John B. Newell

Pathological Correlates of Late Drug-Eluting Stent Thrombosis Strut Coverage as a Marker of Endothelialization

Background— Late stent thrombosis (LST) after Cypher and Taxus drug-eluting stent placement has emerged as a major concern. Although the clinical predictors of LST have been reported, specific morphological and histological correlates of LST remain unknown. Methods and Results— From a registry totaling 81 human autopsies of drug-eluting stents, 46 (62 lesions) had a drug-eluting stent implanted >30 days. We identified 28 lesions with thrombus and compared those with 34 of similar duration without thrombosis using computer-guided morphometric and histological analyses. LST was defined as an acute thrombus within a coronary artery stent in place >30 days. Multiple logistic generalized estimating equations modeling demonstrated that endothelialization was the best predictor of thrombosis. The morphometric parameter that best correlated with endothelialization was the ratio of uncovered to total stent struts per section. A univariable logistic generalized estimating equations model of occurrence of thrombus in a stent section versus ratio of uncovered to total stent struts per section demonstrated a marked increase in risk for LST as the number of uncovered struts increased. The odds ratio for thrombus in a stent with a ratio of uncovered to total stent struts per section >30% is 9.0 (95% CI, 3.5 to 22). Conclusions— The most powerful histological predictor of stent thrombosis was endothelial coverage. The best morphometric predictor of LST was the ratio of uncovered to total stent struts. Heterogeneity of healing is a common finding in drug-eluting stents with evidence of LST and demonstrates the importance of incomplete healing of the stented segment in the pathophysiology of LST.

Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture.

BackgroundRupture of atherosclerotic plaques is probably the most important mechanism underlying the sudden onset of acute coronary syndromes. Macrophages may release lytic enzymes that degrade the fibrous cap and therefore produce rupture of the atherosclerotic plaque. This study was designed to quantify macrophage content in coronary plaque tissue from patients with stable and unstable coronary syndromes. Methods and ResultsHematoxylin and eosin and immuno-staining with anti-human macrophage monoclonal antibody (PG-M1) were performed. Computerized planimetry was used to analyze 26 atherectomy specimens comprising 524 pieces of tissue from 8 patients with chronic stable angina, 8 patients with unstable angina, and 10 patients with non-Q-wave myo-cardial infarction. Total plaque area was 417±87 mm2× 10−2 in patients with stable angina, 601±157 mm2×10−2 in patients with unstable angina, and 499±87 mm2× 10−2in patients with non-Q-wave myocardial infarction (P=NS). The macrophage-rich area was larger in plaques from patients with unstable angina (61±18 mm2x 102) and non-Q-wave myocardial infarction (87±32 mm2× 10−2) than in plaques from patients with stable angina (14±5 mm2×10−2) (P=.024). The percentage of the total plaque area occupied by macrophages was also larger in patients with unstable angina (13.3 ±5.6%) and non-Q-wave myocardial infarction (14.6±4.6%) than in patients with stable angina (3.14±1%) (P=.018). Macrophagerich sclerotic tissue was largest in patients with non-Q-wave myocardial infarction (67±30 mm2× 1010−2) and unstable angina (55±19 mm2× 10−2) than in patients with stable angina (11.5±4.1 mm2× 10−2) (P=.046). Macrophage-rich atheromatous gruel was also larg-est in patients with non-Q-wave myocardial infarction (15±4 mm2×10−2) than in patients with unstable angina (3.3±1.7 mm2×10−2) or stable angina (2.4±1.2 mm2× 10−2) (P=.026). ConclusionsMacrophage-rich areas are more frequently found in patients with unstable angina and non-Q-wave myocardial infarction. This suggests that macrophages are a marker of unstable atherosclerotic plaques and may play a significant role in the pathophysiology of acute coronary syndromes.

Myocardial Phosphocreatine-to-ATP Ratio Is a Predictor of Mortality in Patients With Dilated Cardiomyopathy

BACKGROUND In patients with heart failure due to dilated cardiomyopathy, cardiac energy metabolism is impaired, as indicated by a reduction of the myocardial phosphocreatine-to-ATP ratio, measured noninvasively by 31P-MR spectroscopy. The purpose of this study was to test whether the phosphocreatine-to-ATP ratio also offers prognostic information in terms of mortality prediction as well as how this index compares with well-known mortality predictors such as left ventricular ejection fraction (LVEF) or New York Heart Association (NYHA) class. METHODS AND RESULTS Thirty-nine patients with dilated cardiomyopathy were followed up for 928+/-85 days (2.5 years). At study entry, LVEF and NYHA class were determined, and the cardiac phosphocreatine-to-ATP ratio was measured by localized 31P-MR spectroscopy of the anterior myocardium. During the study period, total mortality was 26%. Patients were divided into two groups, one with a normal phosphocreatine-to-ATP ratio (>1.60; mean+/-SE, 1.98+/-0.07; n=19; healthy volunteers: 1.94+/-0.11, n=30) and one with a reduced phosphocreatine-to-ATP ratio (<1.60; 1.30+/-0.05; n=20). At re-evaluation (mean, 2.5 years), 8 of 20 patients with reduced phosphocreatine-to-ATP ratios had died, all of cardiovascular causes (total and cardiovascular mortality, 40%). Of the 19 patients with normal phosphocreatine-to-ATP ratios, 2 had died (total mortality, 11%), one of cardiovascular causes (cardiovascular mortality, 5%). Kaplan-Meier analysis showed significantly reduced total (P=.036) and cardiovascular (P=.016) mortality for patients with normal versus patients with low phosphocreatine-to-ATP ratios. A Cox model for multivariate analysis showed that the phosphocreatine-to-ATP ratio and NYHA class offered significant independent prognostic information on cardiovascular mortality. CONCLUSIONS The myocardial phosphocreatine-to-ATP ratio, measured noninvasively with 31P-MR spectroscopy, is a predictor of both total and cardiovascular mortality in patients with dilated cardiomyopathy.

