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

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.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201

Therapeutic Potential of Ketone Bodies for Patients With Cardiovascular Disease JACC State-of-the-Art Review

Metabolic perturbations underlie a variety of cardiovascular disease states; yet, metabolic interventions to prevent or treat these disorders are sparse. Ketones carry a negative clinical stigma as they are involved in diabetic ketoacidosis. However, evidence from both experimental and clinical research has uncovered a protective role for ketones in cardiovascular disease. Although ketones may provide supplemental fuel for the energy-starved heart, their cardiovascular effects appear to extend far beyond cardiac energetics. Indeed, ketone bodies have been shown to influence a variety of cellular processes including gene transcription, inflammation and oxidative stress, endothelial function, cardiac remodeling, and cardiovascular risk factors. This paper reviews the bioenergetic and pleiotropic effects of ketone bodies that could potentially contribute to its cardiovascular benefits based on evidence from animal and human studies.Salva R.Yurista, Cher-RinChong, Juan J.Badimon, Daniel P.Kelly, Rudolf A.de Boer, B. Daan Westenbrin

Cardioplegia in paediatric cardiac surgery:a systematic review of randomized controlled trials

Objectives Cardioplegia is the primary method for myocardial protection during cardiac surgery. We conducted a systematic review of randomized controlled trials of cardioplegia in children to evaluate the current evidence base. Methods We searched MEDLINE, CENTRAL and LILACS and manually screened retrieved references and systematic reviews to identify all randomized controlled trials comparing cardioplegia solutions or additives in children undergoing cardiac surgery published in any language; secondary publications and those reporting inseparable adult data were excluded. Two or more reviewers independently screened studies for eligibility and extracted data; the Cochrane Risk of Bias tool was used to assess for potential biases. Results We identified 26 trials randomizing 1596 children undergoing surgery; all were single-centre, Phase II trials, recruiting few patients (median 48, interquartile range 30–99). The most frequent comparison was blood versus crystalloid in 10 (38.5%) trials, and the most common end points were biomarkers of myocardial injury (17, 65.4%), inotrope requirements (15, 57.7%) and length of stay in the intensive care unit (11, 42.3%). However, the heterogeneity of patients, interventions and reported outcome measures prohibited meta-analysis. Overall risk of bias was high in 3 (11.5%) trials, unclear in 23 (88.5%) and low in none. Conclusions The current literature on cardioplegia in children contains no late phase trials. The small size, inconsistent use of end points and low quality of reported trials provide a limited evidence base to inform practice. A core outcome set of clinically important, standardized, validated end points for assessing myocardial protection in children should be developed to facilitate the conduct of high-quality, multicentre trials

Stereoselective handling of perhexiline:Implications regarding accumulation within the human myocardium

Purpose: Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilised in the management of refractory angina. The metabolic clearance of perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to (1) determine whether the acute accumulation of perhexiline in the myocardium is stereoselective and (2) investigate the relationship between duration of short-term therapy and the potential stereoselective effects of perhexiline within myocardium. Method: Patients (n = 129) from the active arm of a randomised controlled trial of preoperative perhexiline in cardiac surgery were treated with oral perhexiline for a median of 9 days. Correlates of atrial and ventricular concentrations of enantiomers were sought via univariate followed by multivariate analyses. Results: Myocardial uptake of both (+) and (−) perhexiline was greater in ventricles than in atria, and there was more rapid clearance of (−) than (+) perhexiline. The main determinants of atrial uptake of both (+) and (−) perhexiline were the plasma concentrations [(+) perhexiline: β = −0.256, p = 0.015; (−) perhexiline: β = −0.347, p = 0.001] and patients’ age [(+) perhexiline: β = 0.300, p = 0.004; (−) perhexiline: β = 0.288, p = 0.005]. Atrial uptake of (+) enantiomer also varied directly with duration of therapy (β = 0.228, p = 0.025), while atrial uptake of (−) perhexiline varied inversely with simultaneous heart rate (β = −0.240, p = 0.015). Conclusion: (1) Uptake of both perhexiline enantiomers into atrium is greater with advanced age and displays evidence of both saturability and minor stereoselectivity. (2) Atrial uptake of (−) perhexiline may selectively modulate heart rate reduction

