Tomas Palecek

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.

Onset and progression of the Anderson–Fabry disease related cardiomyopathy

BACKGROUND Cardiac involvement is responsible for substantial morbidity and mortality in Anderson-Fabry disease (AFD). We sought to document its onset and progression in a population of male and female AFD patients. METHODS We performed a cross sectional echocardiographic study of a cohort of 177 male and female AFD patients with subsequent longitudinal follow-up of 76 patients (38 males and 38 females; mean follow-up 4.5 years) who did not receive enzyme replacement therapy. RESULTS In this population, aged 3.3 to 70.8 years, a strong correlation between age and left ventricular mass indexed (LVMi, g/m(2.7)) was found in both males and females (P<0.0001 for both). At the initial examination 48.6% of the male patients and 36.4% of the female patients were classified as having left ventricular hypertrophy (LVH). The cumulative prevalence of LVH peaked at age 40 years in males and 60 years in females. In patients with longitudinal follow-up, LVMi increased by 4.07+/-1.03 g/m(2.7) per year in males and by 2.31+/-0.81 g/m(2.7) in females (P<0.01, Wilcoxon rank sum). In patients with LVH at baseline, the median progression rate was 5.52 g/m(2.7) per year in males and by 1.80 g/m(2.7) in females (P=0.12). CONCLUSION AFD is associated with high prevalence of LVH in both genders. However, the age of onset is delayed in females and progression rate slower.

Cardiac and Vascular Hypertrophy in Fabry Disease: Evidence for a New Mechanism Independent of Blood Pressure and Glycosphingolipid Deposition

Objectives—Fabry disease is an X-linked disorder resulting from α-galactosidase A deficiency. The cardiovascular findings include left ventricular hypertrophy (LVH) and increased intima-media thickness of the common carotid artery (CCA IMT). The current study examined the possible correlation between these parameters. To corroborate these clinical findings in vitro, plasma from Fabry patients was tested for possible proliferative effect on rat vascular smooth muscle cells (vascular smooth muscle cell [VSMC]) and mouse neonatal cardiomyocytes. Methods and Results—Thirty male and 38 female patients were enrolled. LVH was found in 60% of men and 39% of women. Increased CCA IMT was equally present in males and females. There was a strong positive correlation between LV mass and CCA IMT (r2=0.27; P<0.0001). VSMC and neonatal cardiomyocyte proliferative response in vitro correlated with CCA IMT (r2=0.39; P<0.0004) and LV mass index (r2=0.19; P=0.028), respectively. Conclusions—LVH and CCA IMT occur concomitantly in Fabry suggesting common pathogenesis. The underlying cause may be a circulating growth-promoting factor whose presence has been confirmed in vitro.

Cardiac involvement in Fabry disease

Fabry disease is a rare X‐linked defect of the lysosomal enzyme α‐galactosidase A. The disease is characterized by progressive intracellular accumulation of neutral glycosphingolipids. The storage occurs within various tissues and cells, including cardiocytes, the cardiac conduction system, and valvular fibrocytes. Cardiac involvement may be the sole manifestation of the disease, particularly in individuals with residual enzyme activity. In general, hemizygous men are more seriously affected than heterozygous women. The main cardiac manifestations include myocardial hypertrophy, which, in some patients, mimics hypertrophic cardiomyopathy. Conduction system involvement leads to PR shortening or, in later stages, to AV blocks. Arrhythmias presenting with variable severity also appear to be common. Valvular involvement is frequently noted but generally mild and clinically non‐significant. Newly available enzyme replacement therapy has produced promising results in preventing further functional deterioration of affected organs and possibly also in reversing impaired function.

Right Ventricular Involvement in Fabry Disease

The aim of the study was to describe right ventricular (RV) structural and functional changes in Fabry disease (FD). A detailed echocardiographic examination was performed in 58 patients with proven FD (mean age 40 +/- 16 years, 24 men). RV hypertrophy (RVH) was present in 40% of affected subjects with similar prevalence in both genders. Approximately two thirds of patients with left ventricular hypertrophy (LVH) also exhibited RVH. RV dilatation was not present in any subject. RV systolic dysfunction was noted in only 1 female subject. RV diastolic dysfunction was present in 47% of 45 subjects in whom RV filling was assessed. RV diastolic dysfunction was associated with the presence of RVH. A significant correlation between RV wall thickness and age (r = 0.52, P < .001) and left ventricular mass index (r = 0.70, P < .001) was noted. RVH with normal chamber size and preserved systolic but impaired diastolic function represents a typical RV structural change in FD. Its prevalence and degree are related to the prevalence and degree of LVH and the age of the patient.

