Peripartum Cardiomyopathy Research

Peripartum cardiomyopathy (PPCM) is an uncommon disease with unknown cause of distended cardiomyopathy. It is distinguished with the non-existence of any additional cause of heart failure. It is characterized by heart failure secondary to the left ventricular (LV) systolic disorder in the last month of pregnancy throughout the fifth month of postpartum (Patel et al., 2018). Its diagnosis involved exclusion. There is always an assumption of the absence of known heart disease, as some women may be presented with previous echocardiographic information which may lead to misclassification of some women diagnosed with PPCM. The parameters associated with its echocardiography comprise the presence of one of the following: fractional shortening < 30%, an ejection fraction < 45%, or both, typified by a likelihood of LV end-diastolic dimension > 2.7 cm/m² body surface area (Gupta and Wenger, 2018; Sliwa et al., 2010).

There is a disparity in the prevalence of PPCM by region. Its incidence is rising especially in the developed countries (Kolte et al., 2014; Brar et al., 2007). 0.1% of pregnancies worldwide are affected by PPCM, and it is associated with life-threatening consequences, with morbidity and mortality rates reaching 5% to 32% (Gupta and Wenger, 2018; Johnson-Coyle, Jensen, & Sobey, 2012). In a recent study to investigate the experience of medical care in men whose spouse was having peripartum cardiomyopathy, it was concluded that giving adequate information for men whose partners are suffering from PPCM aids them in gaining a sense of security and control in handling their feeling and individual life throughout the period of becoming a father and caring for an indisposed spouse with PPCM (Patel et al., 2018).Peripartum Cardiomyopathy Research

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EPIDEMIOLOGY

Studies have shown a substantial regional unevenness in the populations having PPCM with Japanese having very low rates of 1:20,000 births and higher rates of 1:100 births in black populations as observed in Nigeria (Gupta and Wenger, 2018; Capriola, 2013). Studies in the USA indicated that PPCM affects between 1 in 1,000 and 1 in 4,000 births (Gupta and Wenger, 2018). The hot spots of PPCM are reported to be Haiti and Northern Nigeria with high rates of incidence (Gupta and Wenger, 2018). However, the causes of the high incidences in these two countries remain unknown.

The risk factors associated with PPCM that are most profound are race, maternal age, the co-occurrence of preeclampsia, and multiple gestations (Ware et al., 2016). For instance, PPCM data from the USA indicates that PPCM has a greater likelihood of affecting mothers of African origin with African-Americans accounting for 40% of cases (Patel et al., 2016). PPCM can happen regardless of age. However, most cases are found in women with ages higher than 30 years. Various studies have indicated that most of the 40% of cases of PPCM is associated with gestational hypertension or preeclampsia (Patel et al., 2016).

In addition, nearly 10% of cases of PPCM globally arise due to twin gestations (Sliwa et al., 2017). Data from Europe revealed that PPCM was dominant among the Caucasians with higher dominance among blacks outside of Europe (Gupta and Wenger, 2018).  The human development Index (HDI) for determining the social and economic ranking of a country was found to be substantially greater in mothers with PPCM within Europe than women outside Europe (Gupta and Wenger, 2018). Invariably, women outside Europe with lower socio-economic profiles have increased vulnerability to PPCM.

Nonetheless, the clinical variables which are the risk factors associated with PPCM were found to be consistent throughout all populations. Recently, the human immunodeficiency virus (HIV) has risen to be a strong risk factor for PPCM. HIV was observed to be regularly associated with patients presented with PPCM outside Europe (Gupta and Wenger, 2018; Sliwa et al., 2017). It is believed that the increased prevalence of HIV in countries outside Europe may be responsible for this correlation.Peripartum Cardiomyopathy Research

ETIOLOGY

What causes PPCM? Why is it a disease of pregnancy? Why does it present typically after delivery, often weeks later? Moreover, why is it a rare disease? The etiology and the exact pathophysiology of PPCM still remain unknown (Kim and Shin, 2017; Ware et al., 2016). Various causes have been linked to the clinical manifestation of PPCM rendering its diagnosis to be all-encompassing which involves heart failure originated from numerous pathologies that happen at a definite time frame (Gupta and Wenger, 2018). Interestingly, the prevailing hypothesis of unbalanced oxidative stress coupled with reduced angiogenesis seems to be a general topic in many detected etiologies. Malnutrition, the hemodynamic stress of pregnancy, viral myocarditis, hypertension, and fetal microchimerism are considered as possible etiology of oxidative stress resulting in PPCM (Johnson-Coyle et al., 2012; Hilfiker-Kleiner et al., 2013).

