CIB2 Is a Novel Endogenous Repressor of Atrial Remodeling.

BACKGROUND: Atrial fibrillation (AF) is a highly prevalent condition that can cause or exacerbate heart failure, is an important risk factor for stroke, and is associated with pronounced morbidity and death. Genes uniquely expressed in the atria are known to be essential for maintaining atrial structure and function. Atrial tissue remodeling contributes to arrhythmia recurrence and maintenance. However, the mechanism underlying atrial remodeling remains poorly understood. This study was designed to investigate whether other uncharacterized atrial specific genes play important roles in atrial physiology and arrhythmogenesis. METHODS: RNA-sequencing analysis was used to identify atrial myocyte specific and angiotensin II-responsive genes. Genetically modified, cardiomyocyte-specific mouse models (knockout and overexpression) were generated. In vivo and in vitro electrophysiological, histology, and biochemical analyses were performed to determine the consequences of CIB2 (calcium and integrin binding family member 2 protein) gain and loss of function in the atrium. RESULTS: Using RNA-sequencing analysis, we identified CIB2 as an atrial-enriched protein that is significantly downregulated in the left atria of patients with AF and mouse models of AF from angiotensin II infusion or pressure overload. Using cardiomyocyte-specific Cib2 knockout (Cib2-/-) and atrial myocyte-specific Cib2-overexpressing mouse models, we found that loss of Cib2 enhances AF occurrence, prolongs AF duration, and correlates with a significant increase in atrial fibrosis under stress. Conversely, Cib2 overexpression mitigates AF occurrence and atrial fibrosis triggered by angiotensin II stress. Mechanistically, we revealed that CIB2 competes with and inhibits CIB1-mediated calcineurin activation, thereby negating stress-induced structural remodeling and AF. CONCLUSIONS: Our data suggest that CIB2 represents a novel endogenous and atrial-enriched regulator that protects against atrial remodeling and AF under stress conditions. Therefore, CIB2 may represent a new potential target for treating AF.

Pathophysiology and clinical relevance of atrial myopathy.

Atrial myopathy is a condition that consists of electrical, structural, contractile, and autonomic remodeling of the atria and is the substrate for development of atrial fibrillation, the most common arrhythmia. Pathophysiologic mechanisms driving atrial myopathy are inflammation, oxidative stress, atrial stretch, and neurohormonal signals, e.g., angiotensin-II and aldosterone. These mechanisms initiate the structural and functional remodeling of the atrial myocardium. Novel therapeutic strategies are being developed that target the pathophysiologic mechanisms of atrial myopathy. In this review, we will discuss the pathophysiology of atrial myopathy, as well as diagnostic and therapeutic strategies.

Heart rate fragmentation and brain MRI markers of small vessel disease in MESA.

INTRODUCTION: Heart rate (HR) fragmentation indices quantify breakdown of HR regulation and are associated with atrial fibrillation and cognitive impairment. Their association with brain magnetic resonance imaging (MRI) markers of small vessel disease is unexplored. METHODS: In 606 stroke-free participants of the Multi-Ethnic Study of Atherosclerosis (mean age 67), HR fragmentation indices including percentage of inflection points (PIP) were derived from sleep study recordings. We examined PIP in relation to white matter hyperintensity (WMH) volume, total white matter fractional anisotropy (FA), and microbleeds from 3-Tesla brain MRI completed 7 years later. RESULTS: In adjusted analyses, higher PIP was associated with greater WMH volume (14% per standard deviation [SD], 95% confidence interval [CI]: 2, 27%, P = 0.02) and lower WM FA (-0.09 SD per SD, 95% CI: -0.16, -0.01, P = 0.03). DISCUSSION: HR fragmentation was associated with small vessel disease. HR fragmentation can be measured automatically from ambulatory electrocardiogram devices and may be useful as a biomarker of vascular brain injury.

Characterization of Biomarkers of Thrombo-Inflammation in Patients with First-Diagnosed Atrial Fibrillation.

