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Objectives: The aim of this study was to assess the capacity of optimized multipoint pacing (MPP) over optimized cardiac resynchronization therapy (CRT), in terms of clinical, functional, and echocardiographic parameters among patients with dyssynchronous heart failure (HF). Methods: Eighty patients (Caucasian, 77.5% male, 68.4 +/- 10.1 years, and 53.8% ischemic cardiomyopathy) sequentially received optimized CRT and optimized MPP over 6-and 12-month periods in a single-arm clinical trial. Clinical, laboratory, and echocardiographic assessment was conducted at baseline and after the completion of each step. Results: Significant additive effects of optimized MPP over optimized CRT were noted with regard to 6 min walking distance (baseline/optCRT/optMPP: 293 +/- 120 m vs 367 +/- 94 m vs 405 +/- 129 m and p < 0.001), NYHA class (2.36 vs 2.19 vs 1.45 and p < 0.001), VTIlvot (14.25 +/- 3.2 cm vs 16.2 +/- 4 cm vs 17.5 +/- 3.4 cm and p < 0.001), stroke volume (48 +/- 13.5 ml vs 55 +/- 15 ml vs 59 +/- 15 ml and p < 0.001), left ventricular ejection fraction (LVEF) (29% +/- 7.1% vs 33% +/- 7.3% vs 37% +/- 7.7% and p < 0.001), maximal left atrial volume (77.2 +/- 34.2 ml vs 74.2 +/- 39.5 ml vs 67.7 +/- 32 ml and p = 0.02), pulmonary artery systolic pressure (35.9 mmHg vs 33.5 mmHg vs 31 mmHg and p < 0.001), and right ventricular strain (-8.3% +/- 6.9% vs-8.8% +/- 6.6% vs-11.8% +/- 6.1% and p = 0.022). With regard to VAC, stroke work (SW), and CP as percentages of maximal, there was a significant difference detected as compared to baseline for both CRT and MPP. Additive effects persisted only if suitable MPP dipoles were present. Exploratory analysis revealed that ischemic cardiomyopathy continued to exhibit significant differences that favor MPP, whereas nonischemic cardiomyopathy had similar findings with regard to total left atrial strain and quality of life. Conclusions: Optimized MPP showed significant improvements in hemodynamic parameters and ventricular function in patients with HF over optimized CRT. The beneficial effect was more prominent in men and in those with rather reduced LVEF, consistent with findings that suggest a beneficial trend in VAC and CP with more homogeneous depolarization offered by optimized MPP. (c) 2021 Hellenic Society of Cardiology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Accelerated biological aging contributes to the evolution of cardiovascular disease. However, its influence on subclinical organ damage remains unclear. Leukocyte telomere length (LTL) is emerging as a marker of biological cardiovascular aging. We performed a systematic review and meta-analysis to assess the association between LTL and measures of end-organ damage. PubMed, Medline, Embase, Cinahl Plus, ClinicalTrials.gov, and grey literature databases were searched for studies that assessed the association of LTL with arterial pulse wave velocity (aPWV), carotid intima-media thickness (cIMT), left ventricular mass (LVM or LVMI), renal outcomes, coronary artery calcium (CAC) and presence of carotid plaques. In a sample of 7256 patients, we found that cIMT (pooled correlation coefficient (r) = -0.249; 95 %CI -0.37, -0.128) and aPWV (pooled r = -0.194; 95 % CI -0.290, -0.100) inversely correlate with LTL. Compared to aPWV, cIMT had a stronger correlation with LTL. Patients without carotid plaques had longer telomeres than patients with carotid plaques. Quantitative analyses documented LTL association with renal outcomes and CAC, but not with LVM/LVMI. Among measures of end-organ damage, cIMT and aPWV provide the most accurate information on the contribution of biological aging to the process of vascular remodeling/damage.

