I. Dima

Acute Systemic Inflammation Increases Arterial Stiffness and Decreases Wave Reflections in Healthy Individuals

Background— Aortic stiffness is a marker of cardiovascular disease and an independent predictor of cardiovascular risk. Although an association between inflammatory markers and increased arterial stiffness has been suggested, the causative relationship between inflammation and arterial stiffness has not been investigated. Methods and Results— One hundred healthy individuals were studied according to a randomized, double-blind, sham procedure-controlled design. Each substudy consisted of 2 treatment arms, 1 with Salmonella typhi vaccination and 1 with sham vaccination. Vaccination produced a significant (P<0.01) increase in pulse wave velocity (at 8 hours by 0.43 m/s), denoting an increase in aortic stiffness. Wave reflections were reduced significantly (P<0.01) by vaccination (decrease in augmentation index of 5.0% at 8 hours and 2.5% at 32 hours) as a result of peripheral vasodilatation. These effects were associated with significant increases in inflammatory markers such as high-sensitivity C-reactive protein (P<0.001), high-sensitivity interleukin-6 (P<0.001), and matrix metalloproteinase-9 (P<0.01). With aspirin pretreatment (1200 mg PO), neither pulse wave velocity nor augmentation index changed significantly after vaccination (increase of 0.11 m/s and 0.4%, respectively; P=NS for both). Conclusions— This is the first study to show through a cause-and-effect relationship that acute systemic inflammation leads to deterioration of large-artery stiffness and to a decrease in wave reflections. These findings have important implications, given the importance of aortic stiffness for cardiovascular function and risk and the potential of therapeutic interventions with antiinflammatory properties.

Acute Effect of Black and Green Tea on Aortic Stiffness and Wave Reflections

Objective: While most studies have shown an inverse relation between tea consumption and cardiovascular risk, other studies have shown opposite results. Aortic stiffness and wave reflections are markers of cardiovascular disease and prognosticators of cardiovascular risk. Methods: The acute effect of black and green tea on aortic stiffness and wave reflections was assessed in 29 healthy volunteers in a randomized, single-blind, sham-procedure controlled, cross-over design. In the black tea sub-study, 16 subjects received 6 gm of tea, caffeine (175 mg), or hot water in 3 different sessions. In the green tea sub-study, 13 subjects received 6 gm of tea, caffeine (125 mg), or hot water. Carotid-femoral pulse wave velocity and wave reflection indices were measured at baseline and for 3 hours after consumption. Results: Black tea increased pulse wave velocity during the first 90 min (increase by 0.49 m/sec, P < 0.05), showing a rapid return towards baseline values thereafter (P = 0.07 for the whole study period); in contrast, green tea had no effect. Both black and green tea increased augmentation index (by 5.0% and by 6.6%, P < 0.01 and P < 0.001, respectively) throughout the study. These changes were less than the respective changes produced by caffeine. Both black and green tea had a significant pressor effect. No change in oxidant status was found with both types of tea. Conclusions: Both black and green tea increases acutely wave reflections and only black tea increases aortic stiffness. Tea flavonoids may play a role in the attenuation of the effects of caffeine contained in tea.

Association of Serum Uric Acid Level With Aortic Stiffness and Arterial Wave Reflections in Newly Diagnosed, Never-Treated Hypertension

BACKGROUND Serum uric acid (UA) plays a key role in the development and progression of hypertension. We investigated the association of UA levels and indices of arterial function in a cohort of newly diagnosed, never-treated hypertensive subjects. METHODS One thousand two hundred and twenty-five patients with a new diagnosis of mild to moderate arterial hypertension for which they had never received treatment were enrolled in the study (mean age 52.9 years, 728 men). Serum UA, carotid-femoral pulse-wave velocity (cfPWV), an index of aortic stiffness and augmentation index (AIx), a composite marker of wave reflections and arterial stiffness were measured. RESULTS In univariable analysis, UA levels correlated with cfPWV (r = 0.23, P < 0.001) and AIx (r = -0.24, P < 0.001). In multiple linear regression analysis, an independent positive association of cfPWV with UA levels was observed after adjusting for confounders (standardized regression coefficient β = 0.169, P < 0.001, adjusted R² = 0.402), indicating an increase in aortic stiffness with higher values of UA. In contrast, an independent negative association of AIx with UA levels was observed after adjusting for confounders (standardized regression coefficient β = -0.064, P = 0.011, adjusted R² = 0.557), indicating a decrease in wave reflections with higher values of UA. In gender-specific analyses, UA positively correlated with cfPWV in both genders, whereas a negative correlation with AIx existed only in females. CONCLUSIONS Serum UA levels are independently associated with aortic stiffening and wave reflections in never-treated hypertensives. Future studies are warranted in order to explore its exact role on arterial function in the hypertensive setting.

The effect of heart rate on wave reflections may be determined by the level of aortic stiffness: clinical and technical implications.