Patients with first-diagnosed atrial fibrillation (FDAF) exhibit major adverse cardiovascular events (MACEs) during follow-up. Preclinical models have demonstrated that thrombo-inflammation mediates adverse cardiac remodeling and atherothrombotic events. We have hypothesized that thrombin activity (FIIa) links coagulation with inflammation and cardiac fibrosis/dysfunction. Surrogate markers of the thrombo-inflammatory response in plasma have not been characterized in FDAF. In this prospective longitudinal study, patients presenting with FDAF (n = 80), and 20 matched controls, were included. FIIa generation and activity in plasma were increased in the patients with early AF compared to the patients with chronic cardiovascular disease without AF (controls; p < 0.0001). This increase was accompanied by elevated biomarkers (ELISA) of platelet and endothelial activation in plasma. Pro-inflammatory peripheral immune cells (TNF-α+ or IL-6+) that expressed FIIa-activated protease-activated receptor 1 (PAR1) (flow cytometry) circulated more frequently in patients with FDAF compared to the controls (p < 0.0001). FIIa activity correlated with cardiac fibrosis (collagen turnover) and cardiac dysfunction (NT-pro ANP/NT-pro BNP) surrogate markers. FIIa activity in plasma was higher in patients with FDAF who experienced MACE. Signaling via FIIa might be a presumed link between the coagulation system (tissue factor-FXa/FIIa-PAR1 axis), inflammation, and pro-fibrotic pathways (thrombo-inflammation) in FDAF.

Left Atrial Myopathy in Heart Failure With Preserved Ejection Fraction.

The left atrium (LA) plays an important role in facilitating left ventricular (LV) filling by acting as a reservoir, passive conduit, and active booster pump, as well as a regulator of blood volume through A-type natriuretic peptide secretion in response to stimulation by mechanical stretch of the cavity. LA myopathy has emerged as one of the most important non-LV contributors to disease progression in heart failure with preserved ejection fraction (HFpEF). LA dysfunction is common in HFpEF and is associated with more severe pulmonary vascular disease and right ventricular dysfunction, and increases the risk of incident atrial fibrillation or atrial functional mitral regurgitation, leading to limitations in cardiac output reserve and reduced exercise capacity. LA deformation assessed by 2-dimensional speckle-tracking echocardiography is useful for estimating abnormal hemodynamics or exercise capacity, discriminating HFpEF from non-cardiac dyspnea and is an independent predictor of adverse outcome in HFpEF. Thus, interventions directly targeting LA myopathy may improve outcomes in HFpEF with LA myopathy. This review provides information regarding the physiology of the LA in patients with HFpEF and discusses the importance of evaluation of LA function, management issues, and future directions through ongoing trials of medical interventions.

Arrythmia-Mediated Valvular Heart Disease.

The aging population is rising at record pace worldwide. Along with it, a steep increase in the prevalence of atrial fibrillation and heart failure with preserved ejection fraction is to be expected. Similarly, both atrial functional mitral and tricuspid regurgitation (AFMR and AFTR) are increasingly observed in daily clinical practice. This article summarizes all current evidence regarding the epidemiology, prognosis, pathophysiology, and therapeutic options. Specific attention is addressed to discern AFMR and AFTR from their ventricular counterparts, given their different pathophysiology and therapeutic needs.

Mitral regurgitation impact on left atrial myopathy in hypertrophic cardiomyopathy.

BACKGROUND: Recent studies have shown that mitral regurgitation (MR) represents a major determinant of left atrial (LA) function in patients with heart failure with preserved ejection fraction. The role of MR in determining LA myopathy in hypertrophic cardiomyopathy (HCM) is unknown. The aim of this study was to examine the association of MR with LA myopathy, assessed by LA strain values in HCM patients. METHODS: In total 250 consecutive patients (mean age 51 ± 16 years, 67.2% male) with an established diagnosis of HCM and with sinus rhythm at index echocardiography evaluation were included. LA reservoir, conduit and booster strain were analyzed, besides LA size, left ventricular (LV) systolic and diastolic function. The predictors of LA strain values were identified with linear regression analysis. RESULTS: Significant (more than mild) MR was a significant univariate predictor of all the three LA strain values. In multivariate linear regression analysis, independent predictors of LA reservoir strain were more than mild MR (r = -.23), LV global longitudinal strain (r = -.49), LA volume index (r = -.27) and patient age (r = -.23). Significant MR was also an independent determinant of LA conduit (r = -.17) and booster strain (r = -.12). In patients with LA volume index < 34 ml/m2 more than mild MR was an independent predictor of LA reservoir (r = -.32) and conduit strain (r = -.27), but not LA booster strain. CONCLUSION: Significant MR is associated with LA myopathy independently of the LV diastolic and systolic function and LA size.

