Subscribe: Circulation Publish Ahead of Print
Added By: Feedage Forager Feedage Grade B rated
Language: English
acc aha  clinical outcomes  clinical  evh  harvesting  outcomes  risk  statin therapy  statin  therapy  trial  vein harvesting  vein 
Rate this Feed
Rate this feedRate this feedRate this feedRate this feedRate this feed
Rate this feed 1 starRate this feed 2 starRate this feed 3 starRate this feed 4 starRate this feed 5 star

Comments (0)

Feed Details and Statistics Feed Statistics
Preview: Circulation Publish Ahead of Print

Circulation Publish Ahead of Print

Circulation RSS feed -- Publish Ahead of Print


High Quality Statin Trials Support the 2013 ACC/AHA Cholesterol Guidelines After HOPE-3: The Multi-Ethnic Study of Atherosclerosis [Research Letter]


The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline on cholesterol treatment to prevent atherosclerotic cardiovascular disease (ASCVD) has been criticized for lowering the risk thresholds for primary prevention with statin therapy. Although the ≥ 7.5% (class I) and ≥ 5% (class IIa) 10-year ASCVD risk thresholds were identified as new indications for treatment by extrapolating results obtained in randomized controlled trials (RCT) of statin therapy, results from population-based European cohorts indicate that >30% of individuals eligible for statin therapy by class I recommendations do not have RCT data supporting statin efficacy. Further, when the US Preventive Services Task Force published their recommendations (based on review of trial evidence), they restricted the indication for statin therapy compared with the ACC/AHA guideline by recommending a higher treatment threshold (10%) combined with ≥1 ASCVD risk factor. However, the evidence base for statins in primary prevention grew substantially in 2016 with publication of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial that enrolled intermediate-risk persons for whom a clear indication for statin therapy was still lacking. The implications of HOPE-3 for the evidence base supporting ACC/AHA risk-based statin allocation remain unknown. Therefore, using MESA (Multiethnic Study of Atherosclerosis, - a population-based US cohort - we assessed the extent to which the ACC/AHA recommendations for statin therapy are supported by currently available high-quality RCT evidence: WOSCOPS, AFCAPS/TexCAPS, ASCOT-LLA, CARDS, MEGA, JUPITER and HOPE-3 (ref. 2 and 4 for details). Given the controversy that exists in whom to treat with statins in primary prevention, such information may provide important insights for clinical practice and future updates of guidelines and recommendations.

A Study Comparing Vein Integrity and Clinical Outcomes (VICO) in Open Vein Harvesting and Two Types of Endoscopic Vein Harvesting for Coronary Artery Bypass Grafting: The VICO Randomised Clinical Trial [Original Research Article]


Background—Current consensus statements maintain that endoscopic vein harvesting (EVH) should be standard care in coronary artery bypass surgery (CABG) but vein quality and clinical outcomes have been questioned. The Vein Integrity and Clinical Outcome (VICO) trial was designed to assess the impact of different vein harvesting methods on vessel damage and if this contributes to clinical outcomes following CABG. Methods—A single centre, randomised clinical trial of patients undergoing CABG with an internal mammary artery, and with one to four vein grafts were recruited. All the veins were harvested by a single experienced practitioner. We randomly allocated n=300 patients into: closed tunnel CO2 EVH (CT-EVH) (n=100), open tunnel CO2 EVH (OT-EVH) (n=100) and traditional open vein harvesting (OVH) (n=100) groups. The primary end-point was endothelial integrity and muscular damages of the harvested vein. Secondary end-points included clinical outcomes (major adverse cardiac events, MACE), use of healthcare resources and impact on health status (quality-adjusted life years, QALYs). Results—The OVH group demonstrated marginally better endothelial integrity in random samples (85% vs. 88% vs. 93% for CT-EVH, OT-EVH and OVH, p<0.001). CT-EVH displayed the lowest longitudinal hypertrophy (1% vs. 13.5% vs. 3%, p=0.001). However, no differences in endothelial stretching were observed between groups (37% vs. 37% vs. 31%, p=0.62). Secondary clinical outcomes demonstrated no significant differences in composite MACE scores at each time point up to 48 months. The QALY gain per patient was: 0.11 (p<0.001) for closed tunnel CO2 EVH and 0.07 (p=0.003) for open tunnel CO2 EVH compared with open vein harvesting. The likelihood of being cost-effective, at a pre-defined threshold of £20,000 per QALY gained was: 75% for closed tunnel, 19% for open tunnel and 6% for open vein harvesting. Conclusions—Our study demonstrates that harvesting techniques do impact upon integrity of different vein layers, albeit with only a small effect. Secondary outcomes suggest that histological findings do not directly contribute to MACE outcomes. Gains in health status were observed and cost-effectiveness was better with CT-EVH. High level experience with endoscopic harvesting performed by a dedicated specialist practitioner gives optimal results which is comparable to open vein harvesting.Clinical Trial Registration—— URL: Unique Identifier: ISRCTN: 91485426

Left Ventricular Assist Device Malfunctions: It's More Than Just The Pump [Original Research Article]


Background—Reports of left ventricular assist device (LVAD) malfunction have focused on pump thrombosis. However, the device consists of the pump, driveline and peripherals, all of which are potentially subject to failure.Methods—Prospectively collected data were reviewed for all LVAD device malfunctions (DM) occurring in rotary LVADs implanted at a single center between April 2004 and May 2016. Durable LVADs included 108 Heartmate II (HMII) and 105 HeartWare ventricular assist devices (HVAD). DM data were categorized according to device type and into categories related to the component that failed: a) controller, b) peripheral components and c) the implantable blood pump or its integral electrical driveline. Pump-related events were analyzed as pump specific (suspected or confirmed thrombosis) or non-pump specific (driveline failure). DM rates were reported as events/1,000 patient-days and Cox proportional hazard models were used for time-to-event analyses. Cumulative rates of malfunction were examined for the main components of each type of LVAD.Results—Types of DM included controller failure (30%), battery failure (19%) or patient cable failure (14%), while only 13% were due to pump failure. DM's were more common in the HM II device (3.73 per 1000 patient-days vs. 3.06 per 1000 patient-days for the HVAD, p< 0.01). There was a higher rate of pump-specific malfunctions in those implanted with a HM II versus an HVAD (0.55 vs. 0.39 respectively p< 0.01) and peripheral malfunctions (2.32 vs. 1.78 for the HM II and HVAD, respectively; p< 0.01); there was no difference in the incidence of controller DM between the two LVADs. HVAD patients were 90% free of a pump-specific malfunction at 3 years compared with 56% for the HM II (log-rank p< 0.003). Only 74% of the HM II patients were free of pump thrombosis at 3 years compared with 90% of the HVAD patients. Freedom from failure of the integrated driveline was 79% at 3 years for the HMII but 100% for the HVAD (log-rank p< 0.02). Conclusions—Device malfunction is much broader than pump failure alone and occurs for different components at different rates based upon the type of LVAD.

The Optimal Timing of Stage-2-Palliation for Hypoplastic Left Heart Syndrome: An analysis of the Pediatric Heart Network Single Ventricle Reconstruction Trial Public Dataset [Original Research Article]


Background—In infants requiring three-stage single ventricle palliation for hypoplastic left heart syndrome, attrition after the Norwood procedure remains significant. The effect of the timing of stage-2-palliation (S2P), a physician-modifiable factor, on long term survival is not well understood. We hypothesized that an optimal interval between the Norwood and S2P that both minimizes pre-S2P attrition and maximizes post-S2P survival exists and is associated with individual patient characteristics. Methods—The NIH/NHLBI Pediatric Heart Network Single Ventricle Reconstruction Trial public dataset was used. Transplant-free survival (TFS) was modeled from (1) Norwood to S2P and (2) S2P to three years, using parametric hazard analysis. Factors associated with death or heart transplantation were determined for each interval. To account for staged procedures, risk-adjusted, three-year, post-Norwood TFS (the probability of TFS at three years given survival to S2P) was calculated using parametric conditional survival analysis. TFS from the Norwood to S2P was first predicted. TFS after S2P to three years was then predicted and adjusted for attrition before S2P by multiplying by the estimate of TFS to S2P. The optimal timing of S2P was determined by generating nomograms of risk-adjusted, three-year, post-Norwood, TFS versus the interval from the Norwood to S2P. Results—Of 547 included patients, 399 survived to S2P (73%). Of the survivors to S2P, 349 (87%) survived to three-year follow-up. The median interval from the Norwood to S2P was 5.1 (IQR 4.1-6.0) months. The risk-adjusted, three-year, TFS was 68±7%. A Norwood-S2P interval of three to six months was associated with greatest three-year TFS overall and in patients with few risk factors. In patients with multiple risk factors, TFS was severely compromised, regardless of the timing of S2P and most severely when S2P was performed early. No difference in the optimal timing of S2P existed when stratified by shunt type. Conclusions—In infants with few risk factors, progressing to S2P at three to six months after the Norwood procedure was associated with maximal TFS. Early S2P did not rescue patients with greater risk factor burdens. Instead, referral for heart transplantation may offer their best chance at long term survival. Clinical Trial Registration—URL: Unique Identifier: NCT00115934.

