C. Morizzo

Effects of age and physical fitness on microcirculatory function

Sedentary aging is associated with endothelial dysfunction and nitric oxide (NO) impairment. The aim of the present study was to assess the effects of regular physical exercise on nitrite/nitrate (NOx) concentrations and microcirculatory function in older men compared with young individuals. We measured NOx plasma concentrations and baseline and stimulated skin blood flow (SBF) by laser Doppler flowmetry in 39 male athletes [range, 22-72 years; maximal oxygen consumption (VO2max), 60.0 +/- 4.7 ml.min(-1).kg of body weight(-1) (mean +/- S.D.)] and 45 age- and sex-matched sedentary controls (VO2max, 38.0 +/- 7.1 ml.min(-1).kg of body weight(-1)). NOx concentrations were higher in athletes than in controls (50.4 +/- 16.3 compared with 39.0 +/- 15.4 micromol/l; P<0.005), whereas baseline SBF was comparable. Hand SBF after heating and ischaemia and foot SBF after heating were higher in athletes (P<0.0001) than in controls. By comparing the lowest and the highest tertile of age, sedentary young subjects had higher NOx concentrations than sedentary older subjects (43.3 +/- 13.4 compared with 31.8 +/- 12.2 micromol/l respectively; P<0.05). Exercise abolished this difference (49.1 +/- 9.6 micromol/l for young subjects and 52.1 +/- 11.5 micromol/l for older subjects; not significant). Resting SBF was similar in all the subgroups, but stimulated SBFs were lower in both subgroups of untrained compared with trained subjects. NOx concentrations were positively correlated with VO2max (r=0.46, P<0.001). Stimulated SBFs were correlated with NOx (r>0.30, P<0.05). These findings show that chronic exercise may improve endothelial function in older (and young) men, probably by increasing NO availability.

Early impairment of coronary flow reserve and increase in minimum coronary resistance in borderline hypertensive patients.

Objective To evaluate relations between coronary flow velocity and myocardial oxygen demand at rest, as well as coronary vasodilator capacity and flow reserve, in asymptomatic subjects with borderline hypertension as compared to normotensive controls and patients with sustained high blood pressure (HBP) and without left ventricular hypertrophy (LVH). Subjects and methods Forty-two asymptomatic males were studied: 13 healthy normotensive volunteers; 12 subjects with borderline HBP and 17 asymptomatic subjects with sustained systemic hypertension. Coronary flow velocity in left anterior descending artery and coronary flow reserve were assessed by transesophageal echodoppler at baseline and during intravenous adenosine infusion. Left ventricular mass, peak systolic wall stress (PSWS; Pa), and midwall fractional shortening (MFS; %) were obtained from M-mode images of the left ventricle in transthoracic long-axis view and in transesophageal transgastric view. Results Coronary flow velocity at baseline was not significantly different in the three groups, despite significantly higher rate-pressure product (RPP) in the hypertensive groups as compared with controls. Only in control subjects, was resting coronary flow velocity significantly correlated with RPP (y = 4279 + 200x, r = + 0.58, P < 0.05) and PSWS (y = 17.2 + 5.1x, r = + 0.62, P < 0.05). Coronary reserve was 3.5 ± 0.65 in controls and significantly lower (P < 0.05) in borderline hypertensive (2.87 ± 0.46) and in sustained hypertensive subjects (2.66 ± 0.56). Minimum coronary resistance was significantly increased in both hypertensive groups (1.30 ± 0.29 and 1.39 ± 0.48 mmHg/s per cm) as compared to normotensive controls (0.93 ± 0.20 mmHg/s per cm, P < 0.01). Conclusions In asymptomatic subjects with borderline hypertension and without LVH, a significant reduction in coronary flow reserve is already detectable and appears almost entirely related to an impaired coronary vasodilator capacity rather than to an increased myocardial oxygen demand.

