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Association Between Right Ventricular Dysfunction and Adverse Outcomes in Peripartum Cardiomyopathy: Insights From the BRO-HF Quebec Cohort Study

Open AccessPublished:May 24, 2022DOI:https://doi.org/10.1016/j.cjco.2022.05.004

      Abstract

      Background

      Peripartum cardiomyopathy (PPCM) is associated with severe morbidity and mortality, and the significance of right ventricular (RV) involvement is unclear. We sought to determine whether RV systolic dysfunction or dilatation is associated with adverse clinical outcomes in women with PPCM.

      Methods

      We conducted a multicentre retrospective cohort study examining the association between echocardiographic RV systolic dysfunction or dilatation at the time of PPCM diagnosis and clinical outcomes. Clinical endpoints of interest were the need for mechanical support, recovery of left ventricular ejection fraction at follow-up, and a combined endpoint of hospitalization for heart failure, cardiac transplant, or death.

      Results

      A total of 67 women, median age 30 years (interquartile range: 7), were diagnosed with PPCM between 1994 and 2015 in 17 participating centres. Twin pregnancies occurred in 11%; 62% of women were multiparous; and 24% had preeclampsia. RV systolic function was impaired in 18 (27%) and dilated in 8 (12%). Seven women required ventricular assistance, and 8 experienced the composite outcome during follow-up (25 [interquartile range 61] months). RV dysfunction was associated with the need for mechanical support (odds ratio 10.10 (95% confidence interval: 1.86-54.81), P = 0.007), but neither RV dysfunction nor dilatation was associated with left ventricular ejection fraction recovery, the need for cardiac transplant, heart failure hospitalization, or death.

      Conclusions

      RV dysfunction is associated with the need for mechanical support in women with PPCM. These findings may improve risk stratification of complications and clinical management.

      Résumé

      Introduction

      La cardiomyopathie du péripartum (CMP-PP) est associée à la morbidité grave et à la mortalité, mais on ignore l’importance de l’atteinte ventriculaire droite (VD). Nous avons cherché à déterminer si la dysfonction systolique ou la dilatation VD sont associées aux résultats cliniques défavorables chez les femmes atteintes de CMP-PP.

      Méthodes

      Nous avons mené une étude de cohorte rétrospective multicentrique sur l’association entre la dysfonction systolique ou la dilatation VD à l’échographie au moment du diagnostic de CMP-PP et les résultats cliniques. Les critères cliniques d’intérêt étaient la nécessité d’une assistance mécanique, la récupération de la fraction d’éjection ventriculaire gauche (FEVG) au suivi et un critère combiné d’hospitalisation liée à l’insuffisance cardiaque (IC), la transplantation cardiaque ou la mort.

      Résultats

      Un total de 67 femmes, dont l’âge médian était de 30 ans (écart interquartile [EI] : 7), ont reçu un diagnostic de CMP-PP entre 1994 et 2015 dans 17 centres participants. Les grossesses gémellaires sont survenues chez 11 % ; 62 % de femmes étaient multipares ; et 24 % souffraient de prééclampsie. La fonction systolique VD était compromise chez 18 (27 %) femmes et le VD, dilaté, chez huit (12 %) femmes. Sept femmes ont eu besoin d’une assistance ventriculaire, et huit ont subi le critère composite durant le suivi (25 [EI : 61] mois). La dysfonction VD a été associée à la nécessité d’une assistance mécanique (rapport de cotes 10,10 [intervalle de confiance à 95 % : 1,86-54,81], P = 0,007), mais ni la dysfonction ni la dilatation VD n’ont été associées à la récupération de la FEVG, à la nécessité d’une transplantation cardiaque, à une hospitalisation liée à l’IC ou à la mort.