Dynamic Edematous Response of the Human Heart to Myocardial Infarction: Implications for Assessing Myocardial Area at Risk and Salvage [Original Research Article]


Background—Clinical protocols aimed to characterize the post-myocardial infarction (MI) heart by cardiac magnetic resonance (CMR) need to be standardized to take account of dynamic biological phenomena evolving early after the index ischemic event. Here we evaluated the time-course of edema reaction in ST-segment elevation MI (STEMI) patients by CMR and assessed its implications for myocardium-at-risk (MaR) quantification both in patients and in a large animal model.Methods—A total of 16 anterior STEMI patients successfully treated by primary angioplasty and 16 matched controls were prospectively recruited. In total, 94 clinical CMR exams were performed: STEMI patients were serially scanned (within the first 3 hours after reperfusion and at 1, 4, 7, and 40 days), and controls only once. T2 relaxation time in the myocardium (T2-mapping) and the extent of edema on T2W-STIR (i.e. CMR-MaR) were evaluated at all time-points. In the experimental study, 20 pigs underwent 40-min-ischemia/reperfusion followed by serial CMR exams at 120-min and 1, 4, and 7 days after reperfusion. Reference MaR was assessed by contrast-multidetector computed tomography (MDCT) during the index coronary occlusion. Generalized linear mixed models were used to take account of repeated measurements.Results—In humans, T2 relaxation time in the ischemic myocardium declines significantly from early after reperfusion to 24 hours, and then increases up to day 4, reaching a plateau from which it decreases from day 7. Consequently, edema extent measured by T2W-STIR ("CMR-MaR") varied with the timing of the CMR exam. These findings were confirmed in the experimental model by showing that only CMR-MaR values for day 4 and day 7 post-reperfusion, coinciding with the deferred edema wave, were similar to values measured by reference MDCT.Conclusions—Post-MI edema in patients follows a bimodal pattern, which affects CMR estimates of MaR. Dynamic changes in post-STEMI edema highlight the need for standardization of CMR timing to retrospectively delineate MaR and quantify myocardial salvage. According to the present clinical and experimental data, a time window between day 4 and 7 post-MI seems a good compromise solution for standardization. Further studies are needed to study the effect of other factors on these variables.

Effect of Ferric Carboxymaltose on Exercise Capacity in Patients with Chronic Heart Failure and Iron Deficiency [Original Research Article]


Background—Iron deficiency is common in patients with heart failure (HF), and is associated with reduced exercise capacity and poor outcomes. Whether correction of iron deficiency with (intravenous) ferric carboxymaltose (FCM) affects peak oxygen consumption [peak VO2], an objective measure of exercise intolerance in HF, has not been examined.Methods—We studied patients with systolic HF (left ventricular ejection fraction [LVEF] ≤45%) and mild to moderate symptoms despite optimal HF medication, Patients were randomized 1:1 to treatment with FCM for 24 weeks or standard of care. The primary endpoint was the change in peak VO2 from baseline to 24 weeks. Secondary endpoints included effect hematinic and cardiac biomarkers, quality of life, and safety. For the primary analysis, patients who died had a value of zero imputed for 24-week peak VO2. Additional sensitivity analyses were performed to determine the impact of imputation of missing peak VO2 data.Results—A total of 172 HF patients were studied are received FCM (n=86) or standard of care (control group, n=86). At baseline, the groups were well-matched; mean age was 64 years, 75% were male, LVEF was 32%, peak VO2 13.5 mL/min/kg. FCM significantly increased serum ferritin and transferrin saturation. At 24 weeks, peak VO2 had decreased in the control group (least square means -1.19±0.389 mL/min/kg), but was maintained on FCM (-0.16±0.387 mL/min/kg; p=0.020 between groups). In a sensitivity analysis, in which missing data were not imputed, peak VO2 at 24 weeks decreased by 0.63±0.375 mL/min/kg in the control group, and by 0.16±0.373 mL/min/kg in the FCM group; p=0.23 between groups). Patients' global assessment and functional class as assessed by New York Heart Association improved on FCM vs. standard of care.Conclusions—Treatment with intravenous FCM in patients with HF and iron deficiency improve iron stores. Although a favourable effect on peak VO2 was observed on FCM, compared to standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak VO2 among patients who died. Whether FCM is associated with an improved outcome in these high-risk patients needs further study. Clinical Trial Registration—URL: Unique identifier: NCT01394562.

High Resolution Mapping of Chromatin Conformation in Cardiac Myocytes Reveals Structural Remodeling of the Epigenome in Heart Failure [Original Research Article]


Background—Cardiovascular disease is associated with epigenomic changes in the heart, however the endogenous structure of cardiac myocyte chromatin has never been determined. Methods—To investigate the mechanisms of epigenomic function in the heart, genome-wide chromatin conformation capture (Hi-C) and DNA sequencing were performed in adult cardiac myocytes following development of pressure overload-induced hypertrophy. Mice with cardiac-specific deletion of CTCF (a ubiquitous chromatin structural protein) were generated to explore the role of this protein in chromatin structure and cardiac phenotype. Transcriptome analyses by RNA-seq were conducted as a functional readout of the epigenomic structural changes.Results—Depletion of CTCF was sufficient to induce heart failure in mice and human heart failure patients receiving mechanical unloading via left ventricular assist devices show increased CTCF abundance. Chromatin structural analyses revealed interactions within the cardiac myocyte genome at 5kb resolution, enabling examination of intra- and inter-chromosomal events, and providing a resource for future cardiac epigenomic investigations. Pressure overload or CTCF depletion selectively altered boundary strength between topologically associating domains and A/B compartmentalization, measurements of genome accessibility. Heart failure involved decreased stability of chromatin interactions around disease-causing genes. In addition, pressure overload or CTCF depletion remodeled long-range interactions of cardiac enhancers, resulting in a significant decrease in local chromatin interactions around these functional elements.Conclusions—These findings provide a high-resolution chromatin architecture resource for cardiac epigenomic investigations and demonstrate that global structural remodeling of chromatin underpins heart failure. The newly identified principles of endogenous chromatin structure have key implications for epigenetic therapy.

A Population-Based Study of Abdominal Aortic Aneurysm Treatment in Finland 2000-2014 [Original Research Article]


Background—In the event of rupture of an abdominal aortic aneurysm (AAA), mortality is very high. AAA prevalence and incidence of ruptures has been reported to be decreasing. The treatment of AAA has also undergone a change in recent decades with a shift towards endovascular aneurysm repair (EVAR). Our aim was to evaluate how these changes have affected the elective and emergency treatment of AAA and their results in Finland. Methods—All patients treated for AAA in Finland, a country with a population of 5.5 million, during 2000-2014 were searched from the registry of the Finnish Institute for Health and Welfare. Data on all patients who had died due to AAA during the same time period was obtained from Statistics Finland. The data was combined and analyzed.Results—The annual incidence of ruptured AAA was 16.4 per 100 000 population over 50 years and decreased significantly during the study period. Over half of the 4949 patients who suffered a ruptured AAA died outside the hospital. Thirty-day mortality after emergency repair was 39.4%. Intact AAA repair numbered 4956. The absolute number of annual repairs increased during the study period and the use of EVAR became the dominant method of elective repair. Thirty-day mortality in elective AAA repair dropped significantly from 6.3% in 2000-2004 to 2.7% in 2010-2014 mostly due to increase number of EVAR procedures with lower mortality. Long-term mortality in patients treated with EVAR was higher than in patients treated with open repair. Mortality after elective AAA repair was primarily due to cardiovascular causes but there was a slightly higher proportion of AAA-related late deaths in EVAR patients. Conclusions—Ruptured AAA incidence for men over 65 years has declined with nearly 30% in Finland, likely due to decrease in AAA prevalence. The treatment results have improved as well for both elective and emergency repair. Increased use of EVAR has resulted in decrease of mortality after elective AAA repair, but results of open repair have improved as well. However, late mortality from elective EVAR is surprisingly high compared to open repair which may have been exaggerated by patient selection.

Experimental Modeling Supports a Role for MyBP-HL as a Novel Myofilament Component in Arrhythmia and Dilated Cardiomyopathy [Original Research Article]


Background—Cardiomyopathy and arrhythmias are under significant genetic influence. Here, we studied a family with dilated cardiomyopathy and associated conduction system disease in whom prior clinical cardiac gene panel testing was unrevealing. Methods—Whole genome sequencing and induced pluripotent stem cells were used to examine a family with dilated cardiomyopathy and atrial and ventricular arrhythmias. We also characterized a mouse model with heterozygous and homozygous deletion of Mybphl. Results—Whole genome sequencing identified a premature stop codon, R255X, in the MYBPHL gene encoding myosin-binding protein-H like (MyBP-HL), a novel member of the myosin binding protein family. MYBPHL was found to have high atrial expression with low ventricular expression. We determined that MyBP-HL protein was myofilament-associated in the atria, and truncated MyBP-HL protein failed to incorporate into the myofilament. Human cell modeling demonstrated reduced expression from the mutant MYBPHL allele. Echocardiography of Mybphl heterozygous and null mouse hearts exhibited a 36% reduction in fractional shortening (FS) and an increased diastolic ventricular chamber size. Atria weight normalized to total heart weight was significantly increased in Mybphl heterozygous and null mice. Using a reporter system, we detected robust expression of Mybphl in the atria as well as in discrete puncta throughout the right ventricular wall and septum. Telemetric electrocardiogram (ECG) recordings in Mybphl mice revealed cardiac conduction system abnormalities with aberrant atrioventricular conduction and an increased rate of arrhythmia in heterozygous and null mice.Conclusions—The findings of reduced ventricular function and conduction system defects in Mybphl mice support that MYBPHL truncations may increase risk for human arrhythmias and cardiomyopathy.

Subclinical Atrial Fibrillation in Older Patients [Original Research Article]


Background—Long-term continuous electrocardiographic monitoring shows a substantial prevalence of asymptomatic, subclinical atrial fibrillation (SCAF) in patients with pacemakers and patients with cryptogenic stroke. It is unknown if SCAF is also common in other patients without these conditions.Methods—We implanted sub-cutaneous electrocardiographic monitors (St. Jude CONFIRM-AF) in patients ≥ 65 years attending cardiovascular or neurology outpatient clinics if they had no history of atrial fibrillation (AF) but did have any of: CHA2DS2-VASc score of ≥ 2, sleep apnea, or body mass index > 30. Eligibility also required either left atrial enlargement (≥ 4.4 cm or volume ≥ 58 mL) or increased serum NT-ProBNP (≥290 pg/mL). Patients were monitored for SCAF lasting ≥ 5 minutes.Results—256 patients were followed for 16.3±3.8 months. Baseline age was 74±6 years, mean CHA2DS2-VASc score was 4.1±1.4, left atrial diameter averaged 4.7±0.8 cm, and 48% had a prior stroke, transient ischemic attack or systemic embolism. SCAF ≥ 5 minutes was detected in 90 patients (detection rate 34.4% per year; 95% confidence interval [CI], 27.7-42.3%). Baseline predictors of SCAF were increased age (HR per decade: 1.55; 1.11-2.15), left atrial dimension (HR per centimeter diameter: 1.43; 1.09-1.86), blood pressure (HR per 10 mmHg 0.87; 0.78-0.98), but not prior stroke. The rate of occurrence of SCAF in those with a history of prior stroke, systemic embolism or TIA was 39.4% per year versus 30.3% per year without (p=0.32). The cumulative SCAF detection rate was higher (51.9% per year) in those with left atrial volume above the median value of 73.5 mL.Conclusions—SCAF is frequently detected by continuous electrocardiographic monitoring in older patients without prior history of AF who are attending outpatient cardiology and neurology clinics. Its clinical significance is unclear.Clinical Trial Registration—URL: Unique Identifier: NCT01694394

In Vivo Functional Selection Identifies Cardiotrophin-1 as a Cardiac Engraftment Factor for Mesenchymal Stromal Cells [Original Research Article]


Background—Transplantation of cells into the infarcted heart has significant potential to improve myocardial recovery; however, low efficacy of cell engraftment still limits therapeutic benefit. Here we describe a method for the unbiased, in vivo selection of cytokines that improve mesenchymal stromal cell (MSC) engraftment into the heart in both normal conditions and after myocardial infarction.Methods—An arrayed library of 80 secreted factors, including most of the currently known interleukins and chemokines, were individually cloned into adeno-associated viral (AAV) vectors. Pools from this library were then used for the batch transduction of bone marrow-derived MSCs ex vivo, followed by intra-myocardial cell administration in normal and infarcted mice. Three weeks after injection, vector genomes were recovered from the few persisting cells and identified by sequencing DNA barcodes uniquely labeling each of the tested cytokines.Results—The most effective molecule identified by this competitive engraftment screening was cardiotrophin 1 (Ctf1), a member of the IL6 family. Intra-cardiac injection of MSCs transiently pre-conditioned with Ctf1 preserved cardiac function and reduced infarct size, parallel to the persistence of the transplanted cells in the healing hearts for at least two months after injection. Engraftment of Cft1-treated MSCs was consequent to STAT3-mediated activation of the focal adhesion kinase (FAK) and its associated focal adhesion complex and the consequent acquisition of adhesive properties by the cells.Conclusions—These results support the feasibility of selecting molecules in vivo for their functional properties using AAV vector libraries and identify Ctf1 as a powerful cytokine promoting cell engraftment and thus improving cell therapy of the infarcted myocardium.

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.

Tomo-seq Identifies SOX9 as a Key Regulator of Cardiac Fibrosis During Ischemic Injury [Original Research Article]


Background—Cardiac ischemic injury induces a pathological remodeling response, which can ultimately lead to heart failure. Detailed mechanistic insights into molecular signaling pathways relevant for different aspects of cardiac remodeling will support the identification of novel therapeutic targets.Methods—While genome-wide transcriptome analysis on diseased tissues has greatly advanced our understanding of the regulatory networks that drive pathological changes in the heart, this approach has been disadvantaged by the fact that the signals are derived from tissue homogenates. Here we used tomo-seq to obtain a genome-wide gene expression signature with high spatial resolution spanning from the infarcted area to the remote to identify new regulators of cardiac remodeling. Cardiac tissue samples from patients suffering from ischemic heart disease were used to validate our findings.Results—Tracing transcriptional differences with a high spatial resolution across the infarcted heart enabled us to identify gene clusters that share a comparable expression profile. The spatial distribution patterns indicated a separation of expressional changes for genes involved in specific aspects of cardiac remodeling, like fibrosis, cardiomyocyte hypertrophy, and calcium-handling (Col1a2, Nppa, and Serca2). Subsequent correlation analysis allowed for the identification of novel factors that share a comparable transcriptional regulation pattern across the infarcted tissue. The strong correlation between the expression levels of these known marker genes and the expression of the co-regulated genes could be confirmed in human ischemic cardiac tissue samples. Follow-up analysis identified SOX9 as common transcriptional regulator of a large portion of the fibrosis-related genes that become activated under conditions of ischemic injury. Lineage-tracing experiments indicated the majority of COL1-positive fibroblasts to stem from a pool of SOX9-expressing cells and in vivo loss of Sox9 blunted the cardiac fibrotic response upon ischemic injury. The co-localization between SOX9 and COL1 could also be confirmed in patients suffering from ischemic heart disease.Conclusions—Based on the exact local expression cues, tomo-seq can serve to reveal novel genes and key transcription factors involved in specific aspects of cardiac remodeling. Using tomo-seq we were able to unveil the unknown relevance of SOX9 as key regulator of cardiac fibrosis, pointing to SOX9 as potential therapeutic target for cardiac fibrosis.

The Fluid Mechanics of Transcatheter Heart Valve Leaflet Thrombosis in the Neo-Sinus [Original Research Article]


Background—Transcatheter heart valve (THV) thrombosis has been increasingly reported. In these studies, thrombus quantification has been based on 2D assessment of a 3D phenomenon.Methods—Post-procedural four-dimensional, volume-rendered CT (4DCT) data of CoreValve, Evolut R, and SAPIEN 3 transcatheter aortic valve replacement (TAVR) patients enrolled in the RESOLVE trial were included in this analysis. Patients on anticoagulation were excluded. SAPIEN 3 and CoreValve/Evolut R patients with and without hypo-attenuated leaflet thickening (HALT) were included in order to study differences between groups. Patients were classified as having THV thrombosis if there was any evidence of HALT. Anatomical and THV deployment geometries were analyzed, and thrombus volumes were computed through manual 3D reconstruction. We aimed to identify and evaluate risk factors that contribute to THV thrombosis through the combination of retrospective clinical data analysis and in vitro imaging in the space between the native and THV leaflets (neo-sinus).Results—SAPIEN 3 valves with leaflet thrombosis were on average 10% further expanded (by diameter) than those without (95.5 ± 5.2% vs. 85.4 ± 3.9%; p<0.001). However, this relationship was not evident with the CoreValve/Evolut R. In CoreValve/Evolut Rs with thrombosis, the thrombus volume increased linearly with implant depth (R2 = 0.7; p < 0.001). This was not seen in the SAPIEN 3. The in vitro analysis showed that a supra-annular THV deployment resulted in a nearly 7-fold decrease in stagnation zone size (velocities less than 0.1 m/s) when compared to an intra-annular deployment. In addition, the in vitro model indicated that the size of the stagnation zone increased as cardiac output decreased.Conclusions—While TAVR thrombosis is a multi-factorial process involving foreign materials, patient-specific blood chemistry and complex flow patterns, our study indicates that deployed THV geometry may have implications on the occurrence of thrombosis. In addition, a supra-annular neo-sinus may reduce thrombosis risk due to reduced flow stasis. While additional prospective studies are needed to further develop strategies for minimizing thrombus burden, these results may help identify patients at higher thrombosis risk and aid in the development of next generation devices with reduced thrombosis risk.

KLF4 Regulation of Ch25h and LXR Mitigates Atherosclerosis Susceptibility [Original Research Article]


Background—Atherosclerosis is a multifaceted inflammatory disease involving cells in the vascular wall [e.g., endothelial cells (ECs)] as well as circulating and resident immunogenic cells (e.g., monocytes/macrophages). Acting as a ligand for liver X receptor (LXR), but an inhibitor of sterol regulatory element binding protein 2 (SREBP2), 25-hydroxycholesterol (25-HC) and its catalyzing enzyme cholesterol-25-hydroxylase (Ch25h) are important in regulating cellular inflammatory status and cholesterol biosynthesis in both ECs and monocytes/macrophages.Methods—Bioinformatic analyses were used to investigate RNA-seq data to identify cholesterol oxidation and efflux genes regulated by KLF4. In vitro experiments involving cultured ECs and macrophages and in vivo methods involving mice with Ch25h ablation were then used to explore the atheroprotective role of KLF4-Ch25h/LXR.Results—Vasoprotective stimuli increased the expression of Ch25h and LXR via krüppel-like factor 4 (KLF4). The KLF4-Ch25h/LXR homeostatic axis functions through suppressing inflammation, evidenced by the reduction of inflammasome activity in ECs and the promotion of M1 to M2 phenotypic transition in macrophages. The increased atherosclerosis in ApoE-/-/Ch25h-/- mice further demonstrates the beneficial role of the KLF4-Ch25h/LXR axis in vascular function and disease. Conclusions—KLF4 transactivates Ch25h and LXR thereby promoting the synergistic effects between ECs and macrophages to protect against atherosclerosis susceptibility.