Ultrafast Three-Dimensional Ultrasound Application to Carotid Artery Imaging

BACKGROUND AND PURPOSE Three-dimensional (3-D) vascular ultrasound can be expected to improve qualitative evaluation of vessel pathology and to provide quantitative data on vascular morphology and function. The objective of this study was to develop an ultrafast 3-D vascular system and to validate its performance for quantitation of atherosclerosis and assessment of regional arterial distensibility. METHODS The quantitative analysis of focal atherosclerotic lesions was validated in vitro on 27 phantoms of fibroadipous plaques of known volume (range, 100 to 600 mm3). In vivo reproducibility of plaque volume measurement was tested in 33 patients who had a total of 47 predominantly fibroadipous carotid plaques. Distensibility assessment was validated indirectly through the evaluation of age-related changes in distensibility of common carotid artery in healthy and hypertensive subjects (25 men in each group). RESULTS The volume of plaque phantoms measured from the 3-D data set showed a very close correlation with the true volume (r=0.99; y=0.96x+12.38; P<0.01), with the mean difference between the 2 measurements being -3.12+/-15.1 mm3. High reproducibility was found for measurement of carotid plaque volume in vivo: the mean difference between measurements from 2 observers for the same data set was 0.60+/-11.2 mm3. Indexes of arterial distensibility decreased with age in healthy population, whereas this relationship was lost in hypertensive subjects. CONCLUSIONS Ultrafast 3-D ultrasound imaging of carotid artery demonstrates good accuracy and reproducibility for atherosclerotic plaque volume measurements. The system also allows the study of age-related degenerative vascular changes.

Effect of sedentary behaviour and vigorous physical activity on segment-specific carotid wall thickness and its progression in a healthy population

AIMS This study investigated whether sedentary behaviour and different activity levels have an independent association with carotid intima-media thickness (IMT) and with the 3-year IMT progression in different carotid segments. METHODS AND RESULTS The study population included 614 healthy men and women (mean age = 44 +/- 8 years) without carotid atherosclerosis and without increased coronary heart disease risk, who underwent B-mode carotid ultrasound and objective physical activity assessment by accelerometer (mean monitoring time = 5.7 +/- 1.5 days). Time spent in sedentary (57.6 +/- 9.1%), light (41.0 +/- 9.2%), moderate and vigorous activities was determined. Sedentary behaviour was expressed as the ratio of time spent in sedentary and light activity (sedentary/light ratio) as these two activities occupied the majority of waking time. In 495 subjects, the carotid ultrasound was repeated 3 years after the baseline examination. After adjustment for age and the established risk factors that were independent determinants of carotid wall thickness in our population, sedentary/light ratio was independently associated only with the common carotid artery (CCA) IMT. The 3-year increase in CCA IMT was significantly lower in subjects with periods of vigorous activity (7 +/- 40 microm) when compared with those with light activity only or with periods of moderate activity (22 +/- 51 and 19 +/- 46 microm, respectively, P < 0.05). CONCLUSION The healthy, young-to-middle age population of this study spent more than half of their waking time in sedentary activities. The proportion of time spent in sedentary activities was directly associated with baseline CCA IMT, independently of age and established atherosclerotic risk factors. In the longitudinal analysis, period of vigorous activity influenced the 3-year IMT progression in CCA.

Circulating endothelial progenitor cells and large artery structure and function in young subjects with uncomplicated Type 1 Diabetes

