Deepak K. Gupta

Natriuretic Peptides and Cardiometabolic Health.

Natriuretic peptides are cardiac-derived hormones with a range of protective functions, including natriuresis, diuresis, vasodilation, lusitropy, lipolysis, weight loss, and improved insulin sensitivity. Their actions are mediated through membrane-bound guanylyl cyclases that lead to production of the intracellular second-messenger cyclic guanosine monophosphate. A growing body of evidence demonstrates that genetic and acquired deficiencies of the natriuretic peptide system can promote hypertension, cardiac hypertrophy, obesity, diabetes mellitus, the metabolic syndrome, and heart failure. Clinically, natriuretic peptides are robust diagnostic and prognostic markers, and augmenting natriuretic peptides is a target for therapeutic strategies in cardiometabolic disease. This review will summarize current understanding and highlight novel aspects of natriuretic peptide biology.

Cardiac Structure and Function Across the Glycemic Spectrum in Elderly Men and Women Free of Prevalent Heart Disease The Atherosclerosis Risk In the Community Study

Background—Individuals with diabetes mellitus and pre–diabetes mellitus are at particularly high risk of incident heart failure or death, even after accounting for known confounders. Nevertheless, the extent of impairments in cardiac structure and function in elderly individuals with diabetes mellitus and pre–diabetes mellitus is not well known. We aimed to assess the relationship between echocardiographic measures of cardiac structure and function and dysglycemia. Methods and Results—We assessed measures of cardiac structure and function in 4419 participants without prevalent coronary heart disease or heart failure who attended the Atherosclerosis Risk In the Community (ARIC) visit 5 examination (2011–2013) and underwent transthoracic echocardiography (age, 75±6 years; 61% women, 23% black). Subjects were grouped across the dysglycemia spectrum as normal (39%), pre–diabetes mellitus (31%), or diabetes mellitus (30%) based on medical history, antidiabetic medication use, and glycated hemoglobin levels. Glycemic status was related to measures of cardiac structure and function. Worsening dysglycemia was associated with increased left ventricular mass, worse diastolic function, and subtle reduction in left ventricular systolic function (P⩽0.01 for all). For every 1% higher glycated hemoglobin, left ventricular mass was higher by 3.0 g (95% confidence interval, 1.5–4.6 g), E/E′ by 0.5 (95% confidence interval, 0.4–0.7), and global longitudinal strain by 0.3% (95% confidence interval, 0.2–0.4) in multivariable analyses. Conclusions—In a large contemporary biracial cohort of elderly subjects without prevalent cardiovascular disease or heart failure, dysglycemia was associated with subtle and subclinical alterations of cardiac structure, and left ventricular systolic and diastolic function. It remains unclear whether these are sufficient to explain the heightened risk of heart failure in individuals with diabetes mellitus.

Racial Differences in Circulating Natriuretic Peptide Levels: The Atherosclerosis Risk in Communities Study

Background Natriuretic peptides promote natriuresis, diuresis, and vasodilation. Experimental deficiency of natriuretic peptides leads to hypertension (HTN) and cardiac hypertrophy, conditions more common among African Americans. Hospital-based studies suggest that African Americans may have reduced circulating natriuretic peptides, as compared to Caucasians, but definitive data from community-based cohorts are lacking. Methods and Results We examined plasma N-terminal pro B-type natriuretic peptide (NTproBNP) levels according to race in 9137 Atherosclerosis Risk in Communities (ARIC) Study participants (22% African American) without prevalent cardiovascular disease at visit 4 (1996–1998). Multivariable linear and logistic regression analyses were performed adjusting for clinical covariates. Among African Americans, percent European ancestry was determined from genetic ancestry informative markers and then examined in relation to NTproBNP levels in multivariable linear regression analysis. NTproBNP levels were significantly lower in African Americans (median, 43 pg/mL; interquartile range [IQR], 18, 88) than Caucasians (median, 68 pg/mL; IQR, 36, 124; P<0.0001). In multivariable models, adjusted log NTproBNP levels were 40% lower (95% confidence interval [CI], −43, −36) in African Americans, compared to Caucasians, which was consistent across subgroups of age, gender, HTN, diabetes, insulin resistance, and obesity. African-American race was also significantly associated with having nondetectable NTproBNP (adjusted OR, 5.74; 95% CI, 4.22, 7.80). In multivariable analyses in African Americans, a 10% increase in genetic European ancestry was associated with a 7% (95% CI, 1, 13) increase in adjusted log NTproBNP. Conclusions African Americans have lower levels of plasma NTproBNP than Caucasians, which may be partially owing to genetic variation. Low natriuretic peptide levels in African Americans may contribute to the greater risk for HTN and its sequalae in this population.

