Massimo Raffaele Mannarino

Metabolic Syndrome Is Associated With Aortic Stiffness in Untreated Essential Hypertension

Metabolic syndrome is a powerful predictor of cardiovascular disease in hypertension, and large-artery stiffness is increasingly recognized as a cardiovascular risk factor. We hypothesized that the adverse prognostic significance of the metabolic syndrome in hypertension might be explained in part by its association with aortic stiffness. A total of 169 newly diagnosed, never treated, nondiabetic patients with essential hypertension (men 55%, 48±11 years) were classified by the presence (n=45) or absence (n=124) of the metabolic syndrome. All patients underwent aortic and upper limb pulse wave velocity determination by means of an applanation tonometry-based method. Aortic pulse wave velocity had a direct correlation with office and 24-hour systolic pressure (r=0.42 and 0.31, respectively), as well as with waist circumference (r=0.35, all P<0.001), but not with body mass index (r=0.10, P=not significant). Aortic pulse wave velocity was higher in the subgroup with the metabolic syndrome (10.0±2.7 versus 8.8±2.1 m/s; P=0.003), whereas upper limb velocity did not differ in the 2 groups (8.6±1.4 versus 8.7±1.5 m/s; P=not significant). In a multiple regression, aortic pulse wave velocity was independently associated with age, systolic blood pressure, and the metabolic syndrome. Only diastolic BP independently predicted upper limb pulse wave velocity. We conclude that in untreated hypertension, the metabolic syndrome is independently associated with a higher aortic, but not upper limb, pulse wave velocity. Central, but not general, adiposity is an important determinant of aortic stiffness in hypertension.

Ambulatory Arterial Stiffness Index Is Not a Specific Marker of Reduced Arterial Compliance

Ambulatory arterial stiffness index (AASI), a measure based on the relative behavior of 24-hour systolic and diastolic blood pressure (BP), has been suggested as a marker of arterial stiffness and a predictor of cardiovascular mortality. However, a narrow range of diastolic BP values over the 24 hours tends to flatten the regression slope and to artificially increase AASI. We explored the possible influence of different ranges of 24-hour diastolic BP fluctuations, such as those related to nocturnal BP fall, on AASI, and on its relationship with target organ damage. In 515 untreated hypertensive patients, AASI was directly related to age (r=0.30) and 24-hour systolic BP (r=0.20), whereas it was inversely related with nocturnal systolic and diastolic BP reduction (r=−0.28 and −0.46, respectively; all P<0.001). A direct relationship was found between AASI and left ventricular mass index (r=0.17; P<0.001), but this relation was no longer significant after adjustment for age, sex, body mass index, daytime systolic BP, and day-night systolic BP reduction (all P<0.05). AASI was directly related to carotid-femoral pulse wave velocity, an intrinsic measure of aortic stiffness (r=0.28; P<0.001), but no independent relation was found in a multiple linear regression. Our conclusions are as follows: (1) AASI is strongly dependent on the degree of nocturnal BP fall in hypertensive patients; (2) there is no significant relation between AASI and left ventricular mass after proper adjustment for confounders; and (3) the relation between AASI and a widely accepted measure of aortic stiffness, such as pulse wave velocity, is weak and importantly affected by other factors.

Obstructive sleep apnea syndrome

Obstructive sleep apnea (OSA) syndrome is a common but often unrecognized disorder caused by pharyngeal collapse during sleep and characterized by frequent awakenings, disrupted sleep and consequent excessive daytime sleepiness. With the increasing epidemic of obesity, the most important risk factor for OSA, prevalence of the disease will increase over the coming years thus representing an important public-health problem. In fact, it is now recognized that there is an association between OSA and hypertension, metabolic syndrome, diabetes, heart failure, coronary artery disease, arrhythmias, stroke, pulmonary hypertension, neurocognitive and mood disorders. Diagnosis is based on the combined evaluation of clinical manifestations and objective sleep study findings. Cardinal symptoms include snoring, sleepiness and significant reports of sleep apnea episodes. Polysomnography represents the gold standard to confirm the clinical suspicion of OSA syndrome, to assess its severity and to guide therapeutic choices. Behavioral, medical and surgical options are available for the treatment. Continuous positive airway pressure (CPAP) represents the treatment of choice in most patients. CPAP has been demonstrated to be effective in reducing symptoms, cardiovascular morbidity and mortality and neurocognitive sequelae, but it is often poorly tolerated. The results of clinical studies do not support surgery and pharmacological therapy as first-line treatment, but these approaches might be useful in selected patients. A better understanding of mechanisms underlying the disease could improve therapeutic strategies and reduce the social impact of OSA syndrome.

