP9) is a novel pro-survival cardiokine with significantly downregulated expression after MI. Here, we tested a hypothesis that CTRP9 might be a cardiokine required for a healthy microenvironment promoting implanted stem cell survival and cardioprotection. Methods—Mice were subjected to MI and treated with adipose-derived mesenchymal stem cells (ADSCs, intramyocardial transplantation), CTRP9, or their combination. Survival, cardiac remodeling and function, cardiomyocytes apoptosis, and ADSCs engraftment were evaluated. Whether CTRP9 directly regulates ADSCs function was determined in vitro. Discovery-drive approaches followed by cause-effect analysis were employed to uncover the molecular mechanisms of CTRP9. Results—Administration of ADSCs alone failed to exert significant cardioprotection. However, administration of ADSCs in addition to CTRP9 further enhanced the cardioprotective effect of CTRP9 (P<0.05 or P<0.01 vs. CTRP9 alone), suggesting a synergistic effect. Administration of CTRP9 at a dose recovering physiological CTRP9 levels significantly prolonged ADSCs retention/survival after implantation. Conversely, the number of engrafted ADSCs was significantly reduced in the CTRP9KO heart. In vitro study demonstrated that CTRP9 promoted ADSCs proliferation and migration, and protected ADSCs against hydrogen peroxide-induced cellular death. CTRP9 enhances ADSCs proliferation/migration by ERK1/2-MMP-9 signaling and promotes anti-apoptotic/cell survival via ERK-Nrf2/anti-oxidative protein expression. N-cadherin was identified as a novel CTRP9 receptor mediating ADSCs signaling. Blockade of either N-cadherin or ERK1/2 completely abolished the above noted CTRP9 effects. Although CTRP9 failed to promote ADSCs cardiogenic differentiation, CTRP9 promotes Sod-3 expression and secretion from ADSCs, protecting cardiomyocytes against oxidative stress-induced cell death. Conclusions—We provide the first evidence that CTRP9 promotes ADSCs proliferation/survival, stimulates ADSCs migration, and attenuates cardiomyocyte cell death by previously unrecognized signaling mechanisms. These include binding with N-cadherin, activation of ERK/MMP-9 and ERK/Nrf2 signaling, and upregulation/secretion of anti-oxidative proteins. These results suggest that CTRP9 is a cardiokine critical in maintaining a healthy microenvironment facilitating stem cell engraftment in infarcted myocardial tissue, thereby enhancing stem cell therapeutic efficacy.

Association of Pediatric Medical Emergency Teams with Hospital Mortality [Original Research Article]


Background—Implementation of a medical emergency teams has been identified as a potential strategy to reduce hospital deaths, as these teams respond to patients with acute physiological decline in an effort to prevent in-hospital cardiac arrest. However, prior studies of the association between medical emergency teams and hospital mortality have been limited and typically have not accounted for pre-implementation mortality trends.Methods—Within the Pediatric Health Information System (PHIS) for freestanding pediatric hospitals, annual risk-adjusted mortality rates were calculated for sites between 2000 and 2015. A random slopes interrupted time series analysis then examined whether implementation of a medical emergency team was associated with lower than expected mortality rates based on pre-implementation trends. Results—Across 38 pediatric hospitals, mean annual hospital admission volume was 15,854 (range: 6,684-33,024), and there were a total of 1,659,059 hospitalizations pre-implementation and 4,392,392 hospitalizations post-implementation. Before medical emergency team implementation, hospital mortality decreased by 6.0% annually (odds ratio [OR] of 0.94 [95% CI: 0.92-0.96]) across all hospitals. After medical emergency team implementation, hospital mortality continued to decrease by 6% annually (OR of 0.94 [95% CI: 0.93-0.95]), with no deepening of the mortality slope (i.e., not lower odds ratio) as compared with the pre-implementation trend, for the overall cohort (P of 0.98) or when analyzed separately within each of the 38 study hospitals. Five years after medical emergency team implementation across study sites, there was no difference between predicted (hospital mean of 6.18 deaths per 1000 admissions based on pre-implementation trends) and actual mortality rates (hospital mean of 6.48 deaths per 1000 admissions; P of 0.57). Conclusions—Implementation of medical emergency teams in a large sample of pediatric hospitals in the U.S was not associated with a reduction in hospital mortality beyond existing pre-implementation trends.

Increase in Endovascular Therapy in Get With The Guidelines-Stroke After The Publication of Pivotal Trials [Original Research Article]


Background—Beginning in December 2014, a series of pivotal trials showed that endovascular thrombectomy (EVT) was highly effective, prompting calls to reorganize stroke systems of care. However, there are few data on how these trials influenced the frequency of EVT in clinical practice. We used data from the Get With The Guidelines-Stroke program to determine how the frequency of EVT changed in U.S. practice.Methods—We analyzed prospectively collected data from a cohort of 2,437,975 ischemic stroke patients admitted to 2,222 participating hospitals between April 2003 and the third quarter (Q3) 2016. Weighted linear regression with two linear splines and a knot at January 2015 was used to compare the slope of the change in EVT use before and after the pivotal trials were published. Potentially eligible patients were defined as last known well to arrival time ≤4.5 hours and NIH Stroke Scale score ≥6.Results—The frequency of EVT use was slowly increasing prior to January 2015 but then sharply accelerated thereafter. In Q3 2016, EVT was provided to 3.3% of all ischemic stroke patients at all hospitals, representing 15.1% of all patients who were potentially eligible for EVT based on stroke duration and severity. At EVT capable hospitals, 7.5% of all ischemic stroke patients were treated in Q3 2016, including 27.3% of the potentially eligible patients. From 2013 to 2016, case volumes nearly doubled at EVT capable hospitals. Mean case volume per EVT capable hospital was 37.6 per year in the last four quarters. EVT case volumes increased in nearly all U.S. states from 2014 to the last four quarters, but with persistent geographic variation unexplained by differences in potential patient eligibility.Conclusions—EVT use is increasingly rapidly; however, there are still opportunities to treat more patients. Reorganizing stroke systems to route patients to adequately resourced EVT capable hospitals might increase treatment of eligible patients, improve outcomes and reduce disparities.

Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling [Original Research Article]


Background—Nitric oxide signaling plays a key role in regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacologic stimulation of the nitric oxide pathway as a therapeutic strategy.Methods—We analyzed the association of common and rare genetic variants in two genes that mediate nitric oxide signaling [Nitric Oxide Synthase 3 (NOS3) and Guanylate Cyclase 1, Soluble, Alpha 3 (GUCY1A3)] with a range of human phenotypes. We selected two common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335,464 participants in the UK Biobank and summary association results from seven large-scale genome wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27,815).Results—A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease [OR 0.37 95% CI 0.31, 0.45; p=5.5*10-26], peripheral arterial disease (OR 0.42 CI 0.26, 0.68; p=0.0005) and stroke (OR 0.53 CI 0.37, 0.76; p=0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (CI 12, 34 mm Hg; p=5.6*10-5) and a three-fold higher risk of coronary heart disease (OR 3.03 CI 1.29, 7.12, p=0.01).Conclusions—A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease and stroke. Pharmacologic stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease.

Carotid Stent Fractures are not Associated with Adverse Events: Results from the ACT 1 Multicenter Randomized Trial [Original Research Article]


Background—The impact of carotid artery stent fractures on the incidence of adverse clinical events remains unclear. The objective of this study is to report the stent fracture rate and its association with in-stent restenosis and adverse outcomes in the Asymptomatic Carotid Trial (ACT)-1. Methods—ACT-1 is a prospective multicenter trial of standard surgical risk patients with severe asymptomatic carotid artery stenosis randomized to carotid artery stenting (CAS) or carotid endarterectomy (CEA) (Abbott Vascular, Santa Clara, California, USA). The primary endpoint was a composite of death, stroke or myocardial infarction during the 30 days after the procedure or ipsilateral stroke during the 365 days after the procedure. After 771 patients were enrolled, successively randomized patients were required to undergo annual radiographic (X-ray) analysis for stent fracture. Images were independently adjudicated by a core laboratory.Results—Of 1021 patients treated with CAS during a mean follow-up of 3.1 ± 1.6 years, 939 had at least one X-ray during the follow-up period. Stent fracture was reported in 51 (5.4%) patients. With a maximum follow up period of 5 years, adverse clinical outcomes occurred in 39 patients with at least one X-ray during the follow-up. Of 826 (80.9%) subjects who underwent both DUS and X-ray, 822 (99.5%) were interpretable. There was no association between stent fracture and the primary endpoint (P=0.86) or with restenosis (P=0.53).Conclusions—In this large, independently-adjudicated, multicenter study, the stent fracture rate was low and not associated with major adverse clinical events or in-stent restenosis.Clinical Trial Registration—URL: Unique Identifier: NCT00106938

Validating Utility of DAPT Score in a Large Pooled Cohort from Three Japanese PCI Studies [Original Research Article]


Background—The DAPT score was developed to estimate ischemic and bleeding risks from the DAPT (Dual Antiplatelet Therapy) study. However, few studies validated its utility externally. We sought to validate the utility of the DAPT score in Japanese population.Methods—In a pooled cohort of three studies conducted in Japan (the CREDO Kyoto registry cohort-2, RESET and NEXT), we compared risks for ischemic and bleeding events from 13 to 36 months after percutaneous coronary intervention (PCI) between patients with DAPT score ≥2 (high-DS) and DAPT score <2 (low-DS). Results—Among 12223 patients receiving drug-eluting stents who were free from ischemic or bleeding events at 13 months after PCI, there were 3944 patients with high-DS, and 8279 with low-DS. The cumulative incidence of primary ischemic end point (myocardial infarction/stent thrombosis) was significantly higher in high-DS than in low-DS (1.5% versus 0.9%, P=0.002), while the cumulative incidence of primary bleeding end point (GUSTO moderate/severe) tended to be lower in high-DS than in low-DS (2.1% versus 2.7%, P=0.07). The cumulative incidences of cardiac death, myocardial infarction and stent thrombosis were also significantly higher in high-DS than in low-DS (2.0% versus 1.4%, P=0.03; 1.5% versus 0.8%, P=0.002; 0.7% versus 0.3%, P<0.001, respectively), while the cumulative incidences of non-cardiac death and GUSTO severe bleeding were significantly lower in high-DS than in low-DS (2.4% versus 3.9%, P<0.001; 1.0% versus 1.6%, P=0.03, respectively). Conclusions—In the current population, the DAPT score successfully stratified ischemic and bleeding risks, although the ischemic event rate was remarkably low even in high-DS. Further studies would be warranted to evaluate the utility of prolonged DAPT guided by the DAPT score.

Exercise Intolerance in HFpEF: Diagnosing and Ranking its Causes Using Personalized O2 Pathway Analysis [Original Research Article]


Background—Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with a pressing shortage of therapies. Exercise intolerance is a cardinal symptom of HFpEF, yet its pathophysiology remains uncertain.Methods—We investigated the mechanism of exercise intolerance in each of 134 patients referred for cardiopulmonary exercise testing (CPET): 79 with HFpEF and 55 controls. We performed CPET with invasive monitoring to measure hemodynamics, blood gases, and gas exchange during exercise. We used these measurements to quantify 6 steps of oxygen transport and utilization (the "O2 pathway") in each HFpEF patient, identifying the defective steps that impair each one's exercise capacity (peak VO2). We then quantified the functional significance of each O2 pathway defect by calculating the improvement in exercise capacity a patient could expect from correcting the defect.Results—Peak VO2)was reduced by 34%±2% (mean±SEM, P<0.001) in HFpEF compared with controls of comparable age, gender, and body mass index. The vast majority (97%) of HFpEF patients harbored defects at multiple steps of the O2 pathway, the identity and magnitude of which varied widely. Two of these steps, cardiac output and skeletal muscle O2 diffusion, were impaired relative to controls by an average of 27±3% and 36±2%, respectively (P<0.001 for both). Due to interactions between a given patient's defects, the predicted benefit of correcting any single one was often minor; on average, correcting a patient's cardiac output led to a 7±0.5% predicted improvement in exercise intolerance, while correcting a patient's muscle diffusion capacity led to a 27±1% improvement. At the individual level, the impact of any given O2 pathway defect on a patient's exercise capacity was strongly influenced by comorbid defects. Conclusions—Systematic analysis of the O2 pathway in HFpEF showed that exercise capacity was undermined by multiple defects, including reductions in cardiac output and skeletal muscle diffusion capacity. An important source of disease heterogeneity stemmed from variation in each patient's personal profile of defects. Personalized O2 pathway analysis could identify patients most likely to benefit from treating a specific defect; however, the system properties of O2 transport favor treating multiple defects at once, as with exercise training.

