Authors: Malamo E. Countouris (a.Department of Medicine, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA), Natalie A. Bello (b.Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA; c.Atria Institute, New York, NY)
Categories: Article, Preeclampsia, hypertension, cardiovascular disease, pregnancy, Pregnancy, Risk Factors, Hypertension, Women, Sex, Gender
Source: Circulation research
Authors: Malamo E. Countouris, Natalie A. Bello
Preeclampsia is a syndrome of hypertension in association with target organ dysfunction, including proteinuria, that manifests during pregnancy and the immediate postpartum period. The pathophysiology of preeclampsia originates from impaired trophoblastic invasion of the placental resulting in malperfusion and involves multiple mechanistic pathways that include anti-angiogenic factors, endothelial dysfunction, and immune dysregulation. Preeclampsia caries an increased risk for subclinical cardiovascular disease - left ventricular remodeling, diastolic dysfunction, coronary artery calcification, peripheral vascular abnormalities, and microvascular dysfunction – as well as increased risk for clinical cardiovascular disease including stroke, heart failure, myocardial infarction, and death from a cardiovascular cause. This review will highlight several common mechanistic pathways shared between preeclampsia and cardiovascular diseases that provide insight into potential targets for risk reduction and disease process mitigation that can be examined in future trials.
Pregnancy serves as a 9-month stress test and, as such, can identify reproductive-age women who may be at heightened risk for cardiovascular disease in later life. Preeclampsia, a hypertensive disorder affecting 5–8% of pregnancies, is a leading contributor to maternal morbidity and mortality, as well as fetal growth restriction, and preterm birth and its incidence is on the rise.^1,2^ Preeclampsia was long regarded as a temporary obstetrical condition with implications limited to pregnancy. However, we now recognize that women with prior preeclampsia are at elevated risk for the development of not only sustained hypertension but also premature cardiovascular disease (CVD).^3–9^ Affected women have an increased incidence as early as one year after pregnancy and remain at heightened risk compared with women who did not have preeclampsia.^4,9–12^
The pathophysiology of preeclampsia includes excessive placental release of anti-angiogenic proteins (sFlt-1, sEng) that lead to systemic manifestations of hypertension, proteinuria, and endothelial dysfunction and may impact long term CVD.^13–15^ Preeclampsia is also associated with left ventricular (LV) hypertrophy and abnormal LV systolic and diastolic function both at the time of delivery and later in life.^16,17^ Meta-analyses have shown that a history of preeclampsia is associated with approximately 4 times increased risk of heart failure and hypertension, 2 times increased risk of coronary artery disease, and more than double the risk of dying from a cardiovascular-related cause.^4,18^ The majority of the data linking preeclampsia to future CVD comes from epidemiologic studies. Because preeclampsia and CVD share many common risk factors (Figure 2) prospective studies in humans and animal models are greatly needed to better understand the independent contributions of preeclampsia to CVD risk and disease. In this review, we will define subtypes and mechanisms contributing to the development of preeclampsia, describe the structural and functional cardiac changes after preeclampsia, and potential mechanisms contributing to CVD in affected individuals.
Preeclampsia is a complex, multi-organ system disorder of pregnancy characterized by the development of hypertension and proteinuria after the 20th week of gestation. Preeclampsia can also be further categorized as early-onset (before 34 weeks) or late-onset (after 34 weeks). Another important distinction is between mild and severe forms of preeclampsia.
