Molecular Mechanisms and Therapeutic Implications of Endothelial Dysfunction in Patients with Heart Failure.

Heart failure is a complex medical syndrome that is attributed to a number of risk factors; nevertheless, its clinical presentation is quite similar among the different etiologies. Heart failure displays a rapidly increasing prevalence due to the aging of the population and the success of medical treatment and devices. The pathophysiology of heart failure comprises several mechanisms, such as activation of neurohormonal systems, oxidative stress, dysfunctional calcium handling, impaired energy utilization, mitochondrial dysfunction, and inflammation, which are also implicated in the development of endothelial dysfunction. Heart failure with reduced ejection fraction is usually the result of myocardial loss, which progressively ends in myocardial remodeling. On the other hand, heart failure with preserved ejection fraction is common in patients with comorbidities such as diabetes mellitus, obesity, and hypertension, which trigger the creation of a micro-environment of chronic, ongoing inflammation. Interestingly, endothelial dysfunction of both peripheral vessels and coronary epicardial vessels and microcirculation is a common characteristic of both categories of heart failure and has been associated with worse cardiovascular outcomes. Indeed, exercise training and several heart failure drug categories display favorable effects against endothelial dysfunction apart from their established direct myocardial benefit.

Diffuse LAD and LV Thrombus as Possible Manifestation of Protein-S Deficiency in a Young Patient.

Patients with inherited hypercoagulopathies such as protein-S deficiency commonly present with venous thrombosis. However, there are rare cases of arterial thrombosis. We describe a rare case of a diffuse left anterior descending and left ventricular thrombus in a young patient with protein-S deficiency complicated with mid cerebral artery occlusion. (Level of Difficulty: Intermediate.).

Correlation of Clinical Outcomes with the Prominent Indication of Transcatheter Paravalvular Leak Closure: A Multicenter Experience.

BACKGROUND: A paravalvular leak (PVL) is a complication following valve replacement, which may lead to heart failure and hemolysis. The aim of this study is to investigate whether the clinical outcome after transcatheter PVL closure differs according to the prominent indication of the procedure (symptoms of heart failure or hemolysis). METHODS: The data of consecutive patients who had transcatheter treatment for PVL between July 2011 and September 2022 in five Greek centers were analyzed. The primary endpoint was the technical, and clinical success rates with regards to the prominent indication of paravalvular leak closure. The secondary endpoints included the evaluation and comparison of the clinical and technical success in relation to the type of valve that was treated (aortic or mitral) as well as the survival analysis in relation to the closure indication and type of valve that was treated. RESULTS: In total, 60 patients were retrospectively studied (39% men, mean age 69.5 ± 11 years). Regarding the primary outcomes, the technical success in patients mainly suffering from hemolysis was 86.1%, while in those presenting heart failure it was 95.8%, p = 0.387. Furthermore, the clinical success was 72.2% and 87.5% among hemolysis and heart failure patients, respectively, p = 0.210. During the follow-up period, the two-year survival rates were significantly better for patients treated for the aortic valve (78.94%) compared to those in the mitral position (48.78%), p = 0.014. In total, 25 patients died (41.7%) during 24 months of follow-up. CONCLUSIONS: Transcatheter paravalvular leak closure can be performed with high technical and clinical success rates without any difference according to the prominent indication of closure.

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.

Impact of Evolution of Self-Expandable Aortic Valve Design: Peri-Operative and Short-Term Outcomes.

A few data exist on the differences of implantable aortic valve bio-prostheses. We investigate three generations of self-expandable aortic valves in terms of the outcomes. Patients undergoing transcatheter aortic valve implantation (TAVI) were allocated into three groups according to the valve type: group A (CoreValveTM), group B (EvolutTMR) and group C (EvolutTMPRO). The implantation depth, device success, electrocardiographic parameters, need for permanent pacemaker (PPM), and paravalvular leak (PVL) were assessed. In the study, 129 patients were included. The final implantation depth did not differ among the groups (p = 0.07). CoreValveTM presented greater upward jump of the valve at release (2.88 ± 2.33 mm vs. 1.48 ± 1.09 mm and 1.71 ± 1.35 mm, for groups A, B, and C, respectively, p = 0.011). The device success (at least 98% for all groups, p = 1.00) and PVL rates (67% vs. 58%, vs. 60% for groups A, B, and C, respectively, p = 0.64) did not differ. PPM implantation within 24 h (33% vs. 19% vs. 7% for groups A, B, and C, respectively, p = 0.006) and until discharge (group A: 38% vs. group B: 19% and group C: 9%, p = 0.005) was lower in the newer generation valves. Newer generation valves present better device positioning, more predictable deployment, and fewer rates of PPM implantation. No significant difference in PVL was observed.

Lipoprotein(a) and calcific aortic valve disease initiation and progression: a systematic review and meta-analysis.

