Long-term vasodilator therapy in patients with severe aortic regurgitation.

BACKGROUND: Vasodilator therapy can reduce the left ventricular volume and mass and improve left ventricular performance in patients with aortic regurgitation. Accordingly, it has been suggested that such therapy may reduce or delay the need for aortic-valve replacement. METHODS: We randomly assigned 95 patients with asymptomatic severe aortic regurgitation and normal left ventricular function to receive open-label nifedipine (20 mg every 12 hours), open-label enalapril (20 mg per day), or no treatment (control group) to identify the possible beneficial effects of vasodilator therapy on left ventricular function and the need for aortic-valve replacement. RESULTS: After a mean of seven years of follow-up, the rate of aortic-valve replacement was similar among the groups: 39 percent in the control group, 50 percent in the enalapril group, and 41 percent in the nifedipine group (P=0.62). In addition, there were no significant differences among the groups in aortic regurgitant volume, left ventricular size, left ventricular mass, mean wall stress, or ejection fraction. One year after valve replacement, the left ventricular end-diastolic diameter and end-systolic diameter had decreased to a similar degree among the patients who underwent surgery in each of the three groups, and all the patients had a normal ejection fraction. CONCLUSIONS: Long-term vasodilator therapy with nifedipine or enalapril did not reduce or delay the need for aortic-valve replacement in patients with asymptomatic severe aortic regurgitation and normal left ventricular systolic function. Furthermore, such therapy did not reduce the aortic regurgitant volume, decrease the size of the left ventricle, or improve left ventricular function.

Effectiveness of beta-blockade in experimental chronic aortic regurgitation.

BACKGROUND: Past studies have suggested that the adrenergic system becomes abnormally activated in chronic volume overload, such as in severe aortic valve regurgitation (AR). However, the effectiveness of agents directed against this adrenergic activation has never been adequately tested in chronic AR. We therefore tested the effects of metoprolol treatment on the left ventricular (LV) function and remodeling in severe chronic AR in rats. METHODS AND RESULTS: Severe AR was created in adult male Wistar rats by retrograde puncture of the aortic leaflets under echocardiographic guidance. Two weeks later, some animals received metoprolol treatment (25 mg/kg) orally for 24 weeks, and some were left untreated. LV dimensions, ejection fraction, and filling parameters were evaluated by echocardiography. Hearts were harvested at 1, 2, 14, and 180 days for the evaluation of hypertrophy, beta-adrenergic receptor status, and extracellular matrix remodeling. We found that metoprolol treatment prevented LV dilatation and preserved the ejection fraction and filling parameters compared with untreated animals. Metoprolol increased the expression of beta1-adrenoreceptor mRNA and reduced G protein receptor kinase 2 levels. Collagen I and III mRNA levels were reduced. Cardiac myocyte hypertrophy was also prevented. CONCLUSIONS: In our experimental model of severe AR, metoprolol treatment had a significant beneficial global effect on LV remodeling and function. These results suggest that the adrenergic system is important in the development of volume-overload cardiomyopathy in AR and that adrenergic-blocking agents may play a role in the treatment of this disease.

[Study on protective effect of shenfu injection on cardiac function of patients undergoing valve replacement].

OBJECTIVE: To investigate the protective effect of Shenfu injection (SFI) on cardiac function of patients undergoing valve replacement operation under cardio-pulmonary bypass. METHODS: One hundred and twenty patients undergoing valve replacement operation under cardio-pulmonary bypass were randomly divided into the SFI group and the control group, 60 in each group. Intravenous infusion of 1 ml/kg SFI was given to the SFI group, 30 min before anesthesia, and to the control group, equal volume of normal saline was given instead. The following indices were observed: (1) the hemodynamic changes occurred in the operational period; (2) the dosage of vaso-active drugs used during and after operation; (3) the post-operational recovery time of patients. RESULTS: The mean arterial pressure and heart rate in the SFI group during operation were higher, while the central venous pressure was lower than those in the control group (P < 0.05). The dosage of vaso-active drugs, such as dopamine, dobutamine, sodium nitroprusside and lidocaine, used during and after operation was lower, and the extubation time and the intensive care unit (ICU) staying time were shorter in the SFI group when compared with those in the control group (P < 0.05). CONCLUSION: SFI has certain protective effects on the cardiac function of patients undergoing valve replacement operation under cardio-pulmonary bypass.

