Steven P. Schulman

Prognostic Significance of Microvascular Obstruction by Magnetic Resonance Imaging in Patients With Acute Myocardial Infarction

BACKGROUND The extent of microvascular obstruction during acute coronary occlusion may determine the eventual magnitude of myocardial damage and thus, patient prognosis after infarction. By contrast-enhanced MRI, regions of profound microvascular obstruction at the infarct core are hypoenhanced and correspond to greater myocardial damage acutely. We investigated whether profound microvascular obstruction after infarction predicts 2-year cardiovascular morbidity and mortality. METHODS AND RESULTS Forty-four patients underwent MRI 10 +/- 6 days after infarction. Microvascular obstruction was defined as hypoenhancement seen 1 to 2 minutes after contrast injection. Infarct size was assessed as percent left ventricular mass hyperenhanced 5 to 10 minutes after contrast. Patients were followed clinically for 16 +/- 5 months. Seventeen patients returned 6 months after infarction for repeat MRI. Patients with microvascular obstruction (n = 11) had more cardiovascular events than those without (45% versus 9%; P=.016). In fact, microvascular status predicted occurrence of cardiovascular complications (chi2 = 6.46, P<.01). The risk of adverse events increased with infarct extent (30%, 43%, and 71% for small [n = 10], midsized [n = 14], and large [n = 14] infarcts, P<.05). Even after infarct size was controlled for, the presence of microvascular obstruction remained a prognostic marker of postinfarction complications (chi2 = 5.17, P<.05). Among those returning for follow-up imaging, the presence of microvascular obstruction was associated with fibrous scar formation (chi2 = 10.0, P<.01) and left ventricular remodeling (P<.05). CONCLUSIONS After infarction, MRI-determined microvascular obstruction predicts more frequent cardiovascular complications. In addition, infarct size determined by MRI also relates directly to long-term prognosis in patients with acute myocardial infarction. Moreover, microvascular status remains a strong prognostic marker even after control for infarct size.

A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells (Prochymal) After Acute Myocardial Infarction

OBJECTIVES Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI). BACKGROUND Bone marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support. METHODS We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n=53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points. RESULTS Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p=0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p=0.003) in the hMSC-treated patients. Global symptom score in all patients (p=0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling. CONCLUSIONS Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells [MSC] to Treat Acute Myocardial Infarction; NCT00114452).

A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis

BACKGROUND Platelet glycoprotein IIb/IIIa is a membrane receptor for fibrinogen and von Willebrand factor, and it has an important role in platelet aggregation. It is known to be involved in the pathogenesis of acute coronary syndromes. Previously, we found a high frequency of a particular polymorphism, PlA2, of the gene encoding glycoprotein IIIa in kindreds with a high prevalence of premature myocardial infarction. METHODS To investigate the relation between the PlA2 polymorphism and acute coronary syndromes, we conducted a case-control study of 71 case patients with myocardial infarction or unstable angina and 68 inpatient controls without known heart disease. The groups were matched for age, race, and sex. We used two methods to determine the PlA genotype: reverse dot blot hybridization and allele-specific restriction digestion. RESULTS The prevalence of PlA2 was 2.1 times higher among the case patients than among the controls (39.4 percent vs. 19.1 percent, P=0.01). In a subgroup of patients whose disease began before the age of 60 years, the prevalence of PlA2 was 50 percent, a value that was 3.6 times that among control subjects under 60 years of age (13.9 percent, P=0.002). Among subjects with the PlA2 polymorphism, the odds ratio for having a coronary event was 2.8 (95 percent confidence interval, 1.2 to 6.4). In the patients less than 60 years of age at the onset of disease, the odds ratio was 6.2 (95 percent confidence interval, 1.8 to 22.4). CONCLUSIONS We observed a strong association between the PlA2 polymorphism of the glycoprotein IIIa gene and acute coronary thrombosis, and this association was strongest in patients who had had coronary events before the age of 60 years.

Regional Heterogeneity of Human Myocardial Infarcts Demonstrated by Contrast-Enhanced MRI Potential Mechanisms

