Role of Echocardiography in the Assessment of Right Ventricular Dysfunction in Peripartum Cardiomyopathy Globally: Current Knowledge and Clinical Implications.

Emmy O and Karen S

Published on: 2022-12-29

Abstract

Aims Peripartum cardiomyopathy is a syndrome that occurs globally in all ethnic groups. PPCM remains a major contributor to maternal morbidity and mortality worldwide with variable disease progression and left ventricular (LV) recovery whose predictors for recovery are not well defined globally. The literature on right ventricular systolic dysfunction (RVSD) in Peripartum Cardiomyopathy patients is scanty as a focal parameter for predicting LV recovery worldwide. We sought to systemically and comprehensively review published literature on the role of Right Ventricular systolic function assessment as a predictor of outcome amongst women with PPCM across different geographical regions.

Methods

Search strategy, selection criteria and data extraction for results: This systematic review was performed as a comprehensive search of relevant literature (2000 to June 2022) across a number of electronic databases for potentially relevant articles using the following search terms: (peripartum cardiomyopathy OR pregnancy) AND (right ventricular systolic dysfunction).

Women with a confirmed diagnosis of PPCM according to the latest European Society of Cardiology (ESC) position statement were considered eligible. References of selected papers were screened, searching for other potentially relevant publications. This yielded results inclusive of cohort, case-control and cross- sectional studies with a focus on the role of RV systolic dysfunction in PPCM globally. A selection of the most relevant studies comprised of fifteen papers (1600 patients across 10 countries) that met the inclusion criteria and were finally included in the review Right Ventricular echocardiographic assessment parameter tools for systolic function were majorly Tricuspid Annular Plane Systolic Excursion (TAPSE), Fractional Area Change (FAC) and Sa? Tricuspid wave which were similar across all continents. All patients had LV dysfunction with an average of 23.01% +/- 9.73% at Simpson biplane. 52.6% had a Sa? tricuspid wave (speed of the systolic wave to the tricuspid ring in tissue Doppler) below the standard. The average RV area shortening was 23.73% +/- 14.16%, as the major study parameters for RV

Conclusion: RV dysfunction is common in PPCM. In view of the prognostic interest of the right ventricle; comprehensive evaluation taking into account all of the measurable parameters in order to have an accurate mode of early detection and prognostication of LV outcome in PPCM

Keywords

Peripartum cardiomyopathy; Systematic review; Right ventricular systolic dysfunction

Introduction

The etiology of cardiomyopathies occurring de novo in association with pregnancy is diverse, therefore Peripartum Cardiomyopathy has to be differentiated from other causes of heart failure.

Peripartum Cardiomyopathy (PPCM) affects women globally, and remains a major risk factor for maternal mortality and morbidity worldwide [1]. PPCM is increasingly recognized as an important medical condition that can complicate pregnancy. The disease is characterized by new onset left ventricular (LV) systolic dysfunction and dilatation that occur in previously healthy women towards the end of pregnancy and up to 5 months postpartum [2]. PPCM is associated with various complications, outcomes and prognostic predictors of LV recovery with RV systolic function taking an emerging role. Over the past two decades a substantial amount of new knowledge on PPCM has been published, including better understanding of the pathophysiology, diagnostic tools, management and outcome. In 2010, the study Group on peripartum cardiomyopathy of the Heart Failure Association of the European Society of Cardiology (ESC) Working Group on PPCM defined PPCM as an idiopathic cardiomyopathy occurring towards the end of pregnancy or in the months following delivery, abortion or miscarriage, without other causes for heart failure, and with a left ventricular (LV) ejection (EF) <45% (see box).

Given the fact that there are some patients with typical features of PPCM and a clear impairment of LVEF, also patients with an EF value between 45% and 50% may occasionally be diagnosed with PPCM. Since no specific test to confirm PPCM exist, it remains a diagnosis of exclusion, and differential diagnoses need to be considered.