Emerging Evidence of Pathological Roles of Very-Low-Density Lipoprotein (VLDL).

Embraced with apolipoproteins (Apo) B and Apo E, triglyceride-enriched very-low-density lipoprotein (VLDL) is secreted by the liver into circulation, mainly during post-meal hours. Here, we present a brief review of the physiological role of VLDL and a systemic review of the emerging evidence supporting its pathological roles. VLDL promotes atherosclerosis in metabolic syndrome (MetS). VLDL isolated from subjects with MetS exhibits cytotoxicity to atrial myocytes, induces atrial myopathy, and promotes vulnerability to atrial fibrillation. VLDL levels are affected by a number of endocrinological disorders and can be increased by therapeutic supplementation with cortisol, growth hormone, progesterone, and estrogen. VLDL promotes aldosterone secretion, which contributes to hypertension. VLDL induces neuroinflammation, leading to cognitive dysfunction. VLDL levels are also correlated with chronic kidney disease, autoimmune disorders, and some dermatological diseases. The extra-hepatic secretion of VLDL derived from intestinal dysbiosis is suggested to be harmful. Emerging evidence suggests disturbed VLDL metabolism in sleep disorders and in cancer development and progression. In addition to VLDL, the VLDL receptor (VLDLR) may affect both VLDL metabolism and carcinogenesis. Overall, emerging evidence supports the pathological roles of VLDL in multi-organ diseases. To better understand the fundamental mechanisms of how VLDL promotes disease development, elucidation of the quality control of VLDL and of the regulation and signaling of VLDLR should be indispensable. With this, successful VLDL-targeted therapies can be discovered in the future.

P-wave indices in Japanese patients with ischemic stroke: Implication of atrial myopathy in subtype of ischemic stroke.

BACKGROUND: P-wave indices have been not fully studied in subtypes of ischemic stroke. We compared P-wave indices among embolic stroke, lacunar stroke and the control. METHODS: P-wave duration, advanced interatrial block (aIAB) defined as P-wave duration ≥120 ms and biphasic (positive negative) morphology in inferior leads, and P-terminal force in lead V1 (PTFV1) were measured at the time of the first episode of cardioembolic stroke in 81 patients with paroxysmal atrial fibrillation (PAF), and in 64 patients with lacunar stroke, and compared with 100 control subjects. The latter two groups had no episode of PAF. RESULTS: The age of participants was 76 ± 11 years. Age, sex distribution, body mass index and CHADS2 score were comparable among three groups. Maximum P-wave duration, the longest across 12 leads, was significantly prolonged in cardioembolic and lacuna stroke compared to the control; 118 ± 12 ms and 118 ± 11 ms vs. 110 ± 11 ms, respectively (P < 0.0001). P-wave duration ≥120 ms and aIAB were more prevalent in ischemic stroke groups than the control, and associated with a higher Odds ratio for stroke, more so in cardioembolic stroke. However, PTFV1 value and the prevalence of PTFV1 ≥ 4.0 ms·mV were significantly not different among the three groups. Abnormal P-wave duration and aIAB indicating the presence of atrial myopathy were present in cardioembolic and lacuna stroke. CONCLUSION: Atrial myopathy was present in cardioembolic and lacunar stroke, but it can't be the direct cause of small vessel occlusion in lacunar stroke. Roles of atrial myopathy in each subtype of ischemic stroke should be studied.

Atrial fibrillation: villain or bystander in vascular brain injury.

