Ronald G. Schwartz

Optimal Medical Therapy With or Without Percutaneous Coronary Intervention to Reduce Ischemic Burden Results From the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial Nuclear Substudy

Background— Extent and severity of myocardial ischemia are determinants of risk for patients with coronary artery disease, and ischemia reduction is an important therapeutic goal. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) nuclear substudy compared the effectiveness of percutaneous coronary intervention (PCI) for ischemia reduction added to optimal medical therapy (OMT) with the use of myocardial perfusion single photon emission computed tomography (MPS). Methods and Results— Of the 2287 COURAGE patients, 314 were enrolled in this substudy of serial rest/stress MPS performed before treatment and 6 to 18 months (mean=374±50 days) after randomization using paired exercise (n=84) or vasodilator stress (n=230). A blinded core laboratory analyzed quantitative MPS measures of percent ischemic myocardium. Moderate to severe ischemia encumbered ≥10% myocardium. The primary end point was ≥5% reduction in ischemic myocardium at follow-up. Treatment groups had similar baseline characteristics. At follow-up, the reduction in ischemic myocardium was greater with PCI+OMT (−2.7%; 95% confidence interval, −1.7%, −3.8%) than with OMT (−0.5%; 95% confidence interval, −1.6%, 0.6%; P<0.0001). More PCI+OMT patients exhibited significant ischemia reduction (33% versus 19%; P=0.0004), especially patients with moderate to severe pretreatment ischemia (78% versus 52%; P=0.007). Patients with ischemia reduction had lower unadjusted risk for death or myocardial infarction (P=0.037 [risk-adjusted P=0.26]), particularly if baseline ischemia was moderate to severe (P=0.001 [risk-adjusted P=0.08]). Death or myocardial infarction rates ranged from 0% to 39% for patients with no residual ischemia to ≥10% residual ischemia on follow-up MPS (P=0.002 [risk-adjusted P=0.09]). Conclusions— In COURAGE patients who underwent serial MPS, adding PCI to OMT resulted in greater reduction in ischemia compared with OMT alone. Our findings suggest a treatment target of ≥5% ischemia reduction with OMT with or without coronary revascularization.

Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy: Seven-year experience using serial radionuclide angiocardiography

To impact on the development of clinical congestive heart failure as a complication of doxorubicin therapy, left ventricular ejection fraction was monitored with serial resting radionuclide angiocardiography in 1,487 patients with cancer over a seven-year period in both university and community hospital environments. A high-risk subset of 282 patients was selected for retrospective analysis of their clinical outcome. High-risk patients were identified by one or two of the following three criteria: decline of 10 percent or more in absolute left ventricular ejection fraction from a normal baseline to 50 percent or less; high cumulative dose of doxorubicin (more than 450 mg/m2); abnormal baseline left ventricular ejection fraction (less than 50 percent). Clinical congestive heart failure occurred in 46 (16 percent) during the treatment period, and in an additional three patients (1.3 percent) at last follow-up examination 11.8 +/- 14.2 months following discontinuation of doxorubicin. Total cumulative dosages of doxorubicin that precipitated congestive heart failure (75 to 1,095 mg/m2) and those that did not (30 to 880 mg/m2) varied widely. Decline of 10 percent or more in absolute left ventricular ejection fraction to a value of 50 percent or less preceded administration of the final dose of doxorubicin that precipitated clinical congestive heart failure in the majority of patients in whom congestive heart failure developed. Clinical congestive heart failure improved in 87 percent given routine therapy with digitalis, diuretics, and/or vasodilators. Criteria for monitoring left ventricular ejection fraction and discontinuing doxorubicin were formulated. The occurrence of clinical congestive heart failure was compared in those patients whose management was concordant with proposed criteria (Group A) and in those whose management was not (Group B). Group A had a lower incidence of congestive heart failure compared with Group B (2.9 percent versus 20.8 percent, p less than 0.001) and had only mild congestive heart failure that resolved with treatment (n = 2) and no deaths due to congestive heart failure. Multivariate analysis with proportional-hazards regression (Coxs model) demonstrated a fourfold reduction in the incidence of congestive heart failure independent of other clinical predictor variables in those patients whose management was concordant with proposed guideline criteria. The incidence, persistence, late development, predictability, and reversibility of clinical congestive heart failure were comparable in university and community hospital settings.(ABSTRACT TRUNCATED AT 400 WORDS)

