Aortic stiffness and systemic inflammation changes predict clinical response to intravitreal anti-vascular endothelial growth factor therapy in patients with age-related macular degeneration.

Aortic stiffness and systemic inflammation are predictors of cardiovascular risk. Anti-vascular endothelial growth factor agents (anti-VEGF), injected intravitreally, can reverse the course of exudate age-related macular degeneration (AMD). We sought to investigate the association of changes in aortic stiffness and systemic inflammation with response to anti-VEGF therapy. 54 patients (mean age: 76 ± 10 years) with AMD received two consecutive monthly intravitreal injections of ranibizumab (0.5 mg). The primary outcome measure was change in carotid-femoral pulse wave velocity (PWV) from baseline to 1 month after the second injection. Secondary endpoint was the change in serum high sensitivity interleukin-6 (hsIL-6) levels. Ranibizumab caused a decrease of PWV after the first (by 0.36 ± 1.4 m/s) and the second injection (by 0.31 ± 1.4 m/s) and remained decreased 1 month after the second injection (overall P < 0.05). PWV decreased significantly in good responders (according to clinical criteria and fundus findings, P = 0.004), whereas it increased numerically in poor responders (P = 0.21) over the study period. In responders, hsIL-6 decreased after the first injection and remained decreased 1 month after the second injection (by 0.63 ± 0.35 pg/ml, overall P = 0.02). PWV (P = 0.005) and hsIL-6 (P = 0.042) were independent predictors of improvement after adjusting for age and presence of hypertension and diabetes. The decrease in PWV through the whole study period was positively correlated with the reduction in hsIL-6 (r = 0.36, P < 0.01). Intravitreal ranibizumab injections lead to a decrease in PWV and hsIL-6. Both parameters predict clinical improvement and may aid to improving treatment targeting and hence therapeutic outcome in patients with AMD.

Effects of Chemotherapy on Aortic 18-Fluorodeoxyglucose Uptake in Patients With Hodgkin and Non-Hodgkin Lymphoma.

Background: Despite advances in the treatment of oncology patients, therapy-related side effects may lead to premature morbidity. Inflammatory activation that has been linked to cardiovascular disease is crucial for the pathogenesis of both Hodgkin (HL) and non-Hodgkin lymphoma (NHL). Objectives: The purpose of this study was to assess the vascular effects of chemotherapy in patients with HL and NHL by positron emission tomography/computed tomography with 18-fluorodeoxyglucose (18-FDG PET/CT) and to investigate interactions with systemic inflammation as assessed by circulating inflammatory markers. Methods: Between July 2015 and July 2019, 65 consecutive patients (mean age 56 ± 17.78 years) with confirmed diagnosis of either HL (n = 33) or NHL (n = 32) were prospectively studied. PET/CT imaging was performed at baseline, at an interim phase, and after first-line treatment. Aortic FDG uptake was assessed by measuring global aortic target-to-background ratio (GLA-TBR). Serum biomarkers interleukin (IL)-6 and IL-1b were measured at each phase. Results: Patients with HL demonstrated significant reduction in aortic TBR after first-line treatment (median GLA-TBR baseline: 1.98, median GLA-TBR third scan: 1.75, median difference = -0.20, 95% CI: -0.07 to -0.33, P = 0.006), which remained significant after adjustment for confounders (adj. R2 of model = 0.53). In contrast, patients with NHL did not demonstrate a significant aortic inflammation response (P = 0.306). Furthermore, patients with HL demonstrated a significant reduction in IL-6 (P = 0.048) and IL-1b (P = 0.045), whereas patients with NHL did not demonstrate significant reduction in IL-6 (P = 0.085) and IL-1b levels (P = 0.476). Conclusions: Aortic inflammation, as assessed by 18-FDG PET/CT, is reduced in HL patients after first-line treatment but not in NHL patients. These findings imply that different pathophysiological pathways and different therapies might affect the arterial bed in different ways for patients with lymphoma.

The cardiovascular burden of light smoking.