Left ventricular outflow tract obstruction unmasked by nifedipine: a therapeutic pitfall in the management of chronic aortic regurgitation.

This case report illustrates the aggravation of a clinically silent left ventricular outflow tract obstruction by maintenance use of nifedipine in a patient with chronic severe aortic regurgitation, and demonstrates a potential limitation of vasodilator therapy in the management of this patient population. Recognition of this clinical scenario is imperative, as decision making in patients with chronic severe aortic regurgitation rests on the development of symptoms and/or left ventricular dysfunction in relation to the regurgitant volume. The importance of echocardiography in the detection of this valvular finding and in the follow up of these patients is emphasized.

Vasodilator therapy for chronic aortic and mitral regurgitation.

The use of vasodilator therapy in chronic AR and MR may be beneficial in selected patients and harmful in others. The hemodynamics of the two conditions are different and must be taken into account. In AR, vasodilators reduce afterload mismatch and can preserve LV function and delay the need for surgery. However, if the patient has severely reduced diastolic blood pressure, vasodilators could potentially impair coronary perfusion. In MR, vasodilators may reduce regurgitant volume and LV preload depending on the mechanism of MR. In patients with MR caused by dilated cardiomyopathy, vasodilators reduce symptoms, and improve functional class. However, in mitral valve prolapse or hypertrophic cardiomyopathy, vasodilators may worsen the MR and should be avoided. In other primary causes of MR, vasodilators could potentially mask the development of LV dysfunction and lead to unnecessary and harmful delays in surgery.

Captopril or nifedipine? Comparison of rest and exercise acute effects and long-term therapy in chronic isolated asymptomatic moderate to severe aortic regurgitation.

UNLABELLED: The effects of both single and long-term oral captopril or nifedipine treatment on cardiac parameters at rest and during exercise in patients with moderate to severe aortic regurgitation was investigated. METHODS: Thirty-one asymptomatic patients with chronic, isolated, previously untreated, moderate to severe aortic regurgitation (AR) of mean grade 3.1 +/- 0.6, had left ventricular end-diastolic diameter (LVEDD) 64 +/- 5 mm, left ventricular end-systolic diameter (LVESD) 41 +/- 5 mm, ejection fraction (EF) 66 +/- 6% and fractional shortening (FS) 37 +/- 5% measured by echo-Doppler. Bedside Swan-Ganz measurements at rest and at peak exercise (75 W) were conducted before (baseline) and at 75-90 min after oral administration of 20 mg nifedipine. Repeat testing was performed 24 h later, at 75-90 min after oral administration of 25 mg captopril. RESULTS: At rest, nifedipine significantly reduced systemic vascular resistance (SVR) compared with baseline (704 +/- 152 versus 880 +/- 216 dynes.s.cm-5; p < 0.0001) and captopril treatment (800 +/- 176 dynes.s.cm-5; p < 0.0001). Despite significant improvement of effective left ventricular (LV) stroke volume (LVSVef) after both nifedipine and captopril over baseline (103 +/- 20 ml), LVSVef did not differ between nifedipine and captopril (110 +/- 17 versus 110 +/- 22 ml; NS). Nifedipine significantly increased effective cardiac output (COef) from baseline (6.7 +/- 1.3 l/min) to 8.2 +/- 1.5 l/min; p < 0.0001, but this was due to an increase in heart rate (HR) (66 +/- 10 versus 75 +/- 1 beats/min; p < 0.0001). In contrast, captopril affected neither COef nor HR. In addition, captopril reduced pulmonary capillary wedge pressure (PCWP) more than nifedipine (8.7 +/- 2.5 versus 11 +/- 2.9 mmHg; p < 0.0001). At exercise, both drugs caused similar reductions in blood pressure and systemic vascular resistance (SVR). By comparison with exercise baseline, LVSVef was increased by captopril (139 +/- 24 versus 147 +/- 27 ml; p < 0.01) but was unchanged after nifedipine. Compared with baseline, nifedipine increased COef (from 14.4 +/- 2.0 to 15.5 +/- 2.1 l/min; p < 0.0001) due to a significantly higher HR, while COef and HR were unchanged after captopril. A smaller increase in PCWP was also seen after captopril than nifedipine and baseline (both p < 0.0001). After long-term therapy (33 +/- 12; range: 12 to 53 months) with captopril (75 mg/day, n = 13) or nifedipine (40 mg/day; n = 12) there was no change in LVESD, and in left ventricular EF and FS in either groups. None of the patients became symptomatic. Compared with baseline, captopril significantly reduced AR grade by 0.9 +/- 0.6 (p < 0.01), but not significantly so versus nifedipine. LVEDD was reduced in captopril patients by 4.0 +/- 2.6 mm (p < 0.0002), but not significantly so in nifedipine patients. LVEDD was normalized in five captopril patients, and in four treated with nifedipine. CONCLUSIONS: Single captopril treatment caused a greater hemodynamic improvement than nifedipine, notably during exercise; these findings were confirmed by long-term therapy with both drugs. Therefore, captopril may delay the development of left ventricular dysfunction and thus the time for corrective surgery.