      Conclusions

      La dysfonction VD est associée à la nécessité d’une assistance mécanique chez les femmes atteintes de CMP-PP. Ces conclusions peuvent permettre d’améliorer la stratification des risques de complications et la prise en charge clinique.
      Peripartum cardiomyopathy (PPCM) is a condition affecting young, previously healthy women.
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      Despite advances in heart failure (HF) therapies, PPCM continues to carry a significant morbidity and mortality burden, including transplantation and death at rates ranging from 13% to 41% at 1-year follow-up.
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      Prognostic implication of right ventricular involvement in peripartum cardiomyopathy: a cardiovascular magnetic resonance study.
      the current burden of severe levels of morbidity and mortality of this disease underscores the importance of identifying additional markers to improve risk stratification and treatment.
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      Indeed, several reports suggest that biventricular dysfunction, in the setting of certain acute cardiomyopathies, is associated with a fulminant initial clinical course.
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      However, worse New York Heart Association class and biventricular failure, interestingly, have been associated with later improvement in left ventricular ejection fraction (LVEF)
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      The effect of bromocriptine on left ventricular functional recovery in peripartum cardiomyopathy: insights from the BRO-HF retrospective cohort study.
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      Fulminant myocarditis.
      RV dysfunction or dilatation specifically may predict worse LVEF recovery
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      • et al.
      Prognostic implication of right ventricular involvement in peripartum cardiomyopathy: a cardiovascular magnetic resonance study.
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      Right ventricular function in peripartum cardiomyopathy at presentation is associated with subsequent left ventricular recovery and clinical outcomes.
      and event-free survival
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      Right ventricular function in peripartum cardiomyopathy at presentation is associated with subsequent left ventricular recovery and clinical outcomes.
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      in PPCM, but some data suggest that no such association holds.
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      Therefore, what remains unclear, particularly in Canadian women diagnosed with PPCM, is whether RV dysfunction or dilatation at diagnosis is associated with a fulminant presentation, a chronic condition, or adverse events, an issue that has major implications for clinical management, prognosis, and risk stratification.
      This study aimed to assess whether RV dysfunction or RV dilatation, at initial presentation, were associated with poor outcomes during short-term and/or long-term follow-up in this population.

      Methods

      Study population

      We conducted a retrospective cohort study within previously collected retrospective data for the Bromocriptine in Heart Failure (BRO-HF) network from 17 hospitals in Quebec, Canada. Methodology has been described previously.
      • Tremblay-Gravel M.
      • Marquis-Gravel G.
      • Avram R.
      • et al.
      The effect of bromocriptine on left ventricular functional recovery in peripartum cardiomyopathy: insights from the BRO-HF retrospective cohort study.
      Briefly, possible cases of PPCM were identified from women hospitalized between January 1st, 1994 and December 31st, 2015 who displayed the International Classification of Diseases (ICD) 9 and 10 codes for [peripartum cardiomyopathy (674.5-O90.3)] or [diseases of the circulatory system (390-459–100-199) + pregnancy, childbirth and the puerperium (630-679–O00-O9A)] in their discharge summary. Peripartum cardiomyopathy was defined per current guideline definitions
      • Sliwa K.
      • Hilfiker-Kleiner D.
      • Petrie M.C.
      • et al.
      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.
      ,
      • Bauersachs J.
      • Konig T.
      • van der Meer P.
      • et al.
      Pathophysiology, diagnosis and management of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy.
      as follows: (i) HF secondary to LV systolic dysfunction toward the end of pregnancy or in the months following delivery; (2) when no other cause of HF is found, in which case ejection fraction is nearly always reduced < 45%. Baseline characteristics were abstracted from medical records in a standardized electronic database. Data collected included ethnicity, which was specified in medical records only if not Caucasian, obstetrical data (number of gestations, pre- or post-delivery PPCM diagnosis, complications of pregnancy), clinical (past medical history, vital signs) and laboratory results, and medication at discharge.

      Echocardiographic data

      The following echocardiographic parameters were abstracted from echocardiogram reports: degree of RV dysfunction (none, mild, moderate, or severe—as reported on the diagnostic echocardiogram report by the original performing physician, based on at least one abnormal value of either tricuspid annular plane systolic excursion [TAPSE], fractional area change [FAC], Doppler tissue imaging-derived tricuspid annular systolic velocity [S’]), or degree of RV dilatation (none, mild, moderate, or severe—as reported on the diagnostic echocardiogram report by the original performing physician). Baseline characteristics in women were compared according to the presence or absence of reported RV dysfunction (normal vs mild, moderate, or severe dysfunction). Baseline characteristics also were compared according to the presence or absence of some degree of reported RV dilatation (Supplemental Table S1). LVEF, left ventricular end diastolic diameter (LVEDD), systolic pulmonary arterial pressure, and degree of mitral regurgitation (none, mild, moderate, severe) were abstracted from echocardiogram reports.

      Quality assessment

      Echocardiograms at diagnosis available in a digital format were reinterpreted in our echocardiography laboratory using an offline workstation (Echopac system, BT 12, General Electric, Boston, MA) by one investigator (C.P.), who was blinded to clinical assessment. RV function parameters obtained on our assessment and reinterpretation were then compared to RV function as abstracted from clinical reports. Intraobserver variability was assessed through the reinterpretation, by C.P., of 10 randomly selected echocardiograms. A second investigator (M.T.G.) blindly reinterpreted 10 randomly chosen echocardiograms to estimate calibration and interobserver variability. RV size was assessed by linear dimensions. RV end-systolic area (ESA) and end-diastolic area (EDA; non-indexed) were used to calculate FAC. The RV base was measured in the apical 4-chamber view (N < 42 mm).
      • Rudski L.G.
      • Lai W.W.
      • Afilalo J.
      • et al.
      Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography.
      RV function was assessed using FAC, calculated using the formula
      • Rudski L.G.
      • Lai W.W.
      • Afilalo J.
      • et al.
      Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography.
      (FAC(%) = ((EDA– ESA)/EDA) x 100), N > 34%), S’ (N > 9.5 cm/s), and measurement of TAPSE using M-Mode (N > 16 mm). Systolic pulmonary arterial pressure was estimated by adding the pressure gradient measured between the RV and the right atrium to estimated central venous pressure, with the assumption of no pathology of the pulmonary valve. LVEDD and LVEF were assessed using the biplane Simpson method (without contrast).

