Js Shah

Effects of enzyme replacement therapy on the cardiomyopathy of Anderson-Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa

Background: Anderson–Fabry disease is an X-linked glycosphingolipid storage disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A. This leads to a progressive accumulation of globotriaosylceramide (Gb3) in the lysosomes of cells throughout the body that ultimately results in premature death from renal, cardiac or cerebrovascular complications. Until recently, there was no effective therapy available for this disease. The present study was designed to assess the safety and efficacy of enzyme replacement therapy with agalsidase alfa on the cardiac manifestations of Anderson–Fabry disease. Method: The effects of therapy with agalsidase alfa on cardiac structure and function were assessed in a randomised, double-blind, placebo-controlled study of 15 adult male patients with Anderson–Fabry disease. The following parameters were measured at baseline and 6 months: left ventricular mass, QRS duration and levels of Gb3 in cardiac tissue, urine sediment and plasma. After 6 months of the randomised trial patients were enrolled in a 2-year open-label extension study. Results: Left ventricular mass, as measured by MRI, was significantly reduced following 6 months of treatment with agalsidase alfa compared with placebo (p = 0.041). A mean 20% reduction in myocardial Gb3 content as assessed by serial transvenous endomyocardial biopsies was demonstrated over the 6 months of enzyme replacement compared to a mean 10% increase in patients receiving placebo (p = 0.42) Conclusion: Enzyme replacement therapy with agalsidase alfa resulted in regression of the hypertrophic cardiomyopathy associated with Anderson–Fabry disease.

Prevalence of exercise-induced left ventricular outflow tract obstruction in symptomatic patients with non-obstructive hypertrophic cardiomyopathy

Background: Resting left ventricular outflow tract obstruction (LVOTO) occurs in 25% of patients with hypertrophic cardiomyopathy (HCM) and is an important cause of symptoms and disease progression. The prevalence and clinical significance of exercise induced LVOTO in patients with symptomatic non-obstructive HCM is uncertain. Methods and results: 87 symptomatic patients (43.3 (13.7) years, 67.8% males) with HCM and no previously documented LVOTO (defined as a gradient ⩾30 mm Hg) underwent echocardiography during upright cardiopulmonary exercise testing: 54 patients (62.1%; 95% CI 51.5 to 71.6) developed LVOTO during exercise (latent LVOTO); 33 (37.9%; 95% CI 28.4 to 48.5) had neither resting nor exercise LVOTO (non-obstructive). Patients with latent LVOTO were more likely to have systolic anterior motion of the mitral valve (SAM) at rest (relative risk 2.1, 95% CI 1.2 to 3.8; p = 0.01), and higher peak oxygen consumption (mean difference: 10.3%, 95% CI 2.1 to 18.5; p = 0.02) than patients with non-obstructive HCM. The only independent predictors of Δ gradient during exercise were a history of presyncope/syncope, incomplete/complete SAM at rest and Wigle score (all p<0.05). Subsequent invasive reduction of LVOTO in 10 patients with latent obstruction and drug refractory symptoms resulted in improved functional class and less syncope/presyncope (all p<0.05). Conclusions: Approximately two-thirds of patients with symptomatic non-obstructive HCM have latent LVOTO. This study suggests that all patients with symptomatic non-obstructive HCM should have exercise stress echocardiography.

Historical trends in reported survival rates in patients with hypertrophic cardiomyopathy

Objective: To determine the range of survival rates of patients with hypertrophic cardiomyopathy (HCM) by comparing and contrasting the natural history of a cohort of patients seen between 1988 and 2002 with that of other published series. Methods: 956 adult (⩾ 16 years old) patients with HCM (572 men, mean (SD) age 42 (15) years, range 16–88) were evaluated by ECG, Holter, exercise testing, and echocardiography. Patient characteristics and survival data were compared with those in natural history studies from referral and non-referral centres published between 1960 and January 2003. Results: The duration of follow up was 69 (45) months. 120 (12.6%) patients died or underwent cardiac transplantation. Sudden cardiac death (n  =  48) was the most common mode of death. The annual rate of sudden death or implantable cardioverter-defibrillator discharge was 1.02 (95% confidence interval (CI) 0.76 to 1.26). Annual rates for heart failure death or transplantation and stroke related death were 0.55% (95% CI 0.37% to 0.78%) and 0.07% (95% CI 0.02% to 0.19%), respectively. When studies published within the last 10 years of the study period were compared with earlier reports, the size of individual study cohorts was larger (309 (240.6) v 136.5 (98.8), p  =  0.058) and the proportion with severe functional limitation NYHA class III/IV lower (12.4% v 24.8%, p < 0.0001), and fewer patients underwent septal myotomy-myectomy (5.2% v 18.7%, p < 0.0001). Published sudden death rates over the last 10 years were lower than previously published figures (median 1.0% (range 0.1–1.7) v 2.0% (0–3.5)). Conclusion: Published survival rates in HCM cohorts have improved progressively over the past 40 years. In the modern era the prevalence of disease related complications is similar in all reporting centres.