[Long-term treatment with quinapril in chronic aortic and mitral insufficiency]. / Langzeittherapie mit Quinapril bei chronischer Aorten- und Mitralinsuffizienz.

The effect on myocardial function and structure of long-term administration of quinapril (10-20 mg daily), an angiotensin-converting-enzyme (ACE) inhibitor, was investigated in 24 patients (18 men, 6 women; mean age 48 [20-65] years) with chronic isolated asymptomatic aortic or mitral regurgitation. Coronary heart disease had been excluded angiographically. After one year's treatment the regurgitation fraction, compared with the pretreatment value, had decreased by 27% in those patients with aortic regurgitation (AR) and 42% in those with mitral regurgitation (MR) (P = 0.0001). The mean left ventricular enddiastolic volume was reduced from 150 +/- 33 to 128 +/- 30 ml/m2 in patients with AR, from 146 +/- 26 to 109 +/- 24 ml/m2 in those with MR (P = 0.0001). The mean endsystolic volume fell from 55 +/- 27 to 44 +/- 28 ml/m2 in patients with AR and from 63 +/- 43 to 47 +/- 29 ml/m2 in those with MR (P = 0.002). The mean left ventricular ejection fraction at rest and on exercise rose slightly in patients with AR, remaining unchanged in those with MR. The left ventricular mass, as measured by echocardiography, was reduced by 35% in patients with AR, and the left ventricular hypertrophy, demonstrated in all patients, regressed. In patients with MR the left ventricular mass decreased by 15% and septal thickness became normal (borderline hypertrophy). These data indicate that, after one year's treatment with quinapril, left ventricular dilatation, mass and hypertrophy regressed and left ventricular function improved in patients with AR or MR.

Nifedipine in asymptomatic patients with severe aortic regurgitation and normal left ventricular function.

