Peripartum cardiomyopathy (PPCM): Definition, Diagnosis, Treatment and prognosis

Definition

The Heart Failure Association (HFA) of the European Society of Cardiology (ESC) has recently published a revised definition of PPCM

Peripartum cardiomyopathy (PPCM) is a life-threatening disease of the heart of unknown cause, which:

1. in previously healthy patients
2. occurs during the last month of pregnancy, at birth or in the first postpartum months.
3. The left ventricular ejection fraction (LVEF) is usually less than 45% without a clearly identifiable cause.
4. The clinical picture shows rapidly progressive myocardial insufficiency, often associated with dilation of all ventricles

Epidemiology

Frequencies for PPCM vary between: (per live birth)

• 1 in 2500-4000 in the US,
• 1 in 1000 in South Africa and
• 1 in 300 in Haiti
• 1 in 1500-2000 in Europe, Asia and Australia

Explanations for the different frequencies of the PPCM in the different geographic regions could be:

• The ethnic background
• Different living conditions and habits
• Sensitivity to the disease
• The different inclusion criteria

Risk factors

• Hypertensive conditions in pregnancy
• Nicotine consumption,
• An increased age at the time of pregnancy
• A multiparity and multiple pregnancy

Can be considered as potential risk factors while gestational diabetes is not associated with PPCM.

It has also been shown that approximately 16% of PPCM patients have a positive family history of cardiomyopathy.

Recent studies show that mutations in genes, eg. Titin, troponin C and myosin heavy chain 7 (MYH7), which are known to cause cardiomyopathies, are more common in families with PPCM and DCM disorders.

The cardiac stress during pregnancy could have led to the unmasking of genetic cardiomyopathies.

This finding again illustrates the difficulty of distinguishing a PPCM from an existing but undiagnosed cardiomyopathy, which may have a worse prognosis than PPCM.

Pathomechanisms of PPCM

In an experimental model of PPCM in mice it could be shown that:

• Increased oxidative stress leads to cleavage of the breastfeeding hormone prolactin by cathepsin D into a pro-apoptotic and anti-angiogenic 16kDa subform.
• The 16kDa prolactin damages the endothelium and thus the microcirculation in the myocardium.
• Pharmacological inhibition of prolactin by the dopamine D2 receptor agonist bromocriptine successfully prevented the development of PPCM in various mouse models, thus supporting the hypothesis that the 16kDa prolactin might be causally involved in PPCM.
• The 16kDa prolactin-induced microRNA, miR-146a, is largely responsible for the endothelium-damaging pro-apoptotic and anti-angiogenic properties of 16kDa prolactin.
• In cardiomyocytes, miR-146a reduces the expression of the ErbB4 receptor, which is essential for survival, metabolism, and endothelial communication.
• Neutralization of miR-146a by antisense technology largely prevented PPCM in the mouse model while allowing normal prolactin signaling because the mice were able to suckle their cubs

As part of the normal changes in late pregnancy it comes, For example, an increased release of sFlt1 from the placenta. SFlt1 is an anti-angiogenic factor that inhibits vascular endothelial growth factor (VEGF). In multiple pregnancies and pre-eclampsia, serum levels are particularly high for sFlt1, but normally normalize rapidly after childbirth, while they remain elevated in PPCM patients.

It now appears that in the maternal heart, pro-angiogenic factors such as VEGF must be expressed more to protect the organ from these anti-angiogenic factors. This hypothesis suggests that in a mouse model combined treatment with recombinant VEGF and the prolactin blocker bromocriptine could prevent PPCM.

Diagnosis

The clinic of PPCM is often characterized by a left-leading cardiac decompensation with dyspnea symptoms, wet fine-bubble rattle sounds and a third heart sound in the auscultation. There may also be signs of global decompensation with peripheral edema and anasarca. In some cases, a recent secondary mitral valve insufficiency can be detected.

In almost all cases a significant increase of the NT-proBNP is found in the laboratory investigation. In contrast, other cardiac markers such as troponin T or creatine kinase (CK) are at most slightly elevated

Echocardiography is regarded as the most important apparatus of investigation. In the case of a PPCM, this typically shows a clear limitation of the global systolic left ventricular function with an LVEF <45%.

Radiographic signs of cardiac decompensation, such as pulmonary congestion signs and pulmonary edema with pleural effusions are often found in the chest X-ray

Cardiac magnetic resonance imaging (MRI) is also useful for the differential diagnosis of PPCM such as Myocarditis.

Invasive cardiac catheterization and biopsy sampling are rarely used.

MANAGEMENT

In the treatment of a PPCM must be noted:

• Stable vs unstable patients
• Präpartale vs postpartum CM

Unstable patients with PPCM

Signs of cardiogenic shock require intensive care treatment:

• diuretics
• Vasodilators at RR> 110 mmHg (hydralazine at pregnancy and NG postpartum(
• Invasive or non-invasive ventilation
• Catecholamines at low RR levels should be used on a restive basis as there is evidence of adverse effects in PPCM patients.
• Calcium sensitizer Levosimendan, unlike catecholamines, seems safe and can be considered.
• If therapy-refractory shock is present, the use of a mechanical circulatory system may be required:

1. Percutaneous microaxial pump (Impella®) in isolated LV failure.
2. Impella® in combination with venoarterial extracorporeal membrane oxygenation ECMO in case of ventricular failure

• In the case of a pre-existing pregnancy an emergency childbirth by means of cesarean section is indicated
• Hemodynamic stabilization is followed by gradual weaning.

