Lynne Williams

Metabolic Modulation With Perhexiline in Chronic Heart Failure: A Randomized, Controlled Trial of Short-Term Use of a Novel Treatment

Background— Chronic heart failure (CHF) is a major cause of morbidity and mortality that requires a novel approach to therapy. Perhexiline is an antianginal drug that augments glucose metabolism by blocking muscle mitochondrial free fatty acid uptake, thereby increasing metabolic efficiency. We assessed the effects of perhexiline treatment in CHF patients. Methods and Results— In a double-blind fashion, we randomly assigned patients with optimally medicated CHF to either perhexiline (n=28) or placebo (n=28). The primary end point was peak exercise oxygen consumption (&OV0312;o2max), an important prognostic marker. In addition, the effect of perhexiline on myocardial function and quality of life was assessed. Quantitative stress echocardiography with tissue Doppler measurements was used to assess regional myocardial function in patients with ischemic CHF. 31P magnetic resonance spectroscopy was used to assess the effect of perhexiline on skeletal muscle energetics in patients with nonischemic CHF. Treatment with perhexiline led to significant improvements in &OV0312;o2max (16.1±0.6 to 18.8±1.1 mL · kg−1 · min−1; P<0.001), quality of life (Minnesota score reduction from 45±5 to 34±5; P=0.04), and left ventricular ejection fraction (24±1% to 34±2%; P<0.001). Perhexiline treatment also increased resting and peak dobutamine stress regional myocardial function (by 15% and 24%, respectively) and normalized skeletal muscle phosphocreatine recovery after exercise. There were no adverse effects during the treatment period. Conclusions— In patients with CHF, metabolic modulation with perhexiline improved &OV0312;o2max, left ventricular ejection fraction, symptoms, resting and peak stress myocardial function, and skeletal muscle energetics. Perhexiline may therefore represent a novel treatment for CHF with a good safety profile, provided that the dosage is adjusted according to plasma levels.

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.

Myocardial fibrosis in hypertrophic cardiomyopathy: accurate reflection of histopathological findings by CMR.

OBJECTIVES In this study we sought to explore the relationship between cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) and histopathological parameters including interstitial fibrosis and replacement fibrosis (scar) in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND CMR-LGE is a well-established tool for the assessment of scar in ischemic heart disease. Its role in HCM has evolved in recent years, and an association with nonsustained ventricular tachycardia has been demonstrated. METHODS HCM patients who underwent septal myectomy during the period 2004 through 2010 and had undergone CMR-LGE no more than 6 months before surgery were selected. Histopathological assessment of the myectomy specimens included quantitative digital analysis (interstitial and replacement fibrosis) and semiquantitative assessment (small intramural coronary arteriole dysplasia and disarray). Correlations between CMR-LGE measured with various techniques, SD above the signal intensity for the normal remote myocardium (2, 4, 5, 6, and 10 SD) and the full width at half maximum (FWHM) technique, at the myectomy site, and interstitial fibrosis, replacement fibrosis (scar), and their sum (fibrosis + scar) were evaluated. RESULTS Twenty-nine patients were included. Statistically significant correlations between CMR-LGE (at 2, 4, 5, 6, 10 SD and by the FWHM technique), and both interstitial fibrosis and the combined interstitial and replacement fibrosis were found. The strongest correlation was between combined interstitial and replacement fibrosis and CMR-LGE measured at 5 SD (r = 0.78, p < 0.0001). LGE measured at 10 SD demonstrated the best correlation with replacement fibrosis (r = 0.42, p = 0.02). Bland-Altman analysis revealed optimum agreement between the combined interstitial and replacement fibrosis found at pathology and LGE measured at 4 SD. In addition, moderate and severe small intramural coronary artery dysplasia showed a statistically significant correlation with replacement fibrosis (p = 0.01) and CMR-LGE at 10 SD (p = 0.04). CONCLUSIONS CMR-LGE measured at 4 SD and 5 SD yields the closest approximation to the extent of total fibrosis measured by the histopathological standard of reference. These findings have implications for future investigations of CMR-LGE and its association with important clinical endpoints in HCM, including sudden cardiac death.

