Sites of action of sodium depletion on aldosterone biosynthesis in the dog.

Secretion of cortisol, corticosterone, and aldosterone was measured in vivo in normal and sodium-depleted hypophysectomized dogs. Biogenesis of steroids was then measured in vitro with outer slices of the adrenals of the same dogs. In some studies, metyrapone or puromycin was added. In vivo, sodium depletion stimulated the production of cortisol, corticosterone, and aldosterone. In vitro, tissues from sodium-depleted animals released more aldosterone, but less corticosterone than those from sodium-replete controls. The results are interpreted to indicate that (a) biosynthesis of aldosterone is regulated at at least two sites in the biosynthetic pathway. The final conversion, that of corticosterone to aldosterone, is stimulated by sodium depletion. This effect persists for at least 3 hr while slices from sodium-depleted dogs are incubated in vitro. Stimulation at this site is thus relatively stable in vitro; its activation by sodium depletion is not inhibited by puromycin in the dog. Stimulation at this site can explain, at least in part, the increased effectiveness of adrenocorticotropin (ACTH) on aldosterone biogenesis during sodium depletion.(b) the earlier site at which sodium depletion stimulates the secretion of aldosterone is "above" the position of desoxycorticosterone in the pathway; it is probably at the conversion of cholesterol to pregnenolone. Stimulation at this site is quickly lost during incubation of adrenal slices. It is thus relatively unstable in vitro; its activation by sodium depletion is inhibited by puromycin in the dog.

Prevalence of and variables associated with silent myocardial ischemia on exercise thallium-201 stress testing.

The prevalence of silent myocardial ischemia was prospectively assessed in a group of 103 consecutive patients (mean age 59 +/- 10 years, 79% male) undergoing symptom-limited exercise thallium-201 scintigraphy. Variables that best correlated with the occurrence of painless ischemia by quantitative scintigraphic criteria were examined. Fifty-nine patients (57%) had no angina on exercise testing. A significantly greater percent of patients with silent ischemia than of patients with angina had a recent myocardial infarction (31% versus 7%, p less than 0.01), had no prior angina (91% versus 64%, p less than 0.01), had dyspnea as an exercise test end point (56% versus 35%, p less than 0.05) and exhibited redistribution defects in the supply regions of the right and circumflex coronary arteries (50% versus 35%, p less than 0.05). The group with exercise angina had more ST depression (64% versus 41%, p less than 0.05) and more patients with four or more redistribution defects. However, there was no difference between the two groups with respect to mean total thallium-201 perfusion score, number of redistribution defects per patient, multi-vessel thallium redistribution pattern or extent of angiographic coronary artery disease. There was also no difference between the silent ischemia and angina groups with respect to antianginal drug usage, prevalence of diabetes mellitus, exercise duration, peak exercise heart rate, peak work load, peak double (rate-pressure) product and percent of patients achieving greater than or equal to 85% of maximal predicted heart rate for age. Thus, in this study group, there was a rather high prevalence rate of silent ischemia (57%) by exercise thallium-201 criteria.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial contrast echocardiography in humans. II. Assessment of coronary blood flow reserve.

The hypothesis that myocardial contrast echocardiography could be used to simultaneously assess coronary blood flow reserve and the size of the perfusion bed supplied by a coronary artery was examined in nine patients and six dogs. All patients were undergoing cardiac catheterization and had single vessel coronary artery disease (greater than or equal to 85% stenosis of either the proximal left anterior descending or the left circumflex coronary artery); the six dogs had a critical stenosis of the left circumflex coronary artery. Three milliliters of sonicated Renografin-76 (mean microbubble size 6 micron) was injected into the left main coronary artery before and after intracoronary administration of papavarine, 6 to 9 mg. The beds supplied by the normal and stenotic vessels could not be differentiated during contrast echocardiography before injection of papavarine. However, after papavarine, the normal vascular bed showed significantly more contrast enhancement than did the bed supplied by the stenotic artery. This disparity in contrast enhancement made it possible to delineate the size of the bed perfused by the stenotic vessels. When quantitative analysis of the time-intensity curves obtained from the echocardiograms was performed in the dogs, the absolute values for the area under the curve, peak contrast intensity and curve width did not correlate with absolute blood flows measured with radiolabeled microspheres. However, the ratios of the areas under the curves derived from the two vascular beds before and after papavarine correlated well with the ratios of blood flows between the two beds during the same stages (r2 = 0.73 by linear regression and r2 = 0.85 by an exponential function). In comparison, the ratios of peak amplitudes and curve widths before and after papavarine had poor correlations with ratios of flows from the two beds (r2 = 0.18 and 0.02, respectively). In conclusion, myocardial contrast echocardiography can be used to simultaneously assess coronary blood flow reserve and the size of the perfusion bed supplied by a stenotic vessel.

