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MECHANISMS OF SMALL ARTERY REMODELLING: TARGETING IMPAIRED MICROCIRCULATION IN ESSENTIAL HYPERTENSION

Ashkan Eftekhari

Summary

Hypertension is major cardiovascular risk factor. Early hypertension is characterized by increased cardiac output whereas in established state peripheral resistance is increased and cardiac output normalized. In hypertension the small arteries have reduced lumen diameter, increased wall thickness but unaltered wall material, caused by of rearrangement of smooth muscle cells. This process is dependent on integrins and extra-cellular enzymes that break and form cross-links in matrix. We hypothesized that the ubiquitous extra-cellular enzyme tissue transglutaminase plays an important role in small artery remodeling.  

Small artery remodeling is prognostic and occurs at the early stages of hypertension causing impairement of tissue perfusion. In the coronary microcirculation as decreased CFR (CFR) and in the forearm skeletal circulation as increased Rmin (Rmin). Although Rmin and CFR have been correlated to media:lumen ratio, no study has investigated whether the changes in these two vascular beds occur in parallel or independent of each other and blood pressure. We hypothesized that impairment of Rmin and CFR occurs at very mild hypertension and that changes in systemic vascular resistance and Rmin reflect changes in CFR.  

The tissue transglutaminae inhibitor cystamine was used as concomitant treatment of small rats that have been treated with phenylephrine for one week and rats that were treated with amlodipine in the second week. Cystamine inhibited both inward and outward remodeling independent of blood pressure levels.

 Never treated hypertensive patients (n=75) and age/gender matched controls (n=25) were recruited through health surveys conducted at private companies and evaluated in outpatient hypertension clinic. All subjects were subjected to: ambulatory blood pressure, echocardiogram, 78  measurement of cardiac output with the breath-by breath method, forearm plethysmography and measurement of CFR with trans-thoracic echocardiography. The hypertensive population was divided into two groups according to 24-hr systolic blood pressure median into Very Mild EH and Mild-Moderate EH Group. The patients were followed for 6 months and the relationship between changes in peripheral resistance and CFR investigated. Blood pressure levels were at mild-moderate level. CFR and Rmin were impaired in both the hypertensive groups. SVRI was normal in the Very Mild EH Group. Changes in systemic vascular resistance reflect changes in CFR independent of blood pressure alterations.  

In conclusion, small artery remodelling is dependent of tissue transglutaminase but evidence suggests that other factors (e.g. integrins) play an important role. CFR and minium forearm resistance are impaired in very mild hypertension which may explain the early prognostic value of small artery structure. The development of peripheral vascular resistance during antihypertensive treatment reflects changes in the coronary microcirculation