Genetic testing for early detection of individuals at risk of coronary heart disease and monitoring response to therapy: challenges and promises.

Coronary heart disease (CHD) often presents suddenly with little warning. Traditional risk factors are inadequate to identify the asymptomatic high-risk individuals. Early identification of patients with subclinical coronary artery disease using noninvasive imaging modalities would allow the early adoption of aggressive preventative interventions. Currently, it is impractical to screen the entire population with noninvasive coronary imaging tools. The use of relatively simple and inexpensive genetic markers of increased CHD risk can identify a population subgroup in which benefit of atherosclerotic imaging modalities would be increased despite nominal cost and radiation exposure. Additionally, genetic markers are fixed and need only be measured once in a patient's lifetime, can help guide therapy selection, and may be of utility in family counseling.

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/m(2)) 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.

Preload dependency of left ventricular torsion: the impact of normal saline infusion.

BACKGROUND: left ventricular (LV) rotation results from contraction of obliquely oriented myocardial fibers. The net difference between systolic apical counterclockwise rotation and basal clockwise rotation is left ventricular torsion (LVT). Although LVT is altered in various cardiac diseases, determinants of LVT are incompletely understood. METHODS AND RESULTS: LV end-diastolic volume, LV apical and basal rotation, peak systolic LVT, and peak early diastolic untwisting rate were measured by speckle-tracking echocardiography in healthy subjects (n=8) before and after infusion of a weight-based normal saline bolus (2.1±0.3 L). Saline infusion led to a significant increase in end-diastolic LV internal diameter (45.9±3.7 versus 47.6±4.2 mm; P=0.002) and LV end-diastolic volume (90.0±21.6 versus 98.3±19.6 mL; P=0.01). Stroke volume (51.3±10.9 versus 63.0±15.5 mL; P=0.003) and cardiac output (3.4±0.8 versus 4.4±1.5 L/min; P=0.007) increased, whereas there was no change in heart rate and blood pressure. There was a significant increase in the magnitude of peak systolic apical rotation (7.5±2.4° versus 10.5±2.8°; P<0.001) but no change in basal rotation (-4.1±2.3° versus -4.8±3.1°; P=0.44). Accordingly, peak systolic LVT increased by 33% after saline infusion (11.2±1.3° versus 14.9±1.7°; P<0.001). This saline-induced increase in LVT was associated with a marked increase in peak early diastolic untwisting rate (72.3±21.4 versus 136.8±30.0 degrees/s; P<0.001). CONCLUSIONS: peak systolic LVT and peak early diastolic untwisting rate are preload-dependent. Changes in LV preload should be considered when interpreting results of future LVT studies.

Effect of weight loss after weight loss surgery on plasma N-terminal pro-B-type natriuretic peptide levels.

Natriuretic peptides have multiple beneficial cardiovascular effects. Previous cross-sectional studies have indicated that obese subjects have lower natriuretic peptide concentrations than those of normal weight. It is not known whether this relative natriuretic peptide deficiency is reversible with weight loss. We studied 132 obese subjects undergoing weight loss surgery with serial measurement of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations at preoperative, early (1 to 2 months), and late postoperative (6 months) points. In addition, 20 subjects also underwent echocardiography at baseline and 6 months after surgery. Significant weight loss was observed after surgery (median body mass index 45.1, 41.0, and 32.9 kg/m(2) for the 3 corresponding points, analysis of variance p <0.001). The median NT-proBNP levels increased substantially (31.6, 66.9, and 84.9 pg/ml; p <0.001). The average intrasubject increase in NT-proBNP at the 2 postoperative points was 3.4 and 5.0 times the preoperative level (p <0.001 for both points vs preoperatively). In the multivariate regression models adjusted for clinical characteristics and insulin resistance, the strongest predictor of the change in NT-proBNP level 6 months after weight loss surgery was the change in weight (p = 0.03). Echocardiography showed a mean intrasubject reduction in left ventricular mass index of 18% (p <0.001) and mild improvements in diastolic function, with no change in ejection fraction. In conclusion, we have demonstrated that weight loss is associated with early and sustained increases in NT-proBNP concentrations, despite evidence of preserved systolic and improved diastolic function. These findings suggest a direct, reversible relation between obesity and reduced natriuretic peptide levels.

Association of HIV infection and HIV/HCV coinfection with C-reactive protein levels: the fat redistribution and metabolic change in HIV infection (FRAM) study.

