Melvin B. Weiss

Angiographic progression of coronary artery disease and the development of myocardial infarction.

There are few data on angiographic coronary artery anatomy in patients whose coronary artery disease progresses to myocardial infarction. In this retrospective analysis, progression of coronary artery disease between two cardiac catheterization procedures is described in 38 patients: 23 patients (Group I) who had a myocardial infarction between the two studies and 15 patients (Group II) who presented with one or more new total occlusions at the second study without sustaining an intervening infarction. In Group I the median percent stenosis on the initial angiogram of the artery related to the infarct at restudy was significantly less than the median percent stenosis of lesions that subsequently were the site of a new total occlusion in Group II (48 versus 73.5%, p less than 0.05). In the infarct-related artery in Group I, only 5 (22%) of 23 lesions were initially greater than 70%, whereas in Group II, 11 (61%) of 18 lesions that progressed to total occlusion were initially greater than 70% (p less than 0.01). In Group I, patients who developed a Q wave infarction had less severe narrowing at initial angiography in the subsequent infarct-related artery (34%) than did patients who developed a non-Q wave infarction (80%) (p less than 0.05). Univariate and multivariate analysis of angiographic and clinical characteristics present at initial angiography in Group I revealed proximal lesion location as the only significant predictor of evolution of lesions greater than or equal to 50% to infarction. This retrospective study suggests that myocardial infarction frequently develops from previously nonsevere lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis and Classification of Myocarditis by Endomyocardial Biopsy

Myocarditis was diagnosed by endomyocardial biopsy in 34 patients with otherwise unexplained heart failure. On the basis of both clinical and histologic findings these patients were divided into three groups. Seven patients had acute myocarditis (mean age, 20 years; mean ejection fraction, 22 per cent) characterized by an interstitial inflammatory infiltrate and extensive, acute cell damage. Five of these patients died after a mean duration of illness of eight weeks. Eighteen patients had rapidly progressive myocarditis (mean age, 35 years; mean ejection fraction, 19 per cent) characterized by patchy acute and healing cell damage and fibrosis; 17 of them died after a mean duration of illness of 23 months. Nine patients had chronic myocarditis (mean age, 31 years; mean ejection fraction, 31 per cent) characterized by focal inflammation and cell damage. All nine were alive after a mean follow-up period of 39 months. In four of these nine, clinical and hemodynamic improvement occurred after one month of immunosuppressive therapy. Our study suggests that a clinically useful classification of myocarditis can be accomplished by endomyocardial biopsy.

Heme Oxygenase-1 Attenuates Glucose-Mediated Cell Growth Arrest and Apoptosis in Human Microvessel Endothelial Cells

Abstract— Heme oxygenase-1 (HO-1) is a stress protein that has been suggested to participate in defense mechanisms against agents that may induce oxidative injury, such as heme and inflammatory molecules. Incubation of endothelial cells in a high-glucose (33 mmol/L) medium for 7 days resulted in a decrease of HO activity by 34% and a decrease in HO-1 and HO-2 proteins compared with cells exposed to low glucose (5 mmol/L) (P <0.05) or cells exposed to mannitol (33 mmol/L). Overexpression of HO-1 was coupled with an increase in HO activity and carbon monoxide synthesis, decreased cellular heme, and acceleration in all phases of the cell cycle (P <0.001). The rate of cell cycle or cell birth rate was increased by 29% (P <0.05) in cells overexpressing HO-1 but decreased by 23% (P <0.05) in cells underexpressing HO-1 compared with control cells. Exposure to high glucose significantly decreased cell-cycle progression in control cells and in cells underexpressing HO-1 but did not decrease cell-cycle progression in cells overexpressing HO-1. High glucose induced p21 and p27 in control cells but not in cells overexpressing HO-1. The addition of tin-mesoporphyrin (SnMP), an inhibitor of HO activity, reversed the HO-1–mediated decrease of p21 and p27 in cells overexpressing HO-1. These findings identify a novel effect of HO-1 on endothelial cell growth and indicate that heme metabolism and HO-1 expression regulate signaling systems in cells exposed to high glucose, which controls cell-cycle progression.

Myocardial blood flow in congestive and hypertrophic cardiomyopathy: relationship to peak wall stress and mean velocity of circumferential fiber shortening.

