OBJECTIVES The aim of this study was to determine whether short-term treatment with perhexiline improves cardiac energetics, left ventricular function, and symptoms of heart failure by altering cardiac substrate utilization.BACKGROUND Perhexiline improves exercise capacity and left ventricular ejection fraction (LVEF) in patients with

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.

Background—Nitrite exhibits hypoxia-dependent vasodilator properties, selectively dilating capacitance vessels in healthy subjects. Unlike organic nitrates, it seems not to be subject to the development of tolerance. Currently, therapeutic options for decompensated heart failure (HF) are limited. We hypothesized that by preferentially dilating systemic capacitance and pulmonary resistance vessels although only marginally dilating resistance vessels, sodium nitrite (NaNO2) infusion would increase cardiac output but reduce systemic arterial blood pressure only modestly. We therefore undertook a first-in-human HF proof of concept/safety study, evaluating the hemodynamic effects of short-term NaNO2 infusion.Methods and Results—Twenty-five patients with severe chronic HF were recruited. Eight received short-term (5 minutes) intravenous NaNO2 at 10 μg/kg/min and 17 received 50 μg/kg/min with measurement of cardiac hemodynamics. During infusion of 50 μg/kg/min, left ventricular stroke volume increased (from 43.22±21.5 to 51.84±23.6 mL; P=0.003), with marked falls in pulmonary vascular resistance (by 29%; P=0.03) and right atrial pressure (by 40%; P=0.007), but with only modest falls in mean arterial blood pressure (by 4 mm Hg; P=0.004). The increase in stroke volume correlated with the increase in estimated trans-septal gradient (=pulmonary capillary wedge pressure–right atrial pressure; r=0.67; P=0.003), suggesting relief of diastolic ventricular interaction as a contributory mechanism. Directionally similar effects were observed for the above hemodynamic parameters with 10 μg/kg/min; this was significant only for stroke volume, not for other parameters.Conclusions—This first-in-human HF efficacy/safety study demonstrates an attractive profile during short-term systemic NaNO2 infusion that may be beneficial in decompensated HF and warrants further evaluation with longer infusion regimens.

The heart consumes huge amounts of energy to fulfil its function as a relentless pump. A highly sophisticated system of energy generation based on flexibility of substrate use and efficient energy production, effective energy sensing and energy transfer ensures function of the healthy heart across a range of physiological situations. In left ventricular hypertrophy and heart failure, these processes become disturbed, leading as will be discussed to impaired cardiac energetic status and to further impairment of cardiac function. These metabolic disturbances form a potential target for therapy.

Background— A paradoxical inspiratory rise in right atrial pressure (in contrast to the normal fall during inspiration), Kussmaul sign, has been described in congestive heart failure (CHF). However, the clinical and hemodynamic characteristics and clinical outcomes of patients with CHF and Kussmaul physiology have not been studied. Methods and Results— This is a single-center study of consecutive ambulant patients with CHF (New York Heart Association class III/IV) referred for assessment for heart transplantation between November 2011 and April 2013. Kussmaul physiology was defined as inspiratory rise in right atrial pressure during right heart catheterization. Clinical, biochemical, echocardiographic, and hemodynamic correlates were studied and outcomes assessed in patients with or without Kussmaul physiology after a mean follow-up of 379±227 days. Ninety ambulant patients (age, 53±12 years; 86% men) with CHF were studied. Kussmaul physiology was demonstrated in 39 (43%) patients, and it was associated with higher pulmonary pressures and lower cardiac index and pulmonary capacitance (all P <0.05). Patients with Kussmaul physiology were more likely to be treated with higher doses of diuretics, while higher filling pressures, N-terminal pro–B natriuretic peptide levels, and hyponatremia reflected greater neurohormonal activation. Echocardiography revealed greater left and right ventricular dimensions/volumes, restrictive transmitral filling pattern, and lower left ventricular ejection fraction and lower tricuspid annular plane systolic excursion. Peak oxygen uptake was low and comparable in both groups, but ventilation slope was higher in patients with Kussmaul physiology who also had a higher incidence of post-transplant right ventricular failure and overall mortality ( P <0.05). Conclusions— Kussmaul physiology is common in patients with CHF referred for heart transplantation and is associated with adverse cardiopulmonary hemodynamics. As a result of the latter, Kussmaul physiology is associated with poorer clinical outcomes. Kussmaul physiology may be useful during assessment of right heart function and pulmonary pressures before transplantation.

The aim of this paper is to present the use of a portable, unshielded magnetocardiograph (MCG) and identify key characteristics of MCG scans that could be used in future studies to identify parameters that are sensitive to cardiac pathology. We recruited 50 patients with confirmed myocardial infarction (MI) within the past 12 weeks and 46 volunteers with no history of cardiac disease. A set of 38 parameters were extracted from MCG features including both signals from the sensor array and from magnetic images obtained from the device and principal component analysis was used to concentrate the information contained in these parameters into uncorrelated predictors. Linear fits of these parameters were then used to examine the ability of MCG to distinguish between sub-groups of patients. In the first instance, the primary aim of this study was to ensure that MCG has a basic ability to separate a highly polarised patient group (young controls from post infarction patients) and to identify parameters that could be used in future studies to build a formal diagnostic tool kit. Parameters that parameterised left ventricular ejection fraction (LVEF) were identified and an example is presented to show differential low and high ejection fractions.

BackgroundHeart 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.MethodsA 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.Trial RegistrationClinicalTrials.gov: NCT00841139ISRCTN: ISRCTN2887836

With increasing awareness of the condition and particular attention being paid to family screening, the number of patients being diagnosed with hypertrophic cardiomyopathy is increasing. Although the majority of patients remain at low risk for sudden cardiac death, all patients need to undergo rigorous and ongoing risk factor stratification in order to best identify those at high risk. Although implantable cardioverter-defibrillators have proven to be effective in the prevention of sudden cardiac death, careful consideration of device implantation in high-risk patients is necessary in view of the potential for device complications and their impact on quality of life.