Exercise Training Attenuates MuRF-1 Expression in the Skeletal Muscle of Patients With Chronic Heart Failure Independent of Age: The Randomized Leipzig Exercise Intervention in Chronic Heart Failure and Aging Catabolism Study Circulation Editors’ Picks Most Read Articles in Exercise Physiology

Summary— Exercise intolerance in chronic heart failure (CHF) is influenced not only by the degree of left ventricular systolic dysfunction but also by peripheral skeletal muscle abnormalities, which commonly develop in advanced CHF and may progress to cardiac cachexia. Despite the clinical importance of muscle wasting in CHF, the molecular mechanisms are still largely unknown, and no specific anticatabolic treatment is currently available. In the Leipzig Exercise Intervention in Chronic Heart Failure and Aging (LEICA) study, skeletal muscle biopsies were obtained from the quadricep muscles in younger and older CHF patients and in age-matched healthy subjects to analyze whether an important signaling system for intracellular protein degradation called the ubiquitin-proteasome system was activated in heart failure and whether activation was higher with older age. We found that one of the key enzymes that marks structural pro-teins for protein degradation (MuRF-1) was significantly elevated in muscle biopsies from CHF patients in both age groups. Four weeks of aerobic exercise training reduced the MuRF-1 expression back to normal values. Importantly, the relative improvement did not differ between younger and older CHF patients. Understanding the specific changes causing the catabolic-anabolic imbalance in CHF is an essential first step in the development of pharmaceutical intervention strategies aimed at blocking muscle catabolism in CHF. Conclusions— MuRF-1, a component of the ubiquitin-proteasome system involved in muscle proteolysis, is increased in the skeletal muscle of patients with heart failure. Exercise training results in reduced MuRF-1 levels, suggesting that it blocks ubiquitin-proteasome system activation and does so in both younger and older CHF patients. 1 Summary— Patients with angina often find their symptoms are less pronounced on second compared with first exertion. This is known as the warm-up angina phenomenon, and despite being described >200 years ago it remains poorly understood. The symptomatic benefit provided by the first exertion is still discernible with standard antianginal medication and is accompanied by less ST-segment depression and ischemia-induced dysrhythmia. In patients with angina we investigated the changes in central aortic pressure and coronary artery pressure and flow beyond the culprit stenosis during first and second supine effort in the cardiac catheterization laboratory. These recordings show a number of adaptations during The following articles are being highlighted as part of Circulation’s Topic Review series. This series will summarize the most impor- tant manuscripts, as selected by the editors, published in Circulation and the Circulation subspecialty journals. The studies included in this article represent the most read manuscripts published on the topic of exercise physiology within the last year. ( Circulation . 2013;127:e627-e632.) act in concert to reduce left ventricular afterload and coronary artery blood flow. Among the most striking alterations occurring during second exercise are a reduction in augmentation of the central aortic systolic pressure and an increase in the intracoronary pressure wave responsible for accelerating blood flow at the onset of diastole. This pressure wave, known as the backward expansion wave, is dependent both on myocardial vascular tone and rate of relaxation. First exercise triggers adaptive changes within the myocardial and systemic circulations that reduce cardiac work and increase myocardial blood flow during subsequent exercise. These features suggest a novel underlying mechanism that may be harnessed for therapeutic benefit. Conclusions— On repeat exercise in patients with effort angina, synergistic changes in the systemic and coronary circulations combine to improve vascular–ventricular coupling and enhance myocardial perfusion, thereby potentially contributing to the warm-up angina phenomenon. Summary— We investigated the adaptation of left ventricular (LV) strains and twist-untwist mechanics in hypertrophic cardiomyopathy (HCM) patients, who typically show exercise-induced At rest, HCM patients showed lower longitudinal strain than control subjects, and this was compensated for by higher circumferential strain and twist. During exercise, however, HCM patients exhibited a severely limited adaptability of all strain components with no LV twisting reserve, reduced and delayed untwist mechanics, and reduced systolic-diastolic coupling efficiency. Exercise echocardiography with evaluation of LV twisting and deformational reserve might be a useful clinical tool in other cardiac pathologies, particularly in dif-ferentiating physiological and pathological hypertrophy. As opposed to pathological hypertrophy, the athlete’s heart would be expected to have an increased twisting and deformational reserve. However, this must be confirmed in further comparative studies. Conclusions— HCM patients had severely limited strain adaptability and no LV twisting reserve at exercise. They had reduced and delayed untwisting rate with reduced systolic-diastolic coupling efficiency by twist-untwist mechanics. 