BackgroundCarotid intima-media thickness (IMT), indices of large artery stiffness and measures of endothelium function may be used as markers of early atherosclerosis in type 1 diabetes mellitus (T1DM). The aim of the present study was to compare the indices of large artery structure and function as well as endothelial function and regenerating capacity between adolescents with T1DM and healthy control of similar age. In addition, the associations of different vascular measures with endothelial progenitor cells (EPCs), glyco-metabolic control and serum levels of advanced glycation endproducts (AGEs), soluble receptors for AGEs (sRAGE) and adiponectin were evaluated.MethodsSixteen uncomplicated young T1DM patients (mean age 18 ± 2 years, history of disease 11 ± 5 years, HbA1c 7.7 ± 1.1%) and 26 controls (mean age 19 ± 2 years) were studied. A radiofrequency-based ultrasound system (Esaote MyLab 70) was used to measure carotid IMT and wave speed (WS, index of local stiffness), applanation tonometry (PulsePen) was applied to obtain central pulse pressure (PP) and augmentation index (AIx), and carotid-femoral pulse wave velocity (PWV, Complior) was used as index of aortic stiffness. Peripheral endothelium-dependent vasodilation was determined as reactive hyperemia index (RHI, EndoPAT). Circulating EPCs, glycometabolic profile, AGEs (autofluorescence method), sRAGE and adiponectin were also measured.ResultsAfter adjusting for age, sex and blood pressure, T1DM adolescents had significantly higher carotid IMT (456 ± 7 vs. 395 ± 63 μm, p < 0.005), carotid WS (p < 0.005), PWV (p = 0.01), AIx (p < 0.0001) and central PP (p < 0.01) and lower EPCs (p = 0.02) as compared to controls. RHI was reduced only in diabetic patients with HbA1c ≥7.5% (p < 0.05). In the overall population, EPCs were an independent determinant of carotid IMT (together with adiponectin), while fasting plasma glucose was an independent determinant of carotid WS, AIx and central PP.ConclusionsOur findings suggest that young subjects with relatively long-lasting T1DM have a generalized preclinical involvement of large artery structure and function, as well as a blunted endothelium regenerating capacity. Hyperglycemia and suboptimal chronic glycemic control seem to deteriorate the functional arterial characteristics, such as large arteries stiffness, wave reflection and peripheral endothelium-dependent vasodilation, whereas an impaired endothelium regenerating capacity and adiponectin levels seem to influence arterial structure.

Large Artery Remodeling and Dynamics following Simulated Microgravity by Prolonged Head-Down Tilt Bed Rest in Humans

The effects of simulated microgravity on the static and dynamic properties of large arteries are still mostly unknown. The present study evaluated, using an integrated vascular approach, changes in structure and function of the common carotid and femoral arteries (CCA and CFA) after prolonged head-down tilt bed rest (HDTBR). Ten healthy men were enrolled in a 5-week HDTBR study endorsed by the Italian Space Agency (ASI). Arterial geometry, flow, stiffness, and shear rate were evaluated by ultrasound. Local carotid pulse pressure and wave reflection were studied by applanation tonometry. After five weeks of HDTBR, CFA showed a decrease in lumen diameter without significant changes in wall thickness (IMT), resulting in an inward remodeling. Local carotid pulse pressure decreased and carotid-to-brachial pressure amplification increased. The ratio of systolic-to-diastolic volumetric flow in CFA decreased, whereas in CCA it tended to increase. Indices of arterial stiffness and shear rate did not change during HDTBR, either in CCA or CFA. In summary, prolonged HDTBR has a different impact on CCA and CFA structure and flow, probably depending on the characteristics of the vascular bed perfused.

Adiponectin and left ventricular structure and function in healthy adults

CONTEXT Adiponectin inhibits protein synthesis in cardiac myocytes, thereby opposing the effect of cardiac workload and trophic factors (in particular, insulin) on left ventricular (LV) mass and wall thickness (WT). OBJECTIVE We tested whether adiponectin and its isoforms are related to LV mass, WT, and function independently of metabolic factors. DESIGN This was a cross-sectional study. SUBJECTS The study included 77 healthy volunteers (42 men) aged 30-59 yr with normal LV structure and function. MAIN OUTCOME MEASURES Insulin response and insulin sensitivity were assessed by oral glucose tolerance test and euglycemic hyperinsulinemic clamp. LV mass, WT, stroke work, chamber function, and myocardial longitudinal function were evaluated by standard Doppler echocardiography and tissue Doppler imaging. Total and molecular isoforms of adiponectin were measured in plasma. RESULTS By multivariate analysis, independent factors affecting LV mass were sex, body mass index, stroke work, and current smoking (R(2) = 0.66). Independent correlates of LV WT were age, stroke work, and plasma adiponectin (standardized r = 0.28, 0.41, and -0.26, P at least < 0.005, R(2) = 0.48). LV longitudinal late diastolic velocity was independently related to age, body mass index, and adiponectin (standardized r = 0.20, 0.26, -0.33, P at least < 0.05, R(2) = 0.30). High-molecular-weight adiponectin (47% of total), but not lower molecular-weight isoforms, insulin sensitivity, or other metabolic factors, was inversely and independently related to WT (standardized r = -0.27, P < 0.01) and myocardial longitudinal late diastolic velocity (standardized r = -0.28, P < 0.05). CONCLUSION In healthy subjects, circulating total and high-molecular-weight adiponectin are related to LV WT and diastolic function, independently of age and metabolic factors.

