Marco Miclini

Prognostic Significance of Small-Artery Structure in Hypertension

Background—The presence of structural alterations in the microcirculation may be considered an important mechanism of organ damage; however, it is not currently known whether structural alterations of small arteries may predict fatal and nonfatal cardiovascular events. Methods and Results—One hundred twenty-eight patients were included in the present study. There were 59 patients with essential hypertension, 17 with pheochromocytoma, 20 with primary aldosteronism, 12 with renovascular hypertension, and 20 normotensive patients with non-insulin-dependent diabetes mellitus. All subjects were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on an isometric myograph, and the tunica media-to-internal lumen ratio (M/L) was measured. The subjects were reevaluated after an average follow-up time of 5.4 years. Thirty-seven subjects had a documented fatal or nonfatal cardiovascular event (5.32 events/100 patients per year). In the subcutaneous small arteries of subjects with cardiovascular events, a smaller internal diameter and a clearly greater M/L was observed. Our subjects were subdivided according to the presence of an M/L greater or smaller than the mean and median values observed in the whole population (0.098) or mean value +2 SD of our normal subjects (0.11). Life-table analyses showed a significant difference in event-free survival between the subgroups. Cox’s proportional hazard model, considering all known cardiovascular risk factors, indicated that only pulse pressure (P =0.009) and M/L (P <0.0001) were significantly associated with the occurrence of cardiovascular events. Conclusions—Our results strongly indicate a relevant prognostic role of structural alterations in small resistance arteries of a high-risk population.

Effect of Treatment With Candesartan or Enalapril on Subcutaneous Small Artery Structure in Hypertensive Patients With Noninsulin-Dependent Diabetes Mellitus

Structural alterations of subcutaneous small resistance arteries are associated with a worse clinical prognosis in hypertension and noninsulin-dependent diabetes mellitus (NIDDM). However, no data are presently available about the effects of antihypertensive therapy on vascular structure in hypertensive patients with NIDDM. Therefore, we have investigated the effect of an angiotensin-converting enzyme inhibitor, enalapril, and a highly selective angiotensin receptor blocker, candesartan cilexetil, on indices of subcutaneous small resistance artery structure in 15 patients with mild hypertension and NIDDM. Eight patients were treated with candesartan (8 to 16 mg per day) and 7 with enalapril (10 to 20 mg per day) for 1 year. Each patient underwent a biopsy of the subcutaneous fat from the gluteal region at baseline and after 1 year of treatment. Small arteries were dissected and mounted on a micromyograph and the media-to-internal lumen ratio was evaluated; moreover, endothelium-dependent vasodilation to acetylcholine was assessed. A similar blood pressure-lowering effect and a similar reduction of the media-to-lumen ratio of small arteries was observed with the 2 drugs. Vascular collagen content was reduced and metalloproteinase-9 was increased by candesartan, but not by enalapril. Changes of circulating indices of collagen turnover and circulating matrix metalloproteinase paralleled those of vascular collagen. The 2 drugs equally improved endothelial function. In conclusion, antihypertensive treatment with drugs that inhibit the renin-angiotensin-aldosterone system activity is able to correct, at least in part, alterations in small resistance artery structure in hypertensive patients with NIDDM. Candesartan may be more effective than enalapril in reducing collagen content in the vasculature.

Morning rise of blood pressure and subcutaneous small resistance artery structure.

Objectives It has been previously demonstrated that the morning rise (MoR) of blood pressure (BP) may predict major cardiovascular events in hypertensive patients. Structural alterations of small resistance arteries, as evaluated by the tunica media to internal lumen ratio (M/L) of subcutaneous small resistance arteries, may also predict cardiovascular events. Because an increased M/L may amplify the effect of hypertensive stimuli, the present study aimed to evaluate the possible relationships between MoR and M/L in a population of hypertensive patients. Methods Sixty-four patients with essential hypertension were included in the present study. All patients were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on an isometric myograph, and the M/L was measured. In addition, MoR was calculated from ambulatory blood pressure monitoring (ABPM) according to four previously published different methods (MoR1 to MoR4). Results A statistically significant correlation was observed between M/L and MoR1 (r = 0.52, P < 0.001), MoR2 (r = 0.32, P < 0.01), MoR3 (r = 0.25, P < 0.05) and MoR4 (r = 0.27, P < 0.05), as well as between internal diameter of subcutaneous small arteries and MoR1 (r = −0.45, P < 0.001) and MoR2 (r = −0.28, P < 0.05). Conclusion Our results indicate that subcutaneous small artery structure is related to MoR, possibly because an altered vascular structure may amplify BP changes or, vice versa, because a greater MoR may further damage peripheral vasculature.

