Determinants of arrhythmic death during coronary artery reperfusion: Effect of perfusion bed size

To further our understanding of the factors determining the consequences of transient episodes of ischemia, we studied the influence of the size of the ischemic bed on the incidence of ventricular fibrillation (VF). The circumflex coronary artery (CFX) was occluded at various locations in 19 dogs. After 20 minutes of occlusion followed by 10 minutes of reperfusion the dogs were killed. The portion of the left ventricle (LV) at risk of infarcting ($\text{R}\text{LV}$) was defined as the region supplied by the occluded CFX and determined by simultaneous perfusion of the CFX with saline solution, just beyond the occlusion site, and of the aorta with Evan's blue. Bread loaf slices of the heart were photographed and projected, and the normal (blue) and risk regions (unstained) traced. The product of area and slice weight yielded mass of normal and risk regions. The $\text{R}\text{LV}$ of dogs that died of reperfusion VF (n = 6) was 42.3 ± 5.0%, larger (p < 0.001) than $\text{R}\text{LV}$ in all surviving dogs (n = 13), 24.2 ± 9.4%. Twelve of the 13 survivors had $\text{R}\text{LV}\text{< 35\%}$, whereas all dogs that died had $\text{R}\text{LV}\text{> 35\%}$ (p = 0.0005). As is true for VF occurring during coronary artery occlusion, the incidence of reperfusion VF is related to the size of the ischemic insult.     

Pyrroline-5-carboxylate in human plasma

Pyrroline-5-carboxylate is the intermediate in the interconversions of proline, ornithine, and glutamate. Recent studies have suggested that pyrroline-5-carboxylate has regulatory properties in a wide range of tissues. Physiologic studies in humans have been limited by the unavailability of a sufficiently sensitive assay for this compound. Until now pyrroline-5-carboxylate has not been detectable in plasma of normal humans or even in plasma of patients with type II hyperprolinemia. We now report a method for measuring pyrroline-5-carboxylate made possible by a preparation of purified Escherichia coli pyrroline-5-carboxylate reductase. This method is more sensitive than currently available methods by two or three logs and is applicable for all biologic fluids. We have quantitated pyrroline-5-carboxylate in normal plasma, urine, and saliva. In addition, we have found pyrroline-5-carboxylate levels 10x to 20x normal in two patients with type II hyperprolinemia. The ability to measure physiologic concentrations of pyrroline-5-carboxylate now enables further characterization of its role as a regulatory molecule.     

The effects of nitroglycerin-methoxamine combination on infarct size in conscious dogs

The effect of nitroglycerin combined with methoxamine in reducing infarct weight was studied in conscious dogs. Ten minutes after permanent left anterior descending (LAD) coronary artery occlusion, 10 dogs received nitroglycerin (450 micrograms bolus IV, then 300 micrograms/min for 4 hours) and methoxamine as needed to maintain blood pressure and heart rate. No dogs in heart failure. Ten control dogs received saline solution. Dogs were sacrificed 3 days later. The region at risk of infarction was delineated by simultaneously perfusing the aortic root with Evans blue and the distal LAD artery with saline solution under equal pressures. Slices of stained hearts were incubated with tetrazolium to identify infarct. Total weight of left ventricle (LV), risk region, and infarct was measured. Nitroglycerin-treated dogs showed no difference from control dogs in infarct weight (26.2 +/- 5.9 gm +/- SE vs 27.7 +/- 5.6 gm), percent risk region/LV (36.0 +/- 1.4% vs 37.9 +/- 3.1%), or present infarct/LV (23.5 +/- 5.2% vs 24.8 +/- 4.9%). In a subgroup with risk region/LV less than or equal to 35%, nitroglycerin reduced infarct weight by 45% (8.8 +/- 8.5% vs 15.9 +/- 7.9%), percent infarct/LV by 49% (7.1 +/- 6.8% vs 13.8 +/- 6.6%), and percent infarct/risk region by 41% (23.0 +/- 22.0% vs 38.9 +/- 15.9%). Because of the small number of dogs in the study, differences were not significant. In dogs with risk region/LV greater than 35%, nitroglycerin had no effect. Thus, in dogs without overt heart failure, nitroglycerin may salvage ischemic tissue within small areas at risk of infarction, but the results are not definitive. However, our results clearly demonstrate that in the absence of failure, nitroglycerin does not reduce the size of large infarcts.     

