Pre-eclampsia and heart failure: a close relationship Rossana ORABONA* 1, Edoardo SCIATTI* 2, Federico PREFUMO 1, Enrico VIZZARDI 2, Accepted Article Ivano BONADEI 2, Adriana VALCAMONICO 1, Marco METRA 2, Tiziana FRUSCA 1,3 1 Maternal Fetal Medicine Unit, Department of Obstetrics and Gynecology, University of Brescia, Italy 2 Section of Cardiovascular Diseases, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Italy 3 Department of Obstetrics and Gynecology, University of Parma, Italy *Both authors contributed equally to this work Corresponding Author: Dr. Federico Prefumo Piazzale Spedali Civili 1 25123 Brescia, Italy Email: [email protected] Short Title: Pre-eclampsia and heart failure Keywords: pre-eclampsia – heart failure – echocardiography – left ventricular – uterine artery – fibrosis – cardiovascular disease – strain – peripartum. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/uog.18987 This article is protected by copyright. All rights reserved. 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 Accepted Article structural and/or functional cardiac abnormalities and leading to elevated intracardiac pressure and/or low cardiac output (CO) at rest or during stress. 1 According to the most recent European survey 2 and guidelines 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 more than 70 years, and reaching a 1year all-cause mortality of 23.6% in the acute setting and of 6.4% in the chronic form. Notably, HF is a still growing burden on healthcare systems worldwide because of frequent re-hospitalization and the introduction of new drugs and devices. 2,3,4 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 years. 1,3 Pre-eclampsia (PE) is most commonly defined by new-onset of hypertension (at least 140/90 mmHg, confirmed on two occasions 4-6 hours apart) after the 20th week of gestation combined with at least one among the following: de novo onset of proteinuria (≥300 mg/24 hours), one (or more) sign of maternal organ dysfunction; fetal growth restriction (FGR). 5 Signs of maternal organ dysfunction include renal insufficiency, liver involvement, neurological or hematological complications. Severe maternal complications include eclampsia, cerebrovascular and cardiovascular (CV) accidents, liver rupture, acute renal failure. 6 PE remains a leading cause of maternal and perinatal morbidity and mortality worldwide complicating 2-8% of all pregnancies. 7 Perinatal outcome primarily depends on preterm delivery, FGR or fetal death. 8 According to PE onset, the disorder is frequently dichotomized into early-onset PE (EOPE) and late-onset PE (LOPE), considering 34 weeks’ gestation as cut-off, 9 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 LOPE, 10 although the risk of complications in LOPE cannot be underestimated. 11 This article is protected by copyright. All rights reserved. Pathophysiologic relationship between pre-eclampsia and heart failure The etiology of HF is heterogeneous and varies worldwide, principally depending on myocardial Accepted Article ischemia/infarction, idiopathic cardiomyopathies, valvular heart disease, hypertensive cardiopathy, congenital defects, cardiac toxicity. 3 In about 50% of cases all etiologies end with 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 perfusion. 1 Consequently, the sympathetic and renin-angiotensin-aldosterone systems react with persistent neurohormonal activation causing sodium retention, fluid overload (i.e., edema), 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 fraction (HFrEF). 1 In the remaining 50% of cases, despite the same etiologies, global pump function is preserved at the expense of increased cardiopulmonary filling pressures, namely HF with preserved LV ejection fraction (HFpEF). This syndrome principally affects women, 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 compliance. 12 PE results from a mismatch between utero-placental supply (with a placenta impaired by ischemic and/or oxidative stress damage) and fetal demands, leading to its systemic inflammatory maternal and fetal manifestations. 6,9 The fetus is not required for the development of PE, since PE can complicate also molar pregnancies where the placenta only – but not the fetus – is present. 13 These factors act in a proinflammatory and prothrombotic way, determining maternal endothelial dysfunction and intravascular inflammation. 14 Inflammatory and autoimmune diseases, as well as immune response to the conceptus, support the role of chronic inflammation as a favorite milieu for PE development. 