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Visit-to-Visit Blood Pressure Variability in Young Adulthood and Hippocampal Volume and Integrity at Middle AgeNovelty and Significance [Epidemiology/Population]

2017-11-08T10:40:41-08:00

The aims of this study are to assess the relationships of visit-to-visit blood pressure (BP) variability in young adulthood to hippocampal volume and integrity at middle age. We used data over 8 examinations spanning 25 years collected in the CARDIA study (Coronary Artery Risk Development in Young Adults) of black and white adults (age, 18–30 years) started in 1985 to 1986. Visit-to-visit BP variability was defined as by SDBP and average real variability (ARVBP, defined as the absolute differences of BP between successive BP measurements). Hippocampal tissue volume standardized by intracranial volume (%) and integrity assessed by fractional anisotropy were measured by 3-Tesla magnetic resonance imaging at the year-25 examination (n=545; mean age, 51 years; 54% women and 34% African Americans). Mean systolic BP (SBP)/diastolic BP levels were 110/69 mm Hg at year 0 (baseline), 117/73 mm Hg at year 25, and ARVSBP and SDSBP were 7.7 and 7.9 mm Hg, respectively. In multivariable-adjusted linear models, higher ARVSBP was associated with lower hippocampal volume (unstandardized regression coefficient [standard error] with 1-SD higher ARVSBP: −0.006 [0.003]), and higher SDSBP with lower hippocampal fractional anisotropy (−0.02 [0.01]; all P<0.05), independent of cumulative exposure to SBP during follow-up. Conversely, cumulative exposure to SBP and diastolic BP was not associated with hippocampal volume. There was no interaction by sex or race between ARVSBP or SDSBP with hippocampal volume or integrity. In conclusion, visit-to-visit BP variability during young adulthood may be useful in assessing the potential risk for reductions in hippocampal volume and integrity in midlife.



Central Iliac Arteriovenous Anastomosis for Uncontrolled HypertensionNovelty and Significance [Clinical Trials]

2017-11-08T10:40:41-08:00

Creation of a central iliac arteriovenous anastomosis using a novel nitinol coupler device results in an immediate, significant reduction of blood pressure (BP). We present efficacy and safety findings at 12 months post-coupler insertion. This open-label, multicenter, prospective, randomized trial enrolled patients with a baseline office systolic BP ≥140 mm Hg and average daytime ambulatory BP ≥135/85 mm Hg. Subjects were randomly allocated to coupler implantation and continuing previous pharmacotherapy or to maintain previous treatment alone. At 12 months, 39 patients who had coupler therapy were included in the intention-to-treat analysis. Office-based systolic BP reduced by 25.1±23.3 mm Hg (baseline, 174±18 mm Hg; P<0.0001) post-coupler placement, and office diastolic BP reduced by 20.8±13.3 mm Hg (baseline, 100±13 mm Hg; P<0.0001). Mean 24-hour ambulatory BP reduced by 12.6±17.4/15.3±9.7 mm Hg (P<0.0001 for both). In a prespecified subset of patients who failed to respond adequately to prior renal denervation, coupler therapy led to highly significant reduction in office systolic/diastolic BP (30.7/24.1 mm Hg) and significant reduction in 24-hour ambulatory systolic/diastolic BP (12.4/14.4 mm Hg) at 12 months (n=9). After coupler therapy, 14 patients (33%) developed ipsilateral venous stenosis; all were treated successfully with venous stenting. These findings confirm the importance of arterial mechanics in the pathophysiology of hypertension and support the clinical use of a central iliac arteriovenous anastomosis.Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01642498.



Blood Pressure Genetic Risk Score Predicts Blood Pressure Responses to Dietary Sodium and PotassiumNovelty and Significance [Genetic Risk Score]

2017-11-08T10:40:41-08:00

We examined the association between genetic risk score (GRS) for blood pressure (BP), based on single nucleotide polymorphisms identified in previous BP genome-wide association study meta-analyses, and salt and potassium sensitivity of BP among participants of the GenSalt study (Genetic Epidemiology Network of Salt Sensitivity). The GenSalt study was conducted among 1906 participants who underwent a 7-day low-sodium (51.3 mmol sodium/d), 7-day high-sodium (307.8 mmol sodium/d), and 7-day high-sodium plus potassium (60 mmol potassium/d) intervention. BP was measured 9× at baseline and at the end of each intervention period using a random zero sphygmomanometer. Associations between systolic BP (SBP), diastolic BP, and mean arterial pressure GRS and respective SBP, diastolic BP, and mean arterial pressure responses to the dietary interventions were assessed using mixed linear regression models that accounted for familial dependencies and adjusted for age, sex, field center, body mass index, and baseline BP. As expected, baseline SBP, diastolic BP, and mean arterial pressure significantly increased per quartile increase in GRS (P=2.7×10−8, 9.8×10−8, and 6.4×10−6, respectively). In contrast, increasing GRS quartile conferred smaller SBP, diastolic BP, and mean arterial pressure responses to the low-sodium intervention (P=1.4×10−3, 0.02, and 0.06, respectively) and smaller SBP responses to the high-sodium and potassium interventions (P=0.10 and 0.05). In addition, overall findings were similar when examining GRS as a continuous measure. Contrary to our initial hypothesis, we identified an inverse relationship between BP GRS and salt and potassium sensitivity of BP. These data may provide novel implications on the relationship between BP responses to dietary sodium and potassium and hypertension.



Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced HypertensionNovelty and Significance [Brain]

2017-11-08T10:40:41-08:00

The brain is highly susceptible to injury caused by hypertension because the increased blood pressure causes artery remodeling that can limit cerebral perfusion. Mineralocorticoid receptor (MR) antagonism prevents hypertensive cerebral artery remodeling, but the vascular cell types involved have not been defined. In the periphery, the endothelial MR mediates hypertension-induced vascular injury, but cerebral and peripheral arteries are anatomically distinct; thus, these findings cannot be extrapolated to the brain. The parenchymal arterioles determine cerebrovascular resistance. Determining the effects of hypertension and MR signaling on these arterioles could lead to a better understanding of cerebral small vessel disease. We hypothesized that endothelial MR signaling mediates inward cerebral artery remodeling and reduced cerebral perfusion during angiotensin II (AngII) hypertension. The biomechanics of the parenchymal arterioles and posterior cerebral arteries were studied in male C57Bl/6 and endothelial cell–specific MR knockout mice and their appropriate controls using pressure myography. AngII increased plasma aldosterone and decreased cerebral perfusion in C57Bl/6 and MR-intact littermates. Endothelial cell MR deletion improved cerebral perfusion in AngII-treated mice. AngII hypertension resulted in inward hypotrophic remodeling; this was prevented by MR antagonism and endothelial MR deletion. Our studies suggest that endothelial cell MR mediates hypertensive remodeling in the cerebral microcirculation and large pial arteries. AngII-induced inward remodeling of cerebral arteries and arterioles was associated with a reduction in cerebral perfusion that could worsen the outcome of stroke or contribute to vascular dementia.



Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated MechanismsNovelty and Significance [Brain]

2017-11-08T10:40:41-08:00

Hypertension is associated with increased activity of the kallikrein–kinin system. Kinin B1 receptor (B1R) activation leads to vasoconstriction and inflammation. Despite evidence supporting a role for the B1R in blood pressure regulation, the mechanisms by which B1R could alter autonomic function and participate in the pathogenesis of hypertension remain unidentified. We sought to explore whether B1R-mediated inflammation contributes to hypertension and investigate the molecular mechanisms involved. In this study, we tested the hypothesis that activation of B1R in the brain is involved in the pathogenesis of hypertension, using the deoxycorticosterone acetate–salt model of neurogenic hypertension in wild-type and B1R knockout mice. Deoxycorticosterone acetate–salt treatment in wild-type mice led to significant increases in B1R mRNA and protein levels and bradykinin levels, enhanced gene expression of carboxypeptidase N supporting an increase in the B1R ligand, associated with enhanced blood pressure, inflammation, sympathoexcitation, autonomic dysfunction, and impaired baroreflex sensitivity, whereas these changes were blunted or prevented in B1R knockout mice. B1R stimulation was further shown to involve activation of the ASK1-JNK-ERK1/2 and NF-κB pathways in the brain. To dismiss potential developmental alterations in knockout mice, we further used B1R blockade selectively in the brain of wild-type mice. Supporting the central origin of this mechanism, intracerebroventricular infusion of a specific B1R antagonist, attenuated the deoxycorticosterone acetate-salt–induced increase in blood pressure in wild-type mice. Our data provide the first evidence of a central role for B1R-mediated inflammatory pathways in the pathogenesis of deoxycorticosterone acetate–salt hypertension and offer novel insights into possible B1R-targeted therapies for the treatment of neurogenic hypertension.



Brain Regional Blood Flow and Working Memory Performance Predict Change in Blood Pressure Over 2 YearsNovelty and Significance [Brain]

2017-11-08T10:40:41-08:00

Hypertension is a presumptive risk factor for premature cognitive decline. However, lowering blood pressure (BP) does not uniformly reverse cognitive decline, suggesting that high BP per se may not cause cognitive decline. We hypothesized that essential hypertension has initial effects on the brain that, over time, manifest as cognitive dysfunction in conjunction with both brain vascular abnormalities and systemic BP elevation. Accordingly, we tested whether neuropsychological function and brain blood flow responses to cognitive challenges among prehypertensive individuals would predict subsequent progression of BP. Midlife adults (n=154; mean age, 49; 45% men) with prehypertensive BP underwent neuropsychological testing and assessment of regional cerebral blood flow (rCBF) response to cognitive challenges. Neuropsychological performance measures were derived for verbal and logical memory (memory), executive function, working memory, mental efficiency, and attention. A pseudo-continuous arterial spin labeling magnetic resonance imaging sequence compared rCBF responses with control and active phases of cognitive challenges. Brain areas previously associated with BP were grouped into composites for frontoparietal, frontostriatal, and insular-subcortical rCBF areas. Multiple regression models tested whether BP after 2 years was predicted by initial BP, initial neuropsychological scores, and initial rCBF responses to cognitive challenge. The neuropsychological composite of working memory (standardized beta, −0.276; se=0.116; P=0.02) and the frontostriatal rCBF response to cognitive challenge (standardized beta, 0.234; se=0.108; P=0.03) significantly predicted follow-up BP. Initial BP failed to significantly predict subsequent cognitive performance or rCBF. Changes in brain function may precede or co-occur with progression of BP toward hypertensive levels in midlife.