SUMMARY Myocardial blood flow/unit mass (MBF) and the determinants of myocardial oxygen consumption were measured in seven control subjects (group I) and 15 patients (pts) with cardiomyopathy (CM), group II (group Ila-congestive CM: 10 pts; group Ilb-hypertrophic CM: 5 pts). In group I left ventricular (LV) MBF was 64±8 (SD) ml/10g - min; it was significantly lower in Ila (45 ± 15 ml/100g. min, P < 0.01) and IIb (39 ± 7 ml/100g min, P < 0.01). However, calculated total LV flow (LV mass X MBF) was increased in the two CM groups. In nine CM pts, LV MBF increased in response to atrial pacing from 41±7 to 63±13 ml/100g * min.In group Ila, calculated peak wall stress was normal (4.39±0.77 dynes/cm2 × 106) but mean velocity of circumferential fiber shortening (MVcf) was significantly reduced (0.53±0.18 vs 1.26±0.12 circum/ sec, P < 0.01). In llb, MVcf was normal but peak stress was significantly reduced (2.80±0.75 vs 4.51±1.10 dynes/cm2 × 106, P < 0.05). Multiple regression analysis based on all pts yielded, MBF = 16.9 MVcf + 9.30 Stress + 0.26 Heart Rate − 26.4, (r = 0.79). The data indicate that MBF is reduced in CM patients and the regression analysis suggests that MBF in these 22 pts with normal coronary arteriograms was determined largely by heart rate, peak stress, and ventricular performance.

Up-Regulation of Heme Oxygenase Provides Vascular Protection in an Animal Model of Diabetes through Its Antioxidant and Antiapoptotic Effects

Heme oxygenase (HO) plays a critical role in the regulation of cellular oxidative stress. The effects of the reactive oxygen species scavenger ebselen and the HO inducers cobalt protoporphyrin and stannous chloride (SnCl2) on HO protein levels and activity, indices of oxidative stress, and the progression of diabetes were examined in the Zucker rat model of type 2 diabetes. The onset of diabetes coincided with an increase in HO-1 protein levels and a paradoxical decrease in HO activity, which was restored by administration of ebselen. Up-regulation of HO-1 expressed in the early development of diabetes produced a decrease in oxidative/nitrosative stress as manifested by decreased levels of 3-nitrotyrosine, superoxide, and cellular heme content. This was accompanied by a decrease in endothelial cell sloughing and reduced blood pressure. Increased HO activity was also associated with a significant increase in the antiapoptotic signaling molecules Bcl-xl and phosphorylation of p38-mitogen-activated protein kinase but no significant increases in Bcl-2 or BAD proteins. In conclusion, 3-nitrotyrosine, cellular heme, and superoxide, promoters of vascular damage, are reduced by HO-1 induction, thereby preserving vascular integrity and protecting cardiac function involving an increase in antiapoptotic proteins.

Circulating endothelial cells are elevated in patients with type 2 diabetes mellitus independently of HbA1c

Aims/hypothesisPatients with diabetes mellitus are well known to be at high risk for vascular disease. Circulating endothelial cells (CECs) have been reported to be an ex vivo indicator of vascular injury. We investigated the presence of CECs in the peripheral blood of 25 patients with diabetes mellitus and in nine non-diabetic control donors.MethodsEndothelial cells were isolated from peripheral blood with anti-CD-146–coated immunomagnetic Dynabeads, and were stained with acridine orange dye and counted by fluorescence microscopy. The cells were also stained for von Willebrand factor and Ulex europaeus lectin 1.ResultsPatients with diabetes mellitus had an elevated number of CECs (mean 69±30 cells/ml, range 35–126) compared with healthy controls (mean 10±5 cells/ml, range 3–18) (p<0.001). The increase in CECs did not correlate with the levels of HbA1c. Circulating endothelial cell numbers were elevated regardless of glucose levels, suggesting that, even with control of glucose levels, there is increased endothelial cell sloughing.ConclusionsOur study suggests that the higher number of CECs in patients with type 2 diabetes may reflect ongoing vascular injury that is not directly dependent on glucose control.

Improved exercise ejection fraction with long-term prazosin therapy in patients with heart failure

To study the effect of prazosin therapy on left ventricular function in patients with chronic stable heart failure, first pass radionuclide angiography at rest and during exercise was performed in 15 patients before the administration of prazosin and after seven to 12 weeks of prazosin therapy. There was no significant change in resting ejection fraction before and during prazosin therapy (36 +/- 14 per cent versus 37 +/- 14 per cent) (mean +/- standard deviation). However, exercise ejection fraction increased from 34 +/- 14 per cent to 42 +/- 17 per cent (p less than 0.01). The difference in ejection fraction from rest to exercise (ejection fraction response) changed significantly from -2 +/- 6 per cent before prazosin therapy to +5 +/- 7 per cent during prazosin therapy (p less than 0.01). Exercise duration increased from 368 +/- 82 seconds to 476 +/- 82 seconds (p less than 0.01). Total work capacity measured in kilojoules increased from 12.6 +/- 8.3 to 18.6 +/- 10.4 (p less than 0.01). The improved ejection fraction response during prazosin therapy correlated with the improved work capacity (r = 0.69, p less than 0.01) and exercise duration (p = 0.59, p less than 0.05). This improvement occurred despite a significant weight gain with prazosin from 72.2 +/- 20.8 kg to 73.5 +/- 20.8 kg (p less than 0.01). These data suggest that long-term prazosin therapy is effective in the treatment of heart failure. However, the beneficial effects of prazosin, an alpha 1 blocking agent, may be evident only during exercise.

