Jaak Kals

Differential Effects of Nebivolol and Metoprolol on Central Aortic Pressure and Left Ventricular Wall Thickness

The aim of this study was to investigate the effects of the vasodilating &bgr;-blocker nebivolol and the cardioselective &bgr;-blocker metoprolol succinate on aortic blood pressure and left ventricular wall thickness. We conducted a randomized, double-blind study on 80 hypertensive patients. The patients received either 5 mg of nebivolol or 50 to 100 mg of metoprolol succinate daily for 1 year. Their heart rate, central and brachial blood pressures, mean arterial pressure, augmentation index, carotid-femoral pulse wave velocity, and left ventricular wall thickness were measured at baseline and at the end of the study. Nebivolol and metoprolol significantly reduced heart rate, brachial blood pressure, and mean arterial pressure to the same degree. However, reductions in central systolic and diastolic blood pressures, central pulse pressure, and left ventricular wall thickness were significant only in the nebivolol group. The change in left ventricular septal wall thickness was significantly correlated with central systolic blood pressure change (r=0.41; P=0.001) and with central pulse pressure change (r=0.32; P=0.01). No significant changes in augmentation index or carotid-femoral pulse wave velocity were detected in either treatment group. This proof-of-principle study provides evidence to suggest that &bgr;-blockers with vasodilating properties may offer advantages over conventional &bgr;-blockers in antihypertensive therapy; however, this remains to be tested in a larger trial.

Arterial stiffness, carotid artery intima-media thickness and plasma myeloperoxidase level in children with type 1 diabetes

OBJECTIVE The present study investigated the functional-structural changes of the arteries along with a new biochemical marker of atherosclerosis, plasma myeloperoxidase level, in children with type 1 diabetes (T1DM). METHODS We studied 30 children with T1DM, aged 4.7-18.6 years (mean T1DM duration 5.4+/-3.4 years, mean HbA(1c) 9.8%) and 30 healthy subjects, matched by sex, age and body mass index. Fasting blood samples were obtained for myeloperoxidase (MPO). Ultrasonography and pulse wave analysis were used to measure carotid intima-media thickness (IMT), augmentation index corrected to a heart rate of 75 (AIx@75) and pulse wave velocity (PWV). RESULTS Children with diabetes had significantly higher plasma MPO levels (p=0.006), increased AIx@75 (p=0.02), IMT (p=0.005) and IMT standard deviation scores (IMT SDS) (p=0.02), compared to the control group. IMT SDS correlated positively with HbA(1c) (r=0.39, p=0.05). PWV, adjusted for age and mean arterial blood pressure, correlated with diabetes duration (r=0.49, p=0.02). CONCLUSIONS Children with T1DM have substantially elevated plasma levels of myeloperoxidase as well as atherosclerosis-related structural and functional changes of the arterial wall.

High-sensitivity C-reactive protein affects central haemodynamics and augmentation index in apparently healthy persons.

Objective Among apparently healthy women and men, elevated levels of high-sensitivity C-reactive protein (hsCRP) predict the risk of cardiovascular events and may be useful for detecting subclinical atherosclerosis. The aim of this study was to investigate the associations between inflammatory markers, augmentation index (AIx), central pulse pressure and central systolic blood pressure in apparently healthy subjects. Design and settings An observational study conducted at a university teaching hospital. Methods and results Apparently healthy subjects (n = 158; 75 males, 83 females) passed a complete history and physical examination, blood tests and pulse wave analysis. AIx was significantly higher in patients with hsCRP levels above 1 mg/l (24.5 ± 9.9 versus 18.1 ± 12.6%, P < 0.001). Central pulse pressure and central systolic blood pressure were significantly higher in the group with hsCRP levels above 1 mg/l. No differences between groups were shown for peripheral pulse pressure, peripheral blood pressures and estimated aortic pulse wave velocity. In multiple regression analysis, AIx correlated positively with age, female gender, short stature, mean arterial pressure, hsCRP (P = 0.026) and white blood cell count (P = 0.01), and negatively with heart rate. Conclusions This study shows that plasma levels of hsCRP are positively correlated with AIx, central pulse pressure and central systolic blood pressure. Apparently healthy subjects with increased inflammatory markers have increased systemic arterial stiffness, which might reflect early atherosclerotic changes. Our results suggest that hsCRP and non-invasively measured arterial stiffness could serve as additional tools, beside conventional cardiovascular risk factors, for assessment of global arterial risk and preclinical atherosclerotic changes in arteries.