Association Between Urinary Sodium and Potassium Excretion and Blood Pressure Among Adults in the United States: National Health and Nutrition Examination Survey, 2014 [Original Research Article]


Background—Higher levels of sodium and lower levels of potassium intake are associated with higher blood pressure. However, the shape and magnitude of these associations can vary by study participant characteristics or intake assessment method. Twenty-four hour urinary excretion of sodium and potassium are unaffected by recall errors and represent all sources of intake, and were collected for the first time in a nationally representative US survey. Our objective was to assess the associations of blood pressure and hypertension with 24-hour urinary excretion of sodium and potassium among US adults. Methods—Cross-sectional data from 766 participants aged 20-69 years with complete blood pressure and 24-hour urine collections in the 2014 National Health and Nutrition Examination Survey, a nationally-representative survey of the US noninstitutionalized population. Usual 24-hour urinary electrolyte excretion (sodium, potassium, and their ratio) was estimated from up to two collections on non-consecutive days, adjusting for day-to-day variability in excretion. Outcomes included systolic and diastolic blood pressure from the average of 3 measures and hypertension status, based on average blood pressure ≥140/90 and anti-hypertensive medication use. Results—After multivariable adjustment, each 1000 mg difference in usual 24-hour sodium excretion was directly associated with systolic (4.58 mmHg, 95% confidence interval 2.64,6.51) and diastolic (2.25 mmHg, 95% CI 0.83,3.67) blood pressures. Each 1000 mg difference in potassium excretion was inversely associated with systolic blood pressure (-3.72 mmHg, 95% CI -6.01,-1.42). Each 0.5 unit difference in sodium-to-potassium ratio was directly associated with systolic blood pressure (1.72 mmHg, 95% CI 0.76, 2.68). Hypertension was linearly associated with progressively higher sodium and lower potassium excretion; compared with the lowest quartiles of excretion, the adjusted odds of hypertension for the highest quartiles were 4.22 (95% CI 1.36, 13.15) for sodium, and 0.38 (95% CI 0.17, 0.87) for potassium, respectively, P<0.01 for trends. Conclusions—These cross-sectional results show a strong dose-response association between urinary sodium excretion and blood pressure, and an inverse association between urinary potassium excretion and blood pressure, in a nationally representative sample of US adults.

Influence of Baseline Diastolic Blood Pressure on Effects of Intensive Compared to Standard Blood Pressure Control [Original Research Article]


Background—In individuals with a low diastolic blood pressure (DBP), potential benefits or risks of intensive systolic blood pressure (SBP) lowering are unclear. Methods—The Systolic Blood Pressure Intervention Trial was a randomized, controlled trial that compared the effects of intensive (target <120 mm Hg) versus standard (target <140 mm Hg) SBP control in 9361 older adults with high blood pressure at increased risk of cardiovascular disease (CVD). The primary outcome was a composite of CVD events. All-cause death and incident CKD were secondary outcomes. This post-hoc analysis examined whether the effects of the SBP intervention differed by baseline DBP. Results—Mean baseline SBP and DBP were 139.7 ± 15.6 and 78.1 ± 11.9 mm Hg, respectively. Irrespective of the randomized treatment, baseline DBP had a U-shaped association with the hazard of the primary CVD outcome. However, the effects of the intensive SBP intervention on the primary outcome was not influenced by baseline DBP level (p for interaction 0.83). The primary outcome hazard ratio for intensive versus standard treatment was 0.78 (95% CI 0.57 to 1.07) in the lowest DBP quintile (mean baseline DBP 61 ± 5 mm Hg) and 0.74 (95% CI 0.61 to 0.90) in the upper four DBP quintiles (mean baseline DBP 82 ± 9 mm Hg), with an interaction p-value = 0.78. Results were similar for all-cause death and kidney events.Conclusions—Low baseline DBP was associated with increased risk of CVD events, but there was no evidence that the benefit of the intensive SBP lowering differed by baseline DBP. Clinical Trial Registration—URL: Unique Identifier: NCT01206062

Pathologic Stimulus Determines Lineage Commitment of Cardiac C-kit+ Cells [Original Research Article]


Background—Although cardiac c-kit+ cells are being tested in clinical trials, the circumstances that determine lineage differentiation of c-kit+ cells in vivo are unknown. Recent findings suggest endogenous cardiac c-kit+ cells rarely contribute cardiomyocytes to the adult heart. We assessed whether various pathological stimuli differentially affect the eventual cell fates of c-kit+ cells.Methods—We employed single cell sequencing and genetic lineage tracing of c-kit+ cells to determine whether various pathologic stimuli would result in different fates of c-kit+ cells.Results—Single cell sequencing of cardiac CD45-c-kit+ cells showed innate heterogeneity, indicative of the existence of vascular and mesenchymal c-kit+ cells in normal hearts. Cardiac pressure overload resulted in a modest increase in c-kit derived cardiomyocytes with significant increases in the numbers of endothelial cells and fibroblasts. Doxorubicin-induced (DOX) acute cardiotoxicity did not increase c-kit derived endothelial cell fates but instead induced cardiomyocyte differentiation. Mechanistically, DOX induced DNA damage in c-kit+ cells resulted in expression of p53. Inhibition of p53 blocked cardiomyocyte differentiation in response to DOX, while the small molecule RITA induced stabilization of p53 was sufficient to increase c-kit derived cardiomyocyte differentiation. Conclusions—These results demonstrate that different pathologic stimuli induce different cell fates of c-kit+ cells in vivo. Although the overall rate of cardiomyocyte formation from c-kit+ cells is still below clinically relevant levels, we show that p53 is central to the ability of c-kit+ cells to adopt cardiomyocyte fates, which could lead to the development of strategies to preferentially generate cardiomyocytes from c-kit+ cells.

Higher Risk of Vascular Dementia in Myocardial Infarction Survivors [Original Research Article]


Background—Increased risk of dementia after myocardial infarction (MI) may be mediated by shared risk factors (e.g., atherosclerosis) and post-MI stroke. We examined risk of dementia in 1-year survivors of MI.Methods—Using Danish medical registries, we conducted a nationwide population-based cohort study of all patients with first-time MI and a sex-, birth year-, and calendar year-matched general population comparison cohort without MI (1980-2012). Cox regression analysis was used to compute 1-35 year adjusted hazard ratios (aHRs) for dementia, controlled for matching factors and adjusted for comorbidities and socioeconomic status.Results—We identified 314,911 patients with MI and 1,573,193 matched comparison cohort members randomly sampled from the general population (median age 70 years, 63% male). After 35 years of follow-up, the cumulative incidence of all-cause dementia in the MI cohort was 9% (2.8% for Alzheimer's disease, 1.6% for vascular dementia, and 4.5% for other dementias). Compared with the general population cohort, MI was not associated with all-cause dementia (aHR = 1.01, 95% confidence interval (CI): 0.98-1.03). Risk of Alzheimer's disease (aHR = 0.92, 95% CI: 0.88-0.95) and other dementias (aHR = 0.98, 95% CI: 0.95-1.01) also approximated unity. However, MI was associated with higher risk of vascular dementia (aHR = 1.35, 95% CI: 1.28-1.43), which was substantially strengthened for patients experiencing stroke after MI (aHR = 4.48, 95% CI: 3.29-6.12).Conclusions—MI was associated with higher risk of vascular dementia throughout follow-up and this asssociation was stronger in patients suffering stroke. The risk of Alzheimer's disease and other dementias was not higher in MI patients.

Long-Term Potassium Monitoring and Dynamics in Heart Failure and Risk of Mortality [Original Research Article]


Background—The prognostic value of long-term potassium monitoring and dynamics in heart failure (HF) has not been characterized completely. We sought to determine the association between serum potassium values collected at follow-up with all-cause mortality in a prospective and consecutive cohort of patients discharged from a previous acute HF admission. Methods—Serum potassium was measured at every physician-patient encounter, including hospital admissions and ambulatory settings. The multivariable-adjusted association of serum potassium with mortality was assessed using comprehensive state-of-the-art regression methods that can accommodate time-dependent exposure modeling.Results—The study sample included 2164 patients with a total of 16,116 potassium observations. Mean potassium at discharge was 4.3±0.48 mEq/L. Hypokalemia (<3.5 mEq/L), normokalemia (3.5 to 5.0 mEq/L), and hyperkalemia (>5 mEq/L) were observed at the index admission in 77 (3.6%), 1965 (90.8%), and 122 (5.6%) patients, respectively. At a median follow-up of 2.8 years (range=0.03-12.8 years), 1090 patients died (50.4%). On a continuous scale, the multivariable-adjusted association of potassium values and mortality revealed a non-linear association (U-shaped) with higher risk at both ends of its distribution (omnibus p-value=0.001). Likewise, the adjusted hazard ratios (HRs) for hypokalemia and hyperkalemia - normokalemia as reference - were 2.35 (95% confidence interval [CI]:1.40-3.93; p=0.001) and 1.55 (95% CI:1.11-2.16; p=0.011), respectively (omnibus p-value=0.0003). Furthermore, dynamic changes in potassium were independently associated with substantial differences in mortality risk. Potassium normalization was independently associated with lower mortality risk (p=0.001). Conclusions—Either modeled continuously or categorically, serum potassium levels during long-term monitoring were independently associated with mortality in patients with HF. Likewise, persistence of abnormal potassium levels was linked to higher risk of death compared with patients who maintained or returned to normal values.

Runx1 Deficiency Protects Against Adverse Cardiac Remodeling Following Myocardial Infarction [Original Research Article]


Background—Myocardial infarction (MI) is a leading cause of heart failure and death worldwide. Preservation of contractile function and protection against adverse changes in ventricular architecture (cardiac remodeling) are key factors to limiting progression of this condition to heart failure. Consequently, new therapeutic targets are urgently required to achieve this aim. Expression of the Runx1 transcription factor is increased in adult cardiomyocytes following MI; however, the functional role of Runx1 in the heart is unknown. Methods—To address this question, we have generated a novel tamoxifen-inducible cardiomyocyte-specific Runx1-deficient mouse. Mice were subjected to MI by means of coronary artery ligation. Cardiac remodeling and contractile function were assessed extensively at the whole heart, cardiomyocyte and molecular levels.Results—Runx1 deficient mice were protected against adverse cardiac remodeling post-MI, maintaining ventricular wall thickness and contractile function. Furthermore, these mice lacked eccentric hypertrophy and their cardiomyocytes exhibited markedly improved calcium handling. At the mechanistic level, these effects were achieved through increased phosphorylation of phospholamban by PKA and relief of sarcoplasmic reticulum calcium pump (SERCA) inhibition. Enhanced SERCA activity in Runx1 deficient mice increased sarcoplasmic reticulum calcium content and sarcoplasmic reticulum-mediated calcium release, preserving cardiomyocyte contraction post-MI. Conclusions—Our data identified Runx1 as a novel therapeutic target with translational potential to counteract the effects of adverse cardiac remodeling, thereby improving survival and quality of life among patients with MI.

Diagnostic Accuracy of the Aortic Dissection Detection Risk Score Plus D-Dimer for Acute Aortic Syndromes: The ADvISED Prospective Multicenter Study [Original Research Article]


Background—Acute aortic syndromes (AAS) are rare and severe cardiovascular emergencies with unspecific symptoms. For AAS, both misdiagnosis and over-testing are key concerns, and standardized diagnostic strategies may help physicians to balance these risks. D-dimer (DD) is highly sensitive for AAS, but is inadequate as a standalone test. Integration of pre-test probability assessment (PPA) with D-dimer (DD) testing is feasible, but the safety and efficiency of such diagnostic strategy are currently unknown.Methods—In a multicenter prospective observational study involving 6 hospitals in 4 countries from 2014 to 2016, consecutive outpatients were eligible if they had ≥1 of the following: chest/abdominal/back pain, syncope, perfusion deficit, and if AAS was in differential diagnosis. The tool for PPA was the aortic dissection detection risk score (ADD-RS, 0 to 3), per current guidelines. DD was considered negative (DD-) if <500 ng/ml. Final case adjudication was based on conclusive diagnostic imaging, autopsy, surgery or on 14-day follow-up. The outcomes were the failure rate and efficiency of a diagnostic strategy ruling-out AAS in patients with ADD-RS=0/DD- or ADD-RS≤1/DD-.Results—1850 patients were analyzed. 438 (24%) patients had ADD-RS=0, 1071 (58%) patients had ADD-RS=1, and 341 (18%) had ADD-RS>1. 241 (13%) patients had AAS: 125 had type A aortic dissection, 53 had type B aortic dissection, 35 had intramural aortic hematoma, 18 had aortic rupture, and 10 had penetrating aortic ulcer. A positive DD test result had an overall sensitivity of 96.7% (95% CI 93.6-98.6%) and a specificity of 64% (95% CI 61.6-66.4%) for diagnosis of AAS; 8 patients with AAS had DD-. Within 294 patients with ADD-RS=0/DD-, 1 case of AAS was observed. This yielded a failure rate of 0.3% (95% CI 0.1-1.9%) and efficiency of 15.9% (95% CI 14.3-17.6%) for the ADD-RS=0/DD- strategy. Within 924 patients with ADD-RS≤1/DD-, 3 cases of AAS were observed. This yielded a failure rate of 0.3% (95% CI 0.1-1%) and efficiency of 49.9% (95% CI 47.7-52.2%) for the ADD-RS≤1/DD- strategy.Conclusions—Integration of ADD-RS (both =0 or ≤1) with DD may be considered to standardize diagnostic rule-out of AAS.Clinical Trial Registration—URL: Unique identifier: NCT02086136

Extracellular Matrix Proteomics Reveals Interplay of Aggrecan and Aggrecanases in Vascular Remodeling of Stented Coronary Arteries [Original Research Article]


Background—Extracellular matrix (ECM) remodeling contributes to in-stent restenosis and thrombosis. Despite its important clinical implications little is known about ECM changes post-stent implantation. Methods—Bare-metal (BMS) and drug-eluting stents (DES) were implanted in pig coronary arteries with an overstretch under optical coherence tomography guidance. Stented segments were harvested 1, 3, 7, 14 and 28 days post-stenting for proteomics analysis of the media and neointima.Results—A total of 151 ECM and ECM-associated proteins were identified by mass spectrometry. After stent implantation, proteins involved in regulating calcification were upregulated in the neointima of DES. The earliest changes in the media were proteins involved in inflammation and thrombosis, followed by changes in regulatory ECM proteins. By day 28, basement membrane proteins were reduced in DES compared with BMS. In contrast, the large aggregating proteoglycan aggrecan was increased. Aggrecanases of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family contribute to the catabolism of vascular proteoglycans. An increase in ADAMTS-specific aggrecan fragments was accompanied by a notable shift from ADAMTS1 and ADAMTS5 to ADAMTS4 gene expression after stent implantation. Immunostaining in human stented coronary arteries confirmed the presence of aggrecan and aggrecan fragments, in particular at the contacts of the stent struts with the artery. Further investigation of aggrecan presence in the human vasculature revealed that aggrecan and aggrecan cleavage were more abundant in human arteries compared to veins. Also, aggrecan synthesis was induced upon grafting a vein into the arterial circulation, suggesting an important role for aggrecan in vascular plasticity. Finally, lack of ADAMTS-5 activity in mice resulted in an accumulation of aggrecan and a dilation of the thoracic aorta, confirming that aggrecanase activity regulates aggrecan abundance in the arterial wall and contributes to vascular remodeling.Conclusions—Significant differences were identified by proteomics in the ECM of coronary arteries after BMS and DES implantation, most notably an upregulation of aggrecan, a major ECM component of cartilaginous tissues that confers resistance to compression. The accumulation of aggrecan coincided with a shift in ADAMTS gene expression. This study provides the first evidence implicating aggrecan and aggrecanases in the vascular injury response after stenting.

