Atrial Myopathy Research Articles

PO-02-205 ELECTROGRAPHIC FLOW CONSISTENCY CORRELATES WITH HIGH-DENSITY BIPOLAR VOLTAGE MAPS IN SINUS RHYTHM AND ATRIAL FIBRILLATION

In patients with atrial fibrillation (AF), left atrial scar revealed by low voltage areas on 3D electroanatomic mapping have been correlated with scar on late gadolinium enhanced cardiac magnetic resonance imaging, which is recognized as a surrogate for fibrosis. Electrographic Flow (EGF) mapping reconstructs global atrial wavefront propagations in near real-time. Electrographic flow consistency (EGFC) quantifies concordance of observed wavefront patterns and may provide insight into the nature of atrial substrate where diseased substrate shows more chaotic wavefront propagation and lower FC. Correlate EGFC with regional bipolar voltage values in patients during AF and sinus rhythm (SR). FLOW EVAL-AF is a single-center, prospective study of 10 AF patients who underwent concomitant high-density bipolar voltage mapping with HD Grid and EGF mapping with 64-pole basket catheter. Biatrial voltage maps and 1-minute EGF maps from 2-3 standard basket positions per atria were made prior to any induction or ablation. Atrial surface area with voltage >0.5 mV was computed from 2D voltage map projections. EGF fields computed per 2-sec segment of recording. Overall EGFC per atrium computed as average of the modulus of individual EGF vectors, where vector length represents consistency of flow patterns in arbitrary units. We compared % atrial surface area with normal voltage v. mean EGFC across EGF recordings per atria in a given rhythm. Data from 8 patients (2 AF; 6 SR) was analyzed; 2 excluded for non-comparable voltage map acquisition parameters. Mean age 70±11 years; 1 female; mean LA size 4.5±0.35 cm. Surface area % with voltage >0.5 mV was 0.24±0.08 in AF v. 0.36±0.05 in SR. Mean EGFC in AF 0.74±0.14 and in SR 1.0±0.11. Intraprocedural rhythm change occurred in 5 (3 induced into AF; 2 converted to SR post-PVI), and all had higher voltage values overall and higher mean EGFC in SR v. AF. Pooling data from all pre-procedure voltage maps and EGF maps revealed overall correlation between EGFC and bipolar voltage from both atria and in both rhythms (r=0.67, p=4.8x10-3). Both EGFC and bipolar voltage values were higher in SR v. AF. EGFC correlated with voltage across both atria and in both SR and AF. Global EGFC can be obtained with 1-minute recordings in 2-3 basket positions per atria and may provide another measure of the degree of atrial myopathy similar to the information gained from high-density bipolar voltage mapping.

PO-02-241 CARDIAC SYMPATHETIC REMODELING AND SK CHANNELS UPREGULATION, THE POSSIBLE MECHANISMS OF NOISE EXPOSURE ASSOCIATED ATRIAL ARRHYTHMOGENESIS

