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.

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; PϽ0.02). Protein levels of Beclin-1, Atg5-Atg12 conjugate, and LC3-II were also significantly reduced after LVAD support (PϽ0.05). 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. (Circulation. 2009;120[suppl 1]:S191-S197.)

Background-Dyspnea and fatigue are the main causes of exercise limitation in chronic heart failure (CHF) patients, whose peak inspiratory (Pi max ) and expiratory pressures (Pe max ) are often reduced. The aim of this study was to examine the relationship between respiratory muscle performance and oxygen kinetics. Methods and Results-A total of 55 patients (NYHA class I to III) and 11 healthy subjects underwent cardiopulmonary exercise tests (CPET) on a treadmill. In 45 of the 55 patients (group I) and in healthy subjects (group II), pulmonary function tests, Pi max , and Pe max were measured before and 10 minutes after exercise, and oxygen kinetics were monitored throughout and during early recovery from CPET. The first degree slope of oxygen consumption (V O 2 ) decline during early recovery (V O 2 /t-slope) and V O 2 half-time (T 1/2 ) were calculated. In 10 of the 55 CHF patients (group III), the measurements of Pi max were repeated 2, 5, and 10 minutes after CPET. A Ͼ10% reduction in Pi max after CPET (subgroup IA) was measured in 11 of 45 patients. In contrast, 34 of 45 CHF patients (subgroup IB) and all control subjects (group II) had Pi max Ͼ90% of baseline value after CPET. Subgroup IA patients had significantly lower peak V O 2 (13.5Ϯ2.1 versus 17.8Ϯ5.6 mL ⅐ kg Ϫ1 ⅐ min Ϫ1 ; PϽ0.001), lower anaerobic thresholds (10.1Ϯ2.4 versus 13.6Ϯ4.6 mL ⅐ kg Ϫ1 ⅐ min

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. Cancer 2008. ©2008 American Cancer Society.

Ž .Ž . Background: Oxygen O uptake at peak exercise VO peak is an objective measurement of functional capacity in patients 2 2 Ž . with chronic heart failure CHF . The significance of recovery O kinetics parameters in predicting exercise capacity, and the 2 Ž parameters of submaximal exercise testing have not been thoroughly examined. Methods and results: Thirty-six patients mean . w x w x w x age s 48 " 14 years with CHF and New York Heart Association functional class I 12 , II 17 , or III 7 , and eight healthy Ž . Ž . volunteers mean age s 39 " 13 years were studied with maximal and submaximal cardiopulmonary exercise testing CPET .Ž . The first degree slope of O uptake decay during early recovery from maximal VO rt-slope , and submaximal exercise . Ž . Ž . P-0.001 , with the VO peak r s 0.87, P -0.001 and with T VO after maximal exercise r sy0.62, P -0.001 .