The diagnostic criteria for preeclampsia^19^ include the presence Hypertension: Defined as a systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg on two occasions at least four hours apart after 20 weeks of gestation.ANDProteinuria: Excretion of ≥ 300 mg of protein per 24 hours, or a protein-to-creatinine ratio ≥ 0.3. In the absence of quantitative studies, 1+ or greater urine dipstick for protein should prompt further evaluation to confirm the diagnosis
In cases of severe preeclampsia, end-organ damage may be part of the initial presentation including any of the following Severe range Defined as systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 110 mmHg on two occasions 15 minutes apartHepatic defined as elevated liver enzymes (AST, ALT) >2x the upper limit of normalNeurologic symptoms of severe headache, visual disturbances, or other signs of cerebral edemaThrombocytopeniaPulmonary edemaHELLP Syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets)
More severe forms of preeclampsia correlate with increased risk for peripartum morbidity^20^ and a more adverse postpartum cardiometabolic profile.^21^ After pregnancy, severe preeclampsia is associated with a higher likelihood and earlier onset of CVD.^4^ Recurrent preeclampsia also carries an increased risk of CVD compared with having just one pregnancy complicated by preeclampsia.^22^
To date, the majority of successful trials aimed at preeclampsia prevention in humans have involved low dose aspirin.^23^ Aspirin is thought to reduce the risk of preeclampsia through several potential mechanisms, including decreased platelet aggregation, inhibition of prostaglandins and thromboxane, suppression of sFlt-1 expression, and increased proliferation and invasion of trophoblasts improving placental growth. It has also been hypothesized that aspirin slows the metabolic clock of gestation by altering metabolites involved in glycerophosphoid metabolism, polyunsaturated fatty acid metabolism and steroid hormone biosynthesis effectively decelerating metabolic gestational age.^24^ These diverse potential mechanistic pathways targeted by aspirin, as well as histopathologic placental analyses have provided insights into the potential pathophysiology of preeclampsia described herein.
Preeclampsia is associated with placental dysfunction, leading to systemic maternal endothelial injury, via mechanisms of angiogenic imbalance, vasoconstriction, increased vascular permeability and senescence (Figure 3). Preeclampsia is thought to arise from impaired trophoblast invasion and abnormal placental vascular remodeling with failure of spiral artery remodeling and impaired extension of invasion, which results in insufficient placental perfusion. There is also increased upstream myometrial artery tone due to decreased vasodilator sensitivity and thus contribute to increased uteroplacental vascular resistance. This ischemic insult leads to a cascade of pathological events, including the release of anti-angiogenic factors, endothelial dysfunction, increased oxidative stress, and activation of the maternal immune system. The hypertensive component of preeclampsia is thought to be due to increased vascular tone and arteriolar vasoconstriction because of endothelial dysfunction, loss of nitric oxide (NO)-mediated vasodilation, and the activation of angiotensin II and endothelin systems. Endothelial dysfunction is also thought to be the main driver of proteinuria, though podocyte injury, increased vascular permeability, and renal vasoconstriction and altered renal hemodynamics also contribute. Key players in the pathophysiology of preeclampsia Placental Syncytiotrophoblasts: Inadequate trophoblast invasion of the uterine spiral arteries leads to shallow placentation and reduced extension, which impairs the blood flow to the placenta.Anti-Angiogenic Factors: The placental release of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) inhibits the bioavailability of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), leading to endothelial dysfunction and hypertension.Endothelial Dysfunction: A key feature of preeclampsia is endothelial cell injury and increased vascular permeability, which results in proteinuria, edema, and multi-organ dysfunction.Immune Dysregulation: Abnormal immune responses, including increased inflammation and immune cell infiltration in the placenta, contribute to the pathophysiology.