Myocardial Deformation Measured by 3-Dimensional Speckle Tracking in Children and Adolescents With Systemic Arterial HypertensionNovelty and Significance [Heart]

2017-11-08T10:40:41-08:00

Systemic arterial hypertension predisposes children to cardiovascular risk in childhood and adult life. Despite extensive study of left ventricular (LV) hypertrophy, detailed 3-dimensional strain analysis of cardiac function in hypertensive children has not been reported. The aim of this study was to evaluate LV mechanics (strain, twist, and torsion) in young patients with hypertension compared with a healthy control group and assess factors associated with functional measurements. Sixty-three patients (26 hypertension and 37 normotensive) were enrolled (mean age, 14.3 and 11.4 years; 54% men and 41% men, respectively). All children underwent clinical evaluation and echocardiographic examination, including 3-dimensional strain. There was no difference in LV volumes and ejection fraction between the groups. Myocardial deformation was significantly reduced in those with hypertension compared with controls. For hypertensive and normotensive groups, respectively, global longitudinal strain was −15.1±2.3 versus −18.5±1.9 (P<0.0001), global circumferential strain −15.2±3 versus −19.9±3.1 (<0.0001), global radial strain +44.0±11.3 versus 63.4±10.5 (P<0.0001), and global 3-dimensional strain −26.1±3.8 versus −31.5±3.8 (P<0.0001). Basal clockwise rotation, apical counterclockwise rotation, twist, and torsion were not significantly different. After multivariate regression analyses blood pressure, body mass index and LV mass maintained a significant relationship with measures of LV strain. Similar ventricular volumes and ejection fraction were observed in hypertensive and normotensive children, but children with hypertension had significantly lower strain indices. Whether reduced strain might predict future cardiovascular risk merits further longitudinal study.



Aldosterone Target NGAL (Neutrophil Gelatinase-Associated Lipocalin) Is Involved in Cardiac Remodeling After Myocardial Infarction Through NF{kappa}B PathwayNovelty and Significance [Heart]

2017-11-08T10:40:41-08:00

Myocardial infarction (MI) is accompanied by cardiac fibrosis, which contributes to cardiac dysfunction. Mineralocorticoid receptor (MR) antagonists have beneficial effects in patients with left ventricular (LV) dysfunction after MI. We herein investigated the role of the MR target NGAL (neutrophil gelatinase–associated lipocalin) in post-MI cardiac damages. Both higher baseline NGAL and a greater increase in serum NGAL levels during follow-up were significantly associated with lower 6-month LV ejection fraction recovery in a cohort of 119 post-MI patients, as assessed by cardiac magnetic resonance imaging. NGAL protein levels increased in the LV at 7 days post-MI in wild-type mice with MI. This effect was prevented by treatment with the nonsteroidal MR antagonist finerenone (1 mg/kg per day). NGAL knockout mice with MI had lower LV interstitial fibrosis and inflammation, better LV contractility and compliance, and greater stroke volume and cardiac output than wild-type mice with MI at 3 months post-MI. Aldosterone (10−8 mol/L) increased NGAL expression in cultured human cardiac fibroblasts. Cells treated with aldosterone or NGAL (500 ng/mL) showed increased production of collagen type I. The effects of aldosterone were abolished by finerenone (10−6 mol/L) or NGAL knockdown. This NGAL-mediated activity relied on NFκB (nuclear factor-κB) activation, confirmed by the use of the NFκB-specific inhibitor BAY11-7082, which prevented the effect of both aldosterone and NGAL on collagen type I production. In conclusion, NGAL, a downstream MR activation target, is a key mediator of post-MI cardiac damage. NGAL may be a potential therapeutic target in cardiovascular pathological situations in which MR is involved.



Relationship Between 24-Hour Ambulatory Central Systolic Blood Pressure and Left Ventricular MassNovelty and Significance [Heart]

2017-11-08T10:40:41-08:00

We investigated the relationship between left ventricular mass and brachial office as well as brachial and central ambulatory systolic blood pressure in 7 European centers. Central systolic pressure was measured with a validated oscillometric device, using a transfer function, and mean/diastolic pressure calibration. M-mode images were obtained by echocardiography, and left ventricular mass was determined by one single reader blinded to blood pressure. We studied 289 participants (137 women) free from antihypertensive drugs (mean age: 50.8 years). Mean office blood pressure was 145/88 mm Hg and mean brachial and central ambulatory systolic pressures were 127 and 128 mm Hg, respectively. Mean left ventricular mass was 93.3 kg/m2, and 25.6% had left ventricular hypertrophy. The correlation coefficient between left ventricular mass and brachial office, brachial ambulatory, and central ambulatory systolic pressure was 0.29, 0.41, and 0.47, respectively (P=0.003 for comparison between brachial office and central ambulatory systolic pressure and 0.32 for comparison between brachial and central ambulatory systolic pressure). The results were consistent for men and women, and young and old participants. The areas under the curve for prediction of left ventricular hypertrophy were 0.618, 0.635, and 0.666 for brachial office, brachial, and central ambulatory systolic pressure, respectively (P=0.03 for comparison between brachial and central ambulatory systolic pressure). In younger participants, central ambulatory systolic pressure was superior to both other measurements. Central ambulatory systolic pressure, measured with an oscillometric cuff, shows a strong trend toward a closer association with left ventricular mass and hypertrophy than brachial office/ambulatory systolic pressure.Clinical Trial Registration—URL: https://www.clinicaltrials.gov. Unique identifier: NCT01278732.



