William J. Bommer

Effect of Oral Milrinone on Mortality in Severe Chronic Heart Failure

BACKGROUND Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP, but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined. METHODS We randomly assigned 1,088 patients with severe chronic heart failure (New York Heart Association class III or IV) and advanced left ventricular dysfunction to double-blind treatment with (40 mg of oral milrinone daily (561 patients) or placebo (527 patients). In addition, all patients received conventional therapy with digoxin, diuretics, and a converting-enzyme inhibitor throughout the trial. The median period of follow-up was 6.1 months (range, 1 day to 20 months). RESULTS As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent confidence interval, 6 to 69 percent; P = 0.016). The adverse effect of milrinone was greatest in patients with the most severe symptoms (New York Heart Association class IV), who had a 53 percent increase in mortality (95 percent confidence interval, 13 to 107 percent; P = 0.006). Milrinone did not have a beneficial effect on the survival of any subgroup. Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P = 0.006) and syncope (P = 0.002), more often than the patients given placebo. CONCLUSIONS Our findings indicate that despite its beneficial hemodynamic actions, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure. The mechanism by which the drug exerts its deleterious effects is unknown.

M-Mode echocardiographic predictors of six- to seven-year incidence of coronary heart disease, stroke, congestive heart failure, and mortality in an elderly cohort (the cardiovascular health study)

Previous studies have identified a number of echocardiographic variables that predict cardiovascular disease (CVD) events and mortality, but have not focused on a large elderly cohort. The purpose of this study was to determine whether M-mode echocardiographic variables predicted all-cause mortality, incident coronary heart disease (CHD), congestive heart failure (CHF), and stroke in a large prospective, multicenter, population-based study. In the Cardiovascular Health Study, a biracial cohort of 5,888 men and women (mean age 73 years) underwent 2-dimensional M-mode echocardiographic measurements of left ventricular (LV) internal dimensions, wall thickness, mass and geometry, as well as measurement of left atrial dimension and assessment for mitral annular calcium. Participants were followed for 6 to 7 years for incident events; analyses excluded subjects with prevalent disease. One or more echocardiographic measurements were independent predictors of all-cause mortality and incident CHD, CHF, and stroke. After adjustment for anthropometric and traditional CVD risk factors, LV mass was significantly related to incident CHD, CHF, and stroke. The highest quartile of LV mass conferred a hazards ratio of 3.36, compared with the lowest quartile, for incident CHF. Furthermore, incident CHF-free survival was significantly lower for participants with LV mass in the highest versus the 2 lowest quartiles (86% vs 97%, respectively, at 2,500 days). Eccentric and concentric LV hypertrophy, respectively, conferred adjusted hazards ratios, compared with normal LV geometry, of 2.05 and 1.61 for incident CHD, and 2.95 and 3.32 for incident CHF. Thus, in an elderly biracial population, selected 2-dimensional M-mode echocardiographic measurements were important markers of subclinical disease and conferred independent prognostic information for incident CVD events, especially CHF and CHD.

Sex, Age, and Disease Affect Echocardiographic Left Ventricular Mass and Systolic Function in the Free-Living Elderly The Cardiovascular Health Study

BACKGROUND Left ventricular (LV) hypertrophy, as measured by M-mode echocardiography, is an independent predictor of mortality and/or morbidity from coronary heart disease (CHD). LV global and segmental systolic dysfunction also have been associated with myocardial ischemia and cardiovascular morbidity and mortality. Echocardiographic data, especially two-dimensional, have not been available previously from multicenter-based studies of the elderly. This report describes the distribution and relation at baseline of echocardiographic LV mass and global and segmental LV wall motion to age, sex, and clinical disease category in the Cardiovascular Health Study (CHS), a cohort of 5201 men and women (4850 white) 65 years of age and older. METHODS AND RESULTS M-mode LV mass adjusted for body weight increased modestly with age (P < .0001), increasing less than one gram per year increase in age for both men and women. After adjustment for weight, LV mass was significantly greater in men than in women and in participants with clinical CHD compared with participants with neither clinical heart disease nor hypertension (both P < .001). Across all CHS age subgroups, the difference in weight-adjusted LV mass by sex was greater in magnitude than the difference related to clinical CHD. M-mode measurements of LV mass could not be made in 34% of CHS participants, and this was highly related to age (29% in the 65 to 69 year versus 50% in the 85+ year age group, P < .001) and other risk factors. In participants with clinical CHD and with neither clinical heart disease nor hypertension, LV ejection fraction and segmental wall motion abnormalities were more prevalent in men than women (all P < .001). Of interest, 0.5% of men and 0.4% of women with neither clinical heart disease nor hypertension had LV segmental wall motion abnormalities, suggesting silent disease, compared with 26% of men and 10% of women in the clinical CHD group (P < .0001). Multivariate analyses revealed male sex and presence of clinical CHD (both P < .001) to be independent predictors of LV akinesis or dyskinesis. CONCLUSIONS Significant baseline relations were detected between differences in sex, prevalent disease status, and echocardiographic measurements of LV mass and systolic function in the CHS cohort. Age was weakly associated with LV mass measurements and LV ejection fraction abnormalities. These relations should be considered in evaluating the preclinical and clinical effects of CHD risk factors in the elderly.

