Heart failure is an increasing cause of cardiovascular (CVD) morbidity and mortality within the Western world Citation[1,2]. Given that its prognosis is recognized to be worse than for some cancers, heart failure is an important public-health concern Citation[3]. In the UK, heart failure affects 1–2% of the population as a whole, and 10–20% of the elderly. This increasingly elderly population will almost certainly lead to more heart failure cases over the next 20 years.
Myocardial infarction is the most common cause of heart failure Citation[4–6], and metabolic deterioration is an integral presentation of the clinical syndrome of this disease Citation[7]. Obesity has a long-established cause–effect relationship with cardiovascular disease Citation[8] and heart failure Citation[9,10]. However, the underlying pathophysiological mechanism(s) of this relationship remains complex.
Indeed, obesity is a risk factor for various aspects along the cardiovascular continuum, including hypertension Citation[11] and diabetes mellitus Citation[12], which themselves increase the risk of myocardial infarction and subsequent cardiac remodeling. This raises an interesting question: can one identify a direct link between obesity and an increased risk of heart failure? The cardio–metabolic consequences of adverse adipose tissue function may be a key driver for the risk of cardiac remodeling associated with obesity. The latter may be mediated by a group of metabolically active hormones, known as ‘adipocytokines’, which have proven atherogenic implications.
Role of adipocytokines in the failing heart
Of the adipocytokines, research into cardiovascular risk has focused on adiponectin, leptin, plasminogen activator inhibitor type 1 (PAI-1) and TNF-α. All are associated with adiposity and play significant roles in the modulation of energy balance Citation[13–19]. Contextually, these hormones are will probably be implicated in the chain of compensatory metabolic reactions that are initiated to preserve cardiac function in the environment of a failing heart. For example, decreasing mitochondrial respiratory chain ATP production by the cardiac muscle in heart failure promotes an increased supply of fuels, such as glucose and nonesterified fatty acids (NEFAs), to the heart and a reduced tissue responsiveness to insulin and resultant hyperinsulinemia Citation[8]. This metabolic response at the cardiac level can lead to excessive lactate, increased proton production, free-radical formation and intracellular acidosis, which are all associated with cardiac membrane damage and arrhythmias Citation[20,21]. Several aspects of physical and metabolic deterioration in heart failure related to humoral regulatory function have been observed. In particular, leptin and adiponectin have received the most attention, possibly due to their profound effects on the maintenance of energy equilibrium.
Leptin & cardiac function
Circulating leptin directs the balance between energy intake and expenditure Citation[22]. Once considered to be solely derived from adipose tissue, leptin is actually made by a number of tissues, including the heart Citation[23]. Leptin acts in a neuro–hormonal manner via receptors expressed in the CNS Citation[22] and in an autocrine manner with receptors on peripheral tissues Citation[24–26]. One possible role that allows leptin to link obesity and heart failure is its impact on blood pressure through sympathetic outflow Citation[27]. Leptin is also implicated in the insulin-resistant state in heart failure Citation[28], where hyperinsulinemia promotes adipogenesis and leptin secretion Citation[29]. These increased leptin levels may attenuate these effects through a feedback loop, via the proposed ‘adipoinsular axis’ Citation[25]. Certainly, circulating levels of leptin are raised in heart failure Citation[30,31] and may have a role in the development of cardiac cachexia Citation[32].
Similar to leptin, TNF-α is predominantly made by adipocytes. TNF-α is a proinflammatory cytokine, and elevated levels have been demonstrated in patients with heart failure, which may be directly related to cardiac function Citation[33] or as a stimulus for leptin secretion Citation[34]. While levels of leptin are increased in obese individuals, raised levels of leptin at the heart are unlikely to promote obesity-related cardiac remodeling. Leptin has antisteatotic effects (promotes fatty-acid oxidation), and increased levels of this adipocytokine do not lead to the accumulation of triglycerides within cardiomyocytes, which, in turn, has been associated with contractile dysfunction Citation[35]. Rather, leptin-deficient ob/ob mice actually exhibit a higher degree of this type of cardiomyocyte toxicity, which can be reversed by leptin administration (albeit in a model of murine obesity) Citation[36]. Other work involving these mice showed that leptin signaling improves functional outcomes in chronic ischemic injury leading to heart failure Citation[37].