OBJECTIVE: Inflammation is a potential mechanism to explain the accelerated atherosclerosis observed in HIV- and hepatitis C virus (HCV)-infected persons. We evaluated C-reactive protein (CRP) in HIV-infected and HIV/HCV-coinfected individuals in the era of effective antiretroviral (ARV) therapy. DESIGN: Cross-sectional study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) cohort and controls from the Coronary Artery Risk Development in Young Adults (CARDIA) study. METHODS: CRP levels were measured in 1135 HIV-infected participants from the FRAM cohort and 281 controls from the CARDIA study. The associations of HIV and HIV/HCV infection with CRP levels were estimated by multivariable linear regression. RESULTS: Compared with controls, HIV monoinfection was associated with an 88% higher CRP level in men (P < 0.0001) but with no difference in women (5%; P = 0.80) in multivariate analysis. CRP levels were not associated with ARV therapy, HIV RNA level, or CD4 cell count. Compared with controls, HIV/HCV coinfection was associated with a 41% lower CRP level in women (P = 0.012) but with no difference in men (+4%; P = 0.90). Among HIV-infected participants, HCV coinfection was associated with 50% lower CRP levels after multivariable analysis (P < 0.0001) in men and women. Greater visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were strongly associated with CRP levels. Among HIV-infected participants, CRP levels were 17% (P < 0.001) and 21% (P = 0.002) higher per doubling of VAT and SAT; among controls, CRP levels were 34% (P < 0.001) and 61% (P = 0.009) higher, respectively. CONCLUSIONS: In the absence of HCV coinfection, HIV infection is associated with higher CRP levels in men. HCV coinfection is associated with lower CRP levels in men and women.

Barbershops as hypertension detection, referral, and follow-up centers for black men.

Barbershops constitute potential sites for community health promotion programs targeting hypertension (HTN) in black men, but such programs have not been evaluated previously. Here we conducted 2 nonrandomized feasibility studies to determine whether an enhanced intervention program of continuous blood pressure (BP) monitoring and peer-based health messaging in a barbershop lowers BP more than standard screening and health education (study 1) and can be implemented by barbers rather than research personnel (study 2). In study 1, we measured changes in HTN treatment and BP in regular barbershop customers with poorly controlled HTN assigned for 8 months to either an enhanced intervention group (n=36) or a contemporaneous comparison group (n=27). Groups were similar at baseline. BP fell by 16+/-3/9+/-2 mm Hg in the enhanced intervention group but was unchanged in the comparison group (P<0.0001, adjusted for age and body mass index). HTN treatment and control increased from 47% to 92% (P<0.001) and 19% to 58% (P<0.001), respectively, in the enhanced intervention group, whereas both remained unchanged in the comparison group. In study 2, barbers were trained to administer the enhanced intervention continuously for 14 months to the entire adult black male clientele (n=321) in 1 shop. Six barbers recorded 8953 BP checks during 11 066 haircuts, thus demonstrating a high degree of intervention fidelity. Furthermore, among 107 regular customers with HTN, treatment and control increased progressively with increasing intervention exposure (P<0.01). Taken together, these data suggest that black-owned barbershops can be transformed into effective HTN detection, referral, and follow-up centers. Further research is warranted.

Determination of triglyceride in the human myocardium by magnetic resonance spectroscopy: reproducibility and sensitivity of the method.

The primary aim of this investigation was to determine the reliability and sensitivity of 1H magnetic resonance spectroscopy (1H-MRS) as a method for quantifying myocardial triglyceride (TG) content in humans over time and in response to metabolic perturbations. Three separate experiments were designed to quantify myocardial TG content 1) over a 90-day period, 2) after a high-fat meal, and 3) after a 48-h fast. Proton spectra were collected from a 10 x 20 x 30-mm3 voxel placed within the intraventricular septum, with measurements acquired at end-systole and end-expiration, using cardiac triggering and respiratory gating. Minimal variation was observed between myocardial TG content determined 90 days apart (r = 0.98, CV = 5%), whereas TG values were unaffected by a high-fat meal despite a significant twofold increase (P < 0.05) in serum TG. In contrast, myocardial TG content increased threefold (P < 0.05) after a 48-h fast despite a 25% reduction in serum TG. Body mass index was significantly related to myocardial TG (r = 0.58, P < 0.05) and the change in myocardial TG after a 48-h fast (r2 = 0.60). 1H-MRS is a reliable method for the determination of myocardial TG in humans and is relatively unaffected by the consumption of one high-fat meal but sensitive to changes following a prolonged fast.

Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population.

Despite the increasing prevalence of nonalcoholic fatty liver disease (NAFLD), the criteria used to diagnose the disorder remain poorly defined. Localized proton magnetic resonance spectroscopy (MRS) accurately measures hepatic triglyceride content (HTGC) but has been used only in small research studies. Here, MRS was used to analyze the distribution of HTGC in 2,349 participants from the Dallas Heart Study (DHS). The reproducibility of the procedure was validated by showing that duplicate HTGC measurements were high correlated (r = 0.99, P < 0.001) and that the coefficient of variation between measurements was low (8.5%). Intake of a high-fat meal did not significantly affect the measurements, and values were similar when measurements were made from the right and left hepatic lobes. To determine the "upper limit of normal" for HTGC, the distribution of HTGC was examined in the 345 subjects from the DHS who had no identifiable risk factors for hepatic steatosis (nonobese, nondiabetic subjects with minimal alcohol consumption, normal liver function tests, and no known liver disease). The 95th percentile of HTGC in these subjects was 5.56%, which corresponds to a hepatic triglyceride level of 55.6 mg/g. With this value as a cutoff, the prevalence of hepatic steatosis in Dallas County was estimated to be 33.6%. Thus MRS provides a sensitive, quantitative, noninvasive method to measure HTGC and, when applied to a large urban US population, revealed a strikingly high prevalence of hepatic steatosis.