Increased Ratio of CD31 + /CD42 − Microparticles to Endothelial Progenitors as a Novel Marker of Atherosclerosis in Hypercholesterolemia

Objectives—Atherosclerosis may be caused by increased endothelial damage and by a consumptive loss of endothelial repair capacity by endothelial progenitors. Arterial stiffness is a reliable marker of atherosclerosis and a positive correlate of endothelial damage. We investigated whether an increased ratio of CD31+/CD42− microparticles to endothelial progenitors, a possible indicator of endothelial damage and impaired endothelium reparation, may contribute to aortic stiffness in hypercholesterolemia. We also studied the in vitro effect of microparticles from hypercholesterolemic patients on endothelial progenitor survival. Methods and Results—Circulating CD31+/CD42− microparticles, endothelial progenitors, and aortic pulse wave velocity (aPWV), a measure of aortic stiffness, were measured in 50 patients with never-treated hypercholesterolemia and 50 normocholesterolemic controls. Hypercholesterolemic patients had more circulating CD31+/CD42− microparticles, less endothelial progenitors, and a stiffer aorta than controls. aPWV was associated with CD31+/CD42− microparticles (r=0.61; P<0.001), endothelial progenitors (r=−0.45, P<0.001), and with cholesterol levels (r=0.51; P<0.001). High plasma cholesterol and a high ratio of CD31+/CD42− microparticles to endothelial progenitors independently predicted an increased aPWV. Microparticles from hypercholesterolemic patients caused a significant endothelial progenitor loss in vitro. Conclusions—Hypercholesterolemia-related aortic stiffness is promoted by plasma cholesterol directly, increased endothelial damage, and reduced endothelium repair capacity by endothelial progenitors.

Different Impact of the Metabolic Syndrome on Left Ventricular Structure and Function in Hypertensive Men and Women

Metabolic syndrome (MS) is increasingly recognized as an important cardiovascular risk factor in hypertension, but its influence on left ventricular (LV) mass and function in the 2 genders has not been specifically addressed. Among 618 nondiabetic, untreated hypertensive subjects, echocardiographically detected LV mass was significantly greater in subjects with MS. A significant interaction was observed between sex and the MS (P<0.003 for the multiplicative interaction term). Compared with women without the MS, those with the syndrome had a 24% greater LV mass (49.5±12 versus 40.0±10 g×m−2.7; P<0.001), whereas the difference was only 9% in men (50.3±12 versus 46.1±10 g×m−2.7; P=0.003). A greater prevalence of LV hypertrophy was found in women (37% versus 14%; P<0.001) but not in men (39% versus 29%; P=0.09) with the MS. After adjustment for the effect of age, body mass index, 24-hour systolic blood pressure, and several confounders, the MS was independently associated with a greater LV mass index in women (regression coefficient, 4.80; P<0.001) but not in men. Women with the MS also had a greater LV relative wall thickness (0.42±0.07 versus 0.39±0.07; P=0.004) and a depressed afterload-corrected midwall fractional shortening (94.0±12% versus 101.0±13%; P<0.001) than women without the syndrome, whereas no differences emerged in men. We conclude that, in untreated hypertension, MS has a different impact on LV hypertrophy and function in men and women. The effect of MS is more pronounced in women and is partly independent from the effect of several hemodynamic and nonhemodynamic determinants of LV mass.