Vitamin D reduces deposition of advanced glycation end-products in the aortic wall and systemic oxidative stress in diabetic rats

AIMS Vitamin D may have an important role in reducing the risk of cardiovascular disease. Advanced glycation end-products (AGEs) such as Nε-(carboxymethyl)lysine (CML), have been implicated in diabetic vascular complications via oxidative stress-mediated pathways. We investigated the potential protective effect of vitamin D on CML accumulation in the diabetic aortic wall. To test the effects of vitamin D on systemic oxidative stress we also assessed liver oxidative stress index (OSI) and serum total antioxidant capacity (TAC). METHODS Male Wistar rats were assigned to three groups: control, untreated diabetes, and diabetes+cholecalciferol. Diabetes was induced by streptozotocin, followed by oral administration of cholecalciferol (500 IU/kg) for 10 weeks in the treatment group. Aortic CML accumulation was determined by ELISA and immunohistochemical assays. OSI was assessed by measuring TAC and the level of total peroxides in the liver and serum using colorimetric assays. RESULTS Untreated diabetes was associated with significantly elevated CML levels in the aortic wall (19.5 ± 3.3 vs 10.2 ± 4.7 ng/mL), increased liver OSI (6.8 ± 1.9 vs 3.1 ± 0.7), and reduced serum TAC (0.4 ± 0.1 vs 0.8 ± 0.3 mmol Trolox/L), in comparison with the control group. Cholecalciferol significantly blocked the accumulation of CML in the aortic wall (10.4 ± 8.4 vs 19.5 ± 3.3 ng/mL), decreased liver OSI (4.2 ± 1.4 vs 6.8 ± 1.9), and improved serum TAC (1.0 ± 0.2 vs 0.4 ± 0.1 mmol Trolox/L), compared with the untreated diabetic group. CONCLUSIONS Streptozotocin-diabetes resulted in increased deposition of AGEs and increased oxidative stress in the serum and liver. Vitamin D supplementation may provide significant protection against oxidative stress-mediated vascular complications in diabetes.

Aortic Stiffness and Vitamin D are Independent Markers of Aortic Calcification in Patients with Peripheral Arterial Disease and in Healthy Subjects

OBJECTIVE Arterial stiffness is a significant determinant of cardiovascular risk and is related to vascular calcification. Vitamin D may regulate arterial calcification and has been associated with cardiovascular survival benefits. However, data about the relationship between arterial stiffness, aortic calcification and vitamin D levels in patients with peripheral arterial disease (PAD) and in healthy subjects are limited. We examined the potential association between aortic calcification, arterial stiffness and vitamin D levels in patients with symptomatic PAD and in healthy individuals. METHODS We studied 78 men with PAD (aged 63 ± 7 years) and 74 healthy men (aged 61 ± 10 years). Aortic pulse wave velocity (aPWV) was determined by applanation tonometry using the Sphygmocor device. Aortic calcification score (ACS) was quantified by computed tomography. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured using a radioimmune assay. RESULTS ACS (4.9(2.3-8.9) vs. 0.2(0.03-1.6) (cm³); p < 0.01), aPWV (9.8 ± 2.4 vs. 8.2 ± 1.6 (m s⁻¹; p < 0.01) and 25(OH)D (15.1 ± 5.4 vs. 19.0 ± 5.9 (ng ml⁻¹); p < 0.01) were different in the patients compared with the controls. In multivariate analysis, ACS was independently determined by 25(OH)D, aPWV, calcium and age in patients with PAD (R² = 0.49; p < 0.001) and by 25(OH)D, aPWV, cholesterol/high-density lipoprotein (HDL) and age in the control group (R² = 0.55; p < 0.001). Increased aPWV and lower levels of 25(OH)D were associated with decreased ankle-brachial pressure index (p = 0.03). CONCLUSION These results indicate that calcification of the aorta is independently associated with aortic stiffness and serum 25(OH)D level in patients with PAD and in healthy subjects. Aortic stiffness and abnormal vitamin D level may contribute to vascular calcification and are related to higher severity grade of atherosclerotic disease.