Metabolic Remodeling in Diabetic Cardiomyopathy

Diabetes is a risk factor for heart failure and cardiovascular mortality with specific changes to myocardial metabolism, energetics, structure, and function. The gradual impairment of insulin production and signalling in diabetes is associated with elevated plasma fatty acids and increased myocardial free fatty acid uptake and activation of the transcription factor PPARα. The increased free fatty acid uptake results in accumulation of toxic metabolites, such as ceramide and diacylglycerol, activation of protein kinase C, and elevation of uncoupling protein-3. Insulin signalling and glucose uptake/oxidation become further impaired, and mitochondrial function and ATP production become compromised. Increased oxidative stress also impairs mitochondrial function and disrupts metabolic pathways. The diabetic heart relies on free fatty acids (FFA) as the major substrate for oxidative phosphorylation and is unable to increase glucose oxidation during ischaemia or hypoxia, thereby increasing myocardial injury, especially in ageing female diabetic animals. Pharmacological activation of PPARγ in adipose tissue may lower plasma FFA and improve recovery from myocardial ischaemic injury in diabetes. Not only is the diabetic heart energetically-impaired, it also has early diastolic dysfunction and concentric remodelling. The contractile function of the diabetic myocardium negatively correlates with epicardial adipose tissue, which secretes proinflammatory cytokines, resulting in interstitial fibrosis. Novel pharmacological strategies targeting oxidative stress seem promising in preventing progression of diabetic cardiomyopathy, although clinical evidence is lacking. Metabolic agents that lower plasma FFA or glucose, including PPARγ agonism and SGLT2 inhibition, may therefore be promising options

Dissociation of early shock in takotsubo cardiomyopathy from either right or left ventricular systolic dysfunction

Takotsubo cardiomyopathy (TTC) is often associated with hypotension and shock. However, development of hypotension/shock in TTC is not closely related to extent of left ventricular (LV) hypokinesis. We sought to determine whether additional right ventricular (RV) involvement in TTC might contribute to hypotension and shock development and thus to prolonged hospital stay (PHS)

Subtle renal dysfunction and bleeding risk in atrial fibrillation : Symmetric dimethylarginine predicts HAS-BLED score

Background: Risk of substantial haemorrhage represents a critically important limitation to effective anti-thrombotic treatment in patients with atrial fibrillation (AF). While it is known that this risk is increased in anticoagulated patients either in the presence of anti-aggregatory drugs or concomitant renal insufficiency, there are currently few data on the potential interactions between endogenous platelet aggregability and bleeding risk. Objective: We therefore evaluated in a cohort of AF patients: (1), the putative relationship between platelet aggregability and HAS-BLED score; (2), the potential biochemical bases for such a relationship. Methods: Patients were included as part of SAFETY, a randomised controlled trial evaluating outpatient management of AF patients. Platelet response to ADP was evaluated via whole blood impedance aggregometry; clinical and biochemical correlates of platelet aggregation were sought via univariate and multivariate analysis. Results: Platelet aggregation correlated inversely (r=-0.220, p < 0.05) with HAS-BLED score. Univariate biochemical correlates of decreased platelet aggregation were plasma concentrations of symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). On multivariate analyses, plasma SDMA concentration (β=-0.318, p < 0.01), platelet content of thioredoxin-interacting protein (Txnip, β=0.261, p < 0.05) and plasma thrombospondin-1 (TSP-1, β=0.249, p < 0.05) concentration were predictive of platelet ADP response. Consistent with previous reports, plasma SDMA concentrations were strongly and inversely correlated with estimated glomerular filtration rate (eGFR, r=-0.780, p < 0.001). Conclusions: These data therefore suggest that (1), physiologically impaired, like pharmacologically impaired, platelet aggregability may increase bleeding risk in anticoagulated AF patients; (2), the biochemical basis for this may include impaired effects of nitric oxide (via Txnip, TSP-1) but also concomitant renal dysfunction