Cardiac manifestations in Fabry disease

Fabry disease is an X-linked recessive genetic disorder of glycosphingolipid metabolism, due to deficiency of the lysosomal enzymeα-galactosidase A. The disease is characterized by the progressive intracellular lysosomal accumulation of neutral glycosphingolipids throughout the body, including the cardiovascular system.It has been reported that cardiac involvement could be the sole manifestation of the disease in some patients. Myocardial abnormalities are characterized mainly by left ventricular (LV) wall thickening without significant cavity dilatation, the most frequent abnormal structural pattern being concentric LV hypertrophy (LVH). In some patients the disease mimics a typical hypertrophic obstructive cardiomyopathy. According to our experience, systolic function is largely preserved in a large majority of affected individuals. In contrast, mild to moderate impairment of diastolic filling is a relatively common finding, representing probably the most important cause of dyspnoea in patients with Fabry disease. However, in a relatively large population of affected patients, severe diastolic dysfunction, typical of restrictive cardiomyopathy, was not found. Valvular structural abnormalities are frequent due to valvular infiltration. In several patients, hypertrophy of papillary muscles and/or systolic anterior motion of the mitral leaflets associated with LV outflow obstruction may aggravate the mitral valve dysfunction. We did not confirm the previously reported high prevalence of mitral valve prolapse. Valvular regurgitation seems to be relatively frequent but mostly non-significant. Electrocardiographic changes in Fabry disease are multiple and include at rioventricular (AV) conduction abnormalities (abbreviation of the P-R interval or AV blocks), signs of LVH and repolarization abnormalities. Our observations suggest that conduction defects and repolarization changes are present predominantly in subjects with LV structural abnormalities. Cardiac symptoms inpatients with Fabry disease include shortness of breath on effort (related to LV diastolic dysfunction), vasospastic and/or exertional angina pectoris (due to LVH, endothelial dysfunction and/or fixed coronary artery stenosis) and syncope (related to AV blocks or LV outflow obstruction). The extent of cardiac involvement, in particular LV mass assessment, could represent an ideal surrogate endpoint for evaluating the efficacy of specific therapies.     

Cardiovascular manifestations in Fabry disease: a clinical and echocardiographic study

This study reviews the clinical and echocardiographic findings in a cohort of Fabry patients (n=12) and compares echocardiographic findings to normal controls. Almost all patients had extracardiac manifestations. Five out of 12 patients had cardiovascular symptoms. Nine out of 12 patients had left ventricular hypertrophy (LVH) on the electrocardiogram (ECG) and one patient had short PR interval. Three patients had epicardial coronary disease. Four patients had 'rat-tail' appearance on left ventriculogram. Six patients who had myocardial biopsy showed extensive vacuolation of the myocytes on light microscopy and concentric, myelinoid lamellar cytoplasmic inclusion bodies on electron microscopy. On echocardiography, LV mass was significantly increased in the Fabry group compared to normal controls. Traditional parameters of diastolic function including peak E velocity, peak A velocity and deceleration time were no different to normal controls. The IVRT was significantly prolonged in the Fabry subjects. The PV atrial reversal duration exceeded that of mitral A wave duration in the Fabry group. The septal E' velocity with Doppler tissue imaging (DTI) was significantly lower in the Fabry group than the normal controls. Fabry disease should be considered in the differential diagnosis in patients with unexplained LVH and late onset hypertrophic cardiomyopathy. Extracardiac manifestations are common.     

SGLT2 inhibitors: a focus on cardiac benefits and potential mechanisms

Heart Failure Reviews - This paper highlights the cardioprotective potential of sodium-glucose cotransporter 2 inhibitors (SLGT2i), as well as several most discussed mechanisms responsible for...     

