Donald V. Unverferth

Factors influencing the one-year mortality of dilated cardiomyopathy

This study was designed to determine prognostic risk indicators of nonischemic dilated cardiomyopathy (DC). Sixty-nine patients were studied. Each patient underwent physical examination (including a history), electrocardiography, echocardiography, cardiac catheterization, 24-hour monitoring and endomyocardial biopsy. The mortality rate at 1 year was 35% (24 deaths). Univariate analysis revealed that the most powerful predictor of prognosis was the left intraventricular conduction delay (p = 0.003). The pulmonary capillary wedge pressure was also predictive of mortality (p = 0.005). Other significant factors, in order of importance, were ventricular arrhythmias (p = 0.007), mean right atrial pressure (p = 0.008), angiographic ejection fraction (p = 0.03), atrial fibrillation or flutter (p = 0.01) and the presence of an S3 gallop (p = 0.05). Factors such as duration of symptoms, presence of mitral regurgitation, end-diastolic diameter, myocardial cell size and percent fibrosis in the biopsy and treatment with vasodilators, antiarrhythmic and anticoagulant drugs were not significant predictors. Multivariate analysis was used to determine which combination of factors could most accurately predict survival and death. The most important factors were left conduction delay, ventricular arrhythmias and mean right atrial pressure. An equation was derived that can be applied to the prognosis of patients with DC. Thus, the clinical assessment of patients with DC can accurately predict the probability of surviving or dying in 1 year.

IMPROVED EXERCISE CAPACITY AND DIFFERING ARTERIAL AND VENOUS TOLERANCE DURING CHRONIC ISOSORBIDE DINITRATE THERAPY FOR CONGESTIVE HEART FAILURE

We studied 30 patients with moderate-to-severe congestive heart failure in a double-blind, randomized, placebo-controlled trial to determine the acute and long-term effects of isosorbide dinitrate on clinical status and on resting and exercise hemodynamics. Seventeen patients received placebo and 13 isosorbide dinitrate. First-dose isosorbide dinitrate (40 mg orally) decreased resting and exercise pulmonary capillary wedge pressure, pulmonic and systemic arterial pressures and pulmonic and systemic vascular resistances without augmenting exercise capacity. Compared with placebo, chronic therapy with isosorbide dinitrate (40 mg orally every 6 hours for 12 weeks) significantly improved clinical status and exercise capacity. Resting and exercise systemic blood pressure and systemic vascular resistance returned to baseline values during chronic isosorbide dinitrate therapy, but pulmonary capillary wedge pressure, pulmonary artery pressure and pulmonary vascular resistance remained improved. In patients with congestive heart failure, 12 weeks of oral isosorbide dinitrate therapy improves resting and exercise hemodynamics, exercise capacity, and clinical status; tolerance develops to the systemic arterial vascular effects without attenuation of the venous and pulmonary vascular effects.

Tolerance to dobutamine after a 72 hour continuous infusion

Abstract In this study we investigated the hemodynamic effects of dobutamine during short-term (2 hour) and long-term (four day) infusions. The heart rate, blood pressure, cardiac output, pulmonary capillary wedge pressure and systolic time intervals were determined at baseline and then at 30 minute intervals up to 120 minutes after the commencement of intravenous dobutamine therapy in nine patients. The same parameters were measured in 14 patients at 2, 24, 48, 72 and 96 hours. The percent change of the hemodynamic measurements over baseline was evaluated relative to the plasma dobutamine level. There was no attenuation of hemodynamic effect in the first 2 hours of dobutamine therapy. Tolerance did develop during the long-term infusion and this was statistically significant at 72 and 96 hours in measurements of the cardiac output, systolic time intervals and heart rate. The hemodynamic response at 72 hours was 66 percent of that noted at 2 hours; the hemodynamic response at 96 hours was 57 percent of that at 2 hours. This study demonstrated that significant hemodynamic tolerance to dobutamine develops after three days of continuous infusion. We suggest that the most appropriate manner of dealing with this attenuation of effect is simply to increase the dose until the desired hemodynamic effect is attained.

Relationship between central hemodynamics and regional blood flow in normal subjects and in patients with congestive heart failure.

