Nicola Rizzardi

Altered structure of small cerebral arteries in patients with essential hypertension.

Objective Structural alterations in the microcirculation may be considered an important mechanism of organ damage. An increased media-to-lumen ratio of subcutaneous small resistance arteries has been demonstrated to predict the development of cardiocerebrovascular events in hypertensive patients. Alterations in the structure of small cerebral arteries have been demonstrated in animal models of experimental or genetic hypertension. However, no evaluation with reliable techniques has ever been performed in humans. Design and methods Twenty-eight participants were included in the present study: they were 13 hypertensive patients and 15 normotensive individuals. All participants underwent a neurosurgical intervention for benign or malign tumors. A small portion of morphologically normal cerebral tissue was excised from surgical samples and examined. Cerebral small resistance arteries (relaxed diameter around 200 μm) were dissected and mounted on an isometric and isobaric myograph, and the tunica media to internal lumen ratio was measured. In addition, cerebral cortical microvessel density (MVD) was also evaluated. The tissue was sectioned and stained for CD31, and MVD was measured with an automated image analyzer (percentage of area stained). Blood pressure values were evaluated, before surgical intervention, by standard sphygmomanometry. Results M/L was significantly greater and MVD significantly lower in hypertensive patients than that in normotensive individuals. No difference between groups in collagen content or mechanical properties of cerebral small arteries was observed. Conclusion Our results indicate that structural alterations of small cerebral vessels are present in hypertensive patients compared with normotensive individuals, similar to those previously observed in subcutaneous small arteries.

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.

Immunohistochemical evaluation of microvascular rarefaction in hypertensive humans and in spontaneously hypertensive rats

OBJECTIVE No data are presently available about changes in capillary density in the skeletal muscle and in the brain of spontaneously hypertensive rats (SHR) in relation to the development of hypertension. DESIGN AND METHODS We have investigated 4 week-old and 12 week-old SHR and age-matched normotensive Wistar-Kyoto controls (WKY). Microvessel density (MVD) in the cerebral cortex and in a skeletal muscle were evaluated in sections stained for CD31. We also evaluated MVD in the dermal tissue of normotensive subjects and essential hypertensive patients. Subcutaneous small resistance arteries were dissected and mounted in a micromyograph and the media to lumen ratio (M/L) was measured. RESULTS A significant reduction in MVD in the skeletal muscle and in the brain of SHR was clearly observed at 12 weeks of age, after the development of hypertension, but not at 4 weeks of age (pre-hypertensive condition). In hypertensive patients a significant reduction in the dermal MVD and an inverse correlation between M/L and MVD was observed. CONCLUSIONS Our results suggest that, in the brain and skeletal muscle of adult SHR after the development of hypertension, and in the derma of adult essential hypertensive patients microvascular rarefaction may occur.

Hypertrophic Remodeling of Subcutaneous Small Resistance Arteries in Patients with Cushing’s Syndrome

OBJECTIVE Structural alterations of small resistance arteries in essential hypertensive patients (EH) are mostly characterized by inward eutrophic remodeling. However, we observed hypertrophic remodeling in patients with renovascular hypertension, in those with acromegaly, as well as in patients with non-insulin-dependent diabetes mellitus, suggesting a relevant effect of humoral growth factors on vascular structure, even independent from the hemodynamic load. Cortisol may stimulate the renin-angiotensin system and may induce cardiac hypertrophy. However, presently no data are available about small artery structure in patients with Cushings syndrome. SUBJECTS We have investigated the structure of sc small resistance arteries in 12 normotensive subjects (NT), in 12 EH subjects, and in eight patients with Cushings syndrome (CS). Small arteries from sc fat were dissected and mounted on a micromyograph. The normalized internal diameter, media thickness, media to lumen ratio, and the media cross-sectional area were measured, as well as indices of oxidative stress. RESULTS Demographic variables were similar in the three groups, except for clinic blood pressure. The media to lumen ratio was significantly greater in EH and CS, compared with NT; no difference was observed between EH and CS. The media cross-sectional area was significantly greater in CS compared with EH and with NT. An increased vascular oxidative stress was present in CS, as demonstrated by increased levels of superoxide anions, cyclooxygenase-1 and endothelial nitric oxide synthase in the microvessels. CONCLUSION Our results suggest the presence of hypertrophic remodeling in sc small resistance arteries of CS, probably as a consequence of growth-promoting properties of circulating cortisol and/or increased vascular oxidative stress.

Decreased number of circulating endothelial progenitor cells in patients with Graves’ hyperthyroidism

Objective: A relevant biological role of circulating endothelial progenitor cells (EPC) was recently demonstrated. EPC are generated in the bone marrow, and interact with damaged endothelium, restoring the integrity of the monolayer. Therefore, aim of the present study was to evaluate EPC in the blood of patients with untreated Graves’ hyperthyroidism (GD), in whom an increased oxidative stress was observed. Design and methods: Twenty-three patients with untreated active GD and 18 matched normal controls (NC) were included in the study. Circulating EPC were isolated from peripheral blood. Mononuclear cells were cultured with endothelial basal medium supplemented with EGM SingleQuots, and were identified by positive double staining after 7 days in culture. Circulating levels of C reactive protein, total antioxidant power, interleukin (IL)-6, IL-18, monocyte chemoattractant protein-1, tumor necrosis facotr-α, soluble vascular cell adhesion molecule (VCAM) and intracellular adhesion molecule were evaluated by enzyme-linked immunosorbent assay kit. EPC number was also evaluated in a subgroup of GD patients after restoration of euthyroidism. Results: Systolic blood pressure resulted increased in GD patients compared with control subjects whereas diastolic blood pressure was not significantly different. Patients with GD showed an increase in circulating levels of IL-18 and VCAM-1 and a reduction of total antioxidant power (p<0.05) compared to NC. Moreover, a reduced number of EPC was observed in patients with GD compared to NC (p<0.05) which turned to NC values after restoring euthyroidism. Conclusion: Patients with GD showed a reduction in the physiological protective mechanisms against endothelial damage, probably induced by increased inflammation and oxidative stress.

