The feasibility of gene therapy for cardiomyopathy, heart failure and other chronic cardiac muscle diseases is so far unproven. Here, we developed an in vivo recombinant adeno-associated virus (rAAV) transcoronary delivery system that allows stable, high efficiency and relatively cardiac-selective gene expression. We used rAAV to express a pseudophosphorylated mutant of human phospholamban (PLN), a key regulator of cardiac sarcoplasmic reticulum (SR) Ca(2+) cycling in BIO14.6 cardiomyopathic hamsters. The rAAV/S16EPLN treatment enhanced myocardial SR Ca(2+) uptake and suppressed progressive impairment of left ventricular (LV) systolic function and contractility for 28-30 weeks, thereby protecting cardiac myocytes from cytopathic plasma-membrane disruption. Low LV systolic pressure and deterioration in LV relaxation were also largely prevented by rAAV/S16EPLN treatment. Thus, transcoronary gene transfer of S16EPLN via rAAV vector is a potential therapy for progressive dilated cardiomyopathy and associated heart failure.
Ablation or inhibition of phospholamban (PLN) has favorable effects in several genetic murine dilated cardiomyopathies, and we showed previously that a pseudophosphorylated form of PLN mutant (S16EPLN) successfully prevented progressive heart failure in cardiomyopathic hamsters. In this study, the effects of PLN inhibition were examined in rats with heart failure after myocardial infarction (MI), a model of acquired disease. S16EPLN was delivered into failing hearts 5 weeks after MI by transcoronary gene transfer using a recombinant adeno-associated virus (rAAV) vector. In treated (MI-S16EPLN, n = 16) and control (MI-saline, n = 18) groups, infarct sizes were closely matched and the left ventricle was similarly depressed and dilated before gene transfer. At 2 and 6 months after gene transfer, MI-S16EPLN rats showed an increase in left ventricular (LV) ejection fraction and a much smaller rise in LV end-diastolic volume, compared with progressive deterioration of LV size and function in MI-saline rats. Hemodynamic measurements at 6 months showed lower LV end-diastolic pressures, with enhanced LV function (contractility and relaxation), lowered LV mass and myocyte size, and less fibrosis in MI-S16EPLN rats. Thus, PLN inhibition by in vivo rAAV gene transfer is an effective strategy for the chronic treatment of an acquired form of established heart failure.
Background-We investigated the possibility that a frequent trigger action might play a role in the development of persistent atrial fibrillation (PeAF) and the presence of a substrate. Methods and Results-In 263 consecutive patients who underwent catheter ablation (CA) for PeAF, electric cardioversion was performed at the beginning of the procedure to determine the presence or absence of an immediate recurrence of AF (IRAF).We defined an IRAF as a reproducible AF recurrence within 90 s after restoration of sinus rhythm by electric cardioversion.We performed a meanϮSD of 1.3Ϯ0.5 sessions of CA, including pulmonary vein isolation and ablation of the premature atrial contractions that triggered the IRAF (IRAF triggers), and observed the patients for 17 (10 -27) months. An IRAF was observed in 70 patients (27%), but we could not ablate the IRAF triggers in 16 (23%) of these IRAF patients. The recurrence rate of PeAF was higher in patients with an unsuccessful IRAF trigger ablation than in those with successful IRAF trigger ablation (63% versus 11%; PϽ0.001). A multivariable analysis also revealed that an unsuccessful IRAF trigger ablation was 1 of the independent predictors of recurrent PeAF (odds ratio, 10.9; 95% CI, 3.4 -36.7). Conclusions-In the PeAF patients with an IRAF, successful elimination of the IRAF triggers, in addition to pulmonary vein isolation, resulted in a successful CA. These results imply that such triggers play a major role in the AF persistence in these PeAF patients. (Circ Arrhythm Electrophysiol. 2012;5:295-301.)
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