Daniel Skudicky

Peripartum cardiomyopathy: analysis of clinical outcome, left ventricular function, plasma levels of cytokines and Fas/APO-1

OBJECTIVES 1) To evaluate the outcome of patients with peripartum cardiomyopathy (PPC) on current treatment for heart failure, 2) to assess the circulating plasma levels of cytokines and Fas receptors and 3) to identify predictors of prognosis. BACKGROUND Previous studies in patients with PPC were done when angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking agents were not routinely used in heart failure. Inflammatory cytokines play an important role in the pathogenesis and progression of heart failure of other etiologies. However, there is a paucity of data regarding cytokine expression in patients with PPC. Plasma concentrations of Fas receptors (an apoptosis-signalling receptor) have not been reported in this population. METHODS We followed prospectively 29 consecutive black women with PPC. All patients were treated with diuretics, digoxin, enalapril and carvedilol. Echocardiograms were performed at baseline and after six months of treatment. Cytokine and soluble Fas/APO-1 plasma levels were measured at baseline. RESULTS Tumor necrosis factor-alpha, interleukin-6 and Fas/APO-1 levels were significantly elevated in the study patients compared with 20 healthy volunteers. Eight patients died. sFas/APO-1 levels were significantly higher in patients who died compared with survivors (8.98 +/- 4.5 vs. 5.33 +/- 3 U/ml, respectively, p = 0.02). At six months, ejection fraction improved from 26.7 +/- 10 to 42.7 +/- 16%, p = 0.00003, with an increment of more than 10 U in 10 patients (28.1 +/- 4 to 51.9 +/- 8%, p = 0.000008). CONCLUSIONS Cytokine and sFas levels are elevated in patients with PPC. Despite treatment with ACE inhibitors and beta-blockers, mortality remains high. However, in 34% of the patients, left ventricular function almost completely normalized.

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.

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.

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.

Beneficial Effects of Pentoxifylline in Patients With Idiopathic Dilated Cardiomyopathy Treated With Angiotensin-Converting Enzyme Inhibitors and Carvedilol Results of a Randomized Study

Background —We previously reported beneficial effects of pentoxifylline, a xanthine-derived agent known to inhibit the production of tumor necrosis factor-&agr;, in patients with idiopathic dilated cardiomyopathy treated with diuretics, digoxin, and ACE inhibitors. Since then, 3 large clinical trials showed important clinical benefits of &bgr;-blockers in this population. Therefore, we designed the present study to establish whether in patients with heart failure already receiving treatment with ACE inhibitors and &bgr;-blockers, the addition of pentoxifylline would have an additive beneficial effect. Methods and Results —In a single-center, prospective, double-blind, randomized, placebo-controlled study, 39 patients with idiopathic dilated cardiomyopathy were randomized to pentoxifylline 400 mg TID (n=20) or placebo (n=19) if they had a left ventricular ejection fraction <40% after 3 months of therapy with digoxin, ACE inhibitors, and carvedilol. Primary end points were New York Heart Association functional class, exercise tolerance, and left ventricular function. Patients were followed up for 6 months. Five patients died (3 in the placebo group). Patients treated with pentoxifylline had a significant improvement in functional class compared with the placebo group (P =0.01), with an increment in exercise time from 9.5±5 to 12.3±6 minutes (P =0.1). Left ventricular ejection fraction improved from 24±9% to 31±13%, P =0.03, in the treatment group. Conclusions —In patients with idiopathic dilated cardiomyopathy, the addition of pentoxifylline to treatment with digoxin, ACE inhibitors, and carvedilol is associated with a significant improvement in symptoms and left ventricular function.

The addition of pentoxifylline to conventional therapy improves outcome in patients with peripartum cardiomyopathy.

We have reported previously that despite treatment with angiotensin‐converting enzyme inhibitors and β blockers, the outcome of patients with peripartum cardiomyopathy (PPC) remains unfavorable. Similar to other etiologies of left ventricular dysfunction, we found elevated levels of tumor necrosis factor‐α (TNF‐α) in this group of patients. In the present study we sought to evaluate the effects of pentoxifylline, a drug known to inhibit the production of TNF‐α, on clinical status, left ventricular function, and circulating plasma levels of TNF‐α, in patients with PPC. We followed prospectively 59 consecutive women with PPC. The first 29 patients (group 1) were treated with diuretics, digoxin, enalapril and carvedilol. The next 30 consecutive patients (group 2) received pentoxifylline 400 mg TID in addition to the previous therapy. Clinical evaluation, echocardiograms and TNF‐α determinations were performed at baseline and after 6 months of treatment. Patients in the pentoxifylline group were older and had a higher E/A ratio. Nine patients died (eight in group 1, P‐0.009 between groups). A combined end‐point of poor outcome defined as either death, failure to improve the left ventricular ejection fraction >10 absolute points or functional class III or IV at latest follow‐up, occurred in 52% of patients in group 1 and 27% of patients in group 2 (P‐0.03). Treatment with pentoxifylline (P‐0.04) was the only independent predictor of outcome. In conclusion, the results of this study suggest that the addition of pentoxifylline to conventional treatment, improves outcome in patients with peripartum cardiomyopathy.

