A Pharmacological Approach towards Myocardial Protection: New Perspectives in Acute and Chronic Cardiac Disease

Abstract

Several cardiac diseases include myocardial ischaemia (acute or chronic), heart failure (systolic or diastolic) and left ventricular hypertrophy (either as a “primary” cause or developed secondary to other diseases) share the commonality of myocardial energetic deficiency or suboptimal myocardial metabolism. Therefore, approaches to modify myocardial metabolism in order to improve energetics present as an attractive therapeutic option. This is particularly useful when other options are limited: for example, lack of optimal symptom control with “maximal” treatment, or contraindications to other pharmacological treatment (by virtue of impairment of left ventricular systolic function and/or hypotension). The objective of this thesis is to examine the biochemical effects of various pharmacological agents towards modulation of myocardial metabolism, both in the acute (e.g. acute coronary syndrome) and chronic cardiac disease settings (e.g. diabetic heart). In particular, the effects of perhexiline, an interesting drug known to possess not only metabolic effects (by virtue of inhibiting carnitine palmitoyl transferase-1 [CPT-1], thereby shifting myocardial fatty acid oxidation towards glycolysis) but also anti-inflammatory effects, will be further explored. First, the pharmacokinetics and myocardial uptake profile of the individual perhexiline enantiomers were examined. This study showed that the myocardial uptake of both perhexiline enantiomers in patients were slow; and that in multivariate backward stepwise analysis, (-)-perhexiline was inversely correlated with on-treatment heart rate. This finding suggested that the weak calcium antagonist effect of perhexiline may potentially lie predominantly within the (-)- enantiomer. Additionally, other aspects of myocardial metabolism, including the nexus between inflammatory activation and metabolic effect, were investigated. In a study involving 12 patients presenting with acute coronary syndrome and hyperglycaemia, rapid reversal of hyperglycaemia with insulin infusion in 12 hours improved the anti-aggregatory effect of platelets, independent of the platelet content of the pro-inflammatory marker thioredoxin-interacting protein (TXNIP). Furthermore, this thesis also investigated the potential insulin sensitization effect of perhexiline in diabetic patients. This is a corollary of increased glucose utilization, which appears to be relevant even against the background of concomitant therapy with other insulin-sensitizing agents such as AMPK activators or ACE-inhibitors. Furthermore, platelet content of TXNIP tended to fall slightly (but not significantly) after perhexiline treatment, implying its lack of significant critical role in the improvement of both nitric oxide responsiveness and insulin sensitization. However, its overall contribution still cannot be completely ruled out. Lastly, in an in vitro experiment, the potency of inhibition of CPT-1 by both perhexiline enantiomers was investigated. It was found that the 50% inhibitory concentrations of both enantiomers were not significantly different. This provided evidence that the (differential) toxicity seen with the individual enantiomers (in previous studies) might be independent of CPT-1 inhibition. The CPT-1 inhibitory potency of several other cardiac drugs, including fluorinated perhexiline (developed by collaborators in Aberdeen, UK) and dronedarone (a benzofluranyl compound, structurally similar to amiodarone) was also determined in this thesis, and it was shown in particular that dronedarone was a potent CPT-1 inhibitor. The overall thrust of this work reinforces the concept that CPT-1 inhibition is seen with a large number of cardiovascular drugs, and is retained by enantiomers and structural analogues of perhexiline. The myocardial uptake of perhexiline and its enantiomers indicates a relatively slow process of equilibration with its primary sites of action.