BACKGROUND Myocardial reperfusion is pivotal to the prognosis of patients with acute myocardial infarction. In these patients, coronary flow is generally assessed by angiography and tissue perfusion by tracer scintigraphy. This study was designed to examine whether magnetic resonance imaging (MRI) provides information on myocardial perfusion and damage beyond that supplied by angiography and thallium scintigraphy after acute myocardial infarction. METHODS AND RESULTS Twenty-two patients with recent myocardial infarction had ECG, echocardiography, coronary angiography, and fast contrast-enhanced MRI. Twelve patients also had exercise thallium scintigraphy. Time-intensity curves obtained from infarcted and noninfarcted regions were correlated with coronary anatomy and left ventricular function. Two perfusion patterns were observed in infarcted regions by comparison with the normal myocardial pattern. All patients but 1 had persistent myocardial hyperenhancement within the infarcted region up to 10 minutes after contrast. In 10 patients, this hyperenhanced region surrounded a subendocardial area of decreased signal at the center of the infarcted region associated with coronary occlusion at angiography, Q waves on ECG, and greater regional dysfunction by echocardiography. Moreover, the extent and location of the MRI abnormalities correlated well with the extent and location of the fixed single-photon emission computed tomography thallium defects. CONCLUSIONS Large human infarcts, associated with prolonged obstruction of the infarct-related artery, are characterized by central dark zones surrounded by hyperenhanced regions on MRI. Conversely, reperfused infarcts with less regional dysfunction have uniform signal hyperenhancement. The MRI hyperenhanced segment correlates well with the fixed scintigraphic defect in patients with acute myocardial infarction.

Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years.

BACKGROUND The benefit of intravenous thrombolytic therapy in elderly patients with myocardial infarction is uncertain. There are no randomized trials of thrombolytic efficacy or observational studies of clinical effectiveness that focus specifically on the elderly. METHODS AND RESULTS To determine whether thrombolytic therapy for elderly patients is associated with a survival advantage in a large observational database, we conducted a retrospective cohort study of 7864 Medicare fee-for-service patients aged 65 to 86 years with the primary discharge diagnosis of acute myocardial infarction who were admitted with clinical and ECG indications for thrombolytic therapy and no absolute contraindications. The study included all US acute care nongovernment hospitals without on-site angioplasty capability. Using proportional-hazards methods, we found that in a comprehensive multivariate model, there was a significant interaction (P<0.001) between age and the effect of thrombolytic therapy on 30-day mortality rates. For patients 65 to 75 years old, thrombolytic therapy was associated with a survival benefit, consistent with randomized trials. Among patients aged 76 to 86 years, thrombolytic therapy was associated with a survival disadvantage, with a 30-day mortality hazard ratio of 1.38 (95% CI 1. 12 to 1.71, P=0.003). For these patients, there was no benefit from thrombolytic therapy in any clinical subgroup. CONCLUSIONS In nationwide clinical practice, thrombolytic therapy for patients >75 years old is unlikely to confer survival benefit and may have a significant survival disadvantage. Reperfusion research that is focused on elderly patients is urgently needed.

The Effects of Antihypertensive Therapy on Left Ventricular Mass in Elderly Patients

Left ventricular mass sometimes decreases during treatment of hypertension, but this response is inconsistent and its effects on left ventricular function are unknown. In a six-month randomized trial, we studied the ability of verapamil and atenolol to reduce left ventricular mass in 42 elderly patients with hypertension and the effects of this reduction in mass on cardiac function. The mean blood pressure (+/- SE) decreased in both the group that received verapamil (from 171.4 +/- 3.2/93.0 +/- 2.5 mm Hg to 142.9 +/- 2.8/79.0 +/- 2.0 mm Hg) and the group that received atenolol (from 179.6 +/- 4.6/98.5 +/- 2.4 mm Hg to 148.1 +/- 3.3/83.4 +/- 1.2 mm Hg), but the atenolol-treated patients more frequently required the addition of chlorthalidone to achieve blood-pressure reduction (P less than 0.01). Verapamil resulted in a reduction in the left-ventricular-mass index from 104 +/- 5 g per square meter of body-surface area to 85 +/- 5 g per square meter (P less than 0.01). Atenolol did not produce a reduction in the left-ventricular-mass index (109 +/- 9 g per square meter before treatment vs. 112 +/- 10 g per square meter after treatment). Two weeks after the withdrawal of antihypertensive therapy, blood pressure returned to pretreatment values. Nevertheless, in patients whose left ventricular mass had decreased, two measures of diastolic filling, the peak diastolic filling rate to the peak ejection rate, were significantly higher than before treatment (2.42 +/- 0.2 vs. 3.31 +/- 0.4 [P less than 0.05] and 0.61 +/- 0.03 to 0.85 +/- 0.05 [P less than 0.05], respectively). Diastolic filling was unchanged in the group that had no reduction in left ventricular mass. Cardiac output and the ejection fraction at rest and during mild exercise were unchanged in both groups as compared with baseline values. We conclude that left ventricular mass can be reduced in elderly patients with hypertension and mild ventricular hypertrophy who receive antihypertensive therapy. Reduction occurs more frequently with verapamil than with atenolol therapy, increases diastolic filling, and does not impair systolic function.

Autologous Mesenchymal Stem Cells Produce Concordant Improvements in Regional Function, Tissue Perfusion, and Fibrotic Burden When Administered to Patients Undergoing Coronary Artery Bypass Grafting The Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) Trial

Rationale: Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis. Objective: To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects. Methods and Results: Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4±1.7%, P=0.0002) and decreased scar mass (−47.5±8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93±0.07), whereas revascularized (0.5±0.21) and nontreated segments (−0.07±0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments). Conclusions: Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications. Clinical Trial Registration: URL: http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.