Pathophysiology of cardiac inflammation: molecular mechanisms

BACKGROUND: Inflammatory processes induced by rival infection are believed to be one of the major pathogenetic mechanisms in inflammatory dilated cardiomyopathy. Although the reason for progression to myocardial failure is not fully understood, postulated mechanisms include persistent viral infection alone or in combination with autoimmune processes. PATHOPHYSIOLOGY: Murine models of myocarditis have provided insight into the mechanisms by which autoimmune responses to cardiac antigens, probably in response to viral infection of the myocardium, arise and cause tissue pathology. Organ-specificity, cross-reactivity between microbial agents and cardiac tissue, and induction of tolerance to self-antigen are issues still at stake. In addition, cytokines mediate activation and effector phase of innate and specific immunity, which are both important in controlling viral infection. The innate immune response not only has an important protective function but also serves to initiate and regulate subsequent specific immune responses. In man, on the one hand specific T cells and antibodies against different cardiac tissue components have been demonstrated in myocardium and sera of patients with inflammatory cardiomyopathy, and on the other hand viral genome has been identified in endomyocardial biopsies due to the rapid development of new molecular biological techniques such as polymerase chain reaction (PCR), southern blot analysis and in-situ hybridization. But it is still a mater of debate whether virus infection itself, the ensuing immune response, or both, contribute to the deterioration of left ventricular function. CONCLUSION: Taking these mechanisms into account, screening for viral genome by PCR and detection of inflammatory infiltrates by immunohistochemistry are considered crucial for the establishment of a definite diagnosis thereby allowing for the initiation of specific therapeutic strategies.     

An expert consensus document on the management of cardiovascular manifestations of Fabry disease

Fabry disease (FD) is an X‐linked lysosomal storage disorder caused by pathogenic variants in the α‐galactosidase A (GLA) gene that leads to reduced or undetectable α‐galactosidase A enzyme activity and progressive accumulation of globotriaosylceramide and its deacylated form globotriaosylsphingosine in cells throughout the body. FD can be multisystemic with neurological, renal, cutaneous and cardiac involvement or be limited to the heart. Cardiac involvement is characterized by progressive cardiac hypertrophy, fibrosis, arrhythmias, heart failure and sudden cardiac death. The cardiac management of FD requires specific measures including enzyme replacement therapy or small pharmacological chaperones in patients carrying amenable pathogenic GLA gene variants and more general management of cardiac symptoms and complications. In this paper, we summarize current knowledge of FD‐related heart disease and expert consensus recommendations for its management.     

Fabry disease female proband with clinical manifestations similar to hypertrophic cardiomyopathy

Fabry's disease is an X-linked inborn error of glycosphingolipid catabolism, resulting from a deficiency in alpha-galactosidase A (alpha-Gal A). A 56-year-old Japanese woman was at first suspected of having hypertrophic cardiomyopathy. The patient and her son had alpha-Gal A activity in leukocytes that was remarkably below the limit of controls. DNA analysis of the alpha-Gal A gene revealed a novel missense mutation at codon 19 in exon 1, resulting in leucine-to-proline substitution. As a result she was confirmed as a classic Fabry heterozygote. Recent advances in enzyme replacement therapy can reverse the storage of glycosphingolipids in Fabry's disease. Thus, in patients with cardiac hypertrophy, it is important to differentiate Fabry's disease from other causes of hypertrophy. Therefore, it is necessary to measure alpha-Gal A activity in all suspected cases and to analyze genetic abnormalities in heterozygotes.     

Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey.

AIMS: Anderson-Fabry disease (AFD) is an uncommon X-linked disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. The Fabry Outcome Survey is a European database designed to monitor the long-term efficacy and safety of enzyme replacement therapy (ERT) with agalsidase alfa. The aim of this study was to determine the prevalence and characteristics of cardiac disease in AFD patients. METHODS AND RESULTS: Clinical and laboratory data were available in 714 patients from 11 countries (mean age 35 +/- 17 years, 369 women, 336 treated). The prevalence of angina was 23 vs. 22%; palpitations and arrhythmias 27 vs. 26%; exertional dyspnoea 23 vs. 23%; and syncope 2 vs. 4%, in women and men, respectively (all P = NS). The frequency of all cardiac symptoms was significantly higher in treated than in untreated patients. Gender, age, and glomerular filtration rate were independent determinants of echocardiographically assessed left ventricular hypertrophy (LVH). CONCLUSION: This study confirms the high prevalence of cardiac morbidity associated with AFD. The disease burden in treated women exceeds that of untreated men, suggesting that most women selected for ERT have advanced disease. The presence of LVH is associated with higher frequency of cardiac signs and symptoms and relates independently to gender, age, and renal function.     