Animal models have been crucial for investigating the pathophysiological mechanisms of preeclampsia, although have somewhat limited relevance to humans as no animal model spontaneously develops preeclampsia. A comprehensive review of preeclampsia models has been recently published.^25^ To summarize, various species have been employed to model aspects of the disease, including dogs, sheep, rhesus monkeys and baboons, with rodent models being the most frequently used. As is the case with many other disease processes, all animal models of preeclampsia have their strengths and weaknesses; for preeclampsia differences in the placental physiology between humans and animals is the greatest weakness, with only non-human primates having a similar haemomonochorial placenta.^26–28^
Rodent models, have been extensively used to study preeclampsia due to their feasibility in genetic manipulation, their ability to mimic many of the hypertensive and renal features of the disease, rapid reproductive cycles, and their small size which facilitates cost-effective housing. The Reduced Uterine Perfusion Pressure (RUPP) rat model involves clipping the ovarian arteries and abdominal aorta above the uterine arteries to reduce placental perfusion. The RUPP model is also used in sheep which have a large, hemochorial placenta which allows for investigations involving the maternal-fetal interface. This results in a preeclampsia-like phenotype of elevated blood pressure, proteinuria, endothelial dysfunction, cardiac remodeling and fetal growth restriction.^29^ Another rat model involves exposure to angiotensin II receptor Type 1 autoantibodies; female rats harboring the human angiotensinogen gene [TGR(hAogen)L1623] develop a preeclamptic phenotype with hypertension and albuminuria during pregnancy when mated with male rats bearing the human renin gene.^30^ Several transgenic mouse models have been developed to study specific molecular pathways implicated in preeclampsia^31^: (1) sFlt-1 Transgenic Mice: Overexpression of sFlt-1 in pregnant mice leads to hypertension, proteinuria, and vascular dysfunction, similar to human preeclampsia. This model is often used to study the role of anti-angiogenic factors in preeclampsia; (2) Mice with mutations in genes encoding the renin-angiotensin system, as well as COMT-, eNOS- and corin-deficient mice develop hypertension and other features of preeclampsia. Although infrequently used, non-human primates, particularly rhesus macaques and baboons are valuable for preeclampsia research because their placental morphology and immune responses are highly similar to humans and these animal models can provide insights into the immune and inflammatory pathways, as well as the effects on placental and fetal development given their longer gestational period.
As previously described, the ischemic placenta releases vasoactive and pro-inflammatory substances that induce oxidative stress and impair vasodilation.^15^ The placenta also overproduces sFlt-1 and sEng, anti-angiogenic proteins which antagonize vascular endothelial growth factor (VEGF) and TGF-β1 signaling, resulting in damage to small vessels, widespread endothelial dysfunction and the aforementioned systemic manifestations (Figure 2).^32–39^ sFlt-1 and PlGF (Placental Growth Factor) are increasingly used in combination for the diagnosis of preeclampsia, particularly to help distinguish preeclampsia from other hypertensive disorders of pregnancy.^40^ The sFLT-1/PlGF ratio reflects the balance between anti-angiogenesis which occurs when sFLT-1 binds to and neutralizes VEGF and PlGF, and pro-angiogenesis reflected by PlGF levels. In a healthy pregnancy, PlGF supports placental development and vascularization and its concentration rises as the placenta matures. A high sFlt-1/PlGF ratio (>85–100) is strongly indicative of preeclampsia and a low ratio (<38) has a high negative predictive value and is reassuring that the clinical presentation is less likely to be preeclampsia. The ratio is also useful to determine disease several and serial testing can be used to monitor disease progression.^41,42^
Preeclampsia is also associated with structural heart disease (Stage B heart failure) characterized by increased LV mass and abnormal diastolic function, the presence of which predisposes to the development of clinical (Stages C and D) heart failure (Figure 4).^43,44^ Preeclampsia was long considered cured at the time of delivery, but there is now accumulating evidence its effects on the vasculature and myocardium are durable.^10,45^ To date, studies examining the associations between preeclampsia and these abnormalities have not been able to ascertain whether the observed cardiovascular changes in women with preeclampsia are a direct effect of the anti-angiogenic and pro-inflammatory substances secreted at high levels in preeclampsia, or a result of increased blood pressure (BP) and other shared risk factors. Another limitation of prior research is that it is unknown if women destined to develop preeclampsia have preexistent cardiac abnormalities, because cardiac imaging is rarely performed in asymptomatic young women of childbearing age.
