Thanh Trung Phan

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 &OV0312;o2 <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 31P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak &OV0312;o2, 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 &OV0312;o2) (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. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00500552.

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.

Impaired Heart Rate Recovery and Chronotropic Incompetence in Patients with Heart Failure with Preserved Ejection Fraction

Background—This study assessed the chronotropic response to exercise and heart rate (HR) recovery after exercise in a carefully phenotyped group of patients with heart failure with preserved left ventricular ejection fraction (HfpEF) and a control group of similar age and gender distribution. Methods and Results—We studied 41 patients with HfpEF, 41 healthy controls, and 16 hypertensive controls. None were taking HR-limiting medications. All study participants had clinical examination, 12-lead ECG, pulmonary function test, echocardiogram, and metabolic exercise test with HR monitoring throughout exercise. Chronotropic response was measured by the percentage of the HR reserve used during maximal exercise and the peak exercise HR as a percentage of predicted maximal HR. Patients with HfpEF were generally women (70%), overweight, aged 69±8 years. Controls were of similar gender (63%) and age (67±6 years). Patients with HfpEF had significantly reduced peak VO2 compared with controls (20±4 mL · kg−1 · min−1 versus 31±6 mL · kg−1 · min−1, P<0.001) and greater minute ventilation-carbon dioxide production relationship (Ve/Vco2 slope) (33±6 versus 29±4, P<0.001). Chronotropic incompetence was significantly more common in patients with HfpEF compared with matched healthy controls as measured by the percentage of the HR reserve used during maximal exercise (63% versus 2%, <0.001) and percentage of predicted maximal HR (34% versus 2%, <0.001). In addition, abnormal HR recovery 1-minute after exercise (defined as the reduction in the HR from peak exercise 1-minute after exercise) was also significantly more common in patients with HfpEF compared with controls (23% versus 2%, P=0.01). Hypertensive controls showed similar chronotropic response to peak exercise and HR recovery after exercise as healthy controls. Conclusions—Patients with HfpEF have impaired chronotropic incompetence during maximal exercise and abnormal HR recovery after exercise.

Left ventricular torsion and strain patterns in heart failure with normal ejection fraction are similar to age-related changes.

AIMS We used speckle tracking echocardiography (STE) to make a comparison between the effects of ageing and of heart failure with normal ejection fraction (HfnEF) on left ventricular (LV) torsion and strain patterns. METHODS AND RESULTS Forty patients with HfnEF, 27 young controls and 26 older controls, were prospectively recruited. All subjects underwent clinical examination, 12-lead electrocardiogram, pulmonary function test, echocardiogram, and metabolic exercise test. LV torsion increases with advancing age (older controls vs. young controls, 2.2 +/- 0.9 vs. 1.4 +/- 0.8 degrees /cm; P = 0.03). Circumferential strain was enhanced in patients with HfnEF (-24.7 +/- 4.7 vs. -20.0 +/- 4.9%; P = 0.003). Rotational deformation delay (time difference between peak basal rotation and peak apical rotation), global circumferential strain, E-velocity deceleration time, and LV end-diastolic volume index were independent predictors of LV torsion. LV torsion and body mass index were independent predictors of LV untwist rate. CONCLUSION Ageing is associated with increased LV torsion secondary to reduced rotational deformation delay and increased peak basal rotation. LV torsion and strain patterns in patients with HfnEF are similar to age-related changes apart from circumferential strain, which is enhanced in patients with HfnEF.

Relationship Between Coronary Microvascular Dysfunction and Cardiac Energetics Impairment in Type 1 Diabetes Mellitus

Background— Asymptomatic subjects with diabetes mellitus have an impaired cardiac energetics status that may play a significant role in the development of heart failure. In the present study, we assessed the role of microvascular dysfunction in the development of impaired cardiac energetics in subjects with type 1 diabetes mellitus. Methods and Results— Twenty-five asymptomatic subjects with type 1 diabetes mellitus (mean age ±1 SD 33±8 years) and 26 age-, sex-, and body mass index-matched healthy control subjects (32±8 years old) were recruited into the study. The type 1 diabetes mellitus subjects were divided into 2 age-matched groups (newly diagnosed [<5 years] and longer-duration [>10 years] diabetes) to assess the impact of microvascular disease. All subjects had an echocardiogram and an exercise ECG performed, followed by magnetic resonance spectroscopy and stress magnetic resonance imaging. Compared with healthy control subjects, the phosphocreatine/&ggr;-ATP ratio was reduced significantly both in subjects with longer-term (2.1±0.5 versus 1.5±0.4, P<0.000) and newly diagnosed (2.1±0.5 versus 1.6±0.2, P<0.000) diabetes. The phosphocreatine/&ggr;-ATP ratio was similar in newly diagnosed diabetes subjects and those with longer-term disease (1.6±0.2 versus 1.5±0.4, P=0.32). The mean myocardial perfusion reserve index in the longer-term type 1 diabetes mellitus subjects was significantly lower than in healthy control subjects (1.7±0.6 versus 2.3±0.4, P=0.005). On univariate analysis, there was no significant correlation of phosphocreatine/&ggr;-ATP ratio with myocardial perfusion reserve index (r=0.21, P=0.26). Conclusions— We demonstrate that young subjects with uncomplicated type 1 diabetes mellitus have impaired myocardial energetics irrespective of the duration of diabetes and that the impaired cardiac energetics status is independent of coronary microvascular function. We postulate that impairment of cardiac energetics in these subjects primarily results from metabolic dysfunction rather than microvascular impairment.