Metabolic dysfunction and cardiovascular disease:molecular mechanisms

Obesity is a common risk factor for the development of cardiovascular disease.It is estimated that 71%of men,61%of women and 33%of children are overweight in the United States,and this trend toward increasing body mass is found world-wide as more cultures acquire a Western lifestyle.In the United States,life expectancy declines by 3 years for those with a body mass index over 30 and by 10 years for those with a body mass index over 40 due,in large part,to the increased prevalence of cardiovascular disease.Over the past decade we have come to appreciate that adipose tissue functions as an endocrine organ,and that obesity contributes to cardiovascular and metabolic disorders through cytokine imbalances that promote the development of a chronic,low grade inflammatory state.Bioactive proteins secreted from fat are generally referred to as adipokines.Under conditions of obesity,adipose tissue expresses higher levels of pro-inflammatory adipokines,such as TNF- and IL- 6,and lower levels of anti-inflammatory cytokines. Adiponectin in the prototypical anti-inflammatory adipokine,and its expression is down-regulated in obese individuals.Low adiponectin levels have shown to be an independent risk factor for developing type 2 diabetes,myocardial infarction and hypertension. Studies with genetically manipulated mice have shown that adiponectin protects against the development of a number of diseases that are prevalent in obese individuals including insulin re- sistance,atherosclerosis,LV hypertrophy,and a peripheral artery disease.However,no adiponectin-based therapies have been successfully launched in the clinic due,in large part,to difficulties associated with the high natural abundance of adiponectin (0.01%of the serum protein) and its complex structure.My laboratory performs genetic screens to identify novel adiponectin-like factors involved in metabolic and cardiovascular regulation.One of these newly discovered factors,referred to as Sfrp5, is a secreted protein that is largely produced by adipocytes.Sfrp5 functions     

Narrative review: Fabry disease

Fabry disease is an X-linked, hereditary, lysosomal storage disease caused by deficiency of the enzyme alpha-galactosidase A, which results in the accumulation of the neutral glycosphingolipid globotriaosylceramide (Gb3) in the walls of small blood vessels, nerves, dorsal root ganglia, renal glomerular and tubular epithelial cells, and cardiomyocytes. It is a complex, multisystem disorder that is characterized clinically by chronic pain and acroparesthesia, gastrointestinal disturbances, characteristic skin lesions (angiokeratomata), progressive renal impairment, cardiomyopathy, and stroke. Enzyme replacement therapy (ERT) with intravenous infusions of recombinant human alpha-galactosidase A consistently decreases Gb3 levels in plasma and clears lysosomal inclusions from vascular endothelial cells. The effects of ERT on other tissues are not as obvious, suggesting that treatment must be initiated early in the course of the disease to be optimally effective or that some complications of the disease are not responsive to enzymes delivered intravenously.     

Apoptosis: molecular mechanisms and implications for human disease

Abstract. Apoptosis is a highly regulated process of cell death with characteristic morphological changes that are distinct from necrosis. The biochemical machinery responsible for apoptotic cell death appears to be constitutively expressed in most, if not all, cells and can be triggered by a variety of signals, including sustained increases in the intracellular Ca²⁺ level. Apoptosis is the main mechanism of cell deletion during development, normal cell turnover, hormone-induced tissue atrophy, and pathological processes such as T-cell depletion in HIV/AIDS and neurodegenerative disease. The aim of this review is to briefly summarize current knowledge of the molecular mechanisms of apoptosis and its role in human disease.     