In particular, aggravation of a pre-existing heart disease by pregnancy-mediated hemodynamics changes should be differentiated from PPCM. The ESC EORP PPCM study has shown that the majority of women present postpartum in Africa (75%), Europe (69%), the Middle East (66%), and Asia-Pacific (57%) [3]. Also, this study group initiated the largest prospective global cohort study, under the umbrella of the EURObservational Research Programmer (EORP), with >750 PPCM patients, providing novel data on presentation in various ethnic groups, as well as maternal and Foetal outcomes [3]. The true prevalence and incidence of Peripartum Cardiomyopathy remains less well documented globally. This is largely because there have been only very few population based studies on PPCM wide- world and the striking hot spots of Peripartum Cardiomyopathy and its cause remains unclear. The incidence of PPCM therefore differs widely depending on the ethnic/racial and regional background of women. Africans and African Americans are at a higher risk for developing PPCM, with an estimated incidence of 1:1000 pregnancies in Nigeria [4], additionally PPCM was described as the most prevalent type of cardiomyopathy in Kanu, north-western Nigeria where it was found at 55 amongst 1296 patients (4.2%) referred for echocardiography over a period of 7 months postpartum, representing 52.4% of all cardiomyopathies. Originally this was ascribed to indigenous customs with specific emphasis on hot baths and high salt intake during Peripartum Cardiomyopathy. Although following a recent case control study of 39 participants, it did not support the above conclusion [5]. Elsewhere, the incidence rates have been found at 1:299 in Haiti whereas incidences in Caucasians populations range from 1:5000 pregnancies in Germany to 10 000 in Denmark [6-13]. The etiology of PPCM is uncertain. A combined ‘two-hit’ model including systematic angiogenic imbalance and host susceptibility (predisposition) is thought to be crucial in the pathophysiology of PPCM.

This is possibly related to the differences in the racial background, nutritional deficiencies or high prevalence of pre-eclampsia as described, the predisposing factors for PPCM seem to be multiparty and multiple pregnancies, family history, ethnicity, smocking, diabetes, hypertension, pre-eclampsia, malnutrition, age of mother (with older mothers being at greater risk), and prolonged use of tocolytics beta-agonists, the oxidative stress-activated cytokines, inflammation, autoimmune reaction, pathophysiological response to hemodynamic stress [5,14-22]. With the background that PPCM is a rare form of heart failure occurring in the last trimester of pregnancy or in the first months after delivery coupled with an element of the etiology remaining unknown with resulting inconsiderable morbidity and mortality in young previously healthy women PPCM raising a big knowledge gap in many parts of the world [23]. The natural history of PPCM seems to be variable although the rarity of this disease and the inconsistent diagnostic criteria that have been used in previous case series and research studies make it difficult to accurately describe the range of disease progression. This results in considerable morbidity and mortality in young, otherwise healthy women. The diagnosis is based on exclusion criteria, and specific biomarkers remain un-identified. The outcome of PPCM remains markedly heterogenous and seems to differ significantly between countries and ethnicities. While about 50% of women have been registered to show recovery of LV function within 6 months after diagnosis, there seems, however to be marked differences in the rate of recovery between ethnicities [3]. The postulated pathophysiological mechanisms of PPCM have been based on various mouse models, therefore the natural history of PPCM seems to be variable although the rarity of this disease and the inconsistent diagnostic criteria that have been used in previous case series and research studies make it difficult to accurately describe the range of disease progression.

Given the relatively high rates of death and persistent LV dysfunction in patients with PPCM, establishing reliable predictors of outcome is important to enable clinicians to provide care for these patients. Previous retrospective studies have shown numerous factors to be associated with the recovery of LV function, but none has been validated in a large prospective cohort and very few have focused on the role of right ventricular (RV) functional assessment in PPCM. Amongst the high income countries, detailed imaging amongst PPCM women with an approach of a detailed RV function assessment at baseline has been shown to predict outcomes among patients with other types of acute cardiomyopathies [24-29]. However, data on advanced cardiac imaging and its role as an emerging predictor of outcome amongst PPCM remains scanty. This literature review aimed to highlight the concept of advanced right ventricular echocardiographic imaging in PPCM and its importance as a predictor of left ventricular recovery in PPCM with emphasis on the underutilization in the diagnosis and prognostication among PPCM women. We emphasize the potential existing knowledge gap and the need to bridge this knowledge gap. Retrospective studies of patients with PPCM in the United States have shown that mortality is as high as 18%. The left ventricular ejection fraction has further been described to return to normal at 6months to 1 year in only 40% to 62% of patients [30, 31]. The role for genetics in the development of PPCM has been supported by multiple reports, with a genetic cause of disease identified in up to 20% of studied patients. The most notable example of this is mutations in the sarcomere gene titin (TTN), a well-established disease gene for DCM. Several rare truncating (i.e nonsense, frameshift, or splice site) mutations in TTN were reported in PPCM patients from European and American populations) [16, 32]. Some PPCM patients have reported a positive first degree family history for heart failure and cardiomyopathy, including those with cardiomyopathy-associated mutations [16]. The mechanism for this genetic mutations predisposition remains unclear as the proteins encoded by these four genes have very different roles in the cardiomyocyte, including roles in the sarcomere (TTN), desmosome (DSP), intercalated discs (FLNC), and autophagy (BAG3).

