Dose-response of chronic beta-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Bucindolol Investigators.

BACKGROUND: Small-scale clinical investigations have demonstrated that single doses of beta-blocking agents can improve left ventricular function in heart failure from idiopathic dilated cardiomyopathy (IDC). The purpose of this multicenter clinical trial was to determine the dose-effect characteristics of beta-blockade in a heart failure population that includes ischemic dilated cardiomyopathy (ISCD). METHODS AND RESULTS: Bucindolol is a nonselective beta-blocking agent with mild vasodilatory properties. One hundred forty-one subjects with class II or III heart failure, left ventricular ejection fraction (LVEF) < or = 0.40, and background therapy of angiotensin-converting enzyme inhibitors, digoxin, and diuretics were given an initial challenge dose of bucindolol 12.5 mg. One hundred thirty-nine subjects (99 with IDC, 40 with ISCDC) tolerated challenge and were randomized to treatment with placebo or bucindolol 12.5 mg/d (low dose), 50 mg/d (medium dose), or 200 mg/d (high dose). At the end of 12 weeks, left ventricular function and other parameters were measured and compared with baseline values. There was a dose-related improvement in left ventricular function in bucindolol-treated subjects. In the high-dose bucindolol group, radionuclide-measured LVEF improved by 7.8 EF units (%) compared with 1.8 units in the placebo group (P < .05), and compared with the placebo group, a greater percentage of subjects had an increase in LVEF by > or = 5 units. In contrast, all three bucindolol doses prevented deterioration of myocardial function as defined by an LVEF decline of > or = 5 units. CONCLUSIONS: In heart failure from systolic dysfunction, beta-blockade with bucindolol produces a dose-related improvement in and prevents deterioration of left ventricular function.

Prediction of outcome after mitral valve replacement in patients with symptomatic chronic mitral regurgitation. The importance of left atrial size.

BACKGROUND: The ability to predict outcome after mitral valve replacement remains limited in patients with symptomatic chronic mitral regurgitation. The aims of this study were to determine the preoperative predictors of postoperative cardiac-related mortality and to assess the additive prognostic value of tests performed in such patients. METHODS AND RESULTS: Accordingly, 176 patients (mean age, 57 +/- 14 years) who underwent mitral valve replacement were followed up for 3.8 +/- 0.5 years. Four categories of variables were analyzed to predict postoperative cardiac-related mortality: clinical, laboratory, two-dimensional echocardiographic (2DE), and cardiac catheterization. There were 39 cardiac-related deaths (29 due to congestive heart failure and 10 sudden). When the four categories were analyzed separately, two clinical, one laboratory, two 2DE, and one catheterization variable best predicted postoperative death. When these six variables were examined simultaneously, only three (one clinical and two 2DE) remained significant predictors of cardiac-related mortality: presence of pulmonary rales, left atrial size, and the ratio of left ventricular wall thickness to left ventricular cavity dimension in end systole. A model based on these three variables may predict cardiac-related death with considerable accuracy. Laboratory data did not add to clinical information for predicting death. 2DE variables provided significant additional information in this regard (p less than 0.001). Further addition of catheterization variables was not useful. Prognostic value did not change significantly when 50 patients with prior mitral valve surgery or 49 patients undergoing concomitant aortic valve replacement or coronary artery bypass surgery were excluded from analysis. CONCLUSIONS: We conclude that 1) measures of both left ventricular systolic function and left atrial size are equally important in predicting postoperative cardiac-related mortality in patients with symptomatic chronic mitral regurgitation undergoing mitral valve replacement; 2) left atrial size may be important because it reflects the "history" (severity and duration) of mitral regurgitation; 3) 2DE assessment of left atrial size and left ventricular function provides prognostic information that is significantly greater than that obtained from clinical and laboratory parameters alone; the addition of catheterization variables does not increase the prognostic value of the clinical and 2DE data.

Salvage from cardiogenic shock by atherectomy after failed emergency coronary artery angioplasty.

In this case report of a patient undergoing angioplasty for cardiogenic shock during acute myocardial infarction, recurrent occlusion resulted in recurrence of shock. Atherectomy reestablished lasting patency and reversed the patient's hemodynamic collapse. Atherectomy deserves further investigation as a means to salvage vessel patency during unsuccessful coronary angioplasty.

