Efficacy, Safety and Feasibility of Superior Vena Cava Isolation in Patients Undergoing Atrial Fibrillation Catheter Ablation: An Up-to-Date Review.

Pulmonary vein isolation (PVI) is the cornerstone in atrial fibrillation (AF) ablation; yet, the role of arrhythmogenic superior vena cava (SVC) is increasingly recognized and different ablation strategies have been employed in this context. SVC can act as a trigger or perpetuator of AF, and its significance might be more pronounced in patients undergoing repeated ablation. Several cohorts have examined efficacy, safety and feasibility of SVC isolation (SVCI) among AF patients. The majority of these studies explored as-needed SVCI during index PVI, and only a minority of them included repeated ablation subjects and non-radiofrequency energy sources. Studies of heterogeneous design and intent have explored both empiric and as-needed SVCI on top of PVI and reported inconclusive results. These studies have largely failed to demonstrate any clinical benefit in terms of arrhythmia recurrence, although safety and feasibility are undisputable. Mixed population demographics, small number of enrollees and short follow-up are the main limitations. Procedural and safety data are comparable between empiric SVCI and as-needed SVCI, and some studies suggested that empiric SVCI might be associated with reduced AF recurrences in paroxysmal AF patients. Currently, no study has compared different ablation energy sources in the setting of SVCI, and no randomized study has addressed as-needed SVCI on top of PVI. Furthermore, data regarding cryoablation are still in their infancy, and regarding SVCI in patients with cardiac devices more safety and feasibility data are needed. PVI non-responders, patients undergoing repeated ablation and patients with long SVC sleeves could be potential candidates for SVCI, especially via an empiric approach. Although many technical aspects remain unsettled, the major question to answer is which clinical phenotype of AF patients might benefit from SVCI?

Targeted Proteomic Analysis of Patients with Ascending Thoracic Aortic Aneurysm.

BACKGROUND: There is a need for clinical markers to aid in the detection of individuals at risk of harboring an ascending thoracic aneurysm (ATAA) or developing one in the future. OBJECTIVES: To our knowledge, ATAA remains without a specific biomarker. This study aims to identify potential biomarkers for ATAA using targeted proteomic analysis. METHODS: In this study, 52 patients were divided into three groups depending on their ascending aorta diameter: 4.0-4.5 cm (N = 23), 4.6-5.0 cm (N = 20), and >5.0 cm (N = 9). A total of 30 controls were in-house populations ethnically matched to cases without known or visible ATAA-related symptoms and with no ATAA familial history. Before the debut of our study, all patients provided medical history and underwent physical examination. Diagnosis was confirmed by echocardiography and angio-computed tomography (CT) scans. Targeted-proteomic analysis was conducted to identify possible biomarkers for the diagnosis of ATAA. RESULTS: A Kruskal-Wallis test revealed that C-C motif chemokine ligand 5 (CCL5), defensin beta 1 (HBD1), intracellular adhesion molecule-1 (ICAM1), interleukin-8 (IL8), tumor necrosis factor alpha (TNFα) and transforming growth factor-beta 1 (TGFB1) expressions are significantly increased in ATAA patients in comparison to control subjects with physiological aorta diameter (p < 0.0001). The receiver-operating characteristic analysis showed that the area under the curve values for CCL5 (0.84), HBD1 (0.83) and ICAM1 (0.83) were superior to that of the other analyzed proteins. CONCLUSIONS: CCL5, HBD1 and ICAM1 are very promising biomarkers with satisfying sensitivity and specificity that could be helpful in stratifying risk for the development of ATAA. These biomarkers may assist in the diagnosis and follow-up of patients at risk of developing ATAA. This retrospective study is very encouraging; however, further in-depth studies may be worthwhile to investigate the role of these biomarkers in the pathogenesis of ATAA.

Left atrial appendage morphofunctional indices could be predictive of arrhythmia recurrence post-atrial fibrillation ablation: a meta-analysis.