Aortic Stiffness in Untreated Adult Patients With Human Immunodeficiency Virus Infection

HIV infection is associated with chronic immune activation, subclinical inflammation, and an atherogenic metabolic profile. It remains controversial whether HIV infection is a risk factor for accelerated arteriosclerosis independent from the effects of antiretroviral drugs. We investigated whether aortic stiffness, an early marker of arteriosclerosis, is increased in HIV patients who were not under antiretroviral treatment. In 39 untreated HIV-infected patients and 78 individually matched age-, sex-, and blood pressure–matched HIV-uninfected control subjects, we determined aortic pulse wave velocity (PWV), a direct noninvasive measure of aortic stiffness, by tonometric method. Subjects with overt cardiovascular disease or major cardiovascular risk factors were excluded from the study. Prevalence of the metabolic syndrome was higher in HIV patients (18% versus 5%; P=0.025). HIV patients had a higher aortic PWV (7.5±1.4 versus 6.7±1.1 m · s−1; P=0.001) than control subjects. Age, mean arterial pressure as a measure of distending pressure, and HIV infection (all P<0.05) independently predicted aortic PWV when a consistent number of cardiovascular risk factors was simultaneously controlled for. Among HIV-infected subjects, serum γ-glutamyl transpeptidase concentration (β=0.46; P=0.003) and mean arterial pressure (β=0.32; P=0.03) were independent determinants of aortic PWV. In conclusion, aortic stiffness is increased in HIV-infected individuals who have never received antiretroviral therapy. PWV increases with increasing serum γ-glutamyl transpeptidase concentration. Our data support the hypothesis that HIV infection is a risk factor for arteriosclerosis.

Relation between renal function within the normal range and central and peripheral arterial stiffness in hypertension.

Chronic kidney disease is accompanied by increased large-artery stiffness, but the relation between glomerular filtration rate within the reference range and central or peripheral arterial stiffness has been understudied. The link between renal function and arterial stiffness was assessed in 305 patients with never-treated essential hypertension (men: 58%; age: 48±11 years, blood pressure: 151/95±20/11 mm Hg), free from overt cardiovascular disease and with serum creatinine values <1.4 mg/dL (men) and <1.2 mg/dL (women), who underwent noninvasive aortic and upper-limb pulse wave velocity (PWV) determination. Aortic PWV was strongly related to age (r=0.55; P<0.001), whereas upper-limb PWV had a weaker nonlinear relation with age (&bgr;=1.392; P<0.001 for age; &bgr;=−1.312; P<0.001 for age squared) and a weak relation with aortic PWV (r=0.22; P<0.001). Glomerular filtration rate (GFR), estimated according to the Mayo clinic equation for healthy subjects, was inversely correlated with large-artery stiffness, as assessed by aortic PWV (r=−0.34; P<0.001), and with peripheral artery stiffness, as assessed by upper-limb PWV (r=−0.25; P<0.001). In a multivariate linear regression, aortic PWV was independently predicted by age (&bgr;=0.48; P<0.001), mean arterial pressure (&bgr;=0.14; P=0.013), and GFR (&bgr;=−0.13, P=0.029). Upper-limb PWV was predicted by GFR (&bgr;=−0.24; P<0.001) and mean arterial pressure (&bgr;=0.20; P<0.001). We conclude that, in hypertensive patients with normal renal function, an inverse relationship exists between GFR and stiffness of both central elastic and peripheral muscular arteries. These relations are in part independent from the effect of several confounders, including age, sex, and blood pressure values.

Reduced number of circulating endothelial progenitors and HOXA9 expression in CD34+ cells of hypertensive patients.