Fasting vs Non-Fasting and Low-Density Lipoprotein-Cholesterol Accuracy [Original Research Article]


Background—Recent recommendations favoring non-fasting lipid assessment may impact low-density lipoprotein-cholesterol (LDL-C) estimation. The novel method of LDL-C estimation (LDL-CN) uses a flexible approach to derive patient-specific triglyceride (TG) to very low-density lipoprotein-cholesterol ratios. This adaptability may confer an accuracy advantage in non-fasting patients over the fixed approach of the classical Friedewald method (LDL-CF). Methods—We used a US cross-sectional sample of 1,545,634 patients (959,153 fasting ≥10-12 hours; 586,481 non-fasting) from the second harvest of the Very Large Database of Lipids study to assess for the first time the impact of fasting status on novel LDL-C accuracy. Rapid ultracentrifugation was used to directly measure LDL cholesterol content (LDL-CD). Accuracy was defined as the percentage of LDL-CD falling within an estimated LDL-C (LDL-CN or LDL-CF) category by clinical cutpoints. For low estimated LDL-C (<70 mg/dL), we evaluated accuracy by TG levels. The magnitude of absolute and percent differences between LDL-CD and estimated LDL-C (LDL-CN or LDL-CF) was stratified by LDL-C and TG categories. Results—In both fasting and non-fasting samples, accuracy was higher with the novel method across all clinical LDL-C categories (range: 87-94%) compared to Friedewald estimation (range: 71-93%) (p≤0.001). With LDL-C <70 mg/dL, non-fasting LDL-CN accuracy (92%) was superior to LDL-CF (71%) (p<0.001). In this LDL-C range, 19% of fasting and 30% of non-fasting patients had differences ≥10 mg/dL between LDL-CF and LDL-CD, whereas only 2% and 3% of patients respectively had similar differences with novel estimation. Accuracy of LDL-C <70 mg/dL further decreased as TG increased, particularly for Friedewald estimation (range: 37-96%) versus the novel method (range: 82-94%). With TG 200-399 mg/dL in non-fasting patients, LDL-CN <70 mg/dL accuracy (82%) was superior to LDL-CF (37%) (p<0.001). In this TG range, 73% of fasting and 81% of non-fasting patients had ≥10 mg/dL differences between LDL-CF and LDL-CD, compared to 25% and 20% of patients respectively with LDL-CN. Conclusions—Novel adaptable LDL-C estimation performs better in non-fasting samples than the fixed Friedewald estimation, with a particular accuracy advantage in settings of low LDL-C and high TG. In addition to stimulating further study, these results may have immediate relevance to guideline committees, laboratory leadership, clinicians and patients. Clinical Trial Registration—URL: Unique Identifier: NCT01698489

Low-Dose Exposure to Ionizing Radiation Deregulates the Brain-Specific miR-134 in Interventional Cardiologists [Research Letter]


In recent years, there has been a growing concern about the health risks for contemporary interventional cardiologists who have a high and unprecedented levels of occupational ionizing radiation (IR) exposure.microRNAs (miRNAs), a class of short and highly conserved non-coding RNA molecules (~22 nucleotides), have been shown to become dysregulated in many human diseases.The stability and tissue specificity of circulating miRNAs make them ideal biomarkers to explore the molecular mechanisms underlying the association between chronic low-dose radiation exposure and potential disease risk. The purpose of this study was to apply a miRNome-wide microarray to characterize the plasma miRNA profiles in interventional cardiologists professionally exposed to IR.

A Comparison Between Patent Ductus Arteriosus Stent and Modified Blalock-Taussig Shunt as Palliation for Infants with Ductal-Dependent Pulmonary Blood Flow: Insights From the Congenital Catheterization Research Collaborative [Original Research Article]


Background—Infants with ductal-dependent pulmonary blood flow may undergo palliation with either a patent ductus arteriosus (PDA) stent or modified Blalock-Taussig (BT) shunt. A balanced multi-center comparison of these two approaches is lacking.Methods—Infants with ductal-dependent pulmonary blood flow, palliated with either PDA stent or BT shunt from 1/08 to 11/15, were reviewed from the four member centers of the Congenital Catheterization Research Collaborative. Outcomes were compared using propensity score adjustment to account for baseline differences between groups.Results—106 PDA stent and 251 BT shunt patients were included. The groups differed in underlying anatomy (expected two-ventricle circulation in 60% of PDA stents v. 45% of BT shunts, p=0.001), and presence of antegrade pulmonary blood flow (61% of PDA stents v. 38% of BT shunts, p<0.001). After propensity score adjustment, there was no difference in the hazard of the primary composite outcome of death or unplanned reintervention to treat cyanosis [HR=0.8 (95% CI: 0.52 - 1.23), p=0.31]. Other reinterventions were more common in the PDA stent group [HR=29.8 (95% CI: 9.8 - 91.1, p<0.001]. However, the PDA stent group had a lower adjusted ICU length of stay [5.3 (95% CI 4.2 - 6.7) v. 9.19 (95% CI 7.9 - 10.6) days, p<0.001], a lower risk of diuretic use at discharge [OR=0.4 (95% CI: 0.25 - 0.64), p<0.001] and procedural complications [OR=0.4 (95% CI: 0.2 - 0.77), p=0.006], and larger [152 (95% CI: 132 - 176) v. 125 (95% CI: 113 - 138) mm2/m2, p=0.029] and more symmetric [symmetry index 0.84 (95% CI: 0.8 - 0.89) v. 0.77 (95% CI: 0.75 - 0.8), p=0.008] pulmonary arteries at the time of subsequent surgical repair or last follow-up.Conclusions—In this multi-center comparison of palliative PDA stent and BT shunt for infants with ductal-dependent pulmonary blood flow, adjusted for differences in patient factors, there was no difference in the primary endpoint, death or unplanned reintervention to treat cyanosis. However, other markers of morbidity and pulmonary artery size favored the PDA stent group, supporting PDA stent as a reasonable alternative to BT shunt in select patients.

Mortality and Cerebrovascular Events Following Heart Rhythm Disorder Management Procedures [Original Research Article]


Background—Recognition of rates and causes of hard, patient-centered outcomes of death and cerebrovascular event (CVE) after heart rhythm disorder management (HRDM) procedures is an essential step for development of quality improvement programs in electrophysiology laboratories. Our primary aim was to assess and characterize death and CVE (stroke or transient ischemic attack) after HRDM procedures over a 17-year period.Methods—We performed a retrospective cohort study of all patients undergoing HRDM procedures between January 2000 and November 2016 at the Mayo Clinic. Patients from all three tertiary academic centers (Rochester, Phoenix and Jacksonville) were included in the study. All cases of in-hospital death and CVE after HRDM procedures were identified and were further characterized as directly or indirectly related to the HRDM procedure. Subgroup analysis of death and CVE rates was performed for ablation, device implantation, EP study, lead extraction, and defibrillation threshold testing procedures.Results—A total of 48,913 patients (65.7±6.6 years, 64% male) who underwent a total of 62,065 HRDM procedures were included in the study. The overall mortality and CVE rate in the cohort was 0.36% (95% CI=0.31-0.42) and 0.12% (95% CI=0.09-0.16) respectively. Patients undergoing lead extraction had the highest overall mortality rate at 1.9% (95% CI=1.34-2.61) and CVE rate at 0.62% (95% CI=0.32-1.07). Among patients undergoing HRDM procedures, 48% of deaths directly related to the HDRM procedure were among patients undergoing device implantation procedures. Overall, cardiac tamponade was the most frequent direct cause of death (40%), and infection was the most common indirect cause of death (29%). The overall 30-day mortality rate was 0.76%, with the highest being in lead extraction procedures (3.08%), followed by device implantation procedures (0.94%).Conclusions—Half of the deaths directly related to a HRDM procedure were among the patients undergoing device implantation procedures, with cardiac tamponade being the most common cause of death. This highlights the importance of development of protocols for quick identification and management of cardiac tamponade even in procedures typically believed to be lower risk such as device implantation.

Effect of Intravenous Fentanyl on Ticagrelor Absorption and Platelet Inhibition Among Patients Undergoing Percutaneous Coronary Intervention: The PACIFY Randomized Clinical Trial [Research Letter]


Fentanyl is a potent opiate commonly administered during cardiac catheterization procedures in North America. The question of whether fentanyl could have adverse consequences in patients undergoing percutaneous coronary intervention (PCI) is raised by recent research demonstrating that intravenous morphine significantly delays the absorption of oral P2Y12 platelet inhibitors. The presumed mechanism is slowed gastric emptying. The single-center Platelet Aggregation with tiCagrelor Inhibition and FentanYl (PACIFY) trial randomized adults undergoing clinically-indicated elective coronary angiography to receive the procedure with or without intravenous fentanyl (NCT02683707). The study was approved by the Johns Hopkins Medicine Institutional Review Board and all participants provided written informed consent. Eligible adults had not received P2Y12 inhibitors for 14 days prior to enrollment. Other exclusion criteria included: pre-procedural treatment with oral anticoagulants or opiates; platelet count <100,000/mm3; and impaired renal or hepatic function. All participants received subcutaneous lidocaine and intravenous midazolam at the start of the catheterization procedure and as needed thereafter. Doses of all drugs were at the discretion of treating providers. Patients and outcomes assessors were blinded, treating providers were not. Participants who required PCI received an oral dose of 180 mg of ticagrelor at the conclusion of diagnostic angiography.

cGMP-Elevating Compounds and Ischemic Conditioning Provide Cardioprotection Against Ischemia and Reperfusion Injury via Cardiomyocyte-Specific BK Channels [Original Research Article]


Background—The nitric oxide-sensitive guanylyl cyclase (NO-GC)/cyclic guanosine-3',5'-monophosphate (cGMP)/cGMP-dependent protein kinase type I (cGKI)-signaling pathway can afford protection against the ischemia and reperfusion (I/R) injury that occurs during myocardial infarction (MI). Reportedly, voltage and Ca2+-activated K+ channels of the BK-type are stimulated by cGMP/cGKI and recent ex-vivo studies implicated that increased BK activity favors the survival of the myocardium at I/R. It remains unclear, however, whether the molecular events downstream of cGMP involve BK channels present in cardiomyocytes (CMs) or in other cardiac cell types. Methods—Gene-targeted mice with a CM- or smooth muscle (SM) cell-specific deletion of the BK were subjected to the open-chest model of MI. Infarct sizes of the conditional mutants were compared to litter-matched controls as well as to global BK knockout (BK-KO) and wildtype mice. Cardiac damage was assessed after mechanical conditioning or pharmacological stimulation of the cGMP pathway and by using direct modulators of BK. Long-term outcome was studied with respect to heart functions and cardiac fibrosis in a chronic MI model.Results—Global BK-KOs as well as CMBK-KOs, in contrast to SMBK-KOs, exhibited significantly larger infarct sizes as compared to their respective controls. Ablation of CMBK resulted in higher serum levels of cardiac troponin I as well as elevated amounts of reactive oxygen species, lower p-ERK/p-AKT levels and an increase in myocardial apoptosis. Moreover, CMBK was required to allow beneficial effects of both NO-GC activation and inhibition of the cGMP-degrading phosphodiesterase-5 (PDE5) as well as ischemic pre- (iPre) and postconditioning (iPost) regimens. To this end, after 4 weeks of reperfusion fibrotic tissue increased and myocardial strain echocardiography was significantly compromised in CMBK-deficient mice. Conclusions—Lack of CMBK channels renders the heart more susceptible to I/R injury, whereas the pathologic events elicited by I/R do not involve BK in SM. BK seems to permit the protective effects triggered by cinaciguat, riociguat and different PDE5 inhibitors as well as beneficial actions of iPre and iPost by a mechanism stemming primarily from CMs. In summary, this study establishes mitochondrial CMBK channels as a promising target for limiting acute cardiac damage as well as adverse long-term events that occur after MI.

