Markers of autophagy are downregulated in failing human heart after mechanical unloading.

BACKGROUND: Autophagy is a molecular process that breaks down damaged cellular organelles and yields amino acids for de novo protein synthesis or energy provision. Mechanical unloading with a left ventricular assist device (LVAD) decreases the energy demand of the failing human heart. We tested the hypothesis that LVAD support reverses activation of autophagy. METHODS AND RESULTS: Paired biopsy samples of left ventricular myocardium were obtained from 9 patients with idiopathic dilated cardiomyopathy (mean duration of LVAD support, 214 days) at the time of implantation and explantation of the LVAD. Transcript and protein levels of markers and mediators of autophagy and apoptosis were measured by quantitative reverse-transcription polymerase chain reaction and Western blotting. TUNEL assays, C9 immunohistochemistry, and 20S proteasome activity assays were also performed. Mechanical unloading significantly decreased mRNA transcript levels of Beclin-1, autophagy-related gene 5 (Atg5), and microtubule-associated protein-1 light chain-3 (MAP1-LC3 or LC3; P<0.02). Protein levels of Beclin-1, Atg5-Atg12 conjugate, and LC3-II were also significantly reduced after LVAD support (P<0.05). A significant increase in 20S proteasome activity was observed with unloading, in parallel to the decrease in autophagic markers. Although BNIP3 and the ratio of activated caspase 3 to procaspase 3 increased after LVAD support, Bcl-2 and TUNEL-positive nuclei were not significantly different between samples. CONCLUSIONS: Mechanical unloading of the failing human heart decreases markers of autophagy. These findings suggest that autophagy may be an adaptive mechanism in the failing heart, and this phenomenon is attenuated by LVAD support.

Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor.

BACKGROUND: Sunitinib malate is a novel multitargeted receptor tyrosine kinase inhibitor with established efficacy in the treatment of metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor. This report describes the development of heart failure in cancer patients who received this novel agent. METHODS: A retrospective study was conducted at M. D. Anderson Cancer Center during a 1-year period on patients who received sunitinib and developed heart failure. RESULTS: During 2006, 6 of 224 (2.7%) patients who received sunitinib developed heart failure (HF) that resulted in substantial morbidity and, in some cases, mortality. Symptomatic heart failure occurred soon after initiation of sunitinib (mean onset 22 days after initiation), was associated with decline in cardiac function and elevations in blood pressure, and was not completely reversible in most patients, even after termination of sunitinib therapy. CONCLUSIONS: These observations suggested that sunitinib-associated heart failure may represent a potentially serious toxicity and underscore the need for careful monitoring of cardiac function and aggressive control of hypertension in these patients. Studies to elucidate potential mechanisms of heart failure and left ventricular dysfunction resulting from treatment with sunitinib are necessary to develop strategies for prevention and treatment of this complication.

Resting lung function and hemodynamic parameters as predictors of exercise capacity in patients with chronic heart failure.

STUDY OBJECTIVES: The aim of this study was to examine the role of resting pulmonary function and hemodynamic parameters as predictors of exercise capacity in patients with chronic heart failure. MEASUREMENTS AND RESULTS: Fifty-one patients with chronic heart failure underwent resting pulmonary function testing, including inspiratory capacity (IC) and symptom-limited, treadmill cardiopulmonary exercise testing (CPET). Right-heart catheterization and radionuclide ventriculography were performed within 2 days of CPET. Mean (+/- SD) left ventricular ejection fraction was 31 +/- 12% and cardiac index was 2.34 +/- 0.77 L/min/m(2). Percentage of predicted FEV(1) was 92 +/- 14%, percentage of predicted FVC was 94 +/- 15%, FEV(1)/FVC was 81 +/- 4%, and percentage of predicted IC was 84 +/- 18%. Mean peak oxygen uptake (peak O(2)) was 17.9 +/- 5.4 mL/kg/min. Analysis of variance among the three functional Weber classes showed statistically significant differences for pulmonary capillary wedge pressure (PCWP) and IC. Specifically, the more severe the exercise intolerance, the lower was IC and the higher was PCWP. In a multivariate stepwise regression analysis, using peak O(2) (liters per minute) as the dependent variable and the pulmonary function test measurements as independent variables, the only significant predictor selected was IC (r = 0.71, p < 0.0001). In a final stepwise regression analysis including all the independent variables of the resting pulmonary function tests and hemodynamic measurements, the two predictors selected were IC and PCWP (r(2) = 0.58). CONCLUSIONS: In patients with chronic heart failure, IC is inversely related to PCWP and is a strong independent predictor of functional capacity.

