Diastolic dysfunction in people with HIV without known cardiovascular risk factors in Western Kenya.

OBJECTIVES: Diastolic dysfunction (DD) has been reported to be highly prevalent in people living with HIV (PLWH) on antiretroviral therapy (ART) leading to the hypothesis that it may be an early marker of myocardial disease. Our objective was to evaluate the prevalence of DD in people living with human immunodeficiency virus without known history of diabetes or hypertension in Western Kenya. METHODS: In this cross-sectional study in western Kenya, 110 PLWH on ART and without known diabetes or hypertension were matched for age ±5 years and sex to HIV-uninfected controls. Study participants underwent a comprehensive two-dimensional echocardiogram and laboratory testing. RESULTS: The mean (SD) age in the HIV-positive group was 42.9 (8.6) years compared with 42.1 (12.9) years in the HIV-uninfected group. Mean (SD) CD4 +T cell count for the HIV-positive group was 557 (220) cells/ml. Mean systolic and diastolic blood pressures were within the normal range and comparable between the two groups. Mean body mass index was 25.2 (5.4) kg/m2 and 26.3 (5.4) kg/m2 in HIV-positive and uninfected participants, respectively. There was only 1 (0.9 %) case of DD in each group. Despite low prevalence of DD, PLWH had 5.76 g/m2 higher left ventricular mass index (p=0.01) and 2.77 mL/m2 larger left atrial volume (p=0.02) compared with the HIV-negative group after adjusting for risk factors associated with DD. CONCLUSION: Contrary to prior reports, DD in PLWH was low. Environmental and cardiovascular disease risk factors such as diabetes and hypertension may be significant modifiers for development and progression of DD in PLWH.

Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart.

Branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) are elevated in an array of cardiometabolic diseases. Here we demonstrate that the major metabolic fate of uniformly-13C-labeled α-ketoisovalerate ([U-13C]KIV) in the heart is reamination to valine. Activation of cardiac branched-chain α-ketoacid dehydrogenase (BCKDH) by treatment with the BCKDH kinase inhibitor, BT2, does not impede the strong flux of [U-13C]KIV to valine. Sequestration of BCAA and BCKA away from mitochondrial oxidation is likely due to low levels of expression of the mitochondrial BCAA transporter SLC25A44 in the heart, as its overexpression significantly lowers accumulation of [13C]-labeled valine from [U-13C]KIV. Finally, exposure of perfused hearts to levels of BCKA found in obese rats increases phosphorylation of the translational repressor 4E-BP1 as well as multiple proteins in the MEK-ERK pathway, leading to a doubling of total protein synthesis. These data suggest that elevated BCKA levels found in obesity may contribute to pathologic cardiac hypertrophy via chronic activation of protein synthesis.

Muscle-Liver Trafficking of BCAA-Derived Nitrogen Underlies Obesity-Related Glycine Depletion.

Glycine levels are inversely associated with branched-chain amino acids (BCAAs) and cardiometabolic disease phenotypes, but biochemical mechanisms that explain these relationships remain uncharted. Metabolites and genes related to BCAA metabolism and nitrogen handling were strongly associated with glycine in correlation analyses. Stable isotope labeling in Zucker fatty rats (ZFRs) shows that glycine acts as a carbon donor for the pyruvate-alanine cycle in a BCAA-regulated manner. Inhibition of the BCAA transaminase (BCAT) enzymes depletes plasma pools of alanine and raises glycine levels. In high-fat-fed ZFRs, dietary glycine supplementation raises urinary acyl-glycine content and lowers circulating triglycerides but also results in accumulation of long-chain acyl-coenzyme As (acyl-CoAs), lower 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in muscle, and no improvement in glucose tolerance. Collectively, these studies frame a mechanism for explaining obesity-related glycine depletion and also provide insight into the impact of glycine supplementation on systemic glucose, lipid, and amino acid metabolism.

Dietary branched-chain amino acid restriction alters fuel selection and reduces triglyceride stores in hearts of Zucker fatty rats.

Elevations in circulating levels of branched-chain amino acids (BCAAs) are associated with a variety of cardiometabolic diseases and conditions. Restriction of dietary BCAAs in rodent models of obesity lowers circulating BCAA levels and improves whole-animal and skeletal-muscle insulin sensitivity and lipid homeostasis, but the impact of BCAA supply on heart metabolism has not been studied. Here, we report that feeding a BCAA-restricted chow diet to Zucker fatty rats (ZFRs) causes a shift in cardiac fuel metabolism that favors fatty acid relative to glucose catabolism. This is illustrated by an increase in labeling of acetyl-CoA from [1-13C]palmitate and a decrease in labeling of acetyl-CoA and malonyl-CoA from [U-13C]glucose, accompanied by a decrease in cardiac hexokinase II and glucose transporter 4 protein levels. Metabolomic profiling of heart tissue supports these findings by demonstrating an increase in levels of a host of fatty-acid-derived metabolites in hearts from ZFRs and Zucker lean rats (ZLRs) fed the BCAA-restricted diet. In addition, the twofold increase in cardiac triglyceride stores in ZFRs compared with ZLRs fed on chow diet is eliminated in ZFRs fed on the BCAA-restricted diet. Finally, the enzymatic activity of branched-chain ketoacid dehydrogenase (BCKDH) is not influenced by BCAA restriction, and levels of BCAA in the heart instead reflect their levels in circulation. In summary, reducing BCAA supply in obesity improves cardiac metabolic health by a mechanism independent of alterations in BCKDH activity.

