Randomised investigation of effects of pentoxifylline on left-ventricular performance in idiopathic dilated cardiomyopathy.

BACKGROUND: There is accumulating evidence that inflammatory cytokines have an important role in the pathogenesis of heart failure. Plasma concentrations of tumour necrosis factor alpha (TNF-alpha) are high in heart failure and have been correlated with the severity of symptoms. Pentoxifylline suppresses the production of TNF-alpha. This study aimed to assess the effects of pentoxifylline on left-ventricular function and functional class in patients with idiopathic dilated cardiomyopathy. METHODS: We undertook a single-centre, prospective, double-blind, randomised, placebo-controlled trial, in which 28 patients with idiopathic dilated cardiomyopathy were assigned pentoxifylline 400 mg three times daily or matching placebo. Clinical, echocardiographic, and radionuclide assessments were done at baseline and after 6 months of treatment. Primary endpoints were New York Heart Association (NYHA) functional class and left-ventricular function. FINDINGS: Baseline characteristics were similar in the two groups. Four patients died during the study period, all in the placebo group. After 6 months of treatment, the proportion of patients in NYHA functional class I or II was higher in the pentoxifylline group than in the placebo group (14/14 vs 10/14; p=0.01), and ejection fraction was higher in the pentoxifylline group than in the placebo group (mean 38.7% [SD 15.0] vs 26.8% [11.0], p=0.04). At 6 months, TNF-alpha plasma concentrations were significantly lower in the pentoxifylline-treated group than in the placebo group (2.1 [1.0] vs 6.5 [5.0] pg/mL, p=0.001). INTERPRETATION: Our results suggest that pentoxifylline improves symptoms and left-ventricular systolic function in patients with idiopathic dilated cardiomyopathy. These results must be confirmed in larger-scale trials.

Frequency of prosthetic valve-related complications with very low level warfarin anticoagulation combined with dipyridamole after valve replacement using St. Jude Medical prostheses.

The safety of a very low level of anticoagulation combined with dipyridamole in a rheumatic population (mean age 31 +/- 13 years) with the St. Jude Medical (SJM) prosthesis has not yet been tested. Furthermore, no data are available on the safety of relatively infrequent monitoring of anticoagulation levels and of the necessity for different therapeutic targets according to valve position, number of risk factors, and other baseline risk factors for thromboembolism. In this study, the performance of the SJM prosthesis was tested using a target international normalized ratio (INR) of 2.0 to 2.5 combined with dipyridamole 300 mg/day applied uniformly to all patients. Clinical, biochemical, and echocardiographic data were acquired prospectively in 200 consecutive patients at 3-month intervals. Follow-up (mean 27 +/- 13 months) was complete in 95% of patients. Thirteen patients died (2.9%/patient year). Severe left ventricular dysfunction was the cause of death in 10 of 13 patients. Probability of survival (Kaplan-Meier) was 0.92 at 36 months and of event-free survival 0.84 at 36 months. The median INR was 2.0 +/- 0.9. Valve obstruction did not occur, and there were 3 thromboembolic events (0.6%/patient year). Incidence of bleeding was 1.6%/patient year (n = 7) and was major (hemorrhagic stroke) in 1 (0.2%/patient year). Thus, the SJM prosthesis performs very well despite the use of very low level warfarin anticoagulation combined with dipyridamole. A 3-month assessment of the anticoagulation level is safe. Left ventricular dysfunction rather than valve-related complications is the leading cause of mortality in this population.

Six month pilot study of captopril for mildly symptomatic, severe isolated mitral and isolated aortic regurgitation.

Long term therapy with vasodilating drugs has been shown to reduce left ventricular size and improve performance in chronic aortic regurgitation (AR). Similar trials in mitral regurgitation (MR) have not been published, nor has the effect of medium or long term therapy with angiotensin-converting enzyme (ACE) inhibitors been examined in either of these regurgitant lesions. Such therapy, if demonstrated to be effective in reducing left ventricular end-systolic size, might be anticipated to delay the need for valve replacement in asymptomatic patients. Medium term studies of the effects of ACE inhibitors on left ventricular size in regurgitant disease would therefore be helpful in designing long term trials to assess their impact on the timing of surgery. Patients with severe isolated MR (n = 32) or isolated AR (n = 23) and mild or no symptoms received either placebo or captopril 25 mg three times daily in a randomized, double blind, six month pilot study of left ventricular size using echocardiography. Treatment was well tolerated with no reported side effects. In MR, there were no significant immediate or 6-month effects of treatment on left ventricular diameter at end-systole (mean change at six months vs. baseline = +1% vs. +3% in placebo, p = 0.58 between groups) or end-diastole (+3% vs. 0% for placebo, p = 0.33). Nor was ejection fraction computed from radionuclide angiography effected by 6-month treatment (0.00 units vs. -0.01 units change in placebo).(ABSTRACT TRUNCATED AT 250 WORDS)

Mitral valve disease.