      Clinical endpoints

      Clinical endpoints of interest included the following: (i) the need for ventricular assist devices; (ii) an LVEF at follow-up of ≥ 50%; and (iii) a combined clinical endpoint of hospitalization for HF, need for cardiac transplant, or death at longest available follow-up. The need for ventricular assist devices was defined as the implantation of an intra-aortic balloon pump, use of extracorporeal membrane oxygenation, or use of a left ventricular assist device (LVAD). HF events were defined per the 2014 American College of Cardiology/American Heart Association Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials.
      • Hicks K.A.
      • Tcheng J.E.
      • Bozkurt B.
      • et al.
      2014 ACC/AHA key data elements and definitions for cardiovascular endpoint events in clinical trials: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards).
      Any hospital admission primarily for HF was considered an endpoint if the patient exhibited clear symptoms, the patient had objective evidence of HF, and treatment was intensified.
      LVEF at follow-up was abstracted from clinical reports 6 ± 3 months following diagnosis and up until the last available echocardiograms thereafter. Patients were followed through medical records until the last available follow-up. Duplicate and parallel medical records, in the case of transfer between institutions, were reconciled using the unique health identification number, as provided by the Régie de l’Assurance Maladie du Québec (RAMQ).

      Statistical analysis

      A D’Agostino–Pearson test was used to assess the normality of distribution. Data are reported as mean and standard deviation, or median (interquartile range). Categorical variables are reported as absolute numbers (%). Continuous variables were compared using a paired t-test, a Wilcoxon signed-rank test, or a Kruskal-Wallis test. Categorical variables were compared with the χ2 or Fisher’s exact test, or with the McNemar test, as appropriate. Statistical significance was determined at the 2-sided α = 0.05. Intraobserver variability was assessed using intraclass correlation coefficients. Univariate logistic regression analyses were performed to identify clinical and echocardiographic characteristics associated with the following: (i) the need of cardiac assist devices in our study group; and (ii) an LVEF ≥ 50% at follow-up. Receiver operating characteristics curve analysis was performed to identify optimal cutoff values of variables predicting a LVEF ≥ 50% at follow-up. Univariate analyses using χ2 tests were also performed to test the association between LV recovery and medications at discharge. Univariate Cox proportional hazards models were used to assess the association between the combined endpoint and the following variables: age, ethnicity, RV dysfunction and dilatation, and LV dysfunction and dilatation. Kaplan–Meier survival analysis was conducted according to identified univariate predictors of the combined endpoint. No data imputation was performed. Patients with missing information concerning RV dysfunction and dilatation were omitted from analyses reported in this article. No correction for multiple comparisons was performed, as all analyses are considered exploratory. Statistical analyses were performed using MedCalc for Windows, version 18 (MedCalc Software, Mariakerke, Belgium). The authors had full access to data and take full responsibility for the integrity of the article content.
      Multicentric approval was granted by the Montreal Heart Institute Ethics Review Board: as this was a retrospective analysis conducted per institutional guidelines for data security and privacy, a waiver of consent was granted. The study was initiated, designed, and conducted by cardiology fellows under the close supervision of attendings with clinical research experience, in compliance with the collectively-operated fellow-initiated research principles.
      • Marquis-Gravel G.
      • Avram R.
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      Collectively operated fellow-initiated research as a novel teaching model to bolster interest and increase proficiency in academic research.

