Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside.

Milrinone is a potent positive inotropic and vascular smooth muscle-relaxing agent in vitro, and therefore, it is not known to what extent each of these actions contributes to the drug's hemodynamic effects in patients with heart failure. In 11 patients with New York Heart Association class III or IV congestive heart failure, incremental intravenous doses of milrinone were administered to determine the dose-response relationships for heart rate, systemic vascular resistance, and inotropic state, the latter measured by peak positive left ventricular derivative of pressure with respect to time (dP/dt). To clarify further the role of a positive inotropic action, the relative effects of milrinone and nitroprusside on left ventricular stroke work and dP/dt were compared in each patient at doses matched to cause equivalent reductions in mean arterial pressure or systemic vascular resistance, indices of left ventricular afterload. Milrinone caused heart rate, stroke volume, and dP/dt to increase, and systemic vascular resistance to decrease in a concentration-related manner. At the two lowest milrinone doses resulting in serum concentrations of 63 +/- 4 and 156 +/- 5 ng/ml, respectively, milrinone caused significant increases in stroke volume and dP/dt, but no changes in systemic vascular resistance or heart rate. At the maximum milrinone dose administered (mean serum concentration, 427 +/- 11 ng/ml), heart rate increased from 92 +/- 4 to 99 +/- 4 bpm (P less than 0.01), mean aortic pressure fell from 82 +/- 3 to 71 +/- 3 mmHg (P less than 0.01), right atrial pressure fell from 15 +/- 2 to 7 +/- 1 mmHg (P less than 0.005), left ventricular end-diastolic pressure fell from 26 +/- 3 to 18 +/- 3 (P less than 0.005), stroke volume index increased from 20 +/- 2 to 30 +/- 2 ml/m2 (P less than 0.005), stroke work index increased from 14 +/- 2 to 21 +/- 2 g X m/m2 (P less than 0.01), and dP/dt increased from 858 +/- 54 to 1,130 +/- 108 mmHg/s (P less than 0.005). When compared with nitroprusside for a matched reduction in mean aortic pressure or systemic vascular resistance, milrinone caused a significantly greater increase in stroke work index at the same or lower left ventricular end-diastolic pressure. Milrinone caused a concentration-related increase in dP/dt (32% increase at maximum milrinone dose), whereas nitroprusside had no effect. These data in patients with severe heart failure indicate that in addition to a vasodilating effect, milrinone exerts a concentration-related positive inotropic action that contributes significantly to the drug's overall hemodynamic effects. The positive inotropic action occurs at drug levels that do not exert significant chronotropic or vasodilator effects.

Early diastolic left ventricular function in children and adults with aortic stenosis.

Pressure overload hypertrophy of the left ventricle is associated with abnormal left ventricular early diastolic filling. The roles of the extent of cardiac hypertrophy, depressed left ventricular systolic function and aging in the pathogenesis of left ventricular diastolic dysfunction have not, however, been fully defined. To determine the relative importance of these factors in the pathogenesis of diastolic dysfunction in pressure overload hypertrophy, 16 children and 25 adults with aortic stenosis were compared with 48 normal children and adults, using rates of left ventricular early diastolic filling and wall thinning derived from M-mode echocardiography. Left ventricular early diastolic filling and wall thinning rates were significantly depressed in both children and adults with aortic stenosis as compared with values in normal subjects. Filling and thinning rates correlated negatively with age, left ventricular peak systolic pressure and wall thickness in all subjects. Furthermore, the effect of age on diastolic function appeared to be mediated by age-related increases in systolic pressure and wall thickness. In adults with aortic stenosis, early diastolic filling and wall thinning rates were depressed to a similar extent in subjects with normal and abnormal systolic function; thus, diastolic dysfunction does not appear to be a manifestation of abnormal systolic loading and ejection performance. These results suggest that extent of hypertrophy itself plays a dominant role in the mechanism of impaired left ventricular early diastolic filling in pressure overload due to aortic stenosis.

Preload dependence of Doppler-derived indexes of left ventricular diastolic function in humans.

