Long-term Effects of Phosphodiesterase-5 Inhibitors on Cardiovascular Outcomes and Death: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Phosphodiesterase 5 inhibitors (PDE-5i), which are widely used for the treatment of erectile dysfunction (ED), have been found to exhibit systemic vascular benefits by improving endothelial function. In this context, we sought to evaluate the effects of PDE5i on long-term cardiovascular outcomes and mortality. METHODS: A comprehensive search of electronic databases was conducted up to May 30, 2023. Cohort studies comparing PDE5i treatment at any dose with other ED treatment, placebo or no treatment and minimum follow-up duration of 6 months were considered eligible. The primary endpoints were: (1) major adverse cardiovascular events (MACE) and (2) all-cause mortality. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated. RESULTS: Sixteen studies were included (1,257,759 subjects - 10.5% treated with PDE5i). The majority of patients (99.4%) were men[median age 61.5 years (range 30 - 72.8)]. The median follow-up duration was 4.3 years (range 6 months - 7.5 years). PDE5i use was associated with a significant reduction in the composite of MACE (RR 0.78, 95% CI 0.69-0.89). Moreover, the analysis of pooled data from 13 studies, demonstrated that the use of PDE5i was associated with a significantly lower risk of all-cause mortality (RR 0.70, 95% CI 0.56-0.87). CONCLUSIONS: The use of PDE5i primarily in men with or without known coronary artery disease was associated with a lower risk for cardiovascular events and overall mortality. This information underlines that PDE5i could provide clinical benefit beyond ED treatment and could instigate the conduction of further, large-scale randomized clinical trials.

Periostin is overexpressed, correlated with fibrosis and differs among grades of cardiomyocyte hypertrophy in myectomy tissue of patients with hypertrophic cardiomyopathy.

Periostin, a secreted matricellular protein, has been implicated in cardiac extracellular matrix remodeling and fibrosis. Evidence suggest that periostin stimulates cardiomyocyte hypertrophy. The current study aims to investigate the extent of periostin expression in patients with advanced Hypertrophic Cardiomyopathy (HCM) and its correlation with fibrosis and hallmark histopathological features of the disease. Interventricular septal tissue from thirty-nine HCM patients who underwent myectomy and five controls who died from non-cardiac causes was obtained. Staining with Masson's Trichrome and immunohistochemistry were used to localize fibrosis and periostin respectively. The extent of fibrosis and the expression of periostin were defined as the stained percentage of total tissue area using digital pathology software. Periostin expression was higher in HCM patients compared to controls (p<0.0001), positively correlated with the extent of fibrosis (r = 0.82, p<0.001), positively correlated with maximal interventricular septal thickness (Rho = 0.33, p = 0.04) and negatively correlated with LVEF (r = -0.416, p = 0.009). Periostin was approximately co-localized with fibrosis. Mean periostin expression was lower in patients with mild grade cardiomyocyte hypertrophy compared to those with moderate grade (p = 0.049) and lower in patients with mild grade replacement fibrosis compared to moderate grade (p = 0.036). In conclusion, periostin is overexpressed in advanced HCM, correlated with fibrosis and possibly related to cardiomyocyte hypertrophy.

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.

Interactions between erectile dysfunction, cardiovascular disease and cardiovascular drugs.