PPCM progression has been linked to many dysregulated immune responses. For instance, maternal immunity often obliterates fetal cells once fetal cells entered maternal circulation. Weakened maternal immunity may result in the escape of these fetal microchimerisms, thereby leading to their nestling in the maternal myocardium. There is an attack on foreign pathogens after delivery by maternal immunity when it goes back to normal. Studies reveal the presence of antibodies in PPCM. Studies also reveal the presence of cardiac myosin heavy chains in women with PPCM, except in the serum of mothers with dilated cardiomyopathy of unknown cause (Gupta and Wenger, 2018). Subsequently, abnormality in prolactin metabolism originated from oxidative stress-associated unfitting hormone conjoining into a dynamic, antiangiogenic type interrupts cardiomyocyte angiogenesis resulting in heart failure (Patten et al., 2012; Johnson-Coyle et al., 2012).

Prolactin theory and oxidative stress

Maternal metabolic changes increase oxidative stress, and during natural pregnancy oxidative stress increases. PPCM is characterized by higher levels of oxidative stress when compared with normal pregnancy (Kim and Shin, 2017). The obliteration of the signal transducer and activator of transcription of three genes in mice leads to the pathologic production of 16-kDa prolactin (Kim and Shin, 2017; Hilfiker-Kleiner et al., 2007). The damage of cardiac and vascular tissue is related to antiangiogenic and proapoptotic properties of 16-kDa cleaved form (Kim and Shin, 2017).

Myocardial inflammation

The significance of inflammation in PPCM has been documented widely in the literature. A study reported an increased rate of active myocarditis in endomyocardial biopsy PPCM samples (Kim and Shin, 2017).  According to Kim and Shin (2017), high concentrations of interferon γ, Fas/apoptosis antigen 1, tumor necrosis factor α, C‑reactive protein, and interleukin six were gotten in PPCM. It is possible that during pregnancy inflammatory cytokines may trigger adverse cardiac adaptations and could also be related to cardiac fibrosis. It has also been reported that viral genomes with interstitial inflammation are associated with 31% of PPCM conditions (Kim and Shin, 2017). Nevertheless, the precise etiology of myocardial inflammation in PPCM still remains uncomprehending.Peripartum Cardiomyopathy Research

Genetic factors

Even though PPCM is categorized as a non-familial, non-genetic type of cardiomyopathy, its inclination in relation to the familial occurrence of PPCM is a pointer to its genetic tendency (van Spaendonck-Zwarts et al., 2010). The early presentation of PPCM could appear as familial dilated cardiomyopathy (DCM) (Kim and Shin, 2017; Ware et al., 2016). It is believed that geographical disparities in the incidence of PPCM may be as a result of genetic variations.

Angiogenic imbalance

The development of PPCM can be linked to the angiogenic factor. In a study, it was reported that mice without cardiac PGC-1α resulted in having severe PPCM. Cardiac PGC-1α regulates pro-angiogenic factors such as VEGF. Both multiple gestations and preeclampsia are potent risk factors in the PPCM progression. The human placenta secretion of VEGF inhibitors is found to be at higher levels during late gestation and in conditions of multiple gestation and preeclampsia.

A study on mice has been associated with angiogenic imbalance with the conjoining of prolactin into an antiangiogenic and proapoptotic 16kDa isoform. This is reported in mice with a knockout mutation of the cardiac tissue-specific signal transduction and activator of transcription 3 (STAT3) gene (Kim and Shin, 2017; Patten et al., 2012).  The expression of microRNA-146a is induced by the 16kDa isoform of prolactin. Women having PPCM are characterized by elevated levels of microRNA-146a when contrasted with healthy postpartum mothers or mothers with other types of cardiomyopathy.  The reduction of the secretion of prolactin in mice with the STAT3 gene mutation by bromocriptine therapy hinders the development of PPCM (Kim and Shin, 2017).  Peripartum Cardiomyopathy Research

MANAGEMENT

There is no disease-definite intervention for treating PPCM for now. The management of PPCM is centered on neutralization of neurohormonal maladaptive responses, controlling volume status, and forestalling complications (Gupta and Wenger, 2018). Medicines namely angiotensin-converting enzyme (ACE) receptor blockers and ACE inhibitors should be used to manage PPCM, but only postpartum. During pregnancy, it is good to use beta blockade. The most widespread complications associated with PPCM are arrhythmias and thromboembolism (Gupta and Wenger, 2018). At least in the period of pregnancy, which is a hypercoagulable condition, and for the earliest two to three months, postpartum anticoagulation is required for ejection fractions < 30%. The use of early implantation of a non-temporal implantable cardioverter defibrillator should be discouraged because of the elevated rate of recuperation in PPCM. Instead, wearable cardiac defibrillators should be used (Hilfiker-Kleiner et al., 2015).

