Introduction
Hypertension (HT) is one of the most common cardiovascular diseases during pregnancy, and its most severe manifestation is preeclampsia, which is a leading cause of mortality for pregnant women and fetuses.
The pathogenesis of preeclampsia begins in the early stages of pregnancy when trophoblast migration ceases, leading to the failure of thick-walled spiral uterine arteries to transform into wide, flaccid, low-resistance uteroplacental vessels. Consequently, abnormal vessels result in hypoperfusion of the placenta and the release of inflammatory factors into the maternal circulation, which causes endothelial dysfunction. In preeclampsia, levels of proangiogenic factors such as placental growth factor (PlGF) or vascular endothelial growth factor (VEGF) are reduced. In contrast, levels of anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) are elevated [1]. The placenta produces sFlt1, which neutralizes maternal proangiogenic factors, further impairing endothelial function.
Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening disease, defined as heart failure with a reduced ejection fraction of the left ventricle, occurring in the last month of pregnancy or in the first few months after delivery in women without any other known cause of heart failure. The etiology of PPCM is not fully understood, and numerous theories are linking the development of the disease with inflammatory, immunological, and hormonal mechanisms [2]. The latest data indicate that preeclampsia is one of the risk factors for PPCM. The following case illustrates the diagnostic path of a patient whose preeclampsia was a prelude to the development of heart failure (HF) with a PPCM diagnosis.
Case report
A 33-year-old woman in her 33rd week of a twin pregnancy was admitted to the obstetrics department due to de novo diagnosed elevated blood pressure (160–170/110 mm Hg). The patient had been monitored in an outpatient clinic since the beginning of the first trimester due to presented tachycardia [without any evidence of electrocardiogram (ECG) abnormalities besides sinus tachycardia], and her blood pressure measures were within the normal range. Since the 13th week of pregnancy, she had been treated with metoprolol.
During admission, physical examination revealed high blood pressure (with an average of three measurements 172/106 mm Hg), tachycardia (112/min), regular heart sounds with a soft systolic murmur localized in the mitral area, vesicular breath sounds and peripheral edema reaching mid-calf. Further examination revealed elevated levels of inflammatory factors, microcytic anemia, leucocytosis with neutrophilia, signs of urinary tract infection, and proteinuria (1.2 g/L). Preeclampsia and urinary tract infections were diagnosed, and the patient was treated with antihypertensive medication and antibiotics. However, considering the features indicating fetal jeopardy, the decision was made to proceed with caesarean section.
After the delivery, the patient’s condition stabilized. Treatment with metoprolol and methyldopa was continued, and the patient’s blood pressure measurements ranged from 130 to 150/80 to 90 mm Hg. Inflammatory markers were normalized. The patient was discharged with recommendations to follow up at the cardiac outpatient clinic.
Three days after her discharge, the patient presented to the emergency department due to increasing edema and dyspnoea. Physical examination revealed bilateral basal crepitations and peripheral edema. The patient’s vital signs were as follows: blood pressure 156/92 mm Hg, heart rate 120/min, SpO2 86% without supplemental oxygen. The ECG showed sinus tachycardia 120/min, with 0.5 mm upsloping ST segment depression in leads II, III, aVF, V4-V5 leads, and T-wave inversion in leads II, III, aVF, V5–V6.
In additional investigations, elevated levels of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), increased inflammatory markers, and negative myocardial necrosis markers were found. Chest X-ray revealed features of severe pulmonary congestion (Fig. 1). Based on the computed tomography (CT) angiography, pulmonary embolism was excluded. Oxygen therapy, empirical antibiotic therapy, intravenous loop diuretic therapy, and prophylactic low molecular weight heparin were initiated. The patient was referred for further diagnostic evaluation and treatment in the cardiology department.
In the echocardiographic examination, a significantly reduced ejection fraction (EF) of the non-dilated left ventricle (LV) was observed (LVEF 34%), along with decreased longitudinal strain parameter and no evidence of valve dysfunction. The right atrium and ventricle were of normal size and function (Fig. 2). Based on clinical evaluation and echocardiography findings, PPCM was suspected. The differential diagnosis included myocarditis and previously undiagnosed dilated cardiomyopathy. Treatment typical for heart failure was initiated, including a loop diuretic, angiotensin-converting enzyme inhibitor (ACEI), beta-blocker, and mineralocorticoid receptor antagonist (ARB). Additionally, bromocriptine was added, and methyldopa was discontinued. Clinical improvement was achieved, confirmed with a chest X-ray.
