Alexandra Dadarlat-Pop1, Dana Pop2, Anca Buzoianu3
1 Department of Cardiology, „Niculae Stăncioiu” Heart Institute, Cluj-Napoca, Romania
2 Department of Cardiology, Clinical Rehabilitation Hospital, Cluj-Napoca, Romania
3 Department of Pharmacology, Toxicology and Clinical Pharmacology, „Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
Abstract: Chronic heart failure and obesity are two conditions which despite all the advances made in the recent years, still represent two of the leading causes of morbidity and mortality worldwide. Moreover, a well-known fact is that the risk of sudden cardiac death, mostly related to malignant arrhythmias is higher in apparently healthy obese individuals in com-parison with lean subjects. On the other hand, obese heart failure patients bring unique challenges in the diagnosis of heart failure, having a better prognosis than their normal or underweight counterparts. Taking into account the above-mentioned existing data, there are questions regarding whether cardiac arrhythmias such as atrial fibrillation or ventricular arrhythmias in this population have certain evolutive particularities. This paper describes various mechanisms of cardiac arrhythmias found in obese heart failure patients, such as myocardial architectural changes, neurohormonal and paracrine modifications. Keywords: heart failure, rhythm disorders, obesity.
Rezumat: Insuficienţa cardiacă cronică şi obezitatea sunt două afecţiuni care, în ciuda tuturor progreselor înregistrate în ultimii ani, reprezintă încă două dintre principalele cauze ale morbidităţii şi mortalităţii la nivel mondial. Mai mult chiar, riscul de moarte subită cardiacă, în cea mai mare parte legat de aritmii maligne, este mai mare la persoanele obeze aparent sănătoase, în comparaţie cu subiecţii normoponderali. Pe de altă parte, pacienţii obezi cu insufi cienţă cardiac, dificil de dia-gnosticat din punct de vedere al afecţiunii cardiace, au un prognostic mai bun decât omologii lor normoponderali şi mai ales subponderali. Ţinând cont de datele existente menţionate, ne-am pus problema dacă aritmiile cardiace, cum ar fi fibrilaţia atrială sau aritmii ventriculare, prezente la această categorie de pacienţi au anumite particularităţi evolutive. Acest referat descrie diferitele mecanisme implicate în apariţia aritmiilor cardiace la pacienţii cu insuficienţă cardiacă şi obezitate, cum ar fi modificările „arhitecturale” miocardice, dar şi cele neurohormonale şi paracrine. Cuvinte-cheie: insuficienţă cardiacă, aritmii cardiace, obezitate.
OBESITY AND HEART FAILURE
Both, heart failure and obesity represent major public health problems with extremely high mortality rates, the mortality due to heart failure being evaluated by up to 50 % at 5 years of evolution, despite the data provided by important studies such as Framingham Heart and Olmsted County Studies, which showed significant improvements in the survival of the patients with heart failure in the last years1,2.
Obesity is an independently acknowledged cardi-ovascular risk factor, being significantly implicated in the development of heart failure. In Europe, obesity affects 21.5% and 24.5% of men, respectively women3.
Age-related relative risk of developing cardiovascu-lar pathology is approximately 20% and 40-60% higher for overweight, respectively obese patients than in the general population4. Approximately 11% of cases of heart failure in men and 14% in women have obesity as a unique aetiology4.
The Framingham study showed an increase in the risk of developing heart failure by 5% for males and 7% for women for every one-point increase in BMI over 25. In comparison with normal weight subjects, the risk of heart failure is two-fold higher in obese pa-tients, with a relative risk of 2.12 for females and 1.90 for males5. Most patients with obesity develop heart failure with preserved left ventricular ejection fraction due to a significant decrease in ventricular distensibi-lity in response with their hypervolemic state6. The cardiac fi brosis leads to impaired ventricular diastolic filling and also, to important microcirculatory deran-gements6.