The Centers for Medicare and Medicaid Services' Decision to Reconsider Coverage Indications for ICDs: Where to Now? [Perspective]


Several well-designed and conducted randomized clinical trials (RCTs) have proven the survival benefit of implantable cardioverter defibrillators (ICDs). This benefit has been demonstrated in patients who survive a cardiac arrest due to a ventricular tachyarrhythmia or have sustained ventricular tachycardia not due to a transient or a reversible cause. The survival benefit of ICDs has also been shown in patients with significant systolic dysfunction (left ventricular ejection fraction (LVEF) ≤35%) due to ischemic or non-ischemic cardiomyopathy. The compelling evidence on the benefits of ICDs led the Centers for Medicare and Medicaid services (CMS) to cover secondary and primary prevention ICDs in Medicare beneficiaries. However, for primary prevention ICDs, CMS provides coverage with evidence development that requires clinicians to enter data on primary prevention ICD implants in Medicare beneficiaries into the National Cardiovascular Data Registry (NCDR) ICD Registry.

The Prognostic Value of Follow-up Hemodynamic Variables After Initial Management in Pulmonary Arterial Hypertension [Original Research Article]


Background—Hemodynamic variables, such as cardiac index and right atrial pressure (RAP), have consistently been associated with survival in pulmonary arterial hypertension (PAH) at the time of diagnosis. Recent studies have suggested pulmonary arterial compliance (PCa) may also predict prognosis in PAH. The prognostic importance of hemodynamic values achieved after treatment initiation is less well established. Methods—Our objective was to evaluate the prognostic importance of clinical and hemodynamic variables during follow-up, including PCa, after initial management in PAH. We evaluated incident patients with idiopathic, drug and toxin-induced or heritable PAH enrolled in the French pulmonary hypertension registry between 2006-2016 who had a follow-up right heart catheterization (RHC). The primary outcome was death or lung transplantation. We used stepwise Cox regression and receiver-operating characteristic analysis to assess variables obtained at baseline and at first follow-up RHC.Results—Of 981 patients, a primary outcome occurred in 331 patients (33.7%) over a median follow-up duration of 2.8 years (IQR25-75% 1.1-4.6). In a multivariable model considering only baseline variables, no hemodynamic variables independently predicted prognosis. Median time to first follow-up RHC was 4.6 months (3.7-7.8). At first follow-up RHC (n=763), New York Heart Association (NYHA) functional class, 6-minute walk distance (6MWD), stroke volume index (SVI), and right atrial pressure (RAP) were independently associated with death or lung transplantation, adjusted for age, gender, and etiology of PAH. PCa did not independently predict outcomes at baseline or during follow-up. The adjusted hazard ratio for SVI was 1.28 (95%CI 1.11-1.49, p<0.01) per 10 mL/m2 decrease, and for RAP was 1.05 (95%CI 1.02-1.09, p<0.01) per mmHg increase. Among patients who had 2 (n=355) or 3 (n=193) low-risk prognostic features at follow-up, including a cardiac index ≥ 2.5 L/min/m2, 6MWD > 440 m and either NYHA I or II functional class, lower SVI was still associated with higher rates of death or lung transplantation (p<0.01).Conclusions—SVI and RAP were the hemodynamic variables independently associated with death or lung transplantation at first follow-up RHC after initial PAH treatment. These findings suggest that the SVI could be a more appropriate treatment target than the cardiac index in PAH.

Derivation and Validation of the CREST Model for Very Early Prediction of Circulatory Etiology Death in Patients without STEMI after Cardiac Arrest [Original Research Article]


Background—No practical tool quantitates the risk of circulatory-etiology death (CED) immediately after successful cardiopulmonary resuscitation in patients without ST-elevation myocardial infarction (STEMI). We developed and validated a prediction model to rapidly determine that risk and facilitate triage to individualized treatment pathways. Methods—Using the International Cardiac Arrest Registry (INTCAR), an 87-question data set representing 44 centers in America and Europe, patients were classified as having had CED or a combined endpoint of neurological-etiology death or survival. Demographics and clinical factors were modeled in a derivation cohort, and backward stepwise logistic regression used to identify factors independently associated with CED. We demonstrated model performance using area under the curve (AUC) and the Hosmer Lemeshow test in the derivation and validation cohorts, and assigned a simplified point scoring system.Results—Among 638 patients in the derivation cohort, 121 (18.9%) had CED. The final model included preexisting Coronary artery disease (OR=2.86, CI 1.83-4.49, p=<0.001), non-shockable Rhythm (OR= 1.75, CI 1.10-2.77, p=0.017), initial Ejection fraction<30% (OR=2.11, CI 1.32-3.37, p0.002), Shock at presentation (OR=2.27,CI 1.42-3.62, p<0.001) and ischemic Time >25 minutes (OR=1.42, CI 0.90-2.23, p=0.13. The derivation model AUC was 0.73, and Hosmer Lemeshow test p=0.47. Outcomes were similar in the 318 patient validation cohort (AUC 0.68, Hosmer Lemeshow test p=0.41). When assigned a point for each associated factor in the derivation model, the average predicted vs. observed probability of CED with a CREST score of 0-5 was: 7.1 vs. 10.2%, 9.5 vs. 11%, 22.5 vs. 19.6%, 32.4 vs. 29.6%, 38.5 vs. 30%, and 55.7 vs. 50%. Conclusions—The CREST model stratified patients immediately after resuscitation according to risk of a circulatory-etiology death. The tool may allow for estimation of circulatory risk, and improve triage of CA survivors without STEMI at the point of care.

Radiation Induced DNA Damage in Operators Performing Endovascular Aortic Repair [Original Research Article]


Background—Radiation exposure during fluoroscopically-guided interventions such as endovascular aortic repair (EVAR) is a growing concern for operators. This study aimed to measure DNA damage/repair markers in operators perfoming EVAR.Methods—Expression of the DNA damage/repair marker, gamma-H2AX (γ-H2AX) and DNA damage response (DDR) marker, phosphorylated ataxia telangiectasia mutated (pATM), were quantified in circulating lymphocytes in operators during the peri-operative period of endovascular (infra-renal [IEVAR], branched [BEVAR] and fenestrated [FEVAR]) and open aortic repair using flow cytometry. These markers were separately measured in the same operators but this time wearing leg lead shielding in addition to upper body protection and compared with those operating with unprotected legs. Susceptibility to radiation damage was determined by irradiating operators' blood in vitro. Results—γ-H2AX and pATM levels increased significantly in operators immediately after BEVAR/FEVAR (P<0.0003 for both). Only pATM levels increased after IEVAR (P<0.04). Expression of both markers fell to baseline in operators after 24hrs (P<0.003 for both). There was no change in γ-H2AX or pATM expression after open repair. Leg protection abrogated γ-H2AX and pATM response after BEVAR/FEVAR. The expression of γ-H2AX varied significantly when operators' blood was exposed to the same radiation dose in vitro (P<0.0001). Conclusions—This is the first study to detect an acute DNA damage response in operators performing fluoroscopically-guided aortic procedures and highlights the protective effect of leg shielding. Defining the relationship between this response and cancer risk may better inform safe levels of chronic low dose radiation exposure.

Duct Stenting versus Modified Blalock Taussig Shunt in Neonates with Duct-Dependent Pulmonary Blood Flow: Associations with Clinical Outcomes in a Multicenter National Study [Original Research Article]


Background—Infants born with cardiac abnormalities causing dependence on the arterial duct for pulmonary blood flow are often palliated with a shunt usually between the subclavian artery and either pulmonary artery. A so-called modified Blalock Taussig shunt (MBTS), allows progress through early life to an age and weight at which repair or further more stable palliation can be safely achieved. MBTSs continue to present concern for post-procedure instability and early mortality such that other alternatives continue to be explored. Duct stenting (DS) is emerging as one such alternative with potential for greater early stability and improved survival.Methods—To compare post-procedure outcomes and survival to next stage palliative or reparative surgery between patients undergoing a MBTS or a DS in infants with duct-dependent pulmonary blood flow. All patients undergoing cardiac surgery and congenital interventions in the UK are prospectively recruited to an externally validated national outcome audit. From this audit, participating UK centers identified infants less than 30 days of age undergoing either a BTS or a DS for cardiac conditions with duct-dependent pulmonary blood flow between January 2012 and end December 2015. 171 patients underwent a MBTS and 83 patients an attempt at DS. Primary and secondary outcomes of survival and need for extra-corporal support (ECMO) were analyzed using multivariable logistic regression. Longer term mortality pre-repair and re-intervention were analyzed using Cox proportional hazards regression. All multivariable analyses accommodated a propensity score to balance patient characteristics between the groups. Results—There was an early (to discharge) survival advantage for infants pre-next stage surgery in the DS group (OR=4.24, 95% CI 1.37 to 13.14, p=0.012). There was also a difference in the need for ECMO support post-procedure in favor of the DS group (OR=0.22, 95% CI 0.05 to 1.05, p=0.058). Longer term survival outcomes showed a reduced risk of death pre-repair in the DS group (HR=0.25, 95% CI 0.07 to 0.85, p=0.026), but a slightly increased risk of re-intervention (HR=1.50, 95% CI 0.85 to 2.64, p=0.165).Conclusions—Duct stenting is emerging as a preferred alternative to a surgical shunt for neonatal palliation with evidence for greater post-procedure stability and improved patient survival to destination surgical treatment.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Therapy: Payer Approvals and Rejections, and Patient Characteristics for Successful Prescribing [Original Research Article]


Background— Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are a novel class of medications for patients with familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease (ASCVD) requiring additional lipid lowering beyond dietary measures and statin use. Because of the drugs' high cost, rates of prescription approval by payers may be low. We aimed to identify payer approval and rejection rates for PCSK9i prescriptions, and potential factors influencing these rates.Methods—This is a retrospective, descriptive cohort study utilizing nationwide pharmacy claims linked to electronic medical records from a nationwide data warehouse. The dataset includes over 220 million patients from all fifty states and all payer types with 5,140 distinct health plans. PCSK9i prescriptions were submitted for 51,422 patients in the pharmacy dataset. The main outcome was approval or rejection of PCSK9i prescription claims. Factors associated with approval and rejection of these medications in the US were assessed.Results—Among patients who were prescribed a PCSK9i, 47.0% were approved for coverage by the payer. Variables that were associated with PCSK9i approval included age >65 years (p<0.01), history of ASCVD (p<0.01) prescription by a cardiologist or non-primary care provider (p<0.01), statin intolerance (p=0.03), longer statin duration (p=0.01), and non-commercial payers (p<0.01). Higher low density lipoprotein cholesterol (LDL-C) levels were not associated with higher approval rates. Commercial third-party payers had the lowest approval rates (24.4%) and Medicare had the highest (60.9%).Conclusions—Rates of approval for PCSK9i therapy are low, even for patients who appear to meet labeled indications. While a combination of clinical characteristics increases the likelihood of approval, payer type is the most significant factor.

Pioglitazone Prevents Stroke in Patients with a Recent TIA or Ischemic Stroke: A Planned Secondary Analysis of the IRIS Trial [Original Research Article]


Background—The Insulin Resistance Intervention after Stroke (IRIS) trial demonstrated that pioglitazone reduced the risk for a composite outcome of stroke or myocardial infarction among non-diabetic patients with insulin resistance and a recent stroke or TIA. The current planned secondary analysis uses updated 2013 consensus criteria for ischemic stroke to examine the effect of pioglitazone on stroke outcomes.Methods—Participants were randomized to receive pioglitazone (45 mg per day target dose) or placebo within 180 days of a qualifying ischemic stroke or transient ischemic attack and were followed for a maximum of 5-years. An independent committee, blinded to treatment assignments, adjudicated all potential stroke outcomes. Time to first stroke event was compared by treatment group, overall and by type of event (ischemic or hemorrhagic), using survival analyses and Cox proportional hazards models.Results—Among 3876 IRIS participants (mean age 63 years, 65% male), 377 stroke events were observed in 319 participants over a median follow-up of 4.8 years. Pioglitazone was associated with a reduced risk for any stroke at 5-years (8.0% compared to 10.7 for placebo group; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60 to 0.94; log-rank p=0.01). Pioglitazone reduced risk for ischemic strokes (HR, 0.72; 95% CI, 0.57 to 0.91; p=0.005) but had no effect on risk for hemorrhagic events (HR, 1.00; 95% CI, 0.50-2.00; p=1.00). Conclusions—Pioglitazone was effective for secondary prevention of ischemic stroke in non-diabetic patients with insulin resistance. Clinical Trial Registration—URL: Unique identifier: NCT00091949

Frequency, Predictors and Impact of Combined Antiplatelet Therapy on Venous Thromboembolism in Patients with Symptomatic Atherosclerosis [Original Research Article]


Background—Observational studies suggest that symptomatic atherosclerosis may be associated with risk of venous thromboembolism (VTE). Prior randomized studies have demonstrated a significant reduction in recurrent VTE with aspirin monotherapy. Whether VTE risk is associated with more severe symptomatic atherosclerosis and whether more intensive antiplatelet therapy reduces VTE risk beyond aspirin monotherapy is unknown.Methods—TRA2P-TIMI 50 (vorapaxar) and PEGASUS-TIMI 54 (ticagrelor) were blinded, randomized placebo-controlled trials of antiplatelet therapy for prevention of ischemic events in stable patients with symptomatic atherosclerosis. Two blinded vascular specialists systematically identified symptomatic venous thromboembolic events in both trials.Results—Of 47,611 patients with stable vascular disease followed for three years in both studies there were 343 VTE events in 301 patients (KM rate at 3 years 0.9% for placebo). The risk of VTE was independently associated with age, body mass index, polyvascular disease, chronic obstructive pulmonary disease and malignancy. The burden of atherosclerosis manifested as increasing number of symptomatic vascular territories was associated with a graded increase in the 3-year rates of VTE (0.76% for one, 1.53% for two and 2.45% for three territories). More intensive antiplatelet therapy (vorapaxar and ticagrelor pooled) significantly reduced the risk of VTE by 29% compared with background antiplatelet therapy, from 0.93% to 0.64% at 3 years (HR 0.71, 95% CI 0.56-0.89; p=0.003).Conclusions—The rate of VTE in patients with atherosclerosis is ~0.3% per year while on treatment with at least one antiplatelet agent with increased risk independently associated with the number of symptomatic vascular territories. More intensive antiplatelet therapy reduces the risk of VTE. These data suggest a relationship between atherosclerosis burden and VTE risk and support inclusion of VTE as a prospective endpoint in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with atherosclerosis.Clinical Trial Registration—URL: Unique Identifier: NCT01225562.