To determine the effect of filling pressure on the pattern of left ventricular filling in humans, the mitral flow velocity profile was measured by pulsed wave Doppler echocardiography during right and left heart catheterization in 11 patients before and during nitroglycerin infusion. Nitroglycerin reduced mean arterial pressure from 90 +/- 9 to 80 +/- 11 mm Hg (p less than 0.001) and mean pulmonary capillary wedge pressure from 9 +/- 4 to 4 +/- 2 mm Hg (p less than 0.001). Cardiac output fell from 6.6 +/- 1.5 to 5.5 +/- 1.4 liters/min (p less than 0.001) and heart rate increased from 60 +/- 13 to 65 +/- 14 beats/min (p less than 0.002). The time constant of isovolumic relaxation (TI.) decreased from 51 +/- 9 to 46 +/- 8 ms (p less than 0.01), indicating faster left ventricular relaxation. Nitroglycerin altered the Doppler characteristics of the early filling (E) wave but not those of the atrial contraction (A) wave. Peak velocity of the E wave decreased from 56 +/- 14 to 44 +/- 9 cm/s (p less than 0.001), peak velocity of the A wave did not change and the ratio of peak velocities of the E and A waves decreased from 0.97 +/- 0.33 to 0.77 +/- 0.20 (p less than 0.02). The deceleration of the E wave decreased from 289 +/- 138 to 186 +/- 71 cm/s2 (p less than 0.02). The ratio of velocity-time integral of the A wave to total velocity-time integral (that is, contribution of atrial contraction to total filling) increased from 0.31 +/- 0.09 to 0.36 +/- 0.08 (p less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Differentiation of restrictive cardiomyopathy from pericardial constriction: assessment of diastolic function by radionuclide angiography.

Diastolic filling variables were studied in 12 patients with the hemodynamic features of constriction, of whom 5 had restrictive cardiomyopathy, 5 had pericardial constriction and 2 had combined pericardial constriction and restrictive cardiomyopathy. The values were compared with those in 10 normal subjects of comparable age. The filling fractions between 10% and 70% of the diastolic time interval were greater in patients with pericardial constriction than in those with restrictive cardiomyopathy (p less than 0.01 between 20% and 50%, p less than 0.05 at 10%, 60% and 70%), with no overlap. The filling fractions in patients with pericardial constriction were also greater than those in normal subjects between 10% and 60% of the diastolic time interval. The filling fraction was lower in patients with restrictive cardiomyopathy than in normal subjects at 40% of the diastolic time interval (p less than 0.05). The time to peak filling rate in patients with pericardial constriction was shorter (110 +/- 14 ms) than in those with restrictive cardiomyopathy (195 +/- 45 ms, p less than 0.01) or in normal subjects (173 +/- 32 ms, p less than 0.01). The percent of atrial contribution to left ventricular filling was higher in those with restrictive cardiomyopathy (45 +/- 17%) than in those with pericardial constriction (21 +/- 6%, p less than 0.05) or in normal subjects (24 +/- 9%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Positive inotropic and lusitropic effects of intravenous flosequinan in patients with heart failure.

OBJECTIVES: This study was designed to assess the direct effects of flosequinan on myocardial function. BACKGROUND: Flosequinan has been shown to improve symptoms and exercise tolerance in patients with heart failure. Although previous studies have established that flosequinan is a vasodilator, it is not known to what extent direct actions of the drug on myocardial contractility or diastolic properties contribute to its beneficial hemodynamic effects. METHODS: Nitroprusside and intravenous flosequinan were administered sequentially to 18 patients with severe heart failure (New York Heart Association functional class III or IV, left ventricular ejection fraction 0.14 +/- 0.02). Micromanometer left ventricular pressure and radionuclide volume data were combined to construct pressure-volume loops during 1) a baseline period, 2) nitroprusside infusion, 3) a second baseline period, and 4) flosequinan infusion. RESULTS: The peak rate of left ventricular pressure development increased from 899 +/- 84 to 1,070 +/- 94 mm Hg/s (p less than 0.05) with flosequinan. The baseline left ventricular end-systolic pressure-volume relation was constructed in 15 patients from the two baseline pressure-volume loops and from that obtained during afterload manipulation with nitroprusside. During flosequinan administration, the relation between end-systolic pressure and volume was shifted upward and leftward, indicating enhanced contractility, in 14 of 15 patients (p less than 0.001). The maximal rate of decrease in left ventricular pressure during isovolumetric relaxation increased in magnitude with flosequinan from 882 +/- 63 to 1,026 +/- 68 mm Hg/s (p less than 0.05). CONCLUSIONS: These results indicate that intravenous flosequinan has positive inotropic and lusitropic effects in patients with heart failure. Further studies are needed to assess the direct myocardial effects of oral flosequinan.