Augmentation index and carotid intima-media thickness are differently related to age, C-reactive protein and oxidized low-density lipoprotein

Objective Ageing, plasma circulating C-reactive protein (CRP), oxidized low-density lipoprotein (OxLDL) and homocysteine (Hcy) are associated with atherosclerosis. The aim of this study was to evaluate the relationship between age, inflammatory and oxidative stress-related markers with functional and structural changes of the arteries in asymptomatic persons. Methods CRP, OxLDL and Hcy were measured in 175 clinically healthy subjects, aged 40–70 years. Ultrasonography and pulse wave analysis were used to measure carotid intima–media thickness (IMT) and augmentation index (AIx). Results OxLDL was correlated with IMT (r = 0.24, P = 0.003), whereas CRP was correlated with AIx (r = 0.21, P = 0.005). No correlation was detected between Hcy and AIx or age-adjusted IMT. There was a significant association between AIx and age ≤50 years (r = 0.33; P = 0.001) and between IMT and age > 50 years (r = 0.40; P = 0.001). In stepwise regression analysis age, weight, white blood cell count, OxLDL, heart rate and timing of the reflected waveform adjusted for height were significantly and independently associated with IMT (R2 = 0.41; P < 0.001). At the same time, AIx as the dependent variable correlated positively with age, gender, CRP and mean arterial pressure, and negatively with heart rate, weight and height, in stepwise regression analysis (R2 = 0.63; P < 0.001). Conclusion The results of the present study showed that CRP, OxLDL, Hcy and age are not similarly related to AIx and IMT in asymptomatic persons. The results suggest that CRP and younger age are related to arterial stiffness, whereas OxLDL and older age become more important determinants of structural changes of the arteries in asymptomatic persons.

Inflammation and oxidative stress are associated differently with endothelial function and arterial stiffness in healthy subjects and in patients with atherosclerosis

Inflammation and oxidative stress (OxS) play key roles in atherogenesis; however, their causal relationship is not yet completely understood. Much attention has been given to the possibility that inflammation is a primary process of atherosclerosis and that OxS may be a by‐product of the inflammatory process. We hypothesized, accordingly, that chronic systemic inflammation affects endothelial vasomotor function in the subclinical condition, whereas oxidative modifications are more involved in the structural stiffening of the arteries in atherosclerosis. The aim of our study was to test this hypothesis. Endothelial function and arterial stiffness were assessed non‐invasively by pulse wave analysis, and blood/urinary samples were taken in 39 patients with peripheral arterial disease as well as in 34 controls. The patients showed significantly reduced endothelial function index (EFI) and increased augmentation index (AIx), as well as higher estimated aortic pulse wave velocity (PWV) and elevated values of the intercellular adhesion molecule‐1 (ICAM‐1), high sensitivity C‐reactive protein, myeloperoxidase and urinary 8‐iso‐prostaglandin F2a (F2‐IsoPs). There was an inverse association between EFI and ICAM‐1 (R = −0.44, p = 0.009) in the controls, but not in the patients. Augmentation index and estimated aortic PWV correlated with F2‐IsoPs only in the patients (R = 0.5, p = 0.001; R = −0.43, p = 0.006, respectively). After controlling for potential confounders, these associations remained significant. The study demonstrates that impairment of endothelial vasomotor capacity is affected by degree of inflammation in the subclinical condition, whereas arterial stiffening is determined by level of oxidative modifications in atherosclerosis.

Effect of vitamin D on aortic remodeling in streptozotocin-induced diabetes

BackgroundDiabetes mellitus is associated with micro- and macrovascular complications and increased cardiovascular risk. Elevated levels of serum asymmetric dimethylarginine (ADMA) may be responsible for endothelial dysfunction associated with diabetes-induced vascular impairment. Vitamin D may have potential protective effects against arterial stiffening. This study aimed to examine both the effects of diabetes on the functional/structural properties of the aorta and the endothelial function and the effects of vitamin D supplementation.MethodsMale Wistar rats (n = 30) were randomly assigned to control untreated, diabetic untreated, and diabetic + cholecalciferol groups. Diabetes was induced by intraperitoneal injection of streptozotocin, followed by oral administration of cholecalciferol (500 IU/kg) for 10 weeks in the treatment group. Aortic pulse wave velocity (PWV) was recorded over a mean arterial pressure (MAP) range of 50 to 200 mmHg using a dual pressure sensor catheter. Intravenous infusion of phenylephrine and nitroglycerine was used to increase and decrease MAP, respectively. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured using a radioimmune assay. ADMA levels in serum were measured by enzyme-linked immunoassay. Aortic samples were collected for histomorphometrical analysis.ResultsPWV up to MAP 170 mmHg did not reveal any significant differences between all groups, but in diabetic rats, PWV was significantly elevated across MAP range between 170 and 200 mmHg. Isobaric PWV was similar between the treated and untreated diabetic groups, despite significant differences in the levels of serum 25(OH)D (493 ± 125 nmol/L vs 108 ± 38 nmol/L, respectively). Serum levels of ADMA were similarly increased in the treated and untreated diabetic groups, compared to the control group. The concentration and integrity of the elastic lamellae in the medial layer of the aorta was impaired in untreated diabetic rats and improved by vitamin D supplementation.ConclusionPWV profile determined under isobaric conditions demonstrated differential effects of uncontrolled diabetes on aortic stiffness. Diabetes was also associated with elevated serum levels of ADMA. Vitamin D supplementation did not improve the functional indices of aortic stiffness or endothelial function, but prevented the fragmentation of elastic fibers in the aortic media.

