Delayed recovery in peripartum cardiomyopathy: an indication for long-term follow-up and sustained therapy

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1 European Journal of Heart Failure (2012) 14, doi: /eurjhf/hfs070 Delayed recovery in peripartum cardiomyopathy: an indication for long-term follow-up and sustained therapy Murat Biteker 1 *, Erkan İlhan 2, Gul Biteker 3, Dursun Duman 1, and Biykem Bozkurt 4 1 Department of Cardiology, Haydarpaşa Numune Education and Research Hospital, Turkey; 2 Department of Cardiology, Siyami Ersek Cardiovascular Surgery Center, Turkey; 3 Department of Obstetrics and Gynecology, Ortaca Yucelen Hospital, Turkey; and 4 Section of Cardiology, Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, and Winters Center For Heart Failure Research, Baylor College of Medicine, Houston, TX, USA Received 21 February 2012; revised 26 March 2012; accepted 12 April 2012; online publish-ahead-of-print 15 May 2012 Aims Persistence of left ventricular (LV) systolic dysfunction after 6 months of diagnosis is believed to be a marker of an irreversible cardiomyopathy in peripartum cardiomyopathy (PPCM). We sought to determine the length of time required for recovery of LV systolic function (LVSF) in patients with PPCM.... Methods Forty-two consecutive women with PPCM were enrolled in this prospective study. The minimum required time of and results follow-up for inclusion was 30 months. Each patient underwent transthoracic echocardiography, and plasma brain natriuretic peptide (BNP) and C-reactive protein measurement at admission, and every 3 months. Early recovery was defined as normalization of LVSF at 6 months post-diagnosis. Delayed recovery was defined if the length of time required for recovery of LVSF was longer than 6 months. Persistent left ventricular dysfunction (PLVD) was defined as an ejection fraction of,50% at the end of follow-up. Twenty patients (47.6%) recovered completely, 10 died (23.8%), and 12 (28.6%) had PLVD. Average time to complete recovery was 19.3 months after initial diagnosis (3 42 months). Early recovery was observed only in six patients (30%), whereas delayed recovery was observed in 14 out of 20 patients (70%). Patients with complete recovery were more likely to have a higher LV ejection fraction and smaller LV end-systolic dimensions at baseline.... Conclusion Full recovery of LVSF in PPCM patients often requires longer than 6 months Keywords Peripartum cardiomyopathy Late recovery Treatment Introduction Peripartum cardiomyopathy (PPCM) is an idiopathic or familial cardiomyopathy presenting with heart failure secondary to left ventricular (LV) systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause of heart failure is found. 1,2 Though no specific treatment strategies exist for PPCM, current therapeutic options consist of conventional supportive therapy for heart failure and it is similar to that of other forms of congestive heart failure in pregnancy. 2 4 This includes mainly symptom control, aiming at reduction in afterload and preload, augmentation of myocardial contractility, and anticoagulation therapy. In spite of the recent advances in the management of PPCM including bromocriptine therapy, 5 the course and outcome are usually unpredictable. Previous reports showed that most of the women with PPCM completely recover normal heart size and function, usually within 6 months of delivery 6 and if cardiac dysfunction persists beyond 6 months it is an indication of irreversible damage and portends worse survival. 3 However, a few recent studies have demonstrated the possibility of late recovery in patients with PPCM. 7 In this study, we aimed to determine the length of time required for recovery of left ventricular systolic function (LVSF) and predictors of recovery in patients with PPCM in Turkey. Methods Patients The inclusion criteria included: (i) symptoms of congestive heart failure that developed towards the end of pregnancy or in the first 5 months post-partum; (ii) no other identifiable cause of heart failure; (iii) * Corresponding author. Bankalar Caddesi, Horoz Apt, 4/7 Cevizli/Kartal, İstanbul, Turkey. Tel: , Fax: , murbit2@yahoo.com Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 896 