The assumption that light cigarette smoking, meaning smoking one to five cigarettes per day, is not so harmful has been dissipated by several studies. Regardless of the quantity of tobacco cigarettes, smoking remains a leading risk factor for the development and progression of cardiovascular diseases. Smoke is a mixture of several toxic chemicals, such as nicotine, carbon monoxide, and oxidants, implicated in the pathogenesis of cardiovascular and pulmonary diseases. Despite anti-smoking campaigns, a misconception concerning "safe smoking" still exists. The purpose of this literature review is to highlight the deleterious effect of light cigarette smoking and claim the consensus that there is no safe smoking.

Update of the position paper on arterial hypertension and erectile dysfunction.

: Sexual health is an integral part of overall health, and an active and healthy sexual life is an essential aspect of a good life quality. Cardiovascular disease and sexual health share common risk factors (arterial hypertension, diabetes mellitus, dyslipidemia, obesity, and smoking) and common mediating mechanisms (endothelial dysfunction, subclinical inflammation, and atherosclerosis). This generated a shift of thinking about the pathophysiology and subsequently the management of sexual dysfunction. The introduction of phosphodiesterase type 5 inhibitors revolutionized the management of sexual dysfunction in men. This article will focus on erectile dysfunction and its association with arterial hypertension. This update of the position paper was created by the Working Group on Sexual Dysfunction and Arterial Hypertension of the European Society of Hypertension. This working group has been very active during the last years in promoting the familiarization of hypertension specialists and related physicians with erectile dysfunction, through numerous lectures in national and international meetings, a position paper, newsletters, guidelines, and a book specifically addressing erectile dysfunction in hypertensive patients. It was noted that erectile dysfunction precedes the development of coronary artery disease. The artery size hypothesis has been proposed as a potential explanation for this observation. This hypothesis seeks to explain the differing manifestation of the same vascular condition, based on the size of the vessels. Clinical presentations of the atherosclerotic and/or endothelium disease in the penile arteries might precede the corresponding manifestations from larger arteries. Treated hypertensive patients are more likely to have sexual dysfunction compared with untreated ones, suggesting a detrimental role of antihypertensive treatment on erectile function. The occurrence of erectile dysfunction seems to be related to undesirable effects of antihypertensive drugs on the penile tissue. Available information points toward divergent effects of antihypertensive drugs on erectile function, with diuretics and beta-blockers possessing the worst profile and angiotensin receptor blockers and nebivolol the best profile.

Effect of Ticagrelor Versus Clopidogrel on Aortic Stiffness in Patients With Coronary Artery Disease.

Background We compared the acute and midterm effect of ticagrelor versus clopidogrel on aortic stiffness. Methods and Results We studied 117 patients in a randomized, assessor-blinded, parallel-group trial. The acute effect of ticagrelor was studied in 58 patients randomized (1:1) to receive a loading dose of clopidogrel (600 mg) or ticagrelor (180 mg). Carotid-femoral pulse wave velocity (cf PWV ) was measured before, 3, and 24 hours after the loading dose. The midterm effect (30-day treatment period) was studied in 59 subjects who underwent percutaneous coronary intervention and were randomized to either clopidogrel (75 mg, OD) or ticagrelor (90 mg BID). cf PWV was measured before and at 30 days of treatment. Circulating markers of inflammation and endothelial function were measured at all study points. Repeated-measures analysis showed a significant main effect for treatment ( P=0.03), with the ticagrelor showing a reduction in cf PWV after treatment. cf PWV at 24 hours was significantly lower in the ticagrelor group compared with the clopidogrel group ( P=0.017) (maximal response reduction by 0.42±0.26 m/s). At 30 days, cf PWV decreased in the ticagrelor group, whereas there was no change with clopidogrel (-0.43±0.57 versus 0.12±0.14 m/s, P=0.004). There were no significant changes in both the acute and midterm study period in the pro-inflammatory and endothelial function parameters. Conclusions URL : https://www.clinicaltrials.gov . Unique identifier: NCT02071212. Ticagrelor decreases cf PWV for 24 hours after the loading dose and at 1 month post-percutaneous coronary intervention compared with clopidogrel. Considering that aortic stiffness is an independent predictor of cardiovascular events, this finding may have clinical implications regarding the beneficial effect of ticagrelor. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT02071212.

