The assessment of circulating matrix metalloproteinases and their inhibitors in health and cardiovascular disease
The thesis objective was to define the variance of circulating MMP-9, TIMP-1 & -2 in healthy controls (HC), and study these in hypertension, diabetes, stable coronary (CAD) and peripheral arterial disease (PAD), in particular the effect of the treatment; the link to coronary collateralisation, inflammation and diastolic dysfunction. In HC, I found no gender differences or diurnal variation in MMP/TIMPs except MMP-9 being lower in the Far Eastern cohort. TIMP-1 & -2 declined with aging and rose with acute exercise. Patients with hypertension had higher MMP-9 and TIMP-1 compared to HC; MMP-9 correlated with cardiovascular risk scores. MMP-9 fell whereas TIMP-1 rose with anti-hypertensive therapy. In diabetic patients, MMP-9, TIMP-1 & -2 were higher compared to HC, but only TIMP-1 fell with treatment. TIMP-1 correlated with echocardiographic indices of impaired diastolic relaxation in diabetes and hypertension. In gestational hypertension MMP-9 was lower and TIMP-1 & -2 higher compared to normotensive pregnant controls. In CAD and PAD MMP-9 and TIMP-1 were raised compared to HC (TIMP-2 also elevated in CAD). In CAD, women had higher MMP-9 and a trend towards lower MMP-9 in patients with collaterals was seen. White cell count correlated with MMP-9. In PAD, MMP-9 and TIMP-1 tracked disease severity. Neutrophil MMP-9 was elevated in CAD and systolic dysfunction. There is a difference in circulating MMP-9, TIMP-1 & -2 in patients with CVD compared to HC. I have shown a link between tissue structure and inflammation and these measures, which are potential markers of tissue turnover and prognosis.