Modification of myocardial substrate utilisation: a new therapeutic paradigm in cardiovascular disease

ABSTRACT Therapies that aim to modify cardiac substrate utilisation are designed to increase metabolic efficiency. Although the main energy supply for the heart is generally provided by the oxidation of fatty acids, the heart is a metabolic omnivore and able to consume glucose as well as lactate and amino acids in varying proportions. A shift from fatty acid oxidation to glucose oxidation leads to lower oxygen consumption per unit of ATP produced. This concept of reduced oxygen utilisation underlies the use of metabolic modulating agents to treat chronic stable angina. Furthermore, the model of an energystarved heart now forms the basis for our understanding of both ischaemic and non-ischaemic heart failure. Potential alterations in substrate utilisation and thus myocardial efficiency underlie the use of metabolic agents in heart failure. This is achieved by either promoting glucose or reducing the utilisation of fatty acids. Such a shift results in a relatively greater production of ATP per unit of oxygen consumed. With an ongoing demand for treatment options in ischaemic heart disease and a growing epidemic of heart failure, new treatment modalities beyond contemporary therapy need consideration

Metabolic manipulation in chronic heart failure: study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Heart failure is a major cause of morbidity and mortality in society. Current medical therapy centres on neurohormonal modulation with angiotensin converting enzyme inhibitors and β-blockers. There is growing evidence for the use of metabolic manipulating agents as adjunctive therapy in patients with heart failure. We aim to determine the effect of perhexiline on cardiac energetics and alterations in substrate utilisation in patients with non-ischaemic dilated cardiomyopathy.</p> <p>Methods</p> <p>A multi-centre, prospective, randomised double-blind, placebo-controlled trial of 50 subjects with non-ischaemic dilated cardiomyopathy recruited from University Hospital Birmingham NHS Foundation Trust and Cardiff and Vale NHS Trust. Baseline investigations include magnetic resonance spectroscopy to assess cardiac energetic status, echocardiography to assess left ventricular function and assessment of symptomatic status. Subjects are then randomised to receive 200 mg perhexiline maleate or placebo daily for 4 weeks with serum drug level monitoring. All baseline investigations will be repeated at the end of the treatment period. A subgroup of patients will undergo invasive investigations with right and left heart catheterisation to calculate respiratory quotient, and mechanical efficiency. The primary endpoint is an improvement in the phosphocreatine to adenosine triphosphate ratio at 4 weeks. Secondary end points are: i) respiratory quotient; ii) mechanical efficiency; iii) change in left ventricular (LV) function.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00841139">NCT00841139</a></p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN2887836">ISRCTN2887836</a></p

Modification of myocardial substrate utilisation:a new therapeutic paradigm in cardiovascular disease

Therapies that aim to modify cardiac substrate utilisation are designed to increase metabolic efficiency. Although the main energy supply for the heart is generally provided by the oxidation of fatty acids, the heart is a metabolic omnivore and able to consume glucose as well as lactate and amino acids in varying proportions. A shift from fatty acid oxidation to glucose oxidation leads to lower oxygen consumption per unit of ATP produced. This concept of reduced oxygen utilisation underlies the use of metabolic modulating agents to treat chronic stable angina. Furthermore, the model of an energy-starved heart now forms the basis for our understanding of both ischaemic and non-ischaemic heart failure. Potential alterations in substrate utilisation and thus myocardial efficiency underlie the use of metabolic agents in heart failure. This is achieved by either promoting glucose or reducing the utilisation of fatty acids. Such a shift results in a relatively greater production of ATP per unit of oxygen consumed. With an ongoing demand for treatment options in ischaemic heart disease and a growing epidemic of heart failure, new treatment modalities beyond contemporary therapy need consideration

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease