Cardioprotective Potential of the Novel Organic Carbon Monoxide Releasing Molecule (oCOm-21) in Normotrophic and Hypertrophic Hearts

Abstract

The imposition of ischaemia reperfusion episodes in frequently used cardiac surgery interventions involving cardiopulmonary bypass can induce perioperative complications, such as myocardial injury, arrhythmias, and end organ injury. The presence of pre-existing cardiac pathologies, such as hypertrophic cardiomyopathy potentiates these perioperative complications and results in reduced outcome benefits. A new class of carbon monoxide delivery molecules (oCOms) have been developed as potential anti-ischaemic agents. The present study investigated the cardioprotective potential of oCOm-21 in normotrophic, moderately and severely hypertrophic hearts subjected to an acute ischaemia reperfusion episode.

Hypertension induced in 8 week old male Cyp1a1-Ren2 rats fed indole-3-carbinol (0.167 % w/w; 8 – 12 weeks) resulted in elevated systolic blood pressures (79.7 % increase), larger heart weights (61 % greater) and increased left ventricular fibrosis (75 % increase) against control littermates. Hearts were isolated and perfused using the Langendorff technique. oCOm-21 (1 – 10 μM), the non-CO releasing derivative of oCOm-21 (DB-21) or vehicle control was infused (10 minutes) prior to a 30 minute warm global ischaemic episode followed by a 60 minute reperfusion period. In normotrophic hearts (n = 3 - 5/group), oCOm-21 (1 and 3 μM) improved left ventricular haemodynamic recovery of left ventricular developed pressure, coronary flow rate, heart rate and dP/dtmax and dP/dtmin to pre-ischaemic baseline values. In hypertrophic hearts (n = 7 - 11/group), left ventricular haemodynamic recovery to respective pre-ischaemic baselines was improved when higher concentrations (3 and 10 μM) of oCOm-21 were applied, with moderately hypertrophic heats showing greater recovery than severely hypertrophic hearts. Furthermore, oCOm-21 (3 and 10 μM) decreased myocardial injury as seen by the reduction of lactate dehydrogenase leakage upon reperfusion in the normotrophic and hypertrophic hearts compared to respective baseline values, and a reduction in apoptotic cell death at 60 minutes of reperfusion with oCOm-21 (1 and 3 μM; P < 0.01).

This study provides valuable evidence supporting oCOm-21 use as a pre-ischaemic agent for acute cardiovascular interventions even in hearts burdened with hypertrophic cardiomyopathy.