Frequency and severity of intravascular hemolysis after left-sided cardiac valve replacement with medtronic hall and St. Jude medical prostheses, and influence of prosthetic type, position, size and number

Intravascular hemolysis occurs often in patients with mechanical heart valve prostheses, but in most cases is of mild degree and subclinical. The severity of hemolysis is reported to be related to the type, position and size of prostheses used, as well as the presence of valve malfunction. Hemolysis was evaluated in 170 patients with St. Jude Medical (SJM) and 80 patients with Medtronic Hall (MH) prostheses, with normal mechanical function. The presence and severity of hemolysis was assessed on the basis of serum lactic dehydrogenase, serum haptoglobin, blood hemoglobin and reticulocyte levels as well as the presence of schistocytes. Overall, patients with SJM prostheses had greater frequency (51.2 vs 18.7%, p < 0.005) and severity (p < 0.005) of hemolysis than patients with MH prostheses, irrespective of position and size. No patient had decompensated anemia. The frequency of hemolysis was similar in both groups with double-valve replacement, whereas severity was greater with SJM than MH prostheses (p < 0.001). The number and position of the prostheses were correlated with severity of hemolysis: Double-valve replacement and mitral position were correlated with greater hemolysis than single-valve replacement (p < 0.01) and aortic position (p < 0.01). Valve size, cardiac rhythm and time from operation did not correlate either with frequency or severity of hemolysis. It is concluded that in normally functioning SJM and MH prostheses: (1) hemolysis is frequent but never severe; (2) SJM demonstrates greater frequency and severity when compared with MH valve; and (3) number, position, but not size, significantly affect the severity of hemolysis.

Long-Term Follow-Up of Rheumatic Patients Undergoing Left-Sided Valve Replacement With Tricuspid Annuloplasty—Validity of Preoperative Echocardiographic Criteria in the Decision to Perform Tricuspid Annuloplasty

Between September 1989 and December 1991, modified De Vega tricuspid annuloplasty was performed in 43 patients who survived surgery for mitral or mitral plus aortic valve replacement. The preoperative indications for tricuspid annuloplasty were moderate to severe tricuspid regurgitation (TR) in 33 patients and mild or no TR but with a dilated tricuspid annulus (> or =30 mm) as measured by 2-dimensional echocardiography at end-diastole in 10 patients. The mean age was 31 +/- 13 years. The mean duration of follow-up was 57 +/- 18 months. Overall long-term mortality was 12%. On Doppler color flow mapping, postoperative severe TR was present in 1 patient and moderate TR in 4 patients at latest follow-up. The tricuspid annulus diameter decreased from 37 +/- 5 mm preoperatively to 24 +/- 6 mm at latest follow-up. During the study period, an additional 77 patients underwent mitral valve replacement or double valve replacement, but without tricuspid annuloplasty. Within this group, 38 patients had a preoperative tricuspid annulus diameter of > or =30 mm, and 5 of these patients (13%) developed moderate or severe TR in the postoperative period, which may have been prevented had clinicians adhered to the preoperative indications for tricuspid annuloplasty. Thus, preoperative echocardiographically documented moderate or severe TR or a tricuspid annulus diameter of > or =30 mm are valid indications for performing tricuspid annuloplasty; modified De Vega tricuspid annuloplasty is a durable procedure in rheumatic patients; it appears that reducing the diastolic tricuspid annulus diameter to 24 mm is adequate to prevent residual TR in the long term.

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.

Efficacy of mitral balloon valvotomy in reducing the severity of associated tricuspid valve regurgitation.

In patients with rheumatic mitral stenosis, concomitant tricuspid regurgitation (TR) has been reported in 22 to 35%.1,2 The mechanism of TR may be due to rheumatic disease of the tricuspid leaflets themselves, or functional secondary to pulmonary hypertension with subsequent dilatation of the right ventricle and tricuspid annulus.2–6 The management of TR in patients undergoing mitral valve replacement has been debated by several investigators and remains controversial.7–14 Although successful mitral valve surgery,2,15 and more recently, mitral balloon valvotomy (MBV)16–17 have both been shown to be associated with reductions in pulmonary arterial pressure and resistance, whether this is necessarily accompanied by an amelioration of TR is unknown. Data after mitral valve surgery are numerous but conflicting,7–14 and no studies are available on the effects of MBV, if any, on the severity of TR.