METABOLIC SYNDROME AND ATRIAL FIBRILLATION

Dalmo Antonio Ribeiro Moreira M.D, PhD - Head of Medical Section of Electrophysiology and Cardiac Arrhythmias of the Institute Dante Pazzanese of Cardiology, So Paulo; Brazil. - Doctor of Science by the Faculty of Medicine, University of So Paulo; Brazil. - Full Professor of Human Physiology, Faculty of Medicine Itajub; Minas Gerais, Brazil.

e-mail: dalmoantonio@gmail.com

Introduction In the process of maintaining homeostasis in living species, the normal heart rhythm is prominent.This rhythm originates and is maintained by a series of electrophysiological events, which includes the formation and conduction of impulses from a specialized structure located in the high right atrium, known as the sinus node. Cells with the capacity to self activate, trigger electrical activity regulated at frequency ranging between 80 and 100 beats per minute.

Cardiac arrhythmias are changes of electrical activity caused by disorders of forming, or conduct, the conduct and forming of the electrical impulse simultaneously. May originate in structures located in the atria, atrioventricular junction or ventricles. Arrhythmias may arise due to the presence of triggers (extrasystoles, for example) that act on an arrhythmogenic substrate, usually composed of diseases affecting the heart itself, such as coronary artery disease or hypertension. On the other hand, may arise as a result of systemic changes that alter functionally cellular electrophysiological properties, such as occurs in autonomic dysfunction characterized by sympathetic hyperactivity or parasympathetic, and metabolic (pH, electrolytes, tissue ischemia, neuro-endocrine factors, free radicals, etc.) known collectively by modulating factors of the substrate.

Metabolic syndrome is a systemic disorder characterized by a set of cardiovascular risk factors that includes dyslipidemia, insulin resistance and increased predisposition to develop type 2 diabetes mellitus, and hypertension. The pathogenesis of this syndrome has not been definitively established but may be related to obesity, sedentary lifestyle and irregular dietary habits, and genetic factors. Metabolic syndrome increases the overall mortality by about twice, and cardiovascular mortality in three times due to cardiac complications (especially coronary insufficiency) and noncardiac, particularly vascular, visceral and cerebral disease.

According to the International Diabetes Federation, metabolic syndrome is present when the following criteria are met: a) central obesity, waist circumference whose values vary according to ethnicity: 94 cm to

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80 cm for men and women in cases of Europeans; 90 and 80 cm respectively for men and Asian women, and 85 and 90 cm for the Japanese. Besides this, two or more of the following criteria can also be considered: a) hypertriglyceridemia 150 mg / dL or being in treatment, b) HDL cholesterol <40 mg / dL in men and <50 mg / dL in women or being in treatment; c) the hypertension 130/85 mmHg or treatment of previously diagnosed hypertension; d) fasting glucose 100 mg / dL or type 2 diabetes mellitus previously diagnosed. Besides these, others are described subclinical abnormalities potentially associated with metabolic syndrome and that are presented in Table 1.

Table 1 - Subclinical metabolic abnormalities potentially related to metabolic syndrome

Changes in the hypothalamic-pituitary axis increased plasma levels of glucocorticoids increase of glucocorticoid receptors Kidney failure increased retention of sodium elevation of renin, angiotensin and aldosterone microalbuminuria Change of fat deposition accumulation of fat in adipose tissue hiperliptinemia, decreased adiponectinemia Disorders of the cardiovascular system increase in sympathetic activity concentric hypertrophy of the smooth muscle of blood vessels reducing the drop in heart rate and blood pressure during night Prothrombotic state increase in fibrinogen increased plasma viscosity increase of factor VIII C Endothelial dysfunction impairment of vascular dilatation in skeletal muscle related to nitric oxide increased plasma levels of C-reactive protein and interleukin 6, system changes of tumor necrosis factor alpha Altered liver function increased production of glucose increasing function of hepatic lipase increased gamma-glutamyl transpeptidase) Changes in skeletal muscle.