Background: We investigated whether fatty liver index (FLI), a surrogate marker of nonalcoholic fatty liver disease (NAFLD), is associated with hypertension-mediated organ damage (HMOD) in never-treated hypertensive patients without diabetes mellitus. Methods: We performed both clinic and ambulatory blood pressure (BP) measurements, and calculated the FLI for all participants. A FLI of no less than 60 indicates a high-risk of underlying NAFLD, whereas a FLI of less than 60 indicates lower risk. We evaluated left ventricular mass (LVM) by echocardiography, arterial stiffness by carotid–femoral pulse wave velocity (PWV), capillary rarefaction by nailfold capillaroscopy, as well as urinary albumin-to-creatinine ratio (ACR). HMOD was defined according to the categorical thresholds for each domain, except for capillary rarefaction in which case the categorization of patients was made by the median. Results: We included 146 hypertensive patients (men, 43.8%; mean age, 56.6 +/- 10.8 years; BMI, 30.3 +/- 4.9 kg/m(2); FLI, 57.2 +/- 27.7; office, systolic/diastolic, and 24-h BP, 153.5 +/- 15.8/94.7 +/- 9.8 mmHg, and 140.5 +/- 9.9/83.8 +/- 9 mmHg, respectively). Patients with FLI at least 60 (n = 76) were younger, with higher BMI and 24-h SBP, compared with patients with FLI less than 60 (n = 70). FLI was associated with HMOD after adjustment (LVM indexed to height, P = 0.004; PWV, P = 0.047; reduced capillary density, P = 0.001; and logACR, P = 0.003). High-risk FLI phenotype and FLI z scores increased the likelihood of any HMOD by 3.8 (95% confidence interval, 1.6-7.1) and 5.4 (95% confidence interval, 2.3-15.0) times, respectively. However, the increased number of HMOD domains has progressively stopped being determined by the FLI z scores (P = 0.65). Conclusion: High-risk FLI pattern was associated with various HMOD, and may re-classify never-treated hypertensive patients without diabetes mellitus into a higher cardiovascular risk level.

Hypertension remains a major public health issue with inadequate control worldwide. The May Measurement Month (MMM) initiative by the International Society of Hypertension was implemented in Greece in 2019 aiming to raise hypertension awareness and control. Adult volunteers (>= 18years) were recruited through opportunistic screening in five urban areas. Information on medical history and triplicate sitting blood pressure (BP) measurements were obtained using validated automated upper-arm devices. Hypertension was defined as systolic BP >= 140mmHg and/or diastolic >= 90mmHg, and/or self-reported use of drugs for hypertension. A total of 5727 were analysed [mean age 52.7 (SD 16.6) years, men 46.5%, 88.3% had BP measurement in the last 18months]. The prevalence of hypertension was (41.6%) and was higher in men and in older individuals. Among individuals with hypertension, 78.7% were diagnosed, 73.1% treated, and 48.3% controlled. Awareness, treatment, and control of hypertension were higher in women and in older individuals. Hypertensives had a higher body mass index (BMI) and were more likely to have diabetes, myocardial infarction and stroke, and less likely to smoke than normotensives (all P

Background: Pro-angiogenic microRNA modulation is a potentially attractive approach in the management of peripheral artery disease (PAD). The aim of this systematic review and meta-analysis was to examine the impact of microRNAs involved in the process of angiogenesis on blood flow recovery following hind limb ischemia induction in animal models. Methods: A literature search was performed to identify studies testing the efficacy of microRNA treatment on animal models of hind limb ischemia. Following that, a meta-analysis of the included studies was executed with the primary outcome being the change in ischemic-to-normal hind limb perfusion ratio assessed via laser Doppler imaging. Moreover, risk of bias, sensitivity analysis and publication bias were evaluated. Results: Studies evaluation led to the inclusion of 18 studies whose meta-analysis suggested that microRNA treatment resulted in improved ischemic hind limb perfusion 7 [standardized mean difference (SMD): 0.93, 95% CI 0.49-1.38], 14 (SMD: 1.31, 95% CI 0.78-1.84), and 21 days (SMD: 1.13, 95% CI 0.59-1.66) after hind limb ischemia induction. Moderate-to-substantial heterogeneity and possible publication bias were noted. Risk of bias was unclear despite the balanced baseline animal characteristics. Conclusion: The present meta-analysis suggests that pro-angiogenic modulation of microRNAs accelerates vascular perfusion recovery in animal models of acute hind limb ischemia. Further studies on animal models with similar characteristics to that of PAD patients are warranted to translate those findings in human PAD setting.