Cardiovascular effects of electronic cigarettes: A systematic review and meta-analysis.

AIMS: The electronic cigarette is marketed as a safe alternative to tobacco smoking, but electronic cigarette cardiovascular effects remain largely unknown. We systematically reviewed and meta-analysed published literature to investigate the cardiovascular effects and associated risk from electronic cigarette use. METHODS AND RESULTS: We searched PubMed from January 2000 to November 2017 for published studies assessing the cardiovascular effects of the electronic cigarette. Evidence suggests that the electronic cigarette negatively affects endothelial function, arterial stiffness and the long-term risk for coronary events, but these findings are from single study reports and have not been confirmed in additional studies. Conflicting evidence exists on the effects of the electronic cigarette on heart rate and blood pressure, which is mainly based on non-randomized clinical studies of moderate quality. The meta-analysis of 14 studies (N + 441 participants) suggested that despite the negative acute effects of the electronic cigarette on heart rate (pooled mean difference (MD) + 2.27, 95% confidence interval (CI): 1.64 to 2.89, p < 0.001), diastolic (pooled MD + 2.01 mmHg, 95% CI: 0.62 to 3.39, p + 0.004) and systolic blood pressure (pooled MD + 2.02 mmHg, 95% CI: 0.07 to 3.97, p + 0.042), benefits may be observed in terms of blood pressure regulation when switching from tobacco smoking to chronic electronic cigarette use (systolic blood pressure pooled MD + -7.00, 95% CI: -9.63 to -4.37, p < 0.001; diastolic blood pressure pooled MD + -3.65, 95% CI: -5.71 to -1.59, p + 0.001). CONCLUSIONS: The existing evidence on the cardiovascular effects of the electronic cigarette is concerning, with several unexplored issues. Unless supported by stronger evidence, the electronic cigarette should not be labelled as a cardiovascular safe product. Future studies should delineate whether electronic cigarette use is less hazardous to cardiovascular health than conventional cigarette smoking.

Smoking cessation strategies in pregnancy: Current concepts and controversies.

Smoking during pregnancy is a risk factor associated with adverse pregnancy outcomes. Despite the fact that these outcomes are well known, a considerable proportion of pregnant women continue to smoke during this critical period. This paper evaluates critically smoking cessation interventions targeting pregnant women. We describe the findings of key published studies, review papers and expert statements to report the efficacy and safety of strategies for smoking cessation in pregnancy, including counselling and pharmacotherapy. Counselling appears to improve quit rates but mainly when used in combination with pharmacological therapy. Pharmacotherapy is recommended for women who are heavy smokers and are unable to quit smoking on their own. Nicotine replacement therapy is a reasonable first-line drug option. It is recommended that women who are pregnant, or planning to become pregnant, should be informed of potential risks for the foetus before considering smoking cessation therapy with bupropion or varenicline. Pregnant women view electronic nicotine delivery systems as being safer than combustible cigarettes, and this indeed may be the case; however, further evidence is required to assess their effectiveness as a smoking cessation aid and their safety for the mother and the child. Postpartum relapse is a significant problem, with approximately one out of two quitters relapsing in the first 2 months after delivery. These women should be considered 'at risk' and provided with ongoing support.

Statin Therapy and Risk of Diabetes Mellitus in Aging Patients With Heterozygous Familial Hypercholesterolemia or Familial Combined Hyperlipidemia: A 10-Year Follow-Up.

We assessed the incidence of diabetes mellitus (DM) in patients with heterozygous familial hypercholesterolemia (HeFH) and familial combined hyperlipidemia (FCH) treated with statins. Participants (n = 280) of mean age 59 ± 5 years were included (90 patients with HeFH, 112 patients with FCH, and 78 aged-matched participants). The median statin intensity treatment product (statin intensity in arbitrary equivalence units × duration of statin therapy in months) was 119 and 85 for patients with HeFH and FCH, respectively, at 10-year follow-up. The incidence of DM was significantly lower in patients with HeFH compared to the patients with FCH (2% vs 20%) and the reference group (2% vs 17%) during the 10-year follow-up period (all Ps < .001). Impaired fasting blood glucose at entry ( P < .001) and central obesity ( P = .02) were the only independent predictors of DM. The incidence of DM was significantly lower in older patients with HeFH compared to either aged-matched patients with FCH or individuals not receiving statins. Statins did not increase risk of DM in aging patients with FCH. These findings have implications, given the importance of high-intensity statin therapy for prevention of cardiovascular events, especially in patients with HeFH, a population with high cardiovascular risk.

