---

PERIPARTUM CARDIOMYOPATHY (PPCM)

Postgraduate Level - Comprehensive Review

---

DEFINITION

1. Development of cardiac failure in the last month of pregnancy or within 5 months of delivery
2. LVEF <45% (or M-mode fractional shortening <30%, or LVEDD >2.7 cm/m² BSA)
3. Absence of another identifiable cause of HF (diagnosis of exclusion)
4. Absence of pre-existing heart disease before the last month of pregnancy

PPCM is a diagnosis of exclusion - all other causes of cardiac dysfunction must be ruled out.

• Braunwald's Heart Disease, 11th Ed.; Goldman-Cecil Medicine; Fuster and Hurst's The Heart, 15th Ed.

---

INCIDENCE & EPIDEMIOLOGY

• Non-Hispanic Black women have a 5-15 fold increased risk compared to other ethnic groups (Goldman-Cecil)
• Black women show more severe disease, slower recovery, lower recovery rates
• One-year mortality in predominantly Black cohorts: 11% vs 4% in mixed cohorts

• Harrison's Principles of Internal Medicine, 22E (2025); Fuster and Hurst's The Heart, 15th Ed.; Goldman-Cecil Medicine

---

RISK FACTORS

• Creasy & Resnik's Maternal-Fetal Medicine; Harrison's 22E; Fuster and Hurst's

---

PATHOPHYSIOLOGY

1. Prolactin/Vasoinhibin Hypothesis (Most Supported)

• STAT3 (Signal Transducer and Activator of Transcription 3) is downregulated in susceptible cardiomyocytes
• Reduced STAT3 → decreased MnSOD (manganese superoxide dismutase) expression
• Mitochondrial reactive oxygen species (ROS) accumulate unchecked
• Elevated ROS activates Cathepsin D (lysosomal protease)
• Cathepsin D cleaves full-length prolactin (23 kDa) into a 16 kDa antiangiogenic, proapoptotic fragment ("vasoinhibin")
• 16 kDa prolactin fragment causes:
  • Endothelial cell apoptosis
  • Impaired cardiomyocyte metabolism
  • Inhibition of cardiomyocyte contraction
  • Packaged into exosomes that also contain miRNA-146a → suppresses ERBB4 signaling in cardiomyocytes

2. Antiangiogenic Hypothesis (sFLT-1)

• The placenta secretes soluble fms-like tyrosine kinase-1 (sFLT-1) in late pregnancy
• sFLT-1 is a VEGF inhibitor - it binds and sequesters VEGF-A and VEGF-B
• This creates an angiogenic imbalance - the myocardial microvasculature cannot adapt adequately
• High sFLT-1 levels predict worse outcome in PPCM
• Shared with the pathophysiology of preeclampsia (explains the association)
• Pro-angiogenic agents are under experimental investigation

3. Genetic Predisposition

• ~15% of PPCM cases harbor rare truncating variants in TTN (titin gene) - the same gene implicated in DCM
• Other implicated genes: TTNC1, STAT3, MYH7, SCN5A, LMNA, DSP
• Among 90 DCM families, 6% had at least one member with PPCM
• Genetic testing reveals undiagnosed DCM in relatives of PPCM non-recoverers
• TTN truncating variants predict lower EF at 1-year follow-up and reduced recovery
• "PPCM may represent DCM occurring during pregnancy" - pregnancy is an environmental trigger for a genetically susceptible heart

4. Other Proposed Mechanisms

• Autoimmune/inflammatory: Lymphocytic myocarditis found in 30-50% of endomyocardial biopsies; cross-reactivity between uterine and cardiac myocyte proteins
• Nutritional: Low selenium levels (especially in Africa)
• Viral myocarditis: Enhanced susceptibility during immunological changes of pregnancy
• Hemodynamic stress: Volume overload + increased cardiac output of pregnancy precipitates failure
• Fuster and Hurst's The Heart, 15th Ed.; Goldman-Cecil Medicine; Harrison's 22E; Braunwald's Heart Disease