Maintenance of endothelial cell integrity is an important component of human health and disease since the endothelium can perform various functions including regulation of vascular tone, control of hemostasis and thrombosis, cellular adhesion, smooth muscle cell proliferation, and vascular inflammation. Endothelial dysfunction is encompassed by complex pathophysiology that is based on endothelial nitric oxide synthase uncoupling and endothelial activation following stimulation from various inflammatory mediators (molecular patterns, oxidized lipoproteins, cytokines). The downstream signaling via nuclear factor-kappa B leads to overexpression of adhesion molecules, selectins, and chemokines that facilitate leukocyte adhesion, rolling, and transmigration to the subendothelial space. Moreover, oscillatory shear stress leads to pro-inflammatory endothelial activation with increased monocyte adhesion and endothelial cell apoptosis, an effect that is dependent on multiple pathways and flow-sensitive microRNA regulation. Moreover, the role of neutrophil extracellular traps and NLRP3 inflammasome as inflammatory mechanisms contributing to endothelial dysfunction has recently been unveiled and is under further investigation. Consequently, and following their activation, injured endothelial cells release inflammatory mediators and enter a pro-thrombotic state through activation of coagulation pathways, downregulation of thrombomodulin, and an increase in platelet adhesion and aggregation owing to the action of von-Willebrand factor, ultimately promoting atherosclerosis progression.

Background: MicroRNAs have been linked to angiogenesis and could prove to be valuable future therapeutic targets in ischemic cardiovascular diseases.Methods: Ten-week-old male C57Bl/6 mice were subjected to left femoral artery ligation and were treated with microRNA-126 mimic at a dose of 5 mg/kg (Group A, n = 10) or 5 mg/kg microRNA mimic negative control (Group B, n = 10) on days 1, 3, and 7. Laser Doppler imaging was performed to verify successful ligation on day 0 and to evaluate differences in the ischemic-to-normal (I/N) hind limb perfusion ratio on day 28. Muscle tissue expression of microRNA-126 and vascular endothelial growth factor (VEGF) was determined via PCR.Results: Following microRNA-126 mimic administration in Group A subjects, we noted a stepwise increase in I/N hind limb perfusion ratio (Day 0: 0.364 +/- 0.032 vs. Day 8: 0.788 +/- 0.049 vs. Day 28: 0.750 +/- 0.039, p = 0.001). In Group B a stepwise increase in I/N hind limb perfusion ratio was observed (Day 0: 0.272 +/- 0.057 vs. Day 8: 0.382 +/- 0.020 vs. Day 28: 0.542 +/- 0.028, p = 0.074). Muscle tissue expression of microRNA-126 in the ischemic hind limb of Group A was 350-fold lower compared to the ischemic hind limb of Group B (p < 0.001). A higher expression (14.2-fold) of VEGF in the ischemic hind limb of microRNA-126-treated mice compared to that of control group was detected (p < 0.001). A statistically significant negative correlation was noted between microRNA-126 and VEGF tissue expression levels in the ischemic limbs of the entire study population.Conclusion: MicroRNA-126 delivery in the ischemic hind limb of mice improved vascular perfusion with VEGF upregulation.

