*6.1. Predisposing Factors for Preeclampsia*

It is not entirely apparent how maternal clinical risk factors for preeclampsia, such as advanced maternal age, ethnicity, obesity, diabetes, hyperlipidemia, renal dysfunction, and chronic hypertension influence trophoblast invasion and spiral artery transformation. However, these are well-recognized risk factors for cardiovascular morbidity, with established and plausible biological mechanisms explaining their pathophysiological roles [43,44]. Apart from these conventional clinical risk factors, systematic reviews of genetic risk factors demonstrated that plasminogen activator inhibitor-1 (PAI-1) and FMS-related tyrosine kinase 1 (FLT1)—known to be linked with risks of coronary heart disease and heart failure—were also strongly associated with preeclampsia [45–47].

### *6.2. Pre-Pregnancy Cardiovascular Function in Preeclampsia*

If maternal risk factors for preeclampsia and adult cardiovascular disease indeed work through the same mechanisms, then there should be evidence for pre-pregnancy cardiovascular impairment in women destined to develop preeclampsia. Although there is a paucity of such pre-conceptual studies, a recent study by Foo et al. longitudinally assessed cardiovascular function in 356 spontaneously conceived pregnancies in apparently healthy women, starting from preconception. The authors noted that the 15 (4.2%) women who developed preeclampsia and fetal growth restriction had lower cardiac output and higher total peripheral resistance before the pre-conceptual period compared to those with uneventful pregnancies [31]. These findings support the concept that suboptimal pre-pregnancy cardiovascular function may predispose the woman to impaired uterine artery blood flow and poor trophoblast development as precursors to the development of preeclampsia. This assertion is supported by pre-conceptual echocardiographic evaluation of formerly preeclamptic women assessing their risk of recurrent preeclampsia. Those with recurrent preeclampsia had lower cardiac left ventricular mass and cardiac stroke volume in the pre-pregnancy period compared to women who had a normal second pregnancy [48].

#### *6.3. Abnormal Cardiovascular Function in Pregnancy and Preeclampsia*

First-trimester maternal cardiovascular parameters, such as mean arterial blood pressure and uterine artery resistance, are key biomarkers in the ASPRE (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention) screening algorithm that have very high accuracy for the prediction of preeclampsia, especially of preterm onset [5]. More sophisticated echocardiographic assessment has shown cardiac remodeling, impaired hemodynamics, and diastolic dysfunction, both in the first trimester and at mid-pregnancy in women destined to develop preeclampsia compared to those with normal outcomes [49–51]. Even in uncomplicated pregnancies, there are well-documented hemodynamic changes which peak in the middle of the third trimester before the cardiac output falls and systemic vascular resistance increases—a paradoxical finding, in view of the fact that maternal respiratory and metabolic demands continue to increase with advancing gestation [52,53]. Echocardiographic studies have demonstrated that in apparently healthy women with normal pregnancies, there are signs of mild cardiac maladaptation to the volume overload, such as an excessive increase in the left ventricular remodeling with associated diastolic dysfunction in a small but significant proportion of cases at term [54,55]. It is apparent that even a normal pregnancy confers a previously unrealized significant workload on the maternal cardiovascular system, and that in some cases, this results in asymptomatic cardiac dysfunction (Figure 3).

**Figure 3.** Left ventricle remodelling caused by pregnancy and preeclampsia. Alteration in (volume and pressure) loading conditions and the interaction with mechanical and neurohormonal factors results in ventricular remodeling. At an organ level, remodeling refers to changes in ventricular geometry, volume, and mass. Although remodelling is compensatory in certain pressure and volume overload conditions, progressive ventricular remodeling is ultimately a maladaptive process, contributing to the progression of symptomatic heart failure and an adverse outcome.