Inotropic, vascular and neuroendocrine effects of nifedipine in heart failure: comparison with nitroprusside.

To evaluate the short-term hemodynamic and neuroendocrine effects of nifedipine in heart failure, it was compared with nitroprusside, a balanced vasodilator without known inotropic effect, in equihypotensive doses during right and left heart catheterization in nine patients with heart failure. Mean arterial pressure decreased from 89 +/- 12 to 76 +/- 14 mm Hg with nitroprusside, and from 90 +/- 12 to 75 +/- 13 mm Hg with sublingual nifedipine. Right atrial, pulmonary artery, pulmonary capillary wedge and left ventricular end-diastolic pressures decreased significantly with nitroprusside, but not with nifedipine. Cardiac index and stroke volume index increased to a similar extent with both drugs; in contrast, stroke work index increased significantly with nitroprusside, but not with nifedipine. Peak rate of left ventricular pressure development (dP/dt) (measured with a micromanometer-tipped catheter in seven patients) was unchanged with nitroprusside, but decreased significantly with nifedipine (747 +/- 292 to 639 +/- 238 mm Hg/s; p less than 0.002). There was no change in heart rate with either medication. Plasma norepinephrine and epinephrine concentrations were not altered significantly by either drug. Plasma renin activity was not changed by nitroprusside infusion, but was increased after the administration of nifedipine. Thus, in contrast to the balanced vasodilator action of nitroprusside, the effect of nifedipine is predominantly on the arterial circulation. In these patients with heart failure, reflex sympathetic stimulation did not occur in response to a decrease in systemic arterial pressure by either vasodilator. A negative inotropic effect occurred after the administration of nifedipine, but not nitroprusside.

Inotropic effect of enoximone in patients with severe heart failure: demonstration by left ventricular end-systolic pressure-volume analysis.

Left ventricular end-systolic pressure-volume analysis was employed to assess the inotropic effect of the phosphodiesterase inhibitor enoximone (formerly MDL-17,043) in nine patients with severe heart failure (New York Heart Association class IV symptoms, mean ejection fraction = 0.22). Left ventricular pressure-volume loops were constructed using high fidelity left ventricular pressure measured with micromanometer-tipped catheters and simultaneous left ventricular volume obtained by gated blood pool imaging. Afterload was reduced with the vasodilator nitroprusside to generate the baseline left ventricular end-systolic pressure-volume relation, a relatively load-independent measure of contractile function. The intravenous administration of enoximone (mean dose 75 mg) shifted the end-systolic pressure-volume point upward and leftward from the baseline pressure-volume relation in eight of the nine patients, demonstrating a positive inotropic effect of this agent. The maximal rate of left ventricular pressure development (peak positive dP/dt) increased from 1,030 +/- 142 to 1,381 +/- 219 mm Hg/s (p less than 0.01) on enoximone despite a significant decrease in preload (as assessed by left ventricular end-diastolic pressure and volume) and a small, insignificant decrease in mean arterial pressure. Two patients developed angina after enoximone administration; both patients had coronary artery disease and experienced a greater than 30% increase in heart rate-systolic blood pressure product. Thus, enoximone has a significant inotropic effect in patients with severe heart failure. Like other inotropic drugs, it has the potential to increase myocardial oxygen demand and thereby precipitate ischemia.

Inotropic effect of nicardipine in patients with heart failure: assessment by left ventricular end-systolic pressure-volume analysis.