Diagnostic Assessment With Emphasis On The Role Of Echocardiography In PPCM

Urgent diagnostic assessment with prompt referral to a specialist is indicated in any peripartum woman with signs or symptoms of heart failure. Pregnancy produces prominent cardiovascular adaptations that become particularly evident in the last trimester and peripartum period. These changes include increase of LV mass, dilatation of LV mass, dilatation of cardiac chambers, increase in cardiac output, and elevation of LV filling pressure due to fluid volume overload [33]. Once a diagnosis of PPCM is established, it is important to have additional tests to enable for phenotyping and prognostication. (See table)

Table 1: Diagnostic tests that are recommended for the diagnosis of peripartum cardiomyopathy at initial diagnosis and at follow-up visits

	Clinical Examination	EGG	Natriuretic Peptides	Echocardiography	Chest X-ray	Cardiac MRI	CT scan	Coronary Angiography
Diagnosis of PPCM	X	X	X	X	X	(X)^b	(X)^b	(X)^b
4-4 weeks after diagnosis	X	X	X	X
3 months after diagnosis	X	X	X^a	X
6 months after diagnosis	X	X	X^a	X		(X)^b
12 months after diagnosis	X	X	X^a	X
18 months after diagnosis	X	X	X^a	X
Annually for at least 5 years after diagnosis (especially if not fully recovered)	X	X	X^a	X
Generally, an individual approach is recommended depending on the severity of the disease and /or potential differential diagnoses. CT, compute tomography; ECG, electrocardiogram; MRI, magnetic resonance imaging; PPCM, peripartum cardiomyopathy. May be considered depending on costs and local availability. May be considered depending on the clinical presentation and/or differential diagnoses.

A basic electrocardiogram (ECG) is a widely available and powerful diagnostic tool in any cardiac condition. It should form the basis of clinical work-up in all women with potentially cardiac-related complaint and, particularly, in those with suspected PPCM. To a varying degree, at the time of diagnosis the ECG is abnormal in almost all women with PPCM.

In a prospective study of women with PPCM in South Africa, > 90% had at least one electrocardiographic abnormality and almost 50% had a significant electrocardiographic abnormality (e.g Q-waves abnormality, ST -segment depression, T-wave inversion, bundle branch block, second -or third-degree atrioventricular block, frequent ectopy, or brady-or tachyarrhythmia) [34]. Echocardiography is the main diagnostic modality used to confirm the presence of cardiac dysfunction in PPCM and quantify severity. Furthermore, it excludes alternative causes of heart failure, such as congenital heart disease, primary valvular disease, and a number of inherited or acquired cardiomyopathies. For its wide availability and low cost, echocardiography, also with recently introduced three-dimensional (3-D), tissue velocity imaging and myocardial strain analysis [35], it is the most commonly used imaging method for cardiac chamber quantification [36]. It provides real-time information on atrioventricular size and function, valvular apparatus and other cardiac structures and forms of the first-line imaging modality for evaluation of pregnant women with suspected CVDs and plays a key role in the differential diagnosis between PPCM and other pregnancy-related cardiac diseases such as preeclampsia [37] in which LV systolic function is mostly unaffected, valvular heart diseases (CHDs), and enables long-term monitoring of cardiac function. Strain has been validated as an important echocardiographic parameter with diagnostic and prognostic utility in various cardiac conditions hence an ideal tool for unmasking early myocardial impairment associated with various degrees of myocardial inflammation, oxidative stress, and fibrosis eventually driving the transition to overt Heart Failure.