M. Biteker et al. absence of recognizable heart disease before the last month of pregnancy; and (iv) left ventricular ejection fraction (LVEF),45% by transthoracic echocardiography. Patients with a history of significant hypertension or valvular heart disease were excluded. We enrolled 49 patients that matched the inclusion criteria. However, five patients were excluded from the study because they were lost to follow-up and two patients were excluded because they were determined to be noncompliant with their therapeutic regimens. Forty-two consecutive women with newly diagnosed PPCM admitted to two tertiary hospitals in Istanbul, Siyami Ersek Cardiovascular Surgery Center and Kosuyolu Kartal Heart Education and Research Hospital, between February 2005 and January 2009, who met the inclusion criteria were included in the study. All patients in the study were diagnosed with PPCM for the first time. Clinical evaluation including history, physical examination, and assessment of LVSF by transthoracic echocardiogram was performed at the time of admission, then every 3 months during the first year, every 6 months thereafter, and whenever clinically indicated. Complete blood count, routine biochemical analyses, and brain natriuretic peptide (BNP) and C-reactive protein concentrations were also determined. Mean follow-up period was months (range 4 65 months) including the patients who died. For the subgroup of 36 patients who survived beyond 12 months, the mean follow-up was months (range months) after the diagnosis of PPCM. Written informed consent was obtained from each patient before entry into the study and the protocol was approved by the Institutional Review Boards. Definition of clinical outcomes Early recovery was defined as resolution of heart failure symptoms or signs and normalization of LVSF (EF.50%) at 6 months post-diagnosis. Recovery was defined as delayed if the length of time required for recovery of LVSF was longer than 6 months. Persistent left ventricular dysfunction (PLVD) was defined as an EF of,50% at the latest follow-up. Delayed deterioration was defined as spontaneous deterioration of LV function after either complete recovery or partial recovery. Therapy All patients were treated with diuretics (furosemide), beta-blockers, and angiotensin-converting enzyme inhibitors. The angiotensin-converting enzyme inhibitor of choice was captopril (6.25 mg initial dose titrated up to 50 mg twice daily) which was used only in patients who were post-partum due to known teratogenic effects. The beta-blocker carvedilol was initiated after stabilization of decompensated heart failure, and the dose was slowly up-titrated to a target of 25 mg twice daily as tolerated. Patients with an EF 25% or LV thrombus received anticoagulation therapy for 6 months. Furosemide dose was adjusted as indicated according to clinical assessment during the study period. Fifteen patients also received digoxin therapy. Six patients required inotropic support, and two required an intra-aortic balloon pump at the time of referral. Standard transthoracic echocardiography was performed in all patients at baseline, then every 3 months during the first year and every 6 months thereafter for the duration of follow-up using the Vivid Three System (Vivid 3 pro, GE Vingmed, Milwaukee, WI, USA). Baseline LVEF was measured by transthoracic echocardiography using the modified Simpson s rule. Standard, two-dimensional, M-mode, and Doppler echocardiographic measurements were obtained in all patients. Left ventricular internal dimensions at end-diastole and endsystole were measured according to American Society of guidelines. 