12 PE and CV diseases are linked to one another by sharing risk conditions such as This article is protected by copyright. All rights reserved. diabetes mellitus and obesity, which suggests overlap in their pathogenesis. Whether the oxidized placenta (i.e., defective and superficial trophoblast invasion) is the cause of systemic CV dysfunction or pre-existing subclinical CV abnormalities lead to placental hypoperfusion (i.e., pregnancy as a failed CV stress test) is still not clear: probably two forms of PE exist, one characterized by a Accepted Article predominant placental defect occurring early in pregnancy (typically EOPE) leading to FGR and preterm birth, and the other due to CV risk factors and/or alterations favoring maternal CV maladaptation to pregnancy (typically LOPE), and lots of mixed features. 15 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 disorder. 13 Cardiovascular adaptation to normal pregnancy In healthy pregnancies, the CV system undergoes hemodynamic changes in order to support the fetalplacental unit in its development. Typically, CO increases by 30-50%, heart rate by 10 bpm on average, with concomitant fall in vascular resistance and blood pressure despite a 50% rise in plasma volume. 16 These changes are accompanied by a 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 (RWT, ratio of LV thickness to LV internal dimension in diastole) < 0.43. 17 Moreover, diastolic dysfunction and impaired myocardial relaxation with preserved myocardial contractility have been reported in 18% and 28% of normal pregnancies at term, respectively. 18 These alterations are benign and fully recover within one year postpartum. 17 However, fatigue, dyspnea, exercise intolerance and edema are frequent in healthy pregnancies making a differential diagnosis with actual pathologic CV symptoms difficult. Heart failure during pre-eclampsia and the postpartum period 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 This article is protected by copyright. All rights reserved. sustaining hypertension itself. Arterial stiffness is a hallmark of the disorder, particularly in EOPE. 19 , 20 , 21 , 22 , 23 All of these features are almost partly responsible of a detrimental form of cardiac remodeling such as concentric hypertrophy, also typical of hypertensive cardiopathy, presumably secondary to the raised LV afterload in absence of adequate preload. 24,25 ,26, 27 ,28,29 LV systolic Accepted Article function during PE is characterized by impaired myocardial contractility, clearly demonstrated by tissue Doppler imaging and speckle tracking echocardiography. 21,22,30,31 LV diastolic function, whose impairment generally precedes the systolic dysfunction, has been demonstrated to be mildly/moderately altered, with reduced regional myocardial relaxation, in both EOPE and LOPE, with a prevalence of about 50% and 20%, respectively. 20,21,22,25 This is a direct consequence of myocardial stiffening due to LV hypertrophy, which reflects on left atrial remodeling by means of elevated left-sided filling pressure, especially in EOPE. 25,26,27 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 (about 30%) and hypertrophy (about 50%) have been documented only in EOPE with severe LV involvement. 26,27 Although most women with PE undergo inadequate cardiac remodeling during pregnancy, only a small number of them develops acute HF. 23 Acute pulmonary edema is the most common cardio- pulmonary complication of PE, occurring in 3% of cases. 32,33,34 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 cardiomyopathy. 35 , 36 Acute pulmonary edema in PE is a life-threatening condition for both mother and child: it is responsible of 30% of maternal deaths in women with hypertensive disorders of pregnancy. 31,37 In 70% of cases it occurs postpartum, 31,32,33 when the plasma oncotic pressure typically decreases (in addition to the 38 along with elevated intravascular hydrostatic pressure and endothelial role of albumin loss), permeability (due to hypertension). A comprehensive overview of precipitating factors is reported in Figure 1. 33,36, 39 In women with a history of hypertensive cardiopathy before pregnancy, acute pulmonary edema in PE is 5-fold more frequent and typically occurs before delivery, because of acute decompensation of biventricular dysfunction. This article is protected by copyright. Allisrights reserved. pregnancy and postpartum myocardial 33, 40 A rare but catastrophic cause of acute HF in infarction, which is favored by hypertension (odds ratio 22) 41 and sometimes related to spontaneous coronary artery dissection. 42 After a multidisciplinary discussion among cardiologist, obstetrician, anesthesiologist, cardiac surgeon and neonatologist, its management implies delivery and medical treatment similar to a hypertensive acute pulmonary edema. 33 A complete description of the differential diagnosis and management of acute pulmonary Accepted Article edema in pregnancy goes beyond the scope of this review and can be found elsewhere. 