Philip F. Binkley

Myocardial Viability and Survival in Ischemic Left Ventricular Dysfunction

BACKGROUND The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a survival benefit. However, the efficacy of this approach is uncertain. METHODS In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds. RESULTS Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval [CI], 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53). CONCLUSIONS The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595.).

Parasympathetic withdrawal is an integral component of autonomic imbalance in congestive heart failure : Demonstration in human subjects and verification in a paced canine model of ventricular failure

Although enhanced sympathetic tone is a well recognized component of the autonomic profile characteristic of congestive heart failure, the contribution of parasympathetic withdrawal to this autonomic imbalance is less well described. The technique of spectral analysis of heart rate variability provides a dynamic map of sympathetic and parasympathetic tone and was thus used to define the nature of sympathetic-parasympathetic interactions in humans with idiopathic dilated cardiomyopathy and in a paced canine model of congestive heart failure. Humans with cardiomyopathy were found to have an augmentation of the sympathetically mediated low frequency area of the power density spectrum. Parasympathetic withdrawal was demonstrated by significant reductions in the parasympathetically mediated high frequency area (p less than 0.05) and the ratio of high to low frequency areas (p less than 0.01). Administration of atropine to normal subjects resulted in a significant reduction in the high frequency area (p less than 0.05) and the high/low frequency area ratio, both of which decreased within the range noted in patients with congestive heart failure. Administration of isoproterenol in normal subjects led to an augmentation of the low frequency area but to only a small decrease in the high/low frequency area ratio. Induction of congestive heart failure in a paced canine model resulted in alterations in the autonomic profile that resembled those seen in humans with ventricular failure. The prominent high frequency region of the spectrum at baseline, indicating a predominance of parasympathetic tone, was absent after the evolution of congestive heart failure, and there was a marked augmentation of the low frequency region of the spectrum.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety and Feasibility of Autologous Myoblast Transplantation in Patients With Ischemic Cardiomyopathy Four-Year Follow-Up

Background—Successful autologous skeletal myoblast transplantation into infarcted myocardium in a variety of animal models has demonstrated improvement in cardiac function. We evaluated the safety and feasibility of transplanting autologous myoblasts into infarcted myocardium of patients undergoing concurrent coronary artery bypass grafting (CABG) or left ventricular assist device (LVAD) implantation. In addition, we sought to gain preliminary information on graft survival and any associated changes in cardiac function. Methods and Results—Thirty patients with a history of ischemic cardiomyopathy participated in a phase I, nonrandomized, multicenter pilot study of autologous skeletal myoblast transplantation concurrent with CABG or LVAD implantation. Twenty-four patients with a history of previous myocardial infarction and a left ventricular ejection fraction <40% were enrolled in the CABG arm. In a second arm, 6 patients underwent LVAD implantation as a bridge to heart transplantation, and patients donated their explanted native hearts for testing at the time of heart transplantation. Myoblasts were successfully transplanted in all patients without any acute injection-related complications or significant long-term, unexpected adverse events. Follow-up positron emission tomography scans showed new areas of glucose uptake within the infarct scar in CABG patients. Echocardiography measured an average change in left ventricular ejection fraction from 28% to 35% at 1 year and of 36% at 2 years. Histological evaluation in 4 of 6 patients who underwent heart transplantation documented survival and engraftment of the skeletal myoblasts within the infarcted myocardium. Conclusions—These results demonstrate the survival, feasibility, and safety of autologous myoblast transplantation and suggest that this modality offers a potential therapeutic treatment for end-stage heart disease.

Sustained augmentation of parasympathetic tone with angiotensin-converting enzyme inhibition in patients with congestive heart failure