Glucose-Insulin-Potassium Reduces the Incidence of Low Cardiac Output Episodes After Aortic Valve Replacement for Aortic Stenosis in Patients With Left Ventricular Hypertrophy Results From the Hypertrophy, Insulin, Glucose, and Electrolytes (HINGE) Trial

Background— Patients undergoing aortic valve replacement for critical aortic stenosis often have significant left ventricular hypertrophy. Left ventricular hypertrophy has been identified as an independent predictor of poor outcome after aortic valve replacement as a result of a combination of maladaptive myocardial changes and inadequate myocardial protection at the time of surgery. Glucose-insulin-potassium (GIK) is a potentially useful adjunct to myocardial protection. This study was designed to evaluate the effects of GIK infusion in patients undergoing aortic valve replacement surgery. Methods and Results— Patients undergoing aortic valve replacement for aortic stenosis with evidence of left ventricular hypertrophy were randomly assigned to GIK or placebo. The trial was double-blind and conducted at a single center. The primary outcome was the incidence of low cardiac output syndrome. Left ventricular biopsies were analyzed to assess changes in 5′ adenosine monophosphate–activated protein kinase (AMPK), Akt phosphorylation, and protein O-linked &bgr;-N-acetylglucosamination (O-GlcNAcylation). Over a 4-year period, 217 patients were randomized (107 control, 110 GIK). GIK treatment was associated with a significant reduction in the incidence of low cardiac output state (odds ratio, 0.22; 95% confidence interval, 0.10 to 0.47; P=0.0001) and a significant reduction in inotrope use 6 to 12 hours postoperatively (odds ratio, 0.30; 95% confidence interval, 0.15 to 0.60; P=0.0007). These changes were associated with a substantial increase in AMPK and Akt phosphorylation and a significant increase in the O-GlcNAcylation of selected protein bands. Conclusions— Perioperative treatment with GIK was associated with a significant reduction in the incidence of low cardiac output state and the need for inotropic support. This benefit was associated with increased signaling protein phosphorylation and O-GlcNAcylation. Multicenter studies and late follow-up will determine whether routine use of GIK improves patient prognosis. Clinical Trial Registration— URL: http://www.controlled-trials.com. Reference number: ISRCTN 05758301.

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.

Echocardiography in hypertrophic cardiomyopathy diagnosis, prognosis, and role in management

Hypertrophic cardiomyopathy (HCM) is diagnosed on the basis of left ventricular (LV) hypertrophy for which there is insufficient explanation (e.g. mild hypertension or mild aortic stenosis with marked hypertrophy). Echocardiography is an invaluable tool in the diagnosis and follow-up of patients with HCM. Echocardiographic assessment requires a comprehensive assessment in several imaging planes with careful attention to correct beam alignment in order to minimize errors in the measurement of LV wall thickness and appropriate identification of hypertrophy with an unusual distribution.

Toronto Hypertrophic Cardiomyopathy Genotype Score for Prediction of a Positive Genotype in Hypertrophic Cardiomyopathy

Background—Genotyping in hypertrophic cardiomyopathy has gained increasing attention in the past decade. Its major role is for family screening and rarely influences decision-making processes in any individual patient. It is associated with substantial costs, and cost-effectiveness can only be achieved in the presence of high-detection rates for disease-causing sarcomere protein gene mutations. Therefore, our aim was to develop a score based on clinical and echocardiographic variables that allows prediction of the probability of a positive genotype. Methods and Results—Clinical and echocardiographic variables were collected in 471 consecutive patients undergoing genetic testing at a tertiary referral center between July 2005 and November 2010. Logistic regression for a positive genotype was used to construct integer risk weights for each independent predictor variable. These were summed for each patient to create the Toronto hypertrophic cardiomyopathy genotype score. A positive genotype was found in 163 of 471 patients (35%). Independent predictors with associated-risk weights in parentheses were as follows: age at diagnosis 20 to 29 (−1), 30 to 39 (−2), 40 to 49 (−3), 50 to 59 (−4), 60 to 69 (−5), 70 to 79 (−6), ≥80 (−7); female sex (4); arterial hypertension (−4); positive family history for hypertrophic cardiomyopathy (6); morphology category (5); ratio of maximal wall thickness:posterior wall thickness <1.46 (0), 1.47 to 1.70 (1), 1.71 to 1.92 (2), 1.93 to 2.26 (3), ≥2.27 (4). The model had a receiver operator curve of 0.80 and Hosmer–Lemeshow goodness-of-fit P=0.22. Conclusions—The Toronto genotype score is an accurate tool to predict a positive genotype in a hypertrophic cardiomyopathy cohort at a tertiary referral center.

Glucose-Insulin-Potassium Reduces the Incidence of Low Cardiac Output Episodes After Aortic Valve Replacement for Aortic Stenosis in Patients With Left Ventricular Hypertrophy