Recent experimental work demonstrates that the cellular contractile dysfunction that occurs after a brief period of mitral regurgitation is potentially reversible, that left ventricular dysfunction may also occur due to interruption of chordal-ventricular continuity, and that muscle dysfunction can be detected independent of loading conditions with measurements of ventricular stress and strain. Experimental work has also shown that hypertrophy after experimental mitral regurgitation may be inadequate for the degree of hemodynamic overload, and that there is lysis of myofibrils. This is consistent with clinical observations that ventricular dilatation and left ventricular hypertrophy may be modest despite long-standing, severe mitral regurgitation. At the moment, end-systolic diameter remains the best predictor of outcome after mitral valve replacement; preservation of chordae has been shown to have an impact on outcome in some but not all studies. Measures of heart rate variability may also have predictive value in mitral regurgitation. The so-called myocardial factor in rheumatic mitral disease appears to be unimportant; excessive vasoconstriction is more responsible for the modest left ventricular dysfunction in mitral stenosis. There is some new information regarding beta-blocking therapy, vasodilator therapy, and antithrombotic therapy.

Prediction of outcome after valve replacement for rheumatic mitral regurgitation in the era of chordal preservation.

BACKGROUND: Noninvasive predictors of important outcomes after valve replacement for mitral regurgitation have not been examined in a rheumatic population (in whom the results of valve repair are suboptimal) in the era of chordal preservation. Timing of valve replacement thus remains a difficult question in rheumatic mitral regurgitation. METHODS AND RESULTS: Of 278 patients followed after valve replacement, 66 had pure or predominant mitral regurgitation, and in 61 of these the etiology was rheumatic. The mean age was 24 years. After a mean follow-up of 24 +/- 10 months, the ability of preoperative clinical and echocardiographic data to predict outcome was assessed prospectively, and the possible impact of chordal preservation (n = 35) on survival and post-operative left ventricular function was examined retrospectively. There were no perioperative deaths. There were six postoperative deaths, all the result of heart failure and all related to left ventricular dysfunction. The mean probability of survival was .90 at 16 months. In a stepwise Cox proportional hazards regression analysis, the only independent predictor of postoperative death was preoperative end-systolic diameter. According to a logistic model, the probabilities of death (n = 6) and death or severe heart failure (n = 7) increased abruptly at a preoperative end-systolic diameter of 51 mm (probabilities, .23 and .31, respectively), and the accuracy of this cut point for predicting outcomes was 97% and 98%, respectively. Multiple linear regression analysis identified a large preoperative end-systolic diameter and the need to use tricuspid annuloplasty as significant independent predictors of postoperative fractional shortening; the use of chordal preservation (n = 35) was not a predictor of postoperative fractional shortening. A good outcome was predicted at a preoperative end-systolic diameter of 40 mm: probability of death or heart failure was .0001, and predicted mean postoperative fractional shortening was 0.27 after mitral valve replacement without tricuspid annuloplasty. CONCLUSIONS: When preoperative end-systolic diameter is more than 50 mm, a poor postoperative outcome is predicted despite chordal preservation in relatively young patients with rheumatic mitral regurgitation, and alternative strategies should therefore be considered. When preoperative end-systolic diameter is 40 mm or less, an excellent outcome is predicted, and close observation without surgery would appear to be reasonable in the absence of symptoms.

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)

Evidence against a myocardial factor as the cause of left ventricular dilation in active rheumatic carditis.