Lack of long-term ventricular arrhythmia reduction by enalapril in heart failure

Previous studies have indicated that angiotensin-converting enzyme inhibitors may reduce the frequency of ventricular arrhythmias in patients with heart failure. These reports were mostly small and of short duration. We prospectively studied 734 patients recruited in 11 universities for 1 year who were enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) to determine the long-term effects of enalapril and placebo on the frequency and complexity of ventricular arrhythmias in patients with symptomatic (treatment trial) or asymptomatic (prevention trial) heart failure and depressed left ventricular function (ejection fraction < or = 35%). Five hundred fifty-three patients from the prevention trial and 181 from the treatment trial of SOLVD underwent ambulatory electrocardiographic monitoring at baseline, and then at 4 and 12 months of double-blind therapy with either placebo or enalapril (2.5 to 10 mg twice daily). The prospectively defined primary analysis was by intent-to-treat and revealed no significant differences in ventricular premature complexes between the placebo and enalapril groups at baseline (87 +/- 13 vs 84 +/- 13/hour), 4 months (100 +/- 15 vs 85 +/- 12/hour), or 12 months (80 +/- 12 vs 90 +/- 14/hour). Likewise, there was no difference between the placebo and enalapril groups in runs of nonsustained ventricular tachycardia: baseline (8.3 +/- 4.1 vs 1.9 +/- 0.4 runs/day), 4 months (16 +/- 12 vs 7.2 +/- 4.1 runs/day), or after 12 months of blinded therapy (11 +/- 7.0 vs 6.1 +/- 4.4 runs/day).(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced left ventricular myocardial blood flow per unit mass in aortic stenosis.

SUMMARYMyocardial blood flow (MBF) per unit mass was measured in 10 patients (pts) with severe aortic stenosis (AS) and no significant aortic Insufficiency, normal ejection fractions, and normal coronary arteriograms, using xenon-133 and a multiple crystal scintillation camera. MBF per unit mass was reduced in AS (53 i 13 ml/lOOg - min) in comparison to a group of seven normal control patients (69 ± 12 ml/lOOg - min) (P < 0.05). When normalized for heart rate, MBF remained depressed in aortic stenosis (0.65 i 0.11 ml/ lOOg - beat). MBF/beat was strongly related to peak left ventricular wall stress in both groups (r- 0.97). Individual values of MBF/beat were normalized for peak stress using an analysis of covariance; the adjusted mean values were 0.62 ± 0.03 mllOOg - beat for the AS patients and 0.84 ± 0.03 ml/lOOg- beat for the control patients. There was no overlap between groups in adjusted MBF per beat. Values of MBF per beat and peak stress for a group of ten cardiomyopathy patients with depressed contractility were observed to fall close to the regression line for AS patients. The results suggest that variability in resting MBF in these AS patients is due primarily to differences in LV stress and that reduction in MBF per beat in this group may be due to reduced contractility.

Regional myocardial perfusion during atrial pacing in patients with coronary artery disease.

Regional myocardial perfusion (RMP) was measured with 133xenon and a multiple-crystal scintillation camera at rest and during atrial pacing in 24 patients with normal coronary arteriograms or <50% lesions, Group 1, and in 24 with significant (>50% lesions) left coronary artery disease (CAD), Group II. Pacinginduced increases in the double product (DP) of heart rate and systolic blood pressure, an index of myocardial oxygen consumption, were not different for Groups I and I1. In Group I average mean LV perfusion rate was subnormal at rest but rose from 49 to 73 ml/100 g.min during pacing to 150/min without angina. A response index (RI) (ΔMP × 103/ΔDP), averaged 2.93. Twenty patients in Group 11 developed angina during pacing. The average mean LV perfusion rose less than in Group 1, from 48 to 64 ml/100 g-min (P < 0.05) and the average RI, 1.76, was lower (P < 0.01). In 19 of these patients, average RMP distal to the major coronary lesion increased from 46 to 58 ml/100 g-min; this increase during pacing was significantly less than in the remainder of the LV of 48 to 66 ml/100 g.min (P < 0.05). Average regional RIs were 1.39 and 2.18, respectively. In three patients the presence of collaterals termed adequate by radiological criteria was not associated with preferential decreases in the distal regional RI. The data support the hypothesis that in some patients with CAD, angina pectoris results when an obstructive coronary lesion restricts the total or regional myocardial blood flow response to an increased rate of myocardial oxygen consumption.