Race, Medical Researcher Distrust, Perceived Harm, and Willingness to Participate in Cardiovascular Prevention Trials

Minority underrepresentation exists in medical research including cardiovascular clinical trials, but the hypothesis that this relates to distrust in medical researchers is unproven. Therefore, we examined whether African American persons differ from white persons in perceptions of the risks/benefits of trial participation and distrust toward medical researchers, and whether these factors influence willingness to participate (WTP) in a clinical drug trial. Participants were self-administered a survey regarding WTP in a cardiovascular drug trial given to 1440 randomly selected patients from 13 Maryland outpatient cardiology and general medicine clinics. Patients reported their WTP, rated their perceived chances of experiencing health benefit and harm, and rated their distrust toward researchers. Of eligible participants, 70% responded, and 717 individuals were included: 36% African American and 64% white. African American participants possessed lower WTP than white participants (27% vs. 39%, p = 0.001) and had higher mean distrust scores than whites (p < 0.0001). African American participants more frequently reported that doctors would less fully explain research participation to them (24% vs. 13%, p < 0.001), use them as guinea pigs without their consent (72% vs. 49%, p < 0.001), prescribe medication as a way of experimenting on people without their knowledge (35% vs. 16%, p < 0.001), and ask them to participate in research even if it could harm them (24% vs. 15%, p = 0.002). African American participants also more often believed they could less freely ask their doctor questions (8% vs. 2%, p < 0.001) and that doctors had previously experimented on them without their consent (58% vs. 25%, p < 0.001). African American participants expressed lesser WTP than white participants after controlling for racial differences in age, sex, socioeconomic status and cardiovascular disease risk profiles (multivariable odds ratio [OR], 0.57; 95% confidence interval [CI], 0.39-0.85). The impact of race was attenuated and nonsignificant after adjustment for potential mediating factors of racial differences in medical researcher distrust and perceived risk of harm (explanatory model OR, 0.84; 95% CI 0.54-1.30). In summary, African American participants expressed markedly greater concerns about experiencing harm from participation in clinical trials and distrust toward medical researchers than white participants. These factors, in turn, appear to explain much of the resistance among African American persons to participate in clinical trials compared to white persons. Abbreviations: AIDS = acquired immunodeficiency syndrome, CI = confidence interval, CVD = cardiovascular disease, HIV = human immunodeficiency virus, OR = odds ratio, WTP = willingness to participate.

Cardiomyopathy Associated with Antiretroviral Therapy in Patients with HIV Infection: A Report of Six Cases

Excerpt Symptomatic congestive heart failure has been described as part of the spectrum of human immunodeficiency virus (HlV)-related cardiac disease (1-3). Echocardiographic studies have further d...

Altered Creatine Kinase Adenosine Triphosphate Kinetics in Failing Hypertrophied Human Myocardium

Background— The progression of pressure-overload left ventricular hypertrophy (LVH) to chronic heart failure (CHF) may involve a relative deficit in energy supply and/or delivery. Methods and Results— We measured myocardial creatine kinase (CK) metabolite concentrations and adenosine triphosphate (ATP) synthesis through CK, the primary energy reserve of the heart, to test the hypothesis that ATP flux through CK is impaired in patients with LVH and CHF. Myocardial ATP levels were normal, but creatine phosphate levels were 35% lower in LVH patients (n=10) than in normal subjects (n=14, P<0.006). Left ventricular mass and CK metabolite levels in LVH were not different from those in patients with LVH and heart failure (LVH+CHF, n=10); however, the myocardial CK pseudo first-order rate constant was normal in LVH (0.36±0.04 s−1 in LVH versus 0.32±0.06 s−1 in normal subjects) but halved in LVH+CHF (0.17±0.06 s−1, P<0.001). The net ATP flux through CK was significantly reduced by 30% in LVH (2.2±0.7 &mgr;mol · g−1 · s−1, P=0.011) and by a dramatic 65% in LVH+CHF (1.1±0.4 &mgr;mol · g−1 · s−1, P<0.001) compared with normal subjects (3.1±0.8 &mgr;mol · g−1 · s−1). Conclusions— These first observations in human LVH demonstrate that it is not the relative or absolute CK metabolite pool sizes but rather the kinetics of ATP turnover through CK that distinguish failing from nonfailing hypertrophic hearts. Moreover, the deficit in ATP kinetics is similar in systolic and nonsystolic heart failure and is not related to the severity of hypertrophy but to the presence of CHF. Because CK temporally buffers ATP, these observations support the hypothesis that a deficit in myofibrillar energy delivery contributes to CHF pathophysiology in human LVH.