BACKGROUND: Left atrium changes are implicated in atrial fibrillation (AF) substrate and are predictive of AF outcomes. Left atrial appendage (LAA) is an integral component of left atrial structure and could be affected by atrial cardiomyopathy. We aimed to elucidate the association between LAA indices and late arrhythmia recurrence after atrial fibrillation catheter ablation (AFCA). METHODS: The MEDLINE database, ClinicalTrials.gov, medRxiv and Cochrane Library were searched for studies evaluating LAA and late arrhythmia recurrence in patients undergoing AFCA. Data were pooled by meta-analysis using a random-effects model. The primary endpoint was pre-ablation difference in LAA anatomic or functional indices. RESULTS: A total of 34 studies were found eligible and five LAA indices were analyzed. LAA ejection fraction and LAA emptying velocity were significantly lower in patients with AF recurrence post-ablation [SMD = - 0.66; 95% CI (- 1.01, - 0.32) and SMD = - 0.56; 95% CI (- 0.73, - 0.40) respectively] as compared to arrhythmia free controls. LAA volume and LAA orifice area were significantly higher in patients with AF recurrence post-ablation (SMD = 0.51; 95% CI 0.35-0.67, and SMD = 0.35; 95% CI 0.20-0.49, respectively) as compared to arrhythmia free controls. LAA morphology was not predictive of AF recurrence post-ablation (chicken wing morphology; OR 1.27; 95% CI 0.79-2.02). Moderate statistical heterogeneity and small case-control studies are the main limitations of our meta-analysis. CONCLUSIONS: Our findings suggest that LAA ejection fraction, LAA emptying velocity, LAA orifice area and LAA volume differ between patients suffering from arrhythmia recurrence post-ablation and arrhythmia free counterparts, while LAA morphology is not predictive of AF recurrence.

Advances in the Management of Heart Failure with Reduced Ejection Fraction; The Role of SGLT2is, ARNI, Myotropes, Vericiguat, and Anti-inflammatory Agents: A Mini-review.

Heart failure with reduced ejection fraction (HFrEF) has been associated with poor prognosis, reduced quality of life, and increased healthcare expenditure. Despite tremendous advances in HFrEF management, reduced survival and a high rate of hospitalization remain unsolved issues. Furthermore, HFrEF morbidity and economic burden are estimated to increase in the following years; hence, new therapies are constantly emerging. In the last few years, a series of landmark clinical trials have expanded our therapeutic armamentarium with a ground-breaking change in HFrEF-related outcomes. Sodium-glucose co-transporter 2 inhibitors (mainly dapagliflozin and empagliflozin) have already revolutionized the management of HFrEF patients via a significant reduction in cardiovascular mortality and heart failure hospitalizations. Furthermore, vericiguat and omecamtiv mecarbil have emerged as promising and novel disease-modifying therapies. The former restores the impaired cyclic guanosine monophosphate pathway, and the latter stimulates cardiac myosin without marked arrhythmogenesis. Both vericiguat and omecamtiv mecarbil have been shown to reduce heart failure admissions. Sacubitril/valsartan is an established and effective therapy in HFrEF patients and should be considered as a replacement for angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs). Lastly, inflammasome activity is implicated in HFrEF pathophysiology, and the role of anti-inflammatory agents in HFrEF trajectories is readily scrutinized, yet available therapies are ineffective. This mini-review summarizes the major and most recent studies in this field, thus covering the current advances in HFrEF therapeutics.

Choroidal thickness in patients with systemic arterial hypertension: a systematic review and meta-analysis.

Background: The global burden of hypertension is constantly increasing with adverse cardiovascular and ocular sequelae. The association between elevated blood pressure and choroidal thickness (CT), as assessed via optical coherence tomography (OCT), is poorly understood. Objectives and Design: Studies including hypertensive adults and normotensive controls undergoing OCT were evaluated for inclusion in this meta-analysis. The primary endpoint was CT difference between hypertensive and normotensive adults. Data Sources and Methods: We conducted a systematic review and after searching 1011 results from MEDLINE, ClinicalTrials.gov, medRxiv and Cochrane Library, six studies were deemed eligible and were pooled according to a random-effect model. Results: A statistically significant reduction in choroidal thickness was found in hypertensive adults (n = 454) as compared with normotensive controls (n = 365) [mean difference: -0.77; 95% confidence intervals: (-1.20, -0.34); p = 0.0004]. The main limitations of this meta-analysis are the relatively small population included and the high statistical heterogeneity (I 2 = 87%) among the various studies. Of note, after excluding one study the heterogeneity was markedly reduced. Conclusion: Choroidal thickness is reduced among hypertensive subjects compared with normotensive controls. This finding mandates further examination in the context of long-term clinical outcomes.

