Angiotensin Regulation of Vascular Homeostasis: Exploring the Role of ROS and RAS Blockers.

Extensive research has been conducted to elucidate and substantiate the crucial role of the Renin-Angiotensin System (RAS) in the pathogenesis of hypertension, cardiovascular disorders, and renal diseases. Furthermore, the role of oxidative stress in maintaining vascular balance has been well established. It has been observed that many of the cellular effects induced by Angiotensin II (Ang II) are facilitated by reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In this paper, we present a comprehensive overview of the role of ROS in the physiology of human blood vessels, specifically focusing on its interaction with RAS. Moreover, we delve into the mechanisms by which clinical interventions targeting RAS influence redox signaling in the vascular wall.

The Effect of Surgical Aortic Valve Replacement on Arterial Stiffness: Does the Valve Type Matter?

Background: Despite the increasing use of transcatheter aortic valve procedures, many patients still require surgical aortic valve replacement (SAVR). Assessing arterial properties in patients undergoing SAVR for aortic valve stenosis can be challenging, and the existing evidence is inconclusive. Our study aimed to investigate the impact of SAVR on vascular stiffness and the quality of life, as well as the different effects of valve type on arterial properties. Methods: We included 60 patients (mean age 70.25 ± 8.76 years, 65% men) with severe symptomatic aortic stenosis who underwent SAVR. Arterial stiffness (cfPWV, baPWV) and vascular parameters (AIx@75, central pressures, SEVR) were measured at baseline, pre-discharge, and 1-year post-operation. The QOL was assessed using the generic questionnaire-short-form health survey 36 (SF-36) pre-operatively and at 1 year. Results: Post-SAVR, cfPWV increased immediately (7.67 ± 1.70 m/s vs. 8.27 ± 1.92 m/s, p = 0.009) and persisted at 1 year (8.27 ± 1.92 m/s vs. 9.29 ± 2.59 m/s, p ≤ 0.001). Similarly, baPWV (n = 55) increased acutely (1633 ± 429 cm/s vs. 2014 ± 606 cm/s, p < 0.001) and remained elevated at 1 year (1633 ± 429 cm/s vs. 1867 ± 408 cm/s, p < 0.001). Acute decrease in Alx@75 (31.16 ± 10% vs. 22.48 ± 13%, p < 0.001) reversed at 1 year (31.16 ± 10% vs. 30.98 ± 9%, p = 0.71). SEVR improved (136.1 ± 30.4% vs. 149.2 ± 32.7%, p = 0.01) and persisted at 1 year (136.1 ± 30.4% vs. 147.5 ± 30.4%, p = 0.01). SV had a greater cfPWV increase at 1 year (p = 0.049). The QOL improved irrespective of arterial stiffness changes. Conclusions: After SAVR, arterial stiffness demonstrates a persistent increase at 1-year, with valve type having a slight influence on the outcomes. These findings remain consistent despite the perceived QOL.

Mitral valve repair with the use of the "Memo 3D ReChord" ring.

BACKGROUND: From a variety of ring types, semirigid ring is more preferred for mitral annuloplasty during mitral valve repair particularly in patients whose native mitral saddle shape annulus is well maintained. During mitral annuloplasty artificial chord implantation with the appropriate neochord length is surgically challenging. We present our experience of using the Memo 3D ReChord, a semirigid ring with additional chordal guiding system for mitral valve repair. PATIENTS AND METHODS: From September 2018 to February 2020, we successfully treated ten patients with severe (4+/4+) degenerative mitral valve regurgitation due to posterior leaflet prolapse with chordal rupture with the implantation Memo 3D ReChord and neo-chords. RESULTS: We implanted from one to three neo-chords and always a ring in our patients. None of the patients had any residual mitral valve regurgitation at the end of the repair and on their discharge evaluated through transesophageal and transthoracic echocardiography respectively. There was no mortality at 30-days or on midterm follow-up. During the 3-month follow-up no regurgitation was noticed either. We included in our study only the patients successfully treated. We also used it in two patients, who underwent valve replacement during the same operation due to mild to moderate mitral valve regurgitation. CONCLUSIONS: This, in our knowledge, is the first Greek series of the implantation of the Memo 3D Rechord. The initial excellent results give us the enthusiasm to continue while long-term results and the durability of this technique are necessary to establish this semirigid annuloplastic ring in our every-day practice.

Late erosion of Amplatzer Septal Occluder device 9 years after the implantation: a case report.

Cardiac erosion is a rare but life-threatening complication after the interventional closure of an atrial septal defect. We present the case of a patient who developed cardiac erosion 9 years after the placement of an Amplatzer Septal Occluder. The patient presented to our hospital with symptoms of tamponade. Surgical exploration revealed a tear in the roof of the left atrium. To our knowledge, this is one of the most delayed presentations reported. In these cases, diagnosis is difficult and a level of clinical suspicion is demanded.

Lipoprotein(a) and inflammation- pathophysiological links and clinical implications for cardiovascular disease.

The role of lipoprotein(a) (Lp[a]) as a significant and possibly causal cardiovascular disease (CVD) risk factor has been well established. Many studies, mostly experimental, have supported inflammation as a mediator of Lp(a)-induced increase in CVD risk. Lp(a), mainly through oxidized phospholipids bound to its apolipoprotein(a) part, leads to monocyte activation and endothelial dysfunction. The relationship between Lp(a) and inflammation is bidirectional as Lp(a) levels, besides being associated with inflammatory properties, are regulated by inflammatory stimuli or anti-inflammatory treatment. Reduction of Lp(a) concentration, especially by potent siRNA agents, contributes to partial reversion of the Lp(a) related inflammatory profile. This review aims to present the current pathophysiological and clinical evidence of the relationship between Lp(a) and inflammation.

Stem Cell-based Therapies in Cardiovascular Diseases: From Pathophysiology to Clinical Outcomes.

Over 20 years of intensified research in the field of stem cells brought about unprecedented possibilities in treating heart diseases. The investigators were initially fascinated by the idea of regenerating the lost myocardium and replacing it with new functional cardiomyocytes, but this was extremely challenging. However, the multifactorial effects of stem cell-based therapies beyond mere cardiomyocyte generation, caused by paracrine signaling, would open up new possibilities in treating cardiovascular diseases. To date, there is a strong body of evidence that the anti-inflammatory, anti-apoptotic, and immunomodulatory effects of stem cell therapy may alleviate atherosclerosis progression. In the present review, our objective is to provide a brief overview of the stem cell-based therapeutic options. We aim to delineate the pathophysiological mechanisms of their beneficial effects in cardiovascular diseases especially in coronary artery disease and to highlight some conclusions from important clinical studies in the field of regenerative medicine in cardiovascular diseases and how we could further move onwards.

Interleukin-6 Signaling in Atherosclerosis: From Molecular Mechanisms To Clinical Outcomes.

Interleukin-6 (IL-6) is a cytokine centrally involved in several immune responses and it has been recognized as a driver of enhanced atherothrombotic risk. Immunity and inflammation are intrinsically involved in atherosclerosis progression. This generated 'inflammation hypothesis', which is now validated in large-scale clinical trials. Abundant evidence supports the distinctive role of IL-6 in coronary artery disease. The focus on this cytokine stems from epidemiological studies linking high plasma concentrations of IL-6 with greater risk for adverse cardiovascular events, genetic studies which implicate a causative role of IL-6 in atherosclerosis and murine data which support the involvement of IL-6 in various pathophysiological cascades of atherothrombosis. The fact that high IL-6 levels are equivalent to increased cardiovascular risk created an unmet need to address those who are at 'residual inflammatory risk'. Moreover, the opposing effects of IL-6 underlined the importance of deciphering specific signaling cascades, which may be responsible for different effects. Finally, murine data and some small clinical trials highlighted the possibility of reversing the pro-atherogenic effects of IL-6 by directly targeting it. While IL-1 blockage was proved effective, it is reasonable to examine if moving more downstream in the inflammation cascade could be more selective and effective than other anti-inflammatory therapies. In the present review, we examine the role of IL-6 as a biomarker of 'residual inflammatory risk', its vital role in the pathophysiology of atherosclerosis progression and the possibility of targeting it to stall coronary artery disease progression.

