Howard Rosman

Left ventricular shape is the primary determinant of functional mitral regurgitation in heart failure

OBJECTIVESnThe aim of this study was to examine the temporal association between the onset of functional mitral regurgitation and the development of changes in left ventricular shape, chamber enlargement, mitral anulus dilation and regional wall motion abnormalities during the course of evolving heart failure.nnnBACKGROUNDnDespite extensive characterization, the exact etiology of functional mitral regurgitation in patients with chronic heart failure remains unknown.nnnMETHODSnHeart failure was produced in seven dogs by multiple sequential intracoronary microembolizations. Serial changes in left ventricular chamber volume and shape were evaluated from ventriculograms. Changes in mitral anulus diameter and ventricular regional wall motion abnormalities were evaluated echocardiographically. The presence and severity of mitral regurgitation were determined with Doppler color flow mapping. Measurements were obtained at baseline and then biweekly until mitral regurgitation was first observed.nnnRESULTSnNo dog had mitral regurgitation at baseline but all developed mild to moderate regurgitation 12 +/- 1 weeks after the first embolization. The onset of mitral regurgitation was not associated with an increase in left ventricular end-diastolic volume relative to baseline (58 +/- 3 vs. 62 +/- 3 ml), mitral anulus diameter (2.4 +/- 0.1 vs. 2.4 +/- 0.1 cm) or wall motion abnormalities of left ventricular wall segments overlying the papillary muscles. In contrast, the onset of mitral regurgitation was accompanied by significant changes in global left ventricular shape evidenced by increased end-systolic chamber sphericity index (0.22 +/- 0.02 vs. 0.30 +/- 0.01) (p < 0.01) and decreased end-systolic major axis/minor axis ratio (1.71 +/- 0.05 vs. 1.43 +/- 0.04) (p < 0.001).nnnCONCLUSIONSnThese data indicate that transformation of left ventricular shape (increased chamber sphericity) is the most likely substrate for the development of functional mitral regurgitation.

Mechanism of functional mitral regurgitation during acute myocardial ischemia

The mechanism and temporal manifestation of functional mitral regurgitation after acute myocardial ischemia were examined in eight dogs. Regional ischemia was produced by selective microembolization of the left circumflex coronary artery. Mitral regurgitation and regional left ventricular wall motion abnormalities were evaluated with use of Doppler color flow mapping and two-dimensional echocardiography, respectively. Measurements were made at baseline (before embolization) and were repeated at 30 min and 3 weeks after embolization. Mitral regurgitation developed in all dogs 30 min after embolization and completely subsided 3 weeks later. There was no evidence of mitral valve prolapse, mitral anulus dilation or left ventricular segmental dyskinesia at any time during the study. Regional wall motion analysis showed only hypokinesia of the left ventricular segment overlying the papillary muscle at 30 min with subsequent normalization of the segment at 3 weeks. Mitral regurgitation was accompanied by an increase of the end-systolic distance between the mitral anulus plane and the point of coaptation of the mitral leaflets. This distance was 0.5 +/- 0.1 cm at baseline, increased to 0.9 +/- 0.1 cm 30 min after the embolization (p less than 0.001) and returned to near baseline (0.6 +/- 0.1 cm) 3 weeks after the embolization. These data indicate that mitral valve prolapse, mitral anulus dilation and regional left ventricular dyskinesia are not necessary conditions for the development of functional mitral regurgitation after acute myocardial ischemia. Instead, hypokinesia of the ventricular segment overlying the papillary muscle and leading to retraction of the mitral leaflets toward the apex appears to be a sufficient condition for incomplete leaflet coaptation.

Effects of Increasing Maintenance Dose of Digoxin on Left Ventricular Function and Neurohormones in Patients With Chronic Heart Failure Treated With Diuretics and Angiotensin-Converting Enzyme Inhibitors