Influence of contrast media on thrombus formation during coronary angioplasty.

The influence of contrast media on thrombus formation during percutaneous transluminal coronary angioplasty was assessed in 124 consecutive patients undergoing coronary angioplasty and receiving either ionic (n = 57) (Group I) or nonionic (n = 67) (Group II) contrast medium. The presence of thrombus was assessed by qualitative analysis of angiograms in identical pre- and postangioplasty projections by four observers who had no knowledge of other data. Quantitation of stenosis severity before and after angioplasty and qualitative analysis of lesion eccentricity and complexity and of the presence of dissection were also performed. Although the baseline clinical characteristics of the two groups (including presenting syndromes and procedural and angiographic variables) did not differ, more patients in Group II than Group I developed new thrombus during coronary angioplasty (18% vs. 4%, p less than 0.02). In particular, patients with a presenting syndrome of recent myocardial infarction or rest angina, or both, and patients with an eccentric coronary plaque were more likely to develop new thrombus if they received nonionic than if they received ionic contrast medium (p less than 0.05). Patients with new thrombus formation and patients with thrombus present both before and after angioplasty had a high incidence of acute procedural complications (36% and 23%, respectively). Patients in Groups I and II had a similar incidence of ischemic events during follow-up.

Relation of therapeutic response to nifedipine to coronary anatomy and motion of S-T segment during unstable angina pectoris.

Of 77 patients hospitalized for unstable angina pectoris and failure of oral, dermal, or intravenous nitrates and/or beta blockade, 81 percent with negligible or single-vessel disease and 55 percent with two- or three-vessel disease showed response (p less than 0.05) to nifedipine therapy. Patients with either S-T elevation or no change during pain responded better (31 of 45) than those with any S-T depression (16 of 32; p less than 0.05). Patients with negligible or single-vessel disease had a higher prevalence of S-T elevation (13 of 16) than patients with two- or three-vessel disease (15 of 31; p = 0.004). S-T motion did not predict response in patients with two- or three-vessel disease, but did predict response in patients with negligible or single-vessel disease. On follow-up study at 9 +/- 8 (range one to 33) months, 39 of 42 who had shown response were free from pain. Three died from infarction without unstable angina. (range one to 33) months, 39 of 42 who had shown response were free from pain. Three died from infarction without unstable angina. Five who showed response had elective bypass surgery. The addition of nifedipine abolished or reduced pain episodes by more than 50 percent in 61 percent of patients with refractory unstable angina pectoris. Patients with negligible or single-vessel disease with S-T elevation benefit most. In patients with two- or three-vessel disease, the type of S-T motion did not predict response. Follow-up of all those with response indicated sustained amelioration by nifedipine therapy. Failure of nifedipine therapy should not be accepted until a dose of 120 mg per day has been achieved, or until intolerable side effects appear.

Quantitative exercise thallium-201 scintigraphy for predicting angina recurrence after percutaneous transluminal coronary angioplasty.

The aim of this prospective study was to determine the value of quantitative exercise thallium-201 scintigraphy for predicting short-term outcome in patients after percutaneous transluminal coronary angioplasty (PTCA). Quantitative exercise thallium-201 scintigraphy was performed 2.2 +/- 1.2 weeks after successful PTCA in 68 asymptomatic patients, 64 (94%) of whom had class III or IV angina before the procedure. Clinical follow-up was obtained in all patients at a mean of 10 +/- 2 months and all were followed for at least 6 months; 45 patients (66%) remained asymptomatic during follow-up and 23 (34%) developed recurrent class III or IV angina at a mean of 2.6 +/- 1.2 months. Multivariate analysis of 22 clinical, angiographic and exercise test variables revealed that thallium-201 redistribution, any thallium scan abnormality, presence of a distal stenosis and treadmill time were the only significant predictors of recurrent angina after PTCA. Using a stepwise discriminant function model, thallium-201 redistribution was the only significant independent predictor. Despite its prognostic value relative to other variables as a predictor, thallium redistribution at 2 weeks after PTCA was only detected in 9 of the 23 patients (39%) who subsequently developed recurrent angina, although only 2 of the 45 patients (9%) who remained asymptomatic during follow-up demonstrated thallium-201 redistribution at the time of early testing. After repeat angiography was performed in 17 of the 23 patients with recurrent angina, 14 (82%) demonstrated restenosis and 3 (18%) had worse narrowing distal to or remote from the site of dilatation.(ABSTRACT TRUNCATED AT 250 WORDS)

