Targeting pulmonary capillary permeability to reduce lung congestion in heart failure: a randomized, controlled pilot trial.

AIMS: Lung congestion in patients with heart failure (HF) has traditionally been treated using interventions that reduce pulmonary capillary hydrostatic pressure. The transient receptor potential vanilloid 4 (TRPV4) channel regulates fluid transit across the pulmonary capillary-interface, and represents a novel target to reduce lung water, independent of pulmonary capillary hypertension. This pilot study examined the safety and potential efficacy of TRPV4 blockade as a novel treatment for HF. METHODS AND RESULTS: In this randomized, double-blind, placebo-controlled crossover pilot trial, 11 subjects with chronic, compensated HF were treated with a novel TRPV4 antagonist (GSK2798745) or placebo. The primary endpoint was lung diffusing capacity for carbon monoxide (DLCO ) after 7 days of treatment with GSK2798745 as compared to placebo. Secondary endpoints included additional diffusion parameters, spirometry and safety assessments. Compared to placebo, treatment with GSK2798745 resulted in a trend to improvement in DLCO (placebo: -0.336 mL/mmHg/min; GSK2798745: +0.458 mL/mmHg/min; treatment difference: +0.793 mL/mmHg/min; 95% confidence interval: -0.925 to 2.512) that was not statistically significant. GSK2798745 was well-tolerated with no serious adverse events. CONCLUSION: In this pilot trial, GSK2798745 was found to be safe and well-tolerated, with a trend toward improved gas transfer. Further investigation is warranted in larger studies to determine whether treatment with TRPV4 antagonists or alternative treatments targeting capillary permeability might be effective to improve lung congestion, pulmonary gas transfer and clinical status in patients with acute or chronic HF.

Revascularization improves survival in ischemic cardiomyopathy regardless of electrocardiographic criteria for prior small-to-medium myocardial infarcts.

BACKGROUND: The purpose of the current study was to determine whether survival after revascularization (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) is influenced by the extent of electrocardiographic (ECG) evidence of previous myocardial infarction (MI) in patients with ischemic cardiomyopathy by use of the 50-criteria, 31-point Selvester QRS scoring system. METHODS: Patients with ischemic cardiomyopathy documented by a left ventricular ejection fraction (LVEF) < or =30% undergoing coronary angiography between January 1984 and July 1996, with no acute MI within the last 30 days, follow-up through 1996, and > or =75% occlusion in at least 1 major coronary artery at catheterization were included. These patients were subdivided on the basis of subsequent treatment: revascularization or no revascularization. The complete Selvester QRS system was applied to each patient's ECG and the subgroups were further subdivided by QRS score. RESULTS: The 141 patients receiving revascularization had better survival at 5 years compared with the 298 patients receiving no revascularization (adjusted 5-year survival rate 73% vs 47%, P =.0001). No significant treatment differences were observed for low (< or =3 points) versus high (>3 points) QRS levels in either of the 2 treatment groups (revascularized patients: P =.215, patients without revascularization: P =.126) between the 2 treatment groups. Although all patients had LVEF < or =30%, only 8% of patients had QRS scores >10 points, the level that would be expected if the decrease in LVEF could be attributed entirely to infarcted myocardium. CONCLUSIONS: Hibernating myocardium may contribute significantly to the decreased function in patients with ischemic cardiomyopathy, and the QRS score cannot be used as an independent predictor of survival in those patients with a marked decrease in LVEF but small to moderate infarct sizes.