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.

Different venous approaches for implantation of cardiac electronic devices. A network meta-analysis.

OBJECTIVES: Many of the complications arising from cardiac device implantation are associated to the venous access used for lead placement. Previous analyses reported that cephalic vein cutdown (CVC) is safer but less effective than subclavian vein puncture (SVP). However, comparisons between these techniques and axillary vein puncture (AVP) - guided either by ultrasound or fluoroscopy - are lacking. Thus, we aimed to compare safety and efficacy of these approaches. METHODS: We searched for articles assessing at least two different approaches regarding the incidence of pneumothorax and/or lead failure (LF). When available, bleeding and infectious complications as well as procedural success were analyzed. A frequentist random effects network meta-analysis model was adopted. RESULTS: Thirty-six studies were analyzed. Most articles assessed SVP versus CVC. Compared to SVP, both CVC and AVP were associated with reduced odds of pneumothorax (OR: 0.193, 95%CI: 0.136-0.275 and OR: 0.128, 95%CI: 0.050-0.329; respectively) and LF (OR: 0.63, 95%CI: 0.406-0.976 and OR: 0.425, 95%CI: 0.286-0.632; respectively). No significant differences between AVP and CVC were demonstrated. Limited data suggests no major impact of different approaches on infectious and bleeding complications. Initial CVC approach required significantly more often an alternate/additional venous access for lead placement, compared to both AVP and SVP. No differences between these two were identified. CONCLUSION: Both AVP and CVC seem to decrease incident pneumothorax and LF, compared to SVP. Initial AVP approach seems to decrease the need of alternate venous access, compared to CVC. These results suggest that AVP should be further clinically tested.

Advances in Heart Failure with Preserved Ejection Fraction Management - The role of Sacubitril-Valsartan, Pirfenidone, Spironolactone and Empagliflozin: Is Success a Series of Small Victories?

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by marked heterogeneity in comorbidities and etiopathology substrates, leading to a diverse range of clinical manifestations and courses. Treatment options have been extremely limited and up to this day, there are virtually no pharmaceutical agents proven to reduce mortality in these patients. OBJECTIVE: The primary objective of this narrative review is to critically summarize existing evidence regarding the use of Angiotensin Receptor-Neprilysin Inhibitor (ARNI), spironolactone, pirfenidone and empagliflozin in HFpEF. METHODS: Medline (via PubMed) and Scopus were searched - from inception up to May 2022- using adequately selected keywords. Additional hand-search was also performed using the references of the articles identified as relevant (snowball strategy). RESULTS: Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and spironolactone, despite being very successful in HFrEF, did not do well in clinical trials of HFpEF, although there appear to be certain subsets of patients who may derive benefit. Data regarding pirfenidone are limited and come from small trials; as a result, it would be premature to draw firm conclusions, although it seems improbable that this agent will ever become a mainstay in the general population of HPpEF patients, while there may be a niche for the drug in individuals with comorbidities associated with an intense fibrotic activity. Finally, empagliflozin, largely welcomed as the first agent to have a "positive" randomized clinical trial in HFpEF, does not seem to evade the general pattern of reduced hospitalizations for HF with no substantial effect on mortality, seen in ARNI and spironolactone HFpEF trials. CONCLUSION: Recent research in drug treatment for HFpEF has resulted in an overall mixed picture, with trials showing potential benefits from certain classes of drugs, such as sodium-glucose co-transporter 2 inhibitors, and no benefit from other drugs, which have shown to be effective in patient with reduced ejection fraction. However, small steps may be the way to go in HFpEF, and success is sometimes just a series of small victories.

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.

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.

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?

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.

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.

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.

"TAVI: Valve in valve. A new field for structuralists? Literature review".

Transcatheter aortic valve implantation (TAVI) led to the foundation of the subspecialty of structural heart interventions and created an emerging area of clinical and technical issues. Soon after TAVI introduction into clinical practice, boundaries were expanded with utilization of valve-in-valve (V-i-V) techniques. V-i-V comprised a diverse subset of patients including TAVI within TAVI, TAVI within a degenerated surgically implanted bioprosthesis, or even TAVI-in-TAVI-in-surgical bioprosthesis. In the present review, we summarize the available literature and present initial experience on the field in Greece.

The Role of Colchicine in Treating Postoperative and Post-catheter Ablation Atrial Fibrillation.