Sexual health has a fundamental role in overall health and well-being, and a healthy and dynamic sex life can make an important contribution to a good quality of life. Sexual dysfunction, and especially erectile dysfunction (ED) in men, is highly prevalent in patients with cardiovascular disease (CVD). CVD and ED have shared risk factors and pathophysiological links, such as endothelial dysfunction, inflammation and low plasma testosterone levels. ED has been shown to be an independent and early harbinger of future CVD events, providing an important window to initiate preventive measures. Therefore, screening and diagnosing ED is essential for the primary and secondary prevention of CVD because the assessment of ED offers an easy and low-cost prognostic tool that is an alternative to other investigational cardiovascular biomarkers. Moreover, ED is a major contributing factor to the discontinuation of, or poor adherence to, cardiovascular therapy. Cardiovascular drugs have divergent effects on erectile function, with diuretics and ß-blockers having the worst profiles, and renin-angiotensin-aldosterone system inhibitors and nebivolol having the best profiles. Pharmacological treatment of ED has an equivocal effect on the risk of CVD, suggesting a complex interaction between ED and drugs for CVD. In this Review, we discuss how sexual function could be incorporated into the patient history taken by physicians treating individuals with CVD, not merely as part of the diagnostic work-up but as a means to pursue tangible and essential benefits in quality of life and cardiovascular outcomes.

Routine histopathology of septal myectomy for hypertrophic obstructive cardiomyopathy in a greek cohort.

Hypertrophic cardiomyopathy (HCM) is a diverse inherited disease affecting 1 in 500 individuals irrespective of gender and ethnicity. A fraction of HCM patients will eventually develop drug refractory dynamic obstruction of the left ventricular outflow tract. For such patients, septal myectomy is the procedure of choice to alleviate their symptoms and improve their quality of life. The current histopathological study, the first from the Greek region, aims to examine the hallmark histopathological characteristics of Hypertrophic Obstructive Cardiomyopathy in a population of patients undergoing septal myectomy at a single center over a ten year period. Medical records and histopathology specimens of thirty nine (n=39) patients were evaluated. The sample comprised 22 males (56.4%) and 17 females (43.6%). Mean patient age at myectomy was 53.9±16.7 years, ranging from 12 to 79 years. Maximal IVS thickness on echocardiography was available for 35 patients with a median value of 2.08cm. Peak resting LVOT Pressure Gradient was available for 33 patients with a mean value of 104.88±44.20 mmHg. Central tendency of each histopathological attribute expressed as the median value was: moderate for myocyte hypertrophy, mild for cytoplasmic vacuolization, moderate for subendocardial fibrosis, moderate for interstitial fibrosis, mild for replacement fibrosis, moderate for myofibrillar disarray and mild for capillary stenosis. Myocyte hypertrophy, present in all specimens, was positively correlated with maximal IVS thickness (tau-b=0.43, p=0.002). Replacement fibrosis was positively correlated with the grade of microvascular stenosis (tau-b=0.45, p=0.004). LVEF was negatively correlated with the grade of interstitial fibrosis (tau-b=-0.43, p=0.035) and with the extent of myocardial fiber disarray (tau-b=-0.42, p=0.034). Histopathological attributes were not correlated with patient gender or age thus proving that HCM has a histological phenotype unique to each patient, mainly depending on each specific sarcomeric mutation.

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.

Congenital Coronary Artery Anomalies: Three Cases and Brief Review of the Literature.

Coronary artery anomalies (CAAs) are congenital vascular defects which can remain hidden and asymptomatic over the complete life course of an individual. They are defined as deviations from the normal coronary anatomy regarding the arterial origin, course, or both. Their incidence varies from 1.3% to 5.64% in coronary angiography cohorts, and they can be detected as incidental findings. In certain cases, CAAs can be hemodynamically significant and unfortunately can be proven lethal. Their link with sudden cardiac death, especially in otherwise healthy competitive athletes, is well established, but their prognostic significance, range of symptoms, and pathophysiology remain to be further elucidated. Here, along with a brief review of related literature, we present a series of three cases: one case of an anomalous origin of the right coronary artery (RCA) from the left coronary sinus, one case of a split RCA originating from the left coronary sinus, and one case of a dual left anterior descending (LAD) artery system.

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.

Effects of Intensive Blood Pressure Control in Patients with Evident Cardiovascular Disease: An Investigation Using the SPRINT Study Data.