      Results

      Study population

      A total of 76 women fulfilled PPCM diagnostic criteria. RV data were available for 67 of them, constituting our study population (Table 1). Most were Caucasian (68%), whereas 26% were African American, and 5% were Native American. Twin pregnancies occurred in 11%; 62% of patients were multiparous. Among the 67 patients, 18 (27%) had an impaired RV function at diagnosis. Among those, the RV function was described as mildly impaired in 7 patients (11%), moderately impaired in 10 patients (15%), and severely impaired in 1 patient (2%). RV dilatation was reported in 8 of the patients (12%). The dilatation was mild in 5 women (8%), moderate in 2 (3%), and severe in 1 patient (2%). Bromocriptine was used in 8 women (12%), more frequently in those with RV dysfunction (P = 0.02). Women with RV dysfunction had higher creatinine levels (P = 0.02), although their creatinine levels were still within normal range. Initial LVEF was lower in these women (P < 0.001). More women with RV dysfunction had at least moderate mitral regurgitation (P = 0.02) and were more likely to be discharged on mineralocorticoid receptor antagonists (P = 0.02).
      Table 1Patients’ baseline characteristics according to right ventricular (RV) function
      CharacteristicsAll patients (n = 67)Preserved RV function (n = 49)Impaired RV function (n = 18)P
      Demographics
       Age, y, median (IQR)30 (7)31 (6)30 (10)0.45
       Ethnicity
      Caucasian43(68)33 (71)10 (59)0.25
      African American17 (26)12 (26)5 (29)
      Native American3 (5)1 (2)2 (12)
      Index pregnancy details
       Postpartum presentation62 (93)45 (92)17 (94)0.72
       Twin pregnancy6 (11)5 (14)1 (6)0.24
       Multiparity38 (62)30 (67)8 (50)0.24
       Preeclampsia16 (24)12 (25)4 (22)0.85
      Medical history
       Pre-existing hypertension10 (15)6 (12)4 (22)0.31
       Pre-existing diabetes8 (12)6 (12)2 (11)0.90
       Hyperlipidemia2 (3)2 (4)0
       Tobacco use16 (25)12 (24)4 (27)0.86
      Clinical characteristics, median (IQR)
       NYHA functional class at diagnosis4 (1)3 (2)4 (0)0.08
       SBP, mm Hg126 (30)129 (33)120 (38)0.20
       Heart rate, bpm115 (35)110 (35)118 (29)0.43
       Creatinine, mmol/L68 (27)65 (21)78 (31)0.02
       Hemoglobin, g/L117 (28)117 (24)110 (31)0.90
      Echocardiographic findings at diagnosis
       LVEF, %, median (IQR)25 (20)33 (19)21 (10)0.001
       LVEDD, %, median (IQR)58 (9)59 (9)56 (11)0.95
       SPAP, %, median (IQR)44 (18)45 (20)43 (12)0.64
       At least moderate MR36 (54)22 (45)14 (78)0.02
      Medication at discharge
       Beta-blockers54 (81)39 (81)15 (83)0.84
       ACEIs/ARBs56 (85)41 (85)15 (83)0.83
       MRA8 (12)3 (6)5 (28)0.02
       Loop diuretics40 (61)28 (58)12 (67)0.54
       Oral anticoagulation18 (27)11 (23)7 (39)0.19
       Digoxin12 (18)6 (13)6 (33)0.05
      Bromocriptine8 (12)3 (6)5 (28)0.02
      CRT2 (3)1 (2)1 (6)0.45
      ICD8 (12)5 (10)3 (17)0.47
      Values are n (%), unless otherwise indicated. Bold font = P < 0.05.
      ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CRT, cardiac resynchronization therapy; ICD, implantable cardiac defibrillator; IQR, interquartile range; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; MRA, mineralocorticoid receptor antagonists; NYHA, New York Heart Association; SBP, systolic blood pressure; SPAP, systolic pulmonary arterial pressure.

      Accuracy of the echocardiography report assessments

      Echocardiograms were available for review in 29 patients. Median measured FAC and TAPSE were 37% (range: 28%-45%) and 18 mm (range: 16-21 mm), respectively. For both FAC and TAPSE, the intraobserver intraclass correlation coefficient (ICC) was 0.95 (P < 0.01), suggesting excellent reliability (Supplemental Table S2). Interobserver ICC for FAC and TAPSE was 0.81 (P < 0.01) and 0.96 (P < 0.01), respectively, suggesting good reliability (Supplemental Table S3). FAC was considered abnormal in 13 patients (45%), and TAPSE in 10 (35%). A significant association was found between measured FAC and reported RV function (Fig. 1), confirming that the estimated grades of RV dysfunction had some accuracy. Median measured FAC was 43% (range: 34%-47%) in women with reported normal function, 32% (range: 26%-36%) in women with reported mild dysfunction, and 30% (range: 21%-36%) in those with reported moderate dysfunction (P = 0.04). Similar findings were observed with measured TAPSE, but with less statistical significance (P = 0.05). Measured RV basal diameter was significantly smaller in patients with no reported dilatation than in those with reported dilatation (P = 0.03). Finally, a strong correlation was seen between both measured and reported LVEF (R2 = 0.79, P < 0.001) and LVEDD (R2 = 0.83, P < 0.001; Supplemental Fig. S1).
      Figure thumbnail gr1
      Figure 1Association between the measured fractional area change (FAC) and the degree of right ventricular (RV) dysfunction abstracted from the echocardiogram reports.