Determinants of the structure of resistance‐sized arteries in hypertensive patients

Objective. It has been previously demonstrated that structural alterations of subcutaneous small resistance arteries of hypertensive patients, as indicated by an increased media to lumen (M/L) ratio, is the most potent predictor of cardiovascular events. The aim of the present study was to identify possible determinants of small resistance artery structure that may be evaluated with non‐invasive approaches. Materials and methods. One hundred and ninety‐nine subjects (normotensives, essential hypertensives and patients with secondary hypertension) were included in the present study. 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 M/L ratio was measured. All patients underwent standard biochemical tests, clinic blood pressure measurement, standard echocardiography and 24‐h ambulatory blood pressure measurement. Glomerular filtration rate (GFR) was calculated according to MDRD study formula and Cockrofts formula. Results. Significant correlation was found between M/L ratio and, respectively: GFR calculated both with MDRD study formula and Cockroft–Gault formula, creatinine serum, blood urea nitrogen, glycaemia, circulating sodium, clinical pulse pressure, stroke volume to pulse pressure ratio, clinical systolic, diastolic and mean arterial pressure, daytime pulse pressure. However, in a multivariate regression analysis, only serum creatinine remained in the model, and proved to be an independent predictor of small artery structure. Conclusions. Indices of renal function and, probably, of large artery distensibility may be related to small arteries remodelling in hypertension.

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.

Role of Heme Oxygenase in Modulating Endothelial Function in Mesenteric Small Resistance Arteries of Spontaneously Hypertensive Rats

It has been proposed that endothelial dysfunction is due to the excessive degradation of nitric oxide (NO) by oxidative stress. The enzyme heme-oxygenase (HO) seems to exert a protective effect on oxidative stress in the vasculature, both in animal models and in humans. The objective of this study is to evaluate the effects of inhibition or activation of HO on endothelial function in mesenteric small resistance arteries of spontaneously hypertensive rats (SHR). Six SHR were treated with cobalt protoporphyrin IX 50 mg/Kg (CoPP), an activator of HO; six SHR with stannous mesoporphyrin 30 mg/Kg (SnMP), an inhibitor of HO, and six SHR with saline. As controls, six Wistar-Kyoto rats (WKY) were treated with CoPP, six WKY with SnMP, and six WKY with saline. Drugs were injected in the peritoneum once a week for 2 weeks. Systolic blood pressure (SBP) was measured (tail cuff method) before and after treatment. Mesenteric small resistance arteries were mounted on a micromyograph. Endothelial function was evaluated as a cumulative concentration-response curve to acetylcholine (ACH), before and after preincubation with N(G)-methyl-L-arginine (L-NMMA, inhibitor of NO synthase), and to bradykinin (BK). In SHR treatment with CoPP, improved ACH-and BK-induced vasodilatation (ANOVA p < 0.001) and this improvement was abolished by L-NMMA (ANOVA p < 0.001). SnMP was devoid of effects on endothelial function. In WKY, both activation and inhibition of HO did not substantially affect endothelium-mediated vasodilatation. The stimulation of HO seems to induce an improvement of endothelial dysfunction in SHR by possibly reducing oxidative stress and increasing NO availability.

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)

A strange chest pain after dental surgery

In May 2007, a 29-year-old man was admitted to our ward complaining of chest pain exacerbated by deep breathing but not by change of position. The chest pain episodes were short-lasting (some minutes), but the patient complained of several relapses. Simultaneously, soft-consistency bilateral swelling of the neck appeared in the submandibular and lateral cervical regions. Ten hours before admission, the patient had undergone dental surgery for removal of the III right inferior wisdom tooth. The procedure was particularly difficult and lasted for more than 90 min. The family history was negative for cardiovascular disease; no relevant previous disease was present. He was not on any medical treatment; however, he smoked 15 cigarettes a day, and his alcohol intake was moderate. Physical examination of the patient showed normal blood pressure (120/80 mmHg) and heart rate (65 beats/ min). He was eupnoeic, and oxygen saturation of the blood was 97% (no oxygen supply). Body temperature was normal. A physical examinations showed bilateral swelling of subcutaneous tissues that were more pronounced on the right side of the neck, chest, and in the submandibular, lateral cervical, supraclavicular, and mammary regions, with modest pain and ‘‘crepitation’’ on digital pressure. The cardiac auscultation produced crackling, bubbling, and rubbing related to systole. The patient’s white cell count was modestly elevated (11,100/mm), while the renal and liver functions and urinalysis were normal. No elevation of troponin I or T and of creatinine–phosphokinase was detected. The ECG showed the presence of sinus rhythm and high-voltage Twaves in peripheral leads. The chest X-ray examination showed no abnormal findings (Fig. 1). Based on these findings, a preliminary diagnosis of acute pericarditis was made.