Heart failure in outpatients: a randomized trial of digoxin versus placebo.

The view that digitalis clinically benefits patients with heart failure and sinus rhythm lacks support from a well-controlled study. Using a randomized, double-blind, crossover protocol, we compared the effects of oral digoxin and placebo on the clinical courses of 25 outpatients without atrial fibrillation. According to a clinicoradiographic scoring system, the severity of heart failure was reduced by digoxin in 14 patients; in nine of these 14, improvement was confirmed by repeated trials (five patients) or right-heart catheterization (four patients). The other 11 patients had no detectable improvement from digoxin. Patients who responded to digoxin had more chronic and more severe heart failure, greater left ventricular dilation and ejection-fraction depression, and a third heart sound. Multivariate analysis showed that the third heart sound was the strongest correlate of the response to digoxin (P less than 0.0001). These data suggest that long-term digoxin therapy is clinically beneficial in patients with heart failure unaccompanied by atrial fibrillation whose failure persists despite diuretic treatment and who have a third heart sound.

Serial thallium-201 myocardial imaging after dipyridamole infusion: diagnostic utility in detecting coronary stenoses and relationship to regional wall motion.

After a 4-minute i.v. dipyridamole infusion, 0.14 mg/kg/min, serial thallium-201 scans were obtained in 60 patients undergoing cardiac catheterization. Forty patients had significant (> 50% stenosis) coronary artery disease (CAD), and 20 patients had normal coronary arteries or trivial lesions. The images were graded qualitatively for thallium activity by three observers. Sensitivity was 93% (37 of 40) and specificity was 80% (16 of 20). The sensitivity and specificity of the thallium-201 study were not affected by the extent of CAD, the presence of Q waves, or propranolol therapy. Twenty-seven of 37 patients who had initial defects (73%) had complete thallium redistribution of one or more defects. Patient-by-patient analysis using a regression model of all patients showed that the fate of a segmental thallium defect predicted abnormal wall motion by angiography better than ECG Q waves. The presence of propranolol therapy or collaterals did not significantly affect the thallium redistribution results.We conclude that qualitative interpretation by multiple observers of thallium images after dipyridamole infusion is a highly sensitive and specific test for CAD. After dipyridamole, as with exercise stress, the extent of thallium redistribution is related to the degree of myocardial wall motion abnormality.

Prognostic value of exercise thallium-201 imaging in patients presenting for evaluation of chest pain

Accurate prognostic information is important in determining optimal management of patients presenting for evaluation of chest pain. In this study, the ability of exercise thallium-201 myocardial imaging to predict future cardiac events (cardiovascular death or nonfatal myocardial infarction) was correlated with clinical, coronary and left ventricular angiographic and exercise electrocardiographic data in 139 consecutive, nonsurgically managed patients followed-up over a 3 to 5 year period (mean follow-up, 3.7 +/- 0.9), using a logistic regression analysis. Among patients without prior myocardial infarction (100 of 139), the number of myocardial segments with transient thallium-201 defects was the only statistically significant predictor of future cardiac events when all patient variables were evaluated. Among patients with myocardial infarction before evaluation (39 of 139), angiographic ejection fraction was the only significant predictor of future cardiac events when all variables were considered. This study suggests an approach to evaluate the risk of future cardiac events in patients with possible ischemic heart disease.

Unstable angina pectoris: National cooperative study group to compare surgical and medical therapy: II. In-Hospital experience and initial follow-up results in patients with one, two and three vessel disease

Abstract A prospective randomized study comparing intensive medical therapy with urgent coronary bypass surgery for the acute management of patients with unstable angina pectoris was carried out by nine cooperating medical centers under the auspices of the National Heart, Lung, and Blood Institute. Between 1972 and 1976, a total of 288 patients were entered into the study. All patients had transient S-T or T wave changes, or both, in the electrocardiogram during pain; 90 percent had pain at rest in the hospital, and 76 percent had multivessel coronary disease. The medically and surgically treated patients were comparable with respect to clinical, electrocardiographic and angiographic characteristics and left ventricular function. During the total study period, the hospital mortality rate was 5 percent in the surgical group and 3 percent in the medical group (difference not significant). The rate of in-hospital myocardial infarction was 17 and 8 percent in the respective groups (P In the 1st year after hospital discharge class III or IV angina (New York Heart Association criteria) was more common in medically than in surgically treated patients with one vessel disease (22 percent versus 3 percent, P The results indicate that patients with unstable angina pectoris can be managed acutely with intensive medical therapy, including the administration of propranolol and long-acting nitrates in pharmacologic doses, with adequate control of pain in most patients and no increase in early mortality or myocardial infarction rates. Later, elective surgery can be performed with a low risk and good clinical results if the patients angina fails to respond to intensive medical therapy.

