Introduction: Coronary heart disease (CHD) is a global health problem with a high prevalence in both developed and developing countries. CHD is the leading cause of death worldwide and accounted for 16.2% of all deaths in 2019. CHD is most commonly manifested as atherosclerotic coronary artery disease (CAD) and it is generally agreed that an obstruction of an epicardial coronary artery greater than or equal to 50% is clinically relevant which is referred to as “obstructive CAD”. The Dutch Lipid Clinic Network Score (DLCNS) guidelines define PCAD in women as a diagnosis of CAD prior to 60 years of age. On the other hand, pregnancy has been described as a “stress test” for the female cardiovascular system due to the significant adaptations and changes it undergoes to support fetal growth and development. Evidence has been generated by researchers globally that pregnancy complications are associated with CAD morbidity and mortality later in life. However, the association between pregnancy complications and risk of PCAD is unclear. To address this gap, a comprehensive data linkage project merging three databases of South Australia and a series of systematic reviews and meta-analyses were conducted. Methods: The three systematic reviews and meta-analyses compared modifiable and non-modifiable risk factors for premature CHD (PCHD) and CHD, for PCHD among men and women, and patients with PCHD and healthy controls. To complement the systematic review series, the data linkage project merged three databases of South Australia using a retrospective, age-match case-control study design. Cases(n=721) were ascertained from the Coronary Angiogram Database of South Australia (CADOSA). Women 50% stenosis in one or more coronary arteries at coronary angiography. Results: First systematic review and meta-analysis of the series identified that women were older than men at the time of presentation with PCHD (age 2 drinks/day), high homocysteine, history of illicit drug use, and be previous or current smokers. Second systematic review demonstrated that individuals with PCHD were approximately 23 years younger than individuals with late-onset CHD and they had higher body mass index (BMI), serum low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and TGs, and had lower serum HDL-C levels compared to those with late onset CHD. Individuals with PCHD were also more likely to be current smokers, and had positive family history of CHD compared to those with late-onset CHD. In contrast, individuals with late-onset CHD had higher systolic blood pressure (SBP), and were more likely to have hypertension and stroke, compared to individuals with PCHD. The last systematic review of the series demonstrated that individuals with PCHD had higher BMI, SBP, DBP, TC, TGs, lipoprotein (a) and lower serum HDL-C levels compared to healthy individuals. Those diagnosed with PCHD were more likely to be obese, had dyslipidaemia, hypertension, T2DM, were current smokers, consumed >2 drinks of alcohol per day and had positive family history of CHD compared to healthy individuals. Major findings of the primary data linkage project demonstrated that women diagnosed with PCAD were two times more likely to have experienced placenta-mediated pregnancy complications including pre-term delivery and having low-birth weight infants compared to women with no history of heart disease. Women who were diagnosed with PCAD were approximately four times more likely to have experienced asthma during pregnancy compared to women without a history of CAD. It also showed that SES at the time of pregnancy in women who had a pre-term delivery (OR:4.77) and was a smoker (OR:8.60) did have a significant effect on future PCAD risk. Conclusion: Based on the systematic review and meta-analysis conducted, risk factor profile in individuals with PCHD has a clear sex difference that supports early, aggressive, holistic, but sex-specific approach to prevention. For the data linkage project, placenta-mediated pregnancy complications should be recognised as clear risk markers for future PCAD and improved recognition of these clinical events as risk factors by the medical and midwifery community for future PCAD risk should be addressed as part of preventative cardiology practice. These findings also confirm the need for postpartum cardiovascular disease screening for women after having a complicated pregnancy.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 202