8 Statistical analysis Data were analysed using SPSS for Windows (version 15, SPSS Inc., Chicago, IL. USA). The continuous variables were expressed as mean + standard deviation and were compared between groups by two-tailed Student t-test. Non-parametric tests were also used when necessary (Mann Whitney U-test). Fisher s exact (x 2 ) test was used in comparison of categorical variables. Statistical differences among groups were tested by one-way analysis of variance (ANOVA) and Kruskal Wallis tests for parametric and non-parametric variables, respectively. Univariate and multivariate logistic regression analyses were conducted to identify variables predictive of recovery and death. Variables related to the hazard (risk) of an event were assessed using stepwise multivariable Cox proportional hazards models. For all analyses, P, 0.05 was considered statistically significant. Results Patients The mean age of the patients was years (range 18 35), and the number of parities ranged from one to four. Two patients (4.8%) had twin pregnancies and seven patients (16.7%) had gestational hypertension. Twelve patients (28.6%) were diagnosed during the pre-partum period and 30 (71.4%) were diagnosed post-partum (Table 1). Clinical outcomes Ten patients (23.8%) died between the sixth day of delivery and 5 years post-partum. Five of the deaths were due to progression of heart failure and the others were due to sudden death. All patients who suffered from sudden cardiac death had an EF of, 40% at their last visit. Of the remaining 32 survivors, 20 completely recovered (6 early recovery and 14 delayed recovery) and 12 were left with PLVD (Figure 1). The shortest time from diagnosis to recovery was 3 months and the longest time was 42 months. The LVEF values at the initial examination and at the last follow-up are shown in Figure 2. In the present study, the time to recovery of LVSF was. 1 year in 60% of the patients. Four patients (2 patients with complete recovery and 2 patients with partial recovery) showed delayed deterioration (12, 24, 26, and 34 months after diagnosis) during the study period. Of the four patients with spontaneous deterioration of LVSF, two patients with partial recovery were receiving full-dosage heart failure treatment, but two patients with complete recovery stopped taking their medications after recovery and had delayed deterioration at 24 and 34 months. Predictors of mortality In the population studied, mortality was high (23.8%). Significant differences were noted in the baseline characteristics between deceased patients and survivors; including LV end-systolic diameter ( cm vs cm, respectively, P ¼ 0.008) and LVEF ( % vs %, respectively, P,0.001) (Table 2).

3 Delayed recovery in peripartum cardiomyopathy 897 Table 1 Characteristics of study population (n 5 42) Age Parity Follow-up (months) Follow-up (months) a Onset of symptom (n,%) Pre-partum 12 (28.6) Post-partum 30 (71.4) NYHA (n,%) II 7 (16.7) III 13 (31.0) IV 22 (52.4) Atrial fibrillation (n, %) 5 (11.9) Hypertension (n, %) 7 (16.7) Diabetes mellitus (n, %) 2 (4.8) LVESD (cm) LVEDD (cm) LVEF (%) PASP (mmhg) Left ventricular thrombus 4 (9.5) Medication (n,%) Digoxin 15 (35.7) ACE inhibitor 34 (81.0) Diuretic 42 (100.0) Beta-blocker 38 (90.5) Intra-aortic balloon pump 2 (4.8) CRP (mg/dl) BNP (pg/ml) Values are given as the mean + SD or number (percentage) unless otherwise indicated. ACE, angiotensin-converting enzyme; BNP, brain natriuretic peptide; CRP, C-reactive protein; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic diameter; NYHA, New York Heart Association functional class; PASP, pulmonary artery systolic pressure. a After excluding six early deaths. Figure 1 Outcome in 42 patients with peripartum cardiomyopathy. PLVD, persistent left ventricular dysfunction. There were no significant differences in age, degree of parity, New York Heart Association (NYHA) functional capacity, pulmonary artery systolic pressure, or presence of LV thrombi at baseline. Sixth-month BNP levels were significantly higher in patients who died compared with patients who survived ( vs , respectively, P ¼ 0.002). On multivariate logistic regression analysis, baseline LVEF [adjusted odds ratio (OR) 2.184, 95% confidence interval (CI) ; P, 0.05] and LV end-systolic diameter (adjusted OR 2.534, 95% CI ; P, 0.05) remained as significant variables associated with death. Predictors of recovery There were no significant differences in age, degree of parity, NYHA functional capacity, medication, pulmonary artery systolic pressure, LV end-diastolic diameter, or presence of LV thrombi between patients who recovered completely and those who did not recover (Table 3). Initial LV end-systolic diameter ( cm vs cm, P ¼ 0.003, respectively) was significantly lower, and initial LVEF ( % vs %, P ¼ 