Quantification of amounts of coronary arterial narrowing in patients with types II and IV hyperlipoproteinemia and in those with known normal lipoprotein patterns

The amount of cross-sectional area narrowing by atherosclerotic plaques in each 5 mm long segment of the left main, left anterior descending, left circumflex, and right coronary arteries was analyzed at necropsy in 15 patients with type II hyperlipoproteinemia (HLP), in 13 with type IV HLP, and in 10 with known normal lipoprotein patterns. All 38 study patients had clinical evidence of coronary heart disease. Of the 2593 five mm segments examined histologically, narrowing of 76% to 100% in cross-sectional area by atherosclerotic plaques was as follows: type II = 39%, type IV = 67%, and normal lipoprotein pattern = 35% (controls = 4%). Utilizing a scoring system of 1 to 4 for the four categories of narrowing (0% to 25%, 26% to 50%, 51% to 75%, 76% to 100%), the mean score per 5 mm segment for the patients with type IV HLP was significantly higher (3.5) than that for the patients with type II HLP (3.0), normal lipoprotein patterns (3.0), and the controls (2.3). Thus, our patients with type II HLP and those with normal lipoprotein patterns had similar amounts of severe coronary narrowing and significantly less severe coronary narrowing than the patients with type IV HLP.     

Effects of calcium channel blocking agents on reperfusion arrhythmias

The effect of the calcium antagonists nifedipine (NF) and diltiazem (DT) on reperfusion after release of circumflex coronary artery (CX) occlusion was studied in open-chest dogs. Dogs were randomized to receive a bolus of 5 μg/kg NF (seven dogs), 1 μg/kg NF (nine dogs), or vehicle (nine dogs). After bolus, high and low dose NF dogs were infused with 1 μg/kg/min NF. All dogs then underwent 30 minutes CX occlusion followed by reperfusion. Dogs that did not develop ventricular fibrillation (VF) in the first 10 minutes of reperfusion were considered survivors. NF caused a dose-related increase in CX blood flow and decrease in mean arterial pressure (MAP), significant at the higher dose. Reperfusion VF occurred in five of nine low dose NF dogs, five of seven high dose NF dogs, and five of nine controls. Another 21 dogs were randomized to receive a bolus of 0.2 mg/kg DT (11 dogs) or vehicle (10 dogs). Infusion rates (and an additional bolus injection, if necessary) were chosen to produce a 10 to 20 mm Hg drop in MAP. CX occlusion and reperfusion were performed as above. Reperfusion VF occurred in 9 of 11 DT dogs vs 8 of 10 controls. Thus neither nifedipine nor diltiazem enhanced survival during reperfusion of myocardium previously subjected to 30 minutes of ischemia.     

Ebstein's anomaly of the tricuspid valve and prolapse of the mitral valve

The hearts from 10 necropsy patients with Ebstein's anomaly of the tricuspid valve were examined for abnormalities of the mitral valve. Five patients were under 1 year of age and none had an abnormal mitral valve. The other five patients were ages 18 to 72 years (mean 36 years); all had focal fibrous thickening of the mitral leaflets and three had prolapse of one or both mitral leaflets. Only one of the three patients with mitral valve prolapse had an atrial septal defect (secundum type), indicating that the association of mitral valve prolapse with Ebstein's anomaly is not due to the presence of an atrial septal defect.     

Extravasated erythrocytes, iron, and fibrin in atherosclerotic plaques of coronary arteries in fatal coronary heart disease and their relation to luminal thrombus: frequency and significance in 57 necropsy patients and in 2958 five mm segments of 224 major epicardial coronary arteries