OBJECTIVES: The aim of this study was to determine whether left ventricular dilation and congestive heart failure in patients with acute rheumatic fever with carditis are accompanied by left ventricular contractile dysfunction. BACKGROUND: Acute rheumatic fever with carditis involves both the myocardium and endocardium, with consequent valvular regurgitation. The relative contribution of volume overload induced by valvular regurgitation and myocardial dysfunction due to rheumatic myocarditis to the overall degree of left ventricular dilation and congestive heart failure in these patients is unknown. METHODS: To investigate this, we evaluated 32 patients (15 male, 17 female, mean age 14 +/- 3 years) with documented active carditis and congestive heart failure. All 32 patients were found to have significant isolated mitral regurgitation or combined mitral and aortic regurgitation. Echocardiographic analysis of left ventricular dimensions and systolic performance was performed before and after isolated mitral or combined mitral and aortic valve replacement and the results were compared with those in 19 control subjects matched for age, gender and body surface area. RESULTS: Both preoperative left ventricular end-diastolic diameter and percent fractional shortening were significantly increased in patients compared with control subjects (57 +/- 7 vs. 43 +/- 3 mm, p < 0.001, and 38 +/- 6% vs. 33 +/- 1%, p < 0.001, respectively). After valve replacement, left ventricular end-diastolic diameter decreased significantly (57 +/- 7 to 47 +/- 6 mm, p < 0.001). Although percent fractional shortening decreased significantly postoperatively (38 +/- 6% to 32 +/- 6%, p < 0.001), the postoperative percent fractional shortening did not differ from that in control subjects (32 +/- 6% vs. 33 +/- 1%, p = NS). CONCLUSIONS: The results of this study indicate that left ventricular dilation and heart failure in patients with acute rheumatic carditis rarely occur in the absence of hemodynamically significant regurgitant valve lesions. Furthermore, rapid reduction in left ventricular dimensions and preservation of fractional shortening after isolated mitral or combined mitral and aortic valve replacement suggest that rheumatic carditis is not accompanied by any significant degree of myocardial contractile dysfunction.

Effectiveness of amiodarone and electrical cardioversion for chronic rheumatic atrial fibrillation after mitral valve surgery.

Thirty consecutive patients with chronic rheumatic atrial fibrillation (AF) > or = 3 months after successful mitral valve surgery and left atrial diameter < or = 60 mm were treated with oral amiodarone. Protocol included high loading dosages of amiodarone for 4 weeks, and if conversion to sinus rhythm (SR) was not achieved then electrical cardioversion was performed. Patients converted to SR were maintained on low-dose amiodarone for another 4 weeks when treatment was discontinued. Overall, 23 patients (77%) converted to SR after 4 weeks of therapy: 12 (40%) taking amiodarone alone and 11 (37%) with the addition of electrical cardioversion. The duration of AF > 48 months was an adverse factor in the ability to restore SR. Sixteen patients (70%) remained in SR at a mean follow-up of 17 months. The duration of AF < or = 48 months alone or in combination with left atrial diameter < or = 45 mm were the best predictors for long-term maintenance of SR. Thus, short-term amiodarone with or without electrical cardioversion is effective and safe in the treatment of chronic rheumatic AF after mitral valve surgery. The duration of AF and left atrial size can be used to identify patients with successful outcome.

Results of percutaneous balloon mitral valvotomy in young adults.

The results of percutaneous balloon mitral valvotomy (PBMV) were evaluated in 235 young patients (mean age 29 +/- 11 years) with symptomatic rheumatic mitral stenosis, and the single-balloon Inoue technique was compared with the double-balloon Mansfield technique. PBMV was associated with a significant increase in Gorlin mitral valve area (0.78 +/- 0.23 to 1.61 +/- 0.64 cm2; p < 0.001), and improvement in New York Heart Association functional class (2.78 +/- 0.59 to 1.28 +/- 0.58; p < 0.001). Mitral regurgitation increased significantly (0.4 +/- 0.6 to 1.3 +/- 1.0; p < 0.001), but was significant (> or = 3+) only in 19 patients (8%). Comparison of the Inoue and Mansfield techniques showed a significantly lower Gorlin mitral valve area after PBMV (1.55 +/- 0.56 vs 1.74 +/- 0.74 cm2; p < 0.05), but a lower incidence of mitral regurgitation by color Doppler echocardiography (1.1 +/- 0.7 vs 1.5 +/- 0.8; p < 0.05) in the Inoue group. Patients were divided into those with nonpliable (valve score > 8; group I) and pliable (score < or = 8; group II) valves. Although significant increases in mitral valve area were obtained in both groups, mitral valve area by planimetry was significantly lower in group I (1.49 +/- 0.46 vs 1.86 +/- 0.44 cm2; p < 0.05), whereas there was no difference in the amount of color Doppler mitral regurgitation (1.5 +/- 1.0 vs 1.2 +/- 0.7; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term (3-month) effects of a new beta-blocker (nebivolol) on cardiac performance in dilated cardiomyopathy.