Clinical Updates in Women's Health Care Summary: Evaluation and Management of Lipid Disorders: Primary and Preventive Care Review.

Cardiovascular disease (CVD) remains the leading cause of mortality for women, and only a small percentage of women have optimally managed risk factors. One of the strongest risk factors for CVD is an increased lipid level. Many women seek primary care from obstetrician-gynecologists who often identify and provide initial management of dyslipidemia in these women. Thus, it is imperative that obstetrician-gynecologists become familiar with the identification and treatment of women with dyslipidemia to minimize their future risk of CVD. This monograph provides a brief primer on the epidemiology, pathophysiology, diagnosis, and management of dyslipidemia in women, as it pertains to CVD risk.

Clinical and Echocardiographic Predictors of Outcomes in Patients With Pulmonary Hypertension.

In pulmonary hypertension (PH), measurement of various echocardiographic parameters that assess right heart function is recommended by current clinical guidelines. Limited data exists on the combined value of clinical and echocardiographic parameters in precapillary PH in the modern era of therapy. We examined the association of clinical and echocardiographic parameters with surrogate outcomes (6-minute walk distance) and hard outcomes (hospitalization or death) in patients with precapillary PH. A cohort of patients with an established diagnosis of precapillary PH who underwent transthoracic echocardiography at the Duke Echo Lab were prospectively enrolled from 2010 to 2014. Univariable and multivariable models were constructed to examine the relation of clinical and echocardiographic parameters with surrogate and hard outcomes. Of the 98 patients with analyzable echocardiograms with good image quality, 85 were woman, mean age was 59.4 years, and 47% had ≥World Health Organization functional class III symptoms. The mean 6-minute walk distance was 354(±132) m, and 83% were on pulmonary arterial hypertension medications. At 24 months, the cumulative incidence rate for hospitalization or death was 47%. In univariable analyses, the REVEAL (Registry to Evaluate Early and Long-term PAH Disease Management) risk score (HR 1.72 per 1 SD (2.81) increment, 95% CI 1.34, 2.22; p=<0.001), RV global longitudinal strain (RVGLS) (HR 1.54 per 1 SD (5.31) worsening, 95% CI , 2.12; p=0.008) and log-2 NT proBNP (HR 1.43 per 1-fold increase, 95% CI 1.25, 1.63; p=<0.001) were significantly associated with hospitalization or death.

Propionate-induced changes in cardiac metabolism, notably CoA trapping, are not altered by l-carnitine.

High concentrations of propionate and its metabolites are found in several diseases that are often associated with the development of cardiac dysfunction, such as obesity, diabetes, propionic acidemia, and methylmalonic acidemia. In the present work, we employed a stable isotope-based metabolic flux approach to understand propionate-mediated perturbation of cardiac energy metabolism. Propionate led to accumulation of propionyl-CoA (increased by ~101-fold) and methylmalonyl-CoA (increased by 36-fold). This accumulation caused significant mitochondrial CoA trapping and inhibited fatty acid oxidation. The reduced energy contribution from fatty acid oxidation was associated with increased glucose oxidation. The enhanced anaplerosis of propionate and CoA trapping altered the pool sizes of tricarboxylic acid cycle (TCA) metabolites. In addition to being an anaplerotic substrate, the accumulation of proprionate-derived malate increased the recycling of malate to pyruvate and acetyl-CoA, which can enter the TCA for energy production. Supplementation of 3 mM l-carnitine did not relieve CoA trapping and did not reverse the propionate-mediated fuel switch. This is due to new findings that the heart appears to lack the specific enzyme catalyzing the conversion of short-chain (C3 and C4) dicarboxylyl-CoAs to dicarboxylylcarnitines. The discovery of this work warrants further investigation on the relevance of dicarboxylylcarnitines, especially C3 and C4 dicarboxylylcarnitines, in cardiac conditions such as heart failure.

Myocardial insulin resistance induced by high fat feeding in heart failure is associated with preserved contractile function.

