Journal of the American College of Cardiology Ó 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
Fat, Cachexia, and the Right Ventricle in Heart Failure A Web of Complicity* Mandeep R. Mehra, MD Boston, Massachusetts
Cachexia, derived from the Greek “kakos” (bad) and “hexis” (condition), is a dreaded yet frequent accompaniment of advanced heart failure (HF) syndromes. This unintentional loss of excess body weight has a serious prognostic connotation and signifies a greater burden of morbidity and mortality (1). Despite knowledge of this condition for over a century and investigations into its putative mechanisms and pathways, little is understood definitively and therapeutic targets have not been forthcoming. On the other extreme, obesity is celebrated in HF as an entity conferring a favorable prognosis, a term referred to as the obesity “paradox.”
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This presumed paradox is founded in the knowledge that although obesity is an undesirable state and associated with a decreased quality of life, patients with HF tend to live longer if they are designated as obese (2). Tantalizingly, Melenovsky et al. (3), in this issue of the Journal, provide observational correlations that connect cardiac cachexia and its prognostic implication to fat mass loss, as well as provide interesting insight into the association and implications of such unintentional weight loss with varying grades of right ventricular dysfunction as evaluated by echocardiography. The investigators defined cachexia by employing a history of >5% unintentional weight loss in 6 months in combination with biochemical evidence of a pro-inflammatory state (elevated C-reactive protein), hematological aberration (anemia), and poor nutritional status (low albumin), and they identified the disorder in 1 in 5 patients with chronic HF and systolic dysfunction within *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. Dr. Mehra has consulting relationships with Abbott Vascular, Boston Scientific, St. Jude’s Medical, Medtronic, Janssen (Johnson and Johnson), Thoratec, American Board of Internal Medicine, and the National Heart, Lung, and Blood Institute; and has served as Editor-in-Chief of the Journal of Heart and Lung Transplantation.
Vol. 62, No. 18, 2013 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2013.07.021
their selected cohort. Their principal observations of interest that deserve further scrutiny include: 1) a finding that the extent of right ventricular (RV) dysfunction independent of left ventricular (LV) systolic dysfunction or dimensions was more strongly correlated with cardiac cachexia and eventual prognosis; and 2) fat mass rather than lean body mass loss was noted in Cachexia, a finding in contradistinction to prevailing thought. The right ventricle (RV), which for decades has been treated as a bystander chamber, is emerging out of its closet. As evidence-based therapy to advance outcomes in LV failure has gained momentum, attention is shifting intensely to the RV with the recognition that eventual prognosis in treated left HF is intricately linked to ongoing deficits in right heart function. The association of pulmonary venous hypertension, RV dysfunction, and adverse outcome is supported by a number of studies (4–6). Even in mechanically supported left hearts, the RV and its aberrations are critically intertwined in the pathophysiology of outcomes with LV assist devices (7). Thus, it is not at all surprising that advancing grades of RV dysfunction appeared to correlate with outcome in the present study, especially in the presence of cardiac cachexia, a signal that the pathological state of HF had advanced egregiously toward inexorable decline. The converse speculation that it is RV dysfunction that leads to the cachectic state is less well supported and difficult to assimilate. The cardio-renal syndrome, a term for aberrations in organ cross talk, have been closely linked to cachexia as well as right HF (8). Indeed, clinical observations suggest that it is unusual to find cardiac cachexia in advanced HF in the absence of renal dysfunction. This was also noted by Melenovsky et al. (3) that cachectic patients exhibited worse estimated glomerular filtration rate than those who were noncachectic did (53 19 ml/min1/1.73 m2 vs. 46 14 ml/min1/1.73 m2, p ¼ 0.0004). The advent of cardio-renal syndrome is thought to arise less through a reduction in forward output but more via mechanisms of congestion arbitrated by RV failure and its hemodynamic consequences (9). Surprisingly, the present study found little elevation in right-sided pressures between cachectic and noncachectic patients and no difference in the estimated glomerular filtration rate between those with and without RV dysfunction. Alas, such are the limitations of observational snapshot-based association trials because diuretic doses and intensification, episodes of decompensation (their number and impact), were not diligently evaluated in this study. If indeed, RV dysfunction is a seminal arbiter in determining the genesis of cachexia, we should be able to find insight from the population of patients with predominantly right HF such as those with pulmonary arterial hypertension or individuals with underlying congenital heart disease. Although protein-wasting syndromes and malnutrition are well described in congenital heart disease syndromes, it is unusual to see severe cachexia in such conditions (10). Similarly, pulmonary arterial hypertension syndromes with
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Mehra Fat, Cachexia, and Heart Failure