Around the time of delivery, individuals with preeclampsia are more likely to have abnormalities of cardiac structure and function compared with women who are normotensive during pregnancy.^46^ Individuals with preeclampsia have more abnormal parameters of diastolic function, including an exaggerated reduction in E/A mitral inflow ratio and increased E/e’ ratio, as measured with spectral and tissue Doppler on transthoracic echocardiogram.^47^ Additionally, individuals with preeclampsia have higher LV mass in late pregnancy.^48^ Individuals with severe and preterm preeclampsia also have more pronounced changes on echocardiogram around the time of delivery compared with women who have normotensive pregnancies including increased estimated mean right ventricular systolic pressure, lower mean global right ventricular longitudinal strain, increased left atrial size, increased LV wall thickness, abnormal LV cardiac relaxation, and increased estimated LV filling pressures.^49,50^ In the years after pregnancy, a history of preeclampsia remains associated with abnormal diastolic function and LV remodeling. In the fifth decade of life, averaging 9–16 years after the index pregnancy, preeclampsia history was associated with higher mean E/e’ ratio, increased LV mass index and increased relative wall thickness compared with those without preeclampsia.^17,43,51^ Individuals with a history of severe forms of preeclampsia such as those with HELLP syndrome have the highest proportion of LV concentric remodeling 6 months to 4 years after delivery.^52^ Preterm preeclampsia also identifies a higher risk phenotype of individuals with Stage B heart failure given its association with lower LV global longitudinal strain in the years after delivery^52^ and in later life.^53^ While many studies have demonstrated the strong associations of preeclampsia history with Stage B heart failure in the months to years after delivery, in other studies the association is attenuated after accounting for potential confounding variables.^54,55^
Mechanisms contributing to the development of abnormal cardiac structure and function in individuals with a history of preeclampsia have not been well studied, however likely have overlap with the mechanisms contributing to its pathogenesis. The anti-angiogenic imbalance in preeclampsia has been correlated with cardiac dysfunction in vivo, and preeclampsia is strongly associated with an increased risk of peripartum cardiomyopathy, a form of severe systolic dysfunction.^56,57^ Small, single center studies around the time of delivery suggest that anti-angiogenic proteins, sFlt1 and sEng, are associated with worse LV global longitudinal strain and increased LV mass index among individuals with preeclampsia.^58^ Similarly, activin A has correlated with reduced LV strain and increased LV wall thickness at 1 year postpartum^59,60^ and at 10 years postpartum.^61^ Antepartum inhibition of activin A may be associated with improved LV function after preeclampsia.^62^ In animal models, statin therapy and renin-angiotensin-aldosterone system blockade during gestation correlated with reduced LV remodeling and improved LV function after preeclampsia suggesting potential ongoing mechanistic contributions of inflammation, NO, and renin-angiotensin-aldosterone system and could serve as targets for future human studies.^63,64^ Additional studies are needed to clarify if there may be differences in mechanisms of cardiac changes by preeclampsia subtypes as preliminary studies have shown there may be differences in circulating biomarkers with early-onset preeclampsia (<34 weeks).^65^
Individuals without a history of hypertension who experience a pregnancy complicated by preeclampsia, exhibit a heightened incidence of chronic hypertension early in the life course. Home BP monitoring programs have shown that ~30% of individuals remain hypertensive at 6 weeks postpartum. Progression to sustained hypertension varies by severity of preeclampsia; 41% of individuals with severe preeclampsia meet criteria for hypertension (sustained hypertension, masked hypertension, or white-coat hypertension) by ambulatory blood pressure monitor at one year postpartum.^66^ This is supported by data from the P4 study where at 2 years postpartum, 60% of individuals after preeclampsia were classified as above-normal BP and 21% had hypertension (BP≥130/80 mmHg) by 24-hour average ambulatory BP measurement.^67^ Data from the NuMom2b-Heart Health Study showed that 35–40% of participants with preeclampsia developed hypertension in the 2–7 years following their first pregnancy at a mean age of 27 at index pregnancy.^68^ The highest risk was experienced by individuals who delivered preterm. These iatrogenic preterm births were likely related to maternal and/or fetal indications resulting from the clinical manifestations of severe preeclampsia. This is supported by data from Thailand showing 32% of individuals with prior preeclampsia developing hypertension with 7 years after delivery.^69^
