Hypertension and target organ damage

The research program microvascular dysfunction and hypertension presently focuses on two aspects of the microcirculation. One line of investigation is dedicated to the study of the intrarenal circulation and the other to the circulation in the brain (the latter in close collaboration with the Department of Neurology). The kidney is our model to assess the role of the renin-angiotensin system and related mechanisms in the adaptation of flow and vascular function when the larger vessels are hit by the atherosclerotic process (renal artery stenosis). The study of the cerebral microcirculation, although independent from the renal research line, is closely related to that. In particular, we are trying to detect mechanisms that both circulatory beds have in common in order to understand the brain better once we know more about the kidney.

The presence of target organ damage in hypertensive patients increases the risk of cardiovascular complications. The brain and the kidneys are major targets of the hypertensive atherosclerotic process. Clinically, however, it is difficult to reliably assess the presence of tissue damage. Kidney damage, for instance, becomes evident only in a late stage when (micro-) albuminuria and/or a rise in serum creatinine are present. Therefore, we have meticulously studied various aspects of the renal circulation and related the results to the degree of gross vascular damage. It turns out that there is already substantial intrarenal involvement with only minor degrees of renal artery stenosis which hither to would have been considered insignificant. It had led to the formation of a national group of researchers who are going to evaluate whether early intervention is able to prevent the kidney damage that we know from high grade stenoses.

Brain damage usually remains undetected up to the moment that gross complications occur. In our program we noticed that the 24-hour blood pressure profile is a major determinant of damage, in particular when nocturnal blood pressure is taken into account. It appears that even in patients without overt cardiac or renal abnormalities, a significant proportion has silent cerebral tissue damage. This includes lacunar infarcts, white matter lesions and microbleeds. In particular, the latter form of microvascular damage appears to be heavily dependent on the 24-hour blood pressure profile. We even found that the estimated risk of future cardiovascular complications was significantly enhanced when the cerebral damage was considered, over and above that conferred by the conventional inventory of risk elements. Microbleeds and ischemic abnormalities in the brain can beviewed upon as manifestations of microcirculatory disease but they correlate closely with measures of large vessel abnormalities such as increased vascular stiffness. This has led to the hypothesis that vascular calcification needs to get more attention. A key element in the calcification process is the regulation of matrix Gla protein (MGP) which is now a focus of study. The first data relate to the renal handling of this protein.

Principal Investigator

Staff