Inverse association of total testosterone with central haemodynamics and left ventricular mass in hypertensive men.

BACKGROUND: There is evidence for inverse association between endogenous testosterone and blood pressure. Furthermore, low plasma testosterone is associated with increased risk of major cardiovascular events in middle-aged hypertensive men. Central (aortic) blood pressures determine left ventricular hypertrophy and predict cardiovascular mortality. The aim of the present study was to assess the relationship of total testosterone (TT) with central haemodynamics and left ventricular mass in hypertensive men. METHODS: We investigated 134 non-diabetic, middle-aged, hypertensive men and 60 age-matched normotensive males. All participants were subject to measurement of aortic systolic (aoSBP) and pulse pressure (aoPP) by pulse wave analysis using the SphygmoCor device. Wave reflections were assessed by the measurement of heart rate corrected augmentation index (AIx75). Echocardiography was performed in all individuals and left ventricular mass (LVM) was calculated using the Devereux's formula. Plasma TT was measured by enzyme immunoassay. RESULTS: In hypertensive men, univariate analysis showed an inverse, significant correlation between TT and aoSBP (r = -20, p = 0.02), aoPP (r = -0.21, p = 0.01), AIx75 (r = -0.22, p = 0.01) and LVM (r = -0.19, p = 0.008). Multivariate regression analysis demonstrated an independent inverse association of TT with aoPP (b = -0.21, p = 0.02), AIx75 (b = -0.19, p = 0.03) and LVM (b = -0.28, p = 0.005) after adjustment for age, BMI, smoking, total cholesterol, triglycerides, fasting glucose, mean arterial pressure, antihypertensive treatment and statin use. Independent associations were retained even after inclusion of normotensive subjects in the analysis. CONCLUSIONS: In hypertensive men, TT is independently and inversely associated with central pulse pressure, wave reflections and left ventricular mass. Considering the adverse prognostic role of central blood pressures and LV hypertrophy on cardiovascular outcomes in hypertensive patients, the present findings might explain part of the increased cardiovascular risk associated with low testosterone. Whether measurement of central haemodynamics may improve risk stratification in hypertensive men with low testosterone warrants further investigation.

Dynamic penile peak systolic velocity predicts major adverse cardiovascular events in hypertensive patients with erectile dysfunction.

OBJECTIVE: Hypertension is associated with an abnormal penile blood flow. Reduced dynamic penile peak systolic velocity (D-PSV) correlates with adverse cardiovascular outcomes. The aim of this study is to investigate whether abnormal penile blood flow predicts major adverse cardiovascular events (MACE) in hypertensive men. METHODS: In total, 298 hypertensive men (55 ±â€Š9 y/o) without known cardiovascular disease or diabetes were evaluated for cavernous vascular disease severity by dynamic penile Doppler ultrasound. The whole population was divided into tertiles according to D-PSV reduction (low tertile <25 cm/s; middle tertile 25-35 cm/s; and high tertile >35 cm/s). Predictive performance was evaluated with calibration, discrimination, and reclassification. RESULTS: During the mean follow-up period of 4.9 years, a total of 22 (7%) MACE occurred. D-PSV level was associated with MACE and the differences between the tertiles were significant (Mantel log-rank test: 6.54; P < 0.01). A Cox proportional hazard model showed that study participants in the lowest D-PSV tertile (<25 cm/s) had an approximately 3.5-fold higher MACE risk compared with those in the highest D-PSV tertile (>35 cm/s) after adjustment for age, systolic pressure, metabolic parameters, smoking, C-reactive protein, and testosterone levels. Low D-PSV did not significantly improve the C-statistic model (0.774 vs. 0.767; P = 0.44), whereas the calibration was satisfactory (Hosmer-Lemeshow X = 8.73, P = 0.30). When only intermediate-risk patients were evaluated, the risk reclassification beyond traditional risk factors resulted in a clinical net reclassification index of 9.2% that was marginally significant (P = 0.07). The integrated discrimination improvement index showed better performance of the model that included D-PSV compared with the reference model in identifying MACE (improvement index: 0.047, P = 0.038). CONCLUSION: Low-penile blood flow predicts MACE in hypertensive patients free of clinical atherosclerosis. This predictive ability is independent of the severity of hypertension and decreased testosterone that is often present in such patients.