Nicardipine, a new dihydropyridine calcium channel blocker, has been investigated for the treatment of coronary artery disease and heart failure. To assess the inotropic effect of nicardipine in humans independent of its vasodilator effect, equihypotensive doses of intravenous nitroprusside (mean infusion rate 65 +/- 13 micrograms/min) and nicardipine (mean dose 5.2 +/- 0.4 mg) were administered to 15 patients with heart failure (New York Heart Association functional classes II to IV, radionuclide left ventricular ejection fraction 0.15 +/- 0.02). Left ventricular micromanometer pressure and simultaneous radionuclide left ventricular volume were obtained at baseline, during nitroprusside infusion, during a second baseline period and during nicardipine infusion. Heart rate did not change significantly with either nitroprusside or nicardipine. Mean systemic arterial pressure decreased by an average of 21 mm Hg with both drugs. A greater decrease in left ventricular end-diastolic pressure occurred with nitroprusside (27 +/- 2 to 14 +/- 2 mm Hg, p less than 0.01) than with nicardipine (27 +/- 2 to 23 +/- 3 mm Hg, p less than 0.05), and pulmonary capillary wedge pressure decreased significantly only with nitroprusside. Cardiac index increased from 1.8 +/- 0.1 to 2.1 +/- 0.1 liters/min per m2 (p less than 0.05) with nitroprusside and to a greater extent from 1.7 +/- 0.1 to 2.4 +/- 0.1 liters/min per m2 (p less than 0.01) with nicardipine. Left ventricular ejection fraction increased with nicardipine (0.15 +/- 0.01 to 0.19 +/- 0.01, p less than 0.01), but not with nitroprusside. Peak positive first derivative of left ventricular pressure (dP/dt) decreased by 9% with both agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Responsiveness of plasma atrial natriuretic factor to short-term changes in left atrial hemodynamics after percutaneous balloon mitral valvuloplasty.

To assess the effect of short-term alteration of left atrial pressure and volume on the circulating plasma level of atrial natriuretic factor, 11 patients with left atrial hypertension due to mitral stenosis were studied at the time of percutaneous balloon mitral valvuloplasty. Hemodynamic measurements and plasma atrial natriuretic factor levels were obtained before, immediately (5 to 10 min) after and 24 h after valvuloplasty, and echocardiographic left atrial size was determined before and 24 h after valvuloplasty. Immediately after valvuloplasty, left atrial pressure decreased from 28 +/- 2 to 10 +/- 1 mm Hg (p less than 0.0005), mitral pressure gradient decreased from 20 +/- 2 to 7 +/- 1 mm Hg (p less than 0.0005), mitral valve area increased from 0.8 +/- 0.1 to 1.9 +/- 0.2 cm2 (p less than 0.0005) and plasma atrial natriuretic factor level rose from 249 +/- 42 to 348 +/- 50 pg/ml (p less than 0.01). This short-term rise in atrial natriuretic factor level may reflect a transient increase in left atrial pressure associated with balloon occlusion of the mitral valve.(ABSTRACT TRUNCATED AT 250 WORDS)

Programmed ventricular stimulation in patients with left ventricular dysfunction and ventricular tachycardia: effects of acute hemodynamic improvement due to nitroprusside.

To assess the electrophysiologic effects of acute hemodynamic improvement in patients with left ventricular systolic dysfunction, 12 patients with a left ventricular ejection fraction less than 0.40 and a history of sustained monomorphic ventricular tachycardia were studied. All patients had underlying coronary artery disease. Patients underwent programmed cardiac stimulation in random order during a baseline period and with nitroprusside infusion. Mean pulmonary capillary wedge pressure decreased from 20 +/- 8 mm Hg at baseline study to 8 +/- 3 mm Hg during nitroprusside infusion (p less than 0.0001). Pulmonary artery, right atrial and systemic arterial pressures also decreased with nitroprusside (p less than 0.01). Cardiac output did not change. Left ventricular dimensions, determined by two-dimensional echocardiography, decreased significantly during nitroprusside infusion. The right ventricular effective refractory period, measured during ventricular drive trains at cycle lengths of 400 and 600 ms, were similar during baseline and nitroprusside periods (271 +/- 30 versus 274 +/- 31 ms at 600 ms, and 249 +/- 25 versus 246 +/- 18 ms at 400 ms). In 2 patients no ventricular arrhythmias were induced during either study period; in the other 10, ventricular tachyarrhythmias were induced during both periods. The mean number of extrastimuli required to induce a ventricular tachyarrhythmia was similar during the baseline period (1.8 +/- 0.6) and during nitroprusside infusion (1.9 +/- 0.7). As well, the mean cycle length of ventricular tachycardia induced was similar during the baseline period (347 +/- 61 ms) and during nitroprusside infusion (342 +/- 70 ms).(ABSTRACT TRUNCATED AT 250 WORDS)

Linearity of the left ventricular end-systolic pressure-volume relation in patients with severe heart failure.

