Abstract 19627: Can Heart Failure Be Caused by Coronary Microvascular Dysfunction
Recently, we reported that Kv1.5 channels in smooth muscle connect myocardial blood flow to cardiac work. When this connection is uncoupled (Kv1.5-/- mice), during an acute metabolic stress induced by norepinephrine infusion acute cardiac failure occurs. Whether a chronic hemodynamic stress (hypertension) would produce heart failure in this model is unknown; accordingly, we hypothesized that in Kv1.5-/- mice with inadequate coronary metabolic dilation the production of hypertension would induce failure. As a corollary to this hypothesis, we also projected that by varying myocardial blood flow (MBF) we would influence whether the heart progresses towards failure (insufficient MBF) or is rescued from the failure phenotype (increased MBF). We subjected Kv1.5-/- mice (two groups, 4-5 months of age, males) with reconstituted doxycycline-inducible expression of Kv1.5 channels in smooth muscle (Kv1.5-/--RC) to transaortic constriction (TAC). Cardiac function (ejection fraction [EF] measured by echocardiography) decreased in both groups of Kv1.5-/--RC mice during 2 weeks of TAC (Figure). Immediately after these measurements doxycycline (DOX) was administered to one group of mice (Kv1.5-/--RC+DOX) to increase MBF. In these DOX-treated mice, EF progressively improved (measured weekly) during a course of 4 weeks (60±3%); whereas in the untreated group (Kv1.5-/--RC NO-DOX) EF progressively declined during the 4 week period (31±2%). At 6 weeks DOX treatment was reversed (NO DOX receiving DOX and DOX withdrawal in the +DOX). Note, withdrawal of DOX caused lower EF, and administration of DOX increased EF. Importantly because in the TAC model afterload is fixed by the stenosis, changes in heart failure induced by DOX were not due to changes in hemodynamics. Because DOX in this model increases MBF, we conclude that insufficient perfusion can cause heart failure and that increases in myocardial perfusion can reverse some consequences of heart failure.
Author Disclosures: V. Ohanyan: None. L. Yin: None. M. Enrick: None. T. Hakobyan: None. C.L. Kolz: None. W.M. Chilian: None.
- © 2016 by American Heart Association, Inc.