ABC | Volume 114, Nº2, February 2020

Review Article Romano et al. Myocardial alterations in familial lipodystrophy Arq Bras Cardiol. 2020; 114(2):305-312 extremity enlargement, acanthosis nigricans, umbilical prominence or hernia, hyperphagia and accelerated growth, menstrual period irregularity , precocious puberty and menarche, among other signs and symptoms that may include cardiac autonomic changes. 10 One of the key points possibly related to the occurrence of cardiomyopathies in patients with lipodystrophy and also associated with all the described types is the accumulation of fat in ectopic tissues, such as the liver and skeletal muscle. Also, the lower capacity to oxidize and store fat promotes dyslipidemia, insulin resistance, development of diabetes mellitus and its complications, which may involve the cardiovascular system. 10 Cardiac impairment in patients with congenital lipodystrophy The World Health Organization, together with the International Society and Federation of Cardiology, has defined cardiomyopathy as a myocardial disease associated or not with cardiac dysfunction and can be classified according to morphological and physiological changes, such as dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic left ventricular cardiomyopathy, metabolic cardiomyopathy, among others. 11 Special attention should be paid, in this context, tometabolic cardiomyopathy, which develops before various pathological conditions associated with systemic metabolic disorders, being characterized by structural and functional changes without concomitant coronary artery disease or hypertension. 12 The condition, known as diabetic cardiomyopathy, is an under classification of metabolic cardiomyopathy and is defined by the presence of myocardial involvement in patients with diabetes, after excluding other causes such as ischemic myocardial disease. In diabetic cardiomyopathy, there may be left ventricular remodeling and dilation, associated with diastolic and, in some cases, systolic dysfunction. 13 The glucose metabolism impairment present in diabetes is associated with the higher consumption of fatty acids as an energy source, which is justified by the lack of insulin or resistance to it. 13 The almost exclusive use of this compound leads to excess lipids, which may be accumulated in the heart muscle or diverted to non-oxidative pathways, disrupting normal cell function and causing organ dysfunction and apoptosis, a fact called lipotoxicity. 14 In addition, permanently hyperglycemia can cause damage to the myocardium through proteins modified by advanced glycation end products, as well as oxygen free radicals, leading to their accumulation andmyocardial fibrosis, which can result in dysfunction, initially only diastolic. 13 Several cardiac alterations have been described in the literature in patients with lipodystrophy, whether solely morphological alterations or alterations associated with cardiac dysfunction, but the pathophysiological basis involved has not been completely elucidated. 10 Early atherosclerosis, especially in patients with familial partial lipodystrophy, may have a prevalence rate of over 60% and manifests before age 45. With such aggressiveness, the pathophysiological mechanisms involved seem not only to be dependent on metabolic changes, but perhaps on a direct effect of gene mutation on endothelial function. 15 In a collection of case series of lipodystrophy prior to the year 2000, several cases with hypertrophic cardiac changes have been described, with or without systolic obstruction to ventricular ejection, many with cardiomegaly and associated systemic arterial hypertension (Table 1). 16 After the 2000s, publications on isolated or grouped cases showing an association between lipodystrophy and ventricular hypertrophy 17 can also been found in the literature, even in very young or still infant patients, 18-20 and, in some cases, the progression of ventricular hypertrophy has been documented. 21 In some of these cases identified at early ages, the evolution of cardiomyopathy to global systolic dysfunction in childhood or youth has been documented. 19,21,22 Hubert Pan et al. 23 considered that LMNA mutations are generically expressed withmuscular dystrophy, lipodystrophies, bone dysplasias, and cardiovascular disease, and, before that, they reported the case of a family with Chinese ancestors with three generations of heart disease, in which 100% of the relatives older than 40 years had the clinical manifestations. The cardiovascular disease shown by the carriers of this mutation consisted of arrhythmias, atrioventricular blocks and dilated cardiomyopathies. Part of these individuals died because of cardiovascular disease. 23 In 2010, Rêgo et al. 24 reported a group of 22 patients with CGL2, of which 86.4% had a family history of the disease. Most patients had the common metabolic signs associated with the pathology, such as diabetes mellitus, insulin resistance, acanthosis nigricans, hepatosplenomegaly, elevated fasting blood glucose and triglyceride levels and low HDL-cholesterol levels, which contributed to many patients being diagnosed with metabolic syndrome. On cardiovascular examination, part of the patients had arterial hypertension, 50% of the patients had left ventricular concentric hypertrophy and 4.5% had left ventricular eccentric hypertrophy, but all cases had normal patterns in both left ventricular systolic and diastolic function, when evaluated by conventional echocardiography. 24 Lupsa et al. 1 studied 44 patients with lipodystrophy, of whom 31 had CGL. The individuals were submitted to genotypic and phenotypic diagnoses, as well as cardiac morphological and geometric analysis. Of the 31 individuals with CGL, 18 had some degree of ventricular hypertrophy, although none of them had LV systolic dysfunction. 1 (Table 2) The pathological analysis of the heart was performed in part of this series; in one of the individuals submitted to heart transplantation because of refractory heart failure, and in two others who died from respiratory failure secondary to pneumonia. Two of the patients had CGL1. In one of them, biventricular dilation and myocyte hypertrophy was evidenced, with the presence of vacuolated subendocardial myocytes, as well as subendocardial and epicardial fibrosis with fat and infiltrated with dispersed lymphocytes. The other individual with CGL1 showed mild left ventricular hypertrophy, especially posterolateral. Finally, in the last individual, who had CGL2, left ventricular hypertrophy and an irregular perivascular and interstitial fibrosis were observed. 1 Nelson et al. 2 studied 5 patients with congenital generalized lipodystrophy (2 of them with CGL1 and 3 with CGL2) and 5 control subjects with similar characteristics of age and 307