Daniel L. Dries

Impact of body mass and body composition on circulating levels of natriuretic peptides: results from the Dallas Heart Study.

Background— The association between higher body mass index (BMI) and lower B-type natriuretic peptide (BNP) level is thought to be mediated by expression of the natriuretic peptide clearance receptor (NPR-C) in adipose tissue. To explore this association, we tested 2 hypotheses: (1) that N-terminal (NT)-proBNP, which is not believed to bind NPR-C, would not be associated with BMI and (2) that lower BNP would be more closely associated with fat mass than with lean mass. Methods and Results— Measurements of BNP, NT-proBNP, and body composition by direct dual energy x-ray absorptiometry (DEXA) were performed in 2707 subjects from the Dallas Heart Study. The associations between obesity and low BNP (<4 ng/L) or low NT-proBNP (lowest sex-specific quartile) were evaluated with multivariable logistic regression models stratified by sex and adjusted for age, race/ethnicity, hypertension, left ventricular mass, and end-diastolic volume. Higher BMI was independently associated with lower BNP and NT-proBNP (all P<0.001). When BMI was replaced with both DEXA-derived lean and fat mass, greater lean mass, but not fat mass, was associated with low BNP and NT-proBNP levels. Conclusions— In a large, population-based cohort, we confirm the previously described association between higher BMI and lower BNP and demonstrate a similar inverse association between BMI and NT-proBNP. Interestingly, both BNP and NT-proBNP are more closely associated with lean mass than with fat mass. These findings do not support the hypothesis that the lower BNP levels seen in obesity are driven by enhanced BNP clearance mediated via NPR-C.

Left Ventricular Hypertrophy Is More Prevalent in Blacks Than Whites in the General Population The Dallas Heart Study

Although recent studies have suggested that blacks compared with whites have an increased prevalence of left ventricular hypertrophy, it remains uncertain whether this is true despite adjustment for body composition (fat mass and fat-free mass) and when assessed by cardiac MRI in the general population. The Dallas Heart Study is a population-based study of Dallas County in which 1335 black and 858 white participants 30 to 67 years of age underwent detailed assessment including dual-energy x-ray absorptiometry scan to measure body composition and cardiac MRI. Left ventricular hypertrophy, whether defined by indexation to body surface area (P<0.001), fat-free mass (P=0.002), or height2.7 (P<0.001) was 2- to 3-fold more common in black versus white women. Similar results were seen when comparing black and white men (P<0.001 when left ventricular hypertrophy was indexed to body surface area or height2.7 and P=0.05 when indexed to fat-free mass). Ethnic disparities in left ventricular mass persisted in multivariable models despite adjustment for fat mass, fat-free mass, systolic blood pressure, age, gender, and measures of socioeconomic status. We conclude that blacks compared with whites have increased left ventricular mass and a 2- to 3-fold higher prevalence of left ventricular hypertrophy in the general population, as assessed by cardiac MRI. The ethnic differences in left ventricular mass are independent of differences in body composition.

Prognostic impact of diabetes mellitus in patients with heart failure according to the etiology of left ventricular systolic dysfunction

OBJECTIVES We sought to determine the relative impact of diabetes mellitus on prognosis in ischemic compared with nonischemic cardiomyopathy. BACKGROUND Ischemic myocardium is characterized by increased reliance on aerobic and anaerobic glycolysis. Because glucose utilization by cardiomyocytes is an insulin-mediated process, we hypothesized that diabetes would have a more adverse impact on mortality and progression of heart failure in ischemic compared with nonischemic cardiomyopathy. METHODS We performed a retrospective analysis of the Studies Of Left Ventricular Dysfunction (SOLVD) Prevention and Treatment trials. RESULTS In adjusted analyses, diabetes mellitus was strongly associated with an increased risk for all-cause mortality in patients with ischemic cardiomyopathy, (relative risk [RR] 1.37, 95% confidence interval [CI] 1.21 to 1.55; p < 0.0001), but not in those with nonischemic cardiomyopathy (RR 0.98, 95% CI 0.76 to 1.32; p = 0.98). The increased mortality in patients with ischemic cardiomyopathy compared with nonischemic cardiomyopathy was limited to those with ischemic cardiomyopathy and diabetes mellitus (RR 1.37, 95% CI 1.21 to 1.56; p < 0.0001). When patients with ischemic cardiomyopathy and diabetes mellitus were excluded, there was no significant difference in mortality risk between the ischemic and nonischemic cardiomyopathy groups after adjusted analysis (RR 0.99, 95% CI 0.86 to 1.15; p = 0.99). Previous surgical revascularization identified patients within the cohort with ischemic cardiomyopathy and diabetes mellitus, with improved prognosis. CONCLUSIONS The differential impact of diabetes on mortality and heart failure progression according to the etiology of heart failure suggests that diabetes and ischemic heart disease interact to accelerate the progression of myocardial dysfunction. Evaluation of the potential for revascularization may be particularly important in patients with ischemic cardiomyopathy and diabetes mellitus.