Coronary microvascular dysfunction in male patients with Anderson-Fabry disease and the effect of treatment with α galactosidase A

Objective: To measure coronary flow reserve (CFR), an index of microvascular function, in Anderson-Fabry disease (AFD) at baseline and after enzyme replacement therapy (ERT). Methods and results: Mean (SD) myocardial blood flow (MBF) at rest and during hyperaemia (adenosine 140 μg/kg/min) was measured in 10 male, non-smoking patients (53.8 (10.9) years, cholesterol 5.5 (1.3) mmol/l) and in 24 age matched male, non-smoking controls (52.0 (7.6) years, cholesterol 4.5 (0.6) mmol/l) by positron emission tomography (PET). Resting and hyperaemic MBF and CFR (hyperaemic/resting MBF) were reduced in patients compared with controls (0.99 (0.17) v 1.17 (0.25) ml/g/min, p < 0.05; 1.37 (0.32) v 3.44 (0.78) ml/g/min, p < 0.0001; and 1.41 (0.39) v 3.03 (0.85), p < 0.0001, respectively). This coronary microvascular dysfunction was independent of cholesterol concentrations. PET was repeated in five patients after 10.1 (2.3) months of ERT; resting and hyperaemic MBF and CFR were unchanged after ERT (0.99 (0.16) v 0.99 (0.16) ml/g/min; 1.56 (0.29) v 1.71 (0.3) ml/g/min; and 1.6 (0.37) v 1.74 (0.28), respectively; all not significant). Conclusions: The results of the present study show that patients with AFD have very abnormal coronary microvascular function. These preliminary data suggest that ERT has no effect on coronary microvascular dysfunction. Further work is necessary to determine whether treatment at an earlier stage in the course of the disease may improve coronary microvascular function in patients with AFD.

A detailed pathologic examination of heart tissue from three older patients with Anderson-Fabry disease on enzyme replacement therapy

BACKGROUND Cardiac disease causes considerable morbidity and mortality in men and women with Anderson-Fabry disease (AFD), an X-linked inborn metabolic defect caused by deficiency of the lysosomal enzyme α-galactosidase A. Treatment with recombinant enzyme preparations aims to attenuate and reverse accumulation of the major enzyme substrate, globotriaosylceramide (Gb3). Pathologic data examining the effect of enzyme replacement therapy (ERT) in vivo are scant. METHODS A detailed examination of three whole hearts from patients (all male, aged 55, 59, 73 years) with AFD that had received ERT prior to death (for between 18 months and 4 years) was performed. RESULTS In spite of ERT, Gb3 accumulation was present in myocytes, within both atria and ventricles, endothelial cells, smooth muscle cells, coronary arteries, aorta, and valve tissue. Nearly all myocytes within the right and left ventricles were hypertrophied with marked vacuolization of the cytoplasm. In all three cases, there was focal myocyte apoptosis and myocyte necrosis associated with macrophage accumulation and a small T-lymphocytic infiltrate. Extensive areas of replacement fibrosis (mean, 15%) associated with areas of myocyte disarray were present in all three hearts. CONCLUSIONS This study highlights the pancardiac nature of AFD; demonstrates the extent of fibrotic changes; and reports, for the first time, myocyte disarray, necrosis, and apoptosis in hearts from patients affected by AFD and receiving ERT. These findings have major implications for the timing and efficacy of ERT in AFD.

Fabry disease and the heart: an overview of the natural history and the effect of enzyme replacement therapy.