Superiority of visual versus computerized echocardiographic estimation of radionuclide left ventricular ejection fraction

An optimal method for determining left ventricular ejection fraction (LVEF) by echocardiography should be rapid, reliable, and widely applicable in order to be utilized routinely in a busy clinical laboratory. Most methods reported in the literature are reliable in selected, high-quality echocardiograms. Most require off-line computer analysis and are time-consuming and poorly suited to the routine of a busy laboratory. We compared in a blinded manner several echocardiographic methods of LVEF determination with the ejection fraction obtained by equilibrium radionuclide angiography (ERNA) in 44 patients unselected for image quality. Echocardiographic methods included: [1] cubed M-mode formula; [2] Teichholz M-mode formula; [3] subjective estimation of LVEF from two-dimensional echocardiographic videotape; [4] area-length method in one four-chamber view; [5] average of area-length method in three four-chamber views; [6] average of area-length method in four-chamber and two-chamber views (one beat each); [7] subjective estimation from stored videoloop of four-chamber and two-chamber view. In 30 cases M-mode tracings were available for analysis. In only 23 of the 44 patients were the apical views suitable for quantitative analysis. The ERNA ejection fraction was 44 +/- 17% (mean +/- 1 SD). The best echocardiographic correlation with ERNA ejection fraction in each patient subgroup studied was obtained by method 3. We concluded that subjective analysis of the videotaped study by an experienced cardiologist/echocardiographer provided the best estimation of ERNA ejection fraction. More time-consuming and costly computer techniques yielded a worse estimate.

Expert Consensus for Multi-Modality Imaging Evaluation of Cardiovascular Complications of Radiotherapy in Adults: A Report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography

Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. The gain in life expectancy obtained with anti-cancer therapy can be compromised by increased morbidity and mortality associated with its cardiac complications. While radiosensitivity of the heart was initially recognized only in the early 1970s, the heart is regarded in the current era as one of the most critical dose-limiting organs in radiotherapy. Several clinical studies have identified adverse clinical consequences of radiation-induced heart disease (RIHD) on the outcome of long-term cancer survivors. A comprehensive review of potential cardiac complications related to radiotherapy is warranted. An evidence-based review of several imaging approaches used to detect, evaluate, and monitor RIHD is discussed. Recommendations for the early identification and monitoring of cardiovascular complications of radiotherapy by cardiac imaging are also proposed.

Symptomatic coronary artery disease after mantle irradiation for Hodgkin's disease