Adiponectin & cardiac function
In contrast to leptin, adiponectin has anti-inflammatory properties and circulating levels correlate inversely with measures of insulin resistance and obesity Citation[38]. Adiponectin holds much potential as a cardiovascular biomarker Citation[39,40], where low levels are used to explicate increased cardiovascular risk Citation[41] in both healthy Citation[42] and high-risk populations Citation[43]. Interestingly, there are also data showing that increasing adiponectin elicits a favorable effect on post-myocardial infarction left ventricular remodeling Citation[44], with the potential to attenuate cardiac myocyte hypertrophy Citation[45] and protect against left ventricular dysfunction and the progression of heart failure Citation[46]. Variants in the adiponectin gene are correlated with left ventricular mass in human genetic studies Citation[47]. Other genetic studies have focused on the expression of mRNA for adiponectin and its receptors in cardiac tissue. Studies in human cardiomyocytes demonstrate a tissue-specific production and metabolism of this hormone Citation[48]. Given the diverse metabolic remit relating to the regulatory role of adiponecitn (e.g., insulin sensitizing, free-fatty-acid oxidation, gluconeogenesis, anti-inflammatory modulation of the endothelium and counteraction of proinflammatory cytokines Citation[49]), its local effects on the heart are unclear. Amongst streptozotocin-induced diabetic rats, the expression of cardiac adiponectin receptors is upregulated Citation[52]. Other studies of animal cardiomyocyte cultures suggest that adiponectin causes an increase in glucose and fatty-acid uptake Citation[50].
Adipocytokines & the obesity paradox
Obesity is strongly implicated in cardiac function and structure Citation[51–53]. However, circulating concentrations of leptin and adiponectin, which reflect obesity (albeit diet-induced obesity), do not appear to carry the same implications for heart failure. Raised levels of leptin appear to reflect reduced cardiomyocyte lipotoxicity Citation[39]. Moreover, several studies conducted in patients with heart failure have found direct correlations between adiponectin and other markers of deteriorating cardiac function (brain-type natriuretic peptides), where high and not low adiponectin levels independently predicted mortality Citation[54–56].
Rather than contributing to the inferred pathophysiological relationship between obesity and heart failure, adipocytokines may explain why the prognosis of heart failure is better in the obese. Various studies have shown that survival in the setting of heart failure is appreciably improved in those patients who are obese Citation[57–59]. Despite more diabetes, hypertension and dsylipidemia amongst obese and overweight groups, higher BMI is associated with a trend toward improved survival among heart failure patients Citation[62]. It is tempting to postulate that the increased circulating concentrations of leptin and increased expression of adiponectin receptors in the heart (as a reponse to low levels of adiponectin), provide an environment that prime the body to compensate for reduced cardiac output. However, this remains a speculation that would be difficult to test. Certainly, such findings would add to the diverse repertoire of pathophysiological implications that are elicited by these hormones in the setting of cardiovascular disease. However, given this paradoxical consequence, it also precludes the diagnostic and prognostic utility of these adipocytokines in a clinical setting Citation[32,60,61].
In summary, obesity carries an increased risk of incident heart failure, which is co-ordinated with abberant circulating concentrations of leptin and adiponectin, which in turn regulate energy homeostasis. While these hormones reflect an increased risk of cardiac dysfunction, their prognostic value has a paradoxical relationship Citation[62], as with the link between obesity and heart failure.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Hobbs FDR, Kenkre J, Roalfe AK, Davis RC, Hare R, Davies MK. Impact of heart failure and left ventricular systolic dysfunction on quality of life. Eur. Heart J.23, 1867–1876 (2002).