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The occurrence of all these abnormalities may be related to insulin resistance and hyperinsulinemia and are jointly significant cardiovascular risk factors.

Hypertension can affect the heart causing muscle hypertrophy and ventricular fibrillation as well (by increased ventricular end diastolic pressure), increase myocardial oxygen consumption, and accelerate fat deposition in the vessels favoring atherosclerosis, both coronary arteries as also systemic arteries. Diabetes mellitus when installed causes, among other complications, retinopathy with progressive and irreversible visual loss, nephropathy with renal insufficiency culminating in addition to neuronal varied involvement. The vascular involvement in diabetes is diffuse, a factor that accelerates the formation of systemic atherosclerosis.

Alone or together, these cardiovascular risk factors can interfere with the heart function, changing its ability to generate stimuli, leading to arrhythmias. Also, indirectly, the metabolic syndrome may alter the autonomic activity influencing the heart and facilitate the emergence of arrhythmias by variable mechanisms, which could increase the morbidity of the syndrome itself or cause more serious events such as sudden death. Among the different types of arrhythmias, atrial fibrillation seems to be the most commom associated with metabolic syndrome. Atrial fibrillation is a cardiac rhythm disorder characterized by the absence of atrial contraction and fast heart rate (usually above 100 beats per minute). It is the most common supraventricular tachyarrhythmia encountered in clinical practice, whose incidence increases with age. It can originate secondary to cardiac and non-cardiac causes, among which the metabolic syndrome is a common cause today. Atrial fibrillation affects greatly the quality of life of affected patients, may cause exuberant symptoms including shortness of breath at major to minor exertion, palpitations, chest pain and, in most advanced cases may be associated with heart failure and increased risk of systemic thromboembolism.

This monograph will discuss the mechanisms responsible for the genesis of atrial fibrillation in patients with metabolic syndrome.

Metabolic Syndrome as a Cause of Atrial Fibrillation

Metabolic syndrome can affect the heart and generate ectopic beats in the atria, can modulate the activity of an arrhythmogenic substrate already installed, causing atrial fibrillation due to autonomic sympathetic hyperactivity, and also secondary to metabolic disorders that affect the electrophysiological function of the atrial myocyte. The different factors that comprise metabolic syndrome facilitates the onset of atrial fibrillation by different mechanisms, as described below.

Obesity The metabolic syndrome is often associated with obesity. It has been shown that obese patients are more

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vulnerable to hypertension and also to atrial fibrillation. Besides ventricular hypertrophy and left atrial enlargement, it is possible that obese patients have higher risk of atrial fibrillation secondary to insulin resistance. The increased sympathetic autonomic activity, as demonstrated in obese patients is another important factor because the adrenergic hyperactivation reduces the atrial refractory period and increases the chance of ectopic tachycardia that culminates with atrial fibrillation. Weight loss can improve this situation by causing a reduction in sympathetic activity. Another arrhythmogenic factor associated with obesity is sleep apnea. Obese patients have a higher predisposition to this disease, which may contribute to the installation of hypertension, atherosclerosis, insulin resistance and also to atrial fibrillation.

Specific inflammatory pathways can also be activated in obese patients who evolve with sleep apnea, and thus are additional important cardiovascular risk factors. Furthermore, this syndrome has been associated with acceleration of atherosclerosis, the increased risk of hypertension, stroke, heart failure, atrial fibrillation, and even sudden death. Therefore, the risk assessment of obese patients with metabolic syndrome should include the research of sleep apnea by the technique of polysomnography.

Sleep apnea syndrome (relation between apnea / hypopnea index> 5) is associated with increased risk of stroke and death, particularly during sleep and increases the risk of bradyarrhythmias (sinus bradycardia, sinus pauses), atrial fibrillation, complex ventricular extra systoles and non-sustained ventricular tachycardia.