Atrial fibrillation (AF) and stroke are inextricably connected, with classical Virchow pathophysiology explaining thromboembolism through blood stasis in the fibrillating left atrium. This conceptualization has been reinforced by the remarkable efficacy of oral anticoagulant (OAC) for stroke prevention in AF. A number of observations showing that the presence of AF is neither necessary nor sufficient for stroke, cast doubt on the causal role of AF as a villain in vascular brain injury (VBI). The requirement for additional risk factors before AF increases stroke risk; temporal disconnect of AF from a stroke in patients with no AF for months before stroke during continuous ECG monitoring but manifesting AF only after stroke; and increasing recognition of the role of atrial cardiomyopathy and atrial substrate in AF-related stroke, and also stroke without AF, have led to rethinking the pathogenetic model of cardioembolic stroke. This is quite separate from recognition that in AF, shared cardiovascular risk factors can lead both to non-embolic stroke, or emboli from the aorta and carotid arteries. Meanwhile, VBI is now expanded to include dementia and cognitive decline: research is required to see if reduced by OAC. A changed conceptual model with less focus on the arrhythmia, and more on atrial substrate/cardiomyopathy causing VBI both in the presence or absence of AF, is required to allow us to better prevent AF-related VBI. It could direct focus towards prevention of the atrial cardiomyopathy though much work is required to better define this entity before the balance between AF as villain or bystander can be determined.

Drugs That Ameliorate Epicardial Adipose Tissue Inflammation May Have Discordant Effects in Heart Failure With a Preserved Ejection Fraction as Compared With a Reduced Ejection Fraction.

Heart failure with a preserved ejection fraction (HFpEF) and heart failure with a reduced ejection fraction (HFrEF) have distinctive pathophysiologies, and thus, therapeutic approaches to the 2 disorders should differ. Neurohormonal activation drives the progression of HFrEF, and neurohormonal antagonists are highly effective in HFrEF, but not in HFpEF. Conversely, a broad range of chronic systemic inflammatory or metabolic disorders cause an expansion and inflammation of epicardial adipose tissue; the secretion of adipocytokines may lead to microvascular dysfunction and fibrosis of the underlying myocardium, which (if the left atrium is affected) may lead to atrial fibrillation (AF) and (if the left ventricle is affected) may lead to HFpEF. Anti-inflammatory drugs (such as statins and anticytokine agents) can ameliorate epicardial adipose tissue dysfunction. Statins appear to ameliorate the development of atrial myopathy (both experimentally and clinically), and in randomized controlled trials, they reduce the incidence of new-onset and recurrent AF and decrease the risk of heart failure with the features of HFpEF; yet, they have no benefits in HFrEF. Similarly, anticytokine agents appear to prevent heart failure in patients with or prone to HFpEF, but adversely affect HFrEF. Several antihyperglycemic agents also reduce epicardial fat mass and inflammation, but this benefit may be offset by additional actions to cause sodium retention and neurohormonal activation. Thiazolidinediones have favorable effects on experimental AF and HFpEF, but their antinatriuretic actions negate these benefits, and they worsen the clinical course of HFrEF. Glucagon-like peptide-1 receptor agonists also ameliorate AF and HFpEF in laboratory models, but their positive inotropic and chronotropic effects may be deleterious in HFrEF. By contrast, metformin and sodium-glucose cotransporter 2 inhibitors alleviate epicardial adipose tissue dysfunction and may reduce the risk of AF and HFpEF; yet, they may have additional actions to promote cardiomyocyte survival that are useful in HFrEF. The concordance of the benefits of anti-inflammatory and antihyperglycemic drugs on AF and HFpEF (but not on HFrEF) supports the paradigm that epicardial adipose tissue is a central pathogenetic mechanism and therapeutic target for both AF and HFpEF in patients with chronic systemic inflammatory or metabolic diseases.

Cardioembolic Stroke.