Echocardiographic assessment of patients with infectious endocarditis: Prediction of risk for complications

To enhance the echocardiographic identification of high risk lesions in patients with infectious endocarditis, the medical records and two-dimensional echocardiograms of 204 patients with this condition were analyzed. The occurrence of specific clinical complications was recorded and vegetations were assessed with respect to predetermined morphologic characteristics. The overall complication rates were roughly equivalent for patients with mitral (53%), aortic (62%), tricuspid (77%) and prosthetic valve (61%) vegetations, as well as for those with nonspecific valvular changes but no discrete vegetations (57%), although the distribution of specific complications varied considerably among these groups. There were significantly fewer complications in patients without discernible valvular abnormalities (27%). In native left-sided valve endocarditis, vegetation size, extent, mobility and consistency were all found to be significant univariate predictors of complications. In multivariate analysis, vegetation size, extent and mobility emerged as optimal predictors and an echocardiographic score based on these factors predicted the occurrence of complications with 70% sensitivity and 92% specificity in mitral valve endocarditis and with 76% sensitivity and 62% specificity in aortic valve endocarditis.

Prognostic Importance of Thallium Uptake by the Lungs during Exercise in Coronary Artery Disease

We studied the value of thallium imaging as compared with clinical and exercise-test variables in predicting cardiac events occurring over five years in 525 consecutive patients referred for thallium-exercise testing in 1979. Follow-up was obtained on 467 patients (89 percent). There were 105 cardiac events--25 cardiac deaths, 33 myocardial infarctions, and 47 coronary bypass procedures. A Cox survival analysis identified increased thallium uptake by the lungs, a marker of left ventricular dysfunction during exercise, as the best predictor of a cardiac event (relative risk ratio = 3.5; 95 percent confidence interval, 2.2 to 5.4). The next most powerful predictors were a history of typical angina, a previous myocardial infarction, and ST-segment depression during exercise (relative risk ratios = 2.1, 1.8, and 1.7, respectively). No combination of variables made up for the loss in prognostic power when the variable of increased thallium uptake by the lungs was removed from the model. Cardiac events occurred over five years in 10 (5 percent) of 192 patients with a normal thallium scan, 41 (25 percent) of 163 patients with an abnormal thallium scan but normal thallium activity in the lungs, and 54 (67 percent) of 81 patients with increased thallium uptake by the lungs (P less than 0.0001). We conclude that increased uptake of thallium by the lungs during exercise predicts a high risk of subsequent cardiac events.

Reconsideration of echocardiographic standards for mitral valve prolapse: lack of association between leaflet displacement isolated to the apical four chamber view and independent echocardiographic evidence of abnormality.

Mitral valve prolapse by current echocardiographic criteria can be diagnosed with surprising frequency in the general population, even when preselected normal subjects are examined. In most of these individuals, however, prolapse is present in the apical four chamber view and absent in roughly perpendicular long-axis views. Previous studies have shown that systolic annular nonplanarity can cause apparent prolapse in the four chamber view without actual leaflet displacement above the most superior points of the anulus, and there is evidence for such nonplanarity in vivo. It is then reasonable to ask whether superior leaflet displacement limited to the four chamber view has any pathologic significance or complications. The purpose of this study, therefore, was to address the following hypothesis: that patients with superior leaflet displacement confined to the four chamber view have no higher frequency of associated echocardiographic abnormalities than do patients without displacement in any view. Such abnormalities, which would provide independent evidence of mitral valve pathology or dysfunction, include leaflet thickening, left atrial enlargement and mitral regurgitation. Leaflet displacement was measured in the parasternal long-axis and apical four chamber views in 312 patients who were studied retrospectively and selected for the absence of forms of heart disease other than mitral valve prolapse. Leaflet thickness and left atrial size were measured and mitral regurgitation was graded. Patients with leaflet displacement limited to the four chamber view were no more likely to have associated abnormalities than were patients without displacement in any view (0 to 2% prevalence, p greater than 0.5). In contrast, patients with leaflet displacement in the long-axis view were significantly more likely to have associated abnormalities (12 to 24%, p less than 0.005), the frequency of which increased with the extent of leaflet displacement in that view (p less than 0.0001). These results suggest that displacement limited to the apical four chamber view is, in general, a normal geometric finding unassociated with echocardiographic evidence of pathologic significance.