Stable patients with PPCM

Pregnancy does not require the termination of pregnancy; vaginal spontaneous childbirth is recommended.

Drug therapy:

• B-blocker (metoprolol in pregnancy is preferred)
• Diuretic (loop diuretics)
• For reducing afterload, if necessary, hydralazine
• fetal lung maturation should be induced

Therapy After childbirth:

Oral heart failure therapy according to the guideline of the ESC (European Society of Cardiology):

• B-blocker
• ACE inhibitor/angiotensin receptor blocker (ARB): in maximum dissolved dosage
• At EF <40%: mineral corticosteroid receptor antagonists (MRAs) prefer eplerenone because of the most favorable hormonal side effects
• in further symptomatic patients despite o.g. Therapy is the conversion of ACE/ARB therapy to angiotensin receptor neprilysin inhibitor (ARNI) Entresto® recommended
• The additional administration of ivabradine is effective at HF> 70/min despite the maximum dose of B-blocker.
• Diuretics for edema or signs of pulmonary congestion are recommended, with a reduction to the lowest possible dosage recommended
• At full recovery, the therapy should be continued for at least 6 months. Then a gradual termination of the therapy is possible under biannual clinical and echocardiographic controls.

Initially the termination of MRA, then the ACE inhibitor/ARB/ARNI, and ultimately the beta-blocker. Diuretics are already discontinued at the time of recovery.

Bromocriptine for the treatment of peripartum cardiomyopathy: a multicentre randomized study 03/2010-08/2016

Methods and results

In this multicenter trial, 63 PPCM patients with left ventricular ejection fraction (LVEF) ≤35% were randomly assigned to:

• short-term (1W: bromocriptine, 2.5 mg, 7 days) or
• long-term bromocriptine treatment (8W: 5 mg for 2 weeks followed by 2.5 mg for 6 weeks)
• in addition to standard heart failure therapy.
• The primary endpoint was LVEF change (delta) from baseline to 6 months assessed by magnetic resonance imaging. Bromocriptine which is well tolerated.
• Left ventricular ejection fraction increased from 28 ± 10% to 49 ± 12% with a delta-LVEF of + 21 ± 11% in the 1W-group, and from 27 ± 10% to 51 ± 10% with a delta-LVEF of + 24 ± 11% in the 8W-group (delta-LVEF: P = 0.381(
• Full recovery (LVEF ≥ 50%) was present in 52% of the 1W and in 68% of the 8W group
• no differences in secondary endpoints between both groups (hospitalizations for heart failure: 1W: 9.7% vs. 8W: 6.5%, P = 0.651). The risk within the 8W-group to fail full-recovery after 6 months tended to be lower. No patient in the study needed a heart transplantation, LV assist device or died.
• Compared to data from non-bromocriptine-treated PPACM patients from the American IPAC Registry (Investigation on Pregnancy-Associated Cardiomyopathy), it can be assumed that there is a clear benefit for bromocriptine therapy in women with EF <35% (heart transplantation, cardiac assistive system, EF <35% or death 37% of all patients in the IPAC registry vs. 2.7% of all patients in bromocriptine study)

Conclusion

Bromocriptine treatment was associated with a high rate of full LV recovery and low morbidity and mortality in PPCM patients compared with other PPCM cohorts not treated with bromocriptine. 1W and 8W treatment suggesting that 1-week addition of bromocriptine to standard heart failure treatment is currently in the 8W group.

Recently, the so-called BOARD-schema for the pharmacological treatment of PPCM was developed at the Hannover Medical School:

1. Bromocriptine
2. Oral heart failure medication
3. Prophylactic Anticoagulation (to prevent thromboembolic events as a side effect of bromocriptine therapy)
4. VasoRelaxanten for reducing the afterload
5. Diuretics in low dosage as possible

For patients with EF <35%, the temporary prescription of LifeWest is indicated for 3-6 months due to the high risk of ventricular tachycardia.

In case of ventricular tachycardia/ventricular fibrillation, the implantation of ICD is indicated.

Although the EF persists <35% at 6 months, implantation of a prophylactic ICD or CRT-D system is indicated.

Prognosis

Overall good prognosis:

• 50% complete recovery with EF> 55%
• 35-40% partial recovery, EF improvement of at least 10% and an NYHA class

Is a new pregnancy possible?

Follow-up pregnancy after previous PPCM is associated with increased maternal and fetal risk.

However, a follow-on pregnancy is not excluded after complete recovery.

In persistent LV dysfunction, women have an unfavorable prognosis (with respect to mortality, LV dysfunction, and NYHA class) when re-pregnant

Heart failure therapy in pregnancy and lactation?

ACE inhibitors/ARB/ARNI/MRA and ivabradine are contraindicated during pregnancy and lactation

B-blocker (metoprolol) may be given

Diuretics are restrictive and should be given only if clearly indicated.

Written by: Ayman Zoaa

I’m a resident doctor living in Bremerhaven-Germany, my goal here is to explain medical stuff as easy and practical as possible. My second purpose is to help those who are trying to begin specializing in Germany.About my profession, I’m 30 years old, was born in Syria on 1989, I studied medicine at the University of Aleppo between 2007 and 2013, then I traveled to Germany and began my actual work before about 3 Years. I have got my medicine certificate recognized in Germany after I had made the recognition test and the medical language test.I’m specializing in internal medicine, and then I’ll proceed to gastroenterology, and hopefully endocrinology.I find writing interesting, and it also helps me to keep my information up to date, what we- medical people - need.Let us keep in touch through singing up, and through the contact-from, i will answer your Questions gladly