Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy patients exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathophysiology of hypertrophic cardiomyopathy remains unproven. We hypothesized that the metabolic modulator perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity. METHODS AND RESULTS: Forty-six consecutive patients with symptomatic exercise limitation (peak Vo(2) <75% of predicted) caused by nonobstructive hypertrophic cardiomyopathy (mean age, 55±0.26 years) were randomized to perhexiline 100 mg (n=24) or placebo (n=22). Myocardial ratio of phosphocreatine to adenosine triphosphate, an established marker of cardiac energetic status, as measured by (31)P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak Vo(2), symptoms, quality of life, and serum metabolites were assessed at baseline and study end (4.6±1.8 months). Perhexiline improved myocardial ratios of phosphocreatine to adenosine triphosphate (from 1.27±0.02 to 1.73±0.02 versus 1.29±0.01 to 1.23±0.01; P=0.003) and normalized the abnormal prolongation of heart rate normalized time to peak filling between rest and exercise (0.11±0.008 to -0.01±0.005 versus 0.15±0.007 to 0.11±0.008 second; P=0.03). These changes were accompanied by an improvement in primary end point (peak Vo(2)) (22.2±0.2 to 24.3±0.2 versus 23.6±0.3 to 22.3±0.2 mL · kg(-1) · min(-1); P=0.003) and New York Heart Association class (P<0.001) (all P values ANCOVA, perhexiline versus placebo). CONCLUSIONS: In symptomatic hypertrophic cardiomyopathy, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction, and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathophysiology and provides a rationale for further consideration of metabolic therapies in hypertrophic cardiomyopathy.

Left ventricular strain and untwist in hypertrophic cardiomyopathy: relation to exercise capacity.

BACKGROUND: Nonobstructive hypertrophic cardiomyopathy (nHCM) is often associated with reduced exercise capacity despite hyperdynamic systolic function as measured by left ventricular ejection fraction. We sought to examine the importance of left ventricular strain, twist, and untwist as predictors of exercise capacity in nHCM patients. METHODS: Fifty-six nHCM patients (31 male and mean age of 52 years) and 43 age- and gender-matched controls were enrolled. We measured peak oxygen consumption (peak Vo(2)) and acquired standard echocardiographic images in all participants. Two-dimensional speckle tracking was applied to measure rotation, twist, untwist rate, strain, and strain rate. RESULTS: The nHCM patients exhibited marked exercise limitation compared with controls (peak Vo(2) 23.28 +/- 6.31 vs 37.70 +/- 7.99 mL/[kg min], P < .0001). Left ventricular ejection fraction in nHCM patients and controls was similar (62.76% +/- 9.05% vs 62.48% +/- 5.82%, P = .86). Longitudinal, radial, and circumferential strain and strain rate were all significantly reduced in nHCM patients compared with controls. There was a significant delay in 25% of untwist in nHCM compared with controls. Both systolic and diastolic apical rotation rates were lower in nHCM patients. Longitudinal systolic and diastolic strain rate correlated significantly with peak Vo(2) (r = -0.34, P = .01 and r = 0.36, P = .006, respectively). Twenty-five percent untwist correlated significantly with peak Vo(2) (r = 0.36, P = .006). CONCLUSIONS: In nHCM patients, there are widespread abnormalities of both systolic and diastolic function. Reduced strain and delayed untwist contribute significantly to exercise limitation in nHCM patients.

Switching from transfemoral to transradial access for PCI: a single-center learning curve over 5 years.