In further diagnostic evaluation, cardiac magnetic resonance imaging (MRI) was performed, revealing reduced LVEF and hypertrabeculation of the left ventricle in the apical and lateral segments (Fig. 3), along with visible small, diffuse (mainly intramuscular) areas of late gadolinium enhancement in the lateral and posterior walls in the middle region as well as the apex. A genetic testing panel for dilated cardiomyopathy was also taken.
Ultimately, the cause of HF was determined to be PPCM, and HF treatment was continued. The patient was instructed on the necessity of monitoring, prognosis, and the risk of subsequent pregnancies and advised to implement effective contraception.
To confirm the diagnosis and assess further prognosis, follow-up echocardiography and cardiac MRI were scheduled.
During the follow-up visit at the cardiac outpatient clinic after three months, the patient was in good condition, without any HF symptoms, and with good exercise tolerance. Echocardiography revealed improved left ventricular function with normalisation of LVEF and strain parameters (Fig. 4). The consistent outcome in cardiac MRI with normalisation of LV structure and function allowed us to diagnose PPCM conclusively. The treatment was continued, and the subsequent follow-up was scheduled in the next 3 months.
Discussion
PPCM is a rare condition with morbidity that varies by geographical region and, in the European population, reaches up to 1:5000 [3]. Pathogenesis of PPCM remains unclear. However, certain risk factors, such as multiple pregnancies or advanced maternal age, have been identified. Moreover, women with elevated blood pressure during pregnancy have a higher risk of PPCM. Additionally, preeclampsia is observed more frequently among patients with PPCM [2, 4]. Recent data published by the European Society of Cardiology’s (ESC) registry revealed that one in four patients with PPCM presented a history of gestational hypertension [5].
Recent theories on PPCM pathogenesis focus on the role of genetic, vascular, and hormonal factors, with prolactin and placenta-released vasoactive factors (similar to those involved in the pathogenesis of preeclampsia) playing the major role. Prolactin exists in two antagonistic forms. The 23 kDa prolactin has a protective effect on endothelial function and promotes angiogenesis. The form cleaved by cathepsin D (16 kDa) acts differently, inducing endothelial cell apoptosis, damaging vascular structures, inhibiting endothelial cell proliferation and migration, and additionally promoting vasoconstriction and impairing myocyte function.
The biologically active form of 16 kDa prolactin, together with vasoactive factors such as soluble VEGF receptor (sFlt1), could initiate and sustain PPCM [6].
PPCM clinically presents with typical HF symptoms such as fatigue, dyspnoea, or peripheral edema. Moreover, cardiac arrhythmia and thrombotic events may occur. The severity of symptoms varies from mild shortness of breath to cardiogenic shock among individual patients [2]. Early symptoms may be mistaken for ailments typical for the last weeks of pregnancy.
PPCM should be differentiated from exacerbation of pre-existing and unrecognised heart conditions, acute coronary syndrome, pulmonary embolism, or myocarditis. The diagnosis of PPCM remains a ‘diagnosis of exclusion’.
A diagnostic approach for women experiencing dyspnoea at the end of pregnancy or after labour involves electrocardiography, echocardiography, and assessment of natriuretic peptides. NT-pro-BNP is an unspecific but highly sensitive marker of HF (Fig. 5).
The most frequent abnormality reported in echocardiography is left ventricular systolic dysfunction, with LVEV < 45%. Cardiac MRI provides more precise information about ventricular measurements and is more effective in detecting thrombi in the left ventricle. However, since there are no specific features of PPCM in MRI, its role is limited to differential diagnosis.
The outcome in patients undergoing treatment is usually satisfactory, with a six-month mortality rate of around 6%. In more than 50% of cases, clinical improvement to NYHA class I and an increase in LVEF to > 55% are observed. Negative prognostic factors include left ventricular end-diastolic volume (LVED) > 60 mm, LVEF < 30%, and primary right ventricle dysfunction [8, 9].
The treatment of PPCM includes standard heart failure treatment. In cases where PPCM manifests with acute, decompensated heart failure (clinical scenario acute heart failure/cardiogenic shock), the guidelines for managing acute heart failure apply. For the treatment of stabilized HF, the pregnancy status of the patient is important. During pregnancy, the use of ACEI or MRA is contraindicated. After delivery, treatment includes ACEI or ARB, or a neprilysin inhibitor (ARNI), beta-adrenolytics, and diuretics. The role of sodium glucose cotransporter inhibitor (SGLTi), currently one of the pillars in HF pharmacotherapy, is not yet established in PPCM. All patients should adhere to the treatment until they achieve complete myocardial recovery and for at least 12–24 months after the full recovery of LV function. Following complete recovery, the duration of medical therapy remains uncertain. Many clinicians advocate for continued long-term treatment for all patients with PPCM to mitigate the potential decline in cardiac function associated with therapy [2, 10]. According to the ESC guidelines for heart diseases in pregnant women, the use of bromocriptine (inhibitor of prolactin release) should be considered as a potentially specific treatment for PPCM [6, 10]. Research suggests that including bromocriptine in therapy improves LVEF and reduces mortality [2]. However, it requires antithrombotic prophylaxis.