Although evidence indicates the association of lipoprotein(a) [Lp(a)] with atherosclerosis, the link with calcific aortic valve disease (CAVD) is unclear. This systematic review and meta-analysis explores the connection between Lp(a) and aortic valve calcification and stenosis (AVS). We included all relevant studies, indexed in eight databases, up to February 2023. A total of 44 studies (163 139 subjects) were included, with 16 of them being further meta-analysed. Despite considerable heterogeneity, most studies support the relationship between Lp(a) and CAVD, especially in younger populations, with evidence of early aortic valve micro-calcification in elevated-Lp(a) populations. The quantitative synthesis showed higher Lp(a) levels, by 22.63 nmol/L (95% CI: 9.98-35.27), for patients with AVS, while meta-regressing the data revealed smaller Lp(a) differences for older populations with a higher proportion of females. The meta-analysis of eight studies providing genetic data, revealed that the minor alleles of both rs10455872 and rs3798220 LPA gene loci were associated with higher risk for AVS (pooled odds ratio 1.42; 95% CI: 1.34-1.50 and 1.27; 95% CI: 1.09-1.48, respectively). Importantly, high-Lp(a) individuals displayed not only faster AVS progression, by a mean difference of 0.09 m/s/year (95% CI: 0.09-0.09), but also a higher risk of serious adverse outcomes, including death (pooled hazard ratio 1.39; 95% CI: 1.01-1.90). These summary findings highlight the effect of Lp(a) on CAVD initiation, progression and outcomes, and support the early onset of Lp(a)-related subclinical lesions before clinical evidence.

Midterm Outcomes in Patients With Aortic Stenosis Treated With Contemporary Balloon-Expandable and Self-Expanding Valves: Does Valve Size Have an Impact on Outcome?

Background No data currently exist comparing the contemporary iterations of balloon-expandable (BE) Edwards SAPIEN 3/Ultra and the self-expanding (SE) Medtronic Evolut PRO/R34 valves. The aim of the study was the comparison of these transcatheter heart valves with emphasis on patients with small aortic annulus. Methods and Results In this retrospective registry, periprocedural outcomes and midterm all-cause mortality were analyzed. A total of 1673 patients (917 SE versus 756 BE) were followed up for a median of 15 months. A total of 194 patients died (11.6%) during follow-up. SE and BE groups showed similar survival at 1 (92.6% versus 90.6%) and 3 (80.3% versus 85.2%) years (Plog-rank=0.136). Compared with the BE group, patients treated with the SE device had lower peak (16.3±8 mm Hg SE versus 21.9±8 mm Hg BE) and mean (8.8±5 mm Hg SE versus 11.5±5 mm Hg BE) gradients at discharge. Conversely, the BE group demonstrated lower rates of at least moderate paravalvular regurgitation postoperatively (5.6% versus 0.7% for SE and BE valves, respectively; P<0.001). In patients treated with small transcatheter heart valves (≤26 mm for SE and ≤23 mm for BE; N=284 for SE and N=260 for BE), survival was higher among patients treated with SE valves at both 1 (96.7% SE versus 92.1% BE) and 3 (91.8% SE versus 82.2% BE) years (Plog-rank=0.042). In propensity-matched patients treated with small transcatheter heart valve, there remained a trend for higher survival among the SE group at both 1 (97% SE versus 92.3% BE) and 3 years (91.8% SE versus 78.7% BE), Plog-rank=0.096). Conclusions Real-world comparison of the latest-generation SE and BE devices demonstrated similar survival up to 3 years' follow-up. In patients with small transcatheter heart valves, there may be a trend for improved survival among those treated with SE valves.

The Role of Cell-derived Microparticles in Cardiovascular Diseases: Current Concepts.

Cardiovascular disease remains the main cause of human morbidity and mortality in developed countries. Microparticles (MPs) are small vesicles originating from the cell membrane as a result of various stimuli and particularly of biological processes that constitute the pathophysiology of atherosclerosis, such as endothelial damage. They form vesicles that can transfer various molecules and signals to remote target cells without direct cell-to-cell interaction. Circulating microparticles have been associated with cardiovascular diseases. Therefore, many studies have been designed to further investigate the role of microparticles as biomarkers for diagnosis, prognosis, and disease monitoring. To this concept, the pro-thrombotic and atherogenic potential of platelets and endothelial-derived MPs have gained research interest, especially concerning accelerated atherosclerosis and triggering as well as prognosis of an acute coronary syndrome. MPs, especially those of endothelial origin, have been investigated in different clinical scenarios of heart failure and in association with left ventricular loading conditions. Finally, most cardiovascular risk factors present unique features in the circulating MPs population, highlighting their pathophysiologic link to cardiovascular disease progression. In this review article, we present a synopsis of the biogenesis and characteristics of microparticles, as well as the most recent data concerning their implication in cardiovascular settings.