Central and regional (hepatic, renal, and limb) hemodynamic data are presented for a normal population (n = 16) and for a group of patients with congestive heart failure (n = 64). The patient population represented a wide spectrum of severity of congestive heart failure. Various relationships between central and regional hemodynamics were analyzed. The results indicate that in congestive heart failure blood flow to hepatic, renal, and limb regions is significantly decreased, and that this decrease is proportional and linearly related to the reduction in cardiac output. The vascular resistances of these regions correlated directly with systemic vascular resistance. Changes in renal vascular resistance and renal blood flow became attenuated as the severity of the heart failure advanced from moderate to severe and at higher levels of systemic vascular resistance. There was little to no correlation between systemic blood pressure and liver, kidney, and limb blood flow for the range of systemic pressures studied.

Extent of myocardial fibrosis and cellular hypertrophy in dilated cardiomyopathy

The distribution of fibrosis and cellular hypertrophy was studied in the hearts of patients with dilated cardiomyopathy (DC). Transmural sections were removed from the left and right ventricular free walls and the ventricular septum of 9 patients with heart failure and 6 control subjects. These sections were stained with hematoxylin-eosin (to determine cell size) and trichrome (to determine percent fibrosis). The sections were separated into equal areas from epicardium to endocardium in the free walls and right to left across the septum. Percent fibrosis was greater in patients with DC (20 +/- 4%) than control subjects (4 +/- 1%, p = 0.0001). A pattern of increasing fibrosis in the left ventricular free wall from epicardium (14 +/- 6%) to endocardium (22 +/- 9%, p less than 0.05) was documented. Fibrosis was greater on the left (21 +/- 12%) than the right (15 +/- 6%, p less than 0.05) side of the septum. No pattern was evident in the right ventricular free wall or in the control group. Myocardial cell diameter was greater in the heart failure group (22 +/- 5 micron) than the control group (17 +/- 2 micron, p less than 0.05), but no pattern of hypertrophy across the walls was seen. The increased fibrosis, the pattern of fibrosis and the increased cell diameter in patients with DC help to characterize DC.

Drugs Five Years Later: Dobutamine

Dobutamine is a synthetic catecholamine developed as a relatively selective positive inotropic drug for short-term parenteral administration. Dobutamines effects are mediated by strong beta 1 adrenergic receptor stimulation and mild stimulation of beta 2 and alpha 1 receptors. Dobutamine should be used to improve ventricular function and cardiac performance in patients in whom ventricular dysfunction has caused a reduced stroke volume and cardiac output, a mild to moderate drop in systemic blood pressure, diminished organ and tissue perfusion, and elevated ventricular filling pressures. When guidelines for patient selection and dosing are adhered to, ventricular dysfunction and cardiac decompensation secondary to atherosclerotic occlusive coronary artery disease can be improved without adversely affecting the myocardial oxygen supply and demand balance. Dobutamine has less vasopressor activity than norepinephrine and dopamine, and should not be the primary treatment in conditions characterized by marked hypotension and shock.

Drug-induced conditioning in congestive heart failure.

Continuous 72-hour infusions of dobutamine reportedly effect sustained clinical improvement in patients with congestive heart failure. This study was designed to determine if shorter, more frequent infusions, delivered in an outpatient setting, elicit a similar response. Twenty-six patients with moderately severe congestive heart failure were randomized, 11 into a control group and 15 into a dobutamine treatment group. Baseline data were collected for 4 weeks in each group. Thereafter, the dobutamine treatment group received 4-hour infusions of dobutamine weekly for 24 weeks. Systolic time intervals, echocardiography, cardiac index and treadmill exercise tolerance were used to follow the progress of the control and dobutamine treatment groups. The ratio of preejection period to left ventricular ejection time and the cardiac index did not change significantly in either group. The velocity of circumferential fiber shortening and the percent change in the minor axis of the left ventricle during systole improved modestly (p less than 0.05) above baseline in the dobutamine group after 14 weeks of treatment and above the corresponding control values (p less than 0.05) after 22 weeks. Exercise tolerance (duration) improved 25--51% (all p less than 0.05) above baseline in the dobutamine group compared with 10--17% (all p greater than 0.05 vs baseline) in the control group. Heart rate at maximal exercise did not change significantly from baseline for either group and did not differ significantly between the two groups. Functional classification improved in 12 of 15 dobutamine treatment patients and in only two of 11 control patients (p less than 0.05). In our patients with congestive heart failure, weekly 4-hour dobutamine infusions did not elicit a major change in resting left ventricular function; however, exercise performance and clinical status improved considerably.

