Effects of the cardiac myosin activator Omecamtiv-mecarbil on severe chronic aortic regurgitation in Wistar rats

Abstract

BackgroundAortic regurgitation (AR) is a valvular disease that can lead to systolic heart failure. Treatment options besides cardiac surgery are limited and consequently severe AR is associated with higher mortality and morbidity when not operated. In this investigation, we examined the effects of a novel cardiac myosin activator, Omecamtiv-mecarbil (OM), in rats with chronic severe AR.MethodsAR was created by retrograde puncture of the aortic valve leaflets in 20 adults Wistar rats. 12 animals survived the acute AR phase and were randomized 2 months thereafter into OM (n = 7) or placebo groups (n = 5). Two rats underwent a sham operation and served as controls. Equal volumes of OM or placebo (NaCl 0.9%) were perfused in the femoral vein by continuous infusion (1.2 mg/kg/hour) during 30 min. Doppler-echocardiography was performed before and at the end of the infusion periods.ResultsOM increased indices of global cardiac function (cardiac output, stroke volume), and increased systolic performance (fractional shortening, ejection fraction, left ventricular end systolic diameter) (all p < 0.05). These effects concurred with decreases in indices of LV preload (left atrial size, left ventricular end diastolic diameter) as well in the aortic pre-ejection period / left ventricular ejection time ratio (all p < 0.05). The severity score of the regurgitant AR jet did not change. Placebo infusion did not affect these parameters.ConclusionThe cardiac myosin activator OM exerts favorable hemodynamic effects in rats with experimental chronic AR.

The myosin activator omecamtiv mecarbil improves wall stress in a rat model of chronic aortic regurgitation

“…OM did not affect the severity of AR, as measured by AR PHT <200 ms. This finding agrees with the results of our previous study (El-Oumeiri et al, 2018). However, in our previous study, we subjectively graded the severity of the AR jet on a scale from 1 to 4, whereas in this study, we used an objective quantification of AR to measure the effect of OM on AR more precisely.…”

“…In our previous study (El Oumeiri et al, 2018), OM increased SV and CO in rats with AR. In that study, the animals were anesthetized with an intraperitoneal injection of ketamine/medetomidine.…”

“…In our previous study (El Oumeiri et al, 2018), we showed that OM significantly decreased both LV endsystolic diameter (LVESD) and LV end-diastolic diameter (LVEDD) in rats with severe chronic AR. However, we lacked information on preload and afterload, and the anesthesia procedure included intraperitoneal ketamine.…”

“…Animals were anesthetized using 1.5% inhaled isoflurane. AR was induced by retrograde puncture of the aortic valve leaflet, as previously described (El Oumeiri et al, 2018). Heart rate (HR) and rhythm were monitored via limb leads throughout the procedure.…”

Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline

“…Alternatively, by stabilizing myosin it may prevent the rate of XB detachment by slowing ADP isomerization 9 . In canine and murine models of heart failure (HF), OM increased stroke volume, cardiac output, and left ventricular (LV) systolic ejection time (SET) 11,12 . However, the increase in SET and reduced relaxation velocities may inversely compromise diastolic filling and reduce coronary perfusion, resulting in myocardial ischemia 13 .…”