Randomized Comparison of Ridaforolimus-Eluting and Zotarolimus-Eluting Coronary Stents in Patients with Coronary Artery Disease: Primary Results from the BIONICS Trial [Original Research Article]


Background—The safety and efficacy of a novel cobalt alloy-based coronary stent with a durable elastomeric polymer eluting the antiproliferative agent ridaforolimus for treatment of patients with coronary artery disease is undetermined.Methods—A prospective, international 1:1 randomized trial was conducted to evaluate in a noninferiority design the relative safety and efficacy of ridaforolimus-eluting stents (RES) and slow-release zotarolimus-eluting stents (ZES) among 1,919 patients at 76 centers undergoing percutaneous coronary intervention. Inclusion criteria allowed enrollment of patients with recent myocardial infarction (MI), total occlusions, bifurcations lesions and other complex conditions. Results—Baseline clinical and angiographic characteristics were similar between the groups. Overall, mean age was 63.4 years, 32.5% were diabetic and 39.7% presented with acute coronary syndromes. At 12 months, the primary endpoint of target lesion failure (composite of cardiac death, target vessel-related MI and target lesion revascularization) was 5.4% for both devices (upper bound of one-sided 95% confidence interval 1.8%, Pnoninferiority=0.001). Definite/probable stent thrombosis rates were low in both groups (0.4% RES vs. 0.6% ZES, P=0.75). 13-month angiographic in-stent late lumen loss was 0.22 ± 0.41 mm and 0.23 ± 0.39 mm (Pnoninferiority=0.004) for the RES and ZES groups, respectively, and intravascular ultrasound percent neointimal hyperplasia was 8.10 ± 5.81 and 8.85 ± 7.77, respectively (Pnoninferiority=0.01). Conclusions—In the present trial which allowed broad inclusion criteria, the novel RES met the prespecified criteria for noninferiority compared with ZES for the primary endpoint of target lesion failure at 12 months, and had similar measures of late lumen loss. These findings support the safety and efficacy of RES in patients representative of clinical practice.Clinical Trial Registration—URL: Unique Identifier: NCT01995487

Outcomes Associated with Extraction versus Capping and Abandoning Pacing and Defibrillator Leads [Original Research Article]


Background—Lead management is an increasingly important aspect of care in patients with cardiac implantable electronic devices (CIED); however, relatively little is known about long-term outcomes after capping and abandoning leads.Methods—Using the 5% Medicare sample, we identified patients with (1) de novo CIED implants between 1/1/2000 and 12/31/2013 and (2) a subsequent lead addition or extraction ≥12 months after the de novo implant. Patients who underwent extraction for infection were excluded. Using multivariable Cox proportional hazards models, cumulative incidence of all-cause mortality, device-related infection, device revision, and lead extraction at 1 and 5 years were compared for the extract versus the cap and abandon groups. Results—Among 6,859 patients, 1,113 (16.2%) underwent extraction, while 5,746 (83.8%) underwent capping and abandonment. Extraction patients tended to be younger (median 78 vs 79 years, p<0.0001), were less likely to be male (65% vs 68%, p=0.05), and had shorter lead dwell time (median 3.0 vs 4.0 years, p<0.0001) and fewer comorbidities. Over a median follow-up of 2.4 years (25th, 75th percentiles: 1.0, 4.3 years) the overall 1-year and 5-year cumulative incidence of mortality was 13.5% (95% CI 12.7%-14.4%) and 54.3% (95% CI 52.8%-55.8%), respectively. Extraction was associated with a lower risk of device infection at 5 years relative to capping (adjusted HR 0.78, 95% CI 0.62-0.97, p=0.027). There was no association between extraction and mortality, lead revision, or lead extraction at 5 years.Conclusions—Elective lead extraction for non-infectious indications had similar long-term survival to capping and abandoning leads in a Medicare population. However, extraction was associated with lower risk of device infections at 5 years.

Prolonged, Uninterrupted Sedentary Behavior and Glycemic Biomarkers Among US Hispanic/Latino Adults: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) [Original Research Article]


Background—Excessive sedentary time is ubiquitous in developed nations and is associated with deleterious health outcomes. Few studies have examined whether the manner in which sedentary time is accrued (in short or long bouts) carries any clinical relevance. The purpose of this study was to examine the association of prolonged-uninterrupted sedentary behavior with glycemic biomarkers in a cohort of U.S. Hispanic/Latino adults.Methods—We studied 12,083 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a population-based study of Hispanic/Latino adults 18-74 years. Homeostatic model assessment of insulin resistance (HOMA-IR) and glycosylated hemoglobin (Hb1Ac) were measured from a fasting blood sample and 2-hour glucose was measured following an oral glucose tolerance test. Sedentary time was objectively measured using a hip-mounted accelerometer. Prolonged, uninterrupted sedentariness was expressed as mean sedentary bout length.Results—Adjusted for potential confounders and moderate-vigorous physical activity, longer sedentary bout duration was dose-dependently associated with increased HOMA-IR (p-trend <0.001) and 2-hour glucose levels (p-trend=0.015). These associations were not independent of total sedentary time, however a significant interaction between sedentary bout duration and total sedentary time was observed. Evaluation of the joint association of total sedentary time and sedentary bout duration showed that participants in the upper quartile for both sedentary characteristics (i.e. high total sedentary time and high sedentary bout duration) had the highest levels of HOMA-IR (p<0.001 vs. low group for both sedentary characteristics) and 2-hour glucose (p=0.002 vs. low group for both sedentary characteristics). High total sedentary time or high sedentary bout duration alone were not associated with differences in any glycemic biomarkers.Conclusions—Accruing sedentary time in prolonged, uninterrupted bouts may be deleteriously associated with biomarkers of glucose regulation.

Epigenome-Wide Association Study Identifies Cardiac Gene Patterning and A Novel Class of Biomarkers for Heart Failure [Original Research Article]


Background—Biochemical DNA modification resembles a crucial regulatory layer between genetic information, environmental factors and the transcriptome. To identify epigenetic susceptibility regions and novel biomarkers linked to myocardial dysfunction and heart failure, we performed the first multi-omics study in myocardial tissue and blood of patients with Dilated Cardiomyopathy (DCM) and controls.Methods—Infinium HumanMethylation450 was used for high-density epigenome-wide mapping of DNA methylation in left ventricular biopsies and whole peripheral blood of living probands. RNA deep sequencing was performed on the same samples in parallel. Whole-genome sequencing of all patients allowed exclusion of promiscuous genotype-induced methylation calls. Results—In the screening stage, we detected 59 epigenetic loci that are significantly associated with DCM (FDR corrected p≤0.05), with three of them reaching epigenome-wide significance at p≤5x10-8. Twenty-seven (46%) of these loci could be replicated in independent cohorts, underlining the role of epigenetic regulation of key cardiac transcription regulators. Using a staged multi-omics study design, we link a subset of 517 epigenetic loci with DCM and cardiac gene expression. Furthermore, we identified distinct epigenetic methylation patterns that are conserved across tissues, rendering these CpGs novel epigenetic biomarkers for heart failure.Conclusions—The present study provides to our knowledge the first epigenome-wide association study in living patients with heart failure using a multi-omics approach.

Acute Myocardial Infarction: Changes in Patient Characteristics, Management, and 6-Month Outcomes Over a Period of 20 Years in the FAST-MI Program (French Registry of Acute ST-Elevation or Non-ST-elevation Myocardial Infarction) 1995 to 2015 [Original Research Article]


Background—ST-segment-elevation myocardial infarction (STEMI) and non-ST-segment-elevation myocardial infarction (NSTEMI) management has evolved considerably over the past 2 decades. Little information on mortality trends in the most recent years is available. We assessed trends in characteristics, treatments, and outcomes for acute myocardial infarction in France between 1995 and 2015.Methods— We used data from 5 one-month registries, conducted 5 years apart, from 1995 to 2015, including 14 423 patients with acute myocardial infarction (59% STEMI) admitted to cardiac intensive care units in metropolitan France.Results—From 1995 to 2015, mean age decreased from 66±14 to 63±14 years in patients with STEMI; it remained stable (68±14 years) in patients with NSTEMI, whereas diabetes mellitus, obesity, and hypertension increased. At the acute stage, intended primary percutaneous coronary intervention increased from 12% (1995) to 76% (2015) in patients with STEMI. In patients with NSTEMI, percutaneous coronary intervention ≤72 hours from admission increased from 9% (1995) to 60% (2015). Six-month mortality consistently decreased in patients with STEMI from 17.2% in 1995 to 6.9% in 2010 and 5.3% in 2015; it decreased from 17.2% to 6.9% in 2010 and 6.3% in 2015 in patients with NSTEMI. Mortality still decreased after 2010 in patients with STEMI without reperfusion therapy, whereas no further mortality gain was found in patients with STEMI with reperfusion therapy or in patients with NSTEMI, whether or not they were treated with percutaneous coronary intervention.Conclusions—Over the past 20 years, 6-month mortality after acute myocardial infarction has decreased considerably for patients with STEMI and NSTEMI. Mortality figures continued to decline in atients with STEMI until 2015, whereas mortality in patients with NSTEMI appears stable since 2010.