Environmental noise exposure may increase sympathetic tone and lead to atrial fibrillation (AF) and mortality. The small conductance Ca2+- activated K+ (SK) channels play important roles in the repolarization of atria. The regulation of SK channels might be involved in modulating cardiac electrophysiology via the autonomic nervous system (ANS). Apamin blocks SK channels specifically and is used for evaluating the roles of SK channels regulation related to noise exposure. To determine how ANS regulates SK channels under noise exposure. We used a noise exposure (NOE) mice model with broad-band noise 20-20k Hz for 28 days to induce atrial myopathy. A total of 12 NOE and 9 control mice were used in the study. Dual optical mapping was performed via Langendorff perfused intact hearts to measure the baseline and post-apamin atrial action potential duration (APD), calcium transient duration (CaTD) and conduction velocity (CV) in the NOE and control mice. The expression of SK channel proteins (SK1-3), tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP43) was detected by immunohistochemistry. The degree of myocardial fibrosis in the atria was detected by Masson's trichrome staining. Optical mapping study showed no APD difference (26.26±3.69 vs 27.76±2.36 ms, p=0.69) but prolonged CaTD (52.67±1.91 vs 49.65±3.4 ms, p=0.03) in NOE compared with control mice atria at baseline. The ratio of ΔAPD (the difference in the APD after and before apamin) and baseline was higher in NOE than in control mice (0.221±0.231 vs 0.011±0.52, p=0.015), meaning that noise exposure contributed to the upregulation of SK channels. Atrial CV was higher in NOE than in control mice (44.9±4 vs 39.2±3.5 cm/s, p=0.019); after apamin administration, it was significantly lower in NOE than in control mice (30.9±4.8 vs 34.2±3.5 cm/s, p=0.045). IHC study showed SK1-3, TH, GAP43 and trichrome staining were significantly higher in NOE than in control atria (18445.3±2527.9 vs 11228.4±2276.9 μm2/ mm2, 16063.6±1974 vs 9760.17±2576.8 μm2/mm2, 9304.3±633.1 vs 5994.7±1131.8 μm2/ mm2, 1019.9±189.8 vs 622.6±252.3 μm2/ mm2, 733.5±449.1 vs 117.4±53.4 μm2/ mm2, 7449.9±4274.7 vs 492.6±353.9 μm2/ mm2, all p≤0.01). Additionally, AF can be induced in 17% (2/12) of NOE but never in control mice (p=0.14). Noise exposure induces cardiac ANS remodeling, fibrosis and SK currents upregulation. It partially explains the mechanism of noise-induced atrial arrhythmia.

PO-01-099 EARLY REMODELING OF THE LEFT ATRIUM FOLLOWING CATHETER ABLATION OF PERSISTENT ATRIAL FIBRILLATION: THE IMPACT OF SUBSTRATE MODIFICATION IN DECAAF II

Left Atrial (LA) enlargement is prevalent amongst atrial fibrillation (AF) patients and constitutes an important marker of underlying atrial myopathy. Several studies have described reduction in LA volume following catheter ablation (CA) of AF, however, none have investigated differences in remodeling related to additional ablation outside of the pulmonary veins. We sought to compare early remodeling of the LA between patients who received pulmonary vein isolation (PVI) only, and those who received additional fibrosis-guided extra-PV ablation. This study was a retrospective analysis of the DECAAF II randomized controlled trial. Patients with persistent AF (perAF) were randomized to receive PVI only or PVI + fibrosis-guided ablation. Late Gadolinium Enhancement Magnetic Resonance Imaging (LGE-MRI) was performed before and three months after CA to measure LA volume. Only patients in sinus rhythm at both MRIs are included. Patients were followed up with single-lead ECG devices for 12-18 months. Arrhythmic burden was calculated as the percentage of ECGs exhibiting AF. Univariate and multivariate regression were used to identify predictors of LA volume change. This analysis included 206 patients who met our inclusion criteria. The mean LA volume before ablation was 114.6 ± 36.9 mm3, and the mean volume post-ablation was 101.2 ± 32.3 mm3, with a mean reduction of 13.5 ± 22.3 mm3 (9.92% reduction, p <0.001). Patients randomized to receive MRI-guided fibrosis ablation had more LA volume reduction than patients who were randomized to PVI only (17.03 ± 25.04 mm3 vs 10.17 ± 18.89 mm3, p=0.03). This association persisted with multivariate analysis where pre-ablation left ventricular ejection fraction (LVEF) and randomization to receive substrate modification were the only predictors of LA volume reduction (table). LA volume reduction was associated with greater improvement in LVEF, regardless of treatment randomization (r = 0.242, p = 0.01). LA volume reduction did not predict arrhythmia recurrence when considered as a continuous variable. We noted more pronounced LA volume reductions in patients randomized to receive PVI + fibrosis-guided ablation when compared to those randomized to receive PVI only. We hypothesize worsened left atrial relaxation and diastolic dysfunction as an etiology for this difference, but further study is needed to better characterize the important structural impacts of extra-PV ablation.