High-Sensitivity ST2 for Prediction of Adverse Outcomes in Chronic Heart Failure

Background—Soluble ST2 reflects activity of an interleukin-33–dependent cardioprotective signaling axis and is a diagnostic and prognostic marker in acute heart failure. The use of ST2 in chronic heart failure has not been well defined. Our objective was to determine whether plasma ST2 levels predict adverse outcomes in chronic heart failure in the context of current approaches. Methods and Results—We determined the association between ST2 level and risk of death or transplantation in a multicenter, prospective cohort of 1141 chronic heart failure outpatients. Adjusted Cox models, receiver operating characteristic analyses, and risk reclassification metrics were used to assess the value of ST2 in predicting risk beyond currently used factors. After a median of 2.8 years, 267 patients (23%) died or underwent heart transplantation. Patients in the highest ST2 tertile (ST2 >36.3 ng/mL) had a markedly increased risk of adverse outcomes compared with the lowest tertile (ST2 ⩽22.3 ng/mL), with an unadjusted hazard ratio of 3.2 (95% confidence interval [CI], 2.2 to 4.7; P<0.0001) that remained significant after multivariable adjustment (adjusted hazard ratio, 1.9; 95% CI, 1.3 to 2.9; P=0.002). In receiver operating characteristic analyses, the area under the curve for ST2 was 0.75 (95% CI, 0.69 to 0.79), which was similar to N-terminal pro-B–type natriuretic peptide (NT-proBNP) (area under the curve, 0.77; 95% CI, 0.72 to 0.81; P=0.24 versus ST2) but lower than the Seattle Heart Failure Model (area under the curve, 0.81 (95% CI, 0.77 to 0.85; P=0.014 versus ST2). Addition of ST2 and NT-proBNP to the Seattle Heart Failure Model reclassified 14.9% of patients into more appropriate risk categories (P=0.017). Conclusions—ST2 is a potent marker of risk in chronic heart failure and when used in combination with NT-proBNP offers moderate improvement in assessing prognosis beyond clinical risk scores.

Chronic kidney disease and prevalent atrial fibrillation: The Chronic Renal Insufficiency Cohort (CRIC)

BACKGROUND The epidemiology of atrial fibrillation (AF) has been mainly investigated in patients with end-stage renal disease, with limited data on less advanced chronic kidney disease (CKD) stages. METHODS A total of 3,267 adult participants (50% non-Hispanic blacks, 46% women) with CKD from the Chronic Renal Insufficiency Cohort were included in this study. None of the study participants had been on dialysis. Those with self-identified race/ethnicity other than non-Hispanic black or white (n = 323) or those without electrocardiographic data (n = 22) were excluded. Atrial fibrillation was ascertained by a 12-lead electrocardiogram and self-report. Age-, sex-, and race/ethnicity-specific prevalence rates of AF were estimated and compared between subgroups. Cross-sectional associations and correlates with prevalent AF were examined using unadjusted and multivariable-adjusted logistic regression analysis. RESULTS The mean estimated glomerular filtration rate was 43.6 (+/-13.0) mL/(min 1.73 m(2)). Atrial fibrillation was present in 18% of the study population and in >25% of those > or =70 years old. In multivariable-adjusted models, 1-SD increase in age (11 years) (odds ratio 1.27, CI 95% 1.13-1.43, P < .0001), male [corrected] sex (0.80, 0.65-0.98, P = .0303), smoking (former vs never) (1.34, 1.08-1.66, P = .0081), history of heart failure (3.28, 2.47-4.36, P < .001), and history of cardiovascular disease (1.94, 1.56-2.43, P < .0001) were significantly associated with AF. Race/ethnicity, hypertension, diabetes, body mass index, physical activity, education, high-sensitivity C-reactive protein, total cholesterol, and alcohol intake were not significantly associated with AF. An estimated glomerular filtration rate <45 mL/(min 1.73 m(2)) was associated with AF in an unadjusted model (1.35, 1.13-1.62, P = .0010), but not after multivariable adjustment (1.12, 0.92-1.35, P = .2710). CONCLUSIONS Nearly 1 in 5 participants in Chronic Renal Insufficiency Cohort, a national study of CKD, had evidence of AF at study entry, a prevalence similar to that reported among patients with end-stage renal disease and 2 to 3 times of that reported in the general population. Risk factors for AF in this CKD population do not mirror those reported in the general population.

Corin Gene Minor Allele Defined by 2 Missense Mutations Is Common in Blacks and Associated With High Blood Pressure and Hypertension