Apelin Is a Negative Regulator of Angiotensin II-Mediated Adverse Myocardial Remodeling and DysfunctionNovelty and Significance [Heart]

2017-11-08T10:40:41-08:00

The apelin pathway has emerged as a critical regulator of cardiovascular homeostasis and disease. However, the exact role of pyr1-apelin-13 in angiotensin (Ang) II–mediated heart disease remains unclear. We used apelin-deficient (APLN−/y) and apolipoprotein E knockout mice to evaluate the regulatory roles of pyr1-apelin-13. The 1-year aged APLN−/y mice developed myocardial hypertrophy and dysfunction with reduced angiotensin-converting enzyme 2 levels. Ang II infusion (1.5 mg kg−1 d−1) for 4 weeks potentiated oxidative stress, pathological hypertrophy, and myocardial fibrosis in young APLN−/y hearts resulting in exacerbation of cardiac dysfunction. Importantly, daily administration of 100 μg/kg pyr1-apelin-13 resulted in upregulated angiotensin-converting enzyme 2 levels, decreased superoxide production and expression of hypertrophy- and fibrosis-related genes leading to attenuated myocardial hypertrophy, fibrosis, and dysfunction in the Ang II–infused apolipoprotein E knockout mice. In addition, pyr1-apelin-13 treatment largely attenuated Ang II–induced apoptosis and ultrastructural injury in the apolipoprotein E knockout mice by activating Akt and endothelial nitric oxide synthase phosphorylation signaling. In cultured neonatal rat cardiomyocytes and cardiofibroblasts, exposure of Ang II decreased angiotensin-converting enzyme 2 protein and increased superoxide generation, cellular proliferation, and migration, which were rescued by pyr1-apelin-13, and Akt and endothelial nitric oxide synthase agonist stimulation. The increased superoxide generation and apoptosis in cultured cardiofibroblasts in response to Ang II were strikingly prevented by pyr1-apelin-13 which was partially reversed by cotreatment with the Akt inhibitor MK2206. In conclusion, pyr1-apelin-13 peptide pathway is a negative regulator of aging-mediated and Ang II–mediated adverse myocardial remodeling and dysfunction and represents a potential candidate to prevent and treat heart disease.



Identifying Hemodynamic Determinants of Pulse PressureNovelty and Significance [Central Pulse Pressure]

2017-11-08T10:40:41-08:00

We examined the ability of a simple reduced model comprising a proximal characteristic impedance linked to a Windkessel element to accurately predict central pulse pressure (PP) from aortic blood flow, verified that parameters of the model corresponded to physical properties, and applied the model to examine PP dependence on cardiac and vascular properties. PP obtained from the reduced model was compared with theoretical values obtained in silico and measured values in vivo. Theoretical values were obtained using a distributed multisegment model in a population of virtual (computed) subjects in which cardiovascular properties were varied over the pathophysiological range. In vivo measurements were in normotensive subjects during modulation of physiology with vasoactive drugs and in hypertensive subjects. Central PP derived from the reduced model agreed with theoretical values (mean difference±SD, −0.09±1.96 mm Hg) and with measured values (mean differences −1.95±3.74 and −1.18±3.67 mm Hg for normotensive and hypertensive subjects, respectively). Parameters extracted from the reduced model agreed closely with theoretical and measured physical properties. Central PP was seen to be determined mainly by total arterial compliance (inversely associated with central arterial stiffness) and ventricular dynamics: the blood volume ejected by the ventricle into the aorta up to time of peak pressure and blood flow into the aorta (corresponding to the rate of ventricular ejection) up to this time point. Increased flow and volume accounted for 20.1 mm Hg (52%) of the 39.0 mm Hg difference in PP between the upper and lower tertiles of the hypertensive subjects.



Aberrant Splicing Induced by Dysregulated Rbfox2 Produces Enhanced Function of CaV1.2 Calcium Channel and Vascular Myogenic Tone in HypertensionNovelty and Significance [Vascular Myogenic Tone]

2017-11-08T10:40:41-08:00

Calcium influx from activated voltage-gated calcium channel CaV1.2 in vascular smooth muscle cells is indispensable for maintaining myogenic tone and blood pressure. The function of CaV1.2 channel can be optimized by alternative splicing, one of post-transcriptional modification mechanisms. The splicing factor Rbfox2 is known to regulate the CaV1.2 pre-mRNA alternative splicing events during neuronal development. However, Rbfox2’s roles in modulating the key function of vascular CaV1.2 channel and in the pathogenesis of hypertension remain elusive. Here, we report that the proportion of CaV1.2 channels with alternative exon 9* is increased by 10.3%, whereas that with alternative exon 33 is decreased by 10.5% in hypertensive arteries. Surprisingly, the expression level of Rbfox2 is increased ≈3-folds, presumably because of the upregulation of a dominant-negative isoform of Rbfox2. In vascular smooth muscle cells, we find that knockdown of Rbfox2 dynamically increases alternative exon 9*, whereas decreases exon 33 inclusion of CaV1.2 channels. By patch-clamp studies, we show that diminished Rbfox2-induced alternative splicing shifts the steady-state activation and inactivation curves of vascular CaV1.2 calcium channel to hyperpolarization, which makes the window current potential to more negative. Moreover, siRNA-mediated knockdown of Rbfox2 increases the pressure-induced vascular myogenic tone of rat mesenteric artery. Taken together, our data indicate that Rbfox2 modulates the functions of vascular CaV1.2 calcium channel by dynamically regulating the expressions of alternative exons 9* and 33, which in turn affects the vascular myogenic tone. Therefore, our work suggests a key role for Rbfox2 in hypertension, which provides a rational basis for designing antihypertensive therapies.