BACKGROUNDnDespite almost three centuries of use, the appropriate dosage of digitalis in patients with chronic heart failure and normal sinus rhythm has not been well studied.nnnMETHODS AND RESULTSnWe studied 22 patients with heart failure who were receiving constant daily doses of digoxin, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. In 18 patients, the oral daily dose of digoxin was increased from a mean of 0.20 +/- 0.07 to 0.39 +/- 0.11 mg/day corresponding to an increase in the serum digoxin concentration from 0.67 +/- 0.22 to 1.22 +/- 0.35 ng/mL. Radionuclide and echocardiographic left ventricular ejection fraction; maximal treadmill time; heart failure score; serum concentrations of norepinephrine, aldosterone, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity were obtained before and after the increase in digoxin dose. Subsequently, 9 patients were randomized to receive digoxin and 9 to receive placebo and radionuclide ejection fraction measured after 12 weeks. With the higher dose of digoxin compared with the lower dose, there was a significant increase in radionuclide ejection fraction from 23.7 +/- 9.6% to 27.1 +/- 11.8% (P = .007). No significant changes were noted in heart failure score; exercise tolerance; serum concentrations of norepinephrine, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity. There was, however, an increase in serum aldosterone concentration. Twelve weeks after the patients were randomized to receive digoxin or placebo, there was a significant decrease in ejection fraction (from 29.4 +/- 10.4% to 23.7 +/- 8.9%) in the placebo group but not in patients who continued to receive digoxin (P = .002).nnnCONCLUSIONSnThe increase in maintenance digoxin dose, while maintaining serum concentrations within therapeutic range, resulted in a significant increase in left ventricular ejection fraction that was not associated with significant changes in heart failure score, exercise tolerance, and neurohumoral profile.

Hemodynamic correlates of the third heart sound during the evolution of chronic heart failure

OBJECTIVESnThe purpose of this study was to examine the temporal relation between the development of a third heart sound during the course of evolving heart failure and associated hemodynamic abnormalities.nnnBACKGROUNDnAlthough various theories have been proposed to explain the origin of the third heart sound, the exact origin of this sound remains unknown.nnnMETHODSnStudies were performed in seven dogs in which heart failure was produced by multiple sequential intracoronary micro-embolizations. Hemodynamic studies including ventriculography, pulsed wave Doppler echocardiography and intracardiac phonocardiography were performed at baseline, at the time at third heart sound was first heard and at 6 and 24 weeks after onset of the third heart sound.nnnRESULTSnAll dogs developed a third heart sound at 9 +/- 2 weeks after the initial embolization. The onset of the sound was accompanied by an increase in left ventricular chamber stiffness relative to the baseline value (0.25 +/- 0.03 vs. 0.14 +/- 0.01 mm Hg/ml) (p < 0.05) and mean deceleration of early mitral inflow velocity (1,040 +/- 90 vs. 590 +/- 40 cm/s per s) (p < 0.05).nnnCONCLUSIONSnThese data indicate that the onset of a third heart sound during the course of evolving heart failure occurs coincident with the development of increased left ventricular chamber stiffness and the manifestation of rapid deceleration of early mitral inflow velocity. These findings are consistent with a myocardial vibratory origin of this sound.

Effects of long-term therapy with enalapril on severity of functional mitral regurgitation in dogs with moderate heart failure

OBJECTIVESnThis study examined the effects of early long-term monotherapy with enalapril on the severity of functional mitral regurgitation in dogs with moderate heart failure.nnnBACKGROUNDnFunctional mitral regurgitation often develops in patients with heart failure and, depending on its severity, can have a marked adverse impact on the stroke output of the failing left ventricle and contribute to progressive deterioration of the heart failure state.nnnMETHODSnLeft ventricular dysfunction (ejection fraction 30% to 40%) was produced in 14 dogs by multiple sequential intracoronary microembolizations. Dogs were randomized to 3 months of therapy with enalapril (10 mg twice daily, n = 7) or no therapy at all (control, n = 7). The severity of functional mitral regurgitation was quantified by Doppler color flow mapping in seven control and six enalapril-treated dogs. Mitral annular diameter was assessed by echocardiography and left ventricular volumes and shape by ventriculography. Measurements were made before initiation and after completion of therapy.nnnRESULTSnIn control dogs, the severity of mitral regurgitation increased during the follow-up period ([mean +/- SEM] 14 +/- 4 vs. 23 +/- 4%, p < 0.001) and was associated with increased left ventricular end-systolic and end-diastolic volumes. In contrast, the severity of regurgitation was not significantly changed in dogs treated with enalapril (18 +/- 3 vs. 16 +/- 6%, p < 0.59) and was associated with preservation of left ventricular volumes.nnnCONCLUSIONSnIn dogs with moderate heart failure, early long-term therapy with enalapril prevents progressive worsening of functional mitral regurgitation. This beneficial effect is most likely achieved by prevention of progressive left ventricular dilation.