PO-02-208 CHARACTERIZATION OF ATRIAL ELECTROPHYSIOLOGICAL PROPERTIES IN PATIENTS WITH HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY

Atrial fibrillation (AF) occurs frequently in patients with hypertrophic obstructive cardiomyopathy (HOCM) and the success rate of pulmonary vein isolation in these patients is less effective compared to other populations. This may be explained by the presence of an extensive arrhythmogenic substrate in both atria due to a primary atrial myopathy, but electrophysiological properties of the right (RA) and left atrium (LA) have never been investigated. The aim of this study is to 1) quantify atrial electrophysiological properties during sinus rhythm and 2) to determine whether atrial electrogram morphology and conduction disorders differ between the RA and LA in patients with HOCM. Intra-operative epicardial mapping of both atria was performed in HOCM patients undergoing surgical myectomy. Conduction delay and/or block (CD, CB), unipolar electrograms characteristics (unipolar voltages, potential fractionation) and low voltage areas (LVA) were quantified during sinus rhythm. Fifteen patients (mean age: 50± 12 years) were included. Conduction disorders were found in both atria in all patients, but did not differ between the RA and LA (CD: 2.9 [1.9-3.6] % versus 2.6 [2.1-6.4] %, p=0.541; CB: 1.7 [0.9-3.1] % versus 1.5 [0.5-2.8] %, p=0.600; respectively). Though unipolar voltages histograms differed significantly between the RA and LA (Table 1), LVA were equally present in both RA and LA (RA: 4.7 % [1.6-7.7] % versus LA: 2.9 % [2.1-7.1] %, p=0.793). The magnitude of unipolar voltages of single- and complex fractionated potentials (SP, CFP) were higher in the LA compared to the RA (SP: P75 10.9 mV versus 7.3 mV, respectively; CFP: P75 3.7 mV versus 2.0 mV, respectively).(Table 1) CFP corresponded to LVA in only 18% of all LA sites compared to 36% of all RA sites. In patients with HOCM, the magnitude of unipolar voltages is considerably higher in the LA compared to the RA. Remarkably, fractionated potentials in both atria mainly contained high voltage deflections. Therefore, substrate modification strategies, consisting of low voltage or other electrogram morphology guided AF ablation strategies, should be disease-tailored in this population. The observed equal amount of conduction disorders and LVA in both atria support the concept of a primary atrial myopathy with a bi-atrial substrate in HOCM patients.

Atrial Fibrillation and Diabetes Mellitus: Dangerous Liaisons or Innocent Bystanders?

Atrial fibrillation (AF) is the most common arrhythmia in adults and diabetes mellitus (DM) is a major risk factor for cardiovascular diseases. However, the relationship between both pathologies has not been fully documented and new evidence supports the existence of direct and independent links. In the myocardium, a combination of structural, electrical, and autonomic remodeling may lead to AF. Importantly, patients with AF and DM showed more dramatic alterations than those with AF or DM alone, particularly in mitochondrial respiration and atrial remodeling, which alters conductivity, thrombogenesis, and contractile function. In AF and DM, elevations of cytosolic Ca2⁺ and accumulation of extra cellular matrix (ECM) proteins at the interstitium can promote delayed afterdepolarizations. The DM-associated low-grade inflammation and deposition/infiltration of epicardial adipose tissue (EAT) enforce abnormalities in Ca2+ handling and in excitation-contraction coupling, leading to atrial myopathy. This atrial enlargement and the reduction in passive emptying volume and fraction can be key for AF maintenance and re-entry. Moreover, the stored EAT can prolong action of potential durations and progression from paroxysmal to persistent AF. In this way, DM may increase the risk of thrombogenesis as a consequence of increased glycation and oxidation of fibrinogen and plasminogen, impairing plasmin conversion and resistance to fibrinolysis. Additionally, the DM-associated autonomic remodeling may also initiate AF and its re-entry. Finally, further evidence of DM influence on AF development and maintenance are based on the anti-arrhythmogenic effects of certain anti-diabetic drugs like SGLT2 inhibitors. Therefore, AF and DM may share molecular alterations related to Ca2+ mobility, mitochondrial function and ECM composition that induce atrial remodeling and defects in autonomic stimulation and conductivity. Likely, some specific therapies could work against the associated cardiac damage to AF and/or DM.