BACKGROUND Augmentation Index (AIx) is related to cardiovascular diseases, risk, and mortality. AIx is associated with heart rate but the effect of aortic stiffness on this relationship has not been studied. The purpose of our study was to investigate the relationship between AIx and heart rate at different aortic stiffness levels. METHODS The study consisted of 425 normotensive and untreated hypertensive subjects. Wave reflections and pulse-wave velocity (PWV) were determined by the Sphygmocor and the Complior systems, respectively. RESULTS AIx was independently associated with heart rate, age, gender, height, mean blood pressure (BP) and the effective reflection site distance (ERD). The population was divided into three groups of those with different PWV levels (tertiles). The regression lines for AIx with heart rate differed significantly between the 3rd and the other two tertiles of PWV (P = 0.039 for slopes and P = 0.002 for intercepts). This difference remained significant even after adjustment for age, gender, height, mean BP, and distance of wave reflections. CONCLUSIONS A significantly stronger correlation of AIx with heart rate was observed in subjects with higher levels of aortic stiffness as compared to those with lower levels; namely, the same increase in the heart rate between subjects, induced a greater decrease in the AIx at higher compared to lower PWV levels. The correction of AIx for heart rate should be reconsidered based on the aortic stiffness level. This finding has implications for interventional studies that aim to improve central hemodynamics but simultaneously affect heart rate. Further studies that show acute modifications of heart rate at different arterial stiffness levels are required to support these findings.

The effect of p22 phox −930A/G, A640G and C242T polymorphisms of NADPH oxidase on peripheral and central pressures in healthy, normotensive individuals

The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase produces superoxide, thus regulating redox state in the vessel wall. Three single-nucleotide polymorphisms (SNPs; −930A/G, A640G and C242T) of the p22phox subunit have been associated with hypertension; however, their role in peripheral and central pressures in normotensive individuals has not been addressed. A total of 210 healthy, normotensive individuals were studied. Genotypes for the −930A/G, A640G and C242T polymorphisms were determined by polymerase chain reaction. Peripheral pressures were measured by mercury sphygmomanometer and aortic pressures by a validated device using applanation tonometry. Both peripheral and central pressures differed across −930A/G genotypes. G allele carriers showed higher levels of peripheral systolic blood pressure (PSBP; AA: 113±12, GG/AG: 119±12 mm Hg; P<0.01) and peripheral diastolic blood pressure (AA: 70±9, GG/AG: 73±10 mm Hg; P<0.05). Regarding central pressures, AA homozygotes had lower central systolic blood pressure (CSBP; AA: 103±12, GG/AG: 108±12 mm Hg; P<0.01) and central diastolic blood pressure (AA: 71±9, GG/AG: 74±10 mm Hg; P<0.05). In multiple linear regression analysis, presence of the G allele (AG or GG) independently predicted CSBP. Blood pressure levels did not differ across A640G and C242T genotypes. The −930A/G polymorphism of p22phox is a determinant of peripheral and central pressures in normotensive individuals. The G allele is associated with higher blood pressure in the brachial artery, as well as in the aorta. These findings further elucidate the role of this polymorphism in the regulation of blood pressure. In contrast, the A640G and C242T SNPs do not influence peripheral and central pressures in normotensives.

Association of Arterial Stiffness With the Angiotensin-Converting Enzyme Gene Polymorphism in Healthy Individuals

BACKGROUND Arterial stiffness is an important determinant of cardiovascular morbidity and mortality. The I/D polymorphism of angiotensin-converting enzyme (ACE) gene is associated with cardiovascular disease. However, the relationship between ACE polymorphism, arterial stiffness, and wave reflections in healthy, low-risk population has not been defined yet. METHODS The study included 282 apparently healthy, low-risk individuals (mean age 39.7 +/- 8.9 years, 178 males). Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness, while wave reflections were assessed by augmentation index (AIx) of the central pressure waveform. I/D polymorphism of the ACE gene was determined in all subjects for the prevalence of the DD, ID, and II genotype (39, 44, and 17%, respectively). C-reactive protein (CRP) levels were determined as a marker of chronic, subclinical inflammation. RESULTS After adjustment for potential confounding factors, presence of D allele was associated with lower values of PWV compared to II genotype (P < 0.05), implying lower aortic stiffness for D allele carriers. There was no association between ACE genotype and wave reflections or peripheral and central systolic pressures. CONCLUSIONS In apparently healthy individuals, D allele is associated with lower aortic stiffness, whereas there is no association of the ACE polymorphism with wave reflections. This finding provides new insights into the possible links between ACE gene, regulation of large artery stiffness, and has implications for cardiovascular risk.