Previous studies have reported that high fat feeding in mild to moderate heart failure (HF) results in the preservation of contractile function. Recent evidence has suggested that preventing the switch from fatty acid to glucose metabolism in HF may ameliorate dysfunction, and insulin resistance is one potential mechanism for regulating substrate utilization. This study was designed to determine whether peripheral and myocardial insulin resistance exists with HF and/or a high-fat diet and whether myocardial insulin signaling was altered accordingly. Rats underwent coronary artery ligation (HF) or sham surgery and were randomized to normal chow (NC; 14% kcal from fat) or a high-fat diet (SAT; 60% kcal from fat) for 8 wk. HF + SAT animals showed preserved systolic (+dP/dt and stroke work) and diastolic (-dP/dt and time constant of relaxation) function compared with HF + NC animals. Glucose tolerance tests revealed peripheral insulin resistance in sham + SAT, HF + NC, and HF + SAT animals compared with sham + NC animals. PET imaging confirmed myocardial insulin resistance only in HF + SAT animals, with an uptake ratio of 2.3 ± 0.3 versus 4.6 ± 0.7, 4.3 ± 0.4, and 4.2 ± 0.6 in sham + NC, sham + SAT, and HF + NC animals, respectively; the myocardial glucose utilization rate was similarly decreased in HF + SAT animals only. Western blot analysis of insulin signaling protein expression was indicative of cardiac insulin resistance in HF + SAT animals. Specifically, alterations in Akt and glycogen synthase kinase-3ß protein expression in HF + SAT animals compared with HF + NC animals may be involved in mediating myocardial insulin resistance. In conclusion, HF animals fed a high-saturated fat exhibited preserved myocardial contractile function, peripheral and myocardial insulin resistance, decreased myocardial glucose utilization rates, and alterations in cardiac insulin signaling. These results suggest that myocardial insulin resistance may serve a cardioprotective function with high fat feeding in mild to moderate HF.

Reduced force production during low blood flow to the heart correlates with altered troponin I phosphorylation.

A rat model of low myocardial blood flow was established to test the hypothesis that post-translational changes to proteins of the thin and thick muscle filaments correlate with decreased cardiac contractility. Following 3 days of low blood flow by constriction of the left anterior descending artery, rat hearts demonstrated a reduction in fractional shortening at rest and a relative decline in fractional shortening when challenged with high dose versus low dose dobutamine, reflecting reduced energy reserves. Permeabilized fibers from low blood flow hearts demonstrated a decline in maximum force per cross-section and Ca2+ sensitivity as compared to their sham operated counterparts. An examination of sarcomeric proteins by twodimensional gel electrophoresis, mass spectrometry, and phospho-specific antibodies provided evidence for Ser23/24 and Ser43/45 phosphorylation of troponin I (TnI). Total TnI phosphorylation was not different between the groups, but Ser23/24 phosphorylation declined with low blood flow, implying an accompanying increase in phosphorylation at other sites of TnI. Affinity chromatography demonstrated that TnI from low blood flow myocardium had reduced relative affinity to Ca2+ bound troponin C compared to TnI from sham operated hearts, providing a mechanism for reduced Ca2+ sensitivity of force production in low blood flow fibers. These findings suggest that altered TnI function, due to changes in the distribution of phosphorylated sites, is an early contributor to reduced contractility of the heart.

Exposure to azide markedly decreases the abundance of mRNAs encoding cholesterol synthetic enzymes and inhibits cholesterol synthesis.

This study was performed to identify genes that are regulated in the adaptive response to prolonged inhibition of oxidative phosphorylation. Gene microarray analysis in control Clone 9 cells and Clone 9 cells exposed to 5 mM azide for 24 h was carried out as a condition of "Chemical hypoxia." Among several hundred mRNAs whose abundances were either increased or decreased, we noted that the abundance of mRNAs encoding enzymes that catalyze the sequential steps of cholesterol synthesis was decreased; this finding was verified by real-time PCR. Exposure to azide for 24 h markedly inhibited the biosynthesis of cholesterol by approximately 90% and decreased the cellular content of cholesterol by 30%, similar results were observed in HepG2 cells. The abundance of sterol regulatory element binding protein (SREBP)-2 mRNA decreased to 0.37 and 0.25 that of controls after 2 and 24 h exposure, respectively. After 24 h of exposure to azide the precursor and nuclear forms of SREBP-2 protein decreased by approximately 80% and approximately 50%, respectively. Stimulation of AMP-activated protein kinase (AMPK) by AICAR in Clone 9 cells increased the abundance of mRNAs encoding cholesterol biosynthetic enzymes and that of SREBP-1c, and had no effect on SREBP-2 mRNA abundance. We conclude that the decrease in the abundance of multiple mRNAs encoding cholesterol biosynthetic enzymes may be mediated by decreased expression of SREBP-2 mRNA and protein and does not involve stimulation of AMPK. The decrease in SREBP-2 mRNA and protein abundance in the face of decreased cell cholesterol content raises the possibility of a novel regulatory pathway.