End-stage cardiac manifestations and autopsy findings in patients with cardiac fabry disease

BACKGROUND: Fabry disease is an X-linked recessive disorder resulting from a deficiency of alpha-galactosidase A with multi-organ dysfunction. Patients with manifestations limited to the heart have been reported recently as a disease variant. We have previously reported a 3% prevalence of this cardiac variant in men with left ventricular hypertrophy, which we designated cardiac Fabry disease. The purposes of the current study were to evaluate the end-stage cardiac manifestations and autopsy findings in patients with cardiac Fabry disease. METHODS and RESULTS: We evaluated five autopsied male patients with cardiac Fabry disease. One died of ventricular fibrillation and four of heart failure. Electrocardiograms obtained at hospitalization revealed the presence of conduction abnormalities and nonsustained ventricular tachycardia. Echocardiograms and autopsy findings showed the presence of left ventricular hypertrophy in all patients. Localized thinning of the basal posterior wall of the left ventricle was detected in four patients who died of heart failure. All patients had severe left ventricular dysfunction. Histologically, myocardial cells showed glycosphingolipid accumulation in all of the patients but no accumulation was observed in other organs or in systemic vascular endothelial cells. CONCLUSIONS: Severe left ventricular dysfunction, conduction disturbances and ventricular arrhythmias occur in end-stage cardiac Fabry patients. Furthermore, left ventricular hypertrophy commonly associated with thinning of the base of the left ventricular posterior wall is present. The accumulation of glycosphingolipids can be observed in myocardial cells but not in other organs.     

Terminal stage cardiac findings in patients with cardiac Fabry disease: an electrocardiographic, echocardiographic, and autopsy study

OBJECTIVES: Fabry disease is caused by deficiency of alpha-galactosidase A, and typically causes multi-organ dysfunction. Patients with manifestations limited to the heart, mainly left ventricular hypertrophy (LVH), have been reported as a disease variation. We have reported a 3% prevalence of this cardiac variant in men with LVH, which we designated 'cardiac Fabry disease'. The purposes of this study were to evaluate the terminal stage cardiac manifestations and autopsy findings in patients with cardiac Fabry disease. METHODS: We examined seven terminal stage patients with cardiac Fabry disease. During hospitalization, standard 12-lead electrocardiograms, Holter electrocardiograms, and echocardiograms were obtained. Autopsies were performed and macroscopic along with microscopic findings were evaluated. RESULTS: Six patients died of heart failure and one of ventricular fibrillation. Electrocardiograms revealed the presence of conduction abnormalities and nonsustained ventricular tachycardia. Echocardiograms and autopsy findings revealed LVH in all patients. Localized basal posterior wall thinning of the left ventricle was detected in the six patients who died of heart failure. All patients had severe left ventricular dysfunction. Histologically, myocardial cells, but not cardiac vascular endothelial cells, showed glycosphingolipid accumulation. No accumulation was observed in other organs or in systemic vascular endothelial cells. CONCLUSIONS: Severe left ventricular dysfunction with associated conduction disturbances and ventricular arrhythmias occur in patients with terminal stage cardiac Fabry disease. Furthermore, LVH is present and associated with thinning of the base of the left ventricular posterior wall. In contrast to typical Fabry disease, accumulation of glycosphingolipids was observed in myocardial cells but not in other organs.     

Pathophysiologic mechanisms in diabetic kidney disease: A focus on current and future therapeutic targets

Diabetic kidney disease (DKD) is the primary cause of chronic kidney disease around the globe and is one of the main complications in patients with type 1 and 2 diabetes. The standard treatment for DKD is drugs controlling hyperglycemia and high blood pressure. Renin angiotensin aldosterone system blockade and sodium glucose cotransporter 2 (SGLT2) inhibition have yielded promising results in DKD, but many diabetic patients on such treatments nevertheless continue to develop DKD, leading to kidney failure and cardiovascular comorbidities. New therapeutic options are urgently required. We review here the promising therapeutic avenues based on insights into the mechanisms of DKD that have recently emerged, including mineralocorticoid receptor antagonists, SGLT2 inhibitors, glucagon-like peptide-1 receptor agonist, endothelin receptor A inhibition, anti-inflammatory agents, autophagy activators and epigenetic remodelling. The involvement of several molecular mechanisms in DKD pathogenesis, together with the genetic and epigenetic variability of this condition, makes it difficult to target this heterogeneous patient population with a single drug. Personalized medicine, taking into account the genetic and mechanistic variability, may therefore improve renal and cardiovascular protection in diabetic patients with DKD.