The left ventricular end-systolic pressure-volume relation is a relatively load-independent measure of left ventricular contractile function. Linearity of the relation derived from full left ventricular pressure-volume loops has not previously been demonstrated for patients with severe heart failure. Therefore, nine patients with markedly depressed left ventricular systolic function (ejection fraction 0.14 +/- 0.08) were studied with micromanometer left ventricular pressure measurement and simultaneous radionuclide ventriculography. Afterload was reduced with graded infusions of nitroprusside, allowing construction of pressure-volume loops under four afterload conditions in four patients and three afterload conditions in the other five patients. The end-systolic pressure-volume relation derived from the pressure-volume loops was found to be linear for the range of pressures and volumes examined, with correlation coefficients in individual patients ranging from 0.936 to 0.999 (mean 0.981). The mean slope of the relation (or end-systolic elastance) was 0.71 mm Hg/ml (range 0.42 to 1.52), and the extrapolated volume intercept at zero pressure was positive in all patients. An exponential relation between end-systolic elastance and ejection fraction was demonstrated for this group of patients. Approximations of end-systolic elastance obtained from measurements other than the full pressure-volume loops correlated variably with "true" elastance obtained from the pressure-volume loops. The relation between stroke work and end-diastolic volume was nonlinear in most patients. Thus, the end-systolic pressure-volume relation is linear in the "physiologic" range in patients with severe heart failure. This finding should permit construction of the relation from two loading conditions in clinical studies, facilitating its use as an index of contractile function in patients with heart failure.

Effects of atrial natriuretic peptide on myocardial contractile and diastolic function in patients with heart failure.

Atrial natriuretic peptide alters left ventricular performance in patients with heart failure. To assess the direct effects of this hormone on myocardial function, its actions were compared with those of the pure vasodilator nitroprusside in 10 patients with heart failure. Simultaneous left ventricular micromanometer pressure and radionuclide volume were obtained during a baseline period, during nitroprusside infusion, during a second baseline period and during atrial natriuretic peptide infusion. The baseline end-systolic pressure-volume relation was generated in nine patients from pressure-volume loops obtained during the two baseline periods and during afterload reduction with nitroprusside. Mean arterial pressure decreased with atrial natriuretic peptide (89 +/- 3 to 80 +/- 2 mm Hg, p less than 0.05) and by a greater amount with nitroprusside (90 +/- 4 to 73 +/- 3 mm Hg, p less than 0.05). Left ventricular end-diastolic pressure also decreased with atrial natriuretic peptide (24 +/- 2 to 16 +/- 3 mm Hg, p less than 0.05) and by a greater amount with nitroprusside (24 +/- 2 to 13 +/- 3 mm Hg, p less than 0.05). Cardiac index increased during infusion of each agent from 2.0 +/- 0.2 to 2.4 +/- 0.2 liters/min per m2 (p less than 0.01). Heart rate increased slightly with nitroprusside but did not change with atrial natriuretic peptide. Peak positive first derivative of left ventricular pressure (dP/dt), ejection fraction and stroke work index were unchanged by either agent. The relation between end-systolic pressure and volume during atrial natriuretic peptide infusion was shifted slightly leftward from the baseline value in four patients, slightly rightward in four and not at all in one patient, indicating no consistent inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary endothelial dysfunction in patients with acute-onset idiopathic dilated cardiomyopathy.

