CLINICAL STUDIES
Peripartum cardiomyopathy: analysis of clinical outcome, left ventricular function, plasma levels of cytokines and Fas/APO-1
Karen Sliwa, MD*  ,
Daniel Skudicky, MD*,
Anette Bergemann, MD* ,
Geoffrey Candy, MSc* ,
Adrian Puren, MD, PhD and
Pinhas Sareli, MD, FACC, FRCP*
* Department of Cardiology and Department of Nuclear Medicine, Baragwanath Hospital, Johannesburg, South Africa
Department of Hematology and Molecular Medicine, University of the Witwatersrand, Johannesburg, South Africa
Manuscript received May 11, 1999;
revised manuscript received October 5, 1999,
accepted November 17, 1999.
Reprint requests and correspondence: Dr. Daniel Skudicky, Department of Cardiology, Baragwanath Hospital, P.O. Bertsham 2013, Johannesburg, South Africa
psareli{at}iafrica.com
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Abstract
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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.
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Abbreviations and Acronyms
| | ACE | = angiotensin-converting enzyme | | FC | = functional class | | iNOS | = inducible nitric oxide | | NYHA | = New York Heart Association | | PPC | = peripartum cardiomyopathy | | TNF | = tumor necrosis factor |
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Peripartum cardiomyopathy (PPC) is a disorder of unknown etiology in which left ventricular dysfunction and symptoms of heart failure occur between the last trimester of pregnancy and up to the first six months postpartum. Estimates of incidence range from 1:15,000 to 1:13,000 live births (1), and it appears to be more common in African women (2–4). A high mortality rate and overall poor clinical outcome has been reported in a high percentage of these patients; however, these data are derived from studies that included a small number of patients, and in many of them there was no echocardiographic data (4–6). Furthermore, most of the previous studies were conducted when angiotensin-converting enzyme (ACE) inhibitors were not routinely used in the treatment of heart failure, and no study reported the use of beta-adrenergic blocking agents. Therefore, the possible impact of these drugs on the outcome of patients with peripartum cardiomyopathy is not well documented.
There is accumulating evidence that inflammatory cytokines play an important role in the pathogenesis and progression of heart failure (7–8). Elevated levels of circulating cytokines have been described in advanced heart failure of other etiologies (9). However, there is a paucity of data regarding cytokine expression in patients with PPC.
Loss of myocytes due to apoptosis or programmed cell death occurs in patients with heart failure and may contribute to progressive myocardial dysfunction (10–11). Fas is an apoptosis-signalling surface receptor known to trigger programmed cell death in a variety of cell types (12–13). Increased plasma levels of soluble Fas receptors have been reported in patients with heart failure (14) although its significance is still not clearly established. There are no data regarding the plasma concentrations of Fas receptors in patients with peripartum cardiomyopathy.
The purpose of the study was: 1) to evaluate the outcome of patients with PPC on current treatment for heart failure, 2) to assess the circulating plasma levels of cytokines tumor necrosis factor (TNF)-alpha and interleukin-6 and Fas receptors in this population, and 3) to identify predictors of prognosis.
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Methods
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Study design and patient enrollment.
The protocol was approved by the ethics committee of the University of the Witwatersrand and the prescription and therapeutic committee of Baragwanath Hospital. All patients gave informed consent before study entry. Between November 1996 and November 1997, we enrolled prospectively 29 consecutive black patients with newly diagnosed PPC attending Baragwanath Hospital cardiac clinic. During that period, more than 17,000 deliveries were performed at the hospital. The study population fulfilled the following inclusion criteria: 1) age  16 years, 2) New York Heart Association (NYHA) functional class (FC) II–IV, 3) symptoms of congestive heart failure that developed in the last trimester of pregnancy or in the first six months postpartum, 4) no other identifiable cause of heart failure and no demonstrable cardiac disease in the last three months of pregnancy, 5) left ventricular ejection fraction  40% by transthoracic echocardiography, 6) sinus rhythm, and 7) eligible patients in whom high quality echocardiographic images could be obtained. Exclusion criteria were: 1) chronic obstructive pulmonary disease, 2) significant organic valvular heart disease, 3) systolic blood pressure >170 mm Hg or diastolic blood pressure >105 mm Hg, 4) clinical conditions other than cardiomyopathy that could increase the cytokine levels, (i.e., rheumatoid arthritis, sepsis, acquired immunodeficiency syndrome), 5) significant liver disease (defined as enzymes >2 times the upper limit of normal), and 6) severe anemia (hemoglobin concentration <9 gm/dl).
All patients received treatment with digoxin, diuretics and enalapril. Patients with an ejection fraction 25% or left ventricular thrombus received anticoagulation therapy. Carvedilol was added after resolution of overt heart failure, and the dose was slowly titrated up to a target of 25 mg twice daily if well tolerated. Patients attended the cardiac clinic at least once a month.