- Ho KK, Anderson KM, Kannel WB, Grossman W, Levy D. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation88, 107–115 (1993).
- McMurray JJ, Stewart S. Epidemiology, aetiology and prognosis of heart failure. Heart83, 596–602 (2000).
- Spencer F, Meyer T, Goldberg R J et al. Twenty year trends (1975–1995) in the incidence, in-hospital and long-term death rates associated with heart failure complicating acute myocardial infarction: a community-wide perspective. J. Am. Coll. Cardiol.34, 1378–1387 (1999).
- Nicod P, Gilpin E, Dittrich H et al. Influence on prognosis and morbidity of left ventricular ejection fraction with and without signs of left ventricular failure after acute myocardial infarction. Am. J. Cardiol.61, 1165–71 (1988).
- Emanuelsson H, Karlson W, Herlitz J. Characteristics and prognosis of patients with acute myocardial infarction in relation to occurrence of congestive heart failure. Eur. Heart J.15, 761–768 (1994).
- Opie LH. The metabolic vicious cycle in heart failure. Lancet364, 1733–1734 (2004).
- Kannel WB, LeBauer EJ, Dawber TR, McNamara PM. Relation of body weight to development of coronary heart disease. The Framingham Study. Circulation35, 734–744 (1967).
- Alpert MA. Obesity cardiomyopathy: pathophysiology and evolution of the clinical syndrome. Am. J. Med. Sci.321, 225–236 (2001).
- Kenchaiah S, Evans JC, Levy D et al. Obesity and the risk of heart failure. N. Engl. J. Med.347(5), 305–13 2002.
- Stamler J. Epidemiologic findings on body mass and blood pressure in adults. Ann. Epidemiol.1, 347–362 (1991).
- Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham Study. Diabetes Care2, 120–126 (1979).
- Considine RV, Subha MK, Heiman ML et al. Serum immunoreactive leptin concentrations in normal-weight and obese humans. N. Engl. J. Med.334, 292–295 (1996).
- Tong J, Fujimoto WY, Kahn SE et al. Insulin, C-peptide, and leptin concentrations predict increased visceral adiposity at 5- and 10- year follow-ups in nondiabetic Japanese Americans. Diabetes54, 985–990 (2004).
- Arita Y, Kihara S, Ouchi N et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Commun.257, 79–83 (1999).
- Cigolini M, Targher G, Bergamo Andreis IA, Tonoli M, Agostino G, De Sandre G. Visceral fat accumulation and its relation to plasma hemostatic factors in healthy men. Arterioscler. Thromb. Vasc. Biol.16, 368–374 (1996).
- Winkler G, Cseh K, Baranyi E et al. Tumor necrosis factor system in insulin resistance in gestational diabetes. Diabetes Res. Clin. Prac.56, 93–99 (2002).
- Chu N-F, Spiegelmann D, Hotamisligil GS, Rifai N, Stampfer M, Rimm EB. Plasma insulin, leptin, and soluble TNF receptor levels in relation to obesity-related atherogenic anf thrombogenic cardiovascular disease risk factors among men. Atherosclerosis157, 495–503 (2001).
- Chu NF, Shen MH, Wu DM, Shieh SM. Plasma TNF-R1 and insulin concentrations in relation to leptin levels among normal and overweight children. Clin. Chem.35, 287–92 (2002).
- Neely JR, Grotyohann LW. Role of glycolytically derived protons and lactate and damage to the myocardium. Dissociation of adenosine triphosphate levels and recovery function of reperfused ischaemic hearts. Circ. Res.55, 816–824 (1984).
- Wolff AA, Rotmensch HH, Stanley WC, Ferrari R. Metabolic approaches to the treatment of ischaemic heart disease: the clinician’s perspective. Heart Fail. Rev.7, 187–203 (2002).