Three-Year Outcomes With the Absorb Bioresorbable Scaffold: Individual-Patient-Data Meta-Analysis From the ABSORB Randomized Trials [Original Research Article]


BACKGROUND: The Absorb bioresorbable vascular scaffold (BVS) completely resorbs within 3 years after coronary artery implantation. The safety and effectiveness of BVS through this critical 3-year period have not been characterized.METHODS: We performed an individual-patient-data pooled meta-analysis of the 4 randomized ABSORB trials in which 3389 patients with coronary artery disease were randomly assigned to everolimus-eluting Absorb BVS (n=2164) or cobalt-chromium everolimus-eluting stents (n=1225). The primary efficacy outcome measure was target lesion failure (cardiac mortality, target vessel myocardial infarction, or ischemia-driven target lesion revascularization), and the primary safety outcome measure was device thrombosis.RESULTS: BVS compared with cobalt-chromium everolimus-eluting stents resulted in higher 3-year rates of target lesion failure (11.7% versus 8.1%; risk ratio [RR], 1.38; 95% confidence interval [CI], 1.10-1.73; P=0.006), driven by greater target vessel myocardial infarction (7.8% versus 4.2%; RR, 1.72; 95% CI, 1.26-2.35; P=0.0006) and ischemia-driven target lesion revascularization (6.6% versus 4.4%; RR, 1.44; 95% CI, 1.05-1.98; P=0.02), with comparable cardiac mortality (1.1% versus 1.1%; RR, 0.93; 95% CI, 0.47-1.88; P=0.85). Device thrombosis rates through 3 years were also higher with BVS (2.4% versus 0.6%; RR, 3.71; 95% CI, 1.70-8.11; P=0.001). Between 1 and 3 years, target lesion failure rates (6.1% versus 3.9%; P=0.02) and device thrombosis rates (1.1% versus 0.0%; P<0.0001) were higher with BVS than cobalt-chromium everolimus-eluting stents.CONCLUSIONS: In the present individual-patient-data pooled meta-analysis of the ABSORB trials, BVS was associated with increased rates of target lesion failure and device thrombosis between 1 and 3 years and cumulatively through 3 years of follow-up compared with everolimus-eluting stents.CLINICAL TRIAL REGISTRATION: URL: Unique identifiers: NCT01751906, NCT01844284, NCT01923740, and NCT01425281.

Atrial Fibrillation Burden in Young Patients with Congenital Heart Disease [Original Research Article]


Background—Patients with congenital heart disease (CHD) are assumed to be vulnerable to atrial fibrillation (AF) due to residual shunts, anomalous vessel anatomy, progressive valvulopathy, hypertension, and atrial scars from previous heart surgery. However, the risk of developing AF as well as the complications associated with AF in children and young adults with CHD have not been compared with those in controls.Methods—Data from the Swedish Patient and Cause of Death Registers were used to identify all patients with a diagnosis of CHD who were born from 1970 to 1993. Each patient with CHD was matched by birth year, sex, and county with 10 controls from the Total Population Register in Sweden. Follow-up data were collected until 2011.Results—Among 21,982 patients (51.6% men) with CHD and 219,816 matched controls, 654 and 328 developed AF, respectively. The mean follow-up was 27 years. The risk of developing AF was 21.99 times higher (95% confidence interval, 19.26-25.12) in patients with CHD than controls. According to a hierarchic CHD classification, patients with conotruncal defects had the highest risk (hazard ratio, 84.27; 95% confidence interval, 56.86-124.89). At the age of 42 years, 8.3% of all patients with CHD had a recorded diagnosis of AF. Heart failure was the quantitatively most important complication in patients with CHD and AF, with a 10.7% (70/654) recorded diagnosis of heart failure.Conclusions—The risk of AF in children and young adults with CHD was 22 times higher than that in matched controls. Up to the age of 42 years, 1 of 12 patients with CHD had developed AF and 1 of 10 patients with CHD with AF had developed heart failure. The patient groups with the most complex congenital defects carried the greatest risk of AF and could be considered for targeted monitoring.

Genetic and Functional Profiling of CD16-Dependent Natural Killer Activation Identifies Patients at Higher Risk of Cardiac Allograft Vasculopathy [Original Research Article]


Background—Cardiac transplantation is an effective therapy for end-stage heart failure. As cardiac allograft vasculopathy (CAV) is the major cause of late mortality after heart transplant (HT), there is a need to identify markers that reflect inflammatory or cytotoxic immune mechanisms contributing to its onset. Non-invasive and early stratification of patients at risk remains a challenge for adapting individualized therapy. The CD16 (Fc-gamma receptor 3A, FCGR3A) receptor was recently identified as a major determinant of antibody-mediated natural killer (NK) cell activation in HT biopsies; however, little is known about the role of CD16 in promoting allograft vasculopathy. This study aimed to investigate whether markers that reflect CD16-dependent circulating NK cell activation may identify patients at higher risk of developing CAV after HT.Methods—Blood samples were collected from 103 patients undergoing routine coronarography angiography for CAV diagnosis (median 5 years since HT). Genomic and phenotypic analyses of FCGR3A/CD16 Fc-receptor (FcR) profiles were compared in CAV-positive (n=52) and CAV-free patients (n=51). The levels of CD16 expression and rituximab-dependent cell cytotoxic activity of peripheral NK cells in heart transplant recipients (HTRs) were evaluated using a non-invasive NK-cellular humoral activation test (NK-CHAT). Results—Enhanced levels of CD16 expression and antibody-dependent NK cell cytotoxic function of HTRs were associated with the FCGR3A-VV genotype. The frequency of the FCGR3A-VV genotype was significantly higher in the CAV+ group (odds ratio (OR): 3.9, p=0.0317) than in the CAV- group. The FCGR3A-VV genotype was identified as an independent marker correlated with the presence of CAV at the time of coronary angiography using multivariate logistic regression models. The FCGR3A-VV genotype was also identified as a baseline independent predictor of CAV risk (OR: 4.7, p=0.023). Conclusions—This study unravels a prominent role for the CD16-dependent NK cell activation pathway in the complex array of factors that favor the progression of transplant arteriosclerosis. It highlights the clinical potential of a non-invasive evaluation of FCGR3A/CD16 in the early stratification of CAV risk. The recognition of CD16 as a major checkpoint that controls immune surveillance may promote the design of individualized NK cell-targeted therapies to limit vascular damage in highly responsive sensitized patients. Clinical Trial Registration—URL: Unique Identifier: NCT01569334

Clinical Outcomes and Cost-Effectiveness of Fractional Flow Reserve-Guided Percutaneous Coronary Intervention in Patients With Stable Coronary Artery Disease: Three-Year Follow-Up of the FAME 2 Trial (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) [Original Research Article]


BACKGROUND: Previous studies found that percutaneous coronary intervention (PCI) does not improve outcome compared with medical therapy (MT) in patients with stable coronary artery disease, but PCI was guided by angiography alone. FAME 2 trial (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) compared PCI guided by fractional flow reserve with best MT in patients with stable coronary artery disease to assess clinical outcomes and cost-effectiveness.METHODS: A total of 888 patients with stable single-vessel or multivessel coronary artery disease with reduced fractional flow reserve were randomly assigned to PCI plus MT (n=447) or MT alone (n=441). Major adverse cardiac events included death, myocardial infarction, and urgent revascularization. Costs were calculated on the basis of resource use and Medicare reimbursement rates. Changes in quality-adjusted life-years were assessed with utilities determined by the European Quality of Life-5 Dimensions health survey at baseline and over follow-up.RESULTS: Major adverse cardiac events at 3 years were significantly lower in the PCI group compared with the MT group (10.1% versus 22.0%; P<0.001), primarily as a result of a lower rate of urgent revascularization (4.3% versus 17.2%; P<0.001). Death and myocardial infarction were numerically lower in the PCI group (8.3% versus 10.4%; P=0.28). Angina was significantly less severe in the PCI group at all follow-up points to 3 years. Mean initial costs were higher in the PCI group ($9944 versus $4440; P<0.001) but by 3 years were similar between the 2 groups ($16 792 versus $16 737; P=0.94). The incremental cost-effectiveness ratio for PCI compared with MT was $17 300 per quality-adjusted life-year at 2 years and $1600 per quality-adjusted life-year at 3 years. The above findings were robust in sensitivity analyses.CONCLUSIONS: PCI of lesions with reduced fractional flow reserve improves long-term outcome and is economically attractive compared with MT alone in patients with stable coronary artery disease.CLINICAL TRIAL REGISTRATION: URL: Unique identifier: NCT01132495.

0/1-Hour Triage Algorithm for Myocardial Infarction in Patients with Renal Dysfunction [Original Research Article]


Background—The European Society of Cardiology (ESC) recommends a 0/1h-algorithm for rapid rule-out and rule-in of Non-ST-Segment-Elevation Myocardial Infarction (NSTEMI) using high-sensitivity cardiac troponin (hs-cTn) concentrations irrespective of renal function. As patients with renal dysfunction (RD) frequently present with increased hs-cTn concentrations even in absence of NSTEMI, concern has been raised regarding the performance of the 0/1h-algorithm in RD. Methods—In a prospective multicenter diagnostic study enrolling unselected patients presenting with suspected NSTEMI to the emergency department, we assessed the diagnostic performance of the ESC 0/1h-algorithm using hs-cTnT and hs-cTnI in patients with RD, defined as an estimated glomerular filtration rate below 60mL/min/1.73m2, and compared it to patients with normal renal function (NRF). The final diagnosis was centrally adjudicated by two independent cardiologists using all available information including cardiac imaging. Safety was quantified as sensitivity in the rule-out zone, accuracy as the specificity in the rule-in zone, and efficacy as the proportion of the overall cohort assigned to either rule-out or rule-in based on the 0h- and 1h-sample. Results—Among 3254 patients, RD was present in 487 patients (15%). The prevalence of NSTEMI was substantially higher in patients with RD as compared to patients with normal renal function (31% versus 13%, p<0.001). Using hs-cTnT, patients with RD had comparable sensitivity of rule-out (100.0% (95%CI, 97.6-100.0) versus 99.2% (95%CI, 97.6-99.8), p=0.559), lower specificity of rule-in (88.7% (95%CI, 84.8-91.9) versus 96.5% (95%CI, 95.7-97.2), p<0.001), and lower overall efficacy (51% versus 81%, p<0.001), mainly driven by a much lower percentage of patients eligible for rule-out (18% versus 68%, p<0.001), as compared to patients with normal renal function. Using hs-cTnI, patients with RD had comparable sensitivity of rule-out (98.6% (95%CI, 95.0-99.8) versus 98.5% (95%CI, 96.5-99.5), p=1.0), lower specificity of rule-in (84.4% (95%CI, 79.9-88.3) versus 91.7% (95%CI, 90.5-92.9), p<0.001), and lower overall efficacy (54% versus 76%, p<0.001; proportion ruled-out, 18% versus 58%, p<0.001) as compared to patients with normal renal function.Conclusions—In patients with RD the safety of the ESC 0/1h-algorithm is very high, but specificity of rule-in and overall efficacy are decreased. Modifications of the rule-in and rule-out thresholds did not improve the safety or overall efficacy of the 0/1h-algorithm.Clinical Trial Registration—URL: Unique Identifier: NCT00470587

Increased Cardiac Arrhythmogenesis Associated with Gap Junction Remodeling with Upregulation of RNA Binding Protein FXR1 [Original Research Article]


Background—Gap junction remodeling is well established as a consistent feature of human heart disease involving spontaneous ventricular arrhythmia. The mechanisms responsible for gap junction remodeling that include alterations in the distribution of, and protein expression within, gap junctions are still debated. Studies reveal that multiple transcriptional and post-transcriptional regulatory pathways are triggered in response to cardiac disease, such as those involving RNA-binding proteins. The expression levels of Fragile X mental retardation autosomal homolog 1 (FXR1), an RNA-binding protein, are critical to maintain proper cardiac muscle function; however, the connection between FXR1 and disease is not clear. Methods—To identify the mechanisms regulating gap junction remodeling in cardiac disease, we sought to identify: the functional properties of FXR1 expression, direct targets of FXR1 in human left ventricle dilated cardiomyopathy (DCM) biopsy samples and mouse models of DCM through BioID proximity assay and RNA immunoprecipitation, how FXR1 regulates it targets through RNA stability and luciferase assays, and functional consequences of altering the levels of this important RNA binding protein through the analysis of cardiac-specific FXR1 knockout mice and mice injected with 3xMyc-FXR1 adeno-associated virus. Results—FXR1 expression is significantly increased in tissue samples from human and mouse models of DCM via western blot analysis. FXR1 associates with intercalated discs and integral gap junction proteins Cx43, Cx45 and ZO-1 were identified as novel mRNA targets of FXR1 using a BioID proximity assay and RNA immunoprecipitation. Our findings show FXR1 is a multifunctional protein involved in translational regulation and stabilization of its mRNA targets in heart muscle. Additionally, introduction of 3xMyc-FXR1 via adeno-associated virus into mice leads to redistribution of gap junctions and promotes ventricular tachycardia showing functional significance of FXR1 upregulation observed in DCM.Conclusions—In DCM, increased FXR1 expression appears to play an important role in disease progression by regulating gap junction remodeling. Together this study provides a novel function of FXR1 namely that it directly regulates major gap junction components, contributing to proper cell-cell communication in the heart.