6 response. Our findings suggest that impaired vascular function may contribute to exaggerated BP responses during daily living, resulting in repetitive increments in load on the heart and vessels and increased cardiovascular disease risk. 7 Summary— The management and timing of surgery in asymptomatic patients with severe aortic stenosis remain matters of concern. The risks of aortic valve surgery and late complications of prosthe-sis in such patients need to be balanced against the possible preven-tion of sudden death and lowering of cardiac mortality. Hence, early elective surgery could be proposed only to well-selected patients considered at high risk of poor outcome. In the present study, 105 consecutive asymptomatic patients with severe aortic stenosis underwent comprehensive resting and exercise stress echocardiography to evaluate the presence of pulmonary hypertension (PHT). The results showed that 55% of asymptomatic patients may develop exercise PHT. Patients with exercise PHT had significantly lower cardiac event-free survival and a markedly higher rate of death than those without exercise PHT. In addition, exercise PHT was associated with poorer outcome independently of demographic and resting echocar-diographic data and exercise-induced changes in mean transaortic pressure gradient. Beyond both resting aortic stenosis severity and systolic pulmonary arterial pressure, the assessment of the presence of exercise PHT provided important incremental predictive value. Even in patients with markedly elevated aortic jet velocity, those with exercise PHT depicted a higher risk of reduced cardiac event-free survival. These results strongly support the use of exercise stress echocardiography in the management of asymptomatic severe aortic stenosis. Early elective aortic valve surgery to prevent irrevers-ible left ventricular myocardial damage, diastolic dysfunction, and symptoms could be advised in patients developing exercise PHT. In contrast, asymptomatic patients with no exercise PHT may be con-servatively followed up. Conclusions— Summary— This is the first study to address the effects of β -blocker cessation on both chronotropic incompetence and exercise tolerance in patients with advanced heart failure. We demonstrate that short-term absence of β -blockers does not affect chronotropic incompetence or heart rate response to norepinephrine in these patients. Therefore, we further support the hypothesis that impaired chronotropic response during exercise is an intrinsic component of advanced heart failure that cannot be overcome by acute withdrawal of β -blockers. It is common that patients with advanced heart failure present to their clinician with complaints of exercise intolerance. The clinician must decide whether discontinuing β -blocker therapy offers an improvement in exercise tolerance and, therefore, perhaps quality of life. The clinician often relies on prior experience and anecdotal data to guide this decision. However, discontinuation of β -blockers is problematic given the substantial survival benefit derived from these agents in advanced heart failure. These data may inform the decision as to whether to continue β -blockers in patients with advanced heart failure and chronotropic incompetence for whom rate-responsive therapy is being considered. Conclusions— Acute β -blocker cessation does not normalize the chronotropic response to exercise in patients with advanced HF and chronotropic incompetence. 12 Summary— A large body of evidence supports a role for exercise training in improving muscle function, quality of life, and hospitaliza-tion rates in patients with heart failure, but few studies have attempted to translate this evidence into programs that can be used by very old patients with heart failure. Results from this randomized controlled trial show a lack of benefit from an exercise program designed spe-cifically for use in very old, functionally impaired patients with heart failure. Six-minute walk distance, quality of life, daily activity, functional ability, psychological state, and carer strain showed no difference between the intervention and control groups at 8 or 24 weeks. Only sit-to-stand time showed improvement with the exercise program compared with the control group. These results suggest that further work is required to design an effective exercise program for use by the oldest patients with heart failure and that programs used in younger patients cannot be assumed to be effective in very old patients. Conclusions— This exercise intervention did not improve exercise capacity or quality of life in older patients with heart failure and was not cost saving to the National Health Service. 13 Summary— Cardiopulmonary exercise testing (CPX) has emerged as an important tool for risk stratification in adult