During pregnancy there is a significant reduction in systemic vascular resistance in order to accommodate a >40% increase in blood volume. This increase is gradual and occurs during the time between the second and third trimesters of pregnancy [
10], resulting in physiological cardiac hypertrophy. It is different from pathological hypertrophy in terms of the histologic feature of fibrosis and reduced LV function later. Balance between cardiac muscle growth and coronary angiogenesis determines physiological
vs pathological cardiac hypertrophy [
11]. In pregnancy the heart develops mild eccentric hypertrophy physiologically [
12], and there is a proportionate increase in chamber dimension and wall thickness [
13]. In addition to mechanical stress, increase in oestrogen at the end of pregnancy is an additional factor for pregnancy related hypertrophy [
12]. The increase in oestrogen, prolactin, and volume overload in combination with increasing stress on the heart could be one of the reasons for development of PPCM as it is commonly seen during last term of pregnancy, but there are no existing studies to support this hypothesis except for prolactin alone as a causative agent of PPCM.
Although it is well understood that physiological hypertrophy of the heart of pregnant women occurs during pregnancy, the process that converts this normal response to pathological hypertrophy and subsequent reduced LV function is unknown. There are several promising theories have been published, but the exact mechanism remains a puzzle. The STAT3 gene is involved in protection of the heart from oxidative stress by up regulating reactive oxygen species (ROS). It is a scavenging enzyme manganese superoxide dismutase [
14] that promotes myocardial angiogenesis in a paracrine and autocrine fashion within
cardiomyocytes and normocytes [
15-
17]. Also, STAT3 promotes anti-apoptotic activity via BCL-XL proteins [
18]. These findings have been tested in CKO mouse by Hilfiker-Kleiner et al., and they found that cardiac STAT3 levels were markedly decreased in insolated cardiomyocyte fraction but not in normocyte fraction [
19]. Increased prolactin levels in pregnant women near term and during the postpartum period are known to increase STAT3 which protects the human heart from oxidative stress [
20] by encoding MnSOD and antiapoptotic proteins (BCL-XL). Infusion of prolactin in vivo as well as adding it to the culture of myocytes in vitro activates STAT3. Furthermore, decreased STAT3 protein levels in LVs of PPCM patients have been reported. As previously discussed, these decreased STAT3 levels increase the oxidative stress due to reduced expression of MnSOD leading to increased ROS. Serum oxidized LDL levels were elevated in PPCM patients in comparison to normal pregnant women, indicating that PPCM patients could be experiencing increased oxidative stress [
19]. Increased oxidative stress up-regulates the activity of proteolytic Cardiac Cathepsin D which is responsible for cleavage of prolactin hormone (PRL) into 16 kDa. This 16 kDa fragment is anti-angiogenic which reduces capillary angiogenesis and is also responsible for apoptosis causing vascular remodelling and regression of blood vessel. Thus a possible explanation for development of PPCM could be a combined effect of increased oxidative stress and cleavage of prolactin hormone (PRL) into 16 kDa [
21-
23]. Hilfiker-Kleiner et al. in their experiment found higher 16 kDa PRL levels were detected in 3 out 5 patients with PPCM, and 16kDa PRL levels were not detected in healthy lactating patients [
19]. This hypothesis is further tested by experiment using bromocriptine, a D2 receptor agonist known to block PRL release was used in a prospective trial against standard medical therapy (ACE/ARB and BB) results showed higher percentage of patients were labelled as improved in bromocriptine group but results were not statistically significant, and BB and percentage of patients who had complete recovery were similar in both the groups. Some shortcoming were, this is an observational non-randomize trial with smaller power and to test effect of bromocriptine more robust multicenter trial is needed [
19]. Another group of researchers Patten et al. conducted experiments to prove cardiac specific PGC-1α knock-out mice develop PPCM [
24]. PGC-1α regulates angiogenesis in heart tissue with the help of angiogenic VEGF [
25,
26]. In late pregnancy, the placenta secretes soluble Flt1 (sFlt1) which reverses the effect of VEGF causing anti-angiogenesis [
27]. VEGF-121 injected knockout mice demonstrated improved survival up to 5 pregnancies and a partial increase in capillary density with marginal improvement in LVEF. High SFlt1, multiple gestation, and preeclampsia together create an anti-angiogenic environment particularly during the late period of pregnancy and postpartum where oxidative stress is elevated, therefore contributing to PPCM in addition to the above mentioned STAT3 pathway [
24]. However correlation of SFlt1 and PPCM is not established and more prospective trials are needed to define its role in pathogenesis of PPCM.
PPCM is a diagnosis of exclusion, as clinical presentation of left ventricular dysfunction such as ankle swelling, shortness of breath could be considered normal during peripartum period specifically during late pregnancy when PPCM is prevalent(3). In addition due to increased hemodynamic stress during pregnancy, pre-existing cardiac conditions can get worsened, resulting in cardiac dysfunction [
3]. Dilated Cardiomyopathy, congenital heart diseases, acquired heart disease during pregnancy; most of these conditions could make diagnosis of PPCM further difficult. Distinguishing characteristic in above mentioned disease state is that, they present during initial terms of pregnancy as opposed to PPCM and one of the diagnostic criteria of PPCM includes absence of identifiable causes of LV dysfunction and normal cardiac function during 1st and 2nd trimester of pregnancy [
1,
2]. Hypertensive heart disease could manifest as heart failure during pregnancy with distinguishing feature as diastolic heart failure and previous history of hypertension [
28]. Bicuspid aortic valve a most common congenital cardiac anomaly with 2% prevalence in general population [
29], Atrial septal defects and ventricular septal defects can deteriorate cardiac function during high output state of pregnancy and mimic in presentation with PPCM, however these conditions can be distinguished from PPCM with echocardiography [
30].