Fabry disease is a genetic disorder caused by the deficiency of α‐galactosidase A, resulting in the lysosomal accumulation of glycosphingolipids. Fabry disease may result in cardiac, cerebral and renal complications. Cardiac abnormalities in patients with Fabry disease were first described in the 1960s. In the 1990s a form of Fabry disease confined to the heart was reported; however, this variant is extremely rare and a more appropriate concept is of cardiac predominance of the disease in some patients. Up to 60% of males with classic Fabry disease have cardiac abnormalities, including left ventricular hypertrophy, valvular dysfunction and conduction abnormalities. Recent data suggest that left ventricular mass and systolic function in patients with Fabry disease improve after 12 months of enzyme replacement therapy (ERT); however, many of the patients studied are relatively young and have mild cardiac abnormalities, suggesting that more research into the efficacy of ERT in older patients is necessary.

Extracellular matrix turnover and disease severity in Anderson-Fabry disease.

SummaryBackground: Anderson–Fabry Disease (AFD) is an inherited metabolic disease associated with premature death secondary to cardiovascular and renal disease. Patients with AFD develop progressive left ventricular (LV) remodelling and heart failure. We hypothesized that altered extracellular matrix (ECM) turnover contributes to the pathophysiology of cardiac disease in AFD. Methods and Results: Twenty-nine consecutive patients (44.1 ± 11.7 years, 15 male) with AFD and 21 normal controls (39.7 ± 11.3 years, 10 male) had serum analysed for matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of matrix metalloproteinase-1 and -2 (TIMP-1, TIMP-2). All patients underwent clinical assessment, echocardiography and Mainz Severity Score Index (MSSI) measurement, a validated severity score in AFD. MMP-9 levels were significantly higher in patients than controls (1003.8 ± 337.8 ng/ml vs 576.7 ± 276.3 ng/ml respectively, p < 0.001). There were no differences in TIMP levels between patients and controls. There was a positive correlation between MMP-9 levels and MSSI (r = 0.5, p = 0.01). There was a negative correlation between MMP-9 and endocardial fractional shortening (FS) (r = −0.5, p = 0.01) and mid-wall FS (r = −0.6, p = 0.001). There was no correlation between other echocardiographic parameters and MMP-9 levels. These relations were independent of age and sex using stepwise linear regression analysis. Conclusions: Patients with AFD have abnormal ECM turnover compared to normal controls. The correlation between MMP-9 levels and systolic function suggests that altered ECM turnover is important in cardiac remodelling. The association between MMP-9 and overall disease severity suggests that circulating levels of MMP-9 may provide a useful marker for assessing the response of patients with AFD to enzyme replacement treatment.

009 Uncovering the mechanism of the paradoxical association between cardiac dyssynchrony and better survival in heart failure

Introduction Paradoxically, dyssynchrony before CRT is associated with a better prognosis. We tested whether this was dependent on device implantation or on how the cohort was defined (EF ≤35 vs All-comers). Methods 419 patients (67.8±11.3 years, 79.2% males, 127 deaths) with heart failure had echocardiographic assessment of mechanical dyssynchrony and were followed up (median 3.1 years). Results 135 had dyssynchrony and 62 received CRT. The mean EF was 33.1±15.0%; 157 (35.2%) had an EF >35%. Among patients with EF≤35% (n=249), shorter aortic pre-ejection time (ie, less dyssynchrony) was associated with a worse prognosis (p<0.05). All dyssynchrony markers were higher in survivors (p<0.001 by sign test, upper panel). EF was not prognostic and depressed by dyssynchrony (r=−0.4, p<0.001). By examining all patients (regardless of EF); the association between dyssynchrony and better survival disappeared (p>0.05, lower panel). EF was restored to its prognostic significance (p=0.02). Taking a different approach to define poor ventricular function—using low S-wave velocity—EF had prognostic significance (p<0.05) and dyssynchrony markers were non-prognostic (p>0.05). Conclusion Dyssynchrony predicts better survival in low EF groups because dyssynchrony artifactually lowers EF without damaging survival. The effect is independent of CRT. Replacement of EF with dyssynchrony-neutral measures of LV function, for example, peak S-wave velocity would avoid the appearance that dyssynchrony is favourable.Abstract 009 Figure 1

Extracellular matrix turnover and disease severity in Anderson-Fabry disease: Abstracts

Background: Anderson–Fabry disease (AFD) is an inherited metabolic disease associated with premature death from cardiovascular and renal disease. Recent studies have shown that patients with AFD develop progressive left‐ventricular (LV) remodelling. We hypothesized that patients with AFD have abnormal extracellular matrix (ECM) turn over compared with normal controls.