Transcatheter aortic valve implantation (TAVI) is an established method for treating patients with aortic valve stenosis. We sought to determine the long-term clinical outcomes and performance of a self-expanding bioprosthesis beyond 5 years. Consecutive patients scheduled for TAVI were included in the analysis. Primary end points were all-cause and cardiovascular mortality, structural valve deterioration (SVD) and bioprosthetic valve failure (BVF), based on the VARC-2 criteria and consensus statement by ESC/EAPCI. The study prospectively evaluated 273 patients (80.61 +/- 7.00 years old, 47% females) who underwent TAVI with CoreValve/Evolut-R (Medtronic Inc.). The median follow-up duration was 5 years (interquartile range: 2.9 to 6; longest: 8 years). At 1, 5, and 8 years, estimated survival rates were 89.0%, 61.1%, and 56.0%, respectively, while cardiovascular mortality was 8% at the end of follow-up. Regarding valve performance, 5% of patients had early BVF and 1% had late BVF. Concerning SVD, 16 patients (6% of the total population) had moderate SVD (91% had an increase in mean gradient), with no severe SVD cases. Five patients with SVD died during follow-up. Actual analysis of the 8-year cumulative incidence of function of moderate SVD was 5.9% (2.5% to 16.2%). At multivariate analysis, the factor that emerged as an independent predictor for future SVD, was smaller bioprosthetic valve size (HR 0.58, 95% CI 0.41 to 0.82, p = 0.002). Long-term evaluation beyond 5 years after TAVI with a self-expanding bioprosthesis demonstrated low rates of cardiovascular mortality and structural valve deterioration. Valve size was an independent predictor for SVD. (C) 2021 Elsevier Inc. All rights reserved.

Background: Atherosclerotic cardiovascular diseases are characterized by a dysregulated inflammatory and thrombotic state, leading to devastating complications with increased morbidity and mortality rates. Summary: In this review article, we present the available evidence regarding the impact of inflammation on platelet activation in atherosclerosis. Key messages: In the context of a dysfunctional vascular endothelium, structural alterations by means of endothelial glycocalyx thinning or functional modifications through impaired NO bioavailability and increased levels of von Willebrand factor result in platelet activation. Moreover, neutrophil-derived mediators, as well as neutrophil extracellular traps formation, have been implicated in the process of platelet activation and platelet-leukocyte aggregation. The role of pro-inflammatory cytokines is also critical since their receptors are also situated in platelets while TNF-alpha has also been found to induce inflammatory, metabolic, and bone marrow changes. Additionally, important progress has been made towards novel concepts of the interaction between inflammation and platelet activation, such as the toll-like receptors, myeloperoxidase, and platelet factor-4. The accumulating evidence is especially important in the era of the coronavirus disease-19 pandemic, characterized by an excessive inflammatory burden leading to thrombotic complications, partially mediated by platelet activation. Lastly, recent advances in anti-inflammatory therapies point towards an anti-thrombotic effect secondary to diminished platelet activation.

Aims: To evaluate whether different hypertension phenotypes, namely, isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH) and systolic/diastolic hypertension (SDH) have a differential outcome effect by clinic and ambulatory blood pressure (BP) measurements. Methods: We prospectively evaluated in 569 never-treated patients with sustained hypertension (age 52.6 +/- 11.6 years; men 55%; clinic BP 150 +/- 15/95.5 +/- 10 mmHg, systolic/diastolic; 24-h ambulatory BP 128.9 +/- 12.6/80.6 +/- 9.7) the incidence of major cardiovascular (CV) events within 5 years, after adjustment for confounders, including the rate of BP control and the weighted follow-up BP. Results: All participants received antihypertensive drug treatment (mean number of drugs 1.9 +/- 1.1; follow-up visits 4.6/patient). Average clinic BP achieved during follow-up was 136 +/- 12.6/83.9 +/- 9.4 mmHg, with 39% of participants having clinic BP less than 140/90 mmHg in at least 75% of their visits, and 24% in 25-75% of visits. Prevalence of hypertension phenotypes defined using BP differed from that using ambulatory BP, whereas integration of both BP measurements reclassified the initial phenotype to another in 18% of participants. Although, no differential outcome effect was observed between clinic IDH and SDH assessed using clinic or ambulatory BP measurements, clinic BP-based ISH was associated with a higher outcome incidence than the IDH and SDH phenotypes (hazard ratio 4.8, 95% confidence interval 1.4-17.0, P = 0.015). ISH diagnosed by integration of clinic and ambulatory BP, also increased the outcome (hazard ratio 4.0, 95% confidence interval 1.0-15.6, P = 0.046). Conclusion: In hypertensive patients at low/moderate CV risk, IDH and SDH phenotypes defined by clinic BP measurements, equally determined CV events but to a lower extent compared with ISH.