      Outcomes of interest in women with PPCM

      Seven women required mechanical circulatory support in the early onset of PPCM (6 required intra-aortic balloon pumps, 1 required an LVAD, and none required extracorporeal membrane oxygenation) (Fig. 2). Univariate logistic regression analysis for factors associated with mechanical circulatory support is shown in Table 2 (excluding LVEF because of collinearity). Only RV dysfunction (moderate or more), and not RV dilatation, LVEDD, mitral regurgitation, or systolic pulmonary arterial pressure, was found to be associated with the need of cardiac assist devices (odds ratio [OR] 10.10, confidence interval [CI] 1.86- 54.81, P = 0.007; Table 2).
      Figure thumbnail gr2
      Figure 2Events according to right ventricular (RV) function. HF, heart failure; MCS, mechanical circulatory support; PPCM, peripartum cardiomyopathy.
      Table 2Univariate analysis for factors associated with the need for ventricular assist devices during index hospitalization
      ParameterUnivariate analysis, n = 67
      OR (95% CI); P
      RV dysfunction (≥ moderate)10.10 (1.86–54.81); 0.007
      RV dilatation (≥ mild)3.60 (0.57–22.76); 0.17
      LVEDD0.99 (0.89–1.11); 0.91
      Mitral regurgitation (≥ moderate)2.34 (0.42–13.01); 0.33
      SPAP1.03 (0.96–1.11); 0.38
      Bold font = P < 0.05.
      CI, confidence interval; LVEDD, left ventricular end diastolic diameter; OR, odds ratio; RV, right ventricular; SPAP, systolic pulmonary arterial pressure.
      The result of an echocardiogram performed 3-9 months after diagnosis was available in 35 of 67 patients (52%; median echo follow-up 5.7 [range: 4.6-7.0] months). In this subgroup of patients, the median LVEF improved (from 25% [range: 20%-39%] to 54% [range: 42%-60%], P < 0.001). LVEDD was the only variable associated with an LVEF ≥ 50% at follow-up (OR 0.82 [CI 0.69-0.96], P = 0.02; Supplemental Table S4). For LVEDD, a value of ≤58 mm was predictive of an LVEF ≥ 50% at follow-up, with a sensitivity of 78% and a specificity of 64% (area under the curve, 0.74; (CI 0.55-0.88); P = 0.008; see Supplemental Fig. S2). Similarly, univariate analyses using χ2 tests also were performed to test the association between LV recovery and the following medications: beta-blockers (n = 31, P = 0.48), mineralocorticoid receptor antagonists (n = 3, P = 0.58), an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker (n = 32, P = 0.75), and bromocriptine (n = 7, P = 0.09).
      Eight patients (12%) reached the composite outcome of admission for HF, cardiac transplant, or death. Using univariate analysis, baseline LVEDD appeared to be the only significant predictor of adverse events (Table 3, hazard ratio 1.16 [CI 1.06-1.26], P < 0.01). Using the cutoff of 58 mm for LVEDD, as defined by the receiver operating characteristics analysis (Supplemental Fig. S2), revealed a trend for a higher event-free survival in patients with an LVEDD ≤58 mm (P = 0.07; Fig. 3).
      Table 3Univariate analysis for predictors of heart failure, cardiac transplant, or death
      ParameterUnivariate analysis, n = 67
      HR (95% CI); P
      Age0.90 (0.78–1.05); 0.17
      African American women0.69 (0.08–5.82); 0.73
      Use of bromocriptine0.91 (0.11–7.39); 0.93
      RV dysfunction (moderate and more)2.06 (0.41–10.27); 0.38
      RV dilatation (mild and more)2.38 (0.48–11.84); 0.29
      LVEDD at diagnosis1.16 (1.06–1.26); 0.002
      LVEF at diagnosis0.93 (0.86–1.01); 0.10
      Bold font = P < 0.05.
      CI, confidence interval; HR, hazard ratio; LVEDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; RV, right ventricular.
      Figure thumbnail gr3
      Figure 3Kaplan-Meier curves for event-free survival according to left ventricular end-diastolic diameter (LVEDD).