OBJECTIVES: This study sought to determine whether coronary endothelial dysfunction exists in patients with acute-onset idiopathic dilated cardiomyopathy (DCM) and to explore its relation to recovery of left ventricular systolic function in this patient population. BACKGROUND: Coronary endothelial dysfunction exists in chronic DCM, but its importance in the development and progression of ventricular dysfunction is not known. To address this issue we studied coronary endothelial function in patients with idiopathic DCM <6 months in duration and explored the relation between coronary endothelial function and subsequent changes in left ventricular ejection fraction (LVEF). METHODS: Ten patients with acute-onset idiopathic DCM (duration of heart failure symptoms 2.0 +/- 0.4 months [mean +/- SEM]) and 11 control patients with normal left ventricular function underwent assessment of coronary endothelial function during intracoronary administration of the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator adenosine. Coronary cross-sectional area (CSA) was determined by quantitative coronary angiography and coronary blood flow (CBF) by the product of coronary CSA and CBF velocity measured by an intracoronary Doppler catheter. Patients with DCM underwent assessment of left ventricular function before and several months after the study. RESULTS: Acetylcholine infusion produced no change in coronary CSA in control patients but significant epicardial constriction in patients with DCM (-36 +/- 11%, p < 0.01). These changes were associated with increases in CBF in control patients (+118 +/- 49%, p < 0.01) but no change in patients with DCM. Infusion of adenosine produced increases in coronary caliber and blood flow in both groups. Follow-up assessment of left ventricular function was obtained in nine patients with DCM 7.0 +/- 1.7 months after initial study, at which time LVEF had improved by > or =0.10 in four patients. Multiple linear regression revealed a positive correlation between both the coronary CSA (r2 = 0.57, p < 0.05) and CBF (r2 = 0.68, p < 0.01) response to acetylcholine and the subsequent improvement in LVEF. CONCLUSIONS: Coronary endothelial dysfunction exists at both the microvascular and the epicardial level in patients with acute-onset idiopathic DCM. The preservation of coronary endothelial function in this population is associated with subsequent improvement in left ventricular function.

Exercise capacity and systolic and diastolic ventricular function after recovery from acute dilated cardiomyopathy.

OBJECTIVES: This study was undertaken to determine whether abnormalities in exercise capacity or ventricular function persist after recovery from acute dilated cardiomyopathy. BACKGROUND: Persistent ventricular structural abnormalities could cause abnormalities in exercise capacity or ventricular function. METHODS: The results of rest and exercise first-pass radionuclide ventriculography in 18 patients who were seen within 6 months of the onset of dilated cardiomyopathy and subsequently had a normal rest left ventricular ejection fraction were compared with those of age- and gender-matched control subjects. RESULTS: Patients were studied 144 +/- 34 (mean +/- SEM) days after the onset of left ventricular dysfunction at a time when heart failure symptoms had resolved. Patients with myocyte necrosis, as assessed by endomyocardial biopsy (n = 13) or antimyosin scintigraphy (n = 12), recovered more rapidly than did those without necrosis. Oxygen consumption both at peak exercise (17.7 +/- 1.2 vs. 26.1 +/- 1.5 ml/kg per min, p < 0.05) and at the anaerobic threshold (11.1 +/- 0.5 vs. 17.1 +/- 1.3 ml/kg per min, p < 0.05) was lower in the patients who had recovered from cardiomyopathy than in control subjects. Rest and exercise end-systolic and end-diastolic left ventricular volumes were greater in the patients than in the control subjects, although stroke volumes were similar. Left ventricular filling at rest was lower at diastolic filling intervals of 40% and 90%, and rest and exercise left ventricular early peak filling rate normalized for end-diastolic volume was slower in the patients than in the control subjects. At long-term follow-up of 1,082 +/- 206 days, two patients had a return of heart failure symptoms and a decrease in left ventricular ejection fraction. CONCLUSIONS: Despite the apparent normalization of rest left ventricular ejection fraction, patients who have recovered from dilated cardiomyopathy have abnormalities in aerobic exercise capacity and in left ventricular systolic and diastolic performance.

Continuous wave Doppler echocardiography for noninvasive assessment of left ventricular dP/dt and relaxation time constant from mitral regurgitant spectra in patients.