Cardiovascular Structure and Function in Children With Middle Aortic Syndrome and Renal Artery StenosisNovelty and Significance [Middle Aortic Syndrome]

2017-11-08T10:40:41-08:00

Middle aortic syndrome (MAS) is a narrowing of the abdominal aorta, often in conjunction with renal artery stenosis (RAS). Structure and function of the cardiovascular system are not well understood. In a prospective cross-sectional study, 35 children with MAS or RAS or both (MAS/RAS) were compared with 140 age-, sex-, and body surface area–matched healthy children. Vascular assessment included carotid intima–media thickness and carotid distensibility using B-mode ultrasound and central and peripheral pulse wave velocities using applanation tonometry. Left ventricular structure and function were assessed by 2-dimensional and speckle-tracking echocardiography. Children with MAS or RAS were 12.5±3.0 years old at enrollment, and 50% were men. Carotid intima–media thickness (0.54±0.10 versus 0.44±0.05 mm; P<0.001) and central pulse wave velocities (5.58±1.83 versus 5.00±0.90 m/s; P=0.01) were significantly higher in children with disease compared with healthy children; however, after adjustment for systolic blood pressure z score, only carotid intima–media thickness remained significantly higher in the MAS/RAS group compared with the controls (β=0.07 [0.03, 0.10]). Peripheral pulse wave velocities and carotid distensibility were normal. Children with disease had significantly increased left ventricular mass and changes in diastolic function (lower E/a ratio and lower e′ velocities). Systolic parameters, including ejection fraction, global longitudinal and circumferential strain, were similar to controls. Our findings demonstrate that children with MAS or RAS have evidence of carotid and left ventricular remodeling, without peripheral arterial involvement, which suggests a localized disease process. Left ventricular systolic function is preserved; however, subtle changes in diastolic function are observed. Carotid vessel changes are consistent with a 5- to 10-year aging, which underscores the importance of blood pressure control.



Inhibition of Aneurysm Progression by Direct Renin Inhibition in a Rabbit ModelNovelty and Significance [Abdominal Aortic Aneurysm]

2017-11-08T10:40:41-08:00

Angiotensin II is thought to participate in aneurysm formation, because of its ability to induce and perpetuate inflammation in the aortic wall. Because activation of renin is the first step of the renin–angiotensin system, renin inhibition could inhibit all components of this system effectively. Therefore, we examined the hypothesis that direct inhibition of renin activity could decrease the expansion of aortic aneurysm using a rabbit model. Aortic dilatation was induced by incubation with elastase around the rabbit abdominal aorta. Continuous administration of a direct renin inhibitor, aliskiren, was started at 1 week before incubation with elastase and continued for 5 weeks. Treatment with aliskiren markedly inhibited tissue renin activation and resulted in a significant reduction in angiotensin I and II production in the aneurysm wall. Consequently, the inhibition of renin activity prevented the expansion of experimental aortic aneurysm associated with preservation of the medial layer, independent of its blood pressure–lowering effect. Administration of aliskiren led to the inhibition of activation of NF-κB (nuclear factor-κB), AP-1 (activator protein-1), and CREB (cAMP response element–binding protein), which are thought to cooperatively regulate the inflammatory gene expression profile associated with aneurysm formation. As a result, treatment with aliskiren inhibited macrophage accumulation through suppression of MCP-1 (monocyte chemoattractant protein-1) and CCL4 (C-C motif chemokine ligand 4) expression, and TNF-α (tumor necrosis factor-α) production and activation of MMP-2 (matrix metalloproteinase-2) and MMP-9 (matrix metalloproteinase-9) were also suppressed in the aneurysm wall. In addition, inhibition of (pro)renin receptor elevation was also observed after treatment with aliskiren. Direct inhibition of renin activity using aliskiren prevented the progression of aortic aneurysm, suggesting it as a therapeutic option to treat abdominal aortic aneurysm.



Longitudinal Blood Pressure in Late-Stage Chronic Kidney Disease and the Risk of End-Stage Kidney Disease or Mortality (Best Blood Pressure in Chronic Kidney Disease Study)Novelty and Significance [Kidney]

2017-11-08T10:40:41-08:00

Whether different methods of quantitating blood pressure (BP) in late chronic kidney disease better mimic pathophysiological processes and clinical outcomes remains unclear. In a retrospective study, we determined the association of BP with end-stage kidney disease (ESKD) and all-cause mortality with BP modeled at baseline versus longitudinally with time-varying Cox models as (1) current (most recent) clinic visit, (2) lag (visit immediately preceding the current), (3) cumulative (average of previous measurements), and (4) change from baseline to the most recent. Among 1203 (6913 visits) study patients, the mean age and baseline estimated glomerular filtration rate were 66 and 18 mL·min−1·1.73 m−2), and 40% were female. Patients had a mean of 6.7 BP measurements, 540 (44.8%) reached ESKD, and 141 (11.7%) died. For systolic BP >160, current (hazard ratio [HR], 1.67), cumulative (HR, 1.58), and a rise to >160 from baseline 120 to 160 (HR, 1.60) were associated with ESKD. Similarly, diastolic BP >85 was associated with ESKD when modeled as current (HR, 1.47), lag (HR, 1.63), cumulative (HR, 2.15), or change from baseline (rise to >85 from a baseline of 60–85; HR, 1.62). Both low SBP (<120), when modeled as current (HR, 1.59), cumulative exposure (HR, 1.76), persistently <120 (HR, 2.28), and high SBP (>140), when modeled as cumulative exposure, were associated with all-cause mortality. For diastolic BP, only cumulative >85 was significantly associated with mortality (HR, 2.75). Thus, in late-stage chronic kidney disease, persistently high or rises in systolic BP or diastolic BP are associated with risk of ESKD, whereas baseline BP measures did not convey information on risk.



Role of Kidneys in Sex Differences in Angiotensin II-Induced HypertensionNovelty and Significance [Kidney]

2017-11-08T10:40:41-08:00

The significance of kidneys in regulation of sodium and water balance and hemodynamics has been demonstrated both in patients and animal models. In the present study, we tested our hypothesis that kidneys play an essential role in control of sex differences in angiotensin II (Ang II)–dependent hypertension. Kidney transplantations (KTXs) were performed between male (M) and female (F) C57BL/6 mice (donor→recipient: F→F, M→M, F→M, and M→F). Radiotelemetry transmitters were implanted for measurement of mean arterial pressure during the infusion of Ang II (600 ng·kg−1·min−1). Gene expressions and inflammatory responses in the transplanted grafts were assessed. We found that same-sex–KTX mice still exhibited sex differences in Ang II–dependent hypertension (31.3±0.8 mm Hg in M→M versus 12.2±0.6 mm Hg in F→F), which were reduced between males and females when they received kidneys of the opposite sex (32.9±1 mm Hg in M→F versus 22.3±0.7 mm Hg in F→M). The sex differences in gene expressions, including AT1R (angiotensin II receptor, type 1), AT1R/AT2R, ET-1 (endothelin-1), ETA (endothelin receptor type A), NHE3 (sodium–hydrogen exchanger 3), α-ENaC (α-epithelial sodium channel), and γ-ENaC, were unaltered in same-sex KTXs and much lessened in cross-sex KTXs. In addition, the cross-sex KTXs exhibited more robust inflammatory responses reflected by higher expression of IL-6 (interleukin 6), TNFα (tumor necrosis factor α), and KC (keratinocyte-derived chemokine) than same-sex KTX. Our results indicate that kidneys play an essential role in sex differences of Ang II–dependent hypertension. KTX of male kidneys to females augmented the blood pressure response, whereas KTX of female kidneys to males attenuated the blood pressure response. The host’s extrarenal systems modulate expressions of many genes and inflammatory response, which may also contribute to the sex differences in blood pressure regulation.



Placental Growth Factor as a Prognostic Tool in Women With Hypertensive Disorders of PregnancyNovelty and Significance [Pregnancy and Hypertension]

2017-11-08T10:40:41-08:00

The PlGF (placental growth factor) has been largely demonstrated to be associated with the diagnosis of the hypertensive disorders of pregnancy (HDPs); however, it is unclear how useful it is for the prognosis of the condition. Our objective was to provide a summary of important findings of its prognostic ability by systematically reviewing studies that examined the ability of the PlGF, either independently or combined with other factors, to predict maternal and fetal complications resulting from the HDPs. We included studies published before January 30, 2017, reporting on the use of the PlGF as a prognostic test for women with confirmed HDPs or suspected preeclampsia. Of the 220 abstracts identified through MEDLINE, Embase, and CINAHL (Cumulative Index to Nursing and Allied Health Literature), 17 studies were eligible for our review. Prognostic performance was evaluated by sensitivity, specificity, likelihood ratios, and area under the receiver operating characteristic curve. PlGF showed moderate-to-high evidence (likelihood ratios of ≥5 or ≤0.2 or area under the receiver operating characteristic curves ≥0.70) for identifying women at the highest risk of preterm delivery or neonatal outcomes (10/12 studies) but showed no clinically useful performance for the prediction of adverse maternal outcomes. PlGF may aid in the management of women with HDPs to avert fetal complications. Future studies should determine an optimum threshold for the marker to guide delivery and should examine whether its use for predicting adverse maternal outcomes in women with HDPs can be improved.



Macrolides Blunt Aldosterone BiosynthesisNovelty and Significance [Aldosterone-Producing Adenoma]

2017-11-08T10:40:41-08:00

Aldosterone-producing adenoma (APA), a major subtype of primary hyperaldosteronism, the main curable cause of human endocrine hypertension, involves somatic mutations in the potassium channel Kir3.4 (KCNJ5) in 30% to 70% of cases, typically the more florid phenotypes. Because KCNJ5 mutated channels were reported to be specifically sensitive to inhibition by macrolide antibiotics, which concentration dependently blunts aldosterone production in HAC15 transfected with the G151R and L168R mutated channel, we herein tested the effect of clarithromycin on aldosterone synthesis and secretion in a pure population of aldosterone-secreting cells obtained by immunoseparation (CD56+ cells) from APA tissues with/without the 2 most common KCNJ5 mutations. From a large cohort of patients with an unambiguous APA diagnosis, we recruited those who were wild type (n=3) or had G151R (n=2) and L168R (n=2) mutations. We found that clarithromycin concentration dependently lowered CYP11B2 gene expression (by 60%) and aldosterone secretion (by 70%; P<0.001 for both) in CD56+ cells isolated ex vivo from KCNJ5 mutated APAs, although it was ineffective in CD56+ cells from wild-type APAs. By proving the principle that the oversecretion of aldosterone can be specifically blunted in APA cells ex vivo with G151R and L168R mutations, these results provide compelling evidence of the possibility of specifically correcting aldosterone excess in patients with APA carrying the 2 most common KCNJ5 somatic mutations.



Estimating the Cost of Preeclampsia in the Healthcare SystemNovelty and Significance [Preeclampsia]

2017-11-08T10:40:41-08:00

To estimate the cost of preeclampsia from the national health payer’s perspective using secondary data from the SCOPE study (Screening for Pregnancy End Points). SCOPE is an international observational prospective study of healthy nulliparous women with singleton pregnancies. Using data from the Irish cohort recruited between November 2008 and February 2011, all women with preeclampsia and a 10% random sample of women without preeclampsia were selected. Additional health service use data were extracted from the consenting participants’ medical records for maternity services which were not included in SCOPE. Unit costs were based on estimates from 3 existing Irish studies. Costs were extrapolated to a national level using a prevalence rate of 5% to 7% among nulliparous pregnancies. Within the cohort of 1774 women, 68 developed preeclampsia (3.8%) and 171 women were randomly selected as controls. Women with preeclampsia used higher levels of maternity services. The average cost of a pregnancy complicated by preeclampsia was €5243 per case compared with €2452 per case for an uncomplicated pregnancy. The national cost of preeclampsia is between €6.5 and €9.1 million per annum based on the 5% to 7% prevalence rate. Postpartum care was the largest contributor to these costs (€4.9–€6.9 million), followed by antepartum care (€0.9–€1.3 million) and peripartum care (€0.6–€0.7 million). Women with preeclampsia generate significantly higher maternity costs than women without preeclampsia. These cost estimates will allow policy-makers to efficiently allocate resources for this pregnancy-specific condition. Moreover, these estimates are useful for future research assessing the cost-effectiveness of preeclampsia screening and treatment.