Usefulness of bucindolol in congestive heart failure.

The sympathetic hyperactivity of congestive heart failure (CHF) may worsen cardiovascular function by down-regulation of myocardial beta-receptors. For this reason, beta blockade is proposed to be useful in CHF. Bucindolol is a new beta blocker that has intrinsic nonadrenergically-mediated vasodilation and may be valuable in treatment of CHF. To test this, 19 patients with CHF were randomized in a double-blind protocol to 3 months of treatment with bucindolol (n = 12) or placebo (n = 7). Significant improvement was seen in the bucindolol group using invasive and noninvasive tests; treadmill time increased from 445 to 530 seconds (p = 0.04), Minnesota Living With Heart Failure Questionnaire score improved from 61 to 40 (p = 0.0001), cardiac output increased from 4.0 to 4.7 (p = 0.02), and systemic vascular resistance decreased from 1,888 to 1,481 (p = 0.04). Also, peak exercise heart rate and pulmonary capillary wedge pressure decreased significantly with treatment. There were no changes in the placebo group. We conclude that bucindolol may be an effective treatment for CHF when administered chronically and that its nonadrenergic vasodilation may be an important feature.

Naturally occurring cardiomyopathy in the Doberman pinscher: a possible large animal model of human cardiomyopathy?

Currently there is no large animal model of dilated cardiomyopathy. The smaller animal models of cardiomyopathy, such as the Syrian hamster, cannot be studied with echocardiography and cardiac catheterization, and the relevance of these models to human dilated cardiomyopathy is open to question. On the basis of some initial observations in Doberman pinschers, it was speculated that these dogs could have occult left ventricular dysfunction. Accordingly, studies were performed in 46 apparently healthy Doberman pinschers and in 41 mongrel dogs: two-dimensional echocardiography (30 dogs in each group), cardiac catheterization (16 Doberman pinschers and 12 mongrels) and coronary blood flow studies (13 Doberman pinschers and 6 mongrels). In the awake, unsedated dogs studied with echocardiography, left ventricular wall thickening was significantly less in the Dobermans than in the mongrels (28% versus 36%, p = 0.0003). In the anesthetized dogs undergoing cardiac catheterization, left ventricular ejection fraction was significantly lower in the Dobermans than in the mongrels (0.38 versus 0.63, p = 0.0001). Rest coronary blood flow and coronary blood flow reserve were similar in the two groups. It is concluded that apparently healthy Doberman pinschers have occult left ventricular dysfunction. These dogs may serve as a large animal model of dilated cardiomyopathy and should not be used experimentally to study normal cardiac physiology.

Functional assessment of elderly patients after percutaneous aortic balloon valvuloplasty: New York Heart Association classification versus functional status questionnaire.

Monitoring functional status in patients with cardiac disease has traditionally been done by using the New York Heart Association (NYHA) classification system. For various reasons, we found the NYHA system difficult to apply to elderly patients. We proposed that the functional status questionnaire (FSQ), which measures the ability to perform tasks, would more accurately assess the functional status of the elderly. In a study in 37 patients with a mean age of 76 years, who had aortic stenosis, we measured FSQ and NYHA scores at baseline, 1 month and 3 months. The difference in questionnaires was evident by the 3-month measurement. Individual patients were better evaluated by the FSQ. Six patients had an FSQ score of less than 72 (suggesting severe functional impairment) at 3 months but only two patients gave symptoms scored as NYHA class III or IV (cardiac disability). Five of six patients had a recurrent cardiac event subsequent to the 3-month follow-up. Changes in functional performance preceded symptomatic deterioration that was reflected only by the FSQ scores. The FSQ system more reliably predicted outcome than the NYHA system and appears to be a more useful tool in the evaluation of elderly patients with cardiac disease.

Is tau a preload-independent measure of isovolumetric relaxation?