Inflammatory Biomarkers in Coronary Artery Ectasia: A Systematic Review and Meta-Analysis.

Isolated coronary artery ectasia (CAE) is a relatively rare clinical entity, the pathogenesis of which is poorly understood. More and more evidence is accumulating to suggest a critical inflammatory component. We aimed to elucidate any association between neutrophil to lymphocyte ratio and coronary artery ectasia. A systematic MEDLINE database, ClinicalTrials.gov, medRxiv, Scopus and Cochrane Library search was conducted: 50 studies were deemed relevant, reporting on difference in NLR levels between CAE patients and controls (primary endpoint) and/or on high-sensitive CRP, IL-6, TNF-a and RDW levels (secondary endpoint), and were included in our final analysis. (PROSPERO registration number: CRD42021224195). All inflammatory biomarkers under investigation were found higher in coronary artery ectasia patients as compared to healthy controls (NLR; SMD = 0.73; 95% CI: 0.27-1.20, hs-CRP; SMD = 0.96; 95% CI: 0.64-1.28, IL-6; SMD = 2.68; 95% CI: 0.95-4.41, TNF-a; SMD = 0.50; 95% CI: 0.24-0.75, RDW; SMD = 0.56; 95% CI: 0.26-0.87). The main limitations inherent in this analysis are small case-control studies of moderate quality and high statistical heterogeneity. Our findings underscore that inflammatory dysregulation is implicated in coronary artery ectasia and merits further investigation.

Early arrhythmia recurrence after cryoballoon ablation in atrial fibrillation: A systematic review and meta-analysis.

INTRODUCTION: Early arrhythmia recurrence within the 3-month blanking period is a common event that historically has been attributed to reversible phenomena. While its mechanistic links remain obscure, accumulating evidence support the argument of shortening the blanking period. We aimed to elucidate the association between early and late arrhythmia recurrence after atrial fibrillation cryoablation. METHODS: The MEDLINE database, ClinicalTrials. gov, medRxiv, and Cochrane Library were searched for studies evaluating early and late arrhythmia recurrence rates in patients undergoing cryoablation for atrial fibrillation. Data were pooled by meta-analysis using a random-effects model. The primary endpoint was late arrhythmia recurrence. RESULTS: Early arrhythmia recurrence was found predictive of decreased arrhythmia-free survival after evaluating 3975 patients with paroxysmal or persistent atrial fibrillation who underwent cryoablation (odds ratio [OR]: 5.31; 95% confidence interval [CI]: 3.75-7.51). This pattern remained unchanged after subanalyzing atrial fibrillation type (paroxysmal; OR: 7.16; 95% CI: 4.40-11.65 and persistent; OR: 7.63; 95% CI: 3.62-16.07) as well as cryoablation catheter generation (first generation; OR: 5.15, 95% CI: 2.39-11.11 and advanced generation; OR: 5.83, 95% CI: 3.68-9.23). Studies permitting antiarrhythmic drug utilization during the blanking period or examining early recurrence as a secondary outcome were found to be a significant source of statistical heterogeneity. CONCLUSION: Our findings suggest that early arrhythmia recurrence is predictive of late outcomes after cryoablation for atrial fibrillation. Identifying which patients deserve earlier reintervention is an open research avenue.

Colchicine in Cardiovascular Disease: In-Depth Review.