0.001, respectively) values were significantly higher in patients with complete recovery (early + delayed recovery) compared with the patients who did not recover. On multivariate logistic regression analysis, only baseline LVEF (adjusted OR 1.193, 95% CI ; P, 0.05) remained as a significant variable associated with recovery. Baseline BNP and C-reactive protein values were similar in patients with early recovery, delayed recovery, and non-recovery (Table 3). Discussion The major finding of our study is that although 30% of patients diagnosed in Turkey who recover do so within the first 6 months post-partum, there is a significant proportion of patients with PPCM who continue to recover beyond 6 months. Indeed in our study, among the patients who recovered, 60% achieved recovery beyond a year. The second important finding is that there is a subgroup of patients who may develop late deterioration after 12 months in LV function after an initial recovery. Finally, we demonstrated that advanced remodelling and low LVEF were predictors of mortality and non-recovery. Previous studies have reported that LVSF recovery usually occurs within 6 months of diagnosis in many of the patients, and if the heart failure persists after 6 months it is probably irreversible and associated with a worse survival in PPCM. 2,3 Elkayam et al. evaluated 40 patients with longitudinal follow-up of months and showed that improvement usually occurred within the first 6 months after the diagnosis. 6 However, two recent studies have demonstrated late recovery in patients with PPCM. 7,9 In the first study, Fett et al. evaluated 116 PPCM patients (mean follow-up time was 35 months) and detected slow responders. 7 Despite the lower recovery rate of Haitian PPCM patients (28%) possibly related to the lack of consistent use of betablockade prior to 2008 due to economic factors, 17 out of the 32 patients (53.1%) recovered over 18 months (range 3 48 months). In the second study, Modi et al. retrospectively evaluated 44 patients with PPCM in the USA. 9 Although the majority of the

4 898 M. Biteker et al. Figure 2 Left ventricular ejection fraction at the initial examination and at the last follow-up in patients with delayed recovery (A), early recovery (B), persistent left ventricular dysfunction (C), and mortality (D). patients were African American and indigent, the 9-year nonrecovery rate was 30% and median time to recovery was 54 months. In our study over an average follow-up period of 38.9 months, the overall non-recovery rate of our Turkish metropolitan cohort was 52%, with a mortality rate of 23.8% despite a high prevalence of use of beta-blockers (91%) and angiotensin-converting enzyme inhibitors (81%). The non-recovery rates in our cohort are lower than in the Haitian cohort described by Fett et al. 7 but higher than the US cohorts described by Modi et al. (mortality rate 15.9%) 9 or others (mortality rates 0 5%). 10 We have recently reported 30% and 25% mortality in Turkish women with PPCM. 11,12 In the present study almost half of the patients recovered completely (47.6%), but the mortality rate was still high (23.8%). This can potentially be explained by higher angiotensin-converting enzyme inhibitor and beta-blocker use than the Haitian patients, but lower use of bromocriptine, devices (implantable cardioverter defibrillator, cardiac resynchronization therapy), or advanced heart failure therapies such as ventricular assist device support or cardiac transplantation than the US patients. Importantly, however, similar to the above studies, we demonstrated that there are late responders who recover beyond 6 or even 12 months on background medical therapy, and full recovery of LVSF in PPCM patients often occurs after the first 6 months following diagnosis. The implications of these findings is that though early recovery may be a good prognosticator, lack of recovery by 6 months should not rule out potential late recovery. These results also implicate that recovery from PPCM can be very prolonged (. 