OBJECTIVES: We previously demonstrated experimentally that the mitral regurgitant velocity spectrum can be used to estimate left ventricular pressure throughout systole and may provide a new noninvasive method for estimating maximal dP/dt and the relaxation time constant. This study was designed to test this method in patients. BACKGROUND: The maximal first derivative of left ventricular pressure (dP/dt) and the time constant of left ventricular isovolumetric relaxation (tau) are important variables of left ventricular function, but the need for invasive measurement with high fidelity catheters has limited their use in clinical cardiology. METHODS: Twelve patients with mitral regurgitation were studied. The Doppler mitral regurgitant velocity spectrum was recorded simultaneously with micromanometer left ventricular pressure tracings in all patients. The regurgitant velocity profiles were digitized and converted to ventriculoatrial (VA) pressure gradient curves using the simplified Bernoulli equation and differentiated into instantaneous dP/dt. The relaxation time constant (tau) was calculated assuming a zero pressure asymptote from catheter left ventricular pressure decay (tau c) and from the Doppler-derived VA gradient curve with corrections. Two methods were used to correct the Doppler gradient curve to better approximate the left ventricular pressure decay before calculating the relaxation time constant: 1) adding an arbitrary 10 mm Hg (tau 10), and 2) adding the actual mean pulmonary capillary pressure (tau LA). RESULTS: The Doppler-derived maximal positive dP/dt (1,394 +/- 302 mm Hg/s [mean +/- SD]) correlated well (r = 0.91) with the catheter-derived maximal dP/dt (1,449 +/- 307 mm Hg/s). Although the Doppler-derived negative maximal dP/dt differed slightly from catheter measurement (1,014 +/- 289 vs. 1,195 +/- 354 mm Hg/s, p < 0.01), the correlation between Doppler and catheter measurements was similarly good (r = 0.89, p < 0.0001). The correlation between tau 10 and tau c was excellent (r = 0.93, p < 0.01), but the Doppler-derived tau 10 (50.0 +/- 11.0 ms) slightly underestimated the catheter-derived tau c (55.5 +/- 12.8 ms, p < 0.01). This slight underestimation could be corrected by adding the actual pulmonary capillary wedge pressure to the Doppler gradient curve. CONCLUSIONS: Doppler echocardiography provides an accurate and reliable method for estimating left ventricular maximal positive dP/dt, maximal negative dP/dt and the relaxation time constant (tau) in patients with mitral regurgitation.

Hemodynamic effects of inhaled nitric oxide in heart failure.

OBJECTIVES: This study was performed to assess the utility of inhaled nitric oxide as a selective pulmonary vasodilator in patients with severe chronic heart failure and to compare its hemodynamic effects with those of nitroprusside, a nonselective vasodilator. BACKGROUND: Preoperative pulmonary vascular resistance is a predictor of right heart failure after heart transplantation. Non-selective vasodilators administered preoperatively to assess the reversibility of pulmonary vasoconstriction cause systemic hypotension, limiting their utility. METHODS: Systemic and pulmonary hemodynamic measurement were made at baseline, during oxygen inhalation and with the addition of graded doses of inhaled nitric oxide or intravenous nitroprusside in 16 patients with New York Heart Association class III or IV heart failure referred for heart transplantation. RESULTS: Pulmonary vascular resistance decreased to a greater extent with 80 ppm nitric oxide (mean +/- SEM 256 +/- 41 to 139 +/- 14 dynes.s.cm-5) than with the maximally tolerated dose of nitroprusside (264 +/- 49 to 169 +/- 30 dynes.s.cm-5, p < 0.05, nitric oxide vs. nitroprusside). Pulmonary capillary wedge pressure increased with 80 ppm nitric oxide (26 +/- 2 to 32 +/- 2 mm Hg, p < 0.05). Mean arterial pressure did not change with nitric oxide but decreased with nitroprusside. Seven of the 16 patients, including 1 patient who did not have an adequate decrease in pulmonary vascular resistance with nitroprusside but did with nitric oxide, have undergone successful heart transplantation. CONCLUSIONS: Inhaled nitric oxide is a selective pulmonary vasodilator in patients with pulmonary hypertension due to left heart failure and may identify patients with reversible pulmonary vasoconstriction in whom agents such as nitroprusside cause systemic hypotension. Inhaled nitric oxide causes an increase in left ventricular filling pressure by an unknown mechanism.

Effects of atrial natriuretic peptide on left ventricular function in hypertension.