Pulmonary arterial hypertension associated with systemic sclerosis in the Czech Republic

BackgroundSystemic sclerosis (SSc) is an important cause of pulmonary arterial hypertension (PAH), with an estimated prevalence of 7.85–26.7%.ObjectiveOur aim was to estimate the prevalence of PAH among patients with SSc in the Czech Republic and to compare haemodynamics in SSc patients diagnosed with PAH through screening with those diagnosed previously, based on symptoms.MethodsDuring 2007, SSc patients in the Czech Republic, without significant pulmonary function impairment or cardiac disease, underwent screening for PAH with transthoracic echocardiography. Those with a tricuspid regurgitant (TR) jet gradient suggestive of PAH (>30 mmHg) underwent subsequent right heart catheterisation (RHC) to confirm the diagnosis (mean pulmonary arterial pressure, mPAP, ≥25 mmHg; pulmonary capillary wedge pressure, ≤15 mmHg). Haemodynamics in patients diagnosed with PAH in this way were compared with those in patients diagnosed previously, based on symptoms.ResultsTwo hundred and three SSc patients (mean age, 53.8 ± 13 years; 82.3% women) from 26 rheumatology practices were screened. Among these, 17 had a TR jet gradient >30 mmHg and underwent RHC; PAH was confirmed in six patients. These six patients were found to have significantly lower mPAP than nine patients diagnosed previously with PAH, based on symptoms (31.17 ± 5.56 vs. 46.89 ± 9.48 mmHg, p = 0.0014).ConclusionPrevalence of PAH in our SSc cohort was 7.08%. SSc patients diagnosed with PAH through screening have less advanced disease in terms of haemodynamics than those with PAH diagnosed previously based on symptoms; their prognosis is therefore likely to be more favourable.

Early diastolic mitral annular velocity and color M-mode flow propagation velocity in the evaluation of left ventricular diastolic function in patients with Fabry disease.

Fabry disease is an X-linked genetic disorder characterized by progressive intracellular accumulation of neutral glycosphingolipids. Cardiac involvement is frequent and left ventricular (LV) diastolic dysfunction is present in most of the affected subjects. Pulsed-wave tissue Doppler echocardiography (PW-TDE) and color M-mode are new Doppler methods for LV diastolic function evaluation. Their role in the assessment of Fabry disease-related cardiomyopathy remains to be established. In this study we aimed to determine the utility of PW-TDE and color M-mode-derived parameters in the assessment of LV diastolic function in patients with Fabry disease. Eighty-one echocardiographic examinations performed in 35 patients affected by Fabry disease were retrospectively analyzed. Early diastolic lateral mitral annular velocity (Em) determined by PW-TDE and color M-mode flow propagation velocity (Vp) were measured and compared to LV filling patterns obtained using standard Doppler indexes. The receiver operating characteristics (ROC) curves method was used to determine the summary measure of relative accuracy for Em and Vp. A comparison of ROC curves showed a significant difference for areas under the curve in favor of Em (P < 0.001). Pseudonormal filling pattern, higher LV mass index, higher relative wall thickness, larger left atrial diameter, and older age were more frequent (all P < 0.001) in patients with incorrect diagnosis of normal LV diastolic function based on the measurement of Vp. Em appears to be superior to Vp in the assessment of LV diastolic function in patients with Fabry disease. Vp fails to detect abnormal LV diastolic function in subjects with pronounced concentric LV remodeling and pseudonormal filling pattern.

Association between cardiac energy metabolism and gain of left ventricular mass in Fabry disease

Left ventricular (LV) hypertrophy is the hallmark of cardiac involvement in Fabry disease (FD). However, its pathogenesis is not clearly understood as pathologic substrate accumulation represents only 1-2% of the total cardiac mass. Abnormal myocardial energy metabolism has been previously demonstrated in different forms of cardiomyopathies. We hypothesized that myocardial energy status at the time of diagnosis could have a relationship to gain of LV mass in FD. In the group of 16 affected subjects, the indicators of energetic state of cardiac muscle determined by magnetic resonance spectroscopy showed significant negative correlation with annual increase in LV mass, evaluated during long-term follow-up (8 ± 3 years). Myocardial energy metabolism may therefore represent one of the mechanisms contributing to development of FD-related cardiomyopathy.

Current Diagnostic and Therapeutic Aspects of Eosinophilic Myocarditis.

Eosinophilic myocarditis (EM) represents a rare form of myocardial inflammation with very heterogeneous aetiology. In developed countries, the most prevalent causes of EM are hypersensitivity or allergic reactions, as well as hematological diseases leading to eosinophilia. The disease may have a variable clinical presentation, ranging from asymptomatic forms to life-threatening conditions. Most patients with EM have marked eosinophilia in peripheral blood. Endomyocardial biopsy needs to be performed in most cases in order to establish a definitive diagnosis of EM. The therapy depends on the underlying aetiology. Immunosuppressive therapy represents the treatment mainstay in the majority of EM forms.

Treatment of Takotsubo Cardiomyopathy

Takotsubo cardiomyopathy (TC) is a condition most prevalent in postmenopausal women, characterized by transient left ventricular dysfunction following acute emotional or physical stress. Direct catecholamine-mediated myocyte injury and microvascular dysfunction leading to myocardial stunning are believed to play a major role in its pathogenesis. The treatment of TC remains empirical. In the acute phase, therapy must be individualized depending on hemodynamic situation. In stable conditions, it appears advantageous to prevent excessive sympathetic activation by combining alpha and beta blockade. Beta blockers are used to treat dynamic left ventricular obstruction. Phenylephrine may represent an alternative approach in patients presenting with outflow tract obstruction and severe hypotension. In hemodynamically unstable patients, early administration of intra-aortic balloon pump counterpulsation should be considered. As no consensus currently exists with respect to the chronic management of TC, randomized clinical trials are urgently needed with focus on treatment strategies.