4 years), and that there is a need for clinical, echocardiographic, or biochemical parameters to predict delayed recovery, PLVD, or clinical deterioration. A number of echocardiographic parameters have been shown to be associated with a higher likelihood of recovery, including LV dimensions and systolic function at the time of diagnosis Our findings are consistent with these former studies, showing that echocardiographic markers of advanced remodelling such as enlarged LV end-diastolic or end-systolic diameter and low LVEF were associated with increased mortality and non-recovery in our study. It is unknown when to discontinue heart failure medications in recovered PPCM patients or whether there is any deterioration in LV function after an initial recovery in these patients. Amos et al. reported a lack of deterioration of LV function during an average follow-up period of 29 months in 15 patients with full recovery who stopped taking medication. 10 On the other hand, Goland et al. 16 demonstrated spontaneous deterioration of LV function in three patients, similar to our results. The findings of late deterioration are very important and support the recent report by Goland et al. 16 indicating the need for a close follow-up with annual determination of cardiac function in women in whom medications are discontinued after complete recovery of LV function. Recent studies showed that right ventricular systolic function in PPCM patients is worse than that of patients with idiopathic dilated

5 Delayed recovery in peripartum cardiomyopathy 899 Table 2 Characteristics of deceased vs. surviving patients Surviving (n 5 32) Deceased (n 510) P-value... Age (years) Parity Follow-up (months) ,0.001 Atrial fibrillation (n, %) 3 (9.4) 2 (20.0) Hypertension (n, %) 5 (15.6) 2 (20.0) Diabetes mellitus (n, %) 1 (3.1) 1 (10.0) Onset of symptom (n,%) Pre-partum 8 (25.0) 4 (40.0) Post-partum 24 (75.0) 6 (60.0) NYHA (n,%) II 6 (18.8) 1 (10.0) III 11 (34.4) 2 (20.0) IV 15 (46.9) 7 (70.0) LVESD (cm) LVEDD (cm) LVEF (%) ,0.001 PASP (mmhg) Left ventricular thrombus (n, %) 2 (6.3) 2 (20.0) CRP (mg/dl) BNP (pg/ml) Medication (n,%) Digoxin 12 (37.5) 3 (30.0) ACE inhibitor 26 (81.3) 8 (80.0) Beta-blocker 30 (93.8) 8 (80.0) Intra-aortic balloon pump 0 (0.0) 2 (20.0) Values are given as the mean + SD or number (percentage) unless otherwise indicated. ACE, angiotensin-converting enzyme; BNP, brain natriuretic peptide; CRP, C-reactive protein; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic diameter; NYHA, New York Heart Association functional class; PASP, pulmonary artery systolic pressure. cardiomyopathy. 17 Although we did not examine right ventricular contractility and systolic function in our patients, the mean pulmonary artery systolic pressure was 44.4 mmhg, which is high for a disease mainly affecting the left ventricle. The prognostic importance of the right ventricular systolic function in patients with PPCM should be evaluated in larger prospective studies. Our study shows that the clinical profile of PPCM is different in different populations. It is therefore extremely important to characterize the geographical and the racial presentation of this disease. Management guidelines for PPCM should not be uniform but should be specific, and may be different in different geographical areas. The outcome of the patients diagnosed in Turkey is very different from that described in the USA and more similar to populations studied in South Africa and in Haiti. Study limitations Although it has the largest series of patients with PPCM in Turkey, our study is limited by the relatively small number of patients and limited power to detect differences in clinical outcomes. We did not use bromocriptine in our patients, which was reported to be effective in patients with PPCM 5 after we have completed the study. Due to limited resources, most of our patients also did not have a implantable cardioverter defibrillator, cardiac resynchronization therapy, ventricular assist device, or cardiac transplant therapy which probably resulted in higher mortality/non-response rates than in the US and European cohorts. 18 Our study findings may not be generalizable to a population of PPCM patients with lesser disease severity and with better access to device or cardiac transplantation therapy. Early diagnosis is essential to identify the disease when the LVSF is relatively intact, since survival and recovery are both improved by early detection. Self-test methods for recognition of heart failure in pregnancy which can be a useful tool in early diagnosis should be used in larger studies. 19 Conclusions In this study we have shown that only 30% of the patients had normal LV function after 6 months of treatment, but continuing improvement was observed up to the 42th month, and that the recovery phase was not limited to the first 6 months and often

