The goal of this proposal is to test the hypothesis that impaired regulation of the coronary microcirculation? more specifically, an inadequate connection between coronary blood flow and the metabolic needs of the myocardium?underlies the development of some types of heart failure (HF). The sequence we propose is that impaired coupling between coronary blood flow and cardiac work results in minute areas of hypoxia in cardiac myocytes, which induces apoptosis in small numbers of cardiac myocytes. Over time these minute areas of tissue death accumulate to an extent that cardiac function is compromised. Current treatments for heart failure are designed to reduce cardiac work, but not directly produce coronary vasodilation. None of these therapies stop or reverse the progression of the disease?progression is only slowed. We speculate that the reason these treatments do not stop or reverse the progression of the disease is that they are not targeting the causal problem of insufficient blood flow to the heart. We propose that by correcting the myocardial perfusion deficiencies in heart failure, we will stop and potentially reverse the progression of heart failure. We propose two aims.
Aim 1 will determine if impaired regulation of myocardial blood flow, i.e., inadequate coupling of flow to metabolism, plays a critical role in the development of heart failure. In this aim we will measure myocardial perfusion, plasma BNP and cardiac troponin I, tissue oxygenation, cardiac metabolism and cardiac myocyte hypoxia (using hypoxia fate mapping) and myocyte apoptosis in the murine transaortic constriction model of heart failure. Measurements will be made at various points during the progression of the disease and in wild type mice and mice with an impairment in myocardial blood flow (Kv1.5 null mice). These measurements will enable precise evaluation of failure and also whether myocardial ischemia occurs during heart failure.
Aim 2 will analyze if the progression of heart failure can be stopped or reversed by increasing blood flow to the heart. In this aim we will increase blood flow to the heart by increasing expression of Kv1.5 channels in smooth muscle or will administer a pharmacological vasodilator at varying times during the progression of the disease. We will compare these interventions to one of the current standards of care for heart failure (beta1-adrenergic antagonist). We will establish if increases in myocardial blood flow to the heart can stop, and/or reverse, the progression of heart failure resulting in a better outcome than the conventional therapy. This application builds upon the expertise of the Principal Investigator, and that of additional laboratories via subcontracts enabling corroborative, interdisciplinary measurements to definitely test whether subtle levels of myocardial ischemia lead to heart failure and if therapies that increase flow to the heart hold promise as a cure.

Public Health Relevance

Heart failure is one of the major health problems facing our society. Our application addresses impairments in the regulation of myocardial blood flow as an underlying cause of failure. We test whether maneuvers designed to increase blood flow to the heart can stop or reverse the consequence of the disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL135024-01A1
Application #
9383841
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Schwartz, Lisa
Project Start
2017-06-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
$456,333
Indirect Cost
$130,979
Name
Northeast Ohio Medical University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
077779882
City
Rootstown
State
OH
Country
United States
Zip Code
44272