- Banks WA. The many lives of leptin. Peptides25, 331–338 (2004).
- Karmazyn M, Purdham DM, Rajapurohitam V, Zeidan A. Leptin as a cardiac hypertrophic factor: a potential target for therapeutics. Trends Cardiovasc. Med.17, 206–211 (2007).
- Tartaglia LA, Dembski M, Weng X et al. Identification and expression cloning of a leptin receptor, OB-R. Cell83, 1263–1271 (1995).
- Keiffer TJ, Habener JF. The adipoinsular axis: effects of leptin on pancreatic β-cells. Am. J. Physiol. Endocrinol. Metab.278, E1–E14 (2000).
- Giandomenico G, Dellas C, Czekay RP, Koschnick S, Loskutoff DJ. The leptin receptor system of human platelets. J. Thromb. Haemost.3, 1042–1049 (2005).
- Quilliot D, Böhme P, Zannad F, Ziegler O. Sympathetic-leptin relationship in obesity: effect of weight loss. Metabolism57, 555–562 (2008).
- Doehner W, Pflaum CD, Rauchhaus M et al. Leptin, insulin sensitivity and growth hormone binding protein in chronic heart failure with and without cardiac cachexia. Eur. J. Endocrinol.145, 727–735 (2001).
- Kolaczynski JW, Nyce MR, Considine RV et al. Acute and chronic effects of insulin on leptin production in humans: studies in vivo and in vitro. Diabetes45(5), 699–701 (1996).
- Perego L, Pizzocri P, Corradi D et al. Circulating leptin correlates with left ventricular mass in morbid (grade III) obesity before and after weight loss induced by bariatric surgery: a potential role for leptin in mediating human left ventricular hypertrophy. J. Clin. Endocrinol. Metab.90, 4087–4093 (2005).
- Patel JV, Sosin M, Lim HS et al. Raised leptin concentrations among South Asian patients with chronic heart failure. Int. J. Cardiol.122, 34–40 (2007).
- Schulze PC, Kratzsch J, Linke A et al. Elevated serum levels of leptin and soluble leptin receptors in patients with advanced chronic heart failure. Eur. J. Heart Fail.5, 33–40 (2003).
- Ferrari R, Bachetti T, Confortini R et al. Circulation. Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation92, 1479–1486 (1995).
- Takahashi N, Waelput W, Guisez Y. Leptin is an endogenous protective protein against the toxicity exerted by tumour necrosis factor. J. Exp. Med.189, 207–212 (1999).
- Szczepaniak LS, Dobbins RL, Metzger GJ et al. Myocardial triglycerides and systolic function in humans: in vivo evaluation by localized proton spectroscopy and cardiac imaging. Magn. Reson. Med.49, 417–423 (2003).
- Barouch LA, Gao D, Chen L et al. Cardiac myocyte apoptosis is associated with increased DNA damage and decreased survival in murine models of obesity. Circ. Res.98, 119–124 (2006).
- McGaffin KR, Sun CK, Rager JJ et al. Leptin signalling reduces the severity of cardiac dysfunction and remodelling after chronic ischaemic injury. Cardiovasc. Res.77, 4–5 (2008).
- Weyer C, Funahashi T, Tanaka S et al. Hypoadiponectinemia in obesity and Type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J. Clin. Endocrinol. Metab.86, 1930–1935 (2001).
- Hara K, Yamauchi T, Imai Y et al. Reduced adiponectin level is associated with severity of coronary artery disease. Int. Heart J.48, 149–153(2007).
- Patel JV, Lim HS, Hughes EA, Lip GY. Adiponectin and hypertension: a putative link between adipocyte function and atherosclerotic risk? J. Hum. Hypertens.21, 1–4 (2007).
- von Eynatten M, Schneider JG, Humpert PM et al. Serum adiponectin levels are an independent predictor of the extent of coronary artery disease in men. J. Am. Coll. Cardiol.47(10), 2124–2126 (2006).