6 900 M. Biteker et al. Table 3 Results from patients who recovered and patients who did not recover from peripartum cardiomyopathy Early recovery (n 5 6) Delayed recovery (n 5 14) Non-recovery (n 5 22) P-value... Age Parity Follow-up (months) Atrial fibrillation (n, %) 0 (0.0) 1 (7.1) 4 (18.2) Hypertension (n, %) 1 (16.7) 2 (14.3) 4 (18.2) Diabetes mellitus (n, %) 0 (0.0) 1 (7.1) 1 (4.5) Onset of symptom (n,%) Pre-partum 2 (33.3) 3 (21.4) 7 (31.8) Post-partum 4 (66.7) 11 (78.6) 15 (68.2) NYHA (n,%) II 1 (16.7) 2 (14.3) 4 (18.2) III 3 (50.0) 5 (35.7) 5 (22.7) IV 2 (33.3) 7 (50.0) 13 (59.1) LVESD (cm)*, LVEDD (cm) LVEF (%)*, ,0.001 PASP (mmhg) Left ventricular thrombus (n, %) 0 (0.0) 0 (0.0) 4 (18.2) CRP (mg/dl) BNP (pg/ml) Medication (n,%) Digoxin 1 (16.7) 2 (14.3) 12 (54.5) ACE inhibitor 5 (83.3) 12 (85.7) 17 (77.3) Beta-blocker 6 (100.0) 13 (92.9) 19 (86.4) Intra-aortic balloon pump 0 (0.0) 0 (0.0) 2 (9.1) Values are given as the mean + SD or number (percentage) unless otherwise indicated. ACE, angiotensin-converting enzyme; BNP, brain natriuretic peptide; CRP, C-reactive protein; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic diameter; NYHA, New York Heart Association functional class; PASP, pulmonary artery systolic pressure. *Statistically significant differences between delayed recovery and non-recovery. Statistically significant differences between early recovery and non-recovery. occurred after the first year following diagnosis. The implications of this study are that because of the probability of either delayed recovery or deterioration of LVSF in PPCM, long-term follow-up may be needed not only in non-recovered patients but also in patients with complete recovery. Conflict of interest: none declared References 1. van Spaendonck-Zwarts KY, van Tintelen JP, van Veldhuisen DJ, van der Werf R, Jongbloed JD, Paulus WJ, Dooijes D, van den Berg MP. Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy. Circulation 2010;121: Sliwa K, Hilfiker-Kleiner D, Petrie MC, Mebazaa A, Pieske B, Buchmann E, Regitz-Zagrosek V, Schaufelberger M, Tavazzi L, van Veldhuisen DJ, Watkins H, Shah AJ, Seferovic PM, Elkayam U, Pankuweit S, Papp Z, Mouquet F, McMurray JJ. Heart Failure Association of the European Society of Cardiology Working Group on Peripartum Cardiomyopathy. Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy. Eur J Heart Fail 2010;12: Pearson GD, Veille JC, Rahimtoola S, Hsia J, Oakley CM, Hosenpud JD, Ansari A, Baughman KL. Peripartum cardiomyopathy: National Heart, Lung and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review. JAMA 2000;283: Biteker M. Current therapeutic perspectives in peripartum cardiomyopathy. Ann Thorac Surg 2011;91: Sliwa K, Blauwet L, Tibazarwa K, Libhaber E, Smedema JP, Becker A, McMurray J, Yamac H, Labidi S, Struman I, Hilfiker-Kleiner D. Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy. A proof-of-concept pilot study. Circulation 2010;121: Elkayam U, Akhter MW, Singh H, Khan S. Pregnancy-associated cardiomyopathy: clinical characteristics and a comparison between early and late presentation. Circulation 2005;111: Fett JD, Sannon H, Thélisma E, Sprunger T, Suresh V. Recovery from severe heart failure following peripartum cardiomyopathy. Int J Gynaecol Obstet 2009; 104: Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, Manning WJ, Morehead A, Kitzman D, Oh J, Quinones M, Schiller NB, Stein JH, Weissman NJ; American Society of. American Society of recommendations for use of echocardiography in clinical trials. JAm Soc of Echocardiogr 2004;17: Modi KA, Illum S, Jariatul K, Caldito G, Reddy PC. Poor outcome of indigent patients with peripartum cardiomyopathy in the United States. Am J Obstet Gynecol 2009;201:171.e1 e5.

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