Lack of prognostic role of endothelial dysfunction in subcutaneous small resistance arteries of hypertensive patients

Objective The presence of endothelial dysfunction in the coronary circulation or in the brachial artery has been found to be associated with a greater incidence of cardiovascular events. However, no data are presently available about the prognostic role of endothelial dysfunction in human small resistance arteries. Design and methods Ninety subjects were included in the present study. They were: 10 normotensive subjects, 36 patients with essential hypertension, 10 patients with phaeochromocytoma, 11 patients with primary aldosteronism, 10 patients with renovascular hypertension, and 13 normotensive patients with non-insulin-dependent diabetes mellitus (NIDDM). All subjects were submitted to a biopsy of subcutaneous fat from the gluteal or the anterior abdominal region. Small resistance arteries were dissected and mounted on an isometric myograph, and the concentration–response curves to acetylcholine (from 10−9 to 10−5 mol/l) (endothelium-dependent vasodilatation) and sodium nitroprusside (from 10−9 to 10−5 mol/l) (endothelium-independent vasodilatation) after precontraction of the vessels with norepinephrine were evaluated. The subjects were re-evaluated (by clinical visits or telephone interviews) after an average follow-up time of 5.5 years. Results Twenty-nine subjects had a documented fatal or non-fatal cardiovascular event (5.87%/year). The endothelium-dependent vasodilatation in the subcutaneous small arteries was similar in subjects with or without cardiovascular events. Also, endothelium-independent vasodilatation to sodium nitroprusside was similar in the two groups. Similar results were obtained by subdividing patients in the different subgroups (essential hypertension, secondary hypertension, etc.). Conclusions Our results indicate that endothelial dysfunction in the microcirculation does not predict cardiovascular events. It is possible that a prognostic role of endothelial dysfunction may be observed when other vascular districts prone to atherosclerosis are evaluated, or it might be detected only in patients at low to medium cardiovascular risk, in whom endothelial dysfunction is less advanced.

Effects of Insulin on Endothelial and Contractile Function of Subcutaneous Small Resistance Arteries of Hypertensive and Diabetic Patients

The effect of insulin on the vasoconstriction induced by norepinephrine is at present controversial. We have previously demonstrated that high-concentration insulin may induce an increased reactivity to norepinephrine in mesenteric small resistance arteries of spontaneously hypertensive rats. The aim of the present study was to evaluate the effects of low- and high-concentration insulin on the concentration-response curves to norepinephrine and acetylcholine in subcutaneous small resistance arteries of hypertensive and diabetic patients. Twelve normotensive subjects (NT), 11 patients with essential hypertension (EH), 8 patients with non-insulin-dependent diabetes mellitus (NIDDM), and 8 patients with both EH and NIDDM (EH + NIDDM) were included in the study. Subcutaneous small resistance arteries were dissected and mounted on an isometric myograph. Concentration-response curves to norepinephrine (from 10–8 to 10–5 mol/l) and acetylcholine (from 10–9 to 10–5 mol/l) were performed in the presence or absence of insulin 715 pmol/l (low concentration) and 715 nmol/l (high concentration). A significant reduction in the contractile response to norepinephrine was observed in NT after preincubation of the vessels with both low- and high-concentration insulin. No reduction was observed in NIDDM and EH + NIDDM, while a significant decrease was obtained in EH with high-concentration insulin. Moreover, a significant difference in reduction in contractile response at maximal concentration of norepinephrine in the presence of low-concentration insulin was observed in NT compared to EH (p = 0.03), NIDDM (p = 0.02), and EH + NIDDM (p = 0.05), whereas no difference was observed with high-concentration insulin. No differences in the concentration-response curves to acetylcholine before or after precontraction with either low- or high-concentration insulin were observed in any group. In conclusion, insulin at low (physiological) concentrations seems to induce a decreased reactivity to norepinephrine in subcutaneous small resistance arteries of NT, but this effect was lost in EH, NIDDM and EH + NIDDM. This effect does not seem to involve acetylcholine-stimulated nitric oxide release.

Contents Vol. 45, 2008

U.H. von Andrian, Boston, Mass. J.E. Brayden, Burlington, Vt. G. Breier, Dresden N.J. Brown, Sheffi eld G. Clough, Southampton M.J. Davis, Columbia, Mo. M.G.A. oude Egbrink, Maastricht J.C. Frisbee, Morgantown, W.Va. C.J. Garland, Bath M. Gassmann, Zürich T. Gloe, Munich M. Gollasch, Berlin T.M. Griffi th, Cardiff A.M. Heagerty, Manchester P. Hellstrand, Lund D. Henrion, Angers C. Hill, Canberra M.A. Hill, Columbia, Miss. V.W. van Hinsbergh, Leiden Y. Huang, Shatin, Hong Kong V.H. Huxley, Columbia, Mo. J.D. Imig, Augusta, Ga. W.F. Jackson, Kalamazoo, Mich. A. Koller, Valhalla, N.Y. I. Laher, Vancouver B.L. Langille, Toronto T.M. Lincoln, Birmingham, Ala. L. Lindbom, Stockholm J. Lopez-Barneo, Sevilla R.M. Lynch, Tucson, Ariz. J.M. Marshall, Birmingham S. Massberg, Boston, Mass. J.C.I. McGrath, Glasgow A.C. Newby, Bristol H. Nilsson, Aarhus A.R. Pries, Berlin I.H. Sarelius, Rochester, N.Y. E.L. Schiff rin, Montréal G.W. Schmid-Schönbein, La Jolla, Calif. S.M. Schwartz, Seattle, Wash. S.S. Segal, New Haven, Conn. A.C. Shore, Exeter U. Simonsen, Aarhus L. Sorokin, Muenster D.W. Stepp, Augusta, Ga. A. Tedgui, Paris J.E. Tooke, Exeter E. Vicaut, Paris B.R. Wamhoff , Charlottesville, Va. C. Webb, Augusta, Ga. C. de Wit, Luebeck Founded 1964 as ‘Angiologica’ by M. Comèl and L. Laszt (1964–1973) continued as ‘Blood Vessels’ by J.A. Bevan (1974–1991) continued as ‘Journal of Vascular Research’ by M.J. Mulvany (1991–2002)