A number of potential mechanisms have been hypothesized to contribute to the development of hypertension after preeclampsia. Angiogenic factors, specifically higher sFlt1/PlGF ratio, have been associated with immediate postpartum hypertension.^70^ Another potential mechanism is related to natriuretic peptide signaling with higher NT-proBNP concentration in early pregnancy being associated with a lower risk of hypertension 2 to 7 years after delivery.^71^ Activin A also has been shown to correlate with BP, 1–2 years postpartum.^59^ These may be targetable pathways for preventing progression to chronic hypertension after preeclampsia.^62,72^
The high rates of chronic hypertension after preeclampsia coupled with the undertreatment of blood pressure in these individuals likely impacts and accelerates CVD.^73^ Individuals with both a history of hypertensive disorder of pregnancy and current hypertension had the highest proportion of LV remodeling (79%) in just the 8 to 10 years after delivery.^17^ A study including Hispanic/Latina individuals showed that the association between hypertensive disorders of pregnancy and LV structure and function (LV hypertrophy, relative wall thickness, and diastolic dysfunction), were only partially mediated by current hypertension.^74^ Further, an echocardiographic study in a cohort of primarily Black individuals, suggested that all LV wall thickness changes after preeclampsia were related to hypertension.^75^ In a meta-analysis, hypertension was shown to significantly increase risk for the development of coronary artery disease after preeclampsia^18^. Additionally, data from the UK Biobank has shown that hypertension mediates 64% of coronary artery disease development and 49% of heart failure development^76^. Similarly, established CVD risk factors (chronic hypertension, hypercholesterolemia, type 2 diabetes mellitus, and changes in body mass index) accounted for 57% of the increased rate for CVD after preeclampsia in the Nurses’ Health Study, with hypertension alone mediating 48% of the association between preeclampsia and CVD.^77^ There is a strong shared genetic background between the preeclampsia, gestational and chronic hypertension, and polygenic risk scores developed to predict preeclampsia perform less well than those derived to predict elevated BP.^78,79^ Taken together, these data suggest that hypertension is a major mediator of subclinical abnormalities of cardiac structure and function and overt CVD after preeclampsia. Thus, highlighting the importance of developing interventions to reduce the chance of progression to chronic hypertension, and, in the interim, strategies to improve hypertension awareness, diagnosis and treatment to goal in this at risk population.
Although preeclampsia is unique to pregnancy, it shares many pathological features, including endothelial dysfunction, increased oxidative stress, and inflammation, with CVD in general and coronary microvascular disease in particular.^12,80–83 84^ Coronary microvascular disease, a form of endothelial dysfunction that manifests as impaired vasodilation of the coronary microcirculation, has been described in up to 30% of women with signs and symptoms of cardiac ischemia who are found to have non-obstructed coronary arteries on invasive angiography.^85^ Despite having ‘normal’ epicardial coronary arteries, these women have elevated rates of CVD and increased mortality.^86,87^ The Women’s Ischemia Syndrome Evaluation (WISE) and other studies have implicated coronary microvascular disease^88^ as a causative factor in female-predominant ischemic heart disease pathophysiology.
A limited number of studies have investigated microvascular function after preeclampsia. In a meta-analysis, studies evaluating flow-mediated dilation suggest impaired endothelial function during pregnancy, at the time of preeclampsia diagnosis, and for 3 years postpartum.^45^ A small, early postpartum study found reduced postpartum coronary flow reserve, a measure of microvascular function, among individuals with severe preeclampsia compared with those without pregnancy complications.^89^ Mechanistically, postpartum coronary endothelial-dependent dysfunction may be related to angiotensin II receptor type 1 autoantibodies.^90^ In the year postpartum, individuals with preeclampsia also had evidence of peripheral microvascular dysfunction measured in the cutaneous microcirculation.^91^ Placental insufficiency and placental vascular lesions related to hypertensive disorders of pregnancy have been associated with evidence of endothelial dysfunction 5 to 10 years after delivery.^92,93^ Later, 8 to 10 years after delivery, individuals with hypertensive disorders of pregnancy were found to have reduced coronary flow reserve and higher proportion of microvascular dysfunction compared with individuals without hypertensive disorders of pregnancy.^94^ In this study, results were attenuated after adjustment for diabetes and pre-pregnancy body mass index.