Obesity leads to systemic inflammatory state, with serious effects on the cardiovascular system. It may in-fluence the coronary arteries, by accelerating the athe-rosclerosis process, even though the exact mechanism remains not entirely described. Also, the accumulation of epicardial adipose tissue has important implications in the development of cardiac mechanical or electrical disturbances. Moreover, it seems to be in close asso-ciation with presence and severity of coronary ischae-mic disease6. The hyperaldosteronism described in obese individuals enhance the fibrotic process, heart failure obese patients responding very well to minera-locorticoid receptor antagonists treatment.
THE OBESITY PARADOX
Heart failure diagnosis poses more challenges in obese patients because the classic signs and symptoms, such as dyspnea, decreased exercise tolerance are more difficult to identify, the echocardiographic window is often inadequate, and the diagnostic and prognostic markers are in lower concentrations1. However, pati-ents with overweight or obesity and heart failure have a better prognosis than normal weight patients or tho-se with cardiac cachexia, phenomenon which is known as the „paradox of obesity”.
A meta-analysis of six studies which included 22.807 patients with heart failure demonstrated that the hi-gher the BMI, the more important cardiovascular events are registered (cardiovascular mortality, mor-tality of any cause, number of rehospitalization for 2.9 years)7. Moreover, a reverse relationship between the level of NT-pro-BNP and BMI has been described8.
Although there is strong evidence supporting this paradox, the relationship between obesity and heart failure’s prognosis is still uncertain. Greater metabo-lic reserves, secretion of protective cytokines, youn-ger age or earlier presentation, different aetiologies of heart failure, increased muscle mass and muscular strength, attenuated response to renin–angiotensin– aldosterone system or non-purposeful weight loss are all responsible for a better prognosis9. On the other hand, this paradox was not found in patients with di-abetes mellitus and heart failure without obesity10,11.
However, the “obesity paradox” seems to disap-pear with an important increase of the BMI12.
POSSIBLE ARRHYTHMIAS’ MECHANISMS IN OBESE HEART FAILURE PATIENTS
There is a strong relationship between obesity, epi-cardial fat and cardiac arrhythmias. The Framingham study has shown that obese individuals apparently healthy have a 40-fold higher risk of sudden cardiac death than lean subjects13. Moreover, one of the lea-ding causes of death in heart failure patients are cardi-ac arrhythmias, which are frequently found in patients with heart failure and obesity in the clinical practice. We summarize below some of the possible mecha-nisms involved in the development and progression of these arrhythmias.
Figure 1. Links between obesity, heart failure and cardiac arrhythmias.
Conduction disorders. The infiltrative and meta-plastic changes described in this category of patients may affect the cardiac conduction system, such as the sinus node, the atrioventricular node, the right bundle branch of the His fascicle, but also the myocardium surrounding the atrioventricular ring, which may lead to various conduction disorders: sinoatrial block, ri-ght bundle branch block, rarely even atrioventricu-lar block14. These changes occur when the adipose cells most often from the epicardial level accumulate between the muscle fibers or lead to their degenera-tion14. In the recent years, the role of epicardial and pericardial fat, two embryologically distinct forms of adipose tissue, was intensively studied in relation to the development of several cardiac arrhythmias15. The epicardial fat is responsible for secreting different me-tabolic factors, such as free fatty acids, angiogenic fac-tors, growth and remodeling factors, adipocytokines (adiponectin, leptin), infl ammatory cytokines and che-mokines and various interleukins, plasminogen activa-tor inhibitor-1, tumour necrosis factor alpha. On the other hand, the pericardial fat serves more as a depot of adipose tissue, sharing similar endocrine, paracrine and autocrine functions with the visceral adipose tis-sue.
Myocardial architectural changes especially left ven-tricular hypertrophy described in this population in-volve coronary flow changes leading to a myocardial arrhythmogenic substrate4. Moreover, sympathetic hyperreactivity and elevated serum catecholamine le-vels have an important additional contribution to the development of cardiac arrhythmias. Moreover, high free fatty acids concentrations may also affect repo-larization. Apparently a 10% increase in body weight decreases the parasympathetic tone and increases the heart rate4. There is recent data showing that remo-deling of calcium homeostasis has an important role in cardiac arrhythmias development in patients with diabetes mellitus and obesity16.