Association of abnormal p-wave parameters with brain MRI morphology: The atherosclerosis risk in communities neurocognitive study (ARIC-NCS).

Recent evidence indicates that abnormal P-wave parameters (PWPs)-ECG markers of atrial myopathy-are associated with incident dementia, independent of atrial fibrillation (AF) and clinical ischemic stroke. However, the mechanisms remain unclear and may include subclinical vascular brain injury. Hence, we evaluated the association of abnormal PWPs with brain MRI correlates of vascular brain injury in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). ARIC-NCS participants who underwent 3T brain MRI scans in 2011-2013 were included. PWPs were measured from standard 12-lead ECGs. Brain MRI outcomes included cortical infarcts, lacunar infarcts, cerebral microhemorrhages, brain volumes, and white matter disease (WMD) volume. We used weighted multivariable logistic and linear regression to evaluate the associations of abnormal PWPs with brain MRI outcomes. Among 1715 participants (mean age, 76.1 years; 61% women; 29% Black), 797 (46%) had ≥1 abnormal PWP. After multivariable adjustment, including adjusting for prevalent AF, abnormal P-wave terminal force in lead V1 (aPTFV1) and prolonged P-wave duration (PPWD) were associated with increased odds of both cortical (OR 1.41; 95% CI, 1.14 to 1.74 and OR 1.30; 95% CI, 1.04 to 1.63, respectively) and lacunar infarcts (OR 1.36; 95% CI, 1.15 to 1.63 and OR 1.37; 95% CI, 1.15 to 1.65, respectively). Advanced interatrial block (aIAB) was associated with higher odds of subcortical microhemorrhage (OR 2.04; 95% CI, 1.36 to 3.06). Other than a significant association between aPTFV1 with lower parietal lobe volume, there were no other significant associations with brain or WMD volume. In this exploratory analysis of a US community-based cohort, ECG surrogates of atrial myopathy are associated with a higher prevalence of brain infarcts and microhemorrhage, suggesting subclinical vascular brain injury as a possible mechanism underlying the association of atrial myopathy with dementia.

Large Animal Models of Cardiovascular Disease: From Training to Translation

ARTICLES DISCUSSED: Blanco-Blázquez, V. et al. Swine models of aneurysmal diseases for training and research. Journal of Visualized Experiments. (181), e63616 (2022). Constantin, I., Tăbăran, A. F. Dissection techniques and histological sampling of the heart in large animal models for cardiovascular diseases. Journal of Visualized Experiments. (184), e63809 (2022). Hao, Y. et al. Transcatheter pulmonary valve replacement from autologous pericardium with a self-expandable nitinol stent in an adult sheep model. Journal of Visualized Experiments. (184), e63661 (2022). Martínez-Falguera, D. et al. Myocardial infarction by percutaneous embolization coil deployment in a swine model. Journal of Visualized Experiments. (177), e63172 (2021). Tubeeckx, M. R. L. et al. Sterile pericarditis in aachener minipigs as a model for atrial myopathy and atrial fibrillation. Journal of Visualized Experiments. (175), e63094 (2021).

Novel filamin C (FLNC) variant causes a severe form of familial mixed hypertrophic-restrictive cardiomyopathy.

Variants of filamin C (FLNC) have been identified as rare genetic substrate for hypertrophic cardiomyopathy (HCM). Data on the clinical course of FLNC-related HCM are conflicting with some studies suggesting mild phenotypes whereas other studies have reported more severe outcomes. In this study, we present a novel FLNC variant (Ile1937Asn) that was identified in a large family of French-Canadian descent with excellent segregation data. FLNC-Ile1937Asn is a novel missense variant characterized by full penetrance and poor clinical outcomes. End stage heart failure requiring transplantation occurred in 43% and sudden cardiac death in 29% of affected family members. Other particular features of FLNC-Ile1937Asn include an early disease onset (mean age of 19 years) and the development of a marked atrial myopathy (severe biatrial dilatation with remodeling and multiple complex atrial arrhythmias) that was present in all gene carriers. The FLNC-Ile1937Asn variant is a novel, pathogenic mutation resulting in a severe form of HCM with full disease penetrance. The variant is associated with a high proportion of end-stage heart failure, heart transplantation, and disease-related mortality. Close follow-up and appropriate risk stratification of affected individuals at specialized heart centers is recommended.