Expression of Tissue microRNAs in Ascending Aortic Aneurysms and Dissections.

Little is known about the role of serum and tissue mediators in the progression of ascending aortic aneurysms and dissections. We examined how the tissue expression of microRNAs and matrix metalloproteinases (MMPs), as well as the serum levels of osteoprotegerin, adiponectin, and high sensitivity C-reactive protein (hsCRP) are associated with these entities. We enrolled 21 patients with ascending aortic aneurysm, 11 with acute Stanford type A aortic dissection and 18 controls. The serum levels of osteoprotegerin, adiponectin, and hsCRP, as well as the tissue expression of MMPs 2 and 9 and tissue microRNAs 29 and 195 were compared among groups. There was no difference regarding serum osteoprotegerin, adiponectin, and tissue MMP2 and MMP9 levels. hsCRP was higher in the dissection group (P = .03). Tissue expression of microRNA 29 was 2.11-fold higher in the dissection (P = .001) and 2.99-fold higher in the aneurysm group (P < .001), compared with the control group. Tissue expression of microRNA 195 was 2.72-fold higher in the dissection (P < .001) and 2.00-fold lower in the aneurysm group (P = .08), compared with to the control group. These findings support the contribution of microRNAs in the progression of aneurysm formation and dissection, suggesting a role as potential biomarkers and future therapeutic targets.

Pro-inflammatory cytokines in acute coronary syndromes: from bench to bedside.

Cytokines are produced in a variety of tissues and regulate the expression of a number of inflammatory molecules, leading to destabilization and finally rupture of vulnerable atheromatic plaques. They also participate in the pathophysiology of acute coronary syndromes (ACS) by direct effects on myocardial contractility and apoptosis. At a clinical level, circulating cytokines have a prognostic role since they are useful markers predicting future coronary events in patients with advanced atherosclerosis and in patients after ACS.

Levosimendan: beyond its simple inotropic effect in heart failure.

Classic inotropic agents provide short-term haemodynamic improvement in patients with heart failure, but their use has been associated with poor prognosis. A new category of inotropic agents, the Ca(2+) sensitizers, may provide an alternative longer lasting solution. Levosimendan is a relatively new Ca(2+) sensitizer which offers haemodynamic and symptomatic improvement by combining a positive inotropic action via Ca(2+) sensitization and a vasodilatory effect via adenosine triphosphate(ATP)-sensitive K(+) (K(ATP)), Ca(2+)-activated K(+) (K(Ca)(2+)) and voltage-dependent K(+) (K(V)) channels activation. Levosimendan also seems to induce a prolonged haemodynamic improvement in patients with heart failure as a result of the long half-life of its active metabolite, OR-1896. Furthermore, there is also evidence that levosimendan may have additional antiinflammatory and antiapoptotic properties, affecting important pathways in the pathophysiology of heart failure. Despite the initial reports for a clear benefit of levosimendan on short- and long-term mortality in patients with severe heart failure, the results from the recent clinical trials are rather disappointing, and it is still unclear whether it is superior to dobutamine in affecting survival of patients with severe heart failure. In conclusion, levosimendan is a promising agent for the treatment of decompensated heart failure. As further to its positive inotropic effect, it affects multiple pathways with key roles in the pathophysiology of heart failure. The results of the ongoing trials examining the effect of levosimendan on mortality in patients with heart failure will hopefully resolve the controversy as to whether levosimendan is superior to classic inotropic agents for the treatment of severe heart failure.

Novel therapies targeting vascular endothelium.