Accordingly, in a single-center experience, global longitudinal strain (GLS) was significantly lower in PPCM patients compared with healthy peripartum women regardless of LVEF values hence a major promise in tracking early remodeling in PPCM and identifying a window of opportunity for preventive measures [38]. A review of retrospective studies have ably demonstrated numerous factors to be associated with recovery or predictors of outcome amongst women with PPCM. However, very few of these studies has focused on baseline right ventricular function parameters as predictors of outcome in PPCM patients specifically [30]. RV function at diagnosis has been shown to predict outcomes among patients with other types of acute cardiomyopathies [26, 28, 29, 39, 40]. This creates justification to expect that RV function at baseline predicts LV recovery and cardiac events in patients with PPCM. Given the relatively high rates of deaths and persistent LV dysfunction in patients with PPCM, establishing reliable predictors of outcome is important to enable provision of optimal care to these patient.

Table 2: Key characteristics of included studies focusing on the role of Echocardiography in PPCM.

Author	Country.	No. of participants.	Study type Predictors of outcome	Other Findings
Arash H, et al	Multicenter	40	Prospective cohort study	24patients had ↓ RVEF
Blauwet, et al(41)	South African	176	Prospective cohort study	Age t ↓LVESD
A Haghikia (11)	Germany	34	Prospective cohort study	NYHA 3 & 4 ↓ LVEF
Fabrizio(42)	Italy & Sweden.		Prospective cohort study	Severe LV EF, RVSD, Intracardiac thrombi, LVEED>60mm, Low tissue doppler imaging increased velocities, Late gadolinium enhancement
Fatou et al	Senegal	19	Prospective cohort study	57.9% had RVSD(52.6% had ↓ Sa tricuspid wave
Kamilu et al	Nigeria	45	Prospective cohort study	17.8% had RV recovery of whom 75.0% recovered in 6 months.
Kamilu et at	Nigeria	90	Prospective cohort study	TAPSE was less(12.58+/-mm) vs DCMP patients (14.46+/- 3.21) of DCM patients
Lori A. et al	IPAC registry	100	Prospective cohort study	75% had LV recovery at 1 year, 13% had LVEF £35%, RV FAC predicted LV recovery, TAPSE & FAC did not predict outcome.
Pacheco et al	Canada	67	Prospective cohort study	11% were multiple pregnancy, 27% had RVSD
Haghikia A		40	Prospective cohort study	58% patients had low RVEF
Karaye K	Nigeria	43	Prospective cohort study	69.8% had RVDD, 88.4% had RVSD
Lucia B et al	Netherlands	4 cases	Case report

FAC, Fractional Area Change; LVEF, Left Ventricular Ejection Fraction; RV, Right Ventricle; RVDD, Right Ventricular Diastolic Dysfunction; RVSD, Right Ventricular Systolic Dysfunction.

Data Extraction And Analysis

Data was extracted using a standardized electronic data, collection form that included study characteristics as well as echocardiographic findings with special emphasis on Right Ventricular Systolic Function findings. Whenever more than one article was found to report on the same cohort, we used the article with the most complete database for data extraction. The main findings of duplicate publications are described in online supplementary Table 2 Data from multinational studies were extracted according to the geographical region.

The aim of this meta-analysis was to describe the role of Right Ventricular Systolic Function parameters in PPCM as prognostic marker.

Table 3: Methods of echocardiographic evaluation of right ventricular function.

*Modality*	*Unit*	*Abnormal*
*M-mode echocardiography*
TAPSE	Mm	<16
*2D echocardiography*
RV FAC	%	<35
RV EF	%	<44
*Doppler echocardiography*
dP/dt	mmHg/s	<400
*RV MPI*
Pulsed Doppler	–	>0.40
Tissue Doppler	–	>0.55
RV S'	cm/s	<10
*Myocardial deformation echocardiography*
RV LS (free wall)	%	>−20
*3D echocardiography*
RV EF	%	<44

Figure 1. Representative baseline echocardiographic apical 4-chamber views from study patients with peripartum cardiomyopathy (PPCM). The right ventricular end-diastolic area (RV EDA) is indicated by orange dashed line. Left, Left ventricular ejection fraction (LVEF) recovered in this patient. Right, LVEF did not recover in this patient. RV ESA indicates right ventricular end-systolic area; RV FAC, right ventricular fractional area change.

Figure 1: Representative baseline echocardiographic apical 4-chamber views from study patients with peripartum cardiomyopathy (PPCM).