Background— The natriuretic peptide system contributes to blood pressure regulation. Atrial and brain natriuretic peptides are cleaved into smaller biologically active molecules by corin, a transmembrane serine protease expressed in cardiomyocytes. Method and Results— This genotype-phenotype genetic association study included replication samples and genomic control to correct for population stratification. Sequencing of the human corin gene identified 2 nonsynonymous, nonconservative single nucleotide polymorphisms (Q568P and T555I) in near-complete linkage disequilibrium, thus describing a single minor I555 (P568) corin gene allele. This allele was present in the heterozygote state in ≈12% of blacks but was extremely rare in whites (<0.5% were homozygous for the minor allele). In our primary population sample, the Dallas Heart Study, after adjustment for potential confounders, including population stratification, the corin I555 (P568) allele remained independently associated with increased risk for prevalent hypertension (odds ratio, 1.63; 95% CI, 1.11 to 2.38; P=0.013). The corin I555 (P568) allele also was associated with higher systolic blood pressure in subjects not using antihypertensive medication in unadjusted (133.7±20.7 versus 129.4±17.4 mm Hg; P=0.029) and adjusted (132.5±1.6 versus 128.9±0.6 mm Hg; P=0.029) analyses. The independent association of the minor corin allele with increased risk for prevalent hypertension was confirmed in the Multi-Ethnic Study of Atherosclerosis (odds ratio, 1.50; 95% CI, 1.09 to 2.06; P=0.014). In addition, the association of the minor corin I555 (P568) allele with higher systolic blood pressure was confirmed in adjusted analysis in the Chicago Genetics of Hypertension Study (125.8±1.9 versus 121.4±0.7 mm Hg; P=0.03). Conclusions— The corin I555 (P568) allele is common in blacks and is associated with higher blood pressure and an increased risk for prevalent hypertension.

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

Comparison of impedance cardiography with invasive hemodynamic measurements in patients with heart failure secondary to ischemic or nonischemic cardiomyopathy.

Right-sided cardiac catheterization is frequently performed in patients with heart failure despite potential complications including arrhythmias, right ventricular or pulmonary artery perforation, pulmonary infarction, infection, 1 and possibly increased mortality. 2,3 A noninvasive measure of cardiac output and left ventricular fi lling pressures would therefore be desirable. Impedance cardiography via a commercially available device (BioZ.com, CardioDynamics International Corporation, San Diego, California) may permit such noninvasive measurement of hemodynamics by assessing the change in impedance of an alternating current applied across the thorax to determine stroke volume, cardiac output, and thoracic fl uid content. 4 However, it is not known how well its as

Associations between Kidney Function and Subclinical Cardiac Abnormalities in CKD

Heart failure is a common consequence of CKD, and it portends high risk for mortality. However, among patients without known heart failure, the associations of different stages of estimated GFR (eGFR) with changes in cardiac structure and function are not well described. Here, we performed a cross-sectional analysis to study these associations among 3487 participants of the Chronic Renal Insufficiency Cohort Study. We estimated GFR using cystatin C. The prevalence of left ventricular hypertrophy (LVH) assessed by echocardiography was 32%, 48%, 57%, and 75% for eGFR categories ≥60, 45-59, 30-44, and <30 ml/min per 1.73 m(2), respectively. In fully adjusted multivariable analyses, subjects with eGFR levels of <30 ml/min per 1.73 m(2) had twofold higher odds of LVH (OR=2.20, 95% CI=1.40-3.40; P<0.001) relative to subjects with eGFR≥60 ml/min per 1.73 m(2). This reduction in kidney function also significantly associated with abnormal LV geometry but not diastolic or systolic dysfunction. An eGFR of 30-44 ml/min per 1.73 m(2) also significantly associated with LVH and abnormal LV geometry compared with eGFR≥60 ml/min per 1.73 m(2). In summary, in this large CKD cohort, reduced kidney function associated with abnormal cardiac structure. We did not detect significant associations between kidney function and systolic or diastolic function after adjusting for potential confounding variables.

Prognostic Importance of Early Worsening Renal Function After Initiation of Angiotensin-Converting Enzyme Inhibitor Therapy in Patients With Cardiac Dysfunction

Background— Worsening renal function (WRF) in the setting of heart failure has been associated with increased mortality. However, it is unclear if this decreased survival is a direct result of the reduction in glomerular filtration rate (GFR) or if the mechanism underlying the deterioration in GFR is driving prognosis. Given that WRF in the setting of angiotensin-converting enzyme inhibitor (ACE-I) initiation is likely mechanistically distinct from spontaneously occurring WRF, we investigated the relative early WRF-associated mortality rates in subjects randomized to ACE-I or placebo. Methods and Results— Subjects in the Studies Of Left Ventricular Dysfunction (SOLVD) limited data set (n=6337) were studied. The interaction between early WRF (decrease in estimated GFR ≥20% at 14 days), randomization to enalapril, and mortality was the primary end point. In the overall population, early WRF was associated with increased mortality (adjusted hazard ratio [HR], 1.2; 95% CI, 1.0–1.4; P=0.037). When analysis was restricted to the placebo group, this association strengthened (adjusted HR, 1.4; 95% CI, 1.1–1.8; P=0.004). However, in the enalapril group, early WRF had no adverse prognostic significance (adjusted HR, 1.0; 95% CI, 0.8–1.3; P=1.0; P=0.09 for the interaction). In patients who continued to receive study drug despite early WRF, a survival advantage remained with enalapril therapy (adjusted HR, 0.66; 95% CI, 0.5–0.9; P=0.018). Conclusions— These data support the notion that the mechanism underlying WRF is important in determining its prognostic significance. Specifically, early WRF in the setting of ACE-I initiation appears to represent a benign event that is not associated with a loss of benefit from continued ACE-I therapy.