Aim: To evaluate the net clinical benefit following direct oral anticoagulants (DOACs) vs warfarin by diabetes status in patients with non-valvular atrial fibrillation. Methods: We searched 3 electronic databases through end-February 2021 to identify relevant outcome trials in patients with and without diabetes mellitus (DM). All-cause death, non-fatal stroke/systemic embolism and major bleedings defined net clinical benefit. Outcome risk ratios and 95% confidence interval (CI), and absolute risk outcome reduction per 1000 treated patients were assessed. Results: Four trials of DOACs vs warfarin compared 22,087 patients with DM to 49,592 patients without DM. CHADS2 and 10-year fatal cardiovascular risk were higher in patients with vs those without DM (3.7 vs 2.5 and 28.4% vs 23.4%, respectively). DOACs were associated with more favorable net clinical benefit compared to warfarin in patients with and without DM (relative risk reduction, 0.85 [95% CI, 0.81-0.89] and 0.87 [95% CI, 0.79-0.96]; absolute risk reduction per 1000 patients treated,-33 [95% CI,-45,-21]) and-24 [95% CI,-43,-5]), but interaction test was not significant by relative and absolute numbers (P = 0.68 and P = 0.44, respectively). Conclusion: Net clinical benefit following DOACs was not different between patients with and without DM over a period of 2.2 years. (c) 2021 Elsevier B.V. All rights reserved.

This ESH Position Paper 2021 with updated proposed recommendations was deemed necessary after the publication of a set of new pivotal sham-controlled randomized clinical trials (RCTs), which provided important information about the efficacy and safety of endovascular device-based renal denervation (RDN) for hypertension treatment. RDN is effective in reducing or interrupting the sympathetic signals to the kidneys and decreasing whole body sympathetic activity. Five independent, fully completed, sham-controlled RCTs provide conclusive evidence that RDN lowers ambulatory and office blood pressure (BP) to a significantly greater extent than sham treatment. BP-lowering efficacy is evident both in patients with and without concomitant antihypertensive medication. The average decrease of 10mmHg in office BP is estimated to lower the incidence of cardiovascular events by 25-30%, based on meta-analyses of RCTs using pharmacological treatment. Neither peri-procedural, nor short-term or long-term adverse events or safety signals (available up to 3 years) have been observed. Implementing RDN as an innovative third option in the armamentarium of antihypertensive treatment requires a structured process that ensures the appropriate performance of the endovascular RDN procedure and adequate selection of hypertensive patients. The latter should also incorporate patients’ perspective and preference that needs to be respected in a shared decision-making process.