Efficacy and Safety of a Pharmaco-Invasive Strategy With Half-Dose Alteplase Versus Primary Angioplasty in ST-Segment-Elevation Myocardial Infarction: EARLY-MYO Trial (Early Routine Catheterization After Alteplase Fibrinolysis Versus Primary PCI in Acute ST-Segment-Elevation Myocardial Infarction) [Original Research Article]


Background—Timely primary percutaneous coronary intervention (PPCI) cannot be offered to all patients with ST-segment-elevation myocardial infarction (STEMI). Pharmaco-invasive (PhI) strategy has been proposed as a valuable alternative for eligible patients with STEMI. We conducted a randomized study to compare the efficacy and safety of a PhI strategy with half-dose fibrinolytic regimen versus PPCI in patients with STEMI.Methods—The EARLY-MYO trial (Early Routine Catheterization After Alteplase Fibrinolysis Versus Primary PCI in Acute ST-Segment-Elevation Myocardial Infarction) was an investigator-initiated, prospective, multicenter, randomized, noninferiority trial comparing a PhI strategy with half-dose alteplase versus PPCI in patients with STEMI 18 to 75 years of age presenting ≤6 hours after symptom onset but with an expected PCI-related delay. The primary end point of the study was complete epicardial and myocardial reperfusion after PCI, defined as thrombolysis in myocardial infarction flow grade 3, thrombolysis in myocardial infarction myocardial perfusion grade 3, and STsegment resolution ≥70%. We also measured infarct size and left ventricular ejection fraction with cardiac magnetic resonance and recorded 30-day clinical and safety outcomes.Results—A total of 344 patients from 7 centers were randomized to PhI (n=171) or PPCI (n=173). PhI was noninferior (and even superior) to PPCI for the primary end point (34.2% versus 22.8%, Pnoninferiority<0.05, Psuperiority=0.022), with no significant differences in the frequency of the individual components of the combined end point: thrombolysis in myocardial infarction flow 3 (91.3% versus 89.2%, P=0.580), thrombolysis in myocardial infarction myocardial perfusion grade 3 (65.8% versus 62.9%, P=0.730), and STsegment resolution ≥70% (50.9% versus 45.5%, P=0.377). Infarct size (23.3%±11.3% versus 25.8%±13.7%, P=0.101) and left ventricular ejection fraction (52.2%±11.0% versus 51.4%±12.0%, P=0.562) were similar in both groups. No significant differences occurred in 30-day rates of total death (0.6% versus 1.2%, P=1.0), reinfarction (0.6% versus 0.6%, P=1.0), heart failure (13.5% versus 16.2%, P=0.545), major bleeding events (0.6% versus 0%, P=0.497), or intracranial hemorrhage (0% versus 0%), but minor bleeding (26.9% versus 11.0%, P<0.001) was observed more often in the PhI group.Conclusions— For patients with STEMI presenting ≤6 hours after symptom onset and with an expected PCI-related delay, a PhI strategy with half-dose alteplase and timely PCI offers more complete epicardial and myocardial reperfusion when compared with PPCI. Adequately powered trials with this reperfusion strategy to assess clinical and safety outcomes are warranted.Clinical Trial Registration— URL: Unique identifier: NCT01930682.

Recalibrating Reperfusion Waypoints [Editorial]


The realization that thrombus was the cause and not the consequence of acute myocardial infarction was a transformative pathophysiologic insight. An even more stunning observation was the subsequent discovery that restoration of coronary patency could salvage ischemic myocardium and improve clinical outcomes in ST-elevation acute myocardial infarction (STEMI). Assertive clinical investigations of both the content and process of STEMI care over the subsequent 4 decades has demonstrated that the ultimate success of reperfusion is modulated by the timeliness, efficiency, and efficacy with which it is applied. Whereas contemporary guidelines indicate that primary percutaneous coronary intervention (PCI) is the preferred strategy for STEMI, most patients with STEMI do not present to a primary PCI (PPCI) center, and ≈50% are walk-ins who do not utilize emergency medical services. Accordingly, persisting delays—attributable to both patients and the healthcare system—in achieving timely PCI (ie, within 60 to 90 minutes of symptoms to first medical contact) are common and exact a price of excess morbidity and mortality. Advances in fibrinolytic, anti-thrombotic, and antiplatelet therapies, coupled with improved pre- and in-hospital systems of care, have evolved dramatically pari passu with these clinical realities. Accumulating contemporary evidence indicates that early fibrinolytic therapy followed by timely PCI, where appropriate, achieves clinical outcomes at least as good as PPCI in the common circumstance, where delay to PPCI is >60 to 90 minutes from first medical contact.

The Prognostic Value of Coronary Artery Calcium in the PROMISE Study [Original Research Article]


Background—Coronary artery calcium (CAC) is an established predictor of future major adverse atherosclerotic cardiovascular events in asymptomatic individuals. However limited data exist as to how CAC compares to functional testing (FT) in estimating prognosis in symptomatic patients.Methods—In the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial, patients with stable chest pain (or dyspnea) and intermediate pre-test probability for obstructive coronary artery disease (CAD) were randomized to FT (exercise electrocardiography, nuclear stress, or stress echocardiography) or anatomic testing. We evaluated those who underwent CAC testing as part of the anatomic evaluation (n=4,209) and compared to results of FT (n=4,602). We stratified CAC and FT results as normal or mildly, moderately or severely abnormal (for CAC: 0, 1-99 Agatston Score [AS], 100-400 AS and >400 AS, respectively; for FT: normal, mild=late positive treadmill, moderate=early positive treadmill or single-vessel ischemia and severe=large ischemic region abnormality). The primary endpoint was all-cause death, myocardial infarction or unstable angina hospitalization over a median follow-up of 26.1 months. Cox regression models were used to calculate hazard ratios and C-statistic to determine predictive and discriminatory value.Results— Overall, the distribution of normal or mildly, moderately or severely abnormal test results was significantly different between FT and CAC (FT = normal 3588 [78.0%], mild 432 [9.4%], moderate 217 [4.7%], severe 365 [7.9%]; CAC = normal 1,457 [34.6%], mild 1340 [31.8%], moderate 772 [18.3%], severe 640 [15.2%], p <0.0001). Moderate and severe abnormalities in both arms robustly predicted events (moderate: CAC HR 3.14, 95% CI 1.81-5.44 and FT HR 2.65, 95% CI 1.46-4.83; severe: CAC HR 3.56, 95% CI 1.99-6.36 and FT HR 3.88, 95% CI 2.58-5.85. In the CAC arm, the majority of events (n=112/133; 84%) occurred in patients with any positive CAC test (score >0) whereas less than half of events occurred in patients with mild, moderate or severely abnormal FT (n=57/132; 43%) (p<0.001). In contrast, any abnormality on FT was significantly more specific for predicting events (78.6% for FT vs 35.2% for CAC, p<0.001). Overall discriminatory ability in predicting the primary endpoint of mortality, nonfatal myocardial infarction, and unstable angina hospitalization was similar and fair for both CAC and FT (c-statistic, 0.67 vs. 0.64). Coronary computed tomographic angiography provided significantly better prognostic information compared to FT and CAC testing (C-index: 0.72). Conclusion—Among stable outpatients presenting with suspected CAD, most patients experiencing clinical events have measurable CAC at baseline while less than half have any abnormalities on FT. However, an abnormal FT was more specific for cardiovascular events, leading to overall similarly modest discriminatory abilities of both tests.Clinical Trial Registration—URL:; Unique Identifier: NCT01174550

Computed Tomography or Functional Stress Testing for the Prediction of Risk: Can I Have My Cake and Eat It? [Editorial]


The clinician now has an overwhelming array of investigations at their disposal for patients with suspected coronary heart disease. These tests are used to diagnose or to risk stratify patients, and thereby enable the clinician to treat their symptoms and to reduce their future risk. Ultimately, these investigations assess either risk factors (such as lipid, glucose and c-reactive protein concentrations) and proxies for disease (such as carotid intima-media thickness and coronary artery calcium score), or they are looking to provide circumstantial downstream evidence of disease (such as markers of ischemia and infarction: Q waves on an electrocardiogram, fibrosis on magnetic resonance imaging or functional stress testing). In this issue of Circulation, Budoff and colleagues compare two of the most widely used approaches, coronary artery calcium scoring and functional stress testing, within the framework of the PROspective Multicenter Imaging Study for Evaluation of chest pain (PROMISE) trial.

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.

Assessment of Remote Heart Rhythm Sampling Using the AliveCor Heart Monitor to Screen for Atrial Fibrillation: The REHEARSE-AF Study [Original Research Article]


Background—Asymptomatic atrial fibrillation (AF) is increasingly common in the aging population and implicated in many ischemic strokes. Earlier identification of AF with appropriate anticoagulation may decrease stroke morbidity and mortality.Methods—We conducted a randomized controlled trial of AF screening using an AliveCor Kardia monitor attached to a WiFi-enabled iPod to obtain ECGs (iECGs) in ambulatory patients. Patients ≥65 years of age with a CHADS-VASc score ≥2 free from AF were randomized to the iECG arm or routine care (RC). iECG participants acquired iECGs twice weekly over 12 months (plus additional iECGs if symptomatic) onto a secure study server with overread by an automated AF detection algorithm and by a cardiac physiologist and/or consultant cardiologist. Time to diagnosis of AF was the primary outcome measure. The overall cost of the devices, ECG interpretation, and patient management were captured and used to generate the cost per AF diagnosis in iECG patients. Clinical events and patient attitudes/experience were also evaluated.Results—We studied 1001 patients (500 iECG, 501 RC) who were 72.6±5.4 years of age; 534 were female. Mean CHADS-VASc score was 3.0 (heart failure, 1.4%; hypertension, 54%; diabetes mellitus, 30%; prior stroke/transient ischemic attack, 6.5%; arterial disease, 15.9%; all CHADS-VASc risk factors were evenly distributed between groups). Nineteen patients in the iECG group were diagnosed with AF over the 12-month study period versus 5 in the RC arm (hazard ratio, 3.9; 95% confidence interval=1.4-10.4; P=0.007) at a cost per AF diagnosis of $10780 (£8255). There was a similar number of stroke/transient ischemic attack/systemic embolic events (6 versus 10, iECG versus RC; hazard ratio=0.61; 95% confidence interval=0.22-1.69; P=0.34). The majority of iECG patients were satisfied with the device, finding it easy to use without restricting activities or causing anxiety.Conclusion— Screening with twice-weekly single-lead iECG with remote interpretation in ambulatory patients ≥65 years of age at increased risk of stroke is significantly more likely to identify incident AF than RC over a 12-month period. This approach is also highly acceptable to this group of patients, supporting further evaluation in an appropriately powered, event-driven clinical trial.Clinical Trial Registration—URL: Unique identifier: ISRCTN10709813.