Several studies have been performed in patients with a variety of myocardial diseases that have identified a prolongation of tau. However, it is not clear whether prolongation of tau represents abnormal myocardial physiology or the effect of excessive load associated with a particular disease process. Accordingly, we evaluate the effect on tau of an isolated decrease in preload induced by inferior vena cava occlusion before the appearance of reflex changes in six patients designated as normal by catheterization criteria. A computer-based digitization routine identified cardiac contractions in all patients early after inferior vena cava occlusion where left ventricular end-diastolic pressure decreased (18.3 +/- 6.3 to 9.3 +/- 5.8, p less than 0.05) while left ventricular systolic pressure (113.3 +/- 13.8 to 111.8 +/- 14.0, p = NS) and heart rate (66.0 +/- 10.0 to 65.9 +/- 10.3, p = NS) did not change. After this alteration in preload, no change in tau from baseline, as calculated by the logarithmic (TL), derivative (TD), or method of Mirsky (T1/2), was noted: TL, 47.4 +/- 6.5 to 44.6 +/- 7.6; TD, 39.3 +/- 8.1 to 39.8 +/- 8.4; T1/2, 33.0 +/- 4.0 to 31.8 +/- 4.6; all p = NS. The baseline pressure extrapolated from isovolumetric relaxation did not change in these preload beats compared with baseline (+4.26 +/- 6.20 to -0.80 +/- 4.87, p = NS). Subsequent beats were identified where left ventricular systolic pressure showed a numeric decrease compared with baseline (113.3 +/- 13.8 to 100.8 +/- 14.3, p = NS) despite no change in heart rate (66.0 +/- 10.0 to 66.8 +/- 10.5, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Preoperative left ventricular wall stress, ejection fraction, and aortic valve gradient as prognostic indicators in aortic valve stenosis.

Patients with aortic valve stenosis (AS) and left ventricular (LV) dysfunction may dramatically improve after aortic valve replacement, but operative risk is high. In an earlier study, all patients with low preoperative wall stress and low ejection fraction, or with low aortic valve gradient, died or had persistent heart failure after operation. Because wall stress is difficult to calculate, we reassessed its effect and the effect of other preoperative characteristics on outcome in 66 consecutive catheterization patients with predominant aortic stenosis referred for valve replacement. Despite ejection fraction that was inordinately low compared with afterloading wall stress in nine patients, seven patients improved with surgery. All three patients with ejection fraction less than 20% improved after surgery. Two of three patients with mean aortic valve gradients of less than 30 mm Hg improved. Mortality was 33% in patients with mean gradient less than 30 mm Hg and 19% with mean gradient less than 50 mm Hg. In the 54 patients with calculated aortic valve areas of less than or equal to 0.8 cm2, 1 (2%) had continuing heart failure, while 6 of 12 (50%, P less than .01) patients with aortic valve areas of 0.9-1.2 cm2 had continued symptoms of or died of heart failure. Patients who died or failed to improve after operation were older (71 +/- 9 years) than those who improved (65 +/- 9 years, P = .02). We conclude that wall stress calculations do not predict which patients with aortic stenosis will benefit from aortic valve replacement and that poor left ventricular function and low mean aortic valve gradient do not absolutely preclude operation. On the other hand, low gradient, non-critical valve area, and advanced age are all relative contraindications to aortic valve replacement in aortic stenosis.

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.

Demonstration of an imbalance between coronary perfusion and excessive load as a mechanism of ischemia during stress in patients with aortic stenosis.

