Cardiac metabolism — A promising therapeutic target for heart failure

Both heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF) are associated with high morbidity and mortality. Although many established pharmacological interventions exist for HFrEF, hospitalization and death rates remain high, and for those with HFpEF (approximately half of all heart failure patients), there are no effective therapies. Recently, the role of impaired cardiac energetic status in heart failure has gained increasing recognition with the identification of reduced capacity for both fatty acid and carbohydrate oxidation, impaired function of the electron transport chain, reduced capacity to transfer ATP to the cytosol, and inefficient utilization of the energy produced. These nodes in the genesis of cardiac energetic impairment provide potential therapeutic targets, and there is promising data from recent experimental and early-phase clinical studies evaluating modulators such as carnitine palmitoyltransferase 1 inhibitors, partial fatty acid oxidation inhibitors and mitochondrial-targeted antioxidants. Metabolic modulation may provide significant symptomatic and prognostic benefit for patients suffering from heart failure above and beyond guideline-directed therapy, but further clinical trials are needed

Dynamic changes of the extracellular matrix after acute tako-tsubo cardiomyopathy

Funding Tenovus Scotland. Grant number G13/10.Peer reviewedPublisher PD

The impact of methodological and temporal variation on infarct size quantification in acute myocardial infarction with late enhancement CMR

Funding This project was funded by a grant from the MRC(UK).Peer reviewedPublisher PD

Ventricular-vascular coupling in heart failure with preserved ejection fraction: A systematic review and meta-analysis

Background: Heart failure with preserved ejection fraction (HFpEF) is a complex disease underlined by impaired ventricular-vascular coupling (VVC). Objectives: To evaluate the VVC ratio in HFpEF patients at rest and during exercise and compare it to the healthy and heart failure with reduced ejection fraction (HFrEF) controls. Methods: PubMed and EMBASE databases were searched for trials that matched the inclusion criteria. Random-effects models were used to estimate the pooled mean difference with 95% confidence interval using Open Meta[Analyst] software. Results: A total of 13 trials met the inclusion criteria. Although VVC ratio was comparable between HFpEF and healthy controls at rest, it was significantly lower in HFrEF compared to HFpEF. During exercise, there was a significant decline in VVC ratio in HFpEF (-0.119, 95% CI (-0.183 to -0.055), p<0.001). Conclusion: VVC ratio, although ‘preserved’ at rest in HFpEF patients, was overtly impaired during exercise highlighting the importance of dynamic testing

Radial dyssynchrony assessed by cardiovascular magnetic resonance in relation to left ventricular function, myocardial scarring and QRS duration in patients with heart failure

Radial dyssynchrony is almost universal in patients with heart failure. This vies against the notion that a lack of response to CRT is related to a lack of dyssynchrony

Development of Fluorinated Analogues of Perhexiline with Improved Pharmacokinetic Properties and Retained Efficacy

We designed and synthesized perhexiline analogues that have the same therapeutic profile as the parent cardiovascular drug but lacking its metabolic liability associated with CYP2D6 metabolism. Cycloalkyl perhexiline analogues 6a–j were found to be unsuitable for further development, as they retained a pharmacokinetic profile very similar to that shown by the parent compound. Multistep synthesis of perhexiline analogues incorporating fluorine atoms onto the cyclohexyl ring(s) provided a range of different fluoroperhexiline analogues. Of these, analogues 50 (4,4-gem-difluoro) and 62 (4,4,4′,4′-tetrafluoro) were highly stable and showed greatly reduced susceptibility to CYP2D6-mediated metabolism. In vitro efficacy studies demonstrated that a number of derivatives retained acceptable potency against CPT-1. Having the best balance of properties, 50 was selected for further evaluation. Like perhexiline, it was shown to be selectively concentrated in the myocardium and, using the Langendorff model, to be effective in improving both cardiac contractility and relaxation when challenged with high fat buffer

MOLLI T1 mapping versus T2 W-SPAIR at 3T : myocardial area at risk measurements and the influence of microvascular obstruction

Funding Information: This study was supported by a Medical Research Council (UK) grant, as a sub-study of Nitrites in Acute Myocardial Infarction, NCT01388504.Peer reviewe

Cardiopulmonary exercise test in myocardial ischemia detection

Exercise electrocardiography has low sensitivity for detection of myocardial ischemia. However, when combined with cardiopulmonary exercise testing (CPEX), the sensitivity and specificity of ischemia detection improves significantly. CPEX offers unique advantages over imaging techniques in tricky situations such as balanced ischemia. Early abnormal oxygen uptake would point toward profound coronary stenosis that could be missed in perfusion imaging. CPEX could be an invaluable tool in asymptomatic left bundle branch block pattern, without exposing patients to the risks of computerized tomography or invasive coronary angiography. Normal oxygen uptake curves would rule out significant coronary stenosis as the cause of left bundle branch block pattern. Elseways, abnormal oxygen uptake in patients with normal coronary arteries could indicate microvascular angina. Furthermore, exercise capacity is an excellent predictor of cardiovascular risk in those with and without heart disease. Using two clinical cases we introduce the concept of gas-exchange and hemodynamic changes encountered in ischemic heart disease