Inflammation plays a prominent role in the development of atherosclerosis and other cardiovascular diseases, and anti-inflammatory agents may improve cardiovascular outcomes. For years, colchicine has been used as a safe and well-tolerated agent in diseases such as gout and familial Mediterranean fever. The widely available therapeutic has several anti-inflammatory effects, however, that have proven effective in a broad spectrum of cardiovascular diseases as well. It is considered standard-of-care therapy for pericarditis, and several clinical trials have evaluated its role in postoperative and postablation atrial fibrillation, postpericardiotomy syndrome, coronary artery disease, percutaneous coronary interventions, and cerebrovascular disease. We aim to summarize colchicine's pharmacodynamics and the mechanism behind its anti-inflammatory effect, outline thus far accumulated evidence on treatment with colchicine in cardiovascular disease, and present ongoing randomized clinical trials. We also emphasize real-world clinical implications that should be considered on the basis of the merits and limitations of completed trials. Altogether, colchicine's simplicity, low cost, and effectiveness may provide an important addition to other standard cardiovascular therapies. Ongoing studies will address complementary questions pertaining to the use of low-dose colchicine for the treatment of cardiovascular disease.

Immunologic Dysregulation and Hypercoagulability as a Pathophysiologic Background in COVID-19 Infection and the Immunomodulating Role of Colchicine.

In 2020, SARS-COV-2 put health systems under unprecedented resource and manpower pressure leading to significant number of deaths. Expectedly, researchers sought to shed light on the pathophysiologic background of this novel disease (COVID-19) as well as to facilitate the design of effective therapeutic modalities. Indeed, early enough the pivotal role of inflammatory and thrombotic pathways in SARS-COV-2 infection has been illustrated. The purpose of this article is to briefly present the epidemiologic and clinical features of COVID-19, analyze the pathophysiologic importance of immunologic dysregulation and hypercoagulability in developing disease complications and finally to present an up-to-date systematic review of colchicine's immunomodulating capacity in view of hindering coronavirus complications.

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review.

The prevalence of atrial fibrillation (AF) is bound to increase globally in the following years, affecting the quality of life of millions of people, increasing mortality and morbidity, and beleaguering health care systems. Increasingly effective therapeutic options against AF are the constantly evolving electroanatomic substrate mapping systems of the left atrium (LA) and ablation catheter technologies. Yet, a prerequisite for better long-term success rates is the understanding of AF pathogenesis and maintenance. LA electrical and anatomical remodeling remains in the epicenter of current research for novel diagnostic and treatment modalities. On a molecular level, electrical remodeling lies on impaired calcium handling, enhanced inwardly rectifying potassium currents, and gap junction perturbations. In addition, a wide array of profibrotic stimuli activates fibroblast to an increased extracellular matrix turnover via various intermediaries. Concomitant dysregulation of the autonomic nervous system and the humoral function of increased epicardial adipose tissue (EAT) are established mediators in the pathophysiology of AF. Local atrial lymphomononuclear cells infiltrate and increased inflammasome activity accelerate and perpetuate arrhythmia substrate. Finally, impaired intracellular protein metabolism, excessive oxidative stress, and mitochondrial dysfunction deplete atrial cardiomyocyte ATP and promote arrhythmogenesis. These overlapping cellular and molecular alterations hinder us from distinguishing the cause from the effect in AF pathogenesis. Yet, a plethora of therapeutic modalities target these molecular perturbations and hold promise in combating the AF burden. Namely, atrial selective ion channel inhibitors, AF gene therapy, anti-fibrotic agents, AF drug repurposing, immunomodulators, and indirect cardiac neuromodulation are discussed here.

Could Sodium/Glucose Co-Transporter-2 Inhibitors Have Antiarrhythmic Potential in Atrial Fibrillation? Literature Review and Future Considerations.