The Efficacy and Safety of the Use of Non-Vitamin-K Antagonist Oral Anticoagulants in Patients with Non-Valvular Atrial Fibrillation and Concomitant Aspirin Therapy: A Meta-Analysis of Randomized Trials [Original Research Article]


Background—Current guidelines recommend non-vitamin-K antagonist oral anticoagulants (NOACs) as the first choice therapy in patients with non-valvular atrial fibrillation, as these drugs have several benefits over the vitamin-K antagonists (VKA). It is unknown whether these benefits remain when NOACs have to be combined with aspirin therapy. To assess the efficacy and safety of NOACs compared with VKA in patients with AF and concomitant aspirin therapy, we conducted a systematic review and study based meta-analysis of published randomized controlled trials (RCTs).Methods—A systematic electronic literature search was done in MEDLINE, EMBASE and Cochrane CENTRAL Register of Controlled Trials for studies including published data (i) of patients age ≥18 y with non-valvular AF; (ii) randomizing to either VKA or NOACs; (iii) patients receiving aspirin therapy at any time during the study; and (iv) reporting on all-cause stroke or systemic embolism, vascular death, myocardial infarction, major bleeding and/or intracranial hemorrhage as an outcome. Hazard ratios (HR) with 95% confidence intervals (CIs) for each outcome were extracted from the individual studies and pooled using random-effects meta-analysis.Results—This study based meta-analysis was restricted to the subgroups of patients on aspirin therapy (n=21,722) from four RCTs comparing VKA and NOACs (N=71,681) in non-valvular AF. In this meta-analysis including patients on mainly low-dose aspirin, NOACs were found to be more effective (outcome stroke or systemic embolism HR: 0.78 [95% CI, 0.67-0.91] and vascular death HR 0.85 [0.76-0.93]) and as safe as VKA with respect to major bleeding (HR: 0.83 [95% CI, 0.69-1.01]). NOACs were safer with respect to the reduction of intracranial hemorrhage (HR: 0.38 [0.26-0.56]). Conclusions—This study based meta-analysis shows that it may be both safer and more effective to use NOACs as compared with VKA to treat patients with non-valvular AF and concomitant aspirin therapy.

Accelerometer-Measured Physical Activity and Sedentary Behavior in Relation to All-Cause Mortality: The Women's Health Study [Research Letter]


Physical inactivity is estimated to cause as many deaths globally each year as smoking. Current guidelines recommend ≥150 min/wk of moderate-intensity aerobic physical activity (PA) and muscle-strengthening exercises on ≥2 d/wk.2 These guidelines are based primarily on studies using self-reported moderate- to vigorous-intensity PA (MVPA). Technological developments now enable device assessments of light-intensity PA (LPA) and sedentary behavior, and well-designed studies with such assessments that investigate clinical outcomes are needed for updating current guidelines. Here, we present data from the WHS (Women's Health Study). (The data, analytical methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.)

2017 American Heart Association Focused Update on Adult Basic Life Support and Cardiopulmonary Resuscitation Quality: An Update to the American Heart Association Guidelines for Cardio pulmonary Resuscitation and Emergency Cardiovascular Care [AHA Focused Update]


Cardiopulmonary resuscitation is a lifesaving technique for victims of sudden cardiac arrest. Despite advances in resuscitation science, basic life support remains a critical factor in determining outcomes. The American Heart Association recommendations for adult basic life support incorporate the most recently published evidence and serve as the basis for education and training for laypeople and healthcare providers who perform cardiopulmonary resuscitation.

2017 American Heart Association Focused Update on Pediatric Basic Life Support and Cardiopulmonary Resuscitation Quality: An Update to the American Heart Association Guidelines for Cardio pulmonary Resuscitation and Emergency Cardiovascular Care [AHA Focused Update]


This focused update to the American Heart Association guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care follows the Pediatric Task Force of the International Liaison Committee on Resuscitation evidence review. It aligns with the International Liaison Committee on Resuscitation’s continuous evidence review process, and updates are published when the International Liaison Committee on Resuscitation completes a literature review based on new science. This update provides the evidence review and treatment recommendation for chest compression–only CPR versus CPR using chest compressions with rescue breaths for children <18 years of age. Four large database studies were available for review, including 2 published after the “2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.” Two demonstrated worse 30-day outcomes with chest compression–only CPR for children 1 through 18 years of age, whereas 2 studies documented no difference between chest compression–only CPR and CPR using chest compressions with rescue breaths. When the results were analyzed for infants <1 year of age, CPR using chest compressions with rescue breaths was better than no CPR but was no different from chest compression–only CPR in 1 study, whereas another study observed no differences among chest compression–only CPR, CPR using chest compressions with rescue breaths, and no CPR. CPR using chest compressions with rescue breaths should be provided for infants and children in cardiac arrest. If bystanders are unwilling or unable to deliver rescue breaths, we recommend that rescuers provide chest compressions for infants and children.

2017 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations Summary [ILCOR Summary Statement]


The International Liaison Committee on Resuscitation has initiated a near-continuous review of cardiopulmonary resuscitation science that replaces the previous 5-year cyclic batch-and-queue approach process. This is the first of an annual series of International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations summary articles that will include the cardiopulmonary resuscitation science reviewed by the International Liaison Committee on Resuscitation in the previous year. The review this year includes 5 basic life support and 1 pediatric Consensuses on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Each of these includes a summary of the science and its quality based on Grading of Recommendations, Assessment, Development, and Evaluation criteria and treatment recommendations. Insights into the deliberations of the International Liaison Committee on Resuscitation task force members are provided in Values and Preferences sections. Finally, the task force members have prioritized and listed the top 3 knowledge gaps for each population, intervention, comparator, and outcome question.

American Heart Association Principles on the Accessibility and Affordability of Drugs and Biologics: A Presidential Advisory From the American Heart Association [AHA Presidential Advisory]


Net US spending on pharmaceuticals reached $309.5 billion in 2015, an 8.5% increase from the year before, and is expected to reach between $370 and $400 billion by 2020. These current and projected levels have raised serious concerns by policy makers, providers, payers, and patient groups that they are unsustainable and threaten the affordability of and accessibility to much-needed therapies for patients. Two trends related to drugs/biologics and generic drugs/biosimilars underlie this overall increase in spending. First, the market entry prices of innovator pharmaceutical products, or brand drugs and biologics, are at levels that some assessments consider unaffordable to the healthcare system. Second, prices for some established generic drugs such as digoxin and captopril have seen sharp and rapid increases. As an evidence-based patient advocacy organization dedicated to improving the cardiovascular health of all Americans, the American Heart Association has a unique role in advocating for treatments, including medicines that are available, affordable, and accessible to patients. This advisory serves to lay out a set of principles that will guide association engagement in pursuit of this goal.

Persistent Long-Term Structural, Functional, and Metabolic Changes After Stress-Induced (Takotsubo) Cardiomyopathy [Original Research Article]


BACKGROUND: Takotsubo cardiomyopathy is an increasingly recognized acute heart failure syndrome precipitated by intense emotional stress. Although there is an apparent rapid and spontaneous recovery of left ventricular ejection fraction, the long-term clinical and functional consequences of takotsubo cardiomyopathy are ill-defined.METHODS: In an observational case-control study, we recruited 37 patients with prior (>12-month) takotsubo cardiomyopathy, and 37 age-, sex-, and comorbidity-matched control subjects. Patients completed the Minnesota Living with Heart Failure Questionnaire. All participants underwent detailed clinical phenotypic characterization, including serum biomarker analysis, cardiopulmonary exercise testing, echocardiography, and cardiac magnetic resonance including cardiac 31P-spectroscopy.RESULTS: Participants were predominantly middle-age (64±11 years) women (97%). Although takotsubo cardiomyopathy occurred 20 (range 13-39) months before the study, the majority (88%) of patients had persisting symptoms compatible with heart failure (median of 13 [range 0-76] in the Minnesota Living with Heart Failure Questionnaire) and cardiac limitation on exercise testing (reduced peak oxygen consumption, 24±1.3 versus 31±1.3 mL/kg/min, P<0.001; increased VE/VCO2 slope, 31±1 versus 26±1, P=0.002). Despite normal left ventricular ejection fraction and serum biomarkers, patients with prior takotsubo cardiomyopathy had impaired cardiac deformation indices (reduced apical circumferential strain, ‒16±1.0 versus ‒23±1.5%, P<0.001; global longitudinal strain, ‒17±1 versus ‒20±1%, P=0.006), increased native T1 mapping values (1264±10 versus 1184±10 ms, P<0.001), and impaired cardiac energetic status (phosphocreatine/γ-adenosine triphosphate ratio, 1.3±0.1 versus 1.9±0.1, P<0.001).CONCLUSIONS: In contrast to previous perceptions, takotsubo cardiomyopathy has long-lasting clinical consequences, including demonstrable symptomatic and functional impairment associated with persistent subclinical cardiac dysfunction. Taken together our findings demonstrate that after takotsubo cardiomyopathy, patients develop a persistent, long-term heart failure phenotype.CLINICAL TRIAL REGISTRATION: URL: Unique identifier: NCT02989454.

Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation [Original Research Article]


Background—The long-term probability of developing atrial fibrillation (AF) considering genetic predisposition and clinical risk factor burden is unknown.Methods—We estimated lifetime risk of AF in individuals from the community-based Framingham Heart Study. Polygenic risk for AF was derived using a score of approximately 1,000 AF-associated single nucleotide polymorphisms. Clinical risk factor burden was calculated for each individual using a validated risk score for incident AF comprised of height, weight, systolic and diastolic blood pressure, current smoking status, antihypertensive medication use, diabetes, history of myocardial infarction, and history of heart failure. We estimated the lifetime risk of AF within tertiles of polygenic and clinical risk.Results—Among 4,606 participants without AF at age 55 years, 580 developed incident AF (median follow-up, 9.4 years; 25th-75th percentile, 4.4-14.3 years). The lifetime risk of AF after age 55 years was 37.1%, and was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of AF at age 55 years, those in low polygenic and clinical risk tertiles had a lifetime risk of AF of 22.3% (95% confidence interval [CI], 15.4%-29.1%), whereas those in high risk tertiles had a risk of 48.2% (95% CI, 41.3%-55.1%). A lower clinical risk factor burden was associated with later AF onset after adjusting for genetic predisposition (P value <0.001).Conclusions—In our community-based cohort, the lifetime risk of AF was 37%. Estimation of polygenic AF risk is feasible, and together with clinical risk factor burden explains a substantial gradient in long-term AF risk.

Potential U.S. Population Impact of the 2017 American College of Cardiology/American Heart Association High Blood Pressure Guideline [Original Research Article]


Background—The 2017 American College of Cardiology/American Heart Association (ACC/AHA) Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults provides recommendations for the definition of hypertension, systolic and diastolic blood pressure (BP) thresholds for initiation of antihypertensive medication and BP target goals. The objective of this study was to determine the prevalence of hypertension, implications of recommendations for antihypertensive medication and prevalence of BP above the treatment goal among US adults using criteria from the 2017 ACC/AHA and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC7) guidelines.Methods—We analyzed data from the 2011-2014 National Health and Nutrition Examination Survey (N=9,623). NHANES (National Health and Nutrition Examination Survey) participants completed study interviews and an examination. For each participant, blood pressure was measured three times following a standardized protocol and averaged. Results were weighted to produce US population estimates.Results—According to the 2017 ACC/AHA and JNC7 guidelines, the overall crude prevalence of hypertension among US adults was 45.6% (95% confidence interval [CI] 43.6%,47.6%) and 31.9% (95%CI 30.1%, 33.7%), respectively, and antihypertensive medication was recommended for 36.2% (95%CI 34.2%, 38.2%) and 34.3% (32.5%, 36.2%) of US adults, respectively. Compared to US adults recommended antihypertensive medication by JNC7, those recommended treatment by the 2017 ACC/AHA guideline but not JNC7 had higher cardiovascular disease (CVD) risk. Non-pharmacological intervention is advised for the 9.4% of US adults with hypertension according to the 2017 ACC/AHA guideline who are not recommended antihypertensive medication. Among US adults taking antihypertensive medication, 53.4% (95%CI 49.9%, 56.8%) and 39.0% (95%CI 36.4%, 41.6%) had BP above the treatment goal according to the 2017 ACC/AHA and JNC7 guidelines, respectively. Overall, 103.3 (95%CI 92.7, 114.0) million US adults had hypertension according to the 2017 ACC/AHA guideline of whom 81.9 (95%CI 73.8, 90.1) million were recommended antihypertensive medication. Conclusions—Comp[...]