Preeclampsia is also highly associated with later life coronary atherosclerotic disease. In a cohort of Swedish women, preeclampsia history was associated with obstructive and non-obstructive coronary atherosclerotic disease by coronary CT angiogram, a median of 29.6 years after delivery^95^. In this study, preeclampsia history carried an 8% higher prevalence difference for any coronary atherosclerosis. Individuals with preeclampsia history also have evidence of accelerated coronary artery calcification in later life.^96,97^
In the peripheral vasculature, preeclampsia has been shown to be associated with subclinical peripheral vascular disease of the carotid and femoral arteries.^98,99^ Overall, these data suggest that earlier onset and more severe subclinical cardiovascular disease is commonly found in individuals with prior preeclampsia. Additionally, hypertensive disorders of pregnancy including preeclampsia, have been associated with pulse wave velocity at 1 year after delivery, results that were primarily driven by blood pressure.^100^
The cerebral vasculature is also impacted by preeclampsia.^101^ Preeclampsia history is associated with earlier age of stroke.^102^ Additionally, individuals with prior preeclampsia exhibit worse cognitive function after delivery and are at increased risk for dementia, potentially due to small vessel disease in the brain.^103,104^ Given the known positive correlations between higher blood pressure and increased rates of cerebrovascular diseases, including stroke, mild cognitive impairment and dementia, clarification as to whether this these associations are independent of the afore mentioned heightened rates of hypertension and other shared risk factors remains to be elucidated. As such, recently updated guidelines for the primary prevention of stroke focus on the importance of hypertension management for risk reduction.^105^
Individuals with a history of preeclampsia have evidence of accelerated vascular aging. Studies have shown that preeclampsia history puts females on a CVD risk trajectory more similar to males than females of a comparable age.^106^ This also includes earlier presentation with myocardial infarction overall and amongst the young (age <65 at presentation).^107,108^ This phenomenon is at least partially mediated through the development of hypertension and a higher burden of other cardiovascular risk factors at a young age.^109^ Other potential mechanisms driving accelerated aging related to the underlying pathophysiology include increased inflammation and the accumulation of senescent cells, which secrete pro-inflammatory molecules that further perpetuate inflammation and oxidative stress.^110^
Despite robust evidence of subclinical and overt atherosclerotic, structural, and functional cardio- and cerebrovascular abnormalities after preeclampsia (Figure 1), there is a paucity of randomized controlled trials among postpartum women that investigate ways to mitigate cardiovascular risk. The renin-angiotensin-aldosterone-system may provide an important target for improving vascular and myocardial measures.^111^ Early postpartum data suggests that angiotensin receptor blockers may improve peripheral vascular endothelial function.^91^ In addition, treatment with postpartum ACE inhibitor has been associated with improved measures of diastolic function and LV remodeling at 6 months postpartum.^112^ In a rat model exposed to angiotensin II receptor type 1 autoantibodies, treatment with an angiotensin receptor blocker blocked changes in cardiac structure and function.^64^ Mouse models also suggest that mineralocorticoid receptor antagonists could reduce the chance of progression to hypertension.^113^ Further supportive, pravastatin therapy reversed post-pregnancy LV remodeling^63^ in rats with the human angiotensinogen gene, suggesting that statins could have a roll in reducing LV remodeling and dysfunction associated with preeclampsia as well.^63^ Although incorporating preeclampsia in the pooled risk cohort equations did not better risk stratify individuals with a history of preeclampsia,^114^ preeclampsia is considered a CVD “risk enhancer” and a lower threshold to initiate statin therapy may be warranted in this at-risk population. Whether all individuals with preeclampsia, or only those with severe or early onset preeclampsia can benefit from early initiation of statins for risk modification should be tested in prospective, randomized clinical trials. Importantly, randomized controlled trials conducted in low to middle income countries may have the most benefit as individuals in those countries have some of the highest risk for preeclampsia-related morbidity and mortality.
For those who develop preeclampsia, pregnancy thus serves as a window to future cardiovascular health. Preeclampsia is associated with changes in LV myocardial structure, atherosclerotic disease, and adverse cardiovascular outcomes both peripartum and later in life. Shared mechanisms contributing to preeclampsia and CVD may include anti-angiogenic proteins, the renin-aldosterone-angiotensin system, endothelial dysfunction, and immune dysregulation. Further research is needed to investigate interventions in humans that are effective at mitigating cardiovascular risk after preeclampsia.