The global burden of atrial fibrillation (AF) is constantly increasing, necessitating novel and effective therapeutic options. Sodium glucose co-transporter 2 (SGLT2) inhibitors have been introduced in clinical practice as glucose-lowering medications. However, they have recently gained prominence for their potential to exert substantial cardiorenal protection and are being evaluated in large clinical trials including patients with type 2 diabetes and normoglycemic adults. In this review we present up-to-date available evidence in a pathophysiology-directed manner from cell to bedside. Preclinical and clinical data regarding a conceivable antiarrhythmic effect of SGLT2 inhibitors are beginning to accumulate. Herein we comprehensively present data that explore the potential pathophysiological link between SGLT2 inhibitors and AF. With regard to clinical data, no randomized controlled trials evaluating SGLT2 inhibitors effects on AF as a pre-specified endpoint are available. However, data from randomized controlled trial post-hoc analysis as well as observational studies point to a possible beneficial effect of SGLT2 inhibitors on AF. Meta-analyses addressing this question report inconsistent results and the real magnitude of AF prevention by SGLT2 inhibition remains unclear. Still, while (i) pathophysiologic mechanisms involved in AF might be favorably affected by SGLT2 inhibitors and (ii) emerging, yet inconsistent, clinical data imply that SGLT2 inhibitor-mediated cardiorenal protection could also exert antiarrhythmic effects, the argument of whether these novel drugs will reduce AF burden is unsettled and mandates appropriately designed and adequately sized randomized controlled studies.

Repurposing colchicine's journey in view of drug-to-drug interactions. A review.

Colchicine's medical evolution is historically bound to the Mediterranean basin, since remarkable researchers from this region underscored its valuable properties. With the passing of years colchicine became an essential pharmaceutical substance for the treatment of rheumatologic and cardiovascular diseases. In light of recent findings, the therapeutic value of colchicine has grown. In clinical practice, colchicine remains underutilized in view of its proven efficacy and safety. Its complex pharmacokinetics and multifaceted anti-inflammatory role remain under investigation. The current review addresses the safe administration of colchicine in view of key drug to drug interactions. Finally, we are briefly presenting colchicine's future potential applications.

Atrial fibrillation risk in patients suffering from type I diabetes mellitus. A review of clinical and experimental evidence.

Atrial fibrillation (AF) and diabetes mellitus (DM) are commonly encountered in clinical practice. Although, the long term macrovascular and microvascular sequela of DM are well validated, the association between the less prevalent type 1 DM (T1DM) and atrial arrhythmogenesis is poorly understood. In the present review we highlight the current experimental and clinical data addressing this complex interaction. Animal studies support that T1DM, characterized by insulin deficiency and glycemic variability, impairs phosphatidylinositol 3­kinase (PI3K)/protein kinase B signaling pathway. This pathway holds a central role in atrial electrical and structural remodeling responsible for arrhythmia initiation and maintenance. The molecular ''footprint'' of T1DM in atrial myocytes seems to involve a state of increased oxidative stress, impaired glucose transportation, ionic channel dysregulation and eventually fibrosis. On the contrary only a few clinical studies have examined the role of T1DM as an independent risk factor for AF development, and are discussed here. Further research is needed to solidify the real magnitude of this association and to investigate the clinical implications of PI3K molecular signaling pathway in atrial fibrillation management.

Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.