Inflammation Inflammatory factors are frequently found in obese subjects with metabolic syndrome and point to another factor related to the occurrence of cardiac arrhythmias. It has been shown that patients who had elevated plasma levels of ultra-sensitive C-reactive protein, have a higher risk of atrial fibrillation, which is present without any involvement of the structure and function of the heart. The systemic inflammatory processes cause the release of biochemical signaling that affect the atrial myocardium and generate the arrhythmia. What is suggested in these cases is that inflammatory processes alter the atrial myocyte cellular electrophysiology, increasing the chance of spontaneous ectopic beats and atrial fibrillation, which would be maintained by a re-entry mechanism generated by atrial electrical and histological remodeling. Another interesting epidemiologic data, according to the National Registry to Advance Heart Health (ADVANCENT), atrial fibrillation is present in about one third of patients with left ventricular dysfunction, and of these, almost one third is suffering from diabetes mellitus. Again, the association between different risk factors favoring the emergence of this very common arrhythmia in clinical practice.

Hypertension Left ventricular hypertrophy in hypertensive patients is the main cause of left atrial enlargement due to retrograde effect of increased end-diastolic pressure on the left atrium. Thus, the distension of the atrial wall followed by their expansion, favors the emergence of ectopic atrial beats, atrial tachycardia and especially atrial fibrillation, with all its complications including tachicardiomyopathy (cardiomyopathy secondary to rapid ventricular rates), heart failure, and sistemic thromboembolism. The formation of thrombi in this

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condition is also favored by increased blood viscosity caused by elevated levels of fibrinogen, cholesterol and triglycerides, which are common in metabolic syndrome. The increasing population of receptors of angiotensin II type, especially in the left atrium, is another important factor in generating arrhythmias, since angiotensin shortens the duration of the atrial effective refractory period, increasing the vulnerability to atrial arrhythmias. There are several studies that demonstrate the benefits of administration of ACE inhibitors or angiotensin receptor blockers, in reducing the incidence of atrial fibrillation in patients with hypertension.

Insulin Resistance and Diabetes Mellitus

Insulin resistance, particularly linked to obesity, is a factor associated with atrial fibrillation. Two factors seem to contribute to this condition: a) the hyperadrenergic state very frequent in hyperinsulinemia, b) the exacerbation of the inflammatory state. In the first case is well known that hyperinsulinemia acts in the central nervous system and enhances the stimulation of the sympathetic system, causing increased heart rate, blood pressure and ventricular muscle mass. Atrial fibrillation occurrs by the direct action action of the sympathetic nervous system in atrial tissue and indirectly through the left ventricular hypertrophy.

As for the inflammatory process, there are recent studies linking insulin resistance with inflammation mediated by adipose tissue. In this case, the accumulation of fat in adipocytes derived from the diet and obesity itself, initiates a state of cellular stress that activates specific pathways (IKKbeta / NF-kB and JNK). Once activated, these routes would cause increased production of pro-inflammatory cytokines, including the tumor necrosis factor alpha, interleukin 6, leptin, resistin, adiponectin, angiotensinogen, and others. Monocytes adhered to the adipose tissue, which later differentiate into macrophages, can produce inflammatory cytokines, amplifying the signal, promoting local tissue inflammation spreading it systemically.

Recent population studies suggest an association between type 2 diabetes mellitus and atrial fibrillation, regardless of the presence of heart disease or hypertension. This finding points to the early identification and treatment of these patients aimed at preventing cardiovascular complications such as thromboembolism and heart failure. Diabetes is considered one of the most important risk factors for the onset of atrial fibrillation.

In conclusion, metabolic syndrome is an important cardiovascular risk factor and can be source of atrial fibrillation, either by direct cardiac complications it brings, but also indirectly through the inflammatory pathways that are stimulated in this condition. Prevention of these complications should be based on early identification of individuals at risk. Often, only measures that effectively control the metabolic syndrome may be sufficient to reverse the progression of clinical status. In this case, the treatment of diabetes, dyslipidemia, sleep apnea, obesity, changes in lifestyle and eating habits are always indicated in this population. Moreover, the antiarrhythmic drugs have no important role in metabolic syndrome and this fact should be highlighted because in this syndrome the basic treatment would be directly addressed to the causal factors responsible for the arrhythmia.

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