No abstract

Obesity may confer cardiac dysfunction due to lipid accumulation in cardiomyocytes. To test this idea, we examined whether obese ob/ob mice display heart lipid accumulation and cardiac dysfunction. Ob/ob mouse hearts had increased expression of genes mediating extracellular generation, transport across the myocyte cell membrane, intracellular transport, mitochondrial uptake, and β-oxidation of fatty acids compared with ob/+ mice. Accordingly, ob/ob mouse hearts contained more triglyceride (6.8 ± 0.4 vs. 2.3 ± 0.4 μg/mg; P < 0.0005) than ob/+ mouse hearts. Histological examinations showed marked accumulation of neutral lipid droplets within cardiac myocytes but not increased deposition of collagen between myocytes in ob/ob compared with ob/+ mouse hearts. On echocardiography, the ratio of E to A transmitral flow velocities (an indicator of diastolic function) was 1.8 ± 0.1 in ob/ob mice and 2.5 ± 0.1 in ob/+ mice (P = 0.0001). In contrast, the indexes of systolic function and heart brain natriuretic peptide mRNA expression were only marginally affected and unaffected, respectively, in ob/ob compared with ob/+ mice. The results suggest that ob/ob mouse hearts have increased expression of cardiac gene products that stimulate myocyte fatty acid uptake and triglyceride storage and accumulate neutral lipids within the cardiac myocytes. The results also suggest that the cardiac lipid accumulation is paralleled by cardiac diastolic dysfunction in ob/ob mice.

Congestive heart failure is accompanied by increased cardiac brain natriuretic peptide (BNP) gene expression with elevated plasma concentrations of BNP and its precursor, proBNP. We investigated if myocardial ischemia in the absence of overt heart failure may be another mechanism for increased myocardial BNP expression. The BNP expression was examined in hypoxic myocardium of patients undergoing coronary bypass grafting surgery, in patients with coronary artery disease and normal left ventricular function undergoing percutaneous transluminal intervention therapy, and in heart failure patients without coronary artery disease. BNP mRNA was quantified by real-time PCR, and plasma BNP and proBNP concentrations were measured with radioimmunoassays. Quantitative analysis of BNP mRNA in atrial and ventricular biopsies from coronary bypass grafting patients revealed close associations of plasma BNP and proBNP concentrations to ventricular, but not atrial, BNP mRNA levels. Plasma BNP and proBNP concentrations were markedly increased in patients with coronary artery disease but without concomitant left ventricular dysfunction. These results are compatible with the notion that myocardial ischemia, even in the absence of left ventricular dysfunction, augments cardiac BNP gene expression and increases plasma BNP and proBNP concentrations. Thus, elevated BNP and proBNP concentrations do not necessarily reflect heart failure but may also result from cardiac ischemia.

Background-Tissue Doppler imaging (TDI) detects left ventricular dysfunction in patients with heart failure and normal ejection fraction, but the prognostic significance of left ventricular dysfunction by TDI in the general population is unknown. Methods and Results-Within the Copenhagen City Heart Study, a large community-based population study, cardiac function was evaluated in 1036 participants by both conventional echocardiography and TDI. Averages of peak systolic (sЈ), early diastolic (eЈ), and late diastolic (aЈ) velocities from 6 mitral annular sites were used. TDI was furthermore quantified by a combined index (eas index) of diastolic and systolic performance: eЈ/(aЈϫsЈ). During follow-up (median, 5.3 years), 90 participants died. Left ventricular dysfunction by TDI, in terms of low sЈ (hazard ratio, 1.23 per 1-cm/s decrease; PϽ0.05) and aЈ (hazard ratio, 1.20 per 1-cm/s decrease; Pϭ0.001), were significant predictors of death in Cox proportional-hazards models adjusted for clinical variables (age, sex, body mass index, heart rate, hypertension, diabetes mellitus, and ischemic heart disease) and conventional echocardiography. The adjusted hazard ratio for death in the third tertile compared with the first tertile of the combined index of systolic and diastolic performance by TDI was 2.5 (PϽ0.005). Conclusions-In