Through the knowledge of hypotheses underlying the etiologies and pathophysiology of PPCM, specific interventions could be used. Bromocriptine is a dopamine D2 receptor agonist endorsed by the United States FDA for treating Parkinson’s disease, galactorrhea and certain pituitary tumors. Bromocriptine can be used for suppression of the secretion of prolactin from the pituitary. According to Hilfiker-Kleiner et al. (2017), women with PPCM that received bromocriptine intervention recorded higher rates of left ventricular recovery, even if only for one week, and it is accompanied with lower mortality and morbidity than women with PPCM from another study that was given bromocriptine. The European Medicine Agency (EMA) recently advocated that restriction on the usage of bromocriptine for mothers in stopping breast milk production because of its harmful impacts on thrombosis and blood pressure (Hilfiker-Kleiner et al., 2015). Peripartum Cardiomyopathy Research

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Presently, the effectiveness of bromocriptine in heart failure treatment is under investigation. The investigation is a large randomized multicenter trial (study number: NCT00998556) being conducted in Germany (Hilfiker-Kleiner et al., 2015). A study conducted in South African showed an enhanced outcome in women with PPCM typified by high serum markers of inflammation (TNF-a, tumour necrosis factor-a, and C-reactive protein) after intervention with pentoxifylline over conventional heart failure treatment. This indicates a vital beneficial effect of anti-TNF-a therapy (Sliwa et al., 2002). Another study also indicated the positive impacts of prolactin-blocker, bromocriptine over the heart failure medicines in patients with acute onset PPCM (Sliwa et al., 2010)

PROGNOSIS

PPCM prognosis is usually more improved than other cardiomyopathies of reduced systolic function. Prognosis is varying from cardiac death to complete recovery. In most conditions, the left ventricular (LV) function is recovered partially or entirely. The definition of complete recuperation of normal LV systolic function is regularly specified as a report of LV EF > 50% in 23% – 72% of PPCM patients (McNamara et al., 2015). There could be a delay in recovery to almost five years; however, recovery happens typically within two to 6 months after diagnosis (Fett et al., 2005). A robust medical recommendation for patients with normalized LV function should be that they should continue medical therapy for not less than six months after full recovery due to the fact that long-term stability is not tantamount to complete recuperation of LV size and EF (Hilfiker-Kleiner et al., 2015).Peripartum Cardiomyopathy Research

Data showed that irrespective of intense medical therapy, 20 per cent to 25 per cent of patients advance to end-stage heart failure as it progresses (Kim and Shin, 2017). 4% to 11% of PPCM patients undergo treatments based on LV assisted device or cardiac transplantation (Silwa et al., 2010; Fett et al., 2005). Maternal mortality for PPCM as reported was 3.3% to 30% over a period of more than six months (Bouabdallaoui et al., 2015; Elkayam, 2014). Prominent causes of death in PPCM cases comprise thromboembolism, ventricular arrhythmia, and advance toward refractive heart failure. Most of the deaths associated with PPCM happen within the earliest 3 to 6 months after diagnosis (Elliott et al., 2008; Whitehead, Berg, and Chang, 2003). Nevertheless, the complete recovery of the LV function is common in PPCM, even in patients having life-threatening LV condition.

OUTCOMES

Recent studies have brought tremendous improvements to the treatment of heart failure. Improved understanding of heart failure interventions has made the mortality rates of PPCM to reduced to nearly 3 percent within six months postpartum (Gupta & Wenger, 2018; Kim and Shin, 2017). Studies showed that the recuperation of the LV function is significantly higher in PPCM than any other dilated cardiomyopathies (Gupta & Wenger, 2018). According to Biteker et al. (2012), nearly 50% of PPCM patients would have recovered to a standard ejection fraction within six months to five years. Transplant may be inevitable in nearly 4% of women with PPCM, irrespective of proper heart failure management (Gupta & Wenger, 2018). Asthma, arrhythmia, hypertensive disorders, anemia and thyroid disorders are common comorbidities of PPCM.  Studies revealed diagnosed with PPCM had a high likelihood of also having asthma, anemia, and thyroid disease (Biteker et al., 2012).Peripartum Cardiomyopathy Research

SUMMARY AND CONCLUSION

PPCM is a threat to the health of pregnant women. Invariably, the early diagnosis of PPCM in pregnant women is critical and would go a long way in saving many lives. The use of echocardiography for screening, diagnosis and follow-up after the intervention has proven to be effective. Interestingly, recent advances in research on PPCM have brought about a remarkable understanding of the etiologies and pathophysiology of PPCM. With these recent advances in research on PPCM, the disease is better comprehended to comprise a permutation of vascular, hormonal and genetic causes. However, further investigations are required to completely expose the implication of hormonal involvement in the etiology of PPCM. These studies have to go beyond prolactin, TTN-truncating variants and other hormones implicated in the development of PPCM.

It is evident that the recent understanding of PPCM based on recent studies has increased the rate of recovery, reduced high morbidity and mortality previously associated with the disease. More studies need to be done in understanding the mechanisms underlying many of the hypotheses behind the etiology and pathophysiology of PPCM. While this may be challenging it is crucial to understand the mechanisms by which peripartum period is implicated in cardiomyopathy. It is crystal clear that this will bring about new therapeutic, prognostic, and diagnostic frameworks for the management of the disease. Further studies should also be carried out to determine preventive measures and disease-specific biomarkers for PPCM.Peripartum Cardiomyopathy Research