Cytokine and Fas/APO-1 plasma levels.
Fifteen milliliters of blood were withdrawn from an antecubital vein and collected into prechilled evacuated tubes containing ethylenediaminetetraacetic acid. Plasma was separated by centrifugation at 2,500 rpm for 12 min within 15 min of collection. Aliquots were stored at –70°C. Cytokine measurements were performed using a commercially available enzyme-linked immunoassay (Amersham, Maidstone). The average of triplicate undiluted determinations was calculated. Fas/APO-1 was measured with a nonisotopic quantitative immunoassay (Calbiochem) appropriately diluted. In order to obtain reference values for the population studied, plasma was obtained from 20 age-matched black healthy volunteers. None of the patients or normal volunteers received anti-inflammatory drugs in the four weeks before the cytokine determination.
Echocardiographic studies.
Two-dimensional targeted M-mode echocardiography with Doppler color flow mapping was performed using a Hewlett Packard Sonos 5500 echocardiograph attached to a 2.5 or 3.5 Mhz transducer. All studies were recorded on videotape and were done by the same operator. Left ventricular dimensions were measured according to the American Society of Echocardiography guidelines (15). For left ventricular measurements, an average of 3 beats was obtained. The left ventricular ejection fraction was determined as previously described (16). None of the patients had paradoxical septal motion (no patient had left bundle branch block). Diastolic mitral flow was assessed by pulsed-wave Doppler echocardiography from the apical four-chamber view. The E-wave deceleration time was measured as the interval between the peak early diastolic velocity and the point at which the steepest deceleration slope was extrapolated to the zero line. A diastolic restrictive pattern was defined if the transmitral E/A ratio was 2 or if it was 1 to 2 with an E-wave deceleration time 140 ms (17). Patients were arbitrarily defined as improvers if they fulfilled all of the following criteria at the end of the study: 1) FC I or II, 2) a relative increment in ejection fraction 20% from baseline, and 3) left ventricular ejection fraction 30%.
Statistical analysis.
Data are presented as mean ± standard deviation. Group comparisons were made by use of Mann-Whitney U test or binomial test as appropriate. Wilcoxon matched pairs test was used for comparison of baseline data and the results after six months. Logistic regression analysis was used to predict the probability of improvement (as defined in the echocardiography section). Data were analyzed on a personal computer by use of a commercially available statistical program (Statistica). Significance was assumed at a two-tailed value of p < 0.05.
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Results
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Baseline characteristics of the study population are shown in Table 1. Six of the 29 patients were primiparous. None of them had twin or multiple pregnancies. All patients started with symptoms in the postpartum period: 17 patients within three months after delivery and 12 patients between three and six months after delivery. At baseline nine patients were in NYHA FC II, 12 in FC III and 8 in FC IV. Left ventricular thrombi were detected on echocardiography in six patients. Eight patients (28%) died during the study period, two patients moved to remote areas and two were lost to follow-up. All deaths were due to progression of heart failure (six patients died in hospital). Seven of the eight deaths occurred during the first three months after onset of symptoms. All patients received furosemide (mean dose 156 ± 27 mg), digitalis 0.25 mg daily and enalapril 20 mg twice a day. Mean dose of carvedilol was 27 ± 8 mg daily. Since all deaths were due to progression of heart failure, patients who died were classified in FC IV at the latest follow-up. There was an improvement in FC in 13 patients. In four patients the FC remained unchanged and deteriorated in eight. The comparison between clinical and echocardiographic variables at baseline and at six months for the 17 patients who completed the study is shown in Table 2.
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Table 2 Clinical Variables, Left-Ventricular Dimensions and Functional Class From the 17 Patients Who Completed the 6 Month Trial
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Left ventricular function and dimensions.
Patients who completed six months of treatment showed a significant improvement in left ventricular ejection fraction (Table 2, Fig. 1). At six months, left ventricular ejection fraction improved from 27 ± 10% to 43 ± 16%, p = 0.00003, with an increment of more than 10 units in 10 patients (28 ± 4% to 52 ± 8%, p = 0.000008). A diastolic restrictive pattern was present in 21 of the 29 patients at baseline. From the 17 patients who completed the study, 13 (76%) had a restrictive pattern at baseline, but only 7 (41%) after six months of treatment.
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Figure 1 Changes in left ventricular ejection fraction from baseline to six months. EF = ejection fraction.
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Cytokine levels.