BACKGROUND: Vasodilator therapy with nifedipine reduces left ventricular volume and mass and increases the ejection fraction in asymptomatic patients with severe aortic regurgitation. METHODS: To assess whether vasodilator therapy reduces or delays the need for valve replacement, we randomly assigned 143 asymptomatic patients with isolated, severe aortic regurgitation and normal left ventricular systolic function to receive either nifedipine (20 mg twice daily, 69 patients) or digoxin (0.25 mg daily, 74 patients). RESULTS: By actuarial analysis, we determined that after six years a mean (+/- SD) of 34 +/- 6 percent of the patients in the digoxin group had undergone valve replacement, as compared with only 15 +/- 3 percent of those in the nifedipine group (P < 0.001). In the digoxin group, valve replacement (in a total of 20 patients) was performed because of left ventricular dysfunction (ejection fraction < 50 percent) in 75 percent, left ventricular dysfunction plus symptoms in 10 percent, and symptoms alone in 15 percent. In the nifedipine group, all six patients who underwent valve replacement did so because of the development of left ventricular dysfunction. In addition, all the patients in both groups who underwent aortic-valve replacement had an increase of 15 percent or more in the left ventricular end-diastolic volume index. After aortic-valve replacement, 12 of the 16 patients (75 percent) in the digoxin group and all six patients in the nifedipine group who had had an abnormal left ventricular ejection fraction before surgery had a normal ejection fraction. CONCLUSIONS: Long-term vasodilator therapy with nifedipine reduces or delays the need for aortic-valve replacement in asymptomatic patients with severe aortic regurgitation and normal left ventricular systolic function.

Comparison of single-dose nifedipine and captopril for chronic severe aortic regurgitation.

The effects of a single dose of either nifedipine 20 mg (n = 10) or captopril 50 mg (n = 10) were compared in 20 patients with symptomatic, chronic severe aortic regurgitation using angiography and micromanometer left ventricular pressure measurements. At 90 minutes, mean arterial pressure was reduced comparably after both drugs (86 +/- 15 to 76 +/- 18 mm Hg for nifedipine vs 95 +/- 19 to 77 +/- 18 mm Hg for captopril, p = NS between groups by analysis of variance), as was wedge pressure (11 +/- 5 to 9 +/- 4 mm Hg vs 13 +/- 9 to 9 +/- 5 mm Hg for captopril). Systemic vascular resistance was reduced more (p = 0.01) after nifedipine than after captopril (1,549 +/- 468 to 1,067 +/- 291 dynes s cm-5 vs 1,632 +/- 559 to 1,436 +/- 392 dynes s cm-5). Heart rate declined after captopril (84 +/- 14/min to 75 +/- 15/min, p = 0.002) but not after nifedipine (78 +/- 13 min to 80 +/- 14 min). Forward stroke volume increased after nifedipine (58 +/- 14 to 70 +/- 16 ml, p < 0.001) but not after captopril (58 +/- 17 to 59 +/- 16 ml). Thus, cardiac output increased after nifedipine (4.4 +/- 0.9 to 5.5 +/- 1.2 liters/min, p < 0.001) but decreased after captopril (4.8 +/- 1.2 to 4.3 +/- 1.0, p = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term nifedipine unloading therapy in asymptomatic patients with chronic severe aortic regurgitation.

Vasodilating agents acutely reduce regurgitant volume and improve left ventricular performance in aortic regurgitation, but more information is necessary about their long-term efficacy. To evaluate the effects of 12 months of therapy with nifedipine, a randomized, double-blind, placebo-controlled trial was performed in 72 asymptomatic patients with severe aortic regurgitation. At 12 months, patients receiving nifedipine had a significant reduction in left ventricular end-diastolic volume index (110 +/- 19 versus 136 +/- 22 ml/m2, p less than 0.01) and mass (115 +/- 19 versus 142 +/- 16 g/m2, p less than 0.01) measured by two-dimensional echocardiography. They also had a reduction in left ventricular mean wall stress (360 +/- 27 versus 479 +/- 36 kdyne/cm2, p less than 0.001) and an increase in ejection fraction (72 +/- 8% versus 60 +/- 6%, p less than 0.05). These data show that the long-term unloading action of nifedipine is able to reverse left ventricular dilation and hypertrophy and suggest that such therapy has the potential to delay the need for valve replacement in asymptomatic patients.