Is Heart Failure A Disorder of the Coronary Microcirculation?

Heart failure (HF) is the cause of death on 1 of 8 people in the US. Current therapies have produced some measure of success in patient outcomes, but they only slow the progression of the disease. We hypothesize that if the causal mechanism was corrected the progression of the disease could be stopped and potentially reversed. More specifically, we hypothesize that the cause of heart failure is insufficient myocardial blood flow (MBF) that fails to meet the needs of the heart. We believe that the insufficiency produces minute areas of ischemia, resulting myocyte loss, and eventual fibrosis. The minute areas of injury accumulate over time leading to failure. Accordingly, we determined the relationship between MBF and cardiac work (wall stress‐rate product [WSRP]) in control C57Bl6/J mice (CTRL), mice with transaortic constriction (TAC or HF), and HF mice treated with the coronary vasodilator, Chromonar (2 weeks of treatment). This latter treatment was devised to show proof of principle, i.e., if flow were increased in the failing heart, would the failure be reversed? MBF and WSRP were measured during norepinephrine‐induced increases in WSRP in anesthetized mice. The figure shows the relationship between WSRP and MBF in the 3 groups. Note the relationship between WSRP and MBF is uncoupled in HF, i.e., when work increases MBF does not. Note that Chromonar recoupled work with MBF and also caused dilation (increased MBF per unit of work). These changes in flow paralleled cardiac function in the HF and HF+Chromonar groups. After TAC cardiac function decreased over 13 weeks to an ejection fraction (EF) of about 40% in both groups. Chromonar treatment increased EF to 67±3%; whereas when untreated cardiac function remained low. Based on these findings, we propose that a cause of HF is inadequate MBF to meet the metabolic demands of the working heart. Pharmacological coronary vasodilation with Chromonar to increase MBF in HF can reverse the functional decline and improve cardiac function.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .