A window of opportunity on cardiovascular prevention: pre-eclampsia and fetal growth restriction

Pre-eclampsia (PE) and fetal growth restriction (FGR) are pregnancy-related disorders almost partly arising from defective trophoblastic invasion with subsequent placental hypoperfusion, imbalance between utero-placental blood supply and fetal demands as well as oxidative stress, endothelial dysfunction and systemic inflammation emanating from an ischaemic placenta.¹ Complicating 2–8% of all pregnancies, PE represents the leading cause of maternal and fetal morbidity and mortality worldwide, and is defined as the new onset of hypertension after 20 weeks’ gestation combined with de novo proteinuria, maternal organ dysfunction (e.g. renal failure, liver involvement, neurological or haematological complications) and/or FGR. PE coexists in up to one-third of cases with FGR, which is defined as estimated fetal weight or fetal abdominal circumference less than the 10th percentile with abnormal umbilical and/or uterine arteries Doppler velocimetry findings.² Although the acute cardiovascular implications of PE, primarily acute pulmonary oedema, are known from the 1970s, more recently a growing body of evidence has demonstrated that PE implies a global cardiovascular rearrangement³ characterised by endothelial dysfunction,⁴ arterial stiffness,^4,5 left atrial remodelling, biventricular hypertrophy with impaired myocardial contractility and relaxation,⁶ inappropriate left ventricular mass⁷ and left ventricular myocardial fibrosis,⁸ both during and many years after the index pregnancy. Moreover, emerging data hypothesise that normotensive FGR carries persistent cardiovascular alterations, similar to those seen after PE.⁹ These data led the scientific community to start considering a history of PE and/or FGR among cardiovascular risk factors.¹⁰ However, the mechanisms linking PE syndrome to maternal cardiovascular diseases later in life are not well understood. Women who experienced PE are at a two to seven-fold increased risk of cardiovascular events (e.g. chronic coronary syndrome, cerebrovascular accidents, arrhythmias and heart failure (HF)) and death.¹¹ In particular, the risk of asymptomatic HF is nearly four times greater in former pre-eclamptics than in women with uncomplicated pregnancy, even after adjustment for interval since pregnancy and traditional cardiovascular risk factors.¹² In addition, it has also been hypothesised that PE impacts on the cardio-metabolic profile of the offspring.¹³

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition configuring as the first unmet clinical need for cardiologists worldwide. According to the most recent theories, microvascular coronary alteration is the hallmark of almost three out of four cases of HFpEF, correlates with systemic endothelial dysfunction and is a strong predictor of HF development.¹⁴ Inflammation and oxidative stress caused by conventional cardiovascular risk factors and comorbidities (e.g. chronic obstructive pulmonary disease, iron deficiency, chronic inflammation) impair the nitric oxide pathway leading to systemic and coronary endothelial dysfunction, arterial stiffness with increased afterload and myocardial activation of intracellular messengers cascade (e.g. sGC, cGMP and PKG). The consequences include cardiomyocyte stiffening and ventricular hypertrophy, by unfolding and rigidity of titin and interstitial connective tissue deposition (e.g. fibrosis), overt diastolic dysfunction, subclinical systolic impairment and relative ischaemia, thus enhancing the vicious cycle.¹⁵ Our data^3–9 together with the reduction of coronary reserve documented in women with a history of PE,¹⁶ let us hypothesise a common pathophysiological pathway going from PE/FGR to HFpEF development through chronic inflammation, oxidative stress, vascular biological aging and myocardial subclinical involvement (Figure 1). Indeed, a recent meta-analysis by Alma et al. shows that PE and HFpEF share a range of biomarkers (e.g. C-reactive protein, natriuretic peptides, troponins, adrenomedullin, glycemic and lipid profile molecules) thus supporting the hypothesis of a common metabolic and biochemical milieu behind both syndromes.¹⁷ These results are consistent with those of Mohseni et al. who found nine microRNAs (miRNAs) whose up or downregulated expression overlaps between PE and concentric left ventricular remodelling.¹⁸

Figure 1

The pathophysiological pathway going from pre-eclampsia (PE)/fetal growth restriction (FGR) to the development of heart failure with preserved ejection fraction (HFpEF). Green checkmarks indicate existing demonstrations in women with a history of PE or FGR.^3–9,16

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Cardiovascular prevention in these young women is crucial because the development of HF symptoms carries a five-fold increased risk of mortality over asymptomatic cardiovascular alterations.¹⁰ We suggest to consider pregnancy as a window of opportunity to test maternal haemodynamics before other cardiovascular risk factors become apparent, and to counsel women with a history of PE and/or FGR about lifestyle modification, referring them for a regular follow-up in order to identify cases requiring individualised intervention early prior to the development of symptomatic cardiovascular diseases. In this way we hope to impact positively on their future cardiovascular morbidity and mortality.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

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