Patients with aortic stenosis are susceptible to myocardial ischemia during hemodynamic stress, which may be caused by two mechanisms. First, vascular abnormalities inherent in myocardial hypertrophy may impair coronary vasodilation, limiting the ability to increase coronary blood flow to meet increased metabolic demands. Second, aortic stenosis itself may cause an imbalance between oxygen supply and demand during hemodynamic stress by decreasing aortic pressure (decreasing coronary perfusion or oxygen supply) and increasing left ventricular pressure (increasing oxygen demand). By decreasing aortic valve gradient without immediately altering ventricular hypertrophy, aortic balloon valvuloplasty offers the opportunity to distinguish these mechanisms. We hypothesized that aortic valvuloplasty would improve the balance between myocardial oxygen supply and demand, especially during isoproterenol infusion. Nine patients undergoing aortic balloon valvuloplasty were assessed at baseline and during isoproterenol infusion (5 +/- 2 micrograms/min, mean +/- SD) before and after valvuloplasty. Valvuloplasty increased myocardial oxygen supply. After valvuloplasty, isoproterenol decreased diastolic pressure time index (DPTI) less and increased coronary sinus blood flow more than before valvuloplasty (-630 +/- 367 vs. -292 +/- 224 mm Hg.sec/min, p = 0.02 and 53 +/- 137 vs. 179 +/- 145 ml/min, p = 0.001, respectively). Valvuloplasty also decreased oxygen demand, decreasing systolic pressure time index (SPTI) from 4,135 +/- 511 to 3,021 +/- 492 mm Hg.sec/min (p = 0.0002). Valvuloplasty improved the balance between myocardial oxygen supply and demand, increasing baseline DPTI:SPTI, decreasing aortocoronary sinus oxygen content difference (0.51 +/- 0.15 to 0.68 +/- 0.14, p = 0.005 and 96 +/- 14 to 78 +/- 15 ml O2/l, p = 0.002, respectively), and decreasing myocardial lactate production during isoproterenol infusion (mean lactate extraction fraction, -0.26 +/- 0.40 to 0.14 +/- 0.17; p = 0.01). We conclude that aortic valvuloplasty improves the balance between myocardial oxygen supply and demand during hemodynamic stress induced by isoproterenol infusion. We speculate that the clinical improvement, which often occurs in these patients after valvuloplasty despite persistence of hemodynamically "critical" aortic stenosis, is in part attributable to immediate improvement in the myocardial oxygen supply:demand ratio.

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.

Left ventricular dysfunction in excess of the size of infarction: a possible management strategy.

In this report we describe two patients whose left ventricular dysfunction was far in excess of infarct size as evidenced by ECG changes and the magnitude of creatine kinase release. Both patients demonstrated redistribution in myocardial beds remote from the infarct zone on delayed rest thallium 201 images and both had multivessel disease evident on coronary angiography. Both patients experienced relief of symptoms and improvement in regional and global left ventricular function after revascularization surgery. The possible mechanisms of left ventricular dysfunction in myocardial beds remote from the zone of infarction are discussed.

Comparison of outcome of asymptomatic to symptomatic patients older than 20 years of age with valvular aortic stenosis.

A 2-part prospective study was performed to evaluate the clinical outcome of patients with hemodynamically confirmed asymptomatic valvular aortic stenosis (AS). During phase 1, linear regression analysis showed continuous wave Doppler to be highly accurate in predicting catheterization measured peak systolic aortic valve pressure gradients in 101 consecutive patients aged 36 to 83 years (mean 65 +/- 8) with symptomatic AS. During phase 2, 90 additional patients (51 asymptomatic and 39 symptomatic) with Doppler-derived peak systolic aortic valve gradients greater than or equal to 50 mm Hg (range 50 to 132 [mean 68 +/- 19]) were followed for 1 to 45 months. Both groups of patients in phase 2 had similar Doppler gradients and clinical and auscultatory evidence of moderate to severe AS at baseline. Asymptomatic patients were younger (p = 0.01), had higher ejection fractions (p = 0.001) and were less likely to have an electrocardiographic strain pattern (p = 0.01) and left atrial enlargement (p = 0.02). End-diastolic wall thickness, left ventricular cross-sectional myocardial area and estimated left ventricular mass were 18% (p = 0.0001), 20% (p = 0.0008), and 29% (p = 0.002) greater in symptomatic patients. During 17 +/- 9 months of follow-up, 21 asymptomatic patients (41%) became symptomatic. Dyspnea was the most common initial complaint, occurring 2.5 and 4.8 times more often than angina and syncope, respectively. Compared with the 39 symptomatic patients, the 51 asymptomatic patients had a lower cumulative life table incidence of death from any cause (p = 0.002), and from cardiac causes (p = 0.0001) including sudden death (p = 0.013).(ABSTRACT TRUNCATED AT 250 WORDS)

Successful combined percutaneous aortic balloon valvuloplasty and coronary angioplasty in two critically ill patients.