- Pischon T, Girman CJ, Hotamisligil GS et al. Plasma adiponectin levels and risk of mycardila infarction in men. JAMA291, 1730–1737 (2004).
- Schulze MB, Shai I, Rimm EB et al. Adiponectin and future coronary heart disease events among men with Type 2 diabetes. Diabetes54, 534–539 (2005).
- Shibata R, Izumiya Y, Sato K et al. Adiponectin protects against the development of systolic dysfunction following myocardial infarction. J. Mol. Cell Cardiol.42, 1065–1074 (2007).
- Shibata R, Ouchi N, Ito M et al. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat. Med.10, 1384–1389 (2004).
- Liao Y, Takashima S, Maeda N et al. Exacerbation of heart failure in adiponectin-deficient mice due to impaired regulation of AMPK and glucose metabolism. Cardiovasc. Res.67, 705–713 (2005).
- Iacobellis G, Petrone A, Leonetti F, Buzzetti R. Left ventricular mass and +276 G/G single nucleotide polymorphism of the adiponectin gene in uncomplicated obesity. Obesity14, 368–372 (2006).
- Pineiro R, Iglesias MJ, Gallego R et al. Adiponectin is synthesized and secreted by human and murine cardiomyocytes. FEBS Lett.579, 5163–5169 (2005).
- Wolf G. Adiponectin: a regulator of energy homeostasis. Nutr. Rev.61, 290–292 (2003).
- Palanivel R, Fang X, Park M . Globular and full-length adiponectin mediate specific changes in glucose and fatty acid uptake and metabolism in cardiomyocytes. Cardiovasc. Res.75, 148–157 (2007).
- Lavie CJ, Messerli FH. Cardiovascular adaptation to obesity and hypertension. Chest90, 275–279 (1986).
- Manson JE, Colditz GA, Stampfer MJ et al. A prospective study of obesity and risk of coronary heart disease in women. N. Engl. J. Med.322, 882–889 (1990)
- Garavaglia GE, Messerli FH, Nunez BD, Schmieder RE, Grossman E. Myocardial contractility and left ventricular function in obese patients with essential hypertension. Am. J. Cardiol.62, 594–597 (1988).
- Nakamura T, Funayama H, Kubo N et al. Association of hyperadiponectinemia with severity of ventricular dysfunction in congestive heart failure. Circ. J.70, 1557–1562 (2006).
- Kistorp C, Faber J, Galatius S et al. Plasma adiponectin, body mass index and mortality in patients with chronic heart failure. Circulation112, 1756–1762 (2005).
- Tamura T, Furukawa Y, Taniguchi R et al. Serum adiponectin as an independent predictor of mortality in patients with congestive heart failure. Circ. J.71, 623–630 (2007).
- Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis in chronic systolic heart failure: the obesity paradox. Am. J. Cardiol.91, 891–894 (2003).
- Horwich TB, Fonarow GC, Hamilton MA et al. The relationship between obesity and mortality in patients with heart failure. J. Am. Coll. Cardiol.38, 789–795 (2001).
- Mosterd A, Cost B, Hoes AW et al. The prognosis of heart failure in the general population: the Rotterdam Study. Eur. Heart J.22, 1318–1327 (2001).
- Lim HS, Tayebjee MH, Tan KT, Patel JV, Macfadyen RJ, Lip GYH. Severity differences and relation to coronary artery disease serum adiponectin in coronary heart disease. Heart91, 1605–1606 (2005).
- Iwashima Y, Katsuya T, Ishikawa K et al. Hypoadiponectinemia is an independent risk factor for hypertension. Hypertension43, 1318–1323 (2003).
- Lieb W, Sullivan LM, Harris TB et al. Plasma leptin levels and incidence of heart failure, cardiovascular disease and total mortality in the elderly. Diabetes Care (2008) (In Press).