Availability and Use of Shared Data From Cardiometabolic Clinical Trials [Original Research Article]


BACKGROUND: Sharing of patient-level clinical trial data has been widely endorsed. Little is known about how extensively these data have been used for cardiometabolic diseases. We sought to evaluate the availability and use of shared data from cardiometabolic clinical trials.METHODS: We extracted data from, a large, multisponsor data-sharing platform hosting individual patient-level data from completed studies sponsored by 13 pharmaceutical companies.RESULTS: From January 2013 to May 2017, the platform had data from 3374 clinical trials, of which 537 (16%) evaluated cardiometabolic therapeutics (phase 1, 36%; phase 2, 17%; phase 2/3, 1%; phase 3, 42%; phase 4, 4%). They covered 74 therapies and 398 925 patients. Diabetes mellitus (60%) and hypertension (15%) were the most common study topics. Median time from study completion to data availability was 79 months. As of May 2017, had received 318 submitted proposals, of which 163 had signed data-sharing agreements. Thirty of these proposals were related to cardiometabolic therapies and requested data from 79 unique studies (15% of all trials, 29% of phase 3/4 trials). Most (96%) data requesters of cardiometabolic clinical trial data were from academic centers in North America and Western Europe, and half the proposals were unfunded. Most proposals were for secondary hypothesis-generating questions, with only 1 proposed reanalysis of the original study primary hypothesis. To date, 3 peer-reviewed articles have been published after a median of 19 months (9-32 months) from the data-sharing agreement.CONCLUSIONS: Despite availability of data from >500 cardiometabolic trials in a multisponsor data-sharing platform, only 15% of these trials and 29% of phase 3/4 trials have been accessed by investigators thus far, and a negligible minority of analyses have reached publication.

Burden of Catastrophic Health Expenditures for Acute Myocardial Infarction and Stroke Among Uninsured in the United States [Research Letter]


Acute myocardial infarction (AMI) and stroke are unanticipated major healthcare events that require emergent and expensive care. Given the potential financial implications of AMI and stroke among uninsured patients, we sought to evaluate rates of catastrophic healthcare expenditures (CHEs), defined as expenses beyond financial means, in a period before the implementation of insurance expansion and protections in the Affordable Care Act.1

Cardiovascular Outcomes and Safety of Empagliflozin in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease: A Subanalysis of EMPA-REG OUTCOME [Research Letter]


Peripheral artery disease (PAD) is one of the most common cardiovascular complications in patients with type 2 diabetes mellitus (T2DM)1 and is a predictor of cardiovascular death.2 Interventions that reduce cardiovascular complications in this patient population are urgently required. In the EMPA-REG OUTCOME trial, the sodium glucose cotransporter 2 inhibitor empagliflozin reduced the risk of cardiovascular death by 38% (hazard ratio [HR], 0.62; 95% confidence interval [CI] 0.49-0.77]) and hospitalization for heart failure (HHF) by 35% (HR, 0.65; 95% CI, 0.50-0.85) versus placebo when given in addition to standard of care.3 We report analyses of the effects of empagliflozin on cardiovascular outcomes, mortality, and renal outcomes in patients with and without PAD at baseline in the EMPA-REG OUTCOME trial.

Canagliflozin: Cui Bono? [Editorial]


Cardiovascular disease accounts for the majority of excess deaths seen in patients with Type 2 diabetes (T2D).1 Thus, in order to improve outcomes in this population, clinicians should focus on therapies that decrease the risk of subsequent cardiovascular events. Over the last two years, randomized controlled clinical trials have identified several agents that decrease cardiovascular events in patients with T2D with or at high risk for cardiovascular disease (CVD) - effects likely unrelated to glucose-lowering, the indication for which they were originally developed.2-5 One of these therapies (empagliflozin), a sodium glucose co-transporter-2 inhibitor (SGLT-2i), was found to reduce the risks of major adverse cardiovascular events (MACE), CV death, hospitalization for heart failure, and progression of nephropathy in patients with CVD.2 However, it is unknown whether SGLT-2i can also reduce cardiovascular events in the lower risk population of patients with T2D but without established CVD.

Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study) [Original Research Article]


BACKGROUND: Canagliflozin is a sodium glucose cotransporter 2 inhibitor that significantly reduces the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and elevated cardiovascular risk. The comparative effects among participants with and without a history of cardiovascular disease (secondary versus primary prevention) were prespecified for evaluation.METHODS: The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) randomly assigned 10 142 participants with type 2 diabetes mellitus to canagliflozin or placebo. The primary prevention cohort comprised individuals ≥50 years of age with ≥2 risk factors for cardiovascular events but with no prior cardiovascular event, and the secondary prevention cohort comprised individuals ≥30 years of age with a prior cardiovascular event. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included heart failure hospitalization and a renal composite (40% reduction in estimated glomerular filtration rate, renal replacement therapy, or renal death).RESULTS: Primary prevention participants (N=3486; 34%) were younger (63 versus 64 years of age), were more often female (45% versus 31%), and had a longer duration of diabetes mellitus (14 versus 13 years) compared with secondary prevention participants (N=6656; 66%). The primary end point event rate was higher in the secondary prevention group compared with the primary prevention group (36.9 versus 15.7/1000 patient-years, P[...]

Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) [Original Research Article]


BACKGROUND: The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events.METHODS: FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of [...]

Effects of Bariatric Surgery in Obese Patients With Hypertension: The GATEWAY Randomized Trial (Gastric Bypass to Treat Obese Patients With Steady Hypertension) [Original Research Article]


BACKGROUND: Recent research efforts on bariatric surgery have focused on metabolic and diabetes mellitus resolution. Randomized trials designed to assess the impact of bariatric surgery in patients with obesity and hypertension are needed.METHODS: In this randomized, single-center, nonblinded trial, we included patients with hypertension (using ≥2 medications at maximum doses or >2 at moderate doses) and a body mass index between 30.0 and 39.9 kg/m2. Patients were randomized to Roux-en-Y gastric bypass plus medical therapy or medical therapy alone. The primary end point was reduction of ≥30% of the total number of antihypertensive medications while maintaining systolic and diastolic blood pressure [...]

Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Co-Transporter 2 Inhibitor: Results From the EASEL Population-Based Cohort Study [Original Research Article]


Background: Clinical trials have shown cardiovascular benefits and potential risks from sodium glucose co-transporter 2 inhibitors (SGLT2i). Trials may have limited ability to address individual endpoints or safety concerns.Methods: We performed a population-based cohort study among type 2 diabetes patients with established cardiovascular disease newly initiated on antihyperglycemic agents (AHAs) within the US Department of Defense Military Health System between 4/1/2013 and 12/31/2016. Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite endpoint of all-cause mortality (ACM) and hospitalization for heart failure (HHF) event, major adverse cardiovascular events (MACE; defined as ACM, nonfatal myocardial infarction, and nonfatal stroke), and individual endpoints were evaluated using conditional Cox models comparing new SGLT2i users with other AHAs. Exploratory safety endpoint was below-knee lower extremity amputation (BKA). Intent-to-treat and on-treatment analyses were performed.Results: After propensity matching, 25,258 patients were followed for a median of 1.6 years. Compared with non-SGLT2i, initiation of SGLT2i was associated with a lower rate of ACM and HHF (1.73 vs. 3.01 events per 100 person-years; HR 0.57; 95% CI: 0.50-0.65) and MACE (2.31 vs. 3.45 events per 100 person-years; HR 0.67, 95% CI: 0.60-0.75). SGLT2i initiation was also associated with a ≈two-fold higher risk of BKA (0.17 vs. 0.09 events per 100 person-years; HR 1.99, 95% CI: 1.12-3.51). Due to the disproportionate canagliflozin exposure in the database, the majority of amputations were observed on canagliflozin. Results were consistent in the on-treatment analysis.Conclusions: In this high-risk cohort, initiation of SGLT2i was associated with lower ACM, HHF, and MACE and higher BKA risk. Findings underscore the potential benefit and risks to be aware of when initiating SGLT2i. It remains unclear whether the BKA risk extends across the class of medication as the study was not powered to make comparisons among individual[...]

Impact of Regionalization of ST Elevation Myocardial Infarction Care on Treatment Times and Outcomes for Emergency Medical Services Transported Patients Presenting to Hospitals with Percutaneous Coronary Intervention: Mission: Lifeline Accelerator-2 [Original Research Article]


Background: Regional variations in reperfusion times and mortality in patients with ST-segment elevation myocardial infarction (STEMI) are influenced by differences in coordinating care between emergency medical services (EMS) and hospitals. Building on the Accelerator-1 Project, we hypothesized that time to reperfusion could be further reduced with enhanced regional efforts. Methods: Between April 2015 and March 2017, we worked with 12 metropolitan regions across the United States with 132 PCI-capable hospitals and 946 EMS agencies. Data were collected in the ACTION-Get With The Guidelines Registry for quarterly Mission: Lifeline reports. The primary endpoint was the change in the proportion of EMS transported patients with first medical contact to device (FMC2D) time ≤90 minutes from baseline to final quarter. We also compared treatment times and mortality to patients treated in hospitals not participating in the project during the corresponding time period. Results: During the study period, 10,730 patients were transported to PCI-capable hospitals, including 974 in the baseline quarter and 972 in the final quarter who met inclusion criteria. Median age was 61 years; 27% were female, 6% had cardiac arrest and 6% had shock on admission; 10% were black, 12% Latino, and 10% were uninsured. By the end of the intervention, all process measures reflecting coordination between EMS and hospitals had improved, including the proportion of patients with a FMC2D time of ≤90 minutes (67% to 74%; P[...]

ICare-ACS (Improving Care Processes for Patients With Suspected Acute Coronary Syndrome): A Study of Cross-System Implementation of a National Clinical Pathway [Original Research Article]


BACKGROUND: Efforts to safely reduce length of stay for emergency department patients with symptoms suggestive of acute coronary syndrome (ACS) have had mixed success. Few system-wide efforts affecting multiple hospital emergency departments have ever been evaluated. We evaluated the effectiveness of a nationwide implementation of clinical pathways for potential ACS in disparate hospitals.METHODS: This was a multicenter pragmatic stepped-wedge before-and-after trial in 7 New Zealand acute care hospitals with 31 332 patients investigated for suspected ACS with serial troponin measurements. The implementation was a clinical pathway for the assessment of patients with suspected ACS that included a clinical pathway document in paper or electronic format, structured risk stratification, specified time points for electrocardiographic and serial troponin testing within 3 hours of arrival, and directions for combining risk stratification and electrocardiographic and troponin testing in an accelerated diagnostic protocol. Implementation was monitored for >4 months and compared with usual care over the preceding 6 months. The main outcome measure was the odds of discharge within 6 hours of presentation.RESULTS: There were 11 529 participants in the preimplementation phase (range, 284-3465) and 19 803 in the postimplementation phase (range, 395-5039). Overall, the mean 6-hour discharge rate increased from 8.3% (range, 2.7%-37.7%) to 18.4% (6.8%-43.8%). The odds of being discharged within 6 hours increased after clinical pathway implementation. The odds ratio was 2.4 (95% confidence interval, 2.3-2.6). In patients without ACS, the median length of hospital stays decreased by 2.9 hours (95% confidence interval, 2.4-3.4). For patients discharged within 6 hours, there was no change in 30-day major adverse cardiac event rates (0.52% versus 0.44%; P=0.96). In these patients, no adverse event occurred when clinical pathways were correctly followed.CONCLUSIONS: Implementation of clinical pathways for sus[...]

Value of Progression of Coronary Artery Calcification for Risk Prediction of Coronary and Cardiovascular Events: Result of the Heinz Nixdorf Recall (HNR) Study [Original Research Article]


Background—Computed tomography (CT) allows estimation of coronary artery calcium (CAC) progression. We evaluated several progression algorithms in our unselected, population-based cohort for risk prediction of coronary and cardiovascular (CV) events. Methods—In 3281 participants (45-74 years), free from CV disease until the 2nd visit, risk factors and CTs at baseline (b) and after a mean of 5.1 years (5y) were measured. Hard coronary and cardiovascular events as well as total CV events including revascularization were recorded during a follow-up time of 7.8±2.2 years after the 2nd CT. The added predictive value of ten CAC progression algorithms on top of risk factors including baseline CAC was evaluated using survival analysis, C-statistics, net reclassification improvement (NRI), and integrated discrimination index (IDI). A subgroup analysis of risk in CAC categories was performed.Results—We observed 85 (2.6%) hard coronary, 161 (4.9%) hard CV and 241 (7.3%) total CV events. Absolute CAC progression was higher with vs. without subsequent coronary events [median 115 (Q1-Q3 23-360) vs. 8 (0-83), p[...]

Effect of Distinct Lifestyle Interventions on Mobilization of Fat Storage Pools: The CENTRAL MRI Randomized Controlled Trial [Original Research Article]


Background—We aimed to assess whether distinct lifestyle strategies can differentially affect specific body adipose depots.Methods—We performed an eighteen-month randomized controlled trial among 278 sedentary adults with abdominal obesity (75%) or dyslipidemia in an isolated workplace with a monitored provided lunch. Participants were randomized to iso-caloric low-fat (LF) or Mediterranean/low-carbohydrate (MED/LC) diet+28g walnuts/day with/without added moderate physical activity (PA;80% aerobic; supervised/free gym membership). Overall primary outcome was body fat re-distribution, and the main specific endpoint was visceral adipose tissue (VAT). We further followed the dynamics of different fat depots [deep/superficial subcutaneous (D/SSAT), liver, pericardial, muscle, pancreas and renal-sinus] by magnetic-resonance-imaging.Results—Of 278 participants (age=48y; 89%men, body-mass-index=30.8kg/m2), 86% completed the trial, with good adherence. The LF group preferentially decreased reported fat intake (-21.0% vs. -11.5% for the MED/LC; P[...]