Atrial natriuretic peptide (ANP) has natriuretic and vasodilator actions that lower arterial pressure and may be beneficial to hypertensive patients. To assess the effects of ANP on left ventricular function in patients with hypertension, we compared it with the pure vasodilator nitroprusside. Simultaneous left ventricular micromanometer pressure and radionuclide volume were obtained at baseline, during nitroprusside infusion, during a second baseline period, and during ANP infusion in 10 patients with hypertension. Mean arterial pressure fell during ANP and nitroprusside. Heart rate and plasma norepinephrine levels increased by similar amounts during the two agents, whereas cardiac index and stroke volume index were unchanged during both. Peak positive left ventricular dP/dt fell similarly during ANP and nitroprusside, but left ventricular dP/dt at a developed pressure of 40 mm Hg, a less load-dependent index of contractility, was unchanged during both. The relation between end-systolic pressure and volume during ANP infusion was not shifted leftward or rightward from that during nitroprusside infusion, indicating no inotropic effect. Both ANP and nitroprusside shortened at time constant of isovolumic relaxation calculated by the logarithmic method but did not change the time constant calculated by the derivative method. Peak filling rate was unchanged from baseline during both agents. ANP did not shift the end-diastolic pressure-volume point away from the relation constructed from baseline and nitroprusside points. We conclude that ANP has no direct effect on myocardial contractile or diastolic function in patients with hypertension.

Studies of the plasma membrane during maturation of the mammalian erythrocyte.

Plasma membranes were obtained from a homogeneous population of rabbit red blood cells at different maturation periods. Minor modifications in membrane proteins and membrane phospholipids and significant decreases in membrane glycoproteins and total lipids were observed with the age of the cell. The ouabain inhibited (Na+K+)-ATPase and the adenylate cyclase decreased with maturation but acetylcholinesterase and 5'-nucleotidase remained almost unchanged. The apparent activation energy of the ATPase increased with maturation. The results indicate that structural and functional modifications of the plasma membrane occur concomitantly with the ageing processes of the red cell.

Calcium channel blockers in congestive heart failure: theoretic considerations and clinical experience.

Although it has been suggested that calcium channel blocking agents may be utilized as vasodilators in patients with congestive heart failure, these agents also have the potential to cause a deterioration in cardiac function because of their negative inotropic actions. There is considerable variation among the available agents with regard to their relative effects on the vasculature, myocardial inotropy, and myocardial chronotropy. Thus, at clinically relevant dosages, nifedipine is a potent systemic and coronary vasodilator, but it has little or no direct effect on inotropy and chronotropy. In contrast, verapamil exerts significant negative inotropic and chronotropic effects at vasodilatory dosages, whereas diltiazem is a potent vasodilator with a negative chronotropic action at dosages that do not affect inotropy. In patients with heart failure, the largest experience so far has been with nifedipine. Data derived from over 100 patients with moderate to severe congestive heart failure indicate a generally beneficial net hemodynamic response to nifedipine, with substantial improvements in cardiac index (+24 percent) and left ventricular filling pressure (-15 percent). The major effect seems to be on arteriolar resistance vessels, resulting in a reduction in afterload, with relatively little effect on venous pressures. Limited data suggest that the initial effect is sustained during long-term therapy. The clinical experience with verapamil and diltiazem in patients with heart failure is at present limited. In patients with normal or mildly impaired left ventricular function, verapamil's vasodilator and negative inotropic effects are counterbalanced. With severe left ventricular dysfunction, however, treatment with verapamil can result in abrupt decompensation and development of overt pulmonary edema and hypotension. Diltiazem's relative lack of negative inotropic effects may allow it to be used safely in patients with congestive heart failure, particularly when control of supraventricular tachyarrhythmia is required.

Myocardial contractile function in aortic stenosis as determined from the rate of stress development during isovolumic systole.

To assess myocardial contractile function in the chronically hypertrophied human left ventricle, the rate of stress development (dsigma/dt) as a function of developed stress (sigmaD) during isovolumic systole was examined. Results for eight patients with aortic stenosis were compared with those for seven subjects with normal left ventricular function and with those for five patients with idiopathic congestive cardiomyopathy. The rate of stress development (dsigma/dt) was nearly identical in patients with aortic stenosis and in normal subjects over a wide range of values of sigmaD but was significantly lower in patients with cardiomyopathy (P less than 0.01 versus control subjects and patients with aortic stenosis). Normal values for dsigma/dt held not only for patients with compensated pressure overload, but also for those patients with aortic stenosis with depressed left ventricular ejection fraction and overt congestive failure. Similar findings were obtained when the first derivative of left ventricular pressure (dP/dt) was examined as a function of developed left ventricular pressure in normal subjects and patients with aortic stenosis or cardiomyopathy. These results indicate that contractile function as characterized by the isovolumic rate of stress development is not necessarily impaired in chronic pressure overload hypertrophy.