Nikolaos Ioakeimidis

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.

Prediction of Cardiovascular Events and All-Cause Mortality With Brachial-Ankle Elasticity Index A Systematic Review and Meta-Analysis

Brachial-ankle elasticity index (baEI; also known as brachial-ankle pulse wave velocity) has been proposed as a surrogate end point for cardiovascular disease. We performed a meta-analysis of longitudinal cohort studies for determining the ability of baEI to predict risk of cardiovascular events and all-cause mortality and dissecting factors influencing this predictive ability. Multiple online databases, reference lists from retrieved articles, and abstracts from international cardiovascular conventions were searched until April 2012. Longitudinal cohort studies that reported associations of baEI with clinical risk were included. Of the 18 studies included (8169 participants; mean follow-up, 3.6 years), 15 reported results on total cardiovascular events (5544 individuals), 7 on cardiovascular mortality (2274 individuals), and 9 on all-cause mortality (5097 individuals). The pooled relative risks for total cardiovascular events, cardiovascular mortality, and all-cause mortality were 2.95 (95% CI, 1.63–5.33), 5.36 (95% CI, 2.17–13.27), and 2.45 (95% CI, 1.56–3.86), respectively, for subjects with high versus low baEI (all P<0.001). An increase in baEI by 1 m/s corresponded with an increase of 12%, 13%, and 6% in total cardiovascular events, cardiovascular mortality, and all-cause mortality, respectively. We conclude that baEI is associated with increased risk of total cardiovascular events and all-cause mortality. Issues such as expansion of data to non-Asian populations, validation of path length estimation, determination of reference values, and prospective comparison with carotid-femoral pulse wave velocity remain to be resolved.

The triad: erectile dysfunction--endothelial dysfunction--cardiovascular disease.

Endothelial dysfunction is an important process in the development of atherosclerotic cardiovascular disease, while it is also a major pathophysiological mechanism underlying vasculogenic erectile dysfunction (ED). Expectedly, these two prevalent disorders are linked also at the clinical level: ED is common in patients with overt and silent coronary artery disease, while ED is increasingly being regarded as the early clinical manifestation of a generalized vascular disease and carries an independent risk for future cardiovascular events. The emerging awareness of ED as a barometer for cardiovascular disease offers a unique opportunity to enhance preventive vascular health in men. Lifestyle and risk factor modification, as well as pharmacologic therapy (both phosphodiesterase type-5 inhibitors and non-ED-targeting drugs), appear to confer additional benefit both in terms of ED treatment and overall cardiovascular risk; this benefit may be related, at least partly, to the improvement of endothelial function and anti-inflammatory effects. The present review identifies pathophysiologic links between endothelial dysfunction, ED and coronary artery disease, presents methodological aspects regarding penile and systemic endothelial function, and discusses the clinical implications in terms of diagnosis of ED, assessment of patient risk, and treatment.

Arterial function and intima-media thickness in hypertensive patients with erectile dysfunction.

Objective Erectile dysfunction is a predictor of cardiovascular risk with high prevalence in hypertensive men. We investigated whether erectile dysfunction is related to arterial structure and function in hypertensive patients. Methods We evaluated arterial structural and functional characteristics and measured systemic endothelial/inflammatory markers in 52 hypertensive men with vasculogenic erectile dysfunction and in 34 hypertensive men with normal erectile function, matched for age, blood pressure, risk factors and treatment. Results Hypertensive patients with erectile dysfunction had higher common carotid intima-media thickness (0.95 ± 0.19 vs. 0.83 ± 0.18 mm, P = 0.003) and carotid–femoral pulse-wave velocity (8.89 ± 1.38 vs. 8.11 ± 1.10 m/s, P = 0.007), lower flow-mediated dilation of the brachial artery (absolute values of 2.96 ± 1.64 vs. 4.07 ± 1.68%, P = 0.003) and a higher level of the systemic endothelial dysfunction marker asymmetric dimethylarginine (0.67 ± 0.13 vs. 0.57 ± 0.16 μmol/l, P = 0.003), and the inflammatory markers high-sensitivity C-reactive protein [2.03 (1.16–2.89) vs. 1.23 (0.67–1.90) mg/l, P = 0.029] and interleukin-6 (4.13 ± 2.38 vs. 2.77 ± 1.92 pg/ml, P = 0.011). Multivariable analysis adjusting for age, mean pressure, other risk factors and treatment showed independent associations between erectile dysfunction and parameters of arterial structure and function. In the erectile dysfunction group, there were no significant relationships between the severity of erectile dysfunction (as expressed by the Sexual Health Inventory for Men score) and the above arterial indices and level of circulating markers (all P = NS). Conclusion In hypertensive men, the presence but not the severity of vasculogenic erectile dysfunction is associated with subclinical atherosclerosis, impairment of arterial function and systemic endothelial and inflammatory activation.

