Right ventricular function and long-term clinical outcomes after cardiac resynchronization therapy: A cardiovascular magnetic resonance study.

BACKGROUND: Right ventricular (RV) dysfunction has been linked to a poor response to cardiac resynchronization therapy (CRT). We sought to determine whether cardiovascular magnetic resonance (CMR)-derived measures of RV function influence clinical outcomes after CRT. METHODS: In this retrospective study, we used CMR to assess pre-implant RV volumes and RV ejection fraction (RVEF) in relation to clinical outcomes after CRT implantation. RESULTS: Among 243 patients (age: 70.3 ± 10.8 years [mean ± SD]; 68.7% male; 121 [49.8%]) with ischemic cardiomyopathy and 122 (50.2%) with nonischemic cardiomyopathy, 141 (58%) after CRT-defibrillation (CRT-D) and 102 (42%) after CRT-pacing (CRT-P), 101 (41.6.0%) patients died, 61 (25.1%) from cardiac causes and 24 (9.88%) from noncardiac causes, over 5.87 years (median; interquartile range: 4.35-7.73). Two (0.82%) patients underwent cardiac transplantation and four (1.64%) had a left ventricular assist device (LVAD). A total of 41 (16.9%) met the composite endpoint of sudden cardiac death (SCD), ventricular tachycardia, or ventricular fibrillation. In univariate analyses, no measure of RV function was associated with total mortality or the arrhythmic endpoint. RVEF was associated with cardiac mortality on univariate analyses (HR per 10%: 0.82, 95% CI 0.70-0.96), but not on multivariate analyses that included left ventricular ejection fraction. CONCLUSIONS: There is no relationship between measures of RV function, such as RV volumes and RVEF, and the long-term clinical outcome of CRT. These findings indicate that such measures should not be considered in patient selection.

Short-term intravenous sodium nitrite infusion improves cardiac and pulmonary hemodynamics in heart failure patients.

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.

Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy.

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 heart failure (HF). (31)P cardiac magnetic resonance spectroscopy can be used to quantify the myocardial phosphocreatine/adenosine triphosphate ratio. Because improvement of HF syndrome can improve cardiac energetics secondarily, we investigated the effects of short-term perhexiline therapy. METHODS: Patients with systolic HF of nonischemic etiology (n = 50, 62 ± 1.8 years of age, New York Heart Association functional class II to IV, LVEF: 27.0 ± 1.44%) were randomized to receive perhexiline 200 mg or placebo for 1 month in a double-blind fashion. Clinical assessment, echocardiography, and (31)P cardiac magnetic resonance spectroscopy were performed at baseline and after 1 month. A substudy of 22 patients also underwent cross-heart blood sampling at completion of the study to quantify metabolite utilization. RESULTS: Perhexiline therapy was associated with a 30% increase in the phosphocreatine/adenosine triphosphate ratio (from 1.16 ± 0.39 to 1.51 ± 0.51; p < 0.001) versus a 3% decrease with placebo (from 1.36 ± 0.31 to 1.34 ± 0.31; p = 0.37). Perhexiline therapy also led to an improvement in New York Heart Association functional class compared with placebo (p = 0.036). Short-term perhexiline therapy did not change LVEF. Cross-heart measures of cardiac substrate uptake and respiratory exchange ratio (which reflects the ratio of substrates used) did not differ between patients who received perhexiline versus placebo. CONCLUSIONS: Perhexiline improves cardiac energetics and symptom status with no evidence of altered cardiac substrate utilization. No change in LVEF is seen at this early stage. (Metabolic Manipulation in Chronic Heart Failure; NCT00841139).

Randomized double-blind placebo-controlled trial of perhexiline in heart failure with preserved ejection fraction syndrome.

Recently heart failure with preserved ejection fraction (HFpEF) has emerged as a huge epidemic. Increasing evidence shows the role of energy deficiency in the pathophysiology of HFpEF. In the current study, we hypothesize that the use of metabolic modulator perhexiline would correct myocardial energy deficiency and improve exercise capacity and diastolic abnormalities in patients with this syndrome.

Kussmaul physiology in patients with heart failure.

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.

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

BACKGROUND: 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 ß-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. METHODS: 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. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00841139 ISRCTN: ISRCTN72887836.

Device therapy in hypertrophic cardiomyopathy.

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.

Drug-implantable cardioverter-defibrillator interactions.

Antiarrhythmic drugs are commonly used synergistically with implantable cardioverter defibrillators in the management of ventricular and supraventricular arrhythmias. However, these drugs may directly or indirectly interact with device function. In addition, expanding indications for implantable cardioverter defibrillators, particularly in patients with multiple comorbidities, further increases the potential for drug-device interactions. These potential drug-device interactions are summarized in this article.

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.

Magnetic resonance spectroscopy in myocardial disease.

31-phosphorous ((31)P) magnetic resonance spectroscopy (MRS) is a technique that allows the noninvasive characterization of the biochemical and metabolic state of the myocardium in vivo. MRS is a pure form of molecular imaging using magnetic resonance signals from nuclei with nuclear spin to assess cardiac metabolism without the need for external radioactive tracers. (31)P MRS provides information on the underlying metabolic abnormalities that are fundamental to common conditions including ischemic heart disease, cardiomyopathy, hypertrophy and valvular disease. (31)P MRS could potentially also have a role to play in assessing response to therapy as well as the effectiveness of metabolic modulating agents. However, the use of MRS is currently limited to research due to its poor reproducibility, low spatial and temporal resolution, and long acquisition times. With technical advances in both the spectrometers and postprocessing, MRS is likely to play a role in the future of multimodal noninvasive cardiac assessment.

Death and dying in heart failure with normal ejection fraction.

The overall mortality rate in patients with heart failure with normal ejection fraction (HFNEF) appears to be comparable to that in patients with heart failure with reduced ejection fraction. In contrast to the latter group of patients, randomized trials with neurohumoral blockade in patients with HFNEF have failed to demonstrate reduction in mortality. This is at least in part related to the lower proportion of heart failure-related death in the overall population of patients with HFNEF. In conclusion, better characterization of patients with HFNEF at greatest risk for heart failure-related death and understanding the risks of the different modes of death would allow more effective use of specific heart failure medical or device therapy in patients with HFNEF.