Continued Investigation Into 17-OHPCNovelty and Significance [Preeclampsia]

2017-11-08T10:40:41-08:00

Preeclampsia is characterized by elevated TNF-α (tumor necrosis factor-α), antiangiogenic factors, such as sFlt-1 (soluble vascular endothelial growth factor receptor 1), increased uterine artery resistance index, and decreased of NO during pregnancy. Previously we showed that 17-hydroxyprogesterone caproate (17-OHPC) administered into reduced uterine perfusion pressure (RUPP) rats on day 18 of gestation improved hypertension without improving pup weight. We hypothesized that earlier administration of 17-OHPC on day 15 of gestation could improve pathophysiology of preeclampsia and fetal outcomes in response to placental ischemia. Carotid catheters were inserted on day 18, and mean arterial blood pressure and samples were collected on day 19. Mean arterial blood pressure in normal pregnant rats was 102±2, 105±2 in normal pregnant+day 15 of gestation (GD15) 17-OHPC, 127±2 in RUPP and 112±1 mm Hg in RUPP+GD15 17-OHPC, P<0.05. Pup weight and litter size were improved from 1.9±0.05, 10.1±1.4 in RUPP to 2.1±0.07 g and 13.2±0.6 in RUPP+GD15 17-OHPC, P<0.05. Uterine artery resistance index was 0.8±0.03 in RUPP, which was decreased to 0.6±0.04 in RUPP+GD15 17-OHPC, P<0.05. Plasma TNF-α levels were 164±34 in RUPP and blunted to 29±9 pg/mL in RUPP+GD15 17-OHPC, P<0.05. Plasma nitrate–nitrite levels were 10.8±2.3 in RUPP rats and significantly increased to 25.5±5.2 µmol/L in RUPP+GD15 17-OHPC, P<0.05. sFlt-1 levels were 386±141 in RUPP rats, which were reduced to 110.2±11 in RUPP+17-OHPC, P<0.05. These data indicate that GD15 17-OHPC improves pathophysiology in RUPP rats, possibly via improving sFlt-1 reduced NO during pregnancy.



Dysregulation of Aldosterone Secretion in Mast Cell–Deficient MiceNovelty and Significance [Renin-Angiotensin System]

2017-11-08T10:40:41-08:00

Resident adrenal mast cells have been shown to activate aldosterone secretion in rat and man. Especially, mast cell proliferation has been observed in adrenal tissues from patients with aldosterone-producing adrenocortical adenoma. In the present study, we show that the activity of adrenal mast cells is stimulated by low-sodium diet and correlates with aldosterone synthesis in C57BL/6 and BALB/c mice. We have also investigated the regulation of aldosterone secretion in mast cell–deficient C57BL/6 KitW-sh/W-sh mice in comparison with wild-type C57BL/6 mice. KitW-sh/W-sh mice submitted to normal sodium diet had basal plasma aldosterone levels similar to those observed in wild-type animals. Conversely, low-sodium diet unexpectedly induced an exaggerated aldosterone response, which seemed to result from an increase in adrenal renin and angiotensin type 1 receptor expression. Severe hyperaldosteronism was associated with an increase in systolic blood pressure and marked hypokalemia, which favored polyuria. Adrenal renin and angiotensin type 1 receptor overexpression may represent a compensatory mechanism aimed at activating aldosterone production in the absence of mast cells. Finally, C57BL/6 KitW-sh/W-sh mice represent an unexpected animal model of primary aldosteronism, which has the particularity to be triggered by sodium restriction.



Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle ArteriesNovelty and Significance [G Protein Signaling and Vasoconstriction]

2017-11-08T10:40:41-08:00

Studies suggest that arteriolar pressure–induced vasoconstriction can be initiated by GPCRs (G protein–coupled receptors), including the AT1R (angiotensin II type 1 receptor). This raises the question, are such mechanisms regulated by negative feedback? The present studies examined whether RGS (regulators of G protein signaling) proteins in vascular smooth muscle cells are colocalized with the AT1R when activated by mechanical stress or angiotensin II and whether this modulates AT1R-mediated vasoconstriction. To determine whether activation of the AT1R recruits RGS5, an in situ proximity ligation assay was performed in primary cultures of cremaster muscle arteriolar vascular smooth muscle cells treated with angiotensin II or hypotonic solution in the absence or presence of candesartan (an AT1R blocker). Proximity ligation assay results revealed a concentration-dependent increase in trafficking/translocation of RGS5 toward the activated AT1R, which was attenuated by candesartan. In intact arterioles, knockdown of RGS5 enhanced constriction to angiotensin II and augmented myogenic responses to increased intraluminal pressure. Myogenic constriction was attenuated to a higher degree by candesartan in RGS5 siRNA-transfected arterioles, consistent with RGS5 contributing to downregulation of AT1R-mediated signaling. Further, translocation of RGS5 was impaired in vascular smooth muscle cells of spontaneously hypertensive rats. This is consistent with dysregulated (RGS5-mediated) AT1R signaling that could contribute to excessive vasoconstriction in hypertension. In intact vessels, candesartan reduced myogenic vasoconstriction to a greater extent in spontaneously hypertensive rats compared with controls. Collectively, these findings suggest that AT1R activation results in translocation of RGS5 toward the plasma membrane, limiting AT1R-mediated vasoconstriction through its role in Gq/11 protein–dependent signaling.