Long-term benefit of dobutamine in patients with congestive cardiomyopathy☆

Dobutamine was given intravenously for three days to 38 patients with congestive cardiomyopathy. The patients were followed by serial determinations of functional class and by non-invasive measurements of left ventricular function-systolic time intervals (PEP/LVET) and echocardiogram (% delta D). The average PEP/LVET declined significantly (p < 0.001) at three days, four and nine weeks, and at 10 months after the discontinuation of dobutamine infusion. Also, 67% (20 of 30) of patients had improvement of the PEP/LVET by greater than -0.04 at seven days. Even two and six months after dobutamine, 58% (15 of 26) and 39% (seven of 18) were improved. Similarly, the % delta D was improved by at least 2% in 60% (18 of 30) at seven days and 55% (16 of 29) at four weeks. At two and six months, 50% (14 of 28) and 42% (10 of 24) were improved. Those patients who did not improve their FC were more likely (five of nine) to have left ventricular free wall thickness (by echocardiogram) less than 0.5 cm./M2. Those who responded usually (22 of 29) had a ventricular wall thickness greater than 0.5 cm./M2. Although the mechanism of the prolonged improvement after a three day infusion of dobutamine is not understood, this study suggests that dobutamine has a role in the therapy of chronic congestive heart failure.

Human myocardial histologic characteristics in congestive heart failure.

The purpose of this study was to identify the histologic characteristics of human myocardium in congestive heart failure (CHF) by cellular hypertrophy, nuclear area, endocardial thickness, and percentage of fibrosis and to correlate histologic findings to cause, severity, and duration of disease. Right ventricular endomyocardial biopsies from 109 patients were quantitatively analyzed. Ten patients with normal cardiac history, physical examination results, and cardiac function served as the control group. The remaining patients were divided into the following groups: those treated with doxorubicin (n = 18), and those with chest pain with normal coronary arteries (n = 8), familial CHF (n = 3), CHF associated with myotonic dystrophy (n = 3), peripartal CHF (n = 2), valvular CHF (n = 9), alcohol-induced CHF (n = 13), postviral CHF (n = 6), or idiopathic CHF (n = 36). Linear regression analyses showed a strong correlation between cell diameter and nuclear area (r = .70, p less than .001) and weaker correlations between amount of fibrosis and cell diameter (r = .30, p less than .005) and fibrosis and nuclear area (r = .29, p less than .005). Results of function studies and histologic measurements (e.g., echocardiographically measured change in the minor-axis dimension of the left ventricle with systole and cell diameter) correlated poorly (r = -.33, p less than .005). Duration of dyspnea did not correlate with any histologic factor. Within the normal group there was a direct correlation of cell diameter with age (r = .67, p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Histologic and biochemical correlates of left ventricular chamber dynamics in man

To investigate the relation between left ventricular chamber dynamics in humans and the quantitative analysis of the histologic and biochemical characteristics of left ventricular endomyocardial biopsy material, 15 patients with a wide range of ventricular function were studied. The pressure-volume relation was determined using simultaneous gated radionuclide angiography, echocardiography and micromanometer pressure. The derived chamber dynamics were then compared with quantitative histologic data (percent fibrosis and cell diameter) and adenosine triphosphate content measurements obtained from the left ventricular biopsy specimen obtained at the time of the pressure-volume studies. The measures of systolic function correlated linearly with high energy phosphate content. The adenosine triphosphate/protein ratio (nanomoles) was shown to parallel ejection fraction (r = 0.81), peak ejection rate (r = -0.73) and peak positive maximal rate of rise in left ventricular pressure (dP/dt) (r = 0.79). No correlation was observed between these variables and the percent fibrosis or cell diameter. Variable results were found in comparing the diastolic properties of the left ventricle with the biopsy data. In general, the high energy phosphate content correlated with measures of active relaxation, but not with the passive filling characteristics of the left ventricle. The adenosine triphosphate/protein ratio was linearly related to peak negative dP/dt (r = -0.74) and the peak filling rate (r = 0.76) but correlated less well with other measures of active and passive diastolic filling. No correlation was found between any diastolic variable and the percent fibrosis or cell diameter.(ABSTRACT TRUNCATED AT 250 WORDS)