Short-Term Hemodynamic Effects of Cardiac Resynchronization Therapy in Patients With Heart Failure, a Narrow QRS Duration, and No Dyssynchrony

Background— Cardiac resynchronization therapy produces both short-term hemodynamic and long-term symptomatic/mortality benefits in symptomatic heart failure patients with a QRS duration >120 ms. This is conventionally believed to be due principally to relief of dyssynchrony, although we recently showed that relief of external constraint to left ventricular filling may also play a role. In this study, we evaluated the short-term hemodynamic effects in symptomatic patients with a QRS duration <120 ms and no evidence of dyssynchrony on conventional criteria and assessed the effects on contractility and external constraint. Methods and Results— Thirty heart failure patients (New York Heart Association class III/IV) with a left ventricular ejection fraction ≤35% who were in sinus rhythm underwent pressure-volume studies at the time of pacemaker implantation. External constraint, left ventricular stroke work, dP/dtmax, and the slope of the preload recruitable stroke work relation were measured from the end-diastolic pressure-volume relation before and during delivery of biventricular and left ventricular pacing. The following changes were observed during delivery of cardiac resynchronization therapy: Cardiac output increased by 25±5% (P<0.05), absolute left ventricular stroke work increased by 26±5% (P<0.05), the slope of the preload recruitable stroke work relation increased by 51±15% (P<0.05), and dP/dtmax increased by 9±2% (P<0.05). External constraint was present in 15 patients and was completely abolished by both biventricular and left ventricular pacing (P<0.05). Conclusion— Cardiac resynchronization therapy results in an improvement in short-term hemodynamic variables in patients with a QRS <120 ms related to both contractile improvement and relief of external constraint. These findings provide a potential physiological basis for cardiac resynchronization therapy in this patient population.

31P magnetic resonance spectroscopy to measure in vivo cardiac energetics in normal myocardium and hypertrophic cardiomyopathy: Experiences at 3 T

BACKGROUND (31)P magnetic resonance spectroscopy (MRS) allows measurement of in vivo high-energy phosphate kinetics in the myocardium. While traditionally (31)P cardiac spectroscopy is performed at 1.5T, cardiac MRS at higher field strength can theoretically increase signal to noise ratio (SNR) and spectral resolution therefore improving sensitivity and specificity of the cardiac spectra. The reproducibility and feasibility of performing cardiac spectroscopy at 3T is presented here in this study in healthy volunteers and patients with hypertrophic cardiomyopathy. METHODS Cardiac spectroscopy was performed using a Phillips 3T Achieva scanner in 37 healthy volunteers and 26 patients with hypertrophic cardiomyopathy (HCM) to test the feasibility of the protocol. To test the reproducibility a single volunteer was scanned eight times on separate occasions. A single voxel (31)P MRS was performed using Image Selected In vivo Spectroscopy (ISIS) volume localization. RESULTS The mean phosphocreatine/adenosine triphosphate (PCr/ATP) ratio of the eight measurements performed on one individual was 2.11+/-0.25. Bland Altman plots showed a variance of 12% in the measurement of PCr/ATP ratios. The PCr/ATP ratio was significantly reduced in HCM patients compared to controls, 1.42+/-0.51 and 2.11+/-0.57, respectively, P<0.0001. (All results are expressed as mean+/-standard deviation). CONCLUSIONS Here we demonstrate that cardiac (31)P MRS at 3T is a reliable method of measuring in vivo high-energy phosphate kinetics in the myocardium for clinical studies and diagnostics. Based on our data an impairment of cardiac energetic state in patients with hypertrophic cardiomyopathy is indisputable.

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 Vo2) 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 Vo2 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 Vo2 (r = −0.34, P = .01 and r = 0.36, P = .006, respectively). Twenty-five percent untwist correlated significantly with peak Vo2 (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.

Multi‐centre experience on the use of perhexiline in chronic heart failure and refractory angina: old drug, new hope

The objective of this study is to report on our 5‐year collective experience on the use of perhexiline in the UK, in patients with chronic heart failure (CHF) and/or refractory angina with respect to ‘real‐life’ drug side effects and toxicity, therapeutic drug level monitoring, 5 year mortality outcomes and predictors of response to perhexiline therapy.

Increased Atrial Contribution to Left Ventricular Filling Compensates for Impaired Early Filling During Exercise in Heart Failure With Preserved Ejection Fraction

BACKGROUND The role of left atrial (LA) function on exercise remains poorly understood in heart failure with preserved ejection fraction (HfpEF) despite its key role in optimizing left ventricular (LV) diastolic function. We used resting and exercise radionuclide ventriculography to investigate the role of LA function in the pathophysiology of HfpEF. METHODS AND RESULTS A total of 25 patients with HfpEF and 15 age- and gender-matched controls were recruited. All subjects underwent resting echocardiogram, metabolic exercise testing to peak effort, and radionuclide ventriculography (at rest and exercise [to 35% of heart rate reserve]). At rest LA and LV function were similar in patients and controls. During exercise, HfpEF patients had lower left ventricular ejection fraction (69 +/- 9% vs. 73 +/- 10%, P < .05) and lower peak early filling rate (387 +/- 109 end-diastolic count/sec vs. 561 +/- 156 end-diastolic count/sec, P < .001). During exercise, the atrial contribution to LV filling was significantly higher in patients than controls (46 +/- 11% vs. 30 +/- 9%, P < .001). Atrial contribution to LV filling correlated negatively with peak early filling rate during exercise (r = -0.6, P < .001). Peak early filling rate correlated positively with peak oxygen consumption (r = 0.485, P = .004) and negatively with minute/carbon dioxide production (r = -0.423, P = .013). CONCLUSION Patients with HfpEF have increased atrial contribution to LV filling as a compensatory response to impaired early LV filling during cycle exercise.