Ventilatory response to exercise and kinetics of oxygen recovery are similar in cardiac transplant recipients and patients with mild chronic heart failure.

BACKGROUND: Exercise capacity, assessed by cardiopulmonary exercise treadmill testing (CPET), does not return to normal following heart transplantation. This study evaluated the ventilatory response to exercise and the kinetics of oxygen (O(2)) recovery in heart transplant recipients (HTR) compared to healthy volunteers (HV) and heart failure patients. METHODS: Eighteen patients with end-stage heart failure (ESHF), 12 with mild heart failure (MHF) matched for peak oxygen consumption (Vo(2)) with the HTR, 12 HTR and 12 HV underwent CPET for measurements of peak Vo(2), Vo(2) at anaerobic threshold (AT), first-degree slope of Vo(2) decline during early recovery (Vo(2)/t-slope), time required for a 50% fall from peak Vo(2) (T(1/2) of Vo(2)) and the slopes of VE/Vco(2) and VE/Vo(2). RESULTS: The MHF and HTR groups had similar ventilatory responses to exercise and O(2) recovery kinetics. Peak Vo(2) (18.5 +/- 5.7 vs 9.4 +/- 0.9 ml/kg/min, p < 0.001), AT (13.8 +/- 4.8 vs 6.7 +/- 1.8 ml/kg/min, p < 0.001) and Vo(2)/t-slope (0.6 +/- 0.2 vs 0.3 +/- 0.2 liter/min/min, p = 0.055) were higher in the HTR than in the ESHF group. In contrast, HTR had lower VE/Vco(2)-slope (31.4 +/- 3.8 vs 39.2 +/- 9.9, p = 0.015) and T(1/2) Vo(2) (1.5 +/- 0.3 vs 2.4 +/- 1.1 minute, p = 0.014) than the ESHF group. Compared to HV, HTR had lower Vo(2) peak (18.5 +/- 5.7 vs 28.4 +/- 6.9 ml/kg/min, p < 0.001), AT (13.8 +/- 4.8 vs 19.8 +/- 4.5 ml/kg/min, p = 0.04), Vo(2)/t-slope (0.6 +/- 0.2 vs 1.0 +/- 0.4 liter/min/min, p = 0.005) and steeper VE/Vco(2) slope (31.4 +/- 3.8 vs 23.6 +/- 2.7, p = 0.062). Heart rate deceleration during recovery was significantly slower in HTR than in all other groups. CONCLUSIONS: Exercise intolerance and delayed O(2) recovery kinetics were only partially reversed after heart transplantation. This finding suggests that some of the pathophysiologic mechanisms of heart failure persist after heart transplantation.

Metabolic reserve of the heart: the forgotten link between contraction and coronary flow.

Myocardial energy substrate metabolism entails a complex system of enzyme catalyzed reactions, in which the heart efficiently converts chemical to mechanical energy. The system is highly regulated and responsive to changes in workload as well as in substrate and hormone supply to the heart. Akin to the terms "contractile reserve" and "coronary flow reserve" we propose the term "metabolic reserve" to reflect the heart's capacity to respond to increases in workload. The heart's metabolic response to inotropic stimulation involves the ability to increase oxidative metabolism over a wide range, by activating the oxidation of glycogen and carbohydrate substrates. Here we review the known biochemical mechanisms responsible for those changes. Specifically, we explore the notion that disturbances in the metabolic reserve result in contractile dysfunction of the stressed heart.

Return to the fetal gene program protects the stressed heart: a strong hypothesis.

A common feature of the hemodynamically or metabolically stressed heart is the return to a pattern of fetal metabolism. A hallmark of fetal metabolism is the predominance of carbohydrates as substrates for energy provision in a relatively hypoxic environment. When the normal heart is exposed to an oxygen rich environment after birth, energy substrate metabolism is rapidly switched to oxidation of fatty acids. This switch goes along with the expression of "adult" isoforms of metabolic enzymes and other proteins. However, the heart retains the ability to return to the "fetal" gene program. Specifically, the fetal gene program is predominant in a variety of pathophysiologic conditions including hypoxia, ischemia, hypertrophy, and atrophy. A common feature of all of these conditions is extensive remodeling, a decrease in the rate of aerobic metabolism in the cardiomyocyte, and an increase in cardiac efficiency. The adaptation is associated with a whole program of cell survival under stress. The adaptive mechanisms are prominently developed in hibernating myocardium, but they are also a feature of the failing heart muscle. We propose that in failing heart muscle at a certain point the fetal gene program is no longer sufficient to support cardiac structure and function. The exact mechanisms underlying the transition from adaptation to cardiomyocyte dysfunction are still not completely understood.