Endothelial dysfunction has been identified as a major mechanism involved in all the stages of atherogenesis. Evaluation of endothelial function seems to have a predictive role in humans, and therapeutic interventions improving nitric oxide bioavailability in the vasculature may improve the long-term outcome in healthy individuals, high-risk subjects, or patients with advanced atherosclerosis. Several therapeutic strategies are now available, targeting both the synthesis and oxidative inactivation of nitric oxide (NO) in human vasculature. Statins seem to be currently the most powerful category of these agents, improving endothelial function and decreasing cardiovascular risk after long-term administration. Other cardiovascular agents improving endothelial function in humans are angiotensin-converting enzyme inhibitors/angiotensin receptors blockers, which increase NO bioavailability by modifying the rennin-angiotensin-aldosterone system. Newer therapeutic approaches targeting endothelial dysfunction in specific disease states include insulin sensitizers, L-arginine (the substrate for endothelial NO synthase [eNOS]) as well as substances that target eNOS "coupling," such as folates or tetrahydrobiopterin. Although there are a variety of strategies to improve NO bioavailability in human endothelium, it is still unclear whether they have any direct benefit at a clinical level.

Myocardial redox state predicts in-hospital clinical outcome after cardiac surgery effects of short-term pre-operative statin treatment.

OBJECTIVES: The purpose of this study was to evaluate the role of the myocardial redox state in the development of in-hospital complications after cardiac surgery and the effect of statins on the myocardial redox state. BACKGROUND: Statins improve clinical outcome after cardiac surgery, but it is unclear whether they exert their effects by modifying the myocardial redox state. METHODS: We quantified myocardial superoxide anion (O(2)(-)) and peroxynitrite (ONOO(-)) and their enzymatic sources in samples of the right atrial appendage (RAA) from 303 patients undergoing cardiac surgery who were followed up until discharge, and in 42 patients who were randomized to receive 3-day treatment with atorvastatin 40 mg/d or placebo before surgery. The mechanisms by which atorvastatin modifies myocardial redox state were investigated in 26 RAA samples that were exposed to atorvastatin ex vivo. RESULTS: Atrial O(2)(-) (derived mainly from nicotinamide adenine dinucleotide phosphate [NADPH] oxidases) and ONOO(-) were independently associated with increased risk of atrial fibrillation, the need for post-operative inotropic support, and the length of hospital stay. Pre-operative atorvastatin treatment suppressed atrial NADPH oxidase activity and myocardial O(2)(-) and ONOO(-) production. Ex vivo incubation of RAA samples with atorvastatin induced a mevalonate-reversible and Rac1-mediated inhibition of NADPH oxidase. CONCLUSIONS: There is a strong independent association between myocardial O(2)(-)/ONOO(-) and in-hospital complications after cardiac surgery. Both myocardial O(2)(-) and ONOO(-) are reduced by pre-operative statin treatment, through a Rac1-mediated suppression of NADPH oxidase activity. These findings suggest that inhibition of myocardial NADPH oxidases may contribute to the beneficial effect of statins in patients undergoing cardiac surgery. (Effects of Atorvastatin on Endothelial Function, Vascular and Myocardial Redox State in High Cardiovascular Risk Patients; NCT01013103).

Therapeutic interventions to renin-angiotensin-aldosterone system, and vascular redox state.

It is well established that RAS plays a key role in the development of hypertension, cardiovascular and renal disease. On the other hand oxidative stress is a key feature in vascular homeostasis. Many of the cellular effects of Ang II appear to be mediated by ROS generated by NAD(P)H oxidase. In this review, we provide an overview of ROS physiology in human vessels especially in relation with RAS. We also discuss how therapeutic interventions on RAS affect redox signaling in the vascular wall at a clinical level with the discussion of recent patents.

Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis.

