Investigation of Cardiovascular Risk: Preeclampsia and Long QT Syndrome

Preeclampsia is a condition characterised by high blood pressure and leakage of protein into the urine in pregnancy. Around 5% of UK pregnancies are affected. In the majority of cases the blood pressure returns to normal after pregnancy, however there is now evidence that women who suffer from preeclampsia have an increased risk of high blood pressure, heart disease, kidney disease and stroke in later life. We aim to examine women with a history of preeclampsia (up to 30 years ago) and women with a history of normotensive pregnancy, to determine whether women with a history of preeclampsia have signs of vascular damage which may put them at increased risk of future development of cardiovascular disease. We also hope to examine the determinants of the relationship between preeclampsia and cardiovascular disease at a molecular and cellular level.

We are also interested in the role of inherited cardiac conditions in overall cardiovascular risk and hope to investigate this further using long QT syndrome as an example. Congenital long QT syndrome is a disorder with a prevalence of up to 1 in 2,000. It is characterised by QT interval prolongation on the electrocardiogram (ECG), with symptoms ranging from loss of consciousness to life-threatening ventricular arrhythmias and sudden death. Unfortunately there is great variation in symptoms between people born with genetic alterations (mutations) responsible for this condition, such that family members with the identical mutation may have completely different outcomes. One may die while the other lives a long life completely free from any cardiac symptoms. The challenge is to explain these differences in outcome and identify those at greatest risk of life-threatening events. I hope to take this work further in the near future.

Preeclampsia

Preeclampsia is predominantly a disease of the vasculature and is characterised by endothelial dysfunction, reduced peripheral blood flow, increased vascular permeability, increased arterial stiffness and hypertension. The extent to which women with a history of preeclampsia should be monitored for target organ damage is currently unknown. We aim to investigate the hypothesis that cardiovascular damage is greater in women who had preeclampsia 10-30 years ago than in women who had a healthy pregnancy 10-30 years ago. Cases and controls will be recruited from the Generation Scotland Study, the PIP study (Proteomics in Preeclampsia) and local blood pressure and cardiovascular risk clinics.  We will assess the consequences of preeclampsia using record-linkage for cardiovascular events, high-fidelity cardiovascular phenotyping for target organ damage assessment, and a biomarker strategy including urinary proteomics.

Long QT syndrome (planned)

Prevention of fatal cardiac events in pathogenic mutation carriers is hindered by current inadequacies in predicting clinical severity (phenotype) from LQTS-related genetic constitution (genotype). Several variants or single nucleotide polymorphisms (SNPs) in the nitric oxide synthase 1 (neuronal) adaptor protein (NOS1AP) and other key genes were recently identified as genetic modifiers of the QT interval and of phenotypic severity in LQTS, but their impact on the risk of life-threatening events in our Scottish patients with known pathogenic LQTS mutations is unknown.

We aim to investigate the possible causes of the wide inter- and intra-familial variation in phenotype in LQTS patients, and further elucidate the role of genetic modifiers in determining the risk of serious cardiac events. We hypothesise that any of several genetic variants may be acting in combination with the recognised main pathogenic gene alteration (mutation) in causing the clinical phenotype. 

Identification of these variants will permit the future identification of those at greatest risk, optimising the utility of life-saving, but expensive, treatments such as the implantable cardioverter defibrillator (ICD).