PURPOSE a) To assess the age-related incidence of morbid cardiac events including cardiac death (CD), nonfatal myocardial infarction (MI), and angina pectoris (AP) in all patients treated for Hodgkins disease at a single institution; b) to examine the prevalence of cardiac risk factors and presence of coronary artery disease (CAD) in affected patients. METHODS AND MATERIALS 475 patients were treated for Hodgkins disease in our institution between 1954 and 1989. The status of 97% of the cohort was established either by patient visit and examination in 1992-1993, personal telephone contact, or documentation of death. The 326 of these patients who had mantle irradiation (RT) and survived 3 years formed the study population. Patients who experienced AP, MI, or CD secondary to CAD were assessed for the presence of specific cardiac risk factors. Cardiac catheterization and necropsy data were reviewed to determine the presence and degree of coronary artery stenosis. RESULTS Eighteen of 326 patients (5.5%) have had a morbid cardiac event directly related to CAD. Seven patients had CD. Seven patients experienced nonfatal MI, and four patients had AP. The mean interval from RT to morbid cardiac event was 13.1 years (range: 4.4-27.0), and the mean age at the time of the event was 39.4 years (range: 24-65). Four of these patients had morbid cardiac events between ages 24-29 years. Based on US statistics of CD secondary to MI, the relative risk of CD for the treated group was 2.8 (3.1 for males and 1.8 for females). Remarkably, no difference was found in the risk of experiencing a morbid cardiac endpoint in patients stratified by either decile of age at which RT was given, or by duration of follow-up. Only one patient experiencing an event (AP) had received an anthracycline. The mean RT dose to the central cardiac volume for the affected patients was 44.3 Gy (range: 35-60.4). Autopsy or catheterization data were available on 15 patients and revealed 90-100% stenosis of at least one major vessel in 11 patients (73%), and no single artery was more commonly stenosed. Specifically, the left anterior descending and right coronary arteries were each greater than or equal to 60% stenosed in 10 out of 15 patients (67%), and either the left main or circumflex arteries were greater than or equal to 50% stenosed in 5 out of 15 patients (33%); triple vessel disease was present in seven patients. Risk factor data were available on all patients experiencing morbid cardiac events: 72% smoked, 72% were male, 78% had hypercholesterolemia, 61% were obese, 28% had a positive family history, 33% had hypertension, and 6% (one) had diabetes. The average number of risk factors per patient was 2.9; seven patients had at least four risk factors, and all patients had at least one risk factor. This frequency of risk factors is elevated when compared to the US population. CONCLUSIONS In our institution, 5.5% of patients treated for Hodgkins disease experienced a morbid cardiac event following RT to the central cardiac volume. The doses given were greater than commonly used today. Some patients experienced events at a young age, and the likelihood of experiencing CD was increased compared to the general population. This observation is consistent with RT as an additional risk factor in the induction of morbid cardiac events. Appropriate cardiac shielding and radiation doses, careful follow-up, which includes monitoring of cardiac function, and a preventative program of sensible dietary habits, exercise, and nonsmoking may be beneficial in reducing cardiac morbidity in long-term survivors of Hodgkins disease.

Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography

Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. The gain in life expectancy obtained with anti-cancer therapy can be compromised by increased morbidity and mortality associated with its cardiac complications. While radiosensitivity of the heart was initially recognized only in the early 1970s, the heart is regarded in the current era as one of the most critical dose-limiting organs in radiotherapy. Several clinical studies have identified adverse clinical consequences of radiation-induced heart disease (RIHD) on the outcome of long-term cancer survivors. A comprehensive review of potential cardiac complications related to radiotherapy is warranted. An evidence-based review of several imaging approaches used to detect, evaluate, and monitor RIHD is discussed. Recommendations for the early identification and monitoring of cardiovascular complications of radiotherapy by cardiac imaging are also proposed.