---

TEMPORAL CLASSIFICATION

---

CLINICAL PRESENTATION

Symptoms

• Dyspnea on exertion (most common)
• Orthopnea, paroxysmal nocturnal dyspnea
• Fatigue, reduced exercise tolerance
• Chest pain (occasionally)
• Palpitations
• Peripheral leg edema

Signs

• Tachycardia (compensatory)
• S3 gallop (volume overload)
• Elevated JVP
• Crackles at lung bases (pulmonary edema)
• Displaced apex (cardiomegaly)
• Mitral/tricuspid regurgitation murmurs
• Peripheral edema

• Elevated BNP/NT-proBNP
• Elevated troponin
• Clinical features inconsistent with normal pregnancy (orthopnea, PND, S3)
• Elevated CVP
• Onset of hypertension (preeclampsia overlap)

Complications

• Atrial and ventricular arrhythmias (life-threatening)
• LV thrombus (particularly with LVEF <30-35%) → systemic emboli
• Cardiogenic shock
• Cardiopulmonary arrest
• Death
• Predictors of complications: LVEF <30%, Black ethnicity, delayed diagnosis

---

DIFFERENTIAL DIAGNOSIS (Exam Critical)

---

INVESTIGATIONS

Echocardiography (Investigation of Choice)

• Global LV systolic dysfunction - LVEF <45%
• Variable LV dilatation (LVEDD >2.7 cm/m² BSA)
• M-mode fractional shortening <30%
• Right ventricular and biatrial dilatation
• Functional MR and TR
• Elevated pulmonary pressures
• LV apical thrombus - seen with severely depressed LV function

ECG

• Non-specific ST-T changes
• Sinus tachycardia
• LV hypertrophy pattern
• Left bundle branch block
• Arrhythmias (AF, VT)

Chest X-Ray

• Cardiomegaly
• Pulmonary venous congestion / pulmonary edema
• Pleural effusions

Biomarkers

• BNP/NT-proBNP: Markedly elevated; high levels predict worse outcome and less recovery
• Troponin: Elevated in myocardial damage; elevated levels = worse prognosis
• sFLT-1: Elevated; correlates with disease severity and poor recovery

Cardiac MRI

• Accurate assessment of chamber volumes and EF
• Detection of mural thrombi
• Late gadolinium enhancement (LGE) - predicts fibrosis and non-recovery
• Gadolinium is CONTRAINDICATED during pregnancy (fetal risk)
• Preferred in complex cases where echocardiography is inconclusive

Endomyocardial Biopsy

• Not routine
• Lymphocytic myocarditis found in 30-50% of specimens
• Reserved for atypical presentations or suspected giant cell myocarditis

Genetic Testing

• Recommended given ~15% yield for TTN truncating variants
• Impacts patient prognosis (TTN+ = lower recovery rates)
• Important for family screening - reveals undiagnosed DCM in relatives

---

MANAGEMENT

A. DURING PREGNANCY (Pre-delivery)

B. AFTER DELIVERY (Postpartum)

• ACE inhibitors/ARBs (enalapril, lisinopril) - reduce afterload, promote recovery
• Beta-blockers (metoprolol tartrate, carvedilol) - shown compatible with breastfeeding
• Spironolactone - shown compatible with breastfeeding
• Loop diuretics (furosemide) - for fluid overload
• Sacubitril/valsartan can be used postpartum (not breastfeeding)
• SGLT2 inhibitors - emerging; limited data in PPCM specifically

C. ANTICOAGULATION

• Indication: LVEF <0.35 OR marked LV dilation (high thrombus/embolic risk)
• Duration: First 6 weeks postpartum (once obstetric bleeding has resolved)
• Agent: LMWH preferred; warfarin can be used postpartum (does NOT cross into breast milk in significant amounts)
• LV thrombus on echo: anticoagulate until thrombus resolves