Relationship between left atrial myopathy and atrial fibrillation in adults with coarctation of aorta

BackgroundAlthough patients with coarctation of aorta (COA) have clinical risk factors for atrial fibrillation (AF), there are limited data about AF prevalence, and role of left atrial (LA) indices for risk stratification in this population. We hypothesized that LA indices (LA reservoir strain and LA volume index) were associated with AF, and would identify patients at risk for AF progression. MethodsWe analyzed electrocardiograms/Holters, and echocardiograms of adult COA patients at Mayo Clinic (2000–2018). ResultsOf 776 patients, 726(94 %), 46(5.9 %) and 4(0.5 %) had no history of AF, paroxysmal AF, and persistent AF respectively; yielding AF prevalence of 6.4 %. LA reservoir strain (AUC 0.782 [0.751–0.808]) had more robust association with AF as compared to LA volume index (AUC difference −0.115, p < 0.001).Among 726 patients without prior AF, 25(3.4 %) had new-onset AF during follow-up. LA reservoir strain <25 % and LA volume index >34 ml/m2 were independent predictors of new-onset AF (HR 1.81 [1.15–3.85], and HR 1.41 [1.03–4.78], respectively). Of 46 patients with paroxysmal AF, 22(48 %) had recurrent AF, and LA reservoir strain <25 % was an independent predictor of recurrent AF (HR 1.94 [1.41–4.17]). LV pressure overload and stiffness indices were associated with progressive LA dysfunction and new-onset AF. ConclusionsCollectively, these data suggest that LA strain can potentially be used for AF risk stratification. Further studies are required to determine whether LA strain can proactively identify patients that will respond favorably to different antiarrhythmic therapies, and whether interventions to reduce LV pressure overload will improve LA function and reduce AF progression.

Empagliflozin suppressed cardiac fibrogenesis through sodium-hydrogen exchanger inhibition and modulation of the calcium homeostasis

BackgroundThe novel sodium-glucose co-transporter 2 inhibitor (SGLT2i) potentially ameliorates heart failure and reduces cardiac arrhythmia. Cardiac fibrosis plays a pivotal role in the pathophysiology of HF and atrial myopathy, but the effect of SGLT2i on fibrogenesis remains to be elucidated. This study investigated whether SGLT2i directly modulates fibroblast activities and its underlying mechanisms.Methods and resultsMigration, proliferation analyses, intracellular pH assay, intracellular inositol triphosphate (IP3) assay, Ca2+ fluorescence imaging, and Western blotting were applied to human atrial fibroblasts. Empagliflozin (an SGLT2i, 1, or 5 μmol/L) reduced migration capability and collagen type I, and III production. Compared with control cells, empagliflozin (1 μmol/L)- treated atrial fibroblasts exhibited lower endoplasmic reticulum (ER) Ca2+ leakage, Ca2+ entry, inositol trisphosphate (IP3), lower expression of phosphorylated phospholipase C (PLC), and lower intracellular pH. In the presence of cariporide (an Na+-H+ exchanger (NHE) inhibitor, 10 μmol/L), control and empagliflozin (1 μmol/L)-treated atrial fibroblasts revealed similar intracellular pH, ER Ca2+ leakage, Ca2+ entry, phosphorylated PLC, pro-collagen type I, type III protein expression, and migration capability. Moreover, empagliflozin (10 mg/kg/day orally for 28 consecutive days) significantly increased left ventricle systolic function, ß-hydroxybutyrate and decreased atrial fibrosis, in isoproterenol (100 mg/kg, subcutaneous injection)-induced HF rats.ConclusionsBy inhibiting NHE, empagliflozin decreases the expression of phosphorylated PLC and IP3 production, thereby reducing ER Ca2+ release, extracellular Ca2+ entry and the profibrotic activities of atrial fibroblasts.