PURPOSE: The goal of this review was to summarize, analyze, and compare trials studying the efficacy of colchicine in the prevention of atrial fibrillation (AF) post-operatively (POAF) and post-catheter ablation. Ongoing studies and current guidelines are also presented and reviewed. METHODS: Published studies on the field were identified through a literature search of the PubMed and clinicaltrials.gov databases. FINDINGS: Four original studies regarding POAF, two original studies regarding post-catheter ablation AF, and six meta-analyses were identified. In addition, the 3 most recent guidelines/expert consensus documents were scrutinized. IMPLICATIONS: AF occurs frequently after cardiac surgery (POAF) and catheter pulmonary vein isolation (postablation AF) and is associated with increased cardiovascular morbidity. A number of trials over the last few years have investigated the role of colchicine in the prevention of POAF and postablation AF targeting the local and systemic inflammatory process that leads to initiation and maintenance of AF. Available data imply that colchicine may have a preventive role in POAF and/or postablation AF. However, certain limitations of these studies underline the need for further investigation.

Interatrial conduction time and incident atrial fibrillation: a prospective cohort study.

BACKGROUND: Atrial electrical conduction properties have been implicated in atrial fibrillation (AF) pathogenesis. OBJECTIVE: The purpose of this study was to prospectively assess the potential association of interatrial conduction time (IACT) with incident AF. METHODS: The study included persons referred for invasive electrophysiologic study (EPS), aged ≥50 years, without AF history or valvular disease. IACT was defined as the interval between the high right atrium electrogram and the distal coronary sinus atrial electrogram. RESULTS: Six hundred twelve subjects were included (median follow-up 43 months, interquartile range 40-47). AF incidence was 21.7 cases per 1000 person-years. IACT was a significant predictor of AF with a c-statistic of 0.770 (95% confidence interval 0.702-0.838). In time-dependent analysis, IACT was a significant stratifier of AF risk (log-rank 28.0, P <.001). The corresponding incidences of AF in each tertile of IACT were 3, 17, and 46 per 1000 person-years, respectively (all differences between tertiles were significant). IACT remained significant in multivariable Cox regression analysis, after adjustment for age, sex, hypertension, and left atrial diameter, with each millisecond of prolonged IACT corresponding to 7% (95% confidence interval 2%-12%) higher adjusted risk of incident AF. CONCLUSION: IACT is independently associated with incident AF. The invasive nature of the measurement is a limitation for its use as a clinical risk stratifier (although it could be used in patients referred for EPS), but these results are of interest in themselves because they suggest a strong pathophysiologic connection between atrial conduction times and substrate alterations ultimately leading to AF.

Association of asymmetric dimethylarginine levels with treadmill-stress-test-derived prognosticators.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide production. The purpose of this study was to assess the correlation between ADMA and treadmill stress test outcome parameters with known prognostic value, in patients with intermediate risk for coronary artery disease (CAD). METHODS: Study participants were referred for treadmill exercise stress test (EST) due to symptoms of suspected CAD. Participants with prior history of CAD, cerebrovascular events, peripheral artery disease, systemic inflammatory disease or use of anti-inflammatory agents were excluded. ADMA levels were measured before EST. RESULTS: The study prospectively enrolled 209 individuals (165 males, aged 58.1±10.9). A significant negative correlation was detected between ADMA and maximal exercise time (r=-0.556, p<0.001), metabolic equivalents (METs) (r=-0.555, p<0.001) and Duke treadmill score (DTS) (r=-0.347, p<0.001). Subjects who exercised to ≥10 METs (n=114) had lower ADMA levels than those who achieved <7 METs (n=30) (0.58±0.06 vs 0.87±0.08µmol/L, p<0.001), and those with DTS<5 (n=63) had higher ADMA (0.75±0.19 vs 0.64±0.15µmol/L, p<0.001) compared to those with DTS ≥5 (n=146). In multivariable analysis, ADMA remained an independent predictor of DTS (R(2)=0.210; beta=-10.5; 95% confidence interval -14.9 to -6.2; adjusted p<0.001) and METs (R(2)=0.500; beta -8.5; 95% confidence interval -9.7 to -6.0; adjusted p<0.001) after adjustment for age, BMI, gender, diabetes, smoking status, dyslipidemia, hypertension and family history of premature CAD. CONCLUSION: ADMA is correlated to EST parameters with proven prognostic value. This implies that ADMA itself might be a useful prognosticator in patients with suspected CAD.