Pankaj Arora

Cardiac Natriuretic Peptides, Obesity, and Insulin Resistance: Evidence from Two Community-Based Studies

BACKGROUND The natriuretic peptides play an important role in salt homeostasis and blood pressure regulation. It has been suggested that obesity promotes a relative natriuretic peptide deficiency, but this has been a variable finding in prior studies and the cause is unknown. AIM The aim of this study was to examine the association between obesity and natriuretic peptide levels and evaluate the role of hyperinsulinemia and testosterone as mediators of this interaction. METHODS We studied 7770 individuals from the Framingham Heart Study (n = 3833, 54% women) and the Malmö Diet and Cancer study (n = 3918, 60% women). We examined the relation of plasma N-terminal pro-B-type natriuretic peptide levels (N-BNP) with obesity, insulin resistance, and various metabolic subtypes. RESULTS Obesity was associated with 6-20% lower levels of N-BNP (P < 0.001 in Framingham, P = 0.001 in Malmö), whereas insulin resistance was associated with 10-30% lower levels of N-BNP (P < 0.001 in both cohorts). Individuals with obesity who were insulin sensitive had only modest reductions in N-BNP compared with nonobese, insulin-sensitive individuals. On the other hand, individuals who were nonobese but insulin resistant had 26% lower N-BNP in Framingham (P < 0.001) and 10% lower N-BNP in Malmö (P < 0.001), compared with nonobese and insulin-sensitive individuals. Adjustment for serum-free testosterone did not alter these associations. CONCLUSIONS In both nonobese and obese individuals, insulin resistance is associated with lower natriuretic peptide levels. The relative natriuretic peptide deficiency seen in obesity could be partly attributable to insulin resistance, and could be one mechanism by which insulin resistance promotes hypertension.

Vitamin D Therapy in Individuals With Prehypertension or Hypertension The DAYLIGHT Trial

Background— A large body of epidemiological and experimental evidence suggests that vitamin D deficiency may promote hypertension. This raises the possibility that vitamin D supplementation could be a simple intervention to reduce blood pressure, but data from prospective, randomized trials are limited. Methods and Results— A double-blind, randomized, controlled trial was conducted at 4 sites in the United States. We enrolled 534 individuals 18 to 50 years of age with low vitamin D status (25-hydroxyvitamin D levels ⩽25 ng/mL) and systolic blood pressure of 120 to 159 mm Hg. Participants were randomized to high-dose (4000 IU/d) versus low-dose (400 IU/d) oral vitamin D3 for 6 months. The primary end point was change in mean 24-hour systolic blood pressure. Secondary end points included change in ambulatory diastolic blood pressure and clinic systolic and diastolic blood pressures. The median age was 38 years, and 62% of participants were men. Forty-six percent of participants were white, and 48% were black. The median 25-hydroxyvitamin D level at baseline was 15.3 ng/mL. Four-hundred fifty-five participants (85%) had at least 1 follow-up blood pressure measurement; 383 participants (72%) completed the full 6-month study. At the end of the study, there was no significant difference in the primary end point (change in mean 24-hour systolic blood pressure, −0.8 versus −1.6 mm Hg in the high-dose and low-dose arms; P=0.71) or in any of the secondary end points. Furthermore, there was no evidence of association between change in 25-hydroxyvitamin D and change in 24-hour systolic blood pressure at 6 months (Spearman correlation coefficient, −0.05, P=0.34). Results were consistent across prespecified subgroups. Conclusions— Vitamin D supplementation did not reduce blood pressure in individuals with prehypertension or stage I hypertension and vitamin D deficiency. Our findings suggest that the association between vitamin D status and elevated blood pressure noted in observational studies is not causal. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01240512.

Implantable Cardioverter-Defibrillator for Nonischemic Cardiomyopathy: An Updated Meta-Analysis

The use of implantable cardioverter-defibrillators (ICDs) has been a major advancement in patients with ischemic cardiomyopathy with reduced ejection fraction 1100 patients with NICM on optimal medical therapy (OMT) and cardiac resynchronization therapy (CRT) to ICD versus no ICD for primary prevention of sudden cardiac death, revealed no difference in all-cause mortality between the 2 groups at 5-year follow-up.4 Although the primary results of DANISH were neutral, the ICD group showed reduction in incidence of sudden cardiac death by half, and there was an interaction …

Soluble Guanylate Cyclase α1–Deficient Mice: A Novel Murine Model for Primary Open Angle Glaucoma

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the α1 subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase α1–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the α1 and β1 subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.

Blood pressure and human genetic variation in the general population.