Proliferative activity in coronary atherectomy tissue. Clinical, histopathologic, and immunohistochemical correlates.

STUDY OBJECTIVE: Although cellular proliferation is considered one of the dominant processes leading to restenosis following coronary intervention, controversy exists over the extent of cellular replication in atherosclerotic tissue. Accordingly, we sought to investigate the level and clinicopathologic correlates of proliferative activity in atherosclerotic tissue obtained via directional coronary atherectomy (DCA). DESIGN: Prospective observational study. SETTING: Tertiary care referral hospital. PATIENTS: Specimens retrieved via DCA from 37 lesions (primary, 26; restenosis, 11) were studied using single-label immunohistochemical staining for the proliferating cell nuclear antigen and basic fibroblast growth factor (bFGF). RESULTS: Restenosis tissue was significantly more likely than primary tissue to contain areas of intimal hyperplasia (64 vs 23%; p < 0.03). However, the frequency of positive staining for proliferating cell nuclear antigen (PCNA) was similar in primary and restenosis lesions (25 vs 30%; p = NS), and the mean percentage of positive cells per slide was similar in the two groups. Positive immunostaining for bFGF was present in 20 lesions (61%), and tended to be more frequently seen in restenotic lesions (80 vs 52%; p = 0.25). However, there was no correlation or colocalization between immunostaining for bFGF and proliferating cell nuclear antigen. We found no clinicopathologic correlations with respect to clinical outcome. CONCLUSIONS: Cellular replication, as measured by expression of the PCNA, occurs in a heterogeneous pattern in both primary and restenotic atherosclerotic tissue obtained from patients undergoing coronary intervention.

Single coronary artery with a fistula to the main pulmonary artery in a patient with tetralogy of Fallot.

The presence of a single coronary artery arising in the anterior cusp and terminating in a large fistula to the main pulmonary artery was noted during the preoperative evaluation of a patient with tetralogy of Fallot. Recognition of this rare association dictated the use of a valved conduit to avoid injury to the left anterior descending coronary as it crossed the right ventricular outflow tract and permitted abolition of intracardiac shunting by ligation of the fistula. It is postulated that the increasing arterial saturation noted in this patient prior to intracardiac repair may have been related in part to progressive augmentation in flow through the coronary fistula to the main pulmonary artery.

Inhibition of the effects of angiotensin II on adrenal steroid production by dietary sodium.

The pressor octapeptide, angiotensin II, can stimulate the production of aldosterone by the adrenal cortex. The present results show that in the dog a high-sodium diet can eliminate the steroidogenic action of angiotensin II, which is thus dissociated from the pressor action which remains. Angiotensin II was infused intravenously for 48 hours into conscious, undisturbed hypophysectomized dogs that were receiving each day either 60 or 200 mEq of dietary sodium. Blood pressure and secretion of aldosterone, corticosterone, and cortisol were measured (1) throughout the infusion in some dogs, and (2) at the end of the infusion in all dogs. In those dogs receiving 60 mEq of sodium, angiotensin II elevated the blood pressure and produced sustained increases of secretion of aldosterone, corticosterone, and cortisol. In those dogs receiving 200 mEq of sodium, angiotensin II, while retaining its pressor activity, had no effect on the production of aldosterone, corticosterone, or cortisol after 24 hours. Thus, if angiotensin II can produce hypertension clinically, there need not be secondary aldosteronism as well.

The clinical efficacy and scintigraphic evaluation of post-coronary bypass patients undergoing percutaneous transluminal coronary angioplasty for recurrent angina pectoris.