OBJECTIVES The objective of this investigation was to evaluate the changes in parasympathetic tone associated with long-term angiotensin-converting enzyme inhibitor therapy in patients with congestive heart failure. BACKGROUND Angiotensin-converting enzyme inhibitors provide hemodynamic and symptomatic benefit and are associated with improved survival in patients with congestive heart failure. Angiotensin II, whose production is ultimately inhibited by these agents, exerts significant regulatory influence on a variety of target organs including the central and peripheral nervous systems. Accordingly, it would be anticipated that angiotensin-converting enzyme inhibitors would significantly alter the autonomic imbalance characteristic of patients with congestive heart failure and that this influence over neural mechanisms of cardiovascular control may significantly contribute to the hemodynamic benefit and improved survival associated with angiotensin-converting enzyme inhibitor therapy. METHODS In the current investigation, changes in autonomic tone associated with long-term administration of an angiotensin-converting enzyme inhibitor were measured using spectral analysis of heart rate variability in 13 patients with congestive heart failure who were enrolled in a double-blind randomized placebo-controlled trial of the angiotensin-converting enzyme inhibitor zofenopril. Both placebo and treatment groups were balanced at baseline study in terms of functional class, ventricular performance and autonomic tone. RESULTS After 12 weeks of therapy with placebo, there was no change in total heart rate variability, parasympathetically governed high frequency heart rate variability or sympathetically influenced low frequency heart rate variability. In contrast, therapy with zofenopril was associated with a 50% increase in total heart rate variability (p = 0.09) and a significant (p = 0.03) twofold increase in high frequency heart rate variability, indicating a significant augmentation of parasympathetic tone. CONCLUSIONS These results demonstrate that long-term treatment of patients having congestive heart failure with an angiotensin-converting enzyme inhibitor is associated with a restoration of autonomic balance, which derives in part from a sustained augmentation of parasympathetic tone. Such augmentation of vagal tone is known to be protective against malignant ventricular arrhythmias in patients with ischemic heart disease and therefore may have similar benefit in the setting of ventricular failure, thus contributing to the improved survival associated with angiotensin-converting enzyme inhibitor therapy in patients with congestive heart failure.

Navigating the Crossroads of Coronary Artery Disease and Heart Failure

Chronic heart failure (HF) affects 5 million patients in the United States and is responsible for &1 million hospitalizations and 300 000 deaths annually.1 The total annual costs associated with this disorder have been estimated to exceed

Cardiotoxicity of Histone Deacetylase Inhibitor Depsipeptide in Patients with Metastatic Neuroendocrine Tumors

40 billion.1,2 Chronic HF is the only category of cardiovascular diseases for which the prevalence, incidence, hospitalization rate, total burden of mortality, and costs have increased in the past 25 years.1,2 Fueling this epidemic is the increasing number of elderly patients developing impaired left ventricular (LV) function as a manifestation of chronic coronary artery disease (CAD).1,2 With the aging of the population and decline in mortality of other forms of cardiovascular diseases, it is likely that the incidence of HF and its impact on public health will continue to increase.1–3 In the past 3 decades, considerable attention has focused on LV dysfunction, loading conditions, neuroendocrine activation, and ventricular remodeling as the principal pathophysiological mechanisms underlying HF progression.4 There has been a fundamental shift, however, in the origin of HF that often is underemphasized.3–5 The Framingham Heart Study suggests that the most common cause of HF is no longer hypertension or valvular heart disease, as it was in previous decades, but rather CAD.4 This shift may be related to improved survival of patients after acute myocardial infarction (MI). Over the past 40 years in the United States, the odds of previous MI as a cause for HF increased by 26% per decade in men and 48% per decade in women. In contrast, there has been a 13% decrease per decade for hypertension as a cause of HF in men and a 25% decrease in women, as well as a decrease in valvular disease by 24% per decade in men and 17% in women. In the 24 …

Transesophageal echocardiographic assessment of the effects of age, gender, and hypertension on thoracic aortic wall size, thickness, and stiffness

Purpose: This phase II study was undertaken to assess objective response and toxicity of histone deacetylase inhibitor depsipeptide in patients with neuroendocrine tumors. Experimental Design: A total of 15 patients with metastatic neuroendocrine tumors received a 4-hour i.v. infusion of depsipeptide at 14 mg/m2 on days 1, 8, and 15 every 28 days. Tumor response was assessed at 8-week intervals using Response Evaluation Criteria in Solid Tumors. Most patients were chemo-naïve (n = 12) but receiving long-acting octreotide for carcinoid syndrome (n = 11). All patients had Eastern Cooperative Oncology Group performance status of 0 to 1. Results: The study was terminated prematurely due to an unexpected high number of serious cardiac adverse events so the objective response rate could not be determined. A total of 77 doses of depsipeptide with a median of four doses (range, 2-13) per patient were administered. The most common adverse events included nausea (86%), anorexia (73%), vomiting (66%), and fatigue (73%). A sudden death attributed to possible fatal ventricular arrhythmia occurred within 24 hours after the fifth dose of depsipeptide. Furthermore, asymptomatic grade 2 ventricular tachycardia (n = 2) and prolonged QTc (n = 3) probably related to depsipeptide were observed. Plasma depsipeptide levels measured in a subset of patients failed to reveal differences among patients with or without cardiac adverse events. Conclusions: Depsipeptide was associated with a high number of potentially serious cardiac adverse events in patients with metastatic neuroendocrine tumor. As sudden death possibly associated with depsipeptide was observed in this trial, the risks for potentially life-threatening arrhythmia associated with this agent need to be comprehensively evaluated.