consequent right HF do exhibit associations with cachexia but the frequency appears low to magnify this link as mechanistically reliable (11). Thus, although the observation of the link between RV dysfunction and cachexia is strong, the 2 likely represent epiphenomenon of advancing stages of HF rather than a cause and effect relationship. The other intriguing finding in this paper is the stronger association of fat mass loss with cachexia and prognosis rather than lean, nonfat mass. Prevailing thought dictates that in cachexia states, one loses both fat and nonfat mass. This data comes from situations where the advanced HF state is often allowed to progress inexorably without the opportunity for remedy with advanced therapeutics (12). In the current investigation, the disease progression was mitigated by the deployment of cardiac transplantation or a ventricular assist device. The event rates (death or urgent transplantation or placement of a LV assist device) were 25% per year (37% over a medial follow-up of 1.48 years), somewhat lower than would be contemporaneously expected from ambulatory risk stratification of ambulatory patients with advanced HF undergoing evaluation for heart transplantation in advanced HF populations (13). Unfortunately, the investigators do not provide the separation of events into the 3 component parts, or characteristics of the patients advancing to these endpoints, which could have allowed us to better understand whether the cachexia encountered in this study was picked up in its early temporal manifestation. Evidence that the investigated cohort was less ill is signaled by the lack of significant anemia or hypoalbuminemia between the distinct cachexia and noncachectic cohorts. It may well be that fat loss precedes lean muscle loss as cachexia becomes manifest. This is an important issue as there is a threshold effect to any therapeutic venture. Targets to ameliorate cachexia in HF may work optimally if applied at earlier stages of the development of this disorder, although this remains highly conjectural. The exploration of this study into the obesity paradox is another issue open to intrigue. Body composition was derived differentially by 2 different techniques including dual-energy x-ray absorptiometry in 35% of the patients and skin fold thickness in most others. Although the 2 techniques were correlated (r ¼ 0.56), this represents a source for some error in estimation of the relative body composition impact. Nevertheless, it is known that advancing HF is associated with increased natriuretic peptide expression, which in turn leads to enhanced lipolysis (14). In other studies, the inhibition of lipolysis through genetic ablation of adipose triglyceride lipase or hormone-sensitive lipase abolishes features of cancerassociated cachexia (15). Although this has not been directly proven in cardiac failure, functional lipolysis may be essential in the pathogenesis of cachexia and, therefore, a viable therapeutic target, especially in early stages. Targeting cachexia will require identifying and tackling early signals such as anorexia and, as this study suggests, early grades of RV dysfunction. Therapy could be aimed at tackling anorexia by hypothalamic inhibition of signaling via the type-4 melanocortin receptor (16) or by using Ghrelin analogues to
stimulate appetite (17). Alternatively, the therapy may exploit lean mass catabolic pathways by using molecules such as soluble myostatin decoy receptors (18) or replenishing reduced testosterone levels (19). In other studies, polyunsaturated fatty acids (fish oils) have been shown to provide anti-inflammatory and anabolic effects while demonstrating signals in improving mortality in HF (20,21). In conclusion, cardiac cachexia is a multifaceted, poorly understood phenomenon. The association of RV dysfunction with cachexia may be important in that it may provide an early screen for its development and therapeutic considerations. Similarly, the loss of fat mass may signal the onset of a declining prognosis. These 2 seemingly epistemological breaks may reflect the discontinuity of scientific progress in our field and allow us to integrate old theories within the context of new paradigms. As enunciated by the French philosopher, Gaston Bachelard, “The characteristic of scientific progress is our knowing that we did not know.” Reprint requests and correspondence: Dr. Mandeep R. Mehra, Brigham and Women's Hospital Heart and Vascular Center, A-3, 75 Francis Street, Boston, Massachusetts 02115. E-mail:
[email protected].
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JACC Vol. 62, No. 18, 2013 October 29, 2013:1671–3 14. Lafontan M, Moro C, Berlan M, Crampes F, Sengenes C, Galitzky J. Control of lipolysis by natriuretic peptides and cyclic GMP. Trends Endocrinol Metab 2008;19:130–7. 15. Das SK, Eder S, Schauer S, et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 2011;333:233–8. 16. Suzuki M, Narita M, Ashikawa M, et al. Changes in the melanocortin receptors in the hypothalamus of a rat model of cancer cachexia. Synapse 2012;66:747–51. 17. Palus S, Schur R, Akashi YJ, et al. Ghrelin and its analogues, BIM28131 and BIM-28125, improve body weight and regulate the expression of MuRF-1 and MAFbx in a rat heart failure model. PLoS One 2011;6:e26865. 18. Han HQ, Zhou X, Mitch WE, Goldberg AL. Myostatin/activin pathway antagonism: molecular basis and therapeutic potential. Int J Biochem Cell Biol 2013;45:2333–47.
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19. Stout M, Tew GA, Doll H, et al. Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study. Am Heart J 2012;164:893–901. 20. Mehra MR, Lavie CJ, Ventura HO, Milani RV. Fish oils produce antiinflammatory effects and improve body weight in severe heart failure. J Heart Lung Transplant 2006;25:834–8. 21. Lavie CJ, Milani RV, Mehra MR, Ventura HO. Omega-3 polyunsaturated fatty acids and cardiovascular diseases. J Am Coll Cardiol 2009;54:585–94.
Key Words: body composition - cardiac cachexia obesity paradox - right ventricular function.
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heart failure
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