This report describes combined aortic balloon valvuloplasty and coronary angioplasty in two critically ill patients with aortic stenosis and coronary artery disease.

Myocardial contrast echocardiography in humans: I. Safety--a comparison with routine coronary arteriography.

Myocardial contrast echocardiography is a new diagnostic cardiovascular imaging technique capable of defining perfusion zones of coronary vessels in vivo; ultimately, it may be used to measure absolute regional myocardial blood flow. However, before it can be used in humans, its safety must be clearly established. Accordingly, the electrocardiographic and hemodynamic effects of intracoronary injections of 2 cc of sonicated Renografin-76 were compared with 5 to 10 cc of non-sonicated Renografin-76 in 10 subjects with normal coronary arteries. Two cubic centimeters of sonicated Renografin provides optimal myocardial opacification during echocardiography, while 5 to 10 cc of Renografin is required for an adequate coronary arteriogram. During coronary arteriography, heart rate decreased while PR and QT intervals and QRS duration increased as compared with baseline and myocardial contrast echocardiography (p less than 0.01). Similarly, the decrease in aortic pressure and first derivative of left ventricular pressure (dP/dt) was significantly (p less than 0.01) greater during routine coronary arteriography than during myocardial contrast echocardiography. Changes in left ventricular end-diastolic or pulmonary capillary wedge pressure were similar during myocardial contrast echocardiography and coronary angiography. There were no significant differences in the duration of electrocardiographic and hemodynamic changes between myocardial contrast echocardiography and coronary arteriography. It is concluded that intracoronary injection of 2 cc of sonicated Renografin-76 provides optimal myocardial opacification. It is safe in humans, producing transient electrocardiographic and hemodynamic alterations that are less pronounced than those seen during routine coronary angiography.

Cardiovascular monitoring of patients with pulmonary disease.

Assessing cardiac function in patients with pulmonary disease requires knowledge of cardiac loading conditions, which can be obtained if the practitioner is aware of physiologic and technical factors that can affect observed pressures and flows. Only with proper care in measuring and interpreting these parameters can therapeutic decisions be made confidently for these patients.

Effects of hydralazine on pressure-volume and stress-volume relations in congestive heart failure secondary to idiopathic dilated cardiomyopathy.

The mechanism by which hydralazine improves cardiac function in patients with heart failure is not well characterized. Hydralazine may improve left ventricular (LV) function by decreasing afterloading wall stress or by increasing myocardial contractility. The effect of intravenous hydralazine was assessed in 8 patients with severe idiopathic dilated cardiomyopathy. Hydralazine increased stroke volume index (from 24 +/- 8 to 40 +/- 9 ml/m2, p less than 0.01) and decreased systemic vascular resistance from 1,603 +/- 619 to 810 +/- 317 dynes s cm-5, p less than 0.01) and peak LV wall stress (from 476 +/- 118 to 410 +/- 68 kdynes/cm2, p = 0.02). Two groups were defined by normal or high LV wall stress. Patients with high LV stress had higher LV end-diastolic pressure (38 +/- 12 vs 17 +/- 8 mm Hg, p less than 0.01), LV end-diastolic volume index (184 +/- 24 vs 149 +/- 7 ml/m2, p less than 0.01) and systemic vascular resistance (1,423 +/- 686 vs 846 +/- 293 dynes s cm-5, p = 0.01). Hydralazine decreased stress more in these patients (-101 +/- 57 vs -6 +/- 9 kdynes/cm2, p = 0.02), LV end-diastolic pressure (-12 +/- 7 vs 2 +/- 2 mm Hg, p = 0.02), systolic pressure (-15 +/- 13 vs 3 +/- 4 mm Hg, p = 0.03) and systemic vascular resistance (-1,053 +/- 247 vs -363 +/- 83 dynes s cm-5, p less than 0.01) than in patients with normal LV stress. Decreased LV stress was caused by decreased systolic and diastolic pressures and/or volumes. Late systolic pressure-volume relations in patients with normal LV stress suggested increased myocardial contractility, but this was not confirmed by LV dP/dt. Hydralazine improves LV function in patients with dilated cardiomyopathy by reducing elevated LV wall stress, with little inotropic effect.