The detection of end-organ changes for predicting premature vascular events

Abstract

Several cardiovascular events including stroke and critical limb ischaemia (CLI) often occur in developing countries at an age where the event is considered to be chronologically premature (often with events noted in teenagers or young adults). Because risk stratification depends so heavily on age, identifying those at a high risk in young adults is fraught with uncertainty. One approach to enhancing risk prediction is to assess end-organ measures. However, the efficacy of end-organ measures in risk prediction over a young adult age range is uncertain. In the present thesis I therefore explored the possible role of several end-organ measures that may be employed to enhance risk prediction for stroke or CLI over a young adult age. Although chronic kidney disease (CKD) as determined from estimated glomerular filtration rate (eGFR) is recommended for affordable risk prediction by current guidelines, the equations to derive eGFR may not perform well in black South Africans. In the present thesis I demonstrated that in 1152 black South Africans, 294 and 186 with CLI and stroke respectively, in whom 37 % of events were premature, and 672 age-sex-matched controls from a randomly selected community sample, that eGFR was not associated with the odds of the event occurring in young adults. However, carotid intima-media thickness (IMT) was strongly and independently associated with the odds of the event occurring at a young adult age. These data suggest that while the current identification of CKD is unlikely to significantly add to the prediction of non-cardiac arterial events, such as stroke and CLI in young adults, IMT may enhance the prediction of these events at a young adult age. Hypertension is thought to play an important role in contributing to premature events, The extent to which IMT is determined by aspects of blood pressure load is nevertheless unknown. In 1384 randomly selected individuals from a community sample I demonstrated that independent of confounders including age, mean arterial pressure (MAP), and forward and backward wave pressures showed associations with indices of cardiac and vascular end-organ changes that were organ and age-specific. Backward wave pressures, but not MAP, showed strong independent relations with left ventricular hypertrophy in individuals younger than 50 years of ages and backward wave and MAP with pulse wave velocity (PWV) in those at any age. However, only MAP (younger than 50 years) and forward wave pressure (older than 50 years), showed independent relations with carotid IMT. Importantly, alternative risk factors failed to associate with IMT beyond age, These data suggest that IMT is primarily an index of the adverse effects of either the steady-state or pulsatile components of an increased blood pressure. Although carotid IMT predicts arterial events, there is nevertheless considerable uncertainty as to the role of IMT in risk prediction beyond the identification of atherosclerotic plaque. In 54 patients with CLI and amputations I showed that histological thrombotic as opposed to atherosclerotic occlusion occurs more frequently at a younger age and is associated with less carotid plaque but similar age-adjusted increases in IMT. In 952 black South Africans, 473 with CLI or stroke and 479 age-sex-matched controls from a randomly selected Johannesburg community sample, I subsequently demonstrated that, over a younger age range, in contrast to stroke where carotid plaque was markedly increased, patients with CLI failed to show an increased carotid plaque whilst increases in carotid IMT were striking. Thus, carotid IMT adds to carotid plaque in a complementary fashion in associations with arterial vascular events at a younger adult age. In conclusion, the results provided in the present thesis have advanced our understanding of how to enhance risk prediction for cardiovascular events occurring at a young adult age (premature events). In this regard, I show that whilst eGFR is too insensitive to predict risk for an early event, IMT, which is determined by the most important risk factor for events at this age (hypertension), is strongly associated with events at a young adult age and that IMT complements the assessment of carotid plaque to enhance risk prediction over this age range.