Cardiac embolism accounts for an increasing proportion of ischemic strokes and might multiply several-fold during the next decades. However, research points to several potential strategies to stem this expected rise in cardioembolic stroke. First, although one-third of strokes are of unclear cause, it is increasingly accepted that many of these cryptogenic strokes arise from a distant embolism rather than in situ cerebrovascular disease, leading to the recent formulation of embolic stroke of undetermined source as a distinct target for investigation. Second, recent clinical trials have indicated that embolic stroke of undetermined source may often stem from subclinical atrial fibrillation, which can be diagnosed with prolonged heart rhythm monitoring. Third, emerging evidence indicates that a thrombogenic atrial substrate can lead to atrial thromboembolism even in the absence of atrial fibrillation. Such an atrial cardiomyopathy may explain many cases of embolic stroke of undetermined source, and oral anticoagulant drugs may prove to reduce stroke risk from atrial cardiomyopathy given its parallels to atrial fibrillation. Non-vitamin K antagonist oral anticoagulant drugs have recently expanded therapeutic options for preventing cardioembolic stroke and are currently being tested for stroke prevention in patients with embolic stroke of undetermined source, including specifically those with atrial cardiomyopathy. Fourth, increasing appreciation of thrombogenic atrial substrate and the common coexistence of cardiac and extracardiac stroke risk factors suggest benefits from global vascular risk factor management in addition to anticoagulation. Finally, improved imaging of ventricular thrombus plus the availability of non-vitamin K antagonist oral anticoagulant drugs may lead to better prevention of stroke from acute myocardial infarction and heart failure.

Clinical and echocardiographic characteristics of cardioembolic stroke.

BACKGROUND AND PURPOSE: Ischaemic stroke frequently has a cardioembolic (CE) source. Clinical and echocardiographic parameters associated with CE stroke were evaluated. METHODS: In all, 93 consecutive ischaemic stroke patients who underwent a transthoracic echocardiogram were retrospectively analysed; strokes were classified by TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria. Echocardiographic parameters related to CE stroke, including left atrial volumes and function, were compared to 73 healthy controls. RESULTS: Of 93 patients (mean age 66.1 years, 56% male), nine (10%) had large artery atherosclerosis, 38 (41%) CE stroke, two (2%) small vessel disease, two (2%) other and 42 (45%) undetermined aetiology. Left atrial (LA) maximum volumes (LAVImax ) and minimum volumes (LAVImin ) were larger in the CE group than the non-CE group (45 vs. 32 ml/m2 , 32 vs. 13 ml/m2 , respectively, P < 0.001), whilst LA function indices including LA emptying fraction and LA function index (LAFI) were lower in the CE group (34% vs. 55%, and 0.12 vs. 0.35, respectively, P < 0.001). Adjusting for clinical characteristics, LAFI ≤0.3 was an independent predictor of CE stroke (adjusted odds ratio 5.3, P = 0.001). Additionally, LAVImax and LAVImin were larger (61 vs. 44 and 32 vs. 24 ml/m2 respectively, P < 0.01) and LAFI significantly lower (0.34 vs. 0.52, P < 0.001) in the undetermined aetiology group versus healthy controls. CONCLUSIONS: Left atrial enlargement with reduced LA function was associated with CE stroke and LAFI was the best independent predictor. LA parameters were also altered in the undetermined aetiology group, suggesting an underlying LA myopathy in this subset.

Heart Failure with Preserved Ejection Fraction Correlates with Fibrotic Atrial Myopathy in Patients Undergoing Atrial Fibrillation Ablation.

Background: The incidence of atrial fibrillation (AF) in patients with heart failure with preserved ejection fraction (HFpEF) is high. Impaired left atrial (LA) function is a major determinant in HFpEF. However, the extent of electrical LA tissue degeneration in HFpEF is unknown. Therefore, we sought to investigate the amount of arrhythmogenic and fibrotic LA tissue degeneration in HFpEF patients presenting for AF ablation. Methods: We prospectively screened consecutive patients presenting for first time AF ablation. The HFA-PEFF score was used to identify HFpEF patients. Bipolar high-density voltage mapping was created in sinus rhythm prior to ablation to evaluate the general LA bipolar voltage and quantify areas of low voltage. LVAs were defined as areas with bipolar voltage < 0.5 mV. Results: In total, 187 patients were prospectively enrolled (age 65 ± 11 years, 45% female, 46% persistent AF, 25% HFpEF) in this study. HFpEF patients were older and had a higher CHA2DS2-VASc score (70 ± 9 vs. 63 ± 11 years and 3.2 ± 1.5 vs. 2.3 ± 1.5, each p < 0.001, respectively). Overall, low-voltage areas (LVAs) were present in 97 patients (52%), whereas 76% of the HFpEF population had LVA, as compared to 44% of patients without HFpEF (p < 0.001). HFpEF was associated with generally decreased LA bipolar voltage (1.09 ± 0.64 vs. 1.83 ± 0.91 mV; p < 0.001) and predictive of the presence of low-voltage areas (76% vs. 44% p < 0.001). The HFA-PEFF score inversely correlated with LA bipolar voltage (=-0.454; p < 0.001). Conclusions: HFpEF closely relates to generally decreased LA bipolar voltage and to the existence of fibrotic and arrhythmogenic LA tissue degeneration.