A Transcatheter InterAtrial Shunt Device for the Treatment of Heart Failure with Preserved Ejection Fraction (REDUCE LAP-HF I): A Phase 2, Randomized, Sham-Controlled Trial [Original Research Article]


Background—In non-randomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), less symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and mid-range or preserved ejection fraction (EF ≥ 40%). We conducted the first randomized, sham-controlled trial to evaluate the IASD in HF with EF ≥ 40%.Methods—REDUCE LAP-HF I was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association (NYHA) class III or ambulatory class IV HF, EF ≥ 40%, exercise PCWP ≥ 25 mmHg, and PCWP-right atrial pressure gradient ≥ 5 mmHg. Participants were randomized (1:1) to the IASD vs. a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness endpoint was exercise PCWP at 1 month. The primary safety endpoint was major adverse cardiac, cerebrovascular, and renal events (MACCRE) at 1 month. PCWP during exercise was compared between treatment groups using a mixed effects repeated measures model analysis of covariance that included data from all available stages of exercise.Results—A total of 94 patients were enrolled, of which n=44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared to sham-control (P=0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mmHg in the treatment group vs. 0.5±5.0 mmHg in the control group (P=0.14). There were no peri-procedural or 1-month MACCRE in the IASD group and 1 event (worsening renal function) in the control group (P=1.0).Conclus[...]

Magnitude of Soluble ST2 as a Novel Biomarker for Acute Aortic Dissection [Original Research Article]


Background—Misdiagnosis of acute aortic dissection (AAD) can lead to significant morbidity and death. Soluble ST2 (sST2) is a cardiovascular injury-related biomarker. The extent to which sST2 is elevated in AAD and whether sST2 can discriminate AAD from other causes of sudden-onset severe chest pain is unknown. Methods—We measured plasma concentrations of sST2 (R&D systems assay) in 1360 patients, including 1027 participants in the retrospective discovery set and 333 patients with initial suspicion of AAD enrolled in the prospective validation cohort. Measures of discrimination for differentiating AAD from other causes of chest pain were calculated. Results—In the acute phase, sST2 levels were higher in patients with AAD than those with either acute myocardial infarction (AMI) in the first case-control discovery set within 24h symptom onset or pulmonary embolism (PE) patients in the second discovery set (medians of 129.2 ng/mL vs. 14.7 with p[...]

PCSK9 Variants, LDL-Cholesterol, and Neurocognitive Impairment: The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study [Original Research Article]


Background—Despite concerns about adverse neurocognitive events raised by prior trials, pharmacologic PCSK9 inhibition was not associated with neurocognitive effects in a recent phase 3 randomized trial. PCSK9 loss-of-function (LOF) variants that result in life-long exposure to low LDL-C can provide information on the potential long-term effects of low LDL-C on neurocognitive impairment and decline.Methods—We investigated the association between PCSK9 LOF variants and neurocognitive impairment and decline among African-American REasons for Geographic and Racial Differences in Stroke (REGARDS) study participants with (n=241) and without (n=10,454) C697X or Y142X LOF variants. Neurocognitive tests included Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery (Word List Learning, Delayed Recall, Animal Fluency) and Six Item Screener (SIS) assessments, administered longitudinally during follow-up. Neurocognitive impairment was defined as a score ≥ 1.5 standard deviations (SD) below age, sex, and education-based stratum-specific means on 2 or 3 CERAD assessments, or, separately, a score 0.10). ORs for neurocognitive impairment per 20 mg/dL LDL-C decrements were 1.02 (95% CI 0.96, 1.08) and 0.99 (95% CI 0.95, 1.02) for the CERAD and SIS definitions of impairment, respectively. Conclusions—These results suggest life-long exposure to low PCSK9 levels and cumulative exposure to lower LDL-C are not associated with neurocognitive effects in African Americans.[...]

Long Term Outcomes in Patients with Type 2 Myocardial Infarction and Myocardial Injury [Original Research Article]


Background—Type 2 myocardial infarction and myocardial injury are common in clinical practice, but long-term consequences are uncertain. We aimed to define long-term outcomes and explore risk stratification in patients with type 2 myocardial infarction and myocardial injury. Methods—We identified consecutive patients (n=2,122) with elevated cardiac troponin I concentrations (≥0.05 μg/L) at a tertiary cardiac center. All diagnoses were adjudicated as per the Universal Definition of Myocardial Infarction. The primary outcome was all-cause death. Secondary outcomes included major adverse cardiovascular events (MACE; non-fatal myocardial infarction or cardiovascular death) and non-cardiovascular death. To explore competing risks, cause-specific hazard ratios were obtained using Cox regression models.Results—The adjudicated index diagnosis was type 1 or type 2 myocardial infarction or myocardial injury in 1,171 (55.2%), 429 (20.2%) and 522 (24.6%) patients, respectively. At five years, all-cause death rates were higher in those with type 2 myocardial infarction (62.5%) or myocardial injury (72.4%) compared with type 1 myocardial infarction (36.7%). The majority of excess deaths in those with type 2 myocardial infarction or myocardial injury were due to non-cardiovascular causes (HR 2.32, 95%CI 1.92-2.81, versus type 1 myocardial infarction). Despite this, the observed crude MACE rates were similar between groups (30.6% versus 32.6%), with differences apparent after adjustment for co-variates (HR 0.82, 95%CI 0.69-0.96). Coronary heart disease was an independent predictor of MACE in those with type 2 myocardial infarction or myocardial injury (HR 1.71, 95%CI 1.31-2.24).Conclusions—Despite an excess in non-cardiovascular death, patients with type 2 myocardial infarction or myocardial injury have a similar crude rate of ma[...]

Thyroid Function Within the Normal Range, Subclinical Hypothyroidism and the Risk of Atrial Fibrillation [Original Research Article]


Background—Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF.Methods—We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF.Results—Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5%) had subclinical hypothyroidism and 2574 individuals (8.6%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in ageand sex-adjusted analyses (hazard ratio, 1.45; 95% confidence interval, 1.26-1.66, for the highest quartile versus the lowest quartile of fT4; P for trend ≤0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardi[...]

Angiography versus Hemodynamics to Predict the Natural History of Coronary Stenoses: A FAME 2-Substudy [Original Research Article]


Background—Among patients with documented stable coronary artery disease (CAD) and in whom no revascularization was performed, we compared the respective values of angiographic diameter stenosis (DS) and of fractional flow reserve (FFR) in predicting natural history. Methods—The present analysis included the 607 patients from the Fractional flow reserve versus angiography in multivessel evaluation 2 (FAME 2) trial in whom no revascularization was performed. FFR varied from 0.20 to 1.00 (average 0.74 ± 0.16) and DS (by QCA) varied from 8% to 98% (average 53 ± 15). The primary end point, defined as VOCE (Vessel oriented clinical endpoint) at 2 years, was a composite of prospectively adjudicated cardiac death, vessel-related myocardial infarction, vessel-related urgent and not urgent revascularization. The stenoses were divided into 4 groups according to FFR and %DS values: Positive Concordance (PC: FFR≤0.80; DS≥50%); Negative Concordance (NC: FFR>0.80; DS0.80, H.R. 1.89, 95% C.I. 0.96 - 3.74; p=0.067). Conclusions—In patients with stable coronary disease, physiology (FFR) is a more important determinant of the natural history of coronary stenoses than anatomy (DS). Clinical Trial Registration—URL: Unique Identifier: NCT01132495. [...]

HDL Subspecies Defined by Presence of Apolipoprotein C-III and Incident Coronary Heart Disease in Four Cohorts [Original Research Article]


Background—The causal role of high density lipoprotein (HDL) cholesterol in cardioprotection has been questioned by genetic and randomized studies. Novel measures that relate to HDL function may contribute new information to prediction of cardiovascular risk. Apolipoprotein C-III (apoC-III) is a key regulator of lipoprotein metabolism. We investigated whether subspecies of HDL defined by apoC-III are associated with coronary heart disease (CHD). Methods—We used immuno-affinity chromatography to measure the apoA-I concentrations of HDL that contains and lacks apoC-III in two prospective studies of adults free of CHD. In the Multi-Ethnic Study of Atherosclerosis (MESA), 5,657 participants (52% women; age 52-72 y) were followed for risk of CHD from 2000-2002 through 2013. In a case-cohort study nested within the Danish Diet, Cancer and Health (DCH) study, 3,642 participants (47% women; age 51-64 y) were followed from 1994-1997 through 2010. Subsequently, we conducted a meta-analysis that combined these results with the previously published findings from two cohort studies that used similar laboratory methodology to measure lipoproteins, totaling 2,997 incident cases. Results—ApoC-III was found on 6-8% of apoA-I. The two HDL subspecies showed opposing associations with risk of CHD in each of the individual cohorts and in the meta-analysis (p-heterogeneity between the two subspecies [...]

Impact of Lipid Measurements in Youth in Addition to Conventional Clinic-Based Risk Factors on Predicting Preclinical Atherosclerosis in Adulthood: The International Childhood Cardiovascular Cohort (i3C) Consortium [Original Research Article]


Background—Data suggest that the prediction of adult cardiovascular disease using a model comprised entirely of adult non-laboratory based risk factors is equivalent to an approach that additionally incorporates adult lipid measures. We assessed and compared the utility of a risk model based solely on non-laboratory risk factors in adolescence vs. a lipid model based on non-laboratory risk factors + lipids for predicting high-risk carotid intima-media thickness (cIMT) in adulthood.Methods—The study comprised 2,893 participants aged 12-18 years from four longitudinal cohort studies from the United States (Bogalusa Heart Study and the Insulin Study), Australia (Childhood Determinants of Adult Health Study) and Finland (The Cardiovascular Risk in Young Finns Study) and followed into adulthood when cIMT was measured (mean follow-up 23.4 years). Overweight status was defined according to the Cole classification. Hypertension was defined according to the Fourth Report on High Blood Pressure in Children and Adolescents from the National High Blood Pressure Education Program. High-risk plasma lipid levels were defined according to the National Cholesterol Education Program (NCEP) Expert Panel on Cholesterol Levels in Children. High cIMT was defined as a study-specific value ≥90th percentile. Age-and sex were included in each model.Results—In univariate models all risk factors except for borderline high-and high triglycerides in adolescence were associated with high cIMT in adulthood. In multivariable models (RR [95% CI]), male sex (2.7 [2.0-2.6]), pre-hypertension (1.4 [1.0-1.9]), hypertension (1.9 [1.3-2.9]), overweight (2.0 [1.4-2.9]), obesity (3.7 [2.0-7.0]), borderline high LDL-cholesterol (1.6 [1.2-2.2]), high LD[...]

Surgical Enlargement of the Aortic Root Does Not Increase the Operative Risk of Aortic Valve Replacement [Original Research Article]


Background—Surgical aortic root enlargement (ARE) during aortic valve replacement (AVR) allows for larger prosthesis implantation and may be an important adjunct to surgical AVR in the transcatheter valve-in-valve era. The incremental operative risk of adding ARE to AVR has not been established. We sought to evaluate the early outcomes of patients undergoing AVR with or without ARE.Methods—From January 1990 to August 2014, 7039 patients underwent AVR (AVR + ARE, n=1854; AVR, n=5185) at a single institution. Patients with aortic dissection and active endocarditis were excluded. Mean age was 65±14 years and 63% were male. Logistic regression and propensity score matching were used to adjust for unbalanced variables in group comparisons.Results—Patients undergoing AVR + ARE were more likely to be female (46% vs. 34%, p[...]

Pericardial Adipose Tissue Regulates Granulopoiesis, Fibrosis and Cardiac Function After Myocardial Infarction [Original Research Article]


Background—The pericardial adipose tissue (AT) contains a high density of lymphoid clusters. Is unknown whether these clusters play a role in post-myocardial infarction (MI) inflammatory responses and cardiac outcome.Methods—Lymphoid clusters were examined in epicardial AT of humans with or without coronary artery disease (CAD). Murine pericardial lymphoid clusters were visualized in mice subjected to coronary artery ligation. To study the relevance of pericardial clusters during inflammatory responses after MI, we surgically removed the pericardial AT, performed B cell depletion and GM-CSF blockade. Leukocytes in murine hearts, pericardial AT, spleen, mediastinal lymph nodes, and bone marrow were quantified by flow cytometry. Cannabinoid receptor CB2 (CB2-/-) mice were used as a model for enhanced B cell responses. The effect of impaired dendritic cell (DC) trafficking on pericardial AT inflammatory responses was tested in CCR7-/- mice subjected to MI. Cardiac fibrosis and ventricular function were assessed by histology and echocardiography.Results—We identified larger B cell clusters in epicardial AT of human CAD patients compared to controls without CAD. Infarcted mice also had larger pericardial clusters and 3-fold upregulated numbers of GM-CSF-producing B cells within pericardial AT, but not spleen or lymph nodes. This was associated with higher DC and T cell counts in pericardial AT, which outnumbered DCs and T cells in lymph nodes. Analysis of DC maturation markers, tracking experiments with fluorescently labelled cells and use of CCR7-deficient mice suggested that activated DCs migrate from infarcts into pericardial AT via CCR7. B cell depletion or GM[...]

Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension [Original Research Article]


Background—Beneficial effects of parasympathetic stimulation have been reported in left heart failure, however, whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in PAH-patients, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase (AchE) inhibition, in experimental pulmonary hypertension (PH).Methods—Heart rate recovery (HRR) after maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction (RVEF) was assessed in 112 PAH-patients. Expression of nicotinic (α-7nAchR) and muscarinic (m2AchR) receptors, and AchE activity were evaluated in RV (n=11) and lungs (n=7) from PAH-patients undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg/day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg; s.c.) injection followed by 4 weeks of hypoxia. In a subgroup sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomized to vehicle or treatment (both n=12). At the end-of-study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological and protein analyses.Results—PAH-patients with lower RVEF ([...]