Acute Mental Stress Has a Prolonged Unfavorable Effect on Arterial Stiffness and Wave Reflections

Objective: Large-artery stiffness and arterial wave reflections have been identified as independent markers and prognosticators of cardiovascular risk. Mental stress is a novel risk factor for coronary artery disease and has been associated with left ventricular dysfunction, myocardial ischemia and infarction, and sudden cardiac death. The purpose of this study was to assess the effect of acute mental stress on aortic stiffness and wave reflections. Methods: The effect of a mental arithmetic test was assessed in 19 healthy individuals using a randomized, sham-procedure-controlled, crossover design. Carotid-femoral pulse wave velocity and augmentation index were measured as indices of aortic stiffness and wave reflections, respectively. Results: Mental stress induced a sustained increase in central systolic and pulse pressure throughout the whole study (systolic: by 7.5 mm Hg, p < .05; pulse: by 5.7 mm Hg, p < .01). The increase in peripheral systolic and pulse pressure was not significant throughout the study, but only when their peak values were compared with baseline (systolic: by 6.2 mm Hg, peak at 0 minutes; pulse: by 6.6 mm Hg, peak at 5 minutes, p < .05 for both). There was a sustained increase in pulse wave velocity (by 0.57 m/s, p < .005) throughout the study denoting a sustained increase in aortic stiffness. Similarly, augmentation index showed a sustained increase with mental stress (by 6.16%, p < .05) denoting increased wave reflections from the periphery. Conclusion: Acute mental stress results in a prolonged increase in aortic stiffness and wave reflections. Given the important pathophysiologic and prognostic role of these parameters, our results provide important mechanistic links between acute mental stress and increased cardiovascular risk. Tr = timing of the reflected wave; ANOVA = analysis of variance.

Cardiovascular effects of phosphodiesterase type 5 inhibitors.

INTRODUCTION Phosphodiesterase type 5 (PDE5) inhibitors are widely used as first-line therapy for erectile dysfunction (ED). Their efficacy and safety combined with an increasing understanding of cyclic guanosine monophosphate (cGMP)-regulated mechanisms have triggered a number of attempts to determine their effects on the cardiovascular system and their potential benefits in cardiovascular conditions. AIM To review and discuss recent findings regarding the cardiovascular effects of PDE5 inhibitors and to highlight current and future clinical applications beyond ED. MAIN OUTCOME MEASURES Results of preclinical and clinical studies evaluating the cardiovascular effects of PDE5 inhibitors are analyzed and critically put into perspective. METHODS Extensive PubMed literature search reviewing relevant data on effects and mechanisms of PDE5 inhibitors on the cardiovascular system. RESULTS In recent years, extensive but very heterogeneous preclinical and clinical evidence has been reported. PDE5 inhibition has proven collateral benefits for a multitude of risk factors or diseases associated with or accompanying ED. However, these agents appear to have the potential of expanding their indications. To date, PDE5 inhibition has been shown to be effective for the treatment of idiopathic pulmonary artery hypertension, and sildenafil is approved for this indication. Importantly, accumulating data show that the therapeutic potential extends to the myocardium, the coronary and peripheral arteries, subliclinical inflammation, oxidative stress, thrombosis, neurological recovery, and pathways of fibrosis. Thus, the spectrum of patients who may benefit has expanded to include, for instance, patients with heart failure or coronary artery disease. CONCLUSIONS PDE5 inhibitors are an exciting class of drugs with pleiotropic effects. Current or future PDE5 inhibitors are a conceptually attractive therapeutic strategy with potential clinical applications in a variety of cardiovascular conditions.

Amino-terminal pro-C-type natriuretic peptide is associated with arterial stiffness, endothelial function and early atherosclerosis.