Figure 2. Representative baseline echocardiographic example of right ventricular (RV) longitudinal strain analysis in a study patient with a lack of recovery of left ventricular ejection fraction (LVEF). The 4-chamber view with endocardial contour traced (green line; left) is shown with the corresponding segmental RV longitudinal strain curves (colored lines; right). RV free wall strain is calculated as the average of the peak strain values of the 3 free wall segments. RV global strain is calculated as the average of the 6 longitudinal strain segments.

Figure 2: Representative baseline echocardiographic example of right ventricular (RV) longitudinal strain analysis in a study patient with a lack of recovery of left ventricular ejection fraction (LVEF).

Baseline LVEF: 16% Baseline RV free wall strain: 12.5%

Follow up LVEF: 25% Baseline RV global strain: -10.4%

Figure 3: Bull's-eye plot of LV GLS from a normal control (A) and patient with PPCM (B). Right ventricular free-wall global longitudinal strain (RV FWLS) from a normal control (C) and patient with PPCM (D).

Figure 3: Bull's-eye plot of LV GLS from a normal control (A) and patient with PPCM (B). Right ventricular free-wall global longitudinal strain (RV FWLS) from a normal control (C) and patient with PPCM (D). LV GLS: left ventricular global longitudinal strain. Clinical implications of RV dysfunction. These findings support the importance of initial RV functional assessment in PPCM as a tool for short and long-term risk stratification. Identification of this more severe PPCM phenotype with biventricular dysfunction may prompt early referral for advanced heart failure therapies and closer follow up. Lastly, further studies are needed to assess the potential for RV functional recovery among patients with PPCM who present with moderate to severe RV dysfunction. Identification of RV functional recovery potential would provide additional long term risk stratification of patients with PPCM.

Point of Echocardiographic assessment

As it has been established that moderate to severe RV dysfunction is more predictive than either left ventricular ejection fraction <30% or left ventricular end-diastolic diameter ≥ 60mm of major adverse clinical outcomes in PPCM this supports the role of mandatory RV systolic functional assessment at point of diagnosis as normalization of RV function has been strongly associated with event free survival.

Therefore, all peripartum mothers with signs and symptoms of heart failure should undergo a comprehensive Echocardiogram with emphasis on assessment of right ventricular systolic functional parameters.

Gaps in knowledge and areas of future investigations

Prompt and correct diagnosis of PPCM is key to initiation of early treatment, plan appropriate follow-up. Future studies are needed to clarify the clinical importance and prognostic relevance of right ventricular systolic assessment by means of advanced echo modules including tissue Doppler imaging, speckle strain analysis, 3-D echocardiography holds promise towards early detection of sub clinical RV dysfunction.

Given the relative rarity of PPCM, prospective multicenter registries would be helpful to identify novel prognostic markers in PPCM, including RV systolic functional assessment parameters. In this way, novel and effective strategies for risk stratification will help counseling for future pregnancies, tailored decisions on HF prevention or treatment may be substantially improved, and potential targets for disease-modifying therapeutic intervention using existing or novel drug therapy may be eventually demonstrated.

Discussion

RV function at presentation has been postulated as a strong independent predictor of LV recovery in PPCM In addition to racial background and in part independently from it, EF at presentation best predicts rate of recovery. The current data about advanced imaging in PPCM is suboptimal. Evidence in the outer SSA reveals a great role for advanced echocardiographic imaging with special focus to include RV imaging. From a SSA perspective, an in-depth imaging offers important insights about early prediction of LV recovery in PPCM to reduce the global burden of maternal mortality and morbidity as a result of PPCM.

Conclusion

PPCM is a heterogenous disease that has been associated with late diagnosis and lack of adequate screening diagnostics, coupled with inadequate comprehensive echocardiographic evaluation with emphasis on RV function.

Initial moderate to severe right ventricular systolic dysfunction has been associated with more advanced cardiomyopathy and increased risk for adverse outcomes in PPCM, within and beyond the first year of diagnosis. This may prompt earlier consideration of advanced heart replacement therapies. With the increasing sensitization and better diagnostic tools the disease is currently described as relatively frequent with better outcomes inclusive of LV recovery.

To address the paucity of clinical studies describing the role of advanced right ventricular imaging in PPCM as a predictor for LV recovery, more large studies comprehensively assessing its role are warranted to further improve maternal morbidity and reduce maternal mortality. This will be key in informing the targeted preventive strategies to reduce maternal mortality and improve outcome amongst PPCM women in an African Population.