Atrial Fibrillation: Atrial High-Rate Events (AHRES): Look and You Will Find-Then What? [Editorial]


The article by Halcox et al describes the REHEARSE-AF study (Assessment of Remote Heart Rhythm Sampling Using the AliveCor Heart Monitor to Screen for Atrial Fibrillation), a randomized trial of screening for atrial fibrillation (AF) with a smartphone-based single-lead electrocardiographic capture system in 1001 patients ≥65 years of age with a CHA2DS2-VASc score of ≥ 2 and without a history of AF. Patients were randomized either to biweekly electrocardiographic recordings with the iPhone device (iECG group; n=500) or to routine care (control group; n=501) over a 12-month period. Not surprisingly, more patients with AF were identified in the iECG group (n=19) than in the control group (n=5).The data from this study confirm results from studies with implanted pacemakers, cardioverter-defibrillators, and loop recorders and other AF screening studies that, in patients unknown to have AF, particularly those with cardiovascular comorbidities, the more we look for AF, the more we will find it. As Sophocles mused more generally, "Look and you will find-what is unsought will go undetected." But is there a need to know about asymptomatic episodes of so-called subclinical AF (SCAF)? What are the implications of such a finding?

Exploring Coronary Circulatory Response to Stenosis and Its Association with Invasive Physiologic Indices Using Absolute Myocardial Blood Flow and Coronary Pressure [Original Research Article]


Background—Although invasive physiologic assessment for coronary stenosis has become a standard practice to guide treatment strategy, coronary circulatory response and changes in invasive physiologic indices, according to different anatomical and hemodynamic lesion severity, have not been fully demonstrated in patients with coronary artery disease. Methods—One hundred fifteen patients with left anterior descending artery stenosis who underwent both 13N-ammonia positron emission tomography (PET) and invasive physiologic measurement were analyzed. Myocardial blood flow (MBF) measured using PET and invasively measured coronary pressures were used to calculate microvascular resistance (MVR) and stenosis resistance. Results—With progressive worsening of angiographic stenosis severity, both resting and hyperemic trans-stenotic pressure gradient and stenosis resistance increased (P<0.001 for all) and hyperemic MBF (P<0.001) and resting MVR (P=0.012) decreased. Resting MBF (P=0.383) and hyperemic MVR (P=0.431) were not changed and maintained stable. Both fractional flow reserve (FFR) and instantaneous wave free ratio (iFR) decreased as angiographic stenosis severity, stenosis resistance, and trans-stenotic pressure gradient increased, and hyperemic MBF decreased (all P values<0.001). When the presence of myocardial ischemia was defined by both low hyperemic MBF and low coronary flow reserve (CFR), the diagnostic accuracy of FFR and iFR did not differ, regardless of cut-off values of hyperemic MBF and CFR.Conclusions—This study demonstrated how the coronary circulation changes in response to increasing coronary stenosis severity using 13N-ammonium PET-derived MBF and invasively measured pressure data. Currently used resting and hyperemic pressure-derived invasive physiologic indices have similar patterns of relationships to the different anatomic and hemodynamic lesion severity. Clinical Trial Registration—URL: Unique Identifier: NCT01366404

Interferon Regulatory Factor 4 Inhibits Neointima Formation by Engaging KLF4 Signaling [Original Research Article]


Background—The mechanisms underlying neointima formation remain unclear. Interferon regulatory factors (IRFs), which are key innate immune regulators, play important roles in cardiometabolic diseases. However, the function of IRF4 in arterial restenosis is unknown.Methods—IRF4 expression was first detected in human and mouse restenotic arteries. Then, the effects of IRF4 on neointima formation were evaluated using universal IRF4-deficient mouse and rat carotid artery injury models. We performed immunostaining to identify IRF4-expressing cells in the lesions. Smooth muscle cell (SMC)-specific IRF4-knockout (SMC-IRF4-KO) and transgenic (SMC-IRF4-TG) mice were generated to evaluate the effects of SMC-IRF4 on neointima formation. We used microarray, bioinformatics analysis and chromatin immunoprecipitation assay to identify the downstream signals of IRF4 and verify the targets in vitro. We compared SMC-specific IRF4-KO/Krüppel-like factor 4 (KLF4)-TG mice with SMC-IRF4-KO mice and SMC-specific IRF4-TG/KLF4-KO mice with SMC-specific IRF4-TG mice to investigate whether the effect of IRF4 on neointima formation is KLF4 dependent. The effect of IRF4 on SMC phenotype switching was also evaluated. Results—IRF4 expression in both the human and mouse restenotic arteries is eventually downregulated. Universal IRF4 ablation potentiates neointima formation in both mice and rats. Immunostaining indicated that IRF4 was primarily expressed in SMCs in restenotic arteries. Post injury, SMC-IRF4-KO mice developed a thicker neointima than control mice. This change was accompanied by increased SMC proliferation and migration. However, SMC-IRF4-TG mice exhibited the opposite phenotype, demonstrating that IRF4 exerts protective effects against neointima formation. The mechanistic study indicated that IRF4 promotes KLF4 expression by directly binding to its promoter. Importantly, genetic overexpression of KLF4 in SMCs largely reversed the neointima-promoting effect of IRF4 ablation, whereas ablation of KLF4 abolished the protective function of IRF4, indicating that the protective effects of IRF4 against neointima formation are KLF4 dependent. In addition, IRF4 also promoted SMC dedifferentiation.Conclusions—IRF4 protects arteries against neointima formation by promoting the expression of KLF4 by directly binding to its promoter. Our findings suggest that this previously undiscovered IRF4-KLF4 axis plays a key role in vasculoproliferative pathology and may be a promising therapeutic target for the treatment of arterial restenosis.

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.

Circular Non-Coding RNA HIPK3 Mediates Retinal Vascular Dysfunction in Diabetes Mellitus [Original Research Article]


Background—The vascular complications of diabetes mellitus are the major causes of morbidity and mortality among people with diabetes. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs that regulate gene expression in eukaryotes. In this study, we investigated the role of circRNA in retinal vascular dysfunction induced by diabetes.Methods—Quantitative polymerase chain reactions, Sanger sequencing, and Northern blots were conducted to detect circHIPK3 expression pattern upon diabetes mellitus-related stresses. MTT assays, EdU incorporation assays, transwell migration assays, and matrigel assays were conducted to detect the role of circHIPK3 in retinal endothelial cell function in vitro. Retinal trypsin digestion, vascular permeability assays, and ELISA assays were conducted to detect the role of circHIPK3 in retinal vascular dysfunction in vivo. Bioinformatics analysis, luciferase activity assays, RNA pull-down assays, and in vitro studies were conducted to reveal the mechanism of circHIPK3-mediated retinal vascular dysfunction.Results—circHIPK3 expression was significantly up-regulated in diabetic retinas and retinal endothelial cells following stressors related to diabetes. circHIPK3 silencing or over-expressing circHIPK3 changed retinal endothelial cell viability, proliferation, migration, and tube formation in vitro. circHIPK3 silencing in vivo alleviated retinal vascular dysfunction, as shown by decreased retinal acellular capillaries, vascular leakage, and inflammation. circHIPK3 acted as an endogenous miR-30a-3p sponge to sequester and inhibit miR-30a-3p activity, which led to increased VEGFC, FZD4, and WNT2 expression. Ectopic expression of miR-30a-3p mimicked the effect of circHIPK3 silencing on vascular endothelial phenotypes in vivo and in vitro.Conclusions—The circular RNA circHIPK3 plays a role in diabetic retinopathy by blocking miR-30a function, leading to increased endothelial proliferation and vascular dysfunction. These data suggest that circular RNA is a potential target to control diabetic proliferative retinopathy.

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.

Hypoplastic Left Heart Syndrome with Intact or Restrictive Atrial Septum: A Report from the International Fetal Cardiac Intervention Registry [Research Letter]


Infants with hypoplastic left heart syndrome and an intact or highly restrictive atrial septum (HLHS-IAS) represent a high risk subset. Fetal cardiac intervention (FCI) for fetuses with HLHS-IAS has been reported in single-institution series as a therapy that may improve outcomes. This study utilizes the International Fetal Cardiac Intervention Registry (IFCIR) to examine fetal and maternal characteristics and pregnancy and neonatal outcome data for FCI in this population.