Nebivolol and metoprolol: long-term effects on inflammation and oxidative stress in essential hypertension

Abstract Arterial hypertension is characterised by increased oxidative stress and inflammation, which are associated with further cardiovascular risk. The aim of our study was to investigate the long-term effects of nebivolol and metoprolol succinate on oxidative stress, and on inflammatory and pro-inflammatory markers in patients with hypertension. Eighty patients with never-treated mild-to-moderate essential hypertension, aged 30–65 years, were randomised to a 5 mg daily dose of nebivolol or a 50–100 mg daily dose of metoprolol succinate. Brachial blood pressure, plasma oxidized LDL (oxLDL), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), fibrinogen, intercellular adhesion molecule-1 (ICAM-1), asymmetric dimethylarginine (ADMA), and urine 8-isoprostane levels were measured before and after 1 year of treatment. Nebivolol and metoprolol reduced equally significantly brachial blood pressure. The oxLDL was significantly reduced in both groups (p < 0.01 and for both drugs), but only nebivolol reduced 8-isoprostanes (p = 0.01). In the metoprolol group, change in oxLDL levels correlated with change in systolic blood pressure (r = 0.45; p < 0.01) and pulse pressure (r = 0.47; p < 0.01). Both metoprolol and nebivolol reduced ICAM-1 (p < 0.01). There was no change in IL-6, hsCRP, fibrinogen, or ADMA levels in either group. These data suggest that in long-term antihypertensive treatment both the cardioselective beta blocker metoprolol succinate and the vasodilating beta blocker nebivolol have inflammation-related effects but only nebivolol has a favourable blood pressure-independent effect on oxidative stress.

Association of Osteoprotegerin With Aortic Stiffness in Patients With Symptomatic Peripheral Artery Disease and in Healthy Subjects

BACKGROUND Arterial stiffening is an independent predictor for cardiovascular mortality. Preliminary studies have shown that arterial calcification may have an impact on increased vascular stiffness. However, there are limited data about the role of calcification inhibitor osteoprotegerin (OPG) as an independent predictor for arterial stiffness in patients with peripheral arterial disease (PAD) and in healthy subjects. The aim of this study was to evaluate the association between OPG and arterial stiffness parameters in patients with PAD and in healthy subjects. METHODS We studied 69 men with PAD (age 63 + or - 7 years) and 68 healthy subjects (age 54 + or - 8 years). Serum OPG and oxidized low-density lipoprotein (oxLDL) were measured using the enzyme-linked immunosorbent assay method. Radial and aortic pulse wave velocity (aPWV) and augmentation index (AIx) were determined by applanation tonometry. RESULTS The OPG (5.4 + or - 1.7 vs. 4.4 + or - 1.1 pmol/l; P < 0.001) and aPWV (10.1 + or - 2.5 vs. 7.6 + or - 1.6 m/s; P < 0.001) were different for the patients and for the controls. There was a linear relationship between OPG and aPWV in patients with PAD (R = 0.37; P = 0.003) and in healthy individuals (R = 0.40; P = 0.001). In multiple regression models after adjustment for potential confounders, OPG was independently associated with aPWV in the patients (R(2) = 0.47; P < 0.0001) and in the controls (R(2) = 0.44; P < 0.0001). The AIx or radial PWV was not correlated with OPG for either group. CONCLUSION The independent association between OPG and aPWV in patients with PAD and in controls suggests that the calcification inhibitor OPG may influence aortic stiffening in atherosclerosis and in clinically healthy subjects.