Biatrial arrhythmogenic substrate in patients with hypertrophic obstructive cardiomyopathy.

BACKGROUND: Atrial fibrillation (AF) in patients with hypertrophic obstructive cardiomyopathy (HOCM) may be caused by a primary atrial myopathy. Whether HOCM-related atrial myopathy affects mainly electrophysiological properties of the left atrium (LA) or also the right atrium (RA) has never been investigated. OBJECTIVE: The purpose of this study was to characterize atrial conduction and explore differences in the prevalence of conduction disorders, potential fractionation, and low-voltage areas (LVAs) between the RA and LA during sinus rhythm (SR) as indicators of potential arrhythmogenic areas. METHODS: Intraoperative epicardial mapping of both atria during SR was performed in 15 HOCM patients (age 50 ± 12 years). Conduction delay (CD) and conductin block (CB), unipolar potential characteristics (voltages, fractionation), and LVA were quantified. RESULTS: Conduction disorders and LVA were found scattered throughout both atria in all patients and did not differ between the RA and LA (CD: 2.9% [1.9%-3.6%] vs 2.6% [2.1%-6.4%], P = .541; CB: 1.7% [0.9%-3.1%] vs 1.5% [0.5%-2.8%], P = .600; LVA: 4.7% [1.6%-7.7%] vs 2.9% [2.1%-7.1%], P = .793). Compared to the RA, unipolar voltages of single potentials (SPs) and fractionated potentials (FPs) were higher in the LA (SP: P75 7.3 mV vs 10.9 mV; FP: P75 2.0 mV vs 3.7 mV). FP contained low-voltage components in only 18% of all LA sites compared to 36% of all RA sites. CONCLUSION: In patients with HOCM, conduction disorders, LVA, and FP are equally present in both atria, supporting the hypothesis of a primary atrial myopathy. Conceptually, the presence of a biatrial substrate and high-voltage FP may contribute to failure of ablative therapy of atrial tachyarrhythmias in this population.

Atrial Fibrillation, Atrial Myopathy, and Thromboembolism: The Additive Value of Echocardiography and Possible New Horizons for Risk Stratification.

Atrial fibrillation (AF) is the most common cardiac sustained arrhythmia, and it is associated with increased stroke and dementia risk. While the established paradigm attributes these complications to blood stasis within the atria and subsequent thrombus formation with cerebral embolization, recent evidence suggests that atrial myopathy (AM) may play a key role. AM is characterized by structural and functional abnormalities of the atria, and can occur with or without AF. Moving beyond classifications based solely on episode duration, the 4S-AF characterization has offered a more comprehensive approach, incorporating patient's stroke risk, symptom severity, AF burden, and substrate assessment (including AM) for tailored treatment decisions. The "ABC" pathway emphasizes anticoagulation, symptom control, and cardiovascular risk modification and emerging evidence suggests broader benefits of early rhythm control strategies, potentially reducing stroke and dementia risk and improving clinical outcomes. However, a better integration of AM assessment into the current framework holds promise for further personalizing AF management and optimizing patient outcomes. This review explores the emerging concept of AM and its potential role as a risk factor for stroke and dementia and in AF patients' management strategies, highlighting the limitations of current risk stratification methods, like the CHA2DS2-VASc score. Echocardiography, particularly left atrial (LA) strain analysis, has shown to be a promising non-invasive tool for AM evaluation and recent studies suggest that LA strain analysis may be a more sensitive risk stratifier for thromboembolic events than AF itself, with some studies showing a stronger association between LA strain and thromboembolic events compared to traditional risk factors. Integrating it into routine clinical practice could improve patient management and targeted therapies for AF and potentially other thromboembolic events. Future studies are needed to explore the efficacy and safety of anticoagulation in AM patients with and without AF and to refine the diagnostic criteria for AM.