OBJECTIVES: This study examined the long-term (3-month) effects of nebivolol, a new beta-adrenergic blocking agent, on cardiac performance in patients with dilated cardiomyopathy. BACKGROUND: Several beta-blocking drugs have been reported to have a beneficial hemodynamic effect in patients with dilated cardiomyopathy, but few data obtained in a placebo-controlled randomized study have addressed the mechanisms of improvement. METHODS: Twenty-four patients with dilated idiopathic (n = 22) or ischemic (n = 2) cardiomyopathy (ejection fraction 0.15 to 0.40) in stable New York Heart Association functional class II or III were entered into a double-blind randomized trial of nebivolol, a new, potent, selective beta 1-antagonist. Exercise time, invasive hemodynamic data (12- and 24-h monitoring) and variables of left ventricular function were examined at baseline and after 3 months of orally administered nebivolol (1 to 5 mg/day, n = 11) or placebo (n = 13). RESULTS: Heart rate decreased (group mean 85 to 71 beats/min vs. 87 to 87 beats/min with placebo) and stroke volume increased significantly (group mean 43 to 55 ml vs. 42 to 43 ml) with nebivolol; decreases in systemic resistance, systemic arterial pressure, wedge pressure and pulmonary artery pressure were not significantly different from those with placebo. Similar hemodynamic results were obtained in the catheterization laboratory. Analysis of high fidelity measurements of left ventricular pressure showed a decrease in left ventricular end-diastolic pressure in the nebivolol group (group mean 21 to 15 vs. 24 to 20 mm Hg with placebo) but no change in the maximal rate of pressure development or in two variables of left ventricular relaxation (maximal negative rate of change of left ventricular pressure [dP/dtmax] and the time constant tau). Left ventricular mass decreased (p = 0.04). Despite a decrease in heart rate with nebivolol, there was a slight decrease in left ventricular end-diastolic volume (p = NS). End-systolic volume tended to decrease (p = 0.07) despite no reduction in end-systolic stress. The net result was a significant increase in ejection fraction (group mean 0.23 to 0.33 vs. 0.21 to 0.23 with placebo), presumably as a result of an increase in contractile performance. This effect was corroborated by an increase in a relatively load-independent variable of myocardial performance. CONCLUSIONS: Nebivolol improved stroke volume, ejection fraction and left ventricular end-diastolic pressure, not through a measurable reduction in afterload or a lusitropic effect, but by improving systolic contractile performance.

Pulmonary hypertension is a contraindication to beta-blockade in patients with severe mitral stenosis.

Intravenous atenolol was given to 31 patients just before balloon mitral valvotomy to assess the hemodynamic efficacy and safety of beta-blockade in mitral stenosis complicated by pulmonary hypertension. Hemodynamic response in patients with pulmonary resistance > 600 dynes.sec.cm-5 (group 2, n = 17) was compared with those (group 1, n = 14) with a resistance below this value. In addition to a higher pulmonary arterial resistance (by design), patients in group 2 had a higher systemic resistance, lower cardiac index, and smaller mitral valve area compared with those in group 1. After atenolol infusion, transmitral gradient and left atrial pressure improved similarly. In spite of the decline in left atrial pressure, pulmonary vascular resistance increased in both groups, more in group 2 (847 +/- 398 dynes.sec.cm-5 to 135 +/- 648 dynes.sec.cm-5) than in group 1 (291 +/- 149 dynes.sec.cm-5 to 363 +/- 200; p < 0.001 for drug effect and p = 0.027 for group effect by two-way analysis of variance). Cardiac index declined similarly from 2.77 +/- 0.51 L/min/m2 to 2.37 +/- 0.37 L/min/m2 in group 1 and from 2.33 +/- 0.58 L/min/m2 to 1.92 +/- 0.54 L/min/m2 in group 2. Systemic pressure tended to decline only in group 2 (mean aortic pressure, 89 +/- 12 mm Hg to 89 +/- 12 mm Hg in group 1 and 90 +/- 9 mm Hg to 83 +/- 12 mm Hg in group 2; p = 0.06 for group effect).(ABSTRACT TRUNCATED AT 250 WORDS)

Complex balloon mitral valvuloplasty.

With increasing operator experience, balloon mitral valvuloplasty, like complex coronary angioplasty, has been successfully attempted on patients with mitral stenosis complicated by a variety of factors, including severe pulmonary hypertension, tricuspid regurgitation, poor ventricular function, previous commissurotomy, extremes of age and suboptimal valve anatomy. Only this latter factor should be considered a major deterrent to BMV, at least in hospitals where the technique has been acquired and where balloon catheters are affordable.

Excessive vasoconstriction in rheumatic mitral stenosis with modestly reduced ejection fraction.