Association of atrial myopathy in mitral valve disease on safety outcomes in left atrial appendage closure

BackgroundPatients undergoing left atrial appendage (LAA) occlusion (LAAO) are multi-morbid, including mitral valve disease (MVD) which is associated with anatomic changes of the left atrium (LA). This study aims to identify how atrial myopathy in MVD influences outcomes in LAAO.MethodsAtrial myopathy in MVD was defined as LA diameter > 45 mm (♀) and > 48 mm (♂) and existing MVD or history of surgical/interventional treatment. Patients were compared with controls from the prospective, multicentre LAArge registry of LAAO.ResultsA total of 528 patients (52 MVD, 476 no-MVD) were included. The MVD group was significantly more likely to be older (78.2 years vs 75.9 years, p = 0.036) and female (59.6% vs 37.8%, p = 0.002). Altered LA anatomy was observed in MVD with significantly larger LA diameter (53 mm vs. 48 mm, p < 0.001) and LAA Ostia [at 135° 23.0 mm (20.5, 26.0) vs 20.0 mm (18.0, 23.0), p = 0.002]. Implant success was high with 96.2% and 97.9%, respectively, without differences in severe complications (7.7% vs 4.6%, p = 0.31). One-year mortality (17.8% vs 11.5%, p = 0.19) and a combined outcome of death, stroke, and systemic embolism (20.3% vs 12.4%, p = 0.13) were not different. Independent predictors of the combined outcome were peripheral artery disease (HR 2.41, 95% CI 1.46–3.98, p < 0.001) and chronic kidney disease (HR 3.46, 95% CI 2.02–5.93, p < 0.001) but not MVD and atrial myopathy.ConclusionPatients with MVD present with altered LA anatomy with increased LA and LAA diameter. However, procedural success and safety in LAAO are not compromised. One-year mortality is numerically higher in patients with MVD but driven by comorbidities.Graphical abstract

Left Atrial Myopathy is Associated With Exercise Incapacity and Ventilatory Inefficiency in Hypertrophic Cardiomyopathy.

Left atrial (LA) myopathy is an established component of hypertrophic cardiomyopathy (HCM); however, the data about its association with exercise incapacity or ventilatory inefficiency that may be seen in HCM patients are limited. This study aimed to explore the association between LA myopathy, evaluated by echocardiography LA strain, and exercise capacity and ventilatory efficiency, evaluated by cardiopulmonary exercise testing (CPET), in HCM patients. This study included 241 consecutive HCM patients (aged 51.2±15.7 years 67.2% male) in sinus rhythm who underwent CPET and transthoracic echocardiography at the same visit. Exercise incapacity (maximal/predicted oxygen consumption [%peakVO2] <80%) and ventilatory inefficiency (ventilation/carbon dioxide output [VE/VCO2] slope >34) were assessed by CPET. Left atrial myopathy was examined by speckle-tracking myocardial deformation parameters: LA reservoir, conduit and booster strain. All three LA strain values were univariate predictors of exercise capacity and ventilatory efficiency. Among them, LA reservoir strain had the higher r correlation coefficient for predicting both %peakVO2 and VE/VCO2 slope. Left atrial reservoir strain, presence of angina and family history of HCM were independent predictors of exercise capacity. Left atrial reservoir strain, male gender and non-sustained ventricular tachycardia were independent predictors of ventilatory efficiency. Left atrial reservoir strain was a significant predictor of %peakVO2<80% with an optimal cut-off value of 27% (sensitivity 87% and specificity 31%) and VE/VCO2>34 with an optimal cut-off value of 18% (sensitivity 71% and specificity 83%). Left atrial myopathy, as reflected by the LA strain values, was associated with exercise incapacity and ventilatory inefficiency in HCM individuals. Left atrial reservoir strain was the only common independent predictor of %peakVO2 and VE/VCO2 slope.