Natriuretic Peptide and High-Sensitivity Troponin for Cardiovascular Risk Prediction in Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study

OBJECTIVE Cardiovascular disease (CVD) is the major cause of morbidity and mortality in diabetes; yet, heterogeneity in CVD risk has been suggested in diabetes, providing a compelling rationale for improving diabetes risk stratification. We hypothesized that N-terminal prohormone brain natriuretic peptide (NTproBNP) and high-sensitivity troponin T may enhance CVD risk stratification beyond commonly used markers of risk and that CVD risk is heterogeneous in diabetes. RESEARCH DESIGN AND METHODS Among 8,402 participants without prevalent CVD at visit 4 (1996–1998) of the Atherosclerosis Risk in Communities (ARIC) study there were 1,510 subjects with diabetes (mean age 63 years, 52% women, 31% African American, and 60% hypertensive). RESULTS Over a median follow-up of 13.1 years, there were 540 incident fatal/nonfatal CVD events (coronary heart disease, heart failure, and stroke). Both troponin T ≥14 ng/L (hazard ratio [HR] 1.96 [95% CI 1.57–2.46]) and NTproBNP >125 pg/mL (1.61 [1.29–1.99]) were independent predictors of incident CVD events at multivariable Cox proportional hazard models. Addition of circulating cardiac biomarkers to traditional risk factors, abnormal electrocardiogram (ECG), and conventional markers of diabetes complications including retinopathy, nephropathy, and peripheral arterial disease significantly improved CVD risk prediction (net reclassification index 0.16 [95% CI 0.07–0.22]). Compared with individuals without diabetes, subjects with diabetes had 1.6-fold higher adjusted risk of incident CVD. However, participants with diabetes with normal cardiac biomarkers and no conventional complications/abnormal ECG (n = 725 [48%]) were at low risk (HR 1.12 [95% CI 0.95–1.31]), while those with abnormal cardiac biomarkers, alone (n = 186 [12%]) or in combination with conventional complications/abnormal ECG (n = 243 [16%]), were at greater risk (1.99 [1.59–2.50] and 2.80 [2.34–3.35], respectively). CONCLUSIONS Abnormal levels of NTproBNP and troponin T may help to distinguish individuals with high diabetes risk from those with low diabetes risk, providing incremental risk prediction beyond commonly used markers of risk.

B-Type Natriuretic Peptide Levels and Mortality in Patients With and Without Heart Failure

BACKGROUNDnCirculating B-type natriuretic peptide (BNP) concentrations strongly predict mortality in patients with heart failure (HF). Both cardiac and extracardiac stimuli influence BNP levels, suggesting that BNP might have similar prognostic value in patients without HF.nnnOBJECTIVESnThe aim of this study was to compare the prognostic value of BNP between patients with and those without HF.nnnMETHODSnUsing the Vanderbilt University Medical Center electronic health record, 30,487 patients (median age 63 years, 50% men, 17% black, 38% with HF) who had a first plasma BNP measurement between 2002 and 2013, with follow-up through 2015, were studied. The risk for death according to BNP level was quantified using multivariate Cox proportional hazards models.nnnRESULTSnBNP levels were lower in patients without HF (median 89 pg/ml; interquartile range: 34 to 238 pg/ml) compared with those with HF (median 388 pg/ml; interquartile range: 150 to 940 pg/ml) (pxa0< 0.0001). Over 90,898 person-years of follow-up, 5,903 patients without HF (31%) and 6,181 patients with HF (53%) died. In multivariate models including demographic and clinical characteristics, BNP and age were the strongest predictors of death in both patients with and those without HF. In acute care settings and even among outpatients with modestly elevated BNP, the risk for death according to BNP was similar between patients with and those without HF. For instance, a BNP level of 400 pg/ml was associated with a 3-year risk for death of 21% (95% confidence interval: 20% to 23%) and 19% (95% confidence interval: 17% to 20%) in patients with and those without HF, respectively.nnnCONCLUSIONSnAmong patients without HF, plasma BNP level is a stronger predictor of death than traditional risk factors. The risk for death associated with any given BNP level is similar between patients with and those without HF,xa0particularly in the acute care setting.

Differences in Natriuretic Peptide Levels by Race/Ethnicity (From the Multi-Ethnic Study of Atherosclerosis)

Natriuretic peptides (NP) are cardiac-derived hormones with favorable cardiometabolic actions. Low NP levels are associated with increased risks of hypertension and diabetes mellitus, conditions with variable prevalence by race and ethnicity. Heritable factors underlie a significant proportion of the interindividual variation in NP concentrations, but the specific influences of race and ancestry are unknown. In 5597 individuals (40% white, 24% black, 23% Hispanic, and 13% Chinese) without prevalent cardiovascular disease at baseline in the Multi-Ethnic Study of Atherosclerosis, multivariable linear regression and restricted cubic splines were used to estimate differences in serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels according to, ethnicity, and ancestry. Ancestry was determined using genetic ancestry informative markers. NT-proBNP concentrations differed significantly by race and ethnicity (black, median 43u2009pg/ml [interquartile range 17 to 94], Chinese 43 [17 to 90], Hispanic 53 [23 to 107], white 68 [34 to 136]; pu2009=u20090.0001). In multivariable models, NT-proBNP was 44% lower (95% confidence interval -48 to -40) in black and 46% lower (-50 to -41) in Chinese, compared with white individuals. Hispanic individuals had intermediate concentrations. Self-identified blacks and Hispanics were the most genetically admixed. Among self-identified black individuals, a 20% increase in genetic European ancestry was associated with 12% higher (1% to 23%) NT-proBNP. Among Hispanic individuals, genetic European and African ancestry were positively and negatively associated with NT-proBNP levels, respectively. In conclusion, NT-proBNP levels differ according to race and ethnicity, with the lowest concentrations in black and Chinese individuals. Racial and ethnic differences in NT-proBNP may have a genetic basis, with European and African ancestry associated with higher and lower NT-proBNP concentrations, respectively.