Residual Right-to-Left-Shunt Following Transcatheter Patent Foramen Ovale Closure: The Role of Antithrombotic Treatment.

BACKGROUND: Transcatheter closure of patent foramen ovale (PFO) is a highly effective therapy for patients with left circulation thromboembolism, not attributable to other conditions. OBJECTIVES: This retrospective cohort study investigates the impact of baseline foramen ovale anatomy on the severity of the postclosure shunt. METHODS: Patients with PFO, who underwent percutaneous closure, were followed up for at least 5 years postimplantation. Patients were classified into two groups based on the presence of high-risk features of the baseline PFO anatomy. At the follow-up follow-up, residual right-to-left shunt was assessed for the high and non-highrisk anatomy groups, via transcranial Doppler at rest and after performing the Valsalva maneuver, with the injection of agitated saline. RESULTS: 38 patients were examined after a mean follow-up period of 9 ± 3 years after implantation. After retrospective evaluation of the baseline transthoracic and transesophageal echo studies, 14 patients with high-risk PFO anatomy were identified. The degree of the residual right-to-left shunt, as assessed by the number of microbubbles was higher in the high-risk PFO anatomy group compared to the non-high-risk group, both at rest [1.50 (IQR: 0.00-3.25) vs. 0.00 (IQR: 0.00-0.00), p < 0.001] and post-Valsalva maneuver [7.50 (IQR: 1.50- 10.25) vs. 0.00 (IQR: 0.00-3.75), p = 0.003]. Furthermore, in the high-risk group, more microbubbles were detected at rest (p = 0.008) and post-Valsalva (p = 0.002) in subjects without antiplatelet treatment compared to subjects on prolonged antiplatelet therapy. CONCLUSION: Baseline PFO anatomy affects the severity of the residual right-to-left shunt. Prolonged antiplatelet therapy may benefit patients with high-risk anatomical features.

Interleukin-1 in Coronary Artery Disease.

Cardiovascular disease is the leading cause of mortality worldwide. Inflammation has long been established as a key component in the pathophysiology of coronary artery disease. The interleukin-1 family consists of 11 members that regulate the inflammatory response through both pro- and anti-inflammatory properties with the Nod-like receptor (NLR) family pyrin domain containing 3 inflammasome having a pivotal role in the process of converting interleukin-1 beta and interleukin- 18, two key inflammatory mediators, into their mature forms. Interleukin-1 affects various cell types that participate in the pathogenesis of atherosclerosis as it enhances the expression of leukocyte adhesion molecules on the surface of endothelial cells and augments the permeability of the endothelial cell barrier, attracting monocytes and macrophages into the vessel wall and aids the migration of smooth muscle cells toward atheroma. It also enhances the aggregation of low-density lipoprotein particles in endothelium and smooth muscle cells and exhibits procoagulant activity by inducing synthesis, cell-surface expression and release of tissue factor in endothelial cells, promoting platelet adhesion. The value of interleukin-1 as a diagnostic biomarker is currently limited, but interleukin-1 beta, interleukin-18 and interleukin-37 have shown promising data regarding their prognostic value in coronary artery disease. Importantly, target anti-inflammatory treatments have shown promising results regarding atherosclerosis progression and cardiovascular events. In this review article, we focus on the immense role of interleukin-1 in atherosclerosis progression, inflammation cascade and in the clinical application of target anti-inflammatory treatments.

Current Concepts and Future Applications of Non-Invasive Functional and Anatomical Evaluation of Coronary Artery Disease.

Over the last decades, significant advances have been achieved in the treatment of coronary artery disease (CAD). Proper non-invasive diagnosis and appropriate management based on functional information and the extension of ischemia or viability remain the cornerstone in the fight against adverse CAD events. Stress echocardiography and single photon emission computed tomography are often used for the evaluation of ischemia. Advancements in non-invasive imaging modalities such as computed tomography (CT) coronary angiography and cardiac magnetic resonance imaging (MRI) have not only allowed non-invasive imaging of coronary artery lumen but also provide additional functional information. Other characteristics regarding the plaque morphology can be further evaluated with the latest modalities achieving a morpho-functional evaluation of CAD. Advances in the utilization of positron emission tomography (PET), as well as software advancements especially regarding cardiac CT, may provide additional prognostic information to a more evidence-based treatment decision. Since the armamentarium on non-invasive imaging modalities has evolved, the knowledge of the capabilities and limitations of each imaging modality should be evaluated in a case-by-case basis to achieve the best diagnosis and treatment decision. In this review article, we present the most recent advances in the noninvasive anatomical and functional evaluation of CAD.

The Role of Endothelial Related Circulating Biomarkers in COVID-19. A Systematic Review and Meta-analysis.

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 (VWFAg), 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.