Pre‐eclampsia and heart failure: a close relationship

Heart failure (HF) is a clinical syndrome characterized by signs (e.g. pulmonary crackles, peripheral edema, jugular turgor) and symptoms (e.g. breathlessness, fatigue, ankle swelling) caused by structural and/or functional cardiac abnormalities and leading to elevated intracardiac pressure and/or low cardiac output (CO) at rest or during stress1. According to the most recent European survey and guidelines2, 3, HF represents one of the pandemics of the 21st century, affecting about 2% of the adult population worldwide and at least 10% of people aged over 70 years, and reaching a 1-year all-cause mortality of 23.6% in the acute setting and of 6.4% in the chronic setting. Notably, HF is a still-growing burden on healthcare systems worldwide, because of a need for frequent rehospitalization and the introduction of new drugs and devices2-4. Acute HF is a life-threatening condition characterized by new onset or recurrence of symptoms and signs of HF, and requires urgent evaluation and treatment. It is the most frequent cause of hospitalization in people older than 65 years1, 3. Pre-eclampsia (PE) is most commonly defined by new-onset hypertension (at least 140/90 mmHg confirmed on two occasions 4–6 h apart) after the 20th week of gestation, combined with at least one of the following: de-novo onset of proteinuria (≥ 300 mg/24 h), one (or more) sign(s) of maternal organ dysfunction or fetal growth restriction (FGR)5. Signs of maternal organ dysfunction include renal insufficiency, liver involvement and neurological or hematological complications. Severe maternal complications include eclampsia, cerebrovascular and cardiovascular (CV) accidents, liver rupture and acute renal failure6. PE remains a leading cause of maternal and perinatal morbidity and mortality worldwide, complicating 2–8% of all pregnancies7. Perinatal outcome depends primarily on the incidence of preterm delivery, FGR or fetal death8. According to the timing of onset of PE, the disorder is frequently dichotomized into early-onset PE (EOPE) and late-onset PE (LOPE), considering 34 weeks' gestation as cut-off9, although gestational age at onset might be related to different pathophysiological mechanisms involving different patterns of cardiac output and peripheral resistance as well as trophoblastic infiltration. EOPE seems to be associated with higher perinatal risks and maternal mortality than does LOPE10, although the risk of complications in LOPE cannot be underestimated11. The etiology of HF is heterogeneous and varies worldwide, depending principally on myocardial ischemia/infarction, idiopathic cardiomyopathies, valvular heart disease, hypertensive cardiopathy, congenital defects and cardiac toxicity3. In about 50% of cases, all etiologies lead to a common pathway characterized by myocyte loss and fibrosis replacement, leading to increased myocardial stretch and left ventricular (LV) remodeling and dilatation, reduced pump efficiency and impaired peripheral perfusion1. Consequently, the sympathetic and renin–angiotensin–aldosterone systems react with persistent neurohormonal activation causing sodium retention, fluid overload (i.e. edema) and renal dysfunction in a vicious cycle. Gut congestion with cachexia, and activated systemic inflammatory pathways with endothelial dysfunction, contribute to the syndrome, defined as HF with reduced LV ejection fraction1. In the remaining 50% of cases, despite having the same etiologies, global pump function is preserved at the expense of increased cardiopulmonary filling pressure, namely HF with preserved LV ejection fraction (HFpEF). This syndrome principally affects women, particularly hypertensive or elderly individuals, and those who suffer from atrial fibrillation, diabetes mellitus, renal failure or chronic pulmonary lung disease. Although the pathophysiology of HFpEF is still debated, it seems to be related to a proinflammatory state enhanced by the cited comorbidities, which leads to endothelial dysfunction, myocyte hypertrophy and collagen deposition together with fibrosis and reduced LV compliance12. PE results from a mismatch between uteroplacental supply (with impaired placenta due to ischemic and/or oxidative stress damage) and fetal demands, leading to systemic inflammatory maternal and fetal manifestations6, 9. The presence of a fetus is not a requirement for the development of PE, since PE can also complicate molar pregnancies in which only the placenta is present13. These factors act in a proinflammatory and prothrombotic way, determining maternal endothelial dysfunction and intravascular inflammation14. Inflammatory and autoimmune diseases, as well as immune response to the conceptus, support the role of chronic inflammation as a favorite milieu for the development of PE12. PE and CV diseases share risk conditions such as diabetes mellitus and obesity, which suggests overlap in their pathogenesis. It is not clear yet whether the oxidized placenta (i.e. defective and superficial trophoblast invasion) is the cause of systemic CV dysfunction, or whether pre-existing subclinical CV abnormalities lead to placental hypoperfusion (i.e. pregnancy as a failed CV stress test). It is possible that two forms of PE exist, one characterized by a predominant placental defect occurring early in pregnancy (typically EOPE) leading to FGR and preterm birth, and the other attributed to CV risk factors and/or alterations favoring maternal CV maladaptation to pregnancy (typically LOPE), with several features in common15. Independent of its etiology, this syndrome may damage every organ by means of hypertension and/or hypoperfusion with oxidative stress, so that PE is typically considered to be primarily a vascular disorder13. In healthy pregnancy, the CV system undergoes hemodynamic changes in order to support the fetal–placental unit in its development. Typically, CO increases by 30–50% and heart rate by an average of 10 bpm, with concomitant falls in vascular resistance and blood pressure despite a 50% rise in plasma volume16. These changes are accompanied by transient LV eccentric hypertrophy as a compensatory mechanism of volume overload, as seen in healthy athletes. It is defined as increased LV mass with relative wall thickness (ratio of LV thickness to LV internal diameter in diastole) < 0.4317. Moreover, diastolic dysfunction and impaired myocardial relaxation with preserved myocardial contractility have been reported in 18% and 28%, respectively, of normal pregnancies at term18. These changes are benign, and fully recover within 1 year of delivery17. However, fatigue, dyspnea, exercise intolerance and edema are frequently seen in healthy pregnant women, making difficult a differential diagnosis of actual pathologic CV symptoms. PE is a hypertensive disorder. Increased vascular resistance with consequent lower plasma expansion and reduced CO triggers neurohormonal overactivity (e.g. sympathetic activity) in a vicious cycle sustaining hypertension itself. Arterial stiffness is a hallmark of the disorder, particularly in EOPE19-23. All these features are also partly responsible for a detrimental form of cardiac remodeling such as concentric hypertrophy, also typical of hypertensive cardiopathy, presumably secondary to the raised LV afterload in the absence of adequate preload24-29. LV systolic function during PE is characterized by impaired myocardial contractility, clearly demonstrated by tissue Doppler imaging and speckle-tracking echocardiography21, 22, 30, 31. LV diastolic function, impairment of which generally precedes systolic dysfunction, has been shown to be mildly/moderately altered, with reduced regional myocardial relaxation, in both EOPE and LOPE, with a prevalence of about 50% and 20%, respectively20-22, 25. This is a direct consequence of myocardial stiffening due to LV hypertrophy, which is reflected on left atrial remodeling by means of elevated left-sided filling pressure, especially in EOPE25-27. Increased right ventricular (RV) afterload determines diastolic dysfunction (in 20% of cases) with impaired myocardial relaxation in both EOPE and LOPE, while RV systolic dysfunction (in about 30% of cases) and hypertrophy (in about 50%) have been documented only in EOPE with severe LV involvement26, 27. Although most women with PE undergo inadequate cardiac remodeling during pregnancy, only a small number of them develop acute HF23. Acute pulmonary edema is the most common cardiopulmonary complication of PE, occurring in 3% of cases32-34. In a Swedish registry of peripartum HF, the presence of PE resulted in a 12-fold increased risk of developing HF during pregnancy or in the postpartum period, sometimes overlapping with peripartum cardiomyopathy35, 36. Acute pulmonary edema in PE is a life-threatening condition for both the mother and her child, and it is responsible for 30% of maternal deaths in women with hypertensive disorders of pregnancy31, 37. In 70% of cases it occurs postpartum31-33, when the plasma oncotic pressure typically decreases (in addition to the role of albumin loss)38, along with elevated intravascular hydrostatic pressure and endothelial permeability (due to hypertension). A comprehensive overview of precipitating factors is shown in Figure 1 33, 36, 39. In women with a history of hypertensive cardiopathy before pregnancy, acute pulmonary edema in PE is five times more frequent and typically occurs before delivery, because of acute decompensation of biventricular dysfunction33, 40. A rare but catastrophic cause of acute HF in pregnancy and postpartum is myocardial infarction, which is favored by hypertension (odds ratio of 22) and sometimes related to spontaneous coronary artery dissection41, 42. Following multidisciplinary discussion between cardiologist, obstetrician, anesthesiologist, cardiac surgeon and neonatologist, its management involves delivery and medical treatment that is similar to that of hypertensive acute pulmonary edema33. A complete description of the differential diagnosis and management of acute pulmonary edema in pregnancy is beyond the scope of this review and can be found elsewhere34. Although a link