CARDIAC FUNCTION, PERFUSION, AND MORBIDITY IN IRRADIATED LONG-TERM SURVIVORS OF HODGKIN'S DISEASE

PURPOSE The incidence of cardiotoxicity and clinical cardiac events following mantle irradiation (RT) in patients with Hodgkins disease using modern techniques is controversial. The use of quantitative, prognostically validated noninvasive tests to assess systolic and diastolic cardiac function and regional myocardial blood flow may reveal preclinical abnormalities associated with subsequent clinical events of myocardial infarction, cardiac death, or angina. The goals of this study are to determine, through noninvasive measures, the presence and time course of alterations in cardiac systolic and diastolic function and of relative myocardial blood flow in long-term survivors of Hodgkins disease, and assess their correlation with subsequent clinical cardiac end points. METHODS AND MATERIALS Equilibrium radionuclide angiocardiography (ERNA) was used to assess left ventricular (LV) systolic and diastolic function by measuring LV ejection fraction (LVEF) and peak filling rate (PFR), respectively, in patients without known ischemic heart disease who received RT. Electrocardiography was performed to assess electrical cardiac function under conditions of rest and either exercise or dipyridamole vasodilator stress. Quantitative rest/stress myocardial perfusion imaging with thallium-201 and/or Tc-99m sestamibi was used to assess myocardial perfusion. Patients at least 1.0 year after RT were eligible if they were <50 years old at RT, had no known cardiac disease, and remained free of clinical recurrence of Hodgkins disease. Fifty patients, ages 10.2-46.1 years (mean 26.0 +/- 8.6) at RT, were tested 1.1 to 29.1 years (mean 9.1 +/- 7.5) after RT. Seventeen of these patients were tested two times separated by 1.1 to 8.1 years. The mean central cardiac RT dose was 35.1 +/- 7.8 Gy (range 18.5-47.5) in daily 15-2.0 Gy fractions. Twelve patients were concomitantly irradiated to the left ventricle, usually through partial transmission left lung shields (mean 17.0 +/- 2.2 Gy, range 14.3-21.3). RESULTS No patients had signs or symptoms of cardiac disease at the time of evaluation. The mean LVEF at the time of initial testing was 59.6 +/- 6.2% (n = 50; range 42-73%; normal > or =50%), and the mean peak filling rate (PFR) was 3.46 +/- 0.88 end diastolic volumes per second (EDV/s) (range 1.5-5.4 EDV/s; normal > or =2.54 EDV/s). The 12 patients also treated to the left ventricle had a normal mean ejection fraction that was lower (56.6 +/- 5.0%) than that of the other 38 patients (LVEF = 60.6 +/- 6.3%, p = 0.051) when initially evaluated. Average PFR was similar in the two groups. For the 15 patients who had repeat tests, changes in LVEF were generally modest in individual patients, and there was no change in the group mean. For all patients, no significant association was found between cardiac function indices and age at RT, dose, or interval from RT to testing. Myocardial perfusion scintigraphy demonstrated mild ischemia in one or more segments in two patients, and borderline normal perfusion in three patients. Rest and stress ECG testing demonstrated mild repolarization abnormalities in three, and one patient was abnormal at rest and had nondiagnostic changes with stress. CONCLUSIONS Patients irradiated to the heart incidental to the treatment of Hodgkins disease using modern techniques have generally normal measures of left ventricular function and myocardial perfusion. Modest differences in the normal left ventricular ejection fraction observed may be attributable to the cardiac volume irradiated. Some patients may manifest improved cardiac function as time from RT elapses, while a significant deterioration of ejection fraction was not observed and reduction in diastolic peak filling rate is uncommon. The previously reported increased risk of cardiac death may relate to use of older techniques of RT employing higher doses and lack of cardiac shielding, and uncontrolled patient selection with additional behaviors and cardiac risk factors.

Regulation by insulin of myocardial glucose and fatty acid metabolism in the conscious dog.

In vivo small doses of insulin inhibit lipolysis, lower plasma FFA, and stimulate glucose disposal. Lowering of plasma FFA, either in the absence of a change in insulin or during combined hyperglycemia and hyperinsulinemia, promotes glucose uptake by heart muscle in vivo. In the isolated perfused heart, large doses of insulin directly stimulate heart glucose uptake. To assess the effect of physiological elevations of plasma insulin upon myocardial glucose and FFA uptake in vivo independent of changes in plasma substrate concentration, we measured arterial and coronary sinus concentrations of glucose, lactate, and FFA, and coronary blood flow in conscious dogs during a 30 min basal and a 2 h experimental period employing three protocols: (a) euglycemic hyperinsulinemia (insulin clamp, n = 5), (b) euglycemic hyperinsulinemia with FFA replacement (n = 5), (c) hyperglycemic euinsulinemia (hyperglycemic clamp with somatostatin, n = 5). In group 1, hyperinsulinemia (insulin = 73 +/- 13 microU/ml) stimulated heart glucose uptake (7.3 +/- 4.4 vs. 28.2 +/- 2.8 mumol/min, P less than 0.002), lowered plasma FFA levels by 80% (P less than 0.05), and decreased heart FFA uptake (28.4 +/- 4 vs. 1.5 +/- 0.9, P less than 0.01). When the fall in plasma FFA was prevented by FFA infusion (group 2), hyperinsulinemia (86 +/- 10 microU/ml) provoked a lesser (P less than 0.05) stimulation of glucose uptake (delta = 8.2 +/- 4.2 mumol/min) than in group 1, and there was no significant change in FFA uptake (25.3 +/- 16 vs. 16.5 +/- 4). Hyperglycemia (plasma glucose = 186 +/- 8 mg/100 ml) during somatostatin infusion resulted in only a small rise in plasma insulin (delta = 12 +/- 7 microU/ml), and although plasma FFA tended to decline, heart glucose uptake did not rise significantly (delta = 5.5 +/- 3.2 mumol/min, P = NS). There was no significant change in coronary blood flow during any of the three study protocols. We conclude that, in the dog, insulin at physiologic concentrations: (a) stimulates heart glucose uptake, both directly and by suppressing the plasma FFA concentration, and (b) does not alter coronary blood flow. Hyperglycemia per se has little effect on heart glucose uptake.