BACKGROUND: Several studies have revealed the link between Coronavirus Disease 2019 (COVID-19) and endothelial dysfunction. To better understand the global pattern of this relationship, we conducted a meta-analysis on endothelial biomarkers related to COVID-19 severity. METHODS: We systematically searched the literature up to March 10, 2021, for studies investigating the association between COVID-19 severity and the following endothelial biomarkers: Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1), E-selectin, P-selectin, Von Willebrand Factor Antigen (VWF-Ag), soluble Thrombomodulin (sTM), Mid-regional pro-adrenomedullin (MR-proADM), and Angiopoietin-2 (Ang-2). Pooled estimates and mean differences (PMD) for each biomarker were reported. RESULTS: A total of 27 studies (n=2213 patients) were included. Critically ill patients presented with higher levels of MR-proADM (PMD: 0.71 nmol/L, 95% CI: 0.22 to 1.20 nmol/L, p=0.02), E-selectin (PMD: 13,32 pg/ml, 95% CI: 4,89 to 21,75 pg/ml, p=0.008), VCAM-1 (PMD: 479 ng/ml, 95% CI: 64 to 896 ng/ml, p=0.03), VWF-Ag (PMD: 110.5 IU/dl, 95% CI: 44.8 to 176.1 IU/dl, p=0.04) and Ang-2 (PMD: 2388 pg/ml, 95% CI: 1121 to 3655 pg/ml, p=0.003), as compared to non-critically ill ones. ICAM-1, P-selectin and thrombomodulin did not differ between the two groups (p>0.05). CONCLUSION: Endothelial biomarkers display significant heterogeneity in COVID-19 patients, with higher MR-proADM, E-selectin, VCAM-1, VWF-Ag, and Ang-2 levels being associated with increased severity. These findings strengthen the evidence on the key role of endothelial dysfunction in disease progress.

Background: High blood pressure (BP) is a leading risk factor for coronary artery disease and other major cardiovascular events. Objective: Blood pressure variability (BPV), ambulatory arterial stiffness index (AASI) and ankle-brachial index (ABI) have been proposed as indices that can improve risk stratification for an adverse cardiac outcome. However, their utility in the setting of acute coronary syndromes (ACS) is unclear. Methods: The AC S-BP study is a single-centre observational cohort study designed to investigate the prognostic role of haemodynamic load and arterial stiffness indices for cardio-renal outcomes in patients with acute myocardial infarction (AMI). All consecutive patients admitted with a diagnosis of acute AMI with or without ST segment elevation were screened for inclusion in the study. Results and Discussion: Data from baseline clinical and laboratory parameters during their hospitalization were collected. The haemodynamic load of each patient was determined by clinical BP values as well as 24-h ambulatory BP monitoring. The AASI was calculated from the raw 24-h BP data and ABI was measured after the third day of hospitalization using a certified device. Patients were followed-up for 12 months in order to collect data for hard cardiovascular and renal endpoints. Conclusion: The study results should clarify the role of these non-invasive tools in secondary risk stratification of such patients.

Background: Microwave radiometry (MWR) assesses non-invasive carotid artery temperatures reflecting inflammation. In the present study, we aimed to investigate the impact of hypolipidemic therapy either with simvastatin or with combination simvastatin plus ezetimibe on carotid artery temperatures of patients with familial hyperlipidemia syndromes (FHS). Methods: Consecutive patients with diagnosis of either familial heterozygous hypercholesterolemia (heFH) or familial combined hyperlipidemia (FCH) were included in the study. Patients were assigned to either simvastatin 40 mg or simvastatin 40 mg plus ezetimibe 10 mg, according to the discretion of the physician. FHS patients who refused statin therapy were used as a control group. Common carotid intima-media thickness (ccIMT) was measured and Delta tau (maximum-minimum) temperature measurements were performed across each carotid during MWR evaluation. RESULTS: In total, 115 patients were included in the study. Of them, 40 patients received simvastatin (19 heFH and 21 FCH), 41 simvastatin + ezetimibe (31 heFH and 10 FCH), and 34 (21 heFH and 13 FCH) no statin. Carotid artery temperatures were significantly reduced at 6 months in FH patients who received hypolipidemic treatment (0.83 +/- 0.34 versus 0.63 +/- 0.24 degrees C, p = 0.004 for simvastatin, 1.00 +/- 0.38 versus 0.69 +/- 0.23 degrees C, p < 0.001 for simvastatin + ezetimibe), but no change was recorded in controls (0.72 +/- 0.26 versus 0.70 +/- 0.26 degrees C, p = 0.86). Conclusions: Hypolipidemic therapy reduced carotid temperatures in FHS patients.