Atrial fibrillation. By far, the most common su-praventricular arrhythmia is atrial fibrillation. Atrial fibrillation is frequently seen in patients with heart failure, irrespective of their left ventricular ejection fraction, complicating their prognosis through the associated thromboembolic risk and by worsening the systolic dysfunction and also exacerbating the sympto-matology1. The occurrence of atrial fibrillation in pati-ents with heart failure is a marker of poor prognosis. The data from a recent registry-EuroObservational Research Program HF Long-Term Registry shows that atrial fibrillation is present in 44% of patients hospita-lized for acute heart failure and in 36.7% of patients with chronic heart failure17.
There are studies suggesting that obesity is an in-dependent risk factor for the development of atrial fibrillation, the risk being directly proportional to the BMI value18,19. Atrial dilatation and atrial dysfunction secondary to the obesity-induced cardiomyopathy are largely responsible for the onset, recurrence or pro-gression of atrial fibrillation. The atrial remodeling is often accompanied by electrophysiological changes, such as shortening of the atrial refractory period, as well as by surface electrocardiogram modifications re-garding the P wave length, PR interval or the negative terminal force of the P wave20.
Other mechanisms incriminated in triggering this arrhythmia in obese heart failure patients are the adi-pose tissue accumulation in the left atrium posterior wall, which independently associates with the deve-lopment of atrial fibrillation, intramyocardial fibrosis favoring the re-entry circuits, as well as the paracrine mechanisms, various adipo-fibrokines having pro- ar-rhythmogenic effects15,20. The release from the epi-cardial fat of several inflammation biomarkers, such as tumour necrosis factor- and interlukin-1 may lead to atrial fibrillation development15. In the Framingham Heart Study, epicardial volume fat was associated with an increase in the prevalence of atrial fi brillation after adjustment for atrial fi brillation risk factors, BMI and other ectopic fat depots21. Recent studies show that obese patients suffering from heart failure with pre-served ejection fraction and atrial fibrillation have a substantial lower risk of death of any cause or of reho-spitalization for decompensated heart failure compa-red to normal weight patients22. Atrial fibrillation is an independent marker of all-cause mortality and rehos-pitalization for decompensated heart failure in patients with heart failure with preserved ejection fraction and a BMI <25 kg /m2 23.
Of note that there is evidence regarding the pre-sence of the “obesity paradox” phenomenon also in overweight/ obesity patients with atrial fibrillation be-ing effi ciently anticoagulated, in terms of complications such as all cause-mortality, stroke incidence, systemic embolism, myocardial infarction to lean AF patients, class 1 obese patients with AF having a 35% lower risk of all-cause mortality than those with normal BMI24,25. The mechanisms underlying this phenomenon are not well understood and many confounding factors may be implicated. First, lean individuals are significantly older in most of the observational cohorts, knowing that age is a powerful predictor of mortality in AF patients. On the other hand, studies suggest a more aggressive ma-nagement of AF in obese patients as compared with their leaner counterparts. Also, a normal BMI may be due to several pathological catabolic conditions26. In the Aristotle study, the presence of obesity was shown to be associated with a better survival in pa-tients with atrial fibrillation efficiently anticoagulated, regardless of the inflammation biomarkers values or the presence of renal impairment27.
However, a meta-analysis of 51 studies involving 626603 patients showed that the presence of obesity in post-operative and post-ablation patients is asso-ciated with an increased risk of recurrence of this arrhythmia, by 19 to 29% for each 5U increment of BMI28. The presence of epicardial fat has also been associated with an increased risk of post-ablation atri-al fi brillation recurrence29.
Ventricular arrhythmias. Usually, patients with heart failure with preserved ejection fraction exhibit supraventricular arrhythmias, while those with heart failure with reduced ejection fraction develop ventri-cular arrhythmias26.