OBJECTIVES: The primary hypothesis examined was that underfilling due to inflow obstruction accounts for modestly depressed ejection performance in mitral stenosis. Having found little evidence to support this hypothesis, we sought to determine other factors that might differentiate patients with different levels of ejection performance. METHODS: Ventricular load and performance were compared in two groups of patients before and immediately after successful balloon valvuloplasty that was not complicated by mitral regurgitation: those in whom prevalvuloplasty ejection fraction was > or = 0.55 (group I, n = 10) and those in whom it was < 0.55 (group II, n = 11). RESULTS: Before valvuloplasty, mitral valve area was less in group II (0.65 cm2) than in group I (0.84 cm2, p = 0.02), but end-diastolic pressure (12 vs. 12 mm Hg in group I), end-diastolic wall stress (46 vs. 44 kdynes/cm2 in group I) and end-diastolic volume (152 vs. 150 ml in group I) were not less in group II, nor were these variables significantly reduced compared with those of a normal control group. In group II, end-systolic volume was larger (77 vs. 55 ml in group I, p = 0.001) and cardiac output was less (3.1 vs. 3.6 liters/min in group I, p = 0.03), possibly owing to higher systemic vascular resistance (2,438 vs. 1,921 dynes.s.cm-5 in group I, p = 0.05) and end-systolic wall stress (273 vs. 226 kdynes/cm2 in group I, p = 0.06), although mean arterial pressure in the two groups was similar (91 vs. 84 mm Hg in group I, p = 0.22). Group II patients also had higher values for pulmonary vascular resistance (712 vs. 269 dynes.s.cm-5 in group I, p = 0.03) and mean pulmonary artery pressure (47 vs. 29 mm Hg in group I, p = 0.02) despite similar values for mean left atrial pressure (20 vs. 18 mm Hg in group I, p = 0.35). After valvuloplasty, mitral valve area increased by 2.5- and 3-fold, respectively, in group I (to 2.1 cm2) and group II (to 2.0 cm2). Modest increases in left ventricular end-diastolic pressure, end-diastolic stress and end-diastolic volume (+9%) after valvuloplasty were statistically significant only for group II. End-systolic wall stress did not decline in either group II (281 kdynes/cm2) or group I (230 kdynes/cm2), and ejection fraction failed to increase significantly (0.49 to 0.51 for group II and 0.62 to 0.61 for group I) after valvuloplasty. Contractile performance estimated with a preload-corrected ejection fraction-afterload relation was within or near normal limits in all 19 patients in whom it was assessed. CONCLUSIONS: Excessive vasoconstriction may account for the higher afterload, lower ejection performance and lower cardiac output observed in a subset of patients with mitral stenosis because contractile dysfunction could not be detected and left ventricular filling--which was not subnormal despite severe inflow obstruction--improved only modestly after valvuloplasty.

Effects of long-acting nifedipine on casual office blood pressure measurements, 24-hour ambulatory blood pressure profiles, exercise parameters and left ventricular mass and function in black patients with mild to moderate systemic hypertension.

Thirty-nine black patients with mild to moderate hypertension were treated for 1 year with various long-acting preparations of nifedipine, during which time serial changes in 24-hour ambulatory blood pressure (BP), exercise performance, left ventricular (LV) mass index and LV systolic function were evaluated. Mean 24-hour ambulatory BP decreased from 156 +/- 15/99 +/- 8 to 125 +/- 10/79 +/- 6 mm Hg at 1 year (p less than 0.0001). LV mass index decreased from 130 +/- 40 to 114 +/- 39 g/m2 at 6 weeks (p less than 0.005) and to 95 +/- 32 at 1 year (p less than 0.0001). There was a significant reduction in septal and posterior wall thickness from 11.0 +/- 2.0 to 9.3 +/- 2.0 mm (p less than 0.0001) and from 10.9 +/- 2.0 to 9.3 +/- 2.0 mm (p less than 0.005), respectively. Cardiac index and fractional shortening changed insignificantly from 2.9 +/- 0.7 to 2.9 +/- 0.6 liters/min/m2, and from 35 +/- 5 to 36 +/- 6%, respectively. At 1 year, using a modified Bruce protocol, exercise time increased from 691 +/- 138 to 845 +/- 183 seconds (p less than 0.05); peak exercise and 1 minute post-effort systolic BP decreased from 240 +/- 26 to 200 +/- 21 mm Hg and from 221 +/- 27 to 169 +/- 32 mm Hg (p less than 0.05), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)