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.

Acute effect of sildenafil on inflammatory markers/mediators in patients with vasculogenic erectile dysfunction.

BACKGROUND: Erectile dysfunction (ED) is associated with an incremental inflammatory activation. Evidence suggests that chronic phosphodiesterase 5 (PDE-5) inhibition may have a favorable effect on inflammatory activation and surrogate markers of ED. The aim of this study is to investigate the acute effect of sildenafil on circulating pro-inflammatory markers/mediators in ED patients. METHODS: The study comprised a randomized, double-blind, crossover trial carried out on two separate arms: one with sildenafil 100mg, and one with placebo. Twenty-seven subjects participated in the study (seven in the pilot and 20 in the main phase). In the main phase, blood samples were collected at baseline and at 2 and 4h after sildenafil or placebo administration to determine fibrinogen, high sensitivity C-reactive protein (hsCRP), high sensitivity interleukin-6 (hsIL-6) and tumor necrosis factor α (TNF-α). RESULTS: Administration of sildenafil produced a significant sustained reduction of fibrinogen, hsCRP and hsIL-6 (maximal absolute response of -44mg/dl, 0.42mg/l and 0.68pg/ml at 4h). Likewise, TNF-α was acutely decreased after sildenafil (maximal response of -13pg/ml, 2h). The effect of sildenafil on fibrinogen, hsCRP and hsIL-6 and TNF-α was independent of the baseline values of these markers/mediators or the baseline testosterone level (all P<0.05). Soluble vascular cell adhesion molecule 1 (sVCAM-1) levels remained unchanged. CONCLUSIONS: The present study shows for the first time the acute effect of sildenafil administration on pro-inflammatory markers/mediators in men with vasculogenic ED. This finding may have important implications in ED patients who are considered to be at increased cardiovascular risk.

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.

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 beta 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 above mentioned confounders were taken into account (beta = -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.

Negative association between serum levels of matrix metalloproteinases-2 and -9 and aortic stiffness in healthy adults.

BACKGROUND: Arterial stiffness is a marker of cardiovascular disease and independent predictor of cardiovascular risk. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade components of the extracellular matrix, which is an important determinant of the arterial elastic properties. This study sought to investigate the association between MMP-2 and MMP-9 (gelatinase A and B respectively) and arterial stiffness in healthy human subjects. METHODS: A total of 213 apparently healthy subjects (mean age 41 years, range 18 to 60, 141 males and 72 females) were studied. Carotid-femoral pulse wave velocity (PWV) and aortic augmentation index (AIx) were measured as indices of aortic stiffness and wave reflections respectively. Associations with serum levels of total MMP-2, total MMP-9 and high-sensitivity C-reactive protein (hsCRP) were evaluated with multiple regression models. RESULTS: In these models, PWV exhibited a significant negative association with both MMP-2 (standardized b=-0.177, P=0.003) and MMP-9 (b=-0.122, P=0.032), after controlling for potential confounding factors such as age, gender, blood pressure, heart rate, body-mass index, smoking habits (pack-years), blood glucose, total cholesterol, and level of subclinical inflammation expressed by hsCRP (adjusted R2 of models 0.352 and 0.338 respectively). On the other hand, no relationship between MMP-2 or MMP-9 and AIx was found. CONCLUSIONS: Circulating MMP-2 and MMP-9 are inversely associated with large artery stiffness but not with wave reflections in healthy persons. This finding implies that these gelatinases may have a possible role in the determination of arterial function and has potential implications for their involvement in the pathophysiology of cardiovascular diseases.