Prospective Serial Evaluation of Myocardial Perfusion and Lipids During the First Six Months of Pravastatin Therapy Coronary Artery Disease Regression Single Photon Emission Computed Tomography Monitoring Trial

OBJECTIVES This study was designed to assess prospectively changes in serum lipid profile and myocardial perfusion with serial radionuclide single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) during the first six months of pravastatin therapy. BACKGROUND Morbid coronary events occur despite statin therapy and lipid-lowering in patients with coronary artery disease (CAD). A reliable strategy to identify responders with effective treatment from nonresponders on statin therapy before clinical events is needed. METHODS Rest and stress SPECT MPI and lipids were assessed serially in 25 patients (36% women) with CAD and dyslipidemia during the first six months of pravastatin therapy. RESULTS Total cholesterol, low-density lipoprotein cholesterol, and triglycerides declined (26%, 32%, and 30%, respectively) by six weeks and remained reduced at six months. Mean stress perfusion defect (summed stress score [SSS]) was severe (13.3 +/- 6.0) at baseline, showed no change at six weeks, and improved significantly at six months (10.3 +/- 7.3, p < 0.01). The six-month study SSS improved in 11 (48%) patients, was unchanged in 10 (43%) patients, and worsened in 2 (9%) patients. Changes in lipid levels did not reliably predict changes in myocardial perfusion at six weeks or six months in this small pilot study. CONCLUSIONS Serial SPECT MPI demonstrated improved stress myocardial perfusion in 48% of patients treated for six months with pravastatin. Time course of improved myocardial perfusion during pravastatin therapy is delayed compared to lipids. Direction and magnitude of changes in the myocardial perfusion vary and do not correlate closely with improvements in lipids.

Traditional and novel methods to assess and prevent chemotherapy-related cardiac dysfunction noninvasively

The field of cardio-oncology is challenged to address an ever greater spectrum of cardiotoxicity associated with combination chemotherapy, greater dose intensity, extremes of age, and enhanced patient survival which exposes more protracted risk of developing congestive heart failure (CHF). Recent reports of chemotherapy-induced hypertension as a common adverse effect of angiogenesis inhibitors and immunosuppressants clarify the need for routine blood pressure (BP) monitoring and guideline-based management of hypertension as an integral strategy to preserve LV function. Serial monitoring of radionuclide left ventricular ejection fraction (LVEF) in adults and echocardiography in children continues to provide outcome based, cost-effective prevention of CHF in high risk patients receiving chemotherapy. To optimize treatment and monitoring strategies to eliminate late-onset LV dysfunction and CHF, traditional and novel candidate methods for assessment of chemotherapy-induced LV dysfunction are reviewed. These include serial assessment of LV volume indices by gated SPECT ERNA and gated SPECT MPI, 3D echocardiography and contrast 2D echocardiography; longitudinal strain imaging, diastolic functional parameters, 123I-MIBG, 111In-Antimyosin antibody imaging, and 99mTc-Annexin V apoptosis imaging, biomarkers including troponins and BNP; genetic markers, and both functional and tissue characterization techniques with T1 weighted and T2 weighted images with cardiac magnetic resonance imaging (CMR). In our quest to optimize strategies for long-term cancer survival and prevention of CHF for patients receiving chemotherapy, rigorous modality and guideline-specific clinical outcome trials are required. A new multi-modality monitoring approach is proposed, which integrates evidence-based strengths of CMR, echocardiography, ERNA, biomarkers, and BP management for surveillance and validation of cardiotoxicity and prevention of clinical heart failure in patients receiving a broad spectrum of cancer therapies.