Can pregnancy hypercholesterolaemia cause myocardial infarction in young adults?

Human pregnancy is characterized by upraised lipid metabolism to meet the lipid demands for foetal growth and development, besides other modifications that are also necessary and are commonly assumed to be a natural phenomenon. Cholesterol the best-known lipid is vital for normal foetal cell membranes development [formation and maintaining integrity (fluidity and passive permeability)] and membrane-associated signalling cascades and is a precursor to many foetal hormones. Foetal cholesterol demands are covered from foetal de novo synthesis and from maternal circulation (supplies >20% to the foetal cholesterol pool).¹ Therefore, serum total cholesterol (TC) levels raise as pregnancy progresses,² causing maternal hypercholesterolaemia in pregnancy (MCP). Of note, that in MCP the maximum serum TC levels are unlikely to exceed 250 mg/dL at any time during normal pregnancy. Although earlier studies have found^2,3 women with TC levels of 280–290 mg/dL at the end of pregnancy and named it maternal supraphysiological hypercholesterolaemia.³ Desoye et al. reported for TC levels to raise from 167 mg/dL (4.3 mmol/L) pre-/early pregnancy to 286 mg/dL (7.3 mmol/L) near term.² This can be particularly seen in pregnant women with heterozygous familial hypercholesterolaemia (heFH).⁴ Although the relative increases of TC do not differ between the heFH and referral women, the absolute increases are much higher in heFH women, since their TC levels are usually >355 mg/dL (9.1 mmol/L) at pre-/early-pregnancy and raised up to 452 mg/dL (11.6 mmol/L) near term.⁴ Studies concerning heFH and cardiovascular disease (CVD) in offspring reported increased risk for CVD. Thus, the presence of MCP (besides maternal and foetal development issues) raises the question of potential risk of atherosclerosis to the offspring. In this issue of Eur J Prev Cardiol, in the study linking to a cohort of patients from seven hospitals in the Regione Campania, the association of offspring’s acute myocardial infarction (AMI) and MCP has been evaluated.⁵ In the MCP cohort, the TC above 240 mg/dL was reported in 72.3%. In the AMI cohort, even though the sample size was small, MCP was correlated with AMI’s severity (number of vessels, left ventricular ejection fraction, creatine kinase/creatine kinase-myocardial band, and survival time).⁵ Furthermore, in the multivariate analysis of patients stratified by AMI severity, MCP predicted AMI severity independently of age, gender, body mass index (BMI), and coronary heart disease risk factors. Although this is a retrospective study, the data likely reflect that MCP is associated with adult BMI, atherosclerosis-related risk, and severity of AMI. MCP is thought to be clinically not significant and, therefore, TC levels are not routinely tested during pregnancy; consequently, there are not many clinical studies.⁶ The first suggestion that MCP may lead to adult CVD came from the Fate of Early Lesions in Children study.⁷ It was found that maternal hypercholesterolaemia increased considerably the number of early fatty streaks, suggesting that the onset of early fatty streaks detected in children and young adults may be formed much earlier than was believed. Direct experimental data for the causal role of MCP and atherosclerosis in offspring came from transgenic [low density lipoprotein (LDL) receptor deficient (LDLR−/−)] pregnant mice and indicated that utero foetus exposure to hypercholesterolaemia may, for long time, modify the gene expression in the aorta,⁸ implicated in early life origins of CVD. The epigenome phenomenon is very active throughout the pregnancy and early postnatal periods. The Framingham Heart Study found that mother’s dyslipidaemia before pregnancy is associated with dyslipidaemia in offspring during adulthood in addition to CVD and genetic risk factors (Table 1).⁹ The maternal epigenetic (DNA methylation, histone acetylation) can lead to constant modifications in the function and structure of genes involved in LDL metabolism and cholesterol transport between mother and foetus across the placenta and interfere, not always beneficially, with utero foetal programming.¹⁰ In contrast, lowering MCP with cholestyramine (recommended by guidelines as safe treatment of hypercholesterolaemia in pregnancy) or with antioxidant or vitamin E reduced the offspring atherosclerosis.¹¹ Also, a treatment of pregnant mice with MCP with statin (cornerstone drug in management dyslipidemias) during pregnancy (not recommended in humans) reduced atherogenic programming in mice.¹² There are still few questions arise such as: (1) Do we deal with new risk factor for adults aged 40–50 years, who were exposed to MCP? (2) Do we have enough evidence? (3) Should they be advice for routine lipid analysis and lifestyle modifications?

Table 1

Maternal hypercholesterolaemia in pregnancy and its potential effect on foetus and on young adults’ health

Mother	Modifications	Foetus	Offspring
Obesity, dyslipidemia, metabolic syndrome, pre-eclampsia, gestational DM, polycystic ovary syndrome, assisted reproductive technique and others ↓ Enhance MCP →	Endothelial dysfunction, Differential expression of LDL receptors Upregulation of lipid metabolism Changes in gene expression Epigenetic effects	High cholesterol Atherogenic programming Lesion formation	Obesity Dyslipidaemia MetS AMI/CHD Unknown disease

The pre-pregnancy mother’s metabolic conditions can further increase levels of total cholesterol observed in MCP. These lipid changes can increase levels of foetal cholesterol and interfere with foetal programming and because of that foetus unfavourable cardiometabolic conditions that are likely to provoke cardiovascular diseases in adult life. AMI, acute myocardial infarction; CHD, coronary heart disease; DM, diabetes mellitus; LDL, low density lipoprotein; MCP, maternal hypercholesterolaemia in pregnancy; MetS, metabolic syndrome.

Therefore, the evaluation of lipid profile routinely in pregnant women may be of great help for managing their offspring lately in their life. Although there are no specific recommendations for such group, until more clinical studies and data will be presented, they can be advised to undergo lifestyle modifications and routine lipid profiling at specific intervals to initiate statin therapies, if required. On the end of the day, the answers to question if the MCP is responsible for myocardial infarction in young adults are still open. It is more likely that foetus exposed to MCP and environmental CVD risk factors lately in their life are more prone to develop CVD in younger age compared with foetus not exposed to MCP.

Funding

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

Conflict of interest: none declared.