Cardiovascular Pharmacology of Dopexamine in Low Output Congestive Heart Failure

Aging is associated with progressive arterial stiffening and widening of the pulse pressure, resulting in a high prevalence of systolic hypertension. The contribution of increased aortic thickness to this process and to essential hypertension has been poorly characterized. With transesophageal echocardiography, aortic thickness and diameter can be measured. Thus, the influence of aging, gender, and hypertension on the geometry and stiffness of the descending thoracic aorta in humans can be determined in vivo. In 83 patients undergoing transesophageal echocardiography for clinical indications, recordings of the descending thoracic aorta were made. There were 53 normotensive subjects (33 men and 20 women, mean age 46 years, range 14 to 79 years) and 25 hypertensive subjects (8 men and 17 women, mean age 67 years, range 50 to 80 years). Measurements of diastolic and systolic aortic thickness and aortic diameter were made, and three measures of the elastic properties of the aorta were calculated: (1) Petersons elastic modulus, (2) Youngs modulus, and (3) the stiffness index (beta). Aortic thickness averaged 1.1 +/- 0.1 mm in both normotensive men and women. Normotensive women had a significantly greater thickness/diameter ratio than men (0.06 +/- 0.01 vs 0.05 +/- 0.01, p < 0.01), but there were no differences in stiffness between men and women. Age was highly positively correlated with thickness (r = 0.74, p < 0.001), diameter (r = 0.67, p < 0.001), beta (r = 0.79, p < 0.001), Petersons modulus (r = 0.78, p < 0.001), and Youngs modulus (r = 0.81, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Feasibility and safety of autologous myoblast transplantation in patients with ischemic cardiomyopathy.

Dose-response infusions (0.25 to 4.0 micrograms/kg/min) and extended infusions of dopexamine, a new synthetic catechol with beta 2 adrenergic and dopaminergic agonist effects, were performed in 12 patients with low output congestive heart failure (CHF). The central and regional hemodynamic effects and responses in renal function were determined and compared with those of saline-placebo control patients in a randomized, double-blind, crossover design. Dopexamine significantly increased cardiac output at a dose greater than or equal to 0.25 micrograms/kg/min secondary to an increase in stroke volume at greater than or equal to 0.25 micrograms/kg/min and heart rate at greater than or equal to 0.50 micrograms/kg/min. Dopexamine evoked a significant decrease in systemic and pulmonary vascular resistances, with mild reductions noted for systemic and pulmonary diastolic pressures. Right and left ventricular filling pressures decreased over the entire dose range of dopexamine concomitant with a demonstrable improvement in the indexes of ventricular performance. Dopexamine preferentially increased visceral (renal, hepatic-splanchnic) blood flow over that of limb. Urine volume and sodium excretion increased slightly with dopexamine. Dopexamine elicits rather prominent vasodilating effects (particularly of visceral vascular beds), some positive inotropy and chronotropy and favorable responses in renal function.

Predicting the potential of wearable technology

Successful autologous skeletal myoblast transplantation into infarcted myocardium in a variety of animal models has demonstrated improvement in cardiac function. We evaluated the safety and feasibility of transplanting autologous myoblasts into infarcted myocardium of patients undergoing concurrent coronary artery bypass grafting (CABG) or left ventricular assist device implantation (LVAD). In addition, we sought to gain preliminary information on graft survival and any potential improvement of cardiac function. Eighteen patients with a history of ischemic cardiomyopathy participated in a phase I, nonrandomized, multicenter pilot study of autologous skeletal myoblast transplantation concurrent with CABG or LVAD implantation. Twelve patients with a history of previous myocardial infarction (MI) and a left ventricular ejection of less than 30% were enrolled in the CABG arm. In a second arm, six patients underwent LVAD implantation as a bridge to heart transplantation and were required to donate their heart for testing at the time of heart transplant. Myoblasts were successfully transplanted in all patients without any acute injection-related complications or significant long-term unexpected adverse events. Follow-up PET scans showed new areas of viability within the infarct scar in CABG patients. Echocardiography measured an average improvement in left ventricular ejection fraction (LVEF) from 25% to 34%. Histological evaluation in four out of five patients who underwent heart transplantation documented survival and engraftment of the skeletal myoblasts within the infarcted myocardium. These interim results demonstrate survival, feasibility, and safety of autologous myoblast transplantation and suggest that this modality may offer a potential therapeutic treatment for end-stage heart disease.