Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy.

BACKGROUND: Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of beta-amyloid impair cell function and lead to cell death. METHODS AND RESULTS: We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca(2+) homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a. CONCLUSIONS: On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca(2+) handling and a direct effect of PSEN1 sequence variants on excitation-contraction coupling protein function.

Linear radiofrequency microcatheter ablation guided by phased array intracardiac echocardiography combined with temperature decay.

BACKGROUND: Fluoroscopy-guided catheter placement is limited in its ability to determine electrode-endocardial contact and involves radiation exposure. We hypothesized that (1) intracardiac echocardiography (ICE) would provide superior assessment of linear electrode contact compared to fluoroscopy and (2) slow temperature decay upon discontinuation of the radiofrequency current (time for temperature to fall 90% after a 10-second test application of the radiofrequency current T90) would indicate optimal electrode-myocardial contact. METHODS: Sixty endocardial lesions were created in the atria and ventricles of six goats by simultaneous delivery of the radiofrequency current through two linear electrodes of a microcatheter with a central interelectrode thermocouple. Catheter placement was guided by fluoroscopy. A 7.5-MHz ICE transducer in the right atrium or ventricle assessed electrode contact. T90 and previously reported parameters of electrode contact and lesion formation were recorded. Histomorphometry was performed on the lesions. RESULTS: T90 was 4.27 +/- 4.98 seconds. Lesion depth significantly correlated with ICE assessment of electrode contact (r = 0.56, P = 0.001); T90 upon radiofrequency current offset (r = 0.48, P = 0.008), impedance fall upon radiofrequency current onset (r = 0.37, P = 0.008), bipolar pacing threshold preablation (r =-0.56, P = 0.001), bipolar electrogram amplitude preablation (r = 0.43, P = 0.02), but not with fluoroscopic assessment of the electrode contact (r = 0.18, n.s.). For the prediction of achieving a lesion depth of >2 mm, a T90 of >4.0 seconds yielded a specificity of 86% and a sensitivity of 52%, ICE yielded a specificity and sensitivity of 58% and 68%, respectively, while the specificity and sensitivity of fluoroscopy were 26% and 68%, respectively. Both ICE and T90 provide additional clinical relevance during guidance of cardiac microcatheter ablation.

Cardiac microvascular pathology in Fabry disease: evaluation of endomyocardial biopsies before and after enzyme replacement therapy.

BACKGROUND: In classic Fabry patients, accelerated coronary atherosclerosis and left ventricular hypertrophy manifest in the fourth decade; however, signs of cardiovascular disease also are observed later in life in "cardiac variant" patients and symptomatic female heterozygotes. These disturbances are caused by globotriaosylceramide (GL-3) accumulation in the heart resulting from lysosomal alpha-galactosidase A deficiency. METHODS AND RESULTS: We analyzed pretreatment and posttreatment endomyocardial biopsies from 58 Fabry patients enrolled in a 5-month, phase 3, double-blind, randomized, placebo-controlled trial, followed by a 54-month open-label extension study of recombinant human alpha-galactosidase A. Baseline evaluations revealed GL-3 deposits in interstitial capillary endothelial cells and large, laminated inclusions within cardiomyocytes. In this study, we evaluated microvascular GL-3 clearance; no clearance of GL-3 was observed in the cardiomyocytes during this trial. Five months of recombinant human alpha-galactosidase A treatment in the phase 3 trial resulted in complete microvascular clearance of GL-3 from 72% of treated patients compared with only 3% of placebo patients (P<0.001). The placebo group achieved similar results after 6 months of treatment in the open-label trial. In addition, the capillary endothelium remained free of GL-3 for up to 60 months in 6 of 8 patients who consented to an end-of-study biopsy. CONCLUSIONS: The findings suggest that long-term treatment with recombinant human alpha-galactosidase A may halt the progression of vascular pathology and prevent the clinical manifestations of atherosclerotic disease. This histopathological study should be a useful guide for clinicians and pathologists who diagnose and follow Fabry patients.