We explored the role of asymmetrical dimethylarginine (ADMA) as a cause of endothelial dysfunction induced by systemic inflammation. In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli, but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans. In study 1 we recruited 351 patients with coronary artery disease (CAD) and 87 healthy controls. In study 2 we recruited 69 CAD, 69 healthy, and 10 patients with rheumatoid arthritis, whereas in study 3, 22 healthy and 70 CAD subjects were randomly assigned to Salmonella typhii vaccination (n=11 healthy and n=60 CAD) or placebo (n=11 healthy and n=10 CAD). Circulating interleukin 6/ADMA and flow-mediated dilation (FMD) were measured at 0 and 8 hours. In study 1, ADMA was inversely correlated with FMD in healthy individuals and CAD patients (P<0.0001 for both). However, interleukin 6 was inversely correlated with FMD (P<0.0001) in healthy subjects but not in CAD patients. The positive correlation between ADMA and interleukin 6 was stronger in healthy (r=0.515; P<0.0001) compared with CAD (r=0.289; P=0.0001) subjects. In study 2, both patients with rheumatoid arthritis and CAD had higher interleukin 6 (P<0.0001) and ADMA (P=0.004) but lower FMD (P=0.001) versus healthy subjects. In study 3, vaccination increased interleukin 6 in healthy (P<0.001) and CAD (P<0.001) subjects. FMD was reduced in healthy subjects (P<0.05), but its reduction in CAD was borderline. Vaccination increased ADMA only in healthy subjects (P<0.001). Systemic, low-grade inflammation leads to increased ADMA that may induce endothelial dysfunction. This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans.

Genetic polymorphism on type 2 receptor of angiotensin II, modifies cardiovascular risk and systemic inflammation in hypertensive males.

BACKGROUND: Angiotensin type 2 receptor (AT2R), plays a crucial role in blood pressure regulation and atherogenesis. AT2R gene is located on chromosome X and the biological effect of polymorphism A1675G in this gene needs to be further specified. We examined the impact of A1675G on the risk and the severity of coronary artery disease (CAD), and the expression of proatherogenic inflammatory molecules in hypertensive patients. METHODS: The study population consisted of 146 with CAD (102 with hypertension) and 266 age-matched individuals without CAD (114 with hypertension). The presence of A1675G polymorphism on AT2R gene was determined by PCR. Serum levels of C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in all the participants. RESULTS: The G allele was associated with decreased risk of CAD among hypertensives (odds ratio (OR) (95% confidence interval (CI))): 0.4 (0.2-0.9), P = 0.01) and less aggressive angiographic CAD (P < 0.001). The G allele was associated with lower IL-6 (median (25-75th percentile): 1.4 (0.6-3.8)), sVCAM-1 (621 (476-799)), CRP (1.2 (0.6-1.7)), and fibrinogen (369 (320-416)) vs. A allele (IL-6: 2.4 (1.1-4.5) P < 0.01, sVCAM-1: 702 (548-925) P < 0.05, CRP: 3.5 (2.0-6.1) P < 0.001, and fibrinogen: 407 (348-514) P < 0.01). The effect of A1675G on serum IL-6, sVCAM-1, and fibrinogen was driven by its effect among hypertensives (IL-6 3.1 (2.1-5.6 in A vs. 1.2 (0.3-3.4) in G P < 0.001, sVCAM-1: 890 (560-1000) in A vs. 556 (377-788) in G P < 0.01, and fibrinogen: 408 (354-510) in A vs. 369 (324-418) in G P < 0.001) whereas it had no effect among nonhypertensives. CONCLUSIONS: Genetic polymorphism A1675G on AT2R gene affects cardiovascular risk and the severity of atherosclerosis by modifying systemic inflammation, especially in hypertensive males.

Valve replacement for Brucella endocarditis: two case reports.

We report two cases of successful treatment of Brucella endocarditis. Both of them were treated with antibiotics and aortic valve replacement after Brucellosis was diagnosed. In one of these cases emergency operation was required. Our observations suggest that a combined surgical and medical treatment is the best option for the management of this disease. B. endocarditis should be operated after improvement of clinical status but emergency cardiac surgery may be required if heart failure develops.