Background— Patients undergoing aortic valve replacement for critical aortic stenosis often have significant left ventricular hypertrophy. Left ventricular hypertrophy has been identified as an independent predictor of poor outcome after aortic valve replacement as a result of a combination of maladaptive myocardial changes and inadequate myocardial protection at the time of surgery. Glucose-insulin-potassium (GIK) is a potentially useful adjunct to myocardial protection. This study was designed to evaluate the effects of GIK infusion in patients undergoing aortic valve replacement surgery. Methods and Results— Patients undergoing aortic valve replacement for aortic stenosis with evidence of left ventricular hypertrophy were randomly assigned to GIK or placebo. The trial was double-blind and conducted at a single center. The primary outcome was the incidence of low cardiac output syndrome. Left ventricular biopsies were analyzed to assess changes in 5′ adenosine monophosphate–activated protein kinase (AMPK), Akt phosphorylation, and protein O-linked &bgr;-N-acetylglucosamination (O-GlcNAcylation). Over a 4-year period, 217 patients were randomized (107 control, 110 GIK). GIK treatment was associated with a significant reduction in the incidence of low cardiac output state (odds ratio, 0.22; 95% confidence interval, 0.10 to 0.47; P=0.0001) and a significant reduction in inotrope use 6 to 12 hours postoperatively (odds ratio, 0.30; 95% confidence interval, 0.15 to 0.60; P=0.0007). These changes were associated with a substantial increase in AMPK and Akt phosphorylation and a significant increase in the O-GlcNAcylation of selected protein bands. Conclusions— Perioperative treatment with GIK was associated with a significant reduction in the incidence of low cardiac output state and the need for inotropic support. This benefit was associated with increased signaling protein phosphorylation and O-GlcNAcylation. Multicenter studies and late follow-up will determine whether routine use of GIK improves patient prognosis. Clinical Trial Registration— URL: http://www.controlled-trials.com. Reference number: ISRCTN 05758301.

The Toronto HCM Genotype Score for Prediction of a Positive Genotype in Hypertrophic Cardiomyopathy

Background—Genotyping in hypertrophic cardiomyopathy has gained increasing attention in the past decade. Its major role is for family screening and rarely influences decision-making processes in any individual patient. It is associated with substantial costs, and cost-effectiveness can only be achieved in the presence of high-detection rates for disease-causing sarcomere protein gene mutations. Therefore, our aim was to develop a score based on clinical and echocardiographic variables that allows prediction of the probability of a positive genotype. Methods and Results—Clinical and echocardiographic variables were collected in 471 consecutive patients undergoing genetic testing at a tertiary referral center between July 2005 and November 2010. Logistic regression for a positive genotype was used to construct integer risk weights for each independent predictor variable. These were summed for each patient to create the Toronto hypertrophic cardiomyopathy genotype score. A positive genotype was found in 163 of 471 patients (35%). Independent predictors with associated-risk weights in parentheses were as follows: age at diagnosis 20 to 29 (−1), 30 to 39 (−2), 40 to 49 (−3), 50 to 59 (−4), 60 to 69 (−5), 70 to 79 (−6), ≥80 (−7); female sex (4); arterial hypertension (−4); positive family history for hypertrophic cardiomyopathy (6); morphology category (5); ratio of maximal wall thickness:posterior wall thickness <1.46 (0), 1.47 to 1.70 (1), 1.71 to 1.92 (2), 1.93 to 2.26 (3), ≥2.27 (4). The model had a receiver operator curve of 0.80 and Hosmer–Lemeshow goodness-of-fit P=0.22. Conclusions—The Toronto genotype score is an accurate tool to predict a positive genotype in a hypertrophic cardiomyopathy cohort at a tertiary referral center.

Significance of left ventricular apical–basal muscle bundle identified by cardiovascular magnetic resonance imaging in patients with hypertrophic cardiomyopathy

AIMS Cardiovascular magnetic resonance (CMR) has improved diagnostic and management strategies in hypertrophic cardiomyopathy (HCM) by expanding our appreciation for the diverse phenotypic expression. We sought to characterize the prevalence and clinical significance of a recently identified accessory left ventricular (LV) muscle bundle extending from the apex to the basal septum or anterior wall (i.e. apical-basal). METHODS AND RESULTS CMR was performed in 230 genotyped HCM patients (48 ± 15 years, 69% male), 30 genotype-positive/phenotype-negative (G+/P-) family members (32 ± 15 years, 30% male), and 126 controls. Left ventricular apical-basal muscle bundle was identified in 145 of 230 (63%) HCM patients, 18 of 30 (60%) G+/P- family members, and 12 of 126 (10%) controls (G+/P- vs. controls; P < 0.01). In HCM patients, the prevalence of an apical-basal muscle bundle was similar among those with disease-causing sarcomere mutations compared with patients without mutation (64 vs. 62%; P = 0.88). The presence of an LV apical-basal muscle bundle was not associated with LV outflow tract obstruction (P = 0.61). In follow-up, 33 patients underwent surgical myectomy of whom 22 (67%) were identified to have an accessory LV apical-basal muscle bundle, which was resected in all patients. CONCLUSION Apical-basal muscle bundles are a unique myocardial structure commonly present in HCM patients as well as in G+/P- family members and may represent an additional morphologic marker for HCM diagnosis in genotype-positive status.