Characterization of patients with extensive left atrial myopathy referred for atrial fibrillation ablation: incidence, predictors, and outcomes.

BACKGROUND: Although atrial fibrosis has a relevant impact on ablation success rate, experimental studies have reported that extensive fibrosis may be accompanied by a reduced burden secondary to a prominent depression of atrial excitability. OBJECTIVES: We aimed to identify clinical and echocardiographic factors associated with extensive left atrial myopathy (ELAM), to analyze the predictive ability of established scores (AF score, APPLE, and DR-FLASH) and assess outcomes in terms of AF recurrence, left atrial flutter, and post-procedural heart failure admissions. METHODS: A total of 950 consecutive patients undergoing the first AF ablation were included. A 3D electroanatomical mapping system (CARTO3, Biosense Webster) was created using a multipolar mapping catheter (PentaRay, Biosense Webster). ELAM was defined as ≥ 50% low voltage area. A subanalysis with four groups was also created (< 10%; 10-20%; 10-20%; and > 30%). Logistic regressions, Cox proportional hazards models, and log-rank test were used to test the predictors independently associated with the presence of ELAM and AF recurrence. The model was prospectively validated in a cohort of 150 patients obtaining an excellent ability for prediction AUC 0.90 (CI 95% 0.84-0.96). RESULTS: Overall, 78 (8.42%) presented ELAM. Age, female sex, persistent AF, first-degree AV block, and E/e' were significant predictors. The model incorporating these factors outperformed the existing scores (AUC = 0.87). During a mean follow-up of 20 months (IQR 9 to 36), patients with ELAM presented a higher rate of AF recurrence (42.02% vs 26.01%, p = 0.030), left atrial flutter (26.03% vs 8.02%, p < 0.001), and post-procedural heart failure admissions (12.01% vs 0.61%, p < 0.001) than non-ELAM patients. CONCLUSIONS: This study reveals the incidence and clinical factors associated with ELAM in AF, highlighting age, female, persistent AF, first-degree AV block, and E/e'. Importantly, the presence of ELAM is associated with poorer outcomes in terms of recurrence and HF admission.

Shorter Premature Atrial Complex Coupling Interval Leads to Mechanical Dysfunction, Fibrosis, and AF in Swine.

BACKGROUND: We have previously shown that dyssynchronous premature atrial complexes (PACs) from the lateral left atrium (LA) lead to greater atrial mechanical dysfunction, remodeling, and sustained atrial fibrillation (AF) than synchronous PACs from the interatrial septum. However, the impact of PAC coupling interval (CI) on atrial remodeling is unclear. OBJECTIVES: This study sought to explore the effect of PAC CI on atrial mechanics and remodeling in the swine model. METHODS: A 2-phase in vivo study was conducted. In the phase 1 acute study, 5 swine underwent acute invasive hemodynamics and echocardiography while delivering single-paced atrial extrastimuli with CIs varying from 450 ms to 200 ms. Peak LA longitudinal strain and intra-LA dyssynchrony were assessed with 2-dimensional strain echocardiography while LA and aortic pressure were directly measured. In the phase 2 chronic study, a group exposed to paced bigeminy from the lateral LA for 16 weeks with a short CI of 250 ms (Short-PAC, n = 10) was compared with groups with PACs at a long CI of 400 ms (Long-PAC, n = 5) and a nonpaced control group (CTRL, n = 10). Detailed electrophysiology and echocardiography studies were performed with histologic quantification of LA fibrosis at baseline and prior to sacrifice. RESULTS: Phase 1 revealed that as PAC CI shortened, peak LA strain decreased (P = 0.003) and LA dyssynchrony increased (P < 0.001). Phase 2 showed that after 16 weeks of PACs, the Short-PAC group had greater LA dilation (terminal baseline: 5.9 ± 1.2 cm2 vs Long-PAC 3.9 ± 0.5 cm2 vs CTRL 0.9 ± 0.4 cm2; P < 0.001) and reduced peak LA strain during sinus rhythm (terminal baseline: -17.3 ± 3.2% vs Long-PAC -12.1 ± 2.1% vs CTRL -0.7 ± 4.2%; P < 0.001). The short-PAC group had a more LA fibrosis (8.6 ± 1.0% vs Long-PAC 6.8 ± 1.0% vs CTRL 4.0 ± 1.5%; P < 0.001) and higher AF inducibility (terminal baseline: 49.3 ± 13.0% vs Long-PAC 29.0 ± 6.4% vs CTRL 2.2 ± 16.2%; P < 0.001) than the other groups. CONCLUSIONS: In this swine model, shorter PAC CI led to increased acute atrial mechanical dysfunction and dyssynchrony. Chronically, short-CI PACs led to greater atrial fibrosis and induced AF, suggesting that frequent, short-coupled PACs pose the highest risk for LA myopathy and AF. These insights underscore the importance of understanding the impact of PAC characteristics on atrial remodeling and arrhythmogenesis.