Relation of left ventricular chamber shape in patients with low (≤40%) ejection fraction to severity of functional mitral regurgitation

Abstract In conclusion, the results of this study indicate that severity of functional MR in patients with low ejection fraction appears to be dictated primarily by increased sphericity of the left ventricle rather than by mitral annular dilatation or LV chamber enlargement.

Effect of β-blockade on left atrial contribution to ventricular filling in dogs with moderate heart failure

Abstract Abnormal left ventricular (LV) filling has been observed in patients with heart failure. One feature of this abnormality is a reduction in the left atrial (LA) contribution to filling, a feature that can adversely affect overall LV stroke output. In this study we examined the effects of early, long-term monotherapy with the β-blocker, metoprolol, on LA contribution to ventricular filling in dogs with moderate heart failure. LV dysfunction (ejection fraction 30% to 40%) was produced in 14 dogs by multiple, sequential intracoronary microembolizations. Dogs were randomized to 3 months therapy with metoprolol (25 mg twice daily; n = 7) or to no therapy at all (control; n = 7). Mitral inflow velocity was measured before randomization and after completion of therapy by using pulsed Doppler echocardiography. The percentage of LA contribution to LV filling was calculated as the ratio of the time-velocity integral of the LA component of mitral inflow vleocity (Ai) to the time-velocity integral of total diastolic, in-flow velocity (Ti) times 100. In control dogs, the percentage of LA contribution to filling decreased after 3 months of follow-up compared with that before randomization (14% ± 3% vs 23% ± 5%; p = 0.02). In contrast, in dogs treated with metoprolol, the percentage of LA contribution to filling increased after 3 months of therapy compared with that before randomization (26% ± 3% vs 21% ± 2%; p = 0.001). Therapy with metoprolol produced a decrease in LV end-diastolic pressure, end-diastolic wall stress and stiffness, and an increase in LA fractional shortening compared with no therapy at all. We conclude that early, long-term therapy with metoprolol improves LA contriobution to LV filling. This beneficial effect is likely caused by the ability of β-blockers to reduce LA workload and consequently improve LA performance.

Divergent effects of intravenous dobutamine and nitroprusside on left atrial contribution to ventricular filling in dogs with chronic heart failure

The left atrial (LA) contribution to left ventricular (LV) filling is often attenuated in patients with heart failure. It remains uncertain, however, whether therapy with positive inotropic agents or vasodilators improves or further impairs this maladaptation. In the present study, the effects of intravenous dobutamine and nitroprusside on the LA contribution to LV filling was examined in seven dogs with chronic heart failure produced by multiple sequential intracoronary microembolizations. Pulsed Doppler echocardiography was used to measure mitral inflow velocity before and after an intravenous infusion of dobutamine (4 micrograms/kg/min) and an intravenous infusion of nitroprusside (3 micrograms/kg/min). The percent LA contribution to LV filling was calculated as the ratio of the time-velocity integral of the LA component of mitral inflow velocity (Ai) to the time-velocity integral of total diastolic inflow velocity (Ti) times 100. Dobutamine increased LV filling pressure, LV end-diastolic wall stress, LV end-diastolic stiffness, and Ei, but had no effect on Ai or the percent LA contribution to filling (14% +/- 3% vs 12% +/- 2%) (p < 0.34). In contrast, nitroprusside decreased LV filling pressure, LV end-diastolic wall stress, and end-diastolic stiffness, and increased Ei, Ai, and the percent LA contribution to LV filling (12% +/- 2% vs 17% +/- 2%) (p < 0.01). The results indicate that dobutamine and nitroprusside have divergent effects on the LA contribution to LV filling. In dogs with chronic heart failure, dobutamine appears to impair LA contribution to the LV filling by augmenting LA workload, whereas nitroprusside appears to elicit greater LA contribution to LV filling by reducing the LA workload.

Left Ventricular Function Immediately after Exercise in Elite Cyclists

To determine the response to exercise of the left ventricle of endurance-trained athletes, 6 elite (world class) cyclists were compared to 6 untrained healthy control subjects. In athletes the stroke volume increased with exercise. In untrained volunteers the stroke volume did not change with exercise. This difference of the response of the stroke volume to exercise reflected a difference of the left ventricular end-diastolic volume. In athletes the left ventricular end-diastolic volume tended to increase. In control subjects the end-diastolic volume decreased. In conclusion, athletes increased cardiac output by increasing stroke volume and heart rate, whereas control subjects increased their cardiac output only by increasing their heart rate.