      Discussion

      This is the first report of echocardiographic RV evaluation in Canadian women diagnosed with PPCM, and the second-largest cohort examining the association between RV function and size and adverse clinical outcomes. To our knowledge, our study is also the first to examine the correlation between qualitative evaluation and quantitative echocardiographic parameters of RV size and function in women with PPCM. In 67 women diagnosed with PPCM in this cohort, RV systolic function was impaired in 27%, and the RV was dilated in 12%. RV dysfunction predicted the need for mechanical support, but neither RV dysfunction nor dilatation was predictive of an LVEF ≥ 50% at follow-up, or the combined clinical endpoint of hospitalization for HF, cardiac transplant, or death.
      One in 4 women presented with RV dysfunction in our population, similar to findings in most previously reported PPCM cohorts,
      • Haghikia A.
      • Rontgen P.
      • Vogel-Claussen J.
      • et al.
      Prognostic implication of right ventricular involvement in peripartum cardiomyopathy: a cardiovascular magnetic resonance study.
      ,
      • Blauwet L.A.
      • Delgado-Montero A.
      • Ryo K.
      • et al.
      Right ventricular function in peripartum cardiomyopathy at presentation is associated with subsequent left ventricular recovery and clinical outcomes.
      ,
      • Karaye K.M.
      • Lindmark K.
      • Henein M.
      Right ventricular systolic dysfunction and remodelling in Nigerians with peripartum cardiomyopathy: a longitudinal study.
      ,
      • Karaye K.M.
      Right ventricular systolic function in peripartum and dilated cardiomyopathies.
      except for the international PPCM registry,
      • Sliwa K.
      • Mebazaa A.
      • Hilfiker-Kleiner D.
      • et al.
      Clinical characteristics of patients from the worldwide registry on peripartum cardiomyopathy (PPCM): EURObservational Research Programme in conjunction with the Heart Failure Association of the European Society of Cardiology Study Group on PPCM.
      in which some degree of RV dysfunction was reported in 47% of women. RV dilatation was described in 12% of women in our cohort, compared to 56% in previous reports.
      • Blauwet L.A.
      • Delgado-Montero A.
      • Ryo K.
      • et al.
      Right ventricular function in peripartum cardiomyopathy at presentation is associated with subsequent left ventricular recovery and clinical outcomes.
      These differences may be due to heterogeneous methodology and classification of RV size and function, or potential regional phenotypical differences. At-least-moderate RV dysfunction was the only predictor for the need for mechanical circulatory support, identifying a subgroup of patients at higher risk of cardiogenic shock requiring LVADs. Three retrospective studies have previously examined RV dysfunction and adverse outcomes in PPCM. A study of 45 PPCM patients in Nigeria found that TAPSE ≤ 16 mm was not associated with 1-year mortality.
      • Karaye K.M.
      • Lindmark K.
      • Henein M.
      Right ventricular systolic dysfunction and remodelling in Nigerians with peripartum cardiomyopathy: a longitudinal study.
      Another study identified moderate-to-severe RV dysfunction as the only independent predictor of adverse clinical events in 53 women, 11 of whom required cardiac transplantation.
      • Peters A.
      • Caroline M.
      • Zhao H.
      • et al.
      Initial right ventricular dysfunction severity identifies severe peripartum cardiomyopathy phenotype with worse early and overall outcomes: a 24-year cohort study.
      Women in this cohort with worse RV dysfunction had an median LVEF of 12.5% vs 32.5% (compared to an LVEF of 33% vs 21% in our cohort)
      • Peters A.
      • Caroline M.
      • Zhao H.
      • et al.
      Initial right ventricular dysfunction severity identifies severe peripartum cardiomyopathy phenotype with worse early and overall outcomes: a 24-year cohort study.
      ; thus, they likely represented a distinct phenotype of PPCM, given the much higher incidence of cardiac transplantation than that in both our cohort and a prospective study examining RV dysfunction in 84 women with PPCM.
      • Blauwet L.A.
      • Delgado-Montero A.
      • Ryo K.
      • et al.
      Right ventricular function in peripartum cardiomyopathy at presentation is associated with subsequent left ventricular recovery and clinical outcomes.
      This prospective study identified FAC < 30% as a predictor of a combined outcome, in which 4 of 6 events were LVAD implantation.
      • Blauwet L.A.
      • Delgado-Montero A.
      • Ryo K.
      • et al.
      Right ventricular function in peripartum cardiomyopathy at presentation is associated with subsequent left ventricular recovery and clinical outcomes.
      Our findings support those previously in the literature suggesting that significant RV dysfunction likely portends more extensive acute myocardial stunning and damage in the acute phase of PPCM,
      • Hilfiker-Kleiner D.
      • Sliwa K.
      Pathophysiology and epidemiology of peripartum cardiomyopathy.
      and predicts the need for aggressive management including temporary mechanical assistance. These echocardiographic findings identify women at higher risk of potential complications who require heightened clinical surveillance, and earlier consideration for mechanical support interventions.
      RV dysfunction was not associated with the composite outcome of hospitalization for HF, cardiac transplant, and death in our cohort. It may not carry the same long-term prognostic significance in PPCM, in which LV recovery occurs more frequently than it does in other types of nonischemic cardiomyopathy.
      • Blechman I.
      • Arad M.
      • Nussbaum T.
      • Goldenberg I.
      • Freimark D.
      Predictors and outcome of sustained improvement in left ventricular function in dilated cardiomyopathy.
      ,
      • Cooper L.T.
      • Mather P.J.
      • Alexis J.D.
      • et al.
      Myocardial recovery in peripartum cardiomyopathy: prospective comparison with recent onset cardiomyopathy in men and nonperipartum women.
      TAPSE has been found to be significantly lower in PPCM patients, compared to the level in those diagnosed with dilated nonischemic cardiomyopathies,
      • Karaye K.M.
      Right ventricular systolic function in peripartum and dilated cardiomyopathies.
      despite a well-established poorer prognosis in the latter.
      • Blechman I.
      • Arad M.
      • Nussbaum T.
      • Goldenberg I.
      • Freimark D.
      Predictors and outcome of sustained improvement in left ventricular function in dilated cardiomyopathy.
      ,
      • Cooper L.T.
      • Mather P.J.
      • Alexis J.D.
      • et al.
      Myocardial recovery in peripartum cardiomyopathy: prospective comparison with recent onset cardiomyopathy in men and nonperipartum women.
      PPCM-related RV dysfunction, therefore, is likely indicative of a more severe clinical phenotype, characterized by acute biventricular dysfunction, lower LVEF at diagnosis, more severely decompensated HF, and cardiogenic shock often requiring urgent intervention, whereas LV dilatation, likely a surrogate for irreversible structural remodelling, fibrosis,
      • Yingchoncharoen T.
      • Jellis C.
      • Popovic Z.B.
      • et al.