D. BROMOCRIPTINE - The Key Exam Drug

• Mechanism: Dopamine D2 agonist → inhibits pituitary prolactin secretion → prevents cleavage into toxic 16 kDa fragment
• Dose: Various regimens studied; Goldman-Cecil: 2.5 mg twice daily for 2 weeks, then once daily for 6 weeks
• Evidence: Small RCTs (notably Sliwa et al., South Africa) showed improved LVEF recovery and reduced mortality
• Status: Still experimental/controversial - no large RCT with placebo control
• 2025 Meta-analysis (PMID 41213878): Confirms potential benefit in LV recovery; awaits large confirmatory RCT
• Important: Bromocriptine suppresses lactation - therefore breastfeeding must be stopped if bromocriptine is used
• Current approach: Reasonable to add if traditional measures are insufficient; supported by ESC Heart Failure guidelines

E. DEVICES AND ADVANCED HEART FAILURE

Important PG Exam point: Because recovery rates in PPCM are higher than in other DCMs, temporary devices as bridge to recovery should be attempted before committing to cardiac transplantation.

• Harrison's 22E; Fuster and Hurst's The Heart, 15th Ed.; Creasy & Resnik's; Goldman-Cecil Medicine

---

PROGNOSIS

Recovery of LV Function

• 50-80% recover to LVEF ≥50%, mostly within 2-6 months of diagnosis
• Later recovery (beyond 6 months) is possible in some patients
• German cohort (IPAC study): ~50% recovery at 12 months
• The one-year mortality in the USA: 4-11% (4% in IPAC study; 11% in predominantly Black women populations)
• Global registry (worldwide): 6-month mortality ~6% (lowest Europe 4%, highest Middle East 10%)

Predictors of POOR Recovery (Exam Favorite!)

Predictors of GOOD Recovery

• LVEF at presentation >30-35%
• White/non-Black ethnicity
• Prompt diagnosis and treatment
• LVEDD <5.5 cm
• No LV thrombus

---

SUBSEQUENT PREGNANCY - Critical Exam Topic

• Even in women with recovered LV function, ~20% have modest EF reduction with subsequent pregnancy (persists in ~10%)
• Isolated cases of severe deterioration and life-threatening arrhythmias have been described even in recovered patients
• Contraception counseling is mandatory - unintended pregnancy should be prevented
• Early termination of unintentional pregnancy should be considered in women with persistent LV dysfunction

Management Algorithm for Subsequent Pregnancy in Women with Persistent LV Dysfunction:

• Baseline echo and BNP before/at first visit
• Monthly symptom monitoring up to 30 weeks, then biweekly
• Continue beta-blockers; switch ACEi/ARB/sacubitril-valsartan to hydralazine/nitrates
• Anticoagulation with LMWH
• Delivery planning with maternal-fetal medicine and cardiology team
• Creasy & Resnik's Maternal-Fetal Medicine; Fuster and Hurst's The Heart, 15th Ed.

---

BREASTFEEDING

• Previously prohibited (concern about fluid balance and prolactin)
• Now generally encouraged in patients where fluid balance can be maintained
• If bromocriptine is used, breastfeeding must be stopped
• Metoprolol tartrate, enalapril, and spironolactone are compatible with breastfeeding

---

GENETIC CONSIDERATIONS (Emerging PG Topic)

• Obtain comprehensive 3-generation family history in all PPCM patients
• Perform clinical cardiac screening of first-degree relatives (echo, ECG)
• Offer genetic testing - TTN truncating variants in ~15%; also DSP, MYH7, LMNA, SCN5A
• Positive genetic test = worse prognosis AND family member risk
• Treat PPCM like DCM genetically - follow same guidelines for family counseling

---

SUMMARY TABLE FOR EXAMS

---

RECENT EVIDENCE (2024-2025) - Stay Updated

---