Purpose of review Hypertension is a complex trait with multiple environmental and genetic contributors. Until recently, linkage studies of rare Mendelian disorders of hypertension and hypotension have produced the most notable progress toward understanding the heritable basis of blood pressure (BP). Association studies to identify common variants have been limited in the past by small sample sizes and most findings have lacked replication. Recent findings Recently, well powered, targeted candidate gene and genome-wide association studies have reported reproducible associations between rare and common genetic variants and BP and hypertension at the population level. Summary Identification of novel genes will lead to an improved understanding of BP regulation and the potential for novel therapies.

Effect of Phosphodiesterase Inhibition on Insulin Resistance in Obese Individuals

Background Obesity is associated with cardiometabolic disease, including insulin resistance (IR) and diabetes. Cyclic guanosine monophosphate (cGMP) signaling affects energy balance, IR, and glucose metabolism in experimental models. We sought to examine effects of phosphodiesterase‐5 inhibition with tadalafil on IR in a pilot study of obese nondiabetic individuals. Methods and Results We conducted a randomized, double‐blinded, placebo‐controlled trial of adults age 18 to 50 years with obesity and elevated fasting insulin levels (≥10 μU/mL). Participants were randomized to tadalafil 20 mg daily or placebo for 3 months. Oral glucose tolerance tests were performed, and the effect of tadalafil on IR was examined. A total of 53 participants (mean age, 33 years; body mass index [BMI], 38 kg/m2) were analyzed, 25 randomized to tadalafil and 28 to placebo. In the overall sample, measures of IR did not differ between tadalafil and placebo groups at 3 months. However, in individuals with severe obesity (BMI ≥36.2 kg/m2), tadalafil use was associated with improved IR (homeostatic model assessment for IR), compared to placebo (P=0.02, respectively). Furthermore, one measure of β‐cell compensation for IR (oral disposition index) improved with tadalafil in the overall sample (P=0.009) and in the subgroup with severe obesity (P=0.01). Conclusion Results of this pilot study did not show improvements in IR with tadalafil, compared to placebo. However, tadalafil may have favorable effects on β‐cell compensation, particularly in individuals with severe obesity. Future studies evaluating the potential metabolic benefits of cGMP modulation in obesity are warranted. Clinical Trial Registration URL: ClinicalTrials.gov. Unique Identifier: NCT01444651.

Weight Loss, Saline Loading, and the Natriuretic Peptide System

Background In epidemiologic studies, obesity has been associated with reduced natriuretic peptide (NP) concentrations. Reduced NP production could impair the ability of obese individuals to respond to salt loads, increasing the risk of hypertension and other disorders. We hypothesized that weight loss enhances NP production before and after salt loading. Methods and Results We enrolled 15 obese individuals (mean BMI 45±5.4 kg/m2) undergoing gastric bypass surgery. Before and 6 months after surgery, subjects were admitted to the clinical research center and administered a large‐volume intravenous saline challenge. Echocardiography and serial blood sampling were performed. From the pre‐operative visit to 6 months after surgery, subjects had a mean BMI decrease of 27%. At the 6‐month visit, N‐terminal pro‐atrial NP (Nt‐proANP) levels were 40% higher before, during, and after the saline infusion, compared with levels measured at the same time points during the pre‐operative visit (P<0.001). The rise in Nt‐pro‐ANP induced by the saline infusion (≈50%) was similar both before and after surgery (saline, P<0.001; interaction, P=0.2). Similar results were obtained for BNP and Nt‐proBNP; resting concentrations increased by 50% and 31%, respectively, after gastric bypass surgery. The increase in NP concentrations after surgery was accompanied by significant decreases in mean arterial pressure (P=0.004) and heart rate (P<0.001), and an increase in mitral annular diastolic velocity (P=0.02). Conclusion In obese individuals, weight loss is associated with a substantial increase in the “setpoint” of circulating NP concentrations. Higher NP concentrations could contribute to an enhanced ability to handle salt loads after weight loss.

Comparison of Approaches to Revascularization in Patients With Multivessel Coronary Artery Disease Presenting With ST-Segment Elevation Myocardial Infarction: Meta-analyses of Randomized Control Trials.

Background Significant controversy exists regarding the best approach for nonculprit vessel revascularization in patients with multivessel coronary artery disease presenting with ST‐segment elevation myocardial infarction. We conducted a systematic investigation to pool data from current randomized controlled trials (RCTs) to assess optimal treatment strategies in this patient population. Methods and Results A comprehensive search of SCOPUS from inception through May 2015 was performed using predefined criteria. We compared efficacy and safety outcomes of different approaches by categorizing the studies into 3 groups: (1) complete revascularization (CR) versus culprit lesion revascularization (CL) at index hospitalization, (2) CR at index hospitalization versus staged revascularization (SR) of nonculprit vessels at a separate hospitalization, and (3) comparison of SR versus CL. Eight eligible RCTs met the inclusion criteria: (1) CR versus CL (6 RCTs, n=1727) (2) CR versus SR (3 RCTs, n=311), and (3) SR versus CL (1 RCT, n=149). We observed significantly lower rates of major adverse cardiovascular events, revascularization, and repeat percutaneous coronary interventions among patients treated with CR and SR compared with a CL approach (P<0.05). The rates of all‐cause mortality, cause‐specific mortality, major bleeding, reinfarction, stroke, and contrast‐induced nephropathy did not differ in the CR arm compared with the CL arm. The rates of these outcomes were similar in the CR and SR arms. Conclusion Results suggest that CR and SR compared with CL reduce major adverse cardiovascular event and revascularization rates primarily by lowering repeated percutaneous coronary intervention rates. We did not observe any increase in the rate of adverse events while using a CR or SR strategy compared with a CL approach. Current guidelines discouraging CR need to be reevaluated, and clinical judgment should prevail in treating multivessel coronary artery disease patients with ST‐segment elevation myocardial infarction as data from larger RCTs accumulate.