Tumor necrosis factor-alpha and interleukin-6 plasma levels were significantly higher in the study population compared with 20 gender and age matched healthy volunteers (6.3 ± 4.7 pg/ml and 7.9 ± 4 pg/ml vs. 1.44 ± 1.3 pg/ml and 1.4 ± 1.8 pg/ml, respectively, p < 0.0001 for both). There was no significant correlation between cytokine or Fas levels and NYHA FC, time of onset of symptoms or left ventricular dimensions and function. Interleukin-6 concentration was significantly higher in the six patients with left ventricular thrombus compared with the rest of the study population (14.4 ± 7 pg/ml vs. 5.7 ± 4 pg/ml, p = 0.0004). There were no other clinical or echocardiographic baseline differences between these two groups.
Fas/APO-1.
The soluble form of the Fas/APO-1 was significantly higher in the PPC patients compared with the healthy volunteers (5.99 ± 4 U/ml vs. 0.84 ± 0.21 U/ml, p = 0.0003). There was no significant correlation between sFas/APO-1 and cytokine levels.
Predictors of outcome.
Twelve patients (48%) were defined as improvers according to our prespecified criteria. Patients who were defined as improvers had a higher baseline ejection fraction compared with the nonimprovers (29 ± 5% vs. 20 ± 10%, p = 0.004) and higher baseline systolic blood pressure (114 ± 14 mm Hg vs. 102 ± 15 mm Hg, p = 0.04). No other significant differences in baseline clinical or echocardiographic variables were observed between these two groups. Of all the baseline variables analyzed, only left ventricular ejection fraction emerged as an independent predictor of improvement in the logistic regression analysis (p = 0.04). Baseline levels of cytokines and Fas receptors were similar in improvers and nonimprovers, but plasma levels of Fas were higher in the eight patients who died compared with the survivors (8.98 ± 4 U/ml vs. 5.33 ± 3 U/ml, p = 0.02).
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Discussion
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Clinical outcome and changes in left ventricular function.
Demakis et al. (5) described the natural history of patients with PPC observed between 1947 and 1967 at Chicago Cook County Hospital. With standard medical therapy for congestive heart failure available at that time, 50% of the patients improved clinically, but the effects on left ventricular function were not reported. In our study, patients with PPC treated with "optimal" current medical therapy for heart failure had a similar clinical outcome compared with earlier reports. The mortality rate was 32% at six months. Seven of the eight deaths occurred within the first three months after onset of symptoms. Consistent with previously published data (5,18), 52% of the patients in this study improved clinically, and 10 patients (34%) showed a remarkable improvement in left ventricular function that could be attributed to the treatment with ACE inhibitors and carvedilol. However, Midei et al. (19) reported an increment in fractional shortening from 17% to 28% in a group of 18 patients with PPC treated with supportive treatment for heart failure, plus the addition of immunosuppressive therapy in 10 of them.
In our study, ejection fraction at presentation was the strongest predictor of outcome, and this was in accordance with previously published data (20). However, variables previously reported by others (4,5,21) as predictors of outcome such as age above 30 years, higher parity, later onset of symptoms after delivery and twin deliveries were not confirmed in this study.
Cytokines and soluble Fas/APO-1 receptors.
In patients with heart failure, inflammatory cytokines are increased and correlate with the severity of symptoms (8–9) and prognosis (8,22). Belder et al. (23) found no detectable plasma TNF-alpha levels in three patients with PPC. However, the calcium-independent inducible nitric oxide iNOS synthase in heart tissue from these patients was elevated. Contrary to that, in this study we found a significant elevation in the plasma levels of cytokines. However, there was no correlation between the cytokine levels and left ventricular function or outcome.
Recent reports have suggested that interleukin-6 has a procoagulant effect via an increase in the expression of prothrombotic proteins such as PAI-1 (24). In 21% of our study group, a thrombus was detected in the left ventricular cavity on echocardiography. Interestingly, the Interleukin-6 levels in patients with left ventricular thrombus were significantly higher compared with the rest of the study population.
Fas and Fas ligand are cell surface proteins playing a key role in programmed cell death (25,26). Increased percentages of apoptotic cardiomyocytes (10,11) and elevated levels of plasma soluble Fas (14) were reported in patients with chronic heart failure of other etiologies, but there are no data regarding soluble Fas levels in patients with PPC. In this study, plasma Fas levels were significantly elevated compared with the normal volunteers. Furthermore, baseline soluble Fas concentrations were higher among the patients who died during the study period. Due to the small sample size, we cannot definitely established the role of Fas levels as a predictor of mortality in this population, but this deserves further investigation.
Conclusions.
Similar to other etiologies of heart failure, we found elevated levels of cytokines and Fas/APO-1 in patients with PPC. Despite the addition of ACE inhibitors and beta-blockers to the therapy, the mortality remains very high. However, most of the patients that were alive six months after the initiation of therapy improved left ventricular function significantly.
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Footnotes
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This study was partially funded by Helen Griffith Fund, University of the Witwatersrand, Johannesburg, South Africa.
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Abstract
Methods