Ventricular arrhythmias occur 40-60 times more frequently in morbidly obese than in general popula-tion of similar age. Ventricular arrhythmias are com-mon in heart failure patients, approximately 87% of them have isolated or coupled premature ventricular contractions and 45% present non-sustained ventri-cular tachycardia30. Ventricular extrasystoles are also 30 times more common in obese patients with left ventricle hypertrophy, and the complexity of ventri-cular ectopicities correlates with left ventricular dias-tolic diameter and left ventricular mass31. A particular feature of this group of patients is the prolongation of the QTc interval. Electrophysiological studies in subjects with obesity have shown increased electrical irritability, which can trigger ventricular arrhythmias, even in the absence of ventricular dysfunction or heart failure. One of the possible mechanisms is the increa-se in insulin resistance commonly described in obese heart failure patients12. The prognosis of obese heart failure patients, who have an indication for implanta-ble cardioverter-defibrillator (ICD) placement in pri-mary prevention is similar to that of normal weight patients32. However, studies show that cardiac-resyn-chronization therapy with an implantable defibrillator in obese patients with advanced chronic non-ischemic heart failure does not bring significant additional bene-fits to ICD, as clearly seen in those with an ischemic aetiology33.
To conclude with, even though the prognosis of obese patients with heart failure is better than in nor-mal weight or cachectic population, arrhythmias occur quite frequently and complicate their evolution, having certain particular features that need to be emphasized and properly treated.
Conflict of interest: none declared.
1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37 (27):2129-200.
2. Bastien M, Poirier P, Lemieux I, Després JP. Overview of epidemiol-ogy and contribution of obesity to cardiovascular disease. Prog Car-diovasc Dis. 2014;56:369-81.
3. Yumuk V1, Tsigos C, Fried M, Schindler K, Busetto L, Micic D, To-plak H. Obesity Management Task Force of the European Associa-tion for the Study of Obesity. European Guidelines for Obesity Man-agement in Adults. Obes Facts. 2015;8(6):402-24.
4. World Health Organization: Obesity and Overweight. WHO fact sheet No 311, Geneva, WHO, 2015. www.who.int/mediacentre/ factsheets/fs311/en/ (last accessed November 30, 2015).
5. Mathew B, Francis L, Kayalar A, Cone J. Obesity: effects on cardio-vascular disease and its diagnosis. J Am Board Fam Med. 2008;21(6): 562-8.
6. Packer M. Epicardial Adipose Tissue May Mediate Deleterious Ef-fects of Obesity and Inflammation on the Myocardium. J Am Coll Cardiol. 2018;71(20):2360-72.
7. Guglin M, Baxi K, Schabath M. Anatomy of the obesity paradox in heart failure. Heart Fail Rev. 2014;19(5):621-35.
8. Horwich TB, Fonarow GC, Clark AL. Obesity and the Obesity Para-dox in Heart Failure. Prog Cardiovasc Dis. 2018;61(2):151-156.
9. López-J, Cortés-Bergoderi M. Update: systemic diseases and the cardiovascular system (i): obesity and the heart. Rev Esp Cardiol. 2011;64(2):140-9.
10. Sharma A, Lavie CJ, Borer JS, Vallakati A, Goel S, Lopez-Jimenez F, Arbab-Zadeh A, Mukherjee D, Lazar JM. Meta-analysis of the rela-tion of body mass index to all-cause and cardiovascular mortality and hospitalization in patients with chronic heart failure. Am J Cardiol. 2015;115:1428-34.
11. Ndumele CE, Matsushita K, Sang Y, Lazo M, Agarwal SK, Nambi V, Deswal A, Blumenthal RS, Ballantyne CM, Coresh J, Selvin E. N-Ter-minal Pro-Brain Natriuretic Peptide and Heart Failure Risk Among Individuals With and Without Obesity: The Atherosclerosis Risk in Communities (ARIC) Study.Circulation. 2016; 133(7):631-8.
12. Lavie CJ, De Schutter A, Parto P, Jahangir E, Kokkinos P, Ortega FB, Arena R, Milani RV. Obesity and Prevalence of Cardiovascular Dis-eases and Prognosis-The Obesity Paradox Updated. Prog Cardio-vasc Dis. 2016;58(5):537-47.