Cytotoxic CD8+ T Cells Are Involved in the Thrombo-Inflammatory Response during First-Diagnosed Atrial Fibrillation.

Atrial myopathy and atrial fibrillation (AF) accompany thrombo-inflammation. This facilitates disease progression and promotes major adverse cardiovascular events (MACEs). Thrombin receptor (protease-activated receptor 1, PAR1) signalling is central in mediating thrombo-inflammation. We hypothesised that PAR1 signalling links coagulation and inflammation through cytotoxic CD8+ T lymphocytes in patients presenting with first-diagnosed AF (FDAF). A total of 210 patients were studied. We included data and blood samples from patients presenting with FDAF (n = 160), cardiac tissue from patients with paroxysmal AF (n = 32) and 20 controls. During early AF, a pro-inflammatory and cytotoxic subset of T lymphocytes (CD8+) circulated more frequently when compared to patients with chronic cardiovascular disease but without AF, accompanied by elevated plasma levels of CD8+ effector molecules, which corresponded to biomarkers of adverse cardiac remodelling and atrial dysfunction. Activation of tissue factor (TF) and PAR1 was associated with pro-inflammatory and cytotoxic effector functions. PAR1-related CD8+ cell activation was more frequent in FDAF patients that experienced a MACE. In patients with FDAF, the TF-factor Xa-factor IIa-axis contributes to thrombo-inflammation via PAR1 in CD8+ T cells. Intervening in this cascade might be a promising synergistic approach to reducing disease progression and the vascular complications of AF.

Intrinsic Atrial Myopathy Precedes Left Ventricular Dysfunction and Predicts Atrial Fibrillation in Lamin A/C Cardiomyopathy.

In Lamin A/C (LMNA) cardiomyopathy, atrial fibrillation (AF) commonly occurs before dilated cardiomyopathy, and the ability to predict its incidence is limited. We hypothesized that left atrial (LA) echocardiographic phenotyping can identify atrial myopathy and harbingers of AF. Echocardiograms from patients with pathogenic or likely pathogenic variants in LMNA (n=77) with and without reduced left ventricular ejection fraction (LVEF, <50%) were compared to healthy individuals (n=70) and patients with Titin truncating variant cardiomyopathy (TTNtv) (n=35) with similar LVEF, sex, and age distributions. Echocardiographic analysis, blinded to genotype, included strain and volumetric measures of left ventricular and atrial function. The primary outcome was incident AF. At baseline, 43% of the patients with pathogenic or likely pathogenic LMNA variants had a history of AF, including 26% of those with LVEF ≥50%. Compared with healthy subjects, the patients with pathogenic or likely pathogenic LMNA variants and LVEF ≥50% had reduced LA contractile strain (LMNA, 11.8±6.1% versus control, 15.0±4.2%; P=0.003). Compared to LVEF-matched (TTNtv) patients, the patients with pathogenic or likely pathogenic LMNA variants and LVEF <50% displayed no difference in LA size, but a worse LA contractile dysfunction (6.4±4.7% versus 12.6±9.6%; P=0.02). Over a median follow-up of 2.8 (1.2-5.7) years, LA contractile strain was the only significant predictor of AF in multivariable Cox regression (hazard ratio, 4.0 [95% CI, 1.04-15.2]). LMNA cardiomyopathy is associated with early intrinsic atrial myopathy reflected by high AF prevalence and reduced LA contractile strain, even in the absence of LV dysfunction and LA dilation. Whether LA strain can be used as a monitoring strategy to detect and mitigate AF complications requires validation.