The described case emphasises a few important practical aspects:
- 1. Twin pregnancy. Multigestational pregnancy is a risk factor for both preeclampsia and PPCM. A higher placental mass and increased concertation of placenta-released vasoactive factors could have a stronger impact on a woman’s systemic circulation if initiation of a pathogenic chain of preeclampsia in the form of impaired embryo implantation occurs early in pregnancy.
- 2. Diagnosis of preeclampsia. Preeclampsia, as a disorder related to endothelial dysfunction, can have multi-organ presentations. The diagnosis requires hypertension and fulfillment of at least one of the criteria listed below [11, 12]:
- • proteinuria ≥ 0.3 g in a 24-hour urine collection;
- • platelet count < 150 tys/μL;
- • creatinine level > 1.1 mg/dL (97.2 μmol/l) or doubled creatinine level without kidney disease;
- • increases in transaminases level;
- • pulmonary edema;
- • clinical symptoms (severe and persistent headaches, visual disturbance, pain in the right epigastric region);
- • symptoms of fetal distress.
- 3. Preeclampsia as a risk factor for PPCM. In clinical practice, preeclampsia occurs in 5–7% of pregnancies, whereas PPCM is significantly less frequent, affecting approximately 0.02% of pregnancies. According to the European Registry of PPCM, 25% of patients with PPCM also presented with preeclampsia, and another 13.5% were diagnosed only with hypertension [5]. Women with PPCM and co-existing preeclampsia have better outcomes in terms of LVEF improvement compared to women with PPCM without hypertension (58% and 41%, respectively) [5].
- 4. Challenges in the differential diagnosis of PPCM. In the above article, the necessity of excluding structural heart disease in pregnant patients presenting with heart failure concerns was emphasized. Physiological changes during pregnancy involve gradual increases in circulating blood volume, leading to increased preload on the heart, elevated heart rate, and enhanced inotropy, which can mimic symptoms of heart failure, reveal previously undiagnosed heart conditions, or lead to the emergence of pregnancy-specific health issues. In the described case, cardiac MRI showed left ventricular hypertrabeculation, which may indicate left ventricular non-compaction cardiomyopathy (LVNC). According to the latest ESC guidelines, LVNC, characterized by prominent left ventricular trabeculae and deep recesses with common myocardial thickening, may be associated with systolic dysfunction of the left ventricle but is not classified as a different type of cardiomyopathy [13]. Moreover, hypertaberculation of the left ventricle may transiently appear during pregnancy. In our patient, the structure of the left ventricle returned to normal after a 6-month follow-up, confirming the thesis above.
Summary
Diagnosing HF during pregnancy poses a challenge for physicians across various specialties and necessitates a multidisciplinary approach. A specific cause of HF is PPCM, which is a rare condition. Early diagnosis and appropriate treatment are crucial for improving patient prognosis. The frequent co-occurrence of gestational hypertension with PPCM warrants special attention from internists, cardiologists, and hypertensiologists. In patients with hypertension during pregnancy who present symptoms of exercise intolerance, dyspnea, or develop cardiac arrhythmias, echocardiography should be considered. Collaboration between cardiologists and obstetricians enhances the likelihood of early diagnosis and treatment, thereby preventing the development of further cardiovascular complications and improving the long-term prognosis.
Conflict of interest
The authors declare no conflicts of interest.
Ethics statement
The publication of this case report has been conducted in accordance with the ethical standards outlined in the Declaration of Helsinki. All patient information has been de-identified to protect confidentiality. All medical procedures performed in this case report were conducted with the patient’s consent and in compliance with relevant regulations and institutional policies.
Author contributions
A.O. initiated the case report, corrected and finalized the manuscript preparation. M.K. admitted the patient and conducted diagnostic and treatment processes. A.O. and W.W. performed and analyzed imaging examinations. O.H., A.I., and D.S. collected patient data, analyzed the literature, and prepared the first draft of the manuscript. M.R. critically reviewed the manuscript.