Atrial cardiopathy biomarkers and atrial fibrillation in the ARCADIA trial.

BACKGROUND: ARCADIA compared apixaban to aspirin for secondary stroke prevention in patients with cryptogenic stroke and atrial cardiopathy. One possible explanation for the neutral result is that biomarkers used did not optimally identify atrial cardiopathy. We examined the relationship between biomarker levels and subsequent detection of AF, the hallmark of atrial cardiopathy. METHODS: Patients were randomized if they met criteria for atrial cardiopathy, defined as P-wave terminal force >5000 µV*ms in ECG lead V1 (PTFV1), NT-proBNP >250 pg/mL, or left atrial diameter index (LADI) ⩾3 cm/m2. For this analysis, the outcome was AF detected per routine care. RESULTS: Of 3745 patients who consented to screening for atrial cardiopathy, 254 were subsequently diagnosed with AF; 96 before they could be randomized and 158 after randomization. In unadjusted analyses, ln(NT-proBNP) (RR per SD, 1.99; 95% CI, 1.85-2.13), PTFV1 (RR per SD, 1.15; 95% CI, 1.03-1.28) and LADI (RR per SD, 1.34; 95% CI, 1.20-1.50) were associated with AF. In a model containing all 3 biomarkers, demographics, and AF risk factors, age (RR per 10 years, 1.24; 95% CI, 1.09-1.41), ln(NT-proBNP) (RR per SD, 1.88; 95% CI, 1.67-2.11) and LADI (RR per SD, 1.25; 95% CI, 1.14-1.37) were associated with AF. These three variables together had a c-statistic of 0.82 (95% CI, 0.79-0.85) but only modest calibration. Discrimination was attenuated in sensitivity analyses of patients eligible for randomization who may have been more closely followed for AF. CONCLUSIONS: Biomarkers used to identify atrial cardiopathy in ARCADIA were moderately predictive of subsequent AF.

Atrial myopathy.

This paper delves into the progressive concept of atrial myopathy, shedding light on its development and its impact on atrial characteristics. It extensively explores the intricate connections between atrial myopathy, atrial fibrillation (AF), and strokes. Researchers have sought additional contributors to AF-related strokes due to the absence of a clear timing correlation between paroxysmal AF episodes and strokes in patients with cardiac implantable electronic devices. Through various animal models and human investigations, a close interrelation among aging, inflammation, oxidative stress, and stretching mechanisms has been identified. These mechanisms contribute to fibrosis, alterations in electrical properties, autonomic remodeling, and a heightened pro-thrombotic state. These interconnected factors establish a detrimental cycle, exacerbating atrial myopathy and elevating the risk of sustained AF and strokes. By emphasizing the significance of atrial myopathy and the risk of strokes that are distinct from AF, the paper also discusses methods for identifying patients with atrial myopathy. Moreover, it proposes an approach to incorporate the concept of atrial myopathy into clinical practice to guide anticoagulation decisions in individuals with AF.