Objective Circulating endothelial progenitor cells (EPCs) differentiate into mature endothelial cells and regenerate the injured endothelium. The role of homeobox A9 (HOXA9) is critical for endothelial commitment during progenitor cell maturation, postnatal neovascularization and vascular repair. The objective of our study was to measure the expression of HOXA9 in CD34+ cells from hypertensive patients and to investigate its correlation with the number of circulating EPCs. Methods Thirty patients with newly diagnosed, never-treated essential hypertension and 30 age- and sex-matched normotensive controls were recruited for the study. Total RNA was extracted from peripheral CD34+ cells and quantitative real-time polymerase chain reaction for measurement of HOXA9 expression was performed. The number of CD34+/human kinase insert domain protein receptor + (KDR+) EPCs was measured and the Framingham risk estimated. Results Hypertensive patients had reduced HOXA9 expression compared to normotensive subjects (−26%, P < 0.001), and lower levels of peripheral CD34+/KDR+ EPCs (421 ± 93 versus 582 ± 101, P < 0.001). HOXA9 expression was inversely associated with systolic blood pressure (r = −0.54, P < 0.001) and the Framingham risk (r = −0.50, P < 0.001). A direct association was observed between the number of EPCs and HOXA9 expression (r = 0.50, P < 0.001), which was independent of blood pressure levels and Framingham risk. In a subgroup of 15 hypertensive patients, a 4-week treatment with ramipril was associated with a significant 15% increase in HOXA9 expression and 25% increase in EPC levels. Conclusions In hypertensive patients, downregulation of HOXA9 expression in peripheral CD34+ cells may have a role in the loss of circulating EPCs, thus potentially impairing postnatal neovascularization and vascular repair.

Impact of Treatment With Protease Inhibitors on Aortic Stiffness in Adult Patients With Human Immunodeficiency Virus Infection

Background—The role of antiretroviral therapy in acceleration of atherosclerosis in patients with human immunodeficiency virus (HIV) infection is controversial. We hypothesized that aortic stiffness, an early marker of arteriosclerosis, may be increased in HIV patients treated with protease inhibitors. Methods and Results—In 32 HIV-infected patients treated with protease inhibitors and 32 age-, sex-, and blood pressure–matched HIV-uninfected control subjects, we obtained aortic pulse wave velocity and central aortic pressure waveform, from which aortic augmentation was calculated. HIV patients had a higher aortic pulse wave velocity (7.6±1.1 versus 6.8±1.2 m×s−1, P=0.015) and aortic augmentation (6.8±5 versus 4.6±4 mm Hg, P=0.037) than control subjects. Age and HIV infection (both P<0.05) independently predicted aortic pulse wave velocity when a consistent number of cardiovascular risk factors was simultaneously controlled for. The cumulative duration of treatment was a predictor of aortic pulse wave velocity, each 5 years of treatment duration being independently related to a 1.35 m×s−1 increase in pulse wave velocity. Conclusions—Aortic stiffness is increased in HIV-positive individuals receiving antiretroviral therapy including a protease inhibitor. Pulse wave velocity increases with longer exposure to protease inhibitors. We hypothesize that arteriosclerosis is a side effect of antiretroviral treatment including a protease inhibitor.

Age-Specific Relationship of Aortic Pulse Wave Velocity With Left Ventricular Geometry and Function in Hypertension

Aortic pulse wave velocity (PWV), generally considered an intrinsic marker of arterial stiffness, might depend in part on the velocity of myocardial fiber shortening, but the relation between PWV and myocardial function in humans has been understudied. A total of 237 untreated hypertensive subjects over a wide age range (18 to 88 years) underwent aortic PWV determination and echocardiography, from which the mean velocity of circumferential fiber shortening was calculated as a measure of the velocity of myocardial shortening, and relative wall thickness was taken as a measure of left ventricular concentric remodeling. Patients were divided in 3 age groups (<40 years, 40 to 59 years, and ≥60 years). In the young, aortic PWV was directly associated with heart rate–corrected velocity of circumferential fiber shortening (r=0.39; P=0.002) but not to relative wall thickness (r=−0.01; P=0.95). The opposite was found in the older group, in which aortic PWV was accompanied by a concentric left ventricular geometric pattern (r=0.44 with relative wall thickness; P=0.009) and a reduced velocity of circumferential fiber shortening (r=−0.54; P<0.001) and stress-corrected midwall fractional shortening (r=−0.56; P<0.001). Intermediate values were found in the middle-aged group (r=0.23; P<0.01 with relative wall thickness; r=−0.07, P value not significant with velocity of circumferential fiber shortening). In conclusion, the relation between aortic PVW and the left ventricle is strongly age dependent. These data suggest that, in young people, aortic PWV is partly determined by an increased velocity of myocardial shortening. With increasing age, a relationship between aortic PWV (as a measure of arterial stiffness) and left ventricular concentric geometry emerges, which ultimately leads to a depressed ventricular systolic function.