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• W1483603610 abstract "The significance of cachexia as a clinical and prognostic factor has been largely underestimated. What is cachexia, anyway? The lack of knowledge about proven common links between cachexia in patients with chronic heart failure (CHF), chronic obstructive pulmonary disease, chronic renal failure, or cancer, as well as the fact that clinicians usually regard cachexia as untreatable, do not make it easy to introduce the term “cachexia” into everyday practice. Moreover, there is no general agreement on how to define cachexia. Nor are there efficient therapeutic regimens or evidence-based guidelines to treat or prevent weight loss in chronic illness. Weight loss is a frequent finding in patients with several chronic illnesses, such as CHF, which itself has a prognosis comparable with that of different types of highly malignant cancers.1 Using retrospective data, it has recently been suggested that cachexia in CHF patients should be diagnosed if there is documented nonintentional and nonedematous weight loss of more than 6% of the premorbid normal weight occurring over a period of more than 6 months.2 Sixteen percent of an unselected population of outpatients with CHF were found to be cachectic.3 The presence of cardiac cachexia was a strong predictor of impaired prognosis, independent of age, functional disease classification, left ventricular ejection fraction, or peak oxygen consumption.4 The mortality of cachectic CHF patients was higher than that of those who were not cachectic.2, 3 Captopril was the first angiotensin-converting enzyme (ACE) inhibitor to be introduced into the market, in 1979, and its development started in the late 60s with the finding that some peptides from the venom of the Brazilian snake Bothrops Jararaca inhibited ACE. Although captopril was primarily used in the treatment of hypertension, it soon emerged that this new class of substances exerts cardioprotective effects that go far beyond mere blood pressure control. Unlike most other antihypertensive agents, ACE inhibitors have been shown to improve endothelial dysfunction.5 They do so by reducing net angiotensin II levels and increasing the amount of the potent vasodilator nitric oxide.6 Another important factor that contributes to the cardioprotective effects of ACE inhibitors is that they reduce or even normalize left ventricular hypertrophy,7 although this finding is not too surprising, because angiotensin II and aldosterone stimulate myocyte hypertrophy and increased formation of extracellular matrix.8 The magnitude of this effect can be huge; a longitudinal study found a 40% ACE inhibitor–induced decrease in left ventricular mass during 3 years of follow-up.9 This is important, because the presence of left ventricular hypertrophy is known to increase the risk of sudden death by approximately five times and the risk of coronary artery disease by approximately three times.10 Other effects are less well understood; ACE inhibitors slightly improve insulin resistance, and they may interfere with platelet aggregation, which angiotensin II physiologically augments,7 although the clinical relevance of this finding remains speculative. The findings by Schellenbaum et al. in this issue of the Journal11 fit well into the picture of Pleiotropic ACE inhibitor actions, i.e., effects beyond those on the tenin-angiotensin-aldosterone system. They analyzed data from the Cardiovascular Health Study, a community-based prospective cohort study of adults aged 65 and older. In this study, baseline assessments were used to identify cardiovascular risk factors such as hypertension, hypercholesterolemia, and glucose intolerance; subclinical disease such as carotid artery atherosclerosis, left ventricular enlargement, and transient ischemia; and clinically overt cardiovascular disease. Schellenbaum et al. analyzed data from 2,834 patients (14,443 person-years) who had had hypertension at baseline or had developed it during follow-up and from 342 patients (980 person-years) who had developed CHF during that time. In those with treated hypertension, 24% of person-years were treated with an ACE inhibitor, and in those with CHF, this proportion was 43% of person-years. In all hypertensive patients, there was an annual weight loss of 0.38 kg, whereas in CHF patients this figure was 0.62 kg. ACE inhibitor use was associated with less annual weight loss in both groups of patients together (+0.18 kg per year, 95% confidence interval (CI)=0.07–0.30) and in the group of hypertensive patients alone (+0.17 kg per year, 95% CI=0.05–0.29). In CHF patients, ACE inhibitor use was associated with an annual weight gain of 0.29 kg (95% CI=−0.25 to +0.83), but this was not significant. In their entirety, these results confirm previous findings.2 The nonsignificant result in the subgroup of CHF patients appears to be mainly due to a lack of power. The authors did not define a specific cutoff that would define “weight loss.” The latter approach could be considered clinically more meaningful. An analysis of the Studies Of Left Ventricular Dysfunction (SOLVD)2 showed that weight loss of 6% or more at any time during follow-up was the strongest predictor of impaired survival (adjusted hazard ratio=2.10, 95% CI=1.77–2.49, P<.001). Patients taking enalapril in SOLVD had a lower hazard of 6% or more weight loss than those on placebo (adjusted reduction 19%, P=.004).2 It is also noteworthy that the proportion of CHF patients treated with an ACE inhibitor was relatively small compared with today's standards and that the follow-up of the patients was, at least in part, performed at a time when newer treatment approaches to CHF, such as beta-blockers and spironolactone, had not yet been approved. Schellenbaum et al. report that beta-blocker use was less frequent in hypertensive patients treated with an ACE inhibitor. It is now known that beta-blocker therapy also has an effect on body weight (reduces weight loss). Hence, the results in the hypertensive subgroup may be underestimates of the true weight-sparing effect of ACE inhibitors. There is currently no general treatment that is effective in preventing or treating any form of cachexia. Assuming that the available data on weight loss–preventing effects of ACE inhibitors in CHF patients and hypertensive patients2, 11 indicate something about elderly chronically ill patients, ACE inhibitors may emerge as the first pan-cachexia treatment. Indeed, imidapril, a highly lipophilic new ACE inhibitor known to readily penetrate tissues, is currently under investigation in a Phase III, multicenter, double-blind, randomized, placebo-controlled study in cachexia caused by gastrointestinal cancer.12 Imidapril is a long-acting ACE inhibitor that is registered in Japan and some European countries for the treatment of cardiovascular disease.13 This drug has been suggested to enhance mitochondrial activity and to reduce protein breakdown in the proteasome,14 which is responsible for muscle wasting in man.15 The anticachectic effects of ACE inhibitors may become at least as important for the general population as their protective cardiovascular effects. Over the next 10 years there will be a series of trials to establish effective anticachexia therapies—and ACE inhibitors are just the beginning. Financial Disclosure: Stephan von Haehling, Anja Sandek, and Stefan D. Anker have no financial support for research, consultantships, and speakers forums and no company holdings (e.g., stocks) or patents in connection with this research. Author Contributions: All authors were equally involved in the study concept and design and preparation of this editorial. Sponsor's Role: There is no sponsor for this manuscript; this was an invited editorial." @default.
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• W1483603610 title "Pleiotropic Effects of Angiotensin-Converting Enzyme Inhibitors and the Future of Cachexia Therapy" @default.
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