OBJECTIVE C-type natriuretic peptide (CNP) is a paracrine molecule with effects on endothelial integrity, vascular tone and atherosclerotic process. Arterial stiffness, wave reflections, endothelial dysfunction and carotid intima-media thickness (IMT) are predictors of cardiovascular events. We investigated whether CNP is related to arterial structure and function in men. METHODS We evaluated arterial structural and functional characteristics in 117 consecutive men (mean age 57.3 + or - 9.2 years), with and without cardiovascular risk factors, who had no established cardiovascular disease. Arterial elastic properties were evaluated with carotid-femoral pulse wave velocity (PWV), wave reflections with augmentation index (AIx), endothelial function with flow-mediated dilatation of the brachial artery (FMD) and early atherosclerosis with carotid IMT. Amino-terminal proCNP (NT-proCNP) was assessed in venous blood. RESULTS The number of cardiovascular risk factors was inversely related to levels of NT-proCNP (P<0.01) and there was a progressive increase in Framingham risk score according to decreasing tertiles of NT-proCNP (P<0.001). In multivariable regression analysis NT-proCNP exhibited significant negative associations with PWV and IMT and positive association with FMD (all P<0.05) that were independent of age, blood pressure, smoking habits, body mass index, blood glucose, total triglycerides, low-density lipoprotein and endothelin-1 or high-sensitivity C-reactive protein. There was no relation between NT-proCNP and AIx. CONCLUSION The present study is the first to demonstrate in a global arterial approach relationship between CNP and functional and early structural arterial changes. These findings elucidate pathophysiological links and may have important clinical implications for the estimation of cardiovascular risk in men.

Relationship of Asymmetric Dimethylarginine With Penile Doppler Ultrasound Parameters in Men with Vasculogenic Erectile Dysfunction

BACKGROUND Asymmetric dimethylarginine (ADMA), a selective endogenous nitric oxide synthase inhibitor, is elevated in many conditions associated with erectile dysfunction (ED), such as hypertension, diabetes, hyperlipidemia, and renal failure; it is also increased in men with coronary artery disease and ED. The dynamic penile colour Doppler ultrasound is considered the gold standard for the evaluation of penile vascular damage. OBJECTIVE We investigated whether the extent of ultrasonographically documented penile vascular disease is associated with higher ADMA levels. DESIGN, SETTING, AND PARTICIPANTS One hundred four consecutive ED patients (mean age: 56 ± 9 yr) without manifest cardiovascular/atherosclerotic disease and 31 subjects with normal erectile function matched for age and traditional risk factors were studied. MEASUREMENTS We evaluated penile dynamic colour Doppler parameters of arterial insufficiency (peak systolic velocity) and veno-occlusive dysfunction (end diastolic velocity) and measured systemic inflammatory markers/mediators. RESULTS AND LIMITATIONS Compared to men without ED, ED patients had significantly higher ADMA levels (p<0.001). ADMA was significantly increased in patients with severe arterial insufficiency (PSV<25 cm/s) compared to subjects with borderline insufficiency and men with normal penile arterial function (p<0.001, by analysis of variance). Multivariable analysis adjusting for age, mean pressure, other risk factors, high-sensitivity C-reactive protein, testosterone, and treatment showed independent inverse association between ADMA level and peak systolic velocity (p<0.01). The combination of higher ADMA level with arterial insufficiency showed greater impact on 10-yr risk of a cardiovascular event compared to either parameter alone. CONCLUSIONS ADMA level is independently associated with ultrasonographically documented poor penile arterial inflow. This finding underlines the important role of ADMA as a marker of penile arterial damage and implies a contribution of this compound to the pathophysiology of generalised vascular disease associated with ED.

Electronic Cigarette Smoking Increases Aortic Stiffness and Blood Pressure in Young Smokers

Smoking increases aortic stiffness and blood pressure (BP) [(1)][1], which are both important predictors of cardiovascular risk and all-cause mortality [(2,3)][2]. Electronic cigarettes (EC) simulate tobacco cigarettes (TC) and have been advocated as a less harmful alternative [(4)][3]. The effect

PDE5 Inhibitors in Non-Urological Conditions

Phosphodiesterase type-5 (PDE5) inhibitors are widely used as first-line therapy for erectile dysfunction (ED). Their efficacy and safety combined with an increasing understanding of cyclic guanosine monophosphate (cGMP)-regulated mechanisms, have triggered a number of attempts to determine their effects and potential benefits in non-urological conditions. In recent years, extensive and diverse preclinical and clinical evidence has been made available. PDE5 inhibition has shown collateral benefits for a multitude of risk factors or diseases associated with, or accompanying ED. To date, PDE5 inhibition has been shown to be effective for the treatment of idiopathic pulmonary arterial hypertension and both sildenafil and tadalafil are approved for this indication. However, PDE5 inhibitors appear to have the potential of further expanding their indications. Importantly, accumulating data show that the therapeutic potential extends to the cardiovascular, gastrointestinal, cutaneous and nervous system and that these agents may be beneficial in a multitude of conditions such as Raynauds phenomenon, heart failure, essential hypertension and stroke. PDE5 inhibitors are a conceptually attractive therapeutic class of agents with pleiotropic effects. The present review discusses recent findings regarding the effects of PDE5 inhibitors on non-urological conditions and highlights current and future clinical applications beyond ED.