Neighborhood Deprivation Predicts Heart Failure Risk in a Low-Income Population of Blacks and Whites in the Southeastern United States

Background: Recent data suggest that neighborhood socioeconomic environment predicts heart failure (HF) hospital readmissions. We investigated whether neighborhood deprivation predicts risk of incident HF beyond individual socioeconomic status in a low-income population. Methods and Results: Participants were 27 078 whites and blacks recruited during 2002 to 2009 in the SCCS (Southern Community Cohort Study), who had no history of HF and were using Centers for Medicare or Medicaid Services. Incident HF diagnoses through December 31, 2010, were ascertained using International Classification of Diseases, Ninth Revision, codes 428.x via linkage with Centers for Medicare or Medicaid Services research files. Participant residential information was geocoded and census tract determined by a spatial join to the US Census Bureau TIGER/Line Shapefiles. The neighborhood deprivation index was constructed using principal components analysis based on census tract-level socioeconomic variables. Cox models with Huber–White cluster sandwich estimator of variance were used to investigate the association between neighborhood deprivation index and HF risk. The study sample was predominantly middle aged (mean, 55.5 years), black (69%), female (63%), low income (70% earned <

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15 000/y), and >50% of participants lived in the most deprived neighborhoods (third neighborhood deprivation index tertile). Over median follow-up of 5.2 years, 4300 participants were diagnosed with HF. After adjustment for demographic, lifestyle, and clinical factors, a 1 interquartile increase in neighborhood deprivation index was associated with a 12% increase in risk of HF (hazard ratio, 1.12; 95% confidence interval, 1.07–1.18), and 4.8% of the variance in HF risk (intraclass correlation coefficient, 4.8; 95% confidence interval, 3.6–6.4) was explained by neighborhood deprivation. Conclusions: In this low-income population, scant neighborhood resources compound the risk of HF above and beyond individual socioeconomic status and traditional cardiovascular risk factors. Improvements in community resources may be a significant axis for curbing the burden of HF.

Left Ventricular Function Across the Spectrum of Body Mass Index in African Americans: The Jackson Heart Study

H ypertension is the most common chronic disease worldwide, affecting 1 billion individuals and contributing to 1 in 8 deaths per year (1). It causes substantial morbidity and mortality, as a major risk factor for heart failure, stroke, coronary artery disease, renal dysfunction, and blindness. The prevalence of hypertension is increasing and uncontrolled hypertension remains a common problem (2,3). Therefore, effective, widely available, low-cost, and sustainable strategies are needed to prevent and treat hypertension. Lifestyle modification, including diet, is a cornerstone for the prevention and treatment of hypertension (4). Reducing dietary sodium below that of typical diets eaten around the world lowers blood pressure (5). The DASH (Dietary Approaches to Stopping Hypertension) diet, comprised of fruits, vegetables, low-fat dairy products, and foods low in saturated fat and cholesterol, has also been shown to reduce blood pressure (6). In the DASH-sodium randomized crossover trial, combining the DASH diet with low sodium was additive for lowering blood pressure (7).

Heart Failure With Preserved Ejection Fraction: An Opportunity for Reflection

OBJECTIVESnThis study sought to assess whether body mass index (BMI) was associated with subclinical left ventricular (LV) systolic dysfunction in African-American individuals.nnnBACKGROUNDnHigher BMI is a risk factor for cardiovascular disease, including heart failure. Obesity disproportionately affects African Americans; however, the association between higher BMI and LV function in African Americans is not well understood.nnnMETHODSnPeak systolic circumferential strain (ECC) was measured by tagged cardiac magnetic resonance in 1,652 adult African-American participants of the Jackson Heart Study between 2008 and 2012. We evaluated the association between BMI and ECC in multivariate linear regression and restricted cubic spline analyses adjusted for prevalent cardiovascular disease, conventional cardiovascular risk factors, LV mass, and ejection fraction. In exploratory analyses, we also examined whether inflammation, insulin resistance, or volume of visceral adipose tissue altered the association between BMI and ECC.nnnRESULTSnThe proportions of female, nonsmokers, diabetic, and hypertensive participants rose with increase in BMI. In multivariate-adjusted models, higher BMI was associated with worse ECC (βxa0= 0.052; 95% confidence interval: 0.028 to 0.075), even in the setting of preserved LV ejection fraction. Higher BMI was also associated with worse ECC when accounting for markers of inflammation (C-reactive protein, E-selection, and P-selectin), insulin resistance, and volume of visceral adipose tissue.nnnCONCLUSIONSnHigher BMI is significantly associated with subclinical LV dysfunction in African Americans, even in thexa0setting of preserved LV ejection fraction.