BACKGROUND: Percutaneous coronary intervention (PCI) via the transradial (TR) route is an increasingly popular alternative to the transfemoral (TF) route. However, there are limiting factors to its adoption. We report the learning curve over 5 years in a high-volume PCI center during the crossover from TF to TR access for PCI. OBJECTIVE: To evaluate clinical characteristics, radiation doses, screening times, and subsequent clinical outcomes in subjects with femoral and radial access sites for PCI. DESIGN: We retrospectively analyzed our databases for PCI procedures/outcomes of all patients from 2006-2010. SETTING: A university teaching hospital PCI center performing cases predominantly femorally at the beginning of the study period, and transitioning to a predominantly radial access center at the end of the study period. PATIENTS: All patients undergoing PCI via either femoral or radial approach over a 5-year period. RESULTS: In year 1, TR access was used in 31.4% of cases; this rate increased to 90.1% in year 5. The switch from TF to TR access was observed among all operators and all groups of patients regardless of presentation, gender, age, and lesion complexity. In year 1, fluoroscopy times and radiation doses were higher in the TR group, but equalized in years 2 and 3 and reversed during years 4 and 5 when the TR rate was >90%. Over 5 years, the rates of vascular complications and major bleeding were higher in the TF cohort and were associated with longer hospital stay. In-hospital mortality was lower in the TR group. CONCLUSION: The change from TF to TR approach for PCI in a high-volume center is achievable within 5 years, and results in marked clinical benefits. There was an initial learning curve for fluoroscopy time and radiation dose, but this improved once an operator performed >60% of cases radially.

Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency.

OBJECTIVES: We sought to evaluate the role of exercise-related changes in left ventricular (LV) relaxation and of LV contractile function and vasculoventricular coupling (VVC) in the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and to assess myocardial energetic status in these patients. BACKGROUND: To date, no studies have investigated exercise-related changes in LV relaxation and VVC as well as in vivo myocardial energetic status in patients with HFpEF. METHODS: We studied 37 patients with HFpEF and 20 control subjects. The VVC and time to peak LV filling (nTTPF, a measure of LV active relaxation) were assessed while patients were at rest and during exercise by the use of radionuclide ventriculography. Cardiac energetic status (creatine phosphate/adenosine triphosphate ratio) was assessed by the use of (31)P magnetic resonance spectroscopy at 3-T. RESULTS: When patients were at rest, nTTPF and VVC were similar in patients with HFpEF and control subjects. The cardiac creatine phosphate/adenosine triphosphate ratio was reduced in patients with HFpEF versus control subjects (1.57 +/- 0.52 vs. 2.14 +/- 0.63; p = 0.003), indicating reduced energy reserves. Peak maximal oxygen uptake and the increase in heart rate during maximal exercise were lower in patients with HFpEF versus control subjects (19 +/- 4 ml/kg/min vs. 36 +/- 8 ml/kg/min, p < 0.001, and 52 +/- 16 beats/min vs. 81 +/- 14 beats/min, p < 0.001). The relative changes in stroke volume and cardiac output during submaximal exercise were lower in patients with HFpEF versus control subjects (ratio exercise/rest: 0.99 +/- 0.34 vs. 1.25 +/- 0.47, p = 0.04, and 1.36 +/- 0.45 vs. 2.13 +/- 0.72, p < 0.001). The nTTPF decreased during exercise in control subjects but increased in patients with HFpEF (-0.03 +/- 12 s vs. +0.07 +/- 0.11 s; p = 0.005). The VVC decreased on exercise in control subjects but was unchanged in patients with HFpEF (-0.01 +/- 0.15 vs. -0.25 +/- 0.19; p < 0.001). CONCLUSIONS: Patients with HFpEF have reduced cardiac energetic reserve that may underlie marked dynamic slowing of LV active relaxation and abnormal VVC during exercise.

Potential of metabolic agents as adjunct therapies in heart failure.

Heart failure continues to have a significant morbidity and mortality rate despite several recent advances in treatment such as additional neurohumoral blockades and cardiac resynchronization therapy. There is emerging evidence that, irrespective of etiology, heart failure is associated with an energetic disorder and that this may contribute to the pathogenesis of the syndrome. Recently, a number of studies have suggested that some metabolic agents may have potential as adjunctive therapy in patients with heart failure. These agents cause a shift of myocardial-substrate utilization away from free fatty acids toward glucose. Free fatty acid utilization consumes more oxygen to generate an equivalent amount of energy compared with glucose. Some of these agents are also effective antianginals, presumably by reducing the myocardial oxygen requirement. In this review we will discuss some of the current issues and progresses relating to metabolic manipulation in heart failure.