Age and Outcomes of Primary Prevention Implantable Cardioverter Defibrillators in Patients with Non-Ischemic Systolic Heart Failure [Original Research Article]


Background—The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators (ICD) in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) did not demonstrate an overall effect on all-cause mortality with ICD implantation. However, the pre-specified subgroup analysis suggested a possible age-dependent association between the ICD and mortality with survival benefit seen only in the youngest patients. The nature of this relationship between age and outcome of a primary prevention ICD in patients with non-ischemic systolic heart failure warrants further investigation. Methods—All 1116 patients from the DANISH study were included in this pre-specified subgroup analysis. We assessed the relationship between the ICD and mortality by age, and an optimal age cut-off was estimated non-parametrically using selection impact curves. Modes of death were divided into sudden cardiac death (SCD) and non-sudden death and compared between patients younger and older than this age cut-off, respectively, with the use of Chi2-analysis. Results—Median age of the study population was 63 years (range 21 - 84 years). There was a linearly decreasing relationship between the ICD and mortality with age, HR 1.03 (95% CI 1.003 - 1.06), p=0.03. An optimal age cut-off for ICD implantation was present at ≤70 years. There was an association between reduced all-cause mortality and the ICD in patients ≤70 years, HR 0.70 (0.51 - 0.96), p=0.03, but not in patients >70 years, HR 1.05 (0.68 - 1.62), p=0.84. For patients ≤70 years, SCD rate was 1.8 (1.3 - 2.5) and non-sudden death rate was 2.7 (2.1 - 3.5) events/100 patient years, whereas for patients older than 70 years SCD rate was 1.6 (0.8 - 3.2) and non-sudden death rate was 5.4 (3.7 - 7.8) events/100 patient years. This difference in modes of death between the two age groups was statistically significant (p=0.01).Conclusions—In patients with systolic heart failure not caused by ischemic heart disease, the association between the ICD and survival decreased linearly with increasing age. In this study population, an age cut-off for ICD implantation at ≤70 years yielded the highest survival for the population as a whole.

Modeling Major Adverse Outcomes of Pediatric and Adult Patients with Congenital Heart Disease Undergoing Cardiac Catheterization: Observations from the NCDR IMPACT Registry [Original Research Article]


Background—Risk-standardization for adverse events following congenital cardiac catheterization is needed to equitably compare patient outcomes among different hospitals as a foundation for quality improvement. The goal of this project was to develop a risk-standardization methodology to adjust for patient characteristics when comparing major adverse outcomes in the NCDR® IMPACTTM (Improving Pediatric and Adult Congenital Treatment) Registry. Methods—39,725 consecutive patients within IMPACT undergoing cardiac catheterization between January 2011 and March 2014 were identified. Given the heterogeneity of interventional procedures for congenital heart disease, new procedure-type risk categories were derived with empiric data and expert opinion, as were markers of hemodynamic vulnerability. A multivariable hierarchical logistic regression model to identify patient and procedural characteristics predictive of a major adverse event (MAE) or death following cardiac catheterization was derived in 70% of the cohort and validated in the remaining 30%. Results—The rate of MAE or death was 7.1% and 7.2% in the derivation and validation cohorts, respectively. Six procedure-type risk categories and six independent indicators of hemodynamic vulnerability were identified. The final risk adjustment model included procedure-type risk category, number of hemodynamic vulnerability indicators, renal insufficiency, single-ventricle physiology, and coagulation disorder. The model had good discrimination with a C-statistic of 0.76 and 0.75 in the derivation and validation cohorts, respectively. Model calibration in the validation cohort was excellent with a slope of 0.97 (standard error [SE] 0.04; p-value [for difference from 1]= 0.53) and an intercept of 0.007 (SE 0.12; p-value [for difference from 0]= 0.95). Conclusions—The creation of a validated risk-standardization model for adverse outcomes following congenital cardiac catheterization can support reporting of risk-adjusted outcomes in the IMPACT Registry as a foundation for quality improvement.

Potential Cardiovascular and Total Mortality Benefits of Air Pollution Control in Urban China [Original Research Article]


Background—Outdoor air pollution ranks fourth among preventable causes of China's burden of disease. We hypothesized that the magnitude of health gains from air quality improvement in urban China could compare with achieving recommended blood pressure or smoking control goals.Methods—The Cardiovascular Disease Policy Model-China projected coronary heart disease, stroke, and all-cause deaths in urban Chinese adults aged 35-84 years from 2017 to 2030 if recent air quality (particulate matter with aerodynamic diameter ≤ 2.5 μm, PM2.5) and traditional cardiovascular risk factor trends continue. We projected life years gained if urban China were to reach one of three air quality goals: Beijing Olympic Games level (mean PM2.5, 55 μg/m3), China Class II standard (35 μg/m3), or World Health Organization (WHO) standard (10 μg/m3). We compared projected air pollution reduction control benefits with potential benefits of reaching WHO hypertension and tobacco control goals.Results—Mean PM2.5 reduction to Beijing Olympic levels by 2030 would gain about 241,000 (95% uncertainty interval, 189,000-293,000) life-years annually. Achieving either the China Class II standard or WHO PM2.5 standard would yield greater health benefits [992,000 (95% uncertainty interval, 790,000-1,180,000) or 1,827,000 (95% uncertainty interval, 1,481,000-2,129,000) annual life years gained, respectively] than WHO-recommended goals of 25% improvement in systolic hypertension control and 30% reduction in smoking combined [928,000 (95% uncertainty interval, 830,000-1,033,000) life years].Conclusions—Air quality improvement at different scenarios could lead to graded health benefits ranging from 241,000 life-years gained to much greater benefits are equal to or greater than the combined benefits of 25% improvement in systolic hypertension control and 30% smoking reduction.

LDL-Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men with Primary Elevations of LDL-Cholesterol Levels of 190 mg/dL or Above: Analyses from the WOSCOPS 5-year Randomised Trial and 20-year Observational Follow-Up [Original Research Article]


Background—Patients with primary elevations of LDL-C ≥190 mg/dL are at a higher risk of atherosclerotic cardiovascular disease as a result of long-term exposure to markedly elevated LDL-C levels. Therefore, initiation of statin therapy is recommended for these individuals. However, there is a lack of randomised trial evidence supporting these recommendations in primary prevention. In the present analysis we provide hitherto unpublished data on the cardiovascular effects of LDL-C lowering among a primary prevention population with LDL-C ≥190 mg/dL.Methods—We aimed to assess the benefits of LDL-C lowering on cardiovascular outcomes among individuals with primary elevations of LDL-C ≥190 mg/dL without pre-exiting vascular disease at baseline. We carried out post-hoc analyses from the West Of Scotland Coronary Prevention Study (WOSCOPS) randomised, placebo-controlled trial, and observational post-trial long-term follow-up, after excluding individuals with evidence of vascular disease at baseline. WOSCOPS enrolled 6595 men aged 45-64 years, who were randomised to pravastatin 40 mg/d or placebo. In the present analyses, 5529 participants without evidence of vascular disease were included, stratified by LDL-C levels into those with LDL-C <190 mg/dL (n=2969; mean LDL-C 178±6 mg/dL) and those with LDL-C ≥190 mg/dL (n=2560; mean LDL-C 206±12 mg/dL).The effect of pravastatin versus placebo on coronary heart disease (CHD) and major adverse cardiovascular events (MACE) were assessed over the 4.9-year randomised-controlled trial phase and on mortality outcomes over a total of 20-years of follow-up.Results—Among 5529 individuals without vascular disease, pravastatin reduced the risk of CHD by 27% (p=0.002) and MACE by 25% (p=0.004) consistently among those with and without LDL-C ≥190 mg/dL (p-interaction >0.9). Among individuals with LDL-C ≥190 mg/dL, pravastatin reduced the risk of CHD by 27% (p=0.033) and MACE by 25% (p=0.037) during the initial trial phase and the risk of CHD death, cardiovascular death and all-cause mortality by 28% (p=0.020), 25% (p=0.009) and 18% (p=0.004), respectively, over a total of 20-years of follow-up.Conclusions—The present analyses provide robust novel evidence for the short and long-term benefits of lowering LDL-C for the primary prevention of cardiovascular disease among individuals with primary elevations of LDL-C ≥190 mg/dL.

Timing of Angiography and Outcomes in High-Risk Patients with Non-ST Segment Elevation Myocardial Infarction Managed Invasively: Insights from the TAO Trial [Original Research Article]


Background—In patients with non ST-elevation myocardial infarction (NSTEMI) and Global Registry of Acute Coronary Events (GRACE) score >140, coronary angiography (CAG) is recommended by European and American guidelines within 24h. We sought to study the association of a "very early" (i.e. ≤12h), early (12-24h) and delayed (>24h) CAG in NSTEMI with GRACE score >140 with ischemic outcomes. Methods—The Treatment of Acute coronary syndrome with Otamixaban (TAO) trial randomized patients with NSTEMI and CAG scheduled within 72h to heparin plus eptifibatide versus otamixaban. In this post hoc analysis, patients with GRACE score > 140 were categorized into 3 groups according to timing of CAG from admission (<12h, ≥12h to <24h, ≥24h). The primary ischemic outcome was the composite of all-cause death and myocardial infarction (MI) within 180 days of randomization.Results—CAG was performed in 4,071 patients (<12h n=1648 (40.5%), 12-24h n=1420 (34.9%), ≥24h n=1003 (24.6%)). With CAG ≥24h as a reference, CAG from 12 to 24 hours was not associated with a lower risk of primary ischemic outcome at 180 days (odds ratio (OR) 0.96, 95% confidence interval (CI) 0.75-1.23), whereas CAG <12h was associated with a lower risk of death and MI (OR 0.71, 95% CI 0.55-0.91). Performing CAG <12h was also associated with a lower risk of death and MI (OR 0.76, 95%IC 0.61-0.94; p=0.01) compared to CAG performed 12-24h. No difference was observed regarding bleeding complications.Conclusions—In patients with high-risk NSTEMI, undergoing CAG within the initial 12 hours after admission (as opposed to later, either 12 to 24 h or ≥24 h) was associated with lower risk of ischemic outcomes at 180 days.

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.

Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker [Original Research Article]


Background—Preeclampsia (PE) is a complex and common human-specific pregnancy syndrome associated with placental pathology. The human-specificity provides both intellectual and methodological challenges, lacking a robust model system. Given the role of imprinted genes in human placentation and the vulnerability of imprinted genes to loss of imprinting changes, there has been extensive speculation, but no robust evidence, that imprinted genes are involved in PE. Our study aims at investigating whether disturbed imprinting contributes to PE. Methods—We first aimed at confirming that PE is a disease of the placenta by generating and analysing genome-wide molecular data on well-characterized patient material. We performed high-throughput transcriptome analyses of multiple placenta samples from normal and PE patients. Next, we identified differentially expressed genes (DEGs) in PE placenta, and intersected them with the list of human imprinted genes. We employed bioinformatics/statistical analyses to confirm association between imprinting and PE, and to predict biological processes affected in PE. Validation included epigenetic and cellular assays. Regarding human-specificity, we established an in vitro invasion-differentiation trophoblast model. Our comparative phylogenetic analysis involved single-cell transcriptome data of human, macaque and mouse preimplantation embryogenesis.Results—We found disturbed placental imprinting in PE and revealed potential candidates, including GATA3 and DLX5, with poorly explored imprinted status and no prior association with PE. Due to loss of imprinting DLX5 was upregulated in 69% of PE placentas. Levels of DLX5 correlated with classical PE marker. DLX5 is expressed in human, but not in murine trophoblast. The DLX5high phenotype resulted in reduced proliferation, increased metabolism and ER stress-response activation in trophoblasts in vitro. The transcriptional profile of such cells mimics the transcriptome of PE placentas. Pan-mammalian comparative analysis identified DLX5 as a part of the human-specific regulatory network of trophoblast differentiation.Conclusions—Our analysis provides evidence of a true association between disturbed imprinting, gene expression and PE. Due to disturbed imprinting, the upregulated DLX5 affects trophoblast proliferation. Our in vitro model might fill a vital niche in PE research. Human-specific regulatory circuitry of DLX5 might help to explain certain aspects of PE.

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.

Inflammation and Atherosclerosis - The End of a Controversy [Perspective]


Does inflammation matter in coronary artery disease? Is it a driving force in atherosclerosis, or merely an epiphenomenon? And is there space for novel therapies besides those targeting cholesterol? The CANTOS trial, which was presented at the European Society of Cardiology meeting in Barcelona a few weeks ago provides answers to these important questions. Indeed, the results of this trial open up a new avenue for cardiovascular prevention.

Contemporary Management of Cardiogenic Shock: A Scientific Statement From the American Heart Association [AHA Scientific Statements]


Cardiogenic shock is a high-acuity, potentially complex, and hemodynamically diverse state of end-organ hypoperfusion that is frequently associated with multisystem organ failure. Despite improving survival in recent years, patient morbidity and mortality remain high, and there are few evidence-based therapeutic interventions known to clearly improve patient outcomes. This scientific statement on cardiogenic shock summarizes the epidemiology, pathophysiology, causes, and outcomes of cardiogenic shock; reviews contemporary best medical, surgical, mechanical circulatory support, and palliative care practices; advocates for the development of regionalized systems of care; and outlines future research priorities.

Endoplasmic Reticulum Membrane Protein Complex Subunit 10 (EMC10) is a Bone Marrow-Derived Angiogenic Growth Factor Promoting Tissue Repair After Myocardial Infarction [Original Research Article]


Background—Clinical trials of bone marrow cell (BMC)-based therapies after acute myocardial infarction (MI) have produced mostly neutral results. Treatment with specific BMC-derived secreted proteins may provide an alternative biologic approach to improving tissue repair and heart function after MI. We recently performed a bioinformatic secretome analysis in BMCs from patients with acute MI and discovered a poorly characterized secreted protein, endoplasmic reticulum membrane protein complex subunit 10 (EMC10), showing activity in an angiogenic screen.Methods—We investigated the angiogenic potential of EMC10 and its mouse homolog (Emc10) in cultured endothelial cells and infarcted heart explants. We defined the cellular sources and function of Emc10 after MI using wild-type (WT), Emc10-deficient (knockout, KO), and Emc10 bone marrow-chimeric mice subjected to transient coronary artery ligation. Further, we explored the therapeutic potential of recombinant Emc10 delivered by osmotic minipumps after MI in heart failure-prone FVB/N mice.Results—Emc10 signaled through small GTPases, p21 activated kinase, and the p38 mitogen-activated protein kinase (MAPK)-MAPK-activated protein kinase 2 (MK2) pathway to promote actin polymerization and endothelial cell migration. Confirming the importance of these signaling events in the context of acute MI, Emc10 stimulated endothelial cell outgrowth from infarcted mouse heart explants via p38 MAPK-MK2. Emc10 protein abundance was increased in the infarcted region of the left ventricle and in the circulation of WT mice after MI. Emc10 expression was also increased in left ventricular (LV) tissue samples from patients with acute MI. Bone marrow-derived monocytes and macrophages were the predominant sources of Emc10 in the infarcted murine heart. Emc10 KO mice showed no cardiovascular phenotype at baseline. After MI, however, capillarization of the infarct border zone was impaired in KO mice, and the animals developed larger infarct scars and more pronounced LV remodeling compared to WT mice. Transplanting KO mice with WT BMCs rescued the angiogenic defect and ameliorated LV remodeling. Treating FVB/N mice with recombinant Emc10 enhanced infarct border zone capillarization and exerted a sustained beneficial effect on LV remodeling.Conclusions—We have identified Emc10 as a previously unknown angiogenic growth factor that is produced by bone marrow-derived monocytes and macrophages as part of an endogenous adaptive response that can be enhanced therapeutically to repair the heart after MI.

Upregulation of HERV-K is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension [Original Research Article]


Background—Immune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue and elevated cytokines have been related to PAH pathogenesis but without clear understanding of how these abnormalities are initiated, perpetuated and connected in the progression of disease. We therefore set out to identify specific target antigens in PAH lung immune complexes as a starting point toward resolving these issues to better inform future application of immunomodulatory therapies. Methods—Lung immune complexes were isolated and PAH target antigens were identified by liquid chromatography tandem mass spectrometry (LCMS), confirmed by ELISA, and localized by confocal microscopy. One PAH antigen linked to immunity and inflammation was pursued and a link to PAH pathophysiology was investigated by next generation sequencing, functional studies in cultured monocytes and endothelial cells (EC) and hemodynamic and lung studies in a rat.Results—SAM domain and HD1 domain-containing protein (SAMHD1), an innate immune factor that suppresses HIV replication was identified and confirmed as highly expressed in immune complexes from 16 hereditary and idiopathic PAH vs. 12 control lungs. Elevated SAMHD1 was localized to endothelial cells (EC), perivascular dendritic cells and macrophages and SAMHD1 antibodies were prevalent in tertiary lymphoid tissue. An unbiased screen using metagenomic sequencing related SAMHD1 to increased expression of human endogenous retrovirus K (HERV-K) in PAH vs. control lungs (n=4 each). HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) mRNAs were elevated in PAH vs. control lungs (n=10) and proteins were localized to macrophages. HERV-K dUTPase induced SAMHD1 and pro-inflammatory cytokines (e.g., IL6, IL1β and TNFα) in circulating monocytes and pulmonary arterial (PA) EC, and activated B cells. Vulnerability of PAEC to apoptosis was increased by HERV-K dUTPase in an IL6 independent manner. Furthermore, three weekly injections of HERV-K dUTPase induced hemodynamic and vascular changes of pulmonary hypertension in rats (n=8), and elevated IL6.Conclusions—Our study reveals that upregulation of the endogenous retrovirus HERV-K could both initiate and sustain activation of the immune system and cause vascular changes associated with PAH.

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.

SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy [Original Research Article]


Background—Pathological cardiac hypertrophy induced by stresses such as aging and neurohumoral activation is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the roles of SIRT2 in aging-related and angiotensin II (Ang II)-induced pathological cardiac hypertrophy.Methods—Male C57BL/6J wild-type (WT) and Sirt2 knockout (Sirt2-KO) mice were subjected to the investigation of aging-related cardiac hypertrophy. Cardiac hypertrophy was also induced by Ang II (1.3 mg/kg/day for four weeks) in male C57BL/6J Sirt2-KO mice, cardiac-specific SIRT2 transgenic (SIRT2-Tg) mice and their respective littermates (8~12-week-old). Metformin (200 mg/kg/day) was used to treat WT and Sirt2-KO mice that were infused with Ang II. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice.Results—SIRT2 protein expression levels were down-regulated in hypertrophic hearts from mice. Sirt2-KO markedly exaggerated cardiac hypertrophy and fibrosis as well as decreases in cardiac ejection fraction and fractional shortening in aged (24-month-old) mice and Ang II-infused mice. Conversely, cardiac-specific SIRT2 overexpression protected the hearts against Ang II-induced cardiac hypertrophy and fibrosis and rescued cardiac function. Mechanistically, SIRT2 maintained the activity of AMP-activated protein kinase (AMPK) in aged and Ang II-induced hypertrophic hearts in vivo as well as in cardiomyocytes in vitro. We identified the liver kinase B1 (LKB1), the major upstream kinase of AMPK, as the direct target of SIRT2. SIRT2 bound to LKB1 and deacetylated it at lysine 48, which promoted the phosphorylation of LKB1 and the subsequent activation of LKB1-AMPK signaling. Remarkably, the loss of SIRT2 blunted the response of AMPK to metformin treatment in mice infused with Ang II and repressed the metformin-mediated reduction of cardiac hypertrophy and protection of cardiac function.Conclusions—SIRT2 promotes AMPK activation by deacetylating the kinase LKB1. Loss of SIRT2 reduces AMPK activation, promotes aging-related and Ang II-induced cardiac hypertrophy and blunts metformin-mediated cardioprotective effects. These findings indicate that SIRT2 will be a potential target for therapeutic interventions in aging and stress-induced cardiac hypertrophy.

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