BACKGROUND: Recent data advocate adoption of a more intensive treatment strategy for management of blood pressure (BP). OBJECTIVE: We investigated whether the overall effects of the Systolic Blood Pressure Intervention Trial (SPRINT) are applicable to cardiovascular disease (CVD) patients. METHODS: In a post hoc analysis we analyzed data from SPRINT that randomly assigned 9361 individuals to a systolic BP (SBP) target of <120 mmHg (intensive treatment) or <140 mmHg (standard treatment). 1562 patients had clinically evident CVD (age=70.3±9.3 years, 24% females) at study entry and were followed for 3.1 years. Further, we assessed the effect of low (<150 mmHg) baseline SBP on outcome. RESULTS: In CVD patients, there was no benefit from the intensive treatment regarding all endpoints, except for a marginally significant benefit on all-cause mortality (hazard ratio [HR]: 0.67; 95% confidence interval [CI], 0.45 to 1.00; p=0.0509). Further, while there was no increase in serious adverse events (SAE) in the intensive group, there was increased risk for study-related SAE, acute renal failure and electrolyte abnormalities. In patients with low baseline SBP there was a beneficial effect on allcause mortality (HR: 0.56; 95% CI: 0.33 to 0.96; p=0.033), but with greater stroke incidence (HR: 2.94; 95% CI: 1.04 to 8.29; p=0.042). CONCLUSION: We confirm the beneficial effect of the intensive strategy in SPRINT study on all-cause mortality and the harmful effect on specific adverse outcomes in patients with CVD. However, in patients with low baseline SBP stroke may increase.

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.

Acute effect of coffee on aortic stiffness and wave reflections in healthy individuals: differential effect according to habitual consumption.

The acute effect of coffee on arterial stiffness and its dependence on habitual consumption was studied in 24 volunteers on four separate occasions during which subjects received: (a) coffee espresso, (b) decaffeinated coffee espresso, (c) caffeine alone and (d) placebo (hot water). The increase in carotid femoral pulse wave velocity (PWV), augmentation index (AIx) and augmented pressure (AP) of the aortic pressure waveform after coffee consumption was more pronounced in non-habitual (n = 13) compared to habitual drinkers (n = 11), (differences of maximal changes between groups in PWV, AIx, AP responses by 0.39 m/s, 4.5% and 1.9 mmHg, respectively, for coffee; and by 0.34 m/s, 5.3% and 2.1 mmHg, respectively, for decaffeinated coffee; all p < .05). Caffeine increased PWV, as well as AIx and AP but differences in responses between the two groups were not significant. Both caffeinated and decaffeinated coffee consumption is associated with a more potent effect on arterial stiffness in non-habitual than habitual coffee consumers, whereas caffeine induces comparable changes in both groups.

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.

Complete Heart Block in a Diabetic Patient with a Preexisting LBBB and Normal Coronaries, Paradoxically Responding to Atropine.

We present a case of a complete atrioventricular block (AV block) with different aberrancy patterns during sinus rhythm and escape rhythm. A 66-year-old woman visited our emergency department complaining of sudden onset dizziness and fatigue over the past thirty minutes. Her medical history was remarkable for arterial hypertension, type 2 diabetes mellitus, and hypothyroidism. The patient had a known Left Bundle Branch Block (LBBB) on past ECGs. Upon palpation of peripheral pulse, a measurement of 32 beats per minute was obtained. No other sign of hemodynamic instability was present. A 12-Lead ECG revealed a complete heart block with sparse QRS complexes with a Right Bundle Branch Block (RBBB) morphology. Before the insertion of a temporary transvenous pacemaker, atropine was administered intravenously. Shortly after the administration, the patient's heart rhythm was restored to sinus rhythm (SR) with LBBB. The patient remained hemodynamically stable and in sinus rhythm at the cardiac ICU and was scheduled for implantation of a permanent pacemaker at a specialized tertiary center. Before successful implantation, a coronary angiography revealed normal coronary anatomy with no atherosclerotic lesions.