      Focal fibrosis and diffuse fibrosis are predictors of reversed left ventricular remodeling in patients with non-ischemic cardiomyopathy.
      and permanent myocardial injury, identifies women at higher risk for persistent LV dysfunction and long-term adverse clinical outcomes.
      RV dysfunction was not associated with worse LVEF recovery in our cohort. These results are in contrast to those in previous reports in the literature, which have suggested that RV dysfunction on cardiac magnetic resonance imaging is associated with poor LV recovery.
      • Haghikia A.
      • Rontgen P.
      • Vogel-Claussen J.
      • et al.
      Prognostic implication of right ventricular involvement in peripartum cardiomyopathy: a cardiovascular magnetic resonance study.
      A recent study examining RV dysfunction as assessed by cardiac magnetic resonance imaging in 40 women with PPCM found that those with reduced RVEF at baseline had significantly lower rates of LVEF recovery (≥ 50%) at 6 months, with all women receiving either a 1-week or an 8-week course of bromocriptine.
      • Haghikia A.
      • Schwab J.
      • Vogel-Claussen J.
      • et al.
      Bromocriptine treatment in patients with peripartum cardiomyopathy and right ventricular dysfunction.
      Possible explanations for our contrasting findings include differences in sample size, the limited number of follow-up echocardiograms performed in our cohort, regional phenotypical differences, and unknown residual confounders. LVEDD ≥ 58 mm was a useful discriminator in identifying women with poor LVEF recovery and was the only echocardiographic parameter associated with transplantation or death. LV dilatation has been previously associated with poor LV recovery or adverse outcomes in several cardiomyopathies, including PPCM.
      • McNamara D.M.
      • Elkayam U.
      • Alharethi R.
      • et al.
      Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC study (Investigations of Pregnancy-Associated Cardiomyopathy).
      ,
      • Chapa J.B.
      • Heiberger H.B.
      • Weinert L.
      • et al.
      Prognostic value of echocardiography in peripartum cardiomyopathy.
      ,
      • Li W.
      • Li H.
      • Long Y.
      Clinical characteristics and long-term predictors of persistent left ventricular systolic dysfunction in peripartum cardiomyopathy.
      ,
      • Liu Y.
      • Zeng Y.
      Clinical characteristics and prognosis of peripartum cardiomyopathy in 28 patients.
      African American women comprised 26% of this cohort, similar to the proportion in the international PPCM registry, but higher than that in European countries, where they only represent 5.1% of cases.
      • Sliwa K.
      • Mebazaa A.
      • Hilfiker-Kleiner D.
      • et al.
      Clinical characteristics of patients from the worldwide registry on peripartum cardiomyopathy (PPCM): EURObservational Research Programme in conjunction with the Heart Failure Association of the European Society of Cardiology Study Group on PPCM.
      In our cohort, African American women had proportions of RV dysfunction and dilatation similar to those among other women. In contrast with previous reports, we found that ethnicity was not a predictor for an LVEF recovery or adverse outcomes.
      • McNamara D.M.
      • Elkayam U.
      • Alharethi R.
      • et al.
      Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC study (Investigations of Pregnancy-Associated Cardiomyopathy).
      ,
      • Blauwet L.A.
      • Delgado-Montero A.
      • Ryo K.
      • et al.
      Right ventricular function in peripartum cardiomyopathy at presentation is associated with subsequent left ventricular recovery and clinical outcomes.
      This finding may be due to environmental and socioeconomic factors differing in the Canadian context, as well as the small size of our study population.
      On quality analysis, RV function and size as assessed on initial diagnosis by the original echocardiographer correlated with precise RV function and size parameters on reinterpretation of echocardiograms obtained. We found that both FAC and TAPSE and RV basal diameter measurements correlated significantly with qualitatively assessed reported RV function and size, respectively. The global assessment of RV function in everyday practice is determined after consideration of one or more of these parameters, as recommended by current guidelines.
      • Rudski L.G.
      • Lai W.W.
      • Afilalo J.
      • et al.
      Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography.
      Previous studies have described a similar correlation between qualitative assessment of RV function using echocardiography and right heart catherization findings indicative of worse RV function in the PPCM population.
      • Peters A.
      • Caroline M.
      • Zhao H.
      • et al.
      Initial right ventricular dysfunction severity identifies severe peripartum cardiomyopathy phenotype with worse early and overall outcomes: a 24-year cohort study.
      Our study has several limitations. As a retrospective trial, it has potential bias and confounders inherent to this type of study. The sample size is relatively small, albeit similar to that of other PPCM cohorts.
      • McNamara D.M.
      • Elkayam U.
      • Alharethi R.
      • et al.
      Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC study (Investigations of Pregnancy-Associated Cardiomyopathy).
      ,
      • Blauwet L.A.
      • Delgado-Montero A.
      • Ryo K.
      • et al.
      Right ventricular function in peripartum cardiomyopathy at presentation is associated with subsequent left ventricular recovery and clinical outcomes.
      ,
      • Karaye K.M.
      • Lindmark K.
      • Henein M.
      Right ventricular systolic dysfunction and remodelling in Nigerians with peripartum cardiomyopathy: a longitudinal study.
      ,
      • Liu Y.
      • Zeng Y.
      Clinical characteristics and prognosis of peripartum cardiomyopathy in 28 patients.
      Reporting of ethnicity was incomplete in medical records, limiting analysis and interpretation of findings. Quantification of RV function was not uniformly performed using a single parameter, and RV dysfunction may have been underdiagnosed, as suggested by the higher proportion of RV dysfunction found in revised echocardiograms; however, correlation between our laboratory reinterpretation of the echocardiogram and the original echocardiographic report suggests adequate assessment of RV function by the initial reader. Given that reported RV size did not correlate with all measured parameters of RV size on echocardiogram reinterpretation, misclassification of RV dilatation in this cohort is possible. Guideline recommendations for RV size measurements also changed over the time period covered by our study. Our study employed frequently obtained measurements, such as FAC, TAPSE, and S’, which are simple to perform and are reproducible.
      • Rudski L.G.
      • Lai W.W.
      • Afilalo J.
      • et al.
      Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography.
      ,
      • Lang R.M.
      • Badano L.P.
      • Mor-Avi V.
      • et al.
      Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      Echocardiograms performed between 3 and 9 months following diagnosis were not available in all women, as follow-up echocardiograms were ordered clinically according to treating physician, introducing loss to follow-up and thus limiting interpretation of findings concerning LVEF recovery.