The efficacy of percutaneous transluminal angioplasty in improving recurrent anginal symptoms and myocardial perfusion after coronary artery bypass graft surgery was assessed prospectively in 55 patients, of whom 50 had an initial angiographic and clinical success. Although 80% of those successfully dilated were initially free of angina at 23 +/- 11 months of follow-up, one half of these patients had recurrent angina. Although only 48% of the patient cohort had complete relief of angina, 94% had less angina than before dilatation and 86% were able to decrease antianginal medications. Fifteen patients with persistent or recurrent angina had from one to five repeat dilatations. After angioplasty, lung thallium uptake, the extent of abnormal scan segments, and the magnitude of redistribution in dilated lesions were significantly reduced (n = 24 patients). Redistribution defects were seen in 38% of patients on postangioplasty scans. All were associated with subsequent angina. Of various clinical, angiographic, exercise, and thallium-201 scan variables, only the presence of delayed redistribution was an independent predictor of recurrent angina. Restenosis was the most common underlying cause for this exercise-induced perfusion defect. Thus percutaneous coronary angioplasty performed as primary therapy for recurrent angina after bypass surgery is moderately successful in long-term follow-up for the amelioration of symptoms and enhancement of regional myocardial perfusion.

An association between collateral blood flow and myocardial viability in patients with recent myocardial infarction.

BACKGROUND: We hypothesized that successful reperfusion of an occluded infarct-related coronary artery even late after acute myocardial infarction would result in improved regional wall motion and that such improvement might be related to the presence of collateral blood flow within the infarct bed. METHODS: We assessed regional wall motion by two-dimensional echocardiography at base line and one month after angioplasty was attempted in the occluded infarct-related artery in 43 patients who had had a myocardial infarction two days to five weeks earlier. A wall-motion score was assigned to each patient on a five-point scale (from 1 [normal function] to 5 [dyskinesia]). The percentage of the infarct bed perfused by collateral flow was assessed with myocardial contrast echocardiography. RESULTS: In the 41 patients who had abnormal wall motion at base line, improvement in function was noted in 25 (78 percent) of the 32 in whom angioplasty was successful, as compared with only 1 (11 percent) of the 9 in whom it was unsuccessful (P < 0.001). The percentage of the infarct bed supplied by collateral flow at base line was directly correlated with wall function and inversely correlated with the wall-motion score one month after successful angioplasty (r = -0.64, P < 0.001). Among the patients in whom angioplasty was successful, the 23 in whom > 50 percent of the infarct bed was supplied by collateral flow had better wall motion (P < 0.001) and greater improvement in wall motion at one month (P = 0.004) than the 9 in whom < or = 50 percent of the bed was supplied by collateral flow. The degree of improvement in function was not influenced by the length of time between the infarction and the attempted angioplasty. CONCLUSIONS: The myocardium remains viable for a prolonged period in many patients with acute infarction and an occluded infarct-related artery. Viability appears to be associated with the presence of collateral blood flow within the infarct bed.

Evaluating candidates for ventricular aneurysmectomy.

Forty consecutive patients having left ventricular (LV) aneurysmectomy were evaluated for surgical risk predictors and were then followed up after operation. Factors evaluated included age, time since last myocardial infarction, NYHA classification, principal indication for surgery, LV end diastolic pressure, LV "A" wave size, number of coronary systems with greater than 70% stenosis, number of coronary bypass grafts, location of aneurysm, and ejection fraction of the nonaneurysmal or "contractile segment," determined by a modification of the method of Watson et al (MCSEF). There was 100% follow-up. There were four perioperative deaths and two late deaths. Operative mortality was 3.4% in patients with MCSEF greater than or equal to 45% and 37.5% in patients with MCSEF less than 45% (P less than .05). None of the other factors evaluated significantly affected mortality independent of MCSEF. Survivors had a mean follow-up of 22 months with a mean improvement in symptoms of 1.6 NYHA class (from 3.3 to 1.7). Forty-four percent have returned to their previous occupations. It is concluded that: (1) the MCSEF is of prime importance in evaluating risk for LV aneurysmectomy; (2) for patients with MCSEF greater than or equal to 45%, LV aneurysmectomy is a low-risk procedure; and (3) LV aneurysmectomy results in sustained relief of symptoms in most patients.

Thallium-201 scintigraphy at rest in ischemia and infarction.