Long Noncoding Mhrt RNA: Molecular Crowbar Unravel Insights into Heart Failure Treatment

Pathological cardiac hypertrophy and heart failure are known to involve changes in cardiac gene expression, particularly downregulation of Myh6 expression and upregulation of Myh7 expression.1 Previous studies have shown that the Brahma Related Gene 1 (Brg1)–histone deacetylase (Hdac)–poly (ADP ribose) polymerase (Parp) chromatin remodeling complex regulates the change in the ratio of Myh6 to Myh7 expression during cardiac stress.2 In the current study, Han et al3 add another layer to this mechanism by presenting evidence that a lncRNA interferes with the ability of the Brg1 complex to interact with its genomic DNA targets, including Myh6 and Myh7 , preventing the aberrant reinduction of fetal-gene expression seen in cardiac hypertrophy and heart failure. The authors3 performed rapid amplification of complementary DNA ends on RNA isolated from murine adult ventricles to identify a cluster of lncRNAs, which the authors named myosin heavy-chain-associated RNA transcripts ( Myheart , or Mhrt ), from the Myh7 loci. By using quantitative polymerase chain reaction with reverse transcription (RT-qPCR), the authors examined the expression levels of Mhrt in various murine tissues and compared the expression levels of Mhrt to the mRNA levels of Myh6 and Myh7 in murine hearts at different ages. The authors also performed RNA in situ hybridization to determine the cellular distribution of Mhrt in adult murine heart tissues. To study the role of Mhrt in cardiac hypertrophy and heart failure, the authors induced pressure overload by subjecting mice to transaortic constriction (TAC) and used RT-qPCR to measure the expression levels of Mhrt at different time points after TAC. The authors then focused on the most abundant Mhrt in murine adult ventricles ( Mhrt779 ) and generated transgenic mice overexpressing Mhrt779 (Tg779 mice) in a doxycycline-dependent and cardiomyocyte-specific manner. The authors subjected Tg779 mice to TAC to see whether overexpression of Mhrt779 could protect …

Vitamin D Supplementation Modulates T Cell–Mediated Immunity in Humans: Results from a Randomized Control Trial

CONTEXT Although studies have linked vitamin D deficiency with immune-mediated diseases, data demonstrating a direct effect on T-cell function are sparse. OBJECTIVE Our objective was to determine whether oral vitamin D3 influences T-cell activation in humans with vitamin D deficiency. DESIGN This was a single-center ancillary study within Vitamin D Therapy in Individuals at High Risk of Hypertension, a double-blind, multicenter, randomized controlled trial. SETTING This study was undertaken in a single academic medical center. PARTICIPANTS Adults with vitamin D deficiency and untreated pre- or early stage I hypertension were included. INTERVENTION In Vitamin D Therapy in Individuals at High Risk of Hypertension, participants were randomized to either low- (400 IU daily) or high- (4000 IU daily) dose oral vitamin D3 for 6 months. In this ancillary study of 38 patients, we measured CD4+ T-cell activation estimated by intracellular ATP release after stimulation of whole blood with plant lectin phytohemagglutinin collected at baseline (pretreatment) and 2-month follow-up. MAIN OUTCOME MEASURE Determining whether ATP level changes were significantly different between treatment groups was the main outcome measure. RESULTS Treatment with 4000 IU of vitamin D3 decreased intracellular CD4+ ATP release by 95.5 ng/ml (interquartile range, -219.5 to 105.8). In contrast, 400 IU of vitamin D3 decreased intracellular CD4+ ATP release by 0.5 ng/ml (interquartile range, -69.2 to 148.5). In a proportional odds model, high-dose vitamin D3 was more likely than low-dose vitamin D3 to decrease CD4+ ATP release (odds ratio, 3.43; 95% confidence interval, 1.06-1.11). CONCLUSIONS In this ancillary study of a randomized controlled trial, we found that high-dose vitamin D3 significantly reduced CD4+ T-cell activation compared to low-dose vitamin D3, providing human evidence that vitamin D can influence cell-mediated immunity.