Coronary vasodilator capacity and hypertension-induced increase in left ventricular mass

Abstract—An increase in left ventricular mass represents a compensatory response of hypertensive heart to augmented loading conditions. The concept of inappropriate mass has been proposed to define an increase in left ventricular mass higher than needed to compensate for increased workload. To assess whether inappropriate left ventricular mass is associated with more severe impairment of coronary vasodilator capacity, 64 untreated middle-aged hypertensive patients without significant coronary artery stenosis and 14 normotensive volunteers comparable for age and gender were studied by transthoracic and transesophageal echocardiography to evaluate left ventricular mass, geometry, and coronary flow velocity response to adenosine. Thirty-three patients had appropriate and 31 had inappropriate increase in left ventricular mass, whereas all normotensive control subjects had appropriate left ventricular mass. Compared with control subjects, minimum coronary resistance (0.87±0.18 mm Hg per second/centimeter) was increased in both hypertensive subgroups, more in those with inappropriate left ventricular mass (1.34±0.23 versus 1.19±0.23 mm Hg per second/centimeter, P <0.01), who also exhibited lower afterload-corrected midwall shortening and ratio of peak early and peak late velocities of transmitral flow profile. In hypertensive patients, minimum coronary resistance was related positively to absolute and relative left ventricular wall thickness (r =+0.33 and +0.35, both P <0.01) and negatively to midwall shortening and ratio of peak early and peak late velocities of transmitral flow (r =−0.32 and −0.31, both P <0.02). Thus, in the hypertensive heart, a deviation of left ventricular mass from values compensatory for increased cardiac workload is associated with lower coronary vasodilator capacity, depressed left ventricular wall mechanics, and abnormal left ventricular diastolic filling pattern.

Measures of atherosclerotic burden are associated with clinically manifest cardiovascular disease in type 2 diabetes: a European cross-sectional study

There is a need to develop and validate surrogate markers of cardiovascular disease (CVD) in subjects with diabetes. The macrovascular changes associated with diabetes include aggravated atherosclerosis, increased arterial stiffness and endothelial dysfunction. The aim of this study was to determine which of these factors is most strongly associated with clinically manifest cardiovascular events.

Impact of prolonged cardiac unloading on left ventricular mass and longitudinal myocardial performance: an experimental bed rest study in humans

Objective This study evaluated the impact of prolonged circulatory unloading and subsequent left ventricular (LV) mass decrease on LV myocardial performance. Five-week head-down tilt (−6°) bed rest (HDTBR) was used as a model of prolonged circulatory unloading. Methods Ten young healthy male volunteers (age 23 ± 2 years) were studied a day before and within the first 24 h after the end of HDTBR by two-dimensional Doppler echocardiography and carotid applanation tonometry. LV preload and afterload, cardiac workload, LV mass and wall stress, LV chamber function and diastolic filling were assessed. Longitudinal, radial and circumferential myocardial strain rate were evaluated by tissue tracking algorithm. Results After HDTBR, stroke volume (P < 0.01), stroke work (P = 0.01) and LV mass (P < 0.001) decreased, whereas relative wall thickness, peak and end-systolic wall stress and ejection fraction remained unchanged. HDTBR was also followed by a decrease in longitudinal systolic strain rate (−1.11 ± 0.05 vs. −1.00 ± 0.05 s−1, P = 0.02) and a prolongation of isovolumic relaxation time (IVRT) (74 ± 2 vs. 82 ± 3 ms, P < 0.01). Bed rest-induced changes in LV mass index were directly related to changes in stroke work index (r = 0.65, P < 0.05), and changes in longitudinal systolic strain rate and IVRT correlated with changes in stroke volume index, directly and inversely, respectively (r = 0.69 and −0.64, P < 0.05 for both). Conclusion A decrease in LV mass following HDTBR parallels the reduction in cardiac workload and is associated with an attenuation of longitudinal systolic myocardial deformation rate and prolongation of IVRT that seem to reflect a functional adaptation of cardiac muscle to lower LV volume load.