Importance: Severe acute respiratory syndrome coronavirus 2 infection has evolved into a global pandemic. Low-dose colchicine combines anti-inflammatory action with a favorable safety profile. Objective: To evaluate the effect of treatment with colchicine on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19). Design, Setting, and Participants: In this prospective, open-label, randomized clinical trial (the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention), 105 patients hospitalized with COVID-19 were randomized in a 1:1 allocation from April 3 to April 27, 2020, to either standard medical treatment or colchicine with standard medical treatment. The study took place in 16 tertiary hospitals in Greece. Intervention: Colchicine administration (1.5-mg loading dose followed by 0.5 mg after 60 min and maintenance doses of 0.5 mg twice daily) with standard medical treatment for as long as 3 weeks. Main Outcomes and Measures: Primary end points were (1) maximum high-sensitivity cardiac troponin level; (2) time for C-reactive protein to reach more than 3 times the upper reference limit; and (3) time to deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death. Secondary end points were (1) the percentage of participants requiring mechanical ventilation, (2) all-cause mortality, and (3) number, type, severity, and seriousness of adverse events. The primary efficacy analysis was performed on an intention-to-treat basis. Results: A total of 105 patients were evaluated (61 [58.1%] men; median [interquartile range] age, 64 [54-76] years) with 50 (47.6%) randomized to the control group and 55 (52.4%) to the colchicine group. Median (interquartile range) peak high-sensitivity cardiac troponin values were 0.0112 (0.0043-0.0093) ng/mL in the control group and 0.008 (0.004-0.0135) ng/mL in the colchicine group (P = .34). Median (interquartile range) maximum C-reactive protein levels were 4.5 (1.4-8.9) mg/dL vs 3.1 (0.8-9.8) mg/dL (P = .73), respectively. The clinical primary end point rate was 14.0% in the control group (7 of 50 patients) and 1.8% in the colchicine group (1 of 55 patients) (odds ratio, 0.11; 95% CI, 0.01-0.96; P = .02). Mean (SD) event-free survival time was 18.6 (0.83) days the in the control group vs 20.7 (0.31) in the colchicine group (log rank P = .03). Adverse events were similar in the 2 groups, except for diarrhea, which was more frequent with colchicine group than the control group (25 patients [45.5%] vs 9 patients [18.0%]; P = .003). Conclusions and Relevance: In this randomized clinical trial, participants who received colchicine had statistically significantly improved time to clinical deterioration. There were no significant differences in high-sensitivity cardiac troponin or C-reactive protein levels. These findings should be interpreted with caution. Trial Registration: ClinicalTrials.gov Identifier: NCT04326790.

Antithrombotics in intracerebral hemorrhage in the era of novel agents and antidotes: A review.

BACKGROUND: Intracerebral hemorrhage (ICH)1 is characterized by the pathological accumulation of blood within the brain parenchyma, most commonly associated with hypertension, arteriovenous malformations, or trauma. However, it can also present in patients receiving antithrombotic drugs, either anticoagulants such as acenocoumarol/warfarin-novel oral anticoagulants or antiplatelets, for the prevention and treatment of thromboembolic disease. OBJECTIVE: The purpose of this review is to present current bibliographic data regarding ICH irrespective of the cause, as well as post-hemorrhage use of antithrombotic agents. Moreover, this review attempts to provide guidelines concerning the termination, inversion, and of course resumption of antithrombotic therapy. METHODS AND MATERIALS: We reviewed the most recently presented available data for patients who dealt with intracerebral hemorrhagic events while on antithrombotic agents (due to atrial fibrillation, prosthetic mechanical valves or recent/recurrent deep vein thrombosis). Furthermore, we examined and compared the thromboembolic risk, the bleeding risk, as well as the re-bleeding risk in two groups: patients receiving antithrombotic therapy versus patients not on antithrombotic therapy. CONCLUSION: Antithrombotic therapy is of great importance when indicated, though it does not come without crucial side-effects, such as ICH. Optimal timing of withdrawal, reversal, and resumption of antithrombotic treatment should be determined by a multidisciplinary team consisting of a stroke specialist, a cardiologist, and a neurosurgeon, who will individually approach the needs and risks of each patient.

The Greek study in the effects of colchicine in COvid-19 complications prevention (GRECCO-19 study): Rationale and study design.

OBJECTIVE: Colchicine has been utilized safely in a variety of cardiovascular clinical conditions. Among its potential mechanisms of action is the non-selective inhibition of NLRP3 inflammasome which is thought to be a major pathophysiologic component in the clinical course of patients with COVID-19. GRECCO-19 will be a prospective, randomized, open-labeled, controlled study to assess the effects of colchicine in COVID-19 complications prevention. METHODS: Patients with laboratory confirmed SARS-CoV-2 infection (under RT PCR) and clinical picture that involves temperature >37.5 oC and at least two out of the: i. sustained coughing, ii. sustained throat pain, iii. Anosmia and/or ageusia, iv. fatigue/tiredness, v. PaO2<95 mmHg will be included. Patients will be randomised (1:1) in colchicine or control group. RESULTS: Trial results will be disseminated through peer-reviewed publications and conference presentations. CONCLUSION: GRECCO-19 trial aims to identify whether colchicine may positively intervene in the clinical course of COVID-19. (ClinicalTrials.gov Identifier: NCT04326790).