Serial imaging of the myocardium in the resting state after intravenous administration of thallium-201 can be employed to differentiate between ischemia or under-perfusion and myocardial infarction or scar. Redistribution of thallium with filling-in of defects on delayed images or rest can be observed in myocardial regions supplied by stenotic coronary arteries (greater than or equal to 70% narrowing). These myocardial segments usually exhibit normal or hypokinetic wall motion. Persistent defects over a two to three hour imaging period at rest correlate highly with Q waves on the electrocardiogram and akinetic or dyskinetic wall motion on ventriculography. Thallium scintigraphy can be successfully utilized for detecting and localizing acutely infarcted myocardium. Sensitivity for infarct detection is higher in the first 24 hours after the onset of chest pain, although with computer-assisted quantitative analysis of images sensitivity for late detection (ten to fourteen days post myocardial infarction) may be improved. Multivessel disease can be predicted in many patients with acute inferior myocardial infarction by demonstrating anteroseptal wall defects with delayed redistribution on rest images prior to hospital discharge. Patients who demonstrate inferior wall persistent defects (infarction) with anterior wall redistribution (hypoperfusion/ischemia) have a worse prognosis characterized by an increased frequency of recurrent angina and infarction compared to the group with only inferior defects. Thallium scintigraphy may also be useful in assessing myocardial infarct size. Patients with large defects during the acute phase of infarction have significantly higher early and late mortality.

Short-term infarct vessel patency with aspirin and dipyridamole started 24 to 36 hours after intravenous streptokinase.

The duration of intravenous heparin therapy required to maintain patency of the infarct-related artery after intravenous streptokinase is uncertain. Twenty-eight patients were prospectively treated with 1.5 million units of intravenous streptokinase within 4 hours of onset of chest pain. Intravenous heparin was begun after the streptokinase infusion was complete and was discontinued within 36 hours. Aspirin, 325 mg daily, and dipyridamole, 75 mg three times a day, was begun before the heparin was discontinued. Coronary angiography was performed both at 2 hours after completion of the streptokinase infusion and again at a mean of 8.7 (+/- 3.2) days after the initial catheterization. One patient died after treatment with streptokinase but before early angiography. In 21 of 27 patients (78%), Thrombolysis in Myocardial Infarction trial (TIMI) grade 2 or 3 perfusion in the infarct vessel was observed on initial angiography. Repeat angiograms were available in 17 of the 21 patients with initially patent vessels. Continued patency (TIMI grade 2 or 3) was found in 15 of the 17 patients (88%). Two of the four patients who did not undergo repeat angiography died, and the remaining two patients required coronary artery bypass grafting for unstable angina. Bleeding complications occurred in 6 of 27 patients (22%), with two (7%) requiring surgical evacuation of a groin hematoma. There were no instances of intracerebral bleeding and only two patients required transfusions. Thus, the combination of aspirin and dipyridamole following 36 hours of systemic heparinization after intravenous streptokinase infusion is associated with a reocclusion rate comparable to that which has been reported for more prolonged systemic anticoagulation with fewer hemorrhagic complications.

Recombinant human superoxide dismutase (h-SOD) fails to improve recovery of ventricular function in patients undergoing coronary angioplasty for acute myocardial infarction.

BACKGROUND: Animal studies have demonstrated a burst of oxygen free radical generation after reperfusion of ischemic myocardium that could be blocked by administration of the free radical scavenger recombinant human superoxide dismutase (h-SOD). A multicenter, randomized, placebo-controlled clinical trial was designed to test the hypothesis that free radical-mediated reperfusion injury could be reduced by intravenous administration of h-SOD begun before percutaneous transluminal coronary angioplasty (PTCA) in patients with acute transmural myocardial infarction. METHODS AND RESULTS: One hundred twenty patients were randomized to receive placebo (n = 59) or h-SOD (n = 61) given as a 10-mg/kg intravenous bolus followed by a 60-minute infusion of 0.2 mg.kg-1.min-1. Left ventricular function was analyzed via paired contrast left ventriculograms performed before PTCA and after 6 to 10 days and paired radionuclide ventriculograms performed within 24 hours of PTCA and after 4 to 6 weeks. Both h-SOD- and placebo-treated patients showed improvement in global and regional left ventricular function after successful reperfusion. Compared with the placebo group, no additional improvement was observed in the patients treated with h-SOD. CONCLUSIONS: The results of this clinical trial failed to demonstrate a beneficial effect of h-SOD on global or regional left ventricular function in patients who underwent successful PTCA for treatment of acute myocardial infarction.