      Conclusions

      Peripartum cardiomyopathy carries significant morbidity risk in both the acute and chronic phase of its clinical course. Women requiring advanced HF therapies in the acute phase of PPCM must be appropriately identified using clinical and paraclinical parameters, including echocardiographic data. Findings in this retrospective cohort are hypothesis-generating, but they suggest that women with PPCM and RV dysfunction are at higher risk of acute morbidity. These findings, if confirmed in larger prospective studies, may help improve appropriate and timely referral of women with PPCM for advanced therapies, improving risk stratification and clinical management.

      Funding Sources

      This work was supported by the Canadian Cardiovascular Society – Bayer Resident Vascular Award and the Quebec Heart Failure Society . C.P. was supported by the 2015 Société Québécoise d’Insuffisance Cardiaque-Pfizer BMS Heart Failure in Women research grant. E.M.J. is supported by research grants from les Fonds de Recherche du Québec - Santé ( FRQS ), the Canadian Institutes for Health Research ( CIHR ), the Canada Foundation for Innovation ( CFI ), the AGE-WELL Networks of Centres of Excellence ( NCE ), and by la Fondation de l’Institut de Cardiologie de Montréal. R.A. is supported by FRQS (Grant 35261 ), the AGE-WELL Networks of Centres of Excellence ( NCE ), the NIH ( U01-HL128606-03S ), the Quebec Cardiology Association , and the University of California , San Francisco Digital Cardiology Fellowship Funds. F.T. is supported by research grants from FRQS and by the Research Centre of the Hospital of the University of of Montreal (Centre de Recherche du Centre Hospitalier de l’Université de Montréal). A.D. holds the University of Montreal chair Fondation Marcelle et Jean Coutu, Cal et Janine Moisan for better practices in advanced heart failure. The other authors have no funding sources to declare.

      Disclosures

      C.P. has received honoraria from Pfizer and Novartis and consulting fees from KYE Pharmaceuticals. The other authors have no conflicts of interest to disclose.

      Supplementary Material

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