Triglyceride level is associated with wave reflections and arterial stiffness in apparently healthy middle-aged men

Objective: To investigate the relationship of arterial stiffness and wave reflections, which are predictors of cardiovascular risk, with serum triglyceride level in healthy adults. Design: Cross-sectional study at the University Department of Cardiology. 213 healthy individuals (141 men and 72 premenopausal women) not taking any medication and without known cardiovascular disease and risk factors, except for smoking. Main outcome measures: Central (aortic) augmentation index (AIx, a composite measure of arterial stiffness and wave reflections), fasting lipid profile (including triglycerides) and 10-year Framingham Risk Score (FRS). Results: Compared with women, men had higher serum triglyceride level (median (interquartile range) (89 (67–117) vs 73 (54–96) mg/dl, p<0.01) and lower AIx (17.7 (1.0) vs 26.3 (1.4), p<0.001). In both genders, serum triglyceride levels were significantly associated with FRS (men: r = 0.43, p<0.001; women: r = 0.37, p<0.01) and AIx (men: r = 0.21, p<0.05; women: r = 0.26, p<0.05). In men, multivariate linear regression analysis showed an association between triglyceride level and AIx (standardised β coefficient = 0.19, p = 0.009), independent of age, blood pressure, heart rate, height, weight, smoking habits, total cholesterol and HDL-cholesterol levels. On the other hand, in women, the unadjusted correlation between triglyceride level and AIx was largely explained when the abovementioned confounders were taken into account (β = −0.016, p = 0.86). Conclusion: In healthy men, serum triglyceride levels are associated with indices of arterial stiffness and wave reflections, which are important determinants of cardiovascular function and risk. The role of triglycerides in the vascular function of women warrants further investigation.

Arterial stiffening and systemic endothelial activation induced by smoking: The role of COX-1 and COX-2

BACKGROUND Arterial stiffness is an established predictor of cardiovascular risk. We explored the effects of acute smoking on arterial stiffness, systemic inflammation and endothelial activation in chronic smokers and the contribution of cyclooxygenases-1 and 2 (COX-1 and COX-2). METHODS AND RESULTS In a randomized, double-blind, cross-over study, we investigated in 28 young smokers the vascular and systemic effects of smoking one cigarette, 3h after receiving 1000 mg of aspirin (a non-selective COX-1 and COX-2 inhibitor) or placebo (aspirin substudy), or 200 mg of celecoxib (a selective COX-2 inhibitor) or placebo (celecoxib substudy). Smoking increased carotid-femoral pulse wave velocity (PWV, a marker of aortic stiffness), indicating an adverse effect on arterial elastic properties. Similarly, circulating levels of asymmetric dimethylarginine (ADMA) were increased after smoking. Aspirin fully prevented the smoking-induced increase of PWV after smoking. In contrast, celecoxib only partially prevented the smoking-induced increase of PWV. Both aspirin and celecoxib prevented to a similar extent the increase of ADMA levels after smoking. CONCLUSIONS Smoking one cigarette is associated with a deterioration of arterial stiffness and with systemic endothelial activation in chronic smokers. Both COX-1 and COX-2, but primarily COX-1, mediate these unfavorable effects of smoking.

Polymorphisms of Inflammatory Markers/Mediators and Arterial Stiffness

To the Editor: We read with interest the article by Schumacher et al,1 which sheds new light into the still-controversial issue of the contribution of C-reactive protein (CRP) in the pathogenesis of cardiovascular disease. To this end, the authors tested the causality of CRP in arterial stiffness using genetically elevated CRP levels. However, such a causal relationship, through the mendelian randomization assumption, could not be established. Although CRP levels were associated with CRP genes and aortic pulse wave velocity (aPWV), none of the CRP genetic variants were associated individually or in combination with aPWV. These findings are supported by our previous study that …

A Hypertensive Response to Exercise Is Prominent in Patients With Obstructive Sleep Apnea and Hypertension: A Controlled Study

Blood pressure (BP) behavior during exercise is not clear in hypertensive patients with obstructive sleep apnea (OSA). The authors studied 57 men with newly diagnosed essential hypertension and untreated OSA (apnea‐hypopnea index [AHI] ≥5) but without daytime sleepiness (Epworth Sleepiness Scale score ≤10), and an equal number of hypertensive controls without OSA matched for age, body mass index, and office systolic BP. All patients underwent ambulatory BP measurements, transthoracic echocardiography, and exercise treadmill testing according to the Bruce protocol. A hypertensive response to exercise (HRE) was defined as peak systolic BP ≥210 mm Hg. Patients with OSA and control patients had similar ambulatory and resting BP, ejection fraction, and left ventricular mass. Peak systolic BP was significantly higher in patients with OSA (197.6±25.6 mm Hg vs 187.8±23.6 mm Hg; P=.03), while peak diastolic BP and heart rate did not differ between groups. Furthermore, an HRE was more prevalent in patients with OSA (44% vs 19%; P=.009). Multiple logistic regression revealed that an HRE is independently predicted by both the logAHI and minimum oxygen saturation during sleep (odds ratio, 3.94; confidence interval, 1.69–9.18; P=.001 and odds ratio, 0.94; confidence interval, 0.89–0.99; P=.02, respectively). Exaggerated BP response is more prevalent in nonsleepy hypertensives with OSA compared with their nonapneic counterparts. This finding may have distinct diagnostic and prognostic implications.