34 Heart failure after a pregnancy complicated by pre-eclampsia Although a link between PE and CV diseases later in life was already suggested almost 50 years ago, PE has only recently been accepted to predispose to CV affections. The subclinical CV involvement during PE does not resolve with delivery. 26,28, 43 , 44 , 45 , 46 , 47 , 48 biventricular alterations in almost 50% of EOPE women. 26 Melchiorre et al found persistent About 40% of these women develop essential hypertension within 1 to 2 years after EOPE, with a 14.5-fold increased risk in the presence of moderate to severe LV alterations. 26 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 HF. 42,49,50 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 aortic. 51,52 Moreover, biventricular myocardial contractility and relaxation as well as LV torsional mechanics, studied by speckle tracking echocardiography, were abnormal in 20% to 50% of EOPE. 53 CV performance, expressed as both the efficiency of LV pump function and stiffness (Ees, LV end-systolic elastance) and the aortic elastic ability to receive blood (Ea, aortic elastance), is summarized in the concept of ventriculararterial coupling (VAC). 54,55 VAC is a pure number, namely the ratio Ea/Ees, referring to the ability of LV and aorta to function together without energy dissipation and its alteration occurs early in HF, particularly of hypertensive origin. 55,56,57 Consistently, we found that both components of VAC were This article is protected by copyright. All rights reserved. altered in the EOPE group. 48 By means of integrated backscatter we described the presence of LV fibrosis in the EOPE group. 58 Our results, highlighting the extent of myocardial damage by structural and functional points of view, identify one of the possible mechanisms of HF development in these Accepted Article women. From epidemiological studies, PE is associated with a two-to-seven-fold risk of CV disease later in life, 59 particularly HF (4-fold), coronary artery disease (2-fold), stroke (2-fold) and CV death (2fold). 60,61 As a consequence, international guidelines on the prevention of CV disease in women clearly include PE among CV risk factors. 62 In addition, PE and HF share several CV risk markers (e.g., lipid and glycemic profile, blood pressure, body mass index, C-reactive protein) 42, 63 and preclinical target organ alterations (increased carotid intima-media thickness, coronary plaques). 64 Notably, a recent meta-analysis by Alma et al 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 metabolically and biochemically predisposition behind the development of both syndromes. 65 Moreover, Mohseni et al found nine microRNAs (miRNAs) whose up- or down-regulated expression overlaps between PE and concentric LV remodeling, suggesting again a common pathophysiologic pathway which partly explains the development of HF after a pregnancy complicated by PE. 66 Finally, the association between cardiac abnormalities and PE 4-10 years postpartum was demonstrated by Ghossein-Doha et al, after correcting for conventional CV risk factors, with an adjusted odds ratio of 4.4. 67 Conclusions We summarized the relevant existing evidence on the close link between PE and CV complications. Such evidence is relevant for multidisciplinary maternity and women’s health care 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 This article is protected by copyright. All rights reserved. considered a failed CV stress test, revealing women at a higher risk of CV sequelae, particularly HF. The independent association between PE and HF, after correcting for CV risk factors, has been recently demonstrated. 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 Accepted Article CV disease or suffer from HF, 68 making CV diseases in women an important public health priority. 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Ultrasound Obstet Gynecol 2017; 49: 143–149. Accepted Article 68 Mosca L, Barrett-Connor E, Wenger NK. Sex/gender differences in cardiovascular disease prevention: what a difference a decade makes. Circulation 2011; 124: 2145–2154. Figure legend: Overview of precipitating factors of acute pulmonary edema. This article is protected by copyright. All rights reserved. Accepted Article HEMODYNAMIC FACTORS Increased intravascular hydrostatic pressure (hypertension) Increased endothelial permeability (hypertension) Reduced plasma colloid pressure (albumin loss) Reduced plasma colloid pressure (postpartum) OTHER FACTORS Pain Exertion Anxiety Uterine contractions Bleeding Anaesthesia CARDIAC FACTORS Acute pulmonary edema in pre‐eclampsia This article is protected by copyright. All rights reserved. FLUID FACTORS Edema resorption (postpartum) Fluid autotransfusion (sympathetic hyperactivity) Fluid autotransfusion (involving uterus) Iatrogenic fluid infusion Systolic dysfunction Diastolic dysfunction Myocardial ischemia Ventricular arrhythmias