Do We Need a Patient-Centered Target for Systolic Blood Pressure in Hypertensive Patients With Type 2 Diabetes Mellitus?Novelty and Significance [Type 2 Diabetes and Hypertension]

2017-11-08T10:40:41-08:00

The current trend on diabetes mellitus management advocates replacing the paradigm from a uniform to an individualized patient-centered systolic blood pressure (SBP), but there is no consensus on the achieved treatment goals of SBP level. The study aimed at evaluating the association between SBP and the risk of cardiovascular diseases (CVD) and all-cause mortality for diabetic patients to identify patient-centered treatment targets. A retrospective study was conducted on 95 086 Chinese adult primary care patients with type 2 diabetes mellitus and hypertension. Using the average of the annual SBP records (updated SBP) over a median follow-up of 5.9 years, the risks of overall CVD, all-cause mortality, and their composite associated with SBP were evaluated using Cox proportional hazards regression. Subgroup analysis was performed on the incidence of CVD by stratifying patient’s baseline characteristics. The SBP range for the lowest risk of CVD and all-cause mortality was 130 to 134 mm Hg among type 2 diabetes mellitus population. A J-shaped curvilinear relationship was identified between SBP and risk of CVD and all-cause mortality, irrespective of patients’ characteristics. The findings showed that all patients with SBP <125 mm Hg or ≥140 mm Hg had an increased risk of CVD and mortality. This large territory-wide study showed the level of achieved SBP of 125 to 139 mm Hg in pharmacological therapy, irrespective of patients’ characteristics, suggested that the SBP treatment goal of <140 mm Hg and individualized SBP target may not be necessary in diabetic management.



Effect of CPAP, Weight Loss, or CPAP Plus Weight Loss on Central Hemodynamics and Arterial StiffnessNovelty and Significance [Obstructive Sleep Apnea]

2017-11-08T10:40:41-08:00

Obesity and obstructive sleep apnea tend to coexist. Little is known about the effects of obstructive sleep apnea, obesity, or their treatment on central aortic pressures and large artery stiffness. We randomized 139 adults with obesity (body mass index >30 kg/m2) and moderate-to-severe obstructive sleep apnea to (1) continuous positive airway pressure (CPAP) therapy (n=45), (2) weight loss (WL) therapy (n=48), or (3) combined CPAP and WL (n=46) for 24 weeks. We assessed the effect of these interventions on central pressures and carotid–femoral pulse wave velocity (a measure of large artery stiffness), measured with arterial tonometry. Central systolic pressure was reduced significantly only in the combination arm (−7.4 mm Hg; 95% confidence interval, −12.5 to −2.4 mm Hg; P=0.004), without significant reductions detected in either the WL-only (−2.3 mm Hg; 95% confidence interval, −7.5 to 3.0; P=0.39) or the CPAP-only (−3.1 mm Hg; 95% confidence interval, −8.3 to 2.0; P=0.23) arms. However, none of these interventions significantly changed central pulse pressure, pulse pressure amplification, or the central augmentation index. The change in mean arterial pressure (P=0.008) and heart rate (P=0.027) induced by the interventions was significant predictors of the change in carotid–femoral pulse wave velocity. However, after adjustment for mean arterial pressure and heart rate, no significant changes in carotid–femoral pulse wave velocity were observed in any group. In obese subjects with obstructive sleep apnea, combination therapy with WL and CPAP is effective in reducing central systolic pressure. However, this effect is largely mediated by changes in mean, rather than central pulse pressure. WL and CPAP, alone or in combination, did not reduce large artery stiffness in this population.Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00371293.



Enjoyment of Spicy Flavor Enhances Central Salty-Taste Perception and Reduces Salt Intake and Blood PressureNovelty and Significance [Behavioral Intervention for Reducing Salt Intake]

2017-11-08T10:40:41-08:00

High salt intake is a major risk factor for hypertension and is associated with cardiovascular events. Most countries exhibit a traditionally high salt intake; thus, identification of an optimal strategy for salt reduction at the population level may have a major impact on public health. In this multicenter, random-order, double-blind observational and interventional study, subjects with a high spice preference had a lower salt intake and blood pressure than subjects who disliked spicy food. The enjoyment of spicy flavor enhanced salt sensitivity and reduced salt preference. Salt intake and salt preference were related to the regional metabolic activity in the insula and orbitofrontal cortex (OFC) of participants. Administration of capsaicin—the major spicy component of chili pepper—enhanced the insula and OFC metabolic activity in response to high-salt stimuli, which reversed the salt intensity–dependent differences in the metabolism of the insula and OFC. In animal study, OFC activity was closely associated with salt preference, and salty-taste information processed in the OFC was affected in the presence of capsaicin. Thus, interventions related to this region may alter the salt preference in mice through fiber fluorometry and optogenetic techniques. In conclusion, enjoyment of spicy foods may significantly reduce individual salt preference, daily salt intake, and blood pressure by modifying the neural processing of salty taste in the brain. Application of spicy flavor may be a promising behavioral intervention for reducing high salt intake and blood pressure.