Long-term cardiac-targeted RNA interference for the treatment of heart failure restores cardiac function and reduces pathological hypertrophy.

BACKGROUND: RNA interference (RNAi) has the potential to be a novel therapeutic strategy in diverse areas of medicine. Here, we report on targeted RNAi for the treatment of heart failure, an important disorder in humans that results from multiple causes. Successful treatment of heart failure is demonstrated in a rat model of transaortic banding by RNAi targeting of phospholamban, a key regulator of cardiac Ca(2+) homeostasis. Whereas gene therapy rests on recombinant protein expression as its basic principle, RNAi therapy uses regulatory RNAs to achieve its effect. METHODS AND RESULTS: We describe structural requirements to obtain high RNAi activity from adenoviral and adeno-associated virus (AAV9) vectors and show that an adenoviral short hairpin RNA vector (AdV-shRNA) silenced phospholamban in cardiomyocytes (primary neonatal rat cardiomyocytes) and improved hemodynamics in heart-failure rats 1 month after aortic root injection. For simplified long-term therapy, we developed a dimeric cardiotropic adeno-associated virus vector (rAAV9-shPLB) to deliver RNAi activity to the heart via intravenous injection. Cardiac phospholamban protein was reduced to 25%, and suppression of sacroplasmic reticulum Ca(2+) ATPase in the HF groups was rescued. In contrast to traditional vectors, rAAV9 showed high affinity for myocardium but low affinity for liver and other organs. rAAV9-shPLB therapy restored diastolic (left ventricular end-diastolic pressure, dp/dt(min), and tau) and systolic (fractional shortening) functional parameters to normal ranges. The massive cardiac dilation was normalized, and cardiac hypertrophy, cardiomyocyte diameter, and cardiac fibrosis were reduced significantly. Importantly, no evidence was found of microRNA deregulation or hepatotoxicity during these RNAi therapies. CONCLUSIONS: Our data show for the first time the high efficacy of an RNAi therapeutic strategy in a cardiac disease.

Coronary vasospasm-induced acute diastolic dysfunction in a patient with Raynaud's phenomenon.

We present the case of a patient with severe dyspnea and Raynaud's phenomenon. We could clarify, using invasive techniques including left ventricular conductance catheterization and coronary ergonovine provocation, that isolated diastolic dysfunction induced by coronary vasospasm were responsible for the symptoms. Systolic function was not affected. Short-term infusions with the prostacyclin analogue iloprost, known to act as a disease-modifying agent in patients suffering from Raynaud's phenomenon, led to an improvement of cardiac function. Thus, episodes of dyspnea in patients with Raynaud's phenomenon might be also interpreted as a coronary ischemia equivalent, which may belong to a visceral form of Raynaud's phenomenon and which are sensitive to iloprost infusions.

The role of NT-proBNP in the diagnostics of isolated diastolic dysfunction: correlation with echocardiographic and invasive measurements.

AIMS: Diastolic heart failure is a frequent entity but difficult to diagnose. N-terminal pro-B type natriuretic peptide (NT-proBNP) was therefore investigated as a possible non-invasive parameter to diagnose isolated diastolic dysfunction. METHODS AND RESULTS: Sixty-eight symptomatic patients with isolated diastolic dysfunction and preserved left ventricular ejection fraction (LVEF) (> or =50%) and 50 patients with regular left ventricular (LV) function were examined by conventional echocardiography, tissue Doppler imaging (TDI), and left and right heart catheterization. Plasma NT-proBNP levels were determined simultaneously. Median NT-proBNP plasma levels were elevated [189.54 pg/mL (86.16-308.27) vs. 51.89 pg/mL (29.94-69.71); P<0.001] and increased with greater severity of the diastolic dysfunction (R=0.67, P<0.001). According to the recevier operating characteristic analysis, LV end-diastolic pressure [area under the curve (AUC) 0.84] was the most specific parameter, which had a low sensitivity (61%), however. The reliability of NT-proBNP was similar to TDI indices (AUC 0.83 vs. 0.81) and improved when compared with conventional echocardiography (AUC 0.59-0.70). NT-proBNP levels had the best negative predictive value of all methods (94%) and correlated strongly with indices of LV filling pressure, as determined by invasive measurements. Multivariable linear regression analysis confirmed NT-proBNP as an independent predictor of diastolic dysfunction with an Odds ratio of 1.2 (1.1-1.4, CI 95%) for every unit increase of NT-proBNP. CONCLUSION: NT-proBNP can reliably detect the presence of isolated diastolic dysfunction in symptomatic patients and is an useful tool to rule out patients with reduced exercise tolerance of non-cardiac origin.

Elevated NT-ProBNP levels in patients with increased left ventricular filling pressure during exercise despite preserved systolic function.

BACKGROUND: The role of brain natriuretic peptides in the detection of mild forms of isolated diastolic dysfunction is still uncertain. We therefore investigated the plasma levels of the N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with heart failure symptoms during exercise, despite preserved systolic cardiac function. METHODS AND RESULTS: Fifteen control subjects and 15 symptomatic patients with preserved left ventricular ejection fraction of > or =50%, near normal Doppler echocardiographic indices, and left and right heart catheter indices at rest but increased filling pressures during exercise were studied. Plasma NT-proBNP levels and surrogate parameters of diastolic function were determined simultaneously. The median NT-proBNP plasma level was elevated (median, 145.2 pg/mL [range, 69.7-273.4 pg/mL] vs 38.3 pg/mL [range, 22.1-64.7 pg/ml]; P < .0001) in patients with increased filling pressure during exercise and correlated strongly with the pulmonary capillary wedge pressure (r = 0.78; P < .001). CONCLUSION: NT-proBNP levels are increased in patients with increased filling pressures during exercise and useful for the detection of diastolic dysfunction in patients with exertional dyspnea.