91 METABOLIC AND CARDIAC MORPHO-FUNCTIONAL IMPROVEMENTS AFTER PCSK9 INHIBITORS ADMINISTRATION

Abstract Aim Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is mainly produced by the liver, but it is also expressed in the heart. It plays a key role in cholesterol's metabolism. Recent studies suggest its possible role in cardiovascular (CV) diseases, promoting vascular inflammation, reactive oxygen species generation and atherosclerotic plaque formation. Global longitudinal strain (GLS), global myocardial work efficiency (GWE), reservoir (PALS) and pump (PACS) atrial function evaluated by speckle-tracking echocardiography are able to identify early subclinical ventricular and atrial myopathy. In the last years PCSK9 inhibitors have been introduced as innovative therapies for LDL plasma levels's reduction. The aim of our study was to investigate PCSK9 inhibitors's effects in secondary prevention's patients, equally assigned to Alirocumab or Evolocumab, who were statin-intolerant and/or not reaching the target of LDL-C &amp;lt;55 mg/dl using the maximum tolerated drugs’ dosage at basal time and on semestral follow-up. Methods We selected 30 patients (24 males and 6 females, mean age 66+8 years old), having several comorbidities: hypertension (97%), ICM (90%), CKD II-III stage (70%), polidistrectual atherosclerosis (67%), T2DM (50%), OSAS-COPD (20%), HF NYHA class II-III (20%). They underwent anthropometrical evaluation, biochemical analysis, oxidative stress markers assessment, liver elastography, and advanced echocardiogram at basal time and after six months of therapy. NOX-2 and Sp-selectin were assessed with ELISA sandwich. Data were analyzed with ANOVA, post-hoc Bonferroni's test and Chi-square. Linear correlation analysis was performed for variables whose variation were statistically significant. Results As expected, lipid profile was greatly improved in all the subjects, reaching the target of LDL-C &amp;lt;55 mg/dl. We obtained a statistically significant reduction of total-cholesterol (32%, p&amp;lt;0,0001), LDL-C (60%, p&amp;lt;0,0001), TG (26%, p&amp;lt;0,0001), TG/HDL ratio (27%, p&amp;lt;0,0001); an increase of HDL-C (9%, p=0.001) and an improvement of glomerular filtrate evaluated by CKD-EPI (6%, p=0.007). We observed a statistically significant reduction of NOX-2 (27%, p&amp;lt;0,0001) and Sp-selectin (36%, p&amp;lt;0,0001). We obtained a statistically significant increase of PALS (16.9%, p&amp;lt;0,0001), PACS (21%, p&amp;lt;0,0001), GWE (9.7%, p&amp;lt;0,0001), GLS (24%, p&amp;lt;0,0001) and a statistically significant reduction of global wasted work (GWW; 15%, p&amp;lt;0,0001), left atrial volume index (LAVI; 8%, p&amp;lt;0,0001) and E/e’ ratio (19%, p&amp;lt;0,0001). The results of linear correlation analysis showed that PACS was significantly and inversely correlated with TG/HDL (r=-0.406, p=0.013) and NOX-2 (r=-0.416, p=0.011); PALS was significantly and inversely correlated with TG/HDL (r=-0.473, p=0.004) and NOX-2 (r=-0.435, p=0.008); E/e’ was significantly and directly correlated with TG/HDL (r=0.654, p&amp;lt;0.0001) and NOX-2 (r=0.438, p=0.008); GWE was inversely correlated with NOX-2 (r=-0.422, p=0.01). Conclusions Our study demonstrated for the first time that PCSK9 inhibitors are able to reduce left ventricular filling pressure, to increase atrial function (reservoir and pump), global cardiac performance (GLS and GWE), and eGFR after six months of treatment in high CV risk population. Our results could be partially explained with a reduction of oxidative stress markers, inflammation and cardio-lipotoxicity, probably linked to a modulation of PCSK9's heart expression and its toxic effect on CV and renal function. In addition, we observed a TG/HDL ratio's reduction, related to cardiometabolic and lipid profile improvement. Further studies are necessary to better investigate systemic benefit in a larger population with longer follow-up.

Association between heart and dementia… keep an eye on the left atrium.

Atrial fibrillation is associated with an increased risk of cognitive impairment and dementia. The mechanisms are not well known, but they are probably multifactorial and involve atrial myopathy, cardio-embolism, cerebral hypoperfusion, and comorbidities (systemic vascular sclerosis, disease of the small cerebral vessels, inflammation