between PE and CV diseases later in life was first suggested almost 50 years ago, it is only recently that it has been accepted that PE predisposes women to CV conditions. The subclinical CV involvement during PE does not resolve with delivery26, 28, 43-48. Melchiorre et al.27 found persistent biventricular alterations in almost 50% of women with EOPE. About 40% of these women developed essential hypertension within 1 to 2 years after EOPE, with a 14.5-fold increased risk in the presence of moderate to severe LV alterations27. Moreover, the vascular involvement (i.e. arterial stiffness and endothelial dysfunction) persists after delivery, leading to a higher risk of hypertension, coronary artery disease and HF42, 49, 50. Recently our group evaluated 30 women with previous EOPE, 30 with previous LOPE and 30 with an uncomplicated pregnancy, at 6 months to 4 years after delivery, by means of transthoracic echocardiography, arterial stiffness measurement and endothelial function assessment; every woman was completely free from CV risk factors (including hypertension). We found that EOPE, rather than LOPE, was characterized by persistent endothelial dysfunction (in up to one-third of women) and arterial stiffness, both peripheral and aortic51, 52. Moreover, biventricular myocardial contractility and relaxation, as well as LV torsional mechanics, studied by speckle-tracking echocardiography, were abnormal in 20% to 50% of patients with EOPE53. CV performance, expressed as both the efficiency of LV pump function and stiffness (LV end-systolic elastance (Ees)) and the aortic elastic ability to receive blood (aortic elastance (Ea)), is summarized in the concept of ventricular–arterial coupling (VAC)54, 55. VAC is a pure number, namely the ratio Ea/Ees, and refers to the ability of the LV and aorta to function together without energy dissipation, and its alteration occurs early in HF, particularly that of hypertensive origin55-57. Consistently, we found that both components of VAC were altered in the EOPE group48. By means of integrated backscatter, we described the presence of LV fibrosis in the EOPE group58. Our results, highlighting the extent of myocardial damage from structural and functional points of view, identify one of the possible mechanisms of HF development in these women. According to epidemiological studies, PE is associated with a two-to-seven-fold increase in risk of CV disease later in life59, particularly HF (four-fold), coronary artery disease (two-fold), stroke (two-fold) and CV death (2-fold)60, 61. As a consequence, international guidelines on the prevention of CV disease in women include PE among CV risk factors62. In addition, PE and HF share several CV risk markers (e.g. lipid and glycemic profile, blood pressure, body mass index, C-reactive protein), and preclinical target organ alterations (increased carotid intima–media thickness, coronary plaques)42, 63, 64. Notably, a recent meta-analysis by Alma et al.65 revealed that PE and HFpEF in women share a range of biomarkers (e.g. C-reactive protein, natriuretic peptides, troponins, adrenomedullin, glycemic and lipid profile molecules), supporting the hypothesis of a metabolic and biochemical predisposition behind the development of both syndromes65. Moreover, Mohseni et al.66 found nine microRNAs whose up- or down-regulated expression overlaps between PE and concentric LV remodeling, again suggesting a common pathophysiologic pathway that partly explains the development of HF after a pregnancy complicated by PE. Finally, the association between PE and cardiac abnormalities 4–10 years postpartum was demonstrated by Ghossein-Doha et al.67, after correcting for conventional CV risk factors, with an adjusted odds ratio of 4.4. We have summarized existing evidence on the close relationship between PE and CV complications. Such evidence is relevant for multidisciplinary maternity and women's healthcare providers from primary to tertiary levels of healthcare. Several studies have demonstrated that PE is characterized by endothelial dysfunction, vascular stiffness and biventricular remodeling, which persist after delivery, leading to the development of hypertension. Furthermore, a pregnancy complicated by PE can be considered a failed CV stress test, revealing women at a higher risk for CV sequelae, particularly HF. The independent association between PE and HF, after correcting for CV risk factors, has been demonstrated recently. HF is one of the major pandemics of the 21st century, with high morbidity, mortality and healthcare costs. In Western countries, more female than male people die because of CV disease or suffer from HF68, making CV diseases in women an important public-health priority. We suggest that, in the context of a reasonable approach to the evaluation, diagnosis, prevention and treatment of CV disease, women who suffer from PE should be offered follow-up programs. We hope that this will improve short- and long-term maternal outcomes, and related cost-effectiveness of interventions.

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