Echocardiographic design of a multicenter investigation of free-living elderly subjects: the Cardiovascular Health Study.

The Framingham study has shown by M-mode echocardiography that left ventricular hypertrophy is a powerful, independent predictor for the development of coronary heart disease and that increased left atrial dimension has been associated with an increased risk of stroke. No previous population-based study has evaluated the risk factor correlates and predictive value for coronary heart disease and stroke of two-dimensional and Doppler, as well as M-mode, echocardiography. The Cardiovascular Health Study is a multi-year prospective epidemiologic study of 5201 men and women older than 65 recruited from four geographic sites in the United States. The main objectives of incorporating echocardiography were to determine whether echocardiographic indices, or changes in these indices, are (1) correlated with traditional risk factors for coronary heart disease and stroke; and (2) independent predictors of morbidity and mortality for coronary heart disease and stroke. Echocardiographic measurements of interest include those related to global and segmental left ventricular systolic and diastolic structure and function and left atrial size. For each subject, a baseline echocardiogram was recorded in super-VHS tape using a standard protocol and equipment. All studies were sent to a reading center where images were digitized and measurements were made using customized computer algorithms. Calculated data and images were stored on optical disks to facilitate retrieval and future comparisons in longitudinal studies. A second echocardiogram is scheduled in year 7, with a goal of determining whether changes in cardiac anatomy or function over a 5-year period are important predictors of morbidity or mortality from coronary heart disease and stroke. Quality control measures included standardized training of echocardiography technicians and readers, technician observation by a trained echocardiographer, periodic blind duplicate readings with reader review sessions, phantom studies, and quality control adults.

Accuracy of echocardiography versus electrocardiography in detecting left ventricular hypertrophy: Comparison with postmortem mass measurements

The accuracy of electrocardiography, M-mode echocardiography and two-dimensional echocardiography in predicting left ventricular hypertrophy was compared in 50 patients who came to autopsy within 6 months after the studies were performed. Several methods for determining left ventricular hypertrophy were examined for each of the three techniques. M-mode echocardiography was technically adequate to evaluate the presence or absence of left ventricular hypertrophy more often than either electrocardiography or two-dimensional echocardiography. Measurements from M-mode echocardiography also correlated best with autopsy measurements. Both echocardiographic techniques had a higher sensitivity than electrocardiographic criteria in diagnosing left ventricular hypertrophy. Two-dimensional echocardiography was not shown to improve the M-mode assessment of left ventricular hypertrophy. In an attempt to simplify both M-mode left ventricular mass calculations and the diagnosis of left ventricular hypertrophy for the clinician, a left ventricular mass nomogram was constructed, enabling quick insertion of standard M-mode echocardiographic measurements.

Left Ventricular Thrombi Identified by Cross-Sectional Echocardiography

We studied 25 patients with anterior myocardial infarction and two with congestive cardiomyopathy to evaluate two-dimensional echocardiography in the diagnosis of left ventricular thrombi. Five coronary patients had systemic emboli. Four of these patients manifested apical filling defects on cineangiogram, while a levophase cine was equivocal for clot in the fifth patient. Neither echocardiography nor cineangiography visualized ventricular thrombi in the nonembolus coronary patients. Echoes from a distinct apical mass, however, were visualized in all five patients in the embolus group by two-dimensional echocardiography at the cardiac apex. Apical thrombi were confirmed in all four patients in the embolus group undergoing surgery. The irregular configuration of recent thrombi in the coronary patients differed from the circumscribed appearance of chronic thrombi in the cardiomyopathy patients on two-dimensional echocardiogram. Thus, two-dimensional echocardiography can be used to detect and characterize left ventricular thrombi.

The safety of contrast echocardiography: Report of the committee on contrast echocardiography for the American Society of Echocardiography

The results of a survey of 363 physicians performing echocardiography were evaluated to assess the relative safety of contrast echocardiography. Fifteen physicians reported a variety of transient side effects, including neurologic and respiratory symptoms. Although contrast echocardiography appeared to carry some risk for side effects, that risk was low (0.062%) and no residual side effects or complications were observed. In view of the significant benefits reported for contrast echocardiography, it appears to remain a valuable technique that is safer than currently available alternative diagnostic modalities. However, during contrast echocardiography, precautions should be taken to prevent the injection of visible amounts of air, especially in patients with a right to left shunt or arterial catheters.