The presence of extravasated erythrocytes (EE), iron (I), and fibrin (F) within coronary atherosclerotic plaques and their relation to intraluminal coronary thrombus was determined in 2958 five-mm segments of 224 major epicardial coronary arteries in 57 patients with fatal coronary heart disease and in 1290 five-mm segments of 103 coronary arteries in 27 control (c) subjects. Intraplaque EE were present in 10% of the segments (controls [c] = 1%), in 35% of the arteries (c = 5%), and in 84% of the patients (c = 19%); I was present in 4% of the segments (c = less than 1%), in 14% of the arteries (c = 4%), and in 57% of the patients (c = 22%); intraplaque F was present in 2% of the segments (c = less than 1%), in 17% of the arteries (c = 3%), and in 63% of the patients (c = 7%). Intraluminal thrombus, present only in the patients with acute myocardial infarction and in none of the controls, occurred in 3% of the segments, in 8% of the arteries and in 26% of the patients. Intraplaque hemorrhage or EE occurred usually in the absence of intraluminal thrombus and conversely intraluminal thrombus occurred more frequently without than with underlying plaque hemorrhage. The frequency of intraplaque EE, I, and F was proportional to the amount of coronary atherosclerotic plaque present. Intraplaque I and F infrequently were observed in the absence of EE. The significance of extravasated erythrocytes, iron, and fibrin in atherosclerotic plaques remains unclear.     

Noncardiovascular findings associated with heart disease in the idiopathic hypereosinophilic syndrome

Heart disease characterized by endomyocardial fibrosis is one of the major causes of morbidity and mortality in the idiopathic hypereosinophilic syndrome. From our series of 50 patients with idiopathic hypereosinophilia, we defined the noncardiovascular characteristics that distinguish patients at risk of developing endomyocardial fibrosis from those who remain free of heart disease. These groups did not differ with respect to the extent of eosinophilia or the duration of disease. Patients with clinically overt heart disease were more likely (p < 0.05) to be male and HLA-Bw44 positive and have splenomegaly, thrombocytopenia, elevated serum levels of vitamin B₁₂, and hypogranular or vacuolated eosinophils and abnormal early myeloid precursors in the peripheral blood. These idiopathic hypereosinophilic patients with heart disease were also more likely to have fibrosis and decreased megakaryocytes in the bone marrow. In contrast, those who remained free of heart disease tended to be female and have angioedema, hypergammaglobulinemia, elevated serum levels of immunoglobulin E (IgE), and circulating immune complexes.Therefore, in the idiopathic hypereosinophilic syndrome, male patients with a myeloproliferative type disorder and the HLA-Bw44 haplotype were at a much increased risk for the development of endomyocardial fibrosis. However, those patients with a hypersensitivity-like illness and angioedema who were female did not develop heart disease. Appreciation of this relative degree of risk for the major complication of the idiopathic hypereosinophilic syndrome should prove useful in the early identification and appropriate treatment of patients in whom endomyocardial fibrosis might develop.     

Electrocardiographic observations in severe aortic valve stenosis: correlative necropsy study to clinical, hemodynamic,, and ECG variables demonstrating relation of 12-lead QRS amplitude to peak systolic transaortic pressure gradient

Most ECG studies in patients with aortic valve stenosis (AS) have involved living patients in whom the status of the left ventricular (LV) myocardium, epicardial coronary arteries, and mitral valve was not precisely known. We examined the 12-lead ECG recorded within 2 months of death in 50 patients aged 16 to 65 years (mean 48) with peak systolic pressure gradients (PSPG) across the aortic valve ranging from 52 to 180 mm Hg (mean 98) and anatomically normal mitral valves. Excluding four patients with complete left bundle branch block (LBBB), 44 (96%) of the other 46 patients had the usual voltage criteria for LV hypertrophy (LVH). Measurement of the total 12-lead QRS amplitude, which ranged from 144 to 417 mm (10 mm = 1 mV), (mean 257) proved useful for it correlated directly with PSPG across the aortic valve and, when the four LBBB patients were excluded, with the peak LV systolic pressure. The total 12-lead QRS amplitude (mm) was similar in most patients to the LV systolic pressure (mm Hg). Thus, subtraction of the indirect systemic arterial systolic pressure (mm Hg) from the total 12-lead QRS amplitude (mm) provides a reasonable noninvasive prediction of the PSPG across the aortic valve in patients with moderate to severe AS. Additionally, the mean of the total 12-lead QRS amplitude was significantly (p less than 0.05) greater in the 11 younger (less than or equal to 40 years) than in the 39 older patients (278 mm vs 257 mm), in the 14 women than in the 36 men (277 mm vs 240 mm), in the 22 patients with heavier (greater than 600 gm) hearts (274 mm vs 244 mm), in the 34 patients without compared to the 16 with significant coronary arterial narrowing (270 mm vs 238 mm), and in the 22 patients without compared to the 24 with ECG myocardial damage patterns (269 mm vs 236 mm).