Hemodynamic assessment of oral peripheral vasodilator therapy in chronic congestive heart failure: prolonged effectiveness of isosorbide dinitrate.

To evaluate the effectiveness of oral vasodilator therapy in chronic congestive heart failure, 20 mg of isosorbide dinitrate or placebo was administered orally in double-blind fashion to 25 patients with congestive heart failure. In 15 patients receiving isosorbide dinitrate, pulmonary arterial wedge pressure decreased 5 minutes to 5 hours after drug administration; the peak reduction was observed at 1 hour (from 23 to 14 mm Hg; P less than 0.001). Wedge pressure decreased to normal (12 mm Hg or less) in 8 of the 15 patients (Group I) but remained greater than 12 mm Hg in 7 (Group II). Reductions in mean systemic arterial pressure, systemic vascular resistance and pressure-time per minute also occurred. Indexes of pump output were unchanged in the 15 who received isosorbide dinitrate but tended to decrease slightly in Group I. Stroke index (from 23 to 26 cc/m2) and stroke work index (from 21.4 to 24.1 g-m/m2) increased slightly but significantly (P less than 0.05) in Group II. Thus the prinicpal hemodynamic action of isorbide dinitrate is marked and sustained reduction in left ventricular filling pressure without pronounced effect on cardiac output. This agent should be used in congestive heart failure primarily for relief of congestive symptoms.

Value and limitations of cross-sectional echocardiography of the aortic valve in the diagnosis and quantification of valvular aortic stenosis.

Few data are available regarding cross-sectional echocardiography (2-D) in the diagnosis and quantification of valvular aortic stenosis. Therefore, we compared echographic measurements obtained by 2-D echo with aortic gradient and aortic valve area and index calculated by the Gorlin formula in 20 normal subjects and 85 patients with clinical evidence of aortic stenosis. Technically adequate echograms were obtained in 72 patients (85%). Forty-six patients with satisfactory echograms were classified as having critical aortic stenosis, while 26 were designated as having noncritical obstruction. Aortic leaflet separation (SEP) was measured as the maximal intercusp distance visualized in either long, apical or short axis of the 2-D echo. SEP was less in critical aortic stenosis patients than in normal subjects and those with noncritical aortic stenosis (4.6 ± 0.4, 19.4 ± 0.5, and 10.0 ± 0.8 mm, respectively [mean ± SEMI [both p < 0.0011) and was greater than 15 mm in all normal subjects and 11 mm or less in all patients in the critical group. SEP correlated poorly with peak systolic gradient and calculated aortic valve area and index in aortic stenosis patients. Forty-two of 46 patients in the critical group had SEP of 8 mm or less, yielding a sensitivity of 91%. However, only 17 of 26 patients with noncritical aortic stenosis had a SEP of greater than 8 mm, for a specificity of 65%. Therefore, the predictive value of SEP 8 mm or less on 2-D echo in the recognition of critical aortic stenosis was 82%. Two-dimensional echocardiography is a sensitive method to detect valvular aortic stenosis, and accurately separates patients with aortic stenosis from normal subjects. However, the specificity of 2-D echo in distinguishing critical from noncritical aortic stenosis is limited.

Identification and localization of aneurysms of the ascending aorta by cross-sectional echocardiography.

Although the ascending aorta may be readily examined by cross-sectional echocardiography (2-D), no data are available regarding the ability of 2-D to detect and localize aneurysms of this structure. Therefore, we compared M-mode and 2-D echograms to cineangiograms of the aorta in 32 normal subjects and 12 patients with aortic aneurysms. Measurement of aortic width was performed in the longitudinal axis just above the sinus of Valsalva in normal subjects and at the point of maximal aortic width in aneurysm patients. A good correlation (r = 0.88) was observed between M-mode and angiographic measurements of aortic diameter for all subjects. However, M-mode and angiographic values of aortic diameter correlated less well (r = 0.55) in patients with aortic aneurysms. Values for aortic size by cineangiogram and 2-D were similar for both normal subjects (mean 34 and 33 mm, respectively) and aneurysm patients (62 and 65 mm, respectively). There was an excellent correlation (r = 0.94) between cineangiogram and 2-D for all patients evaluated, and for patients with aneurysms (r = 0.91). By 2-D we detected enlargement of the aorta in all 12 aneurysm patients, and mean aortic size by 2-D was greater (63 mm) than in normal subjects (33 mm) (p>0.001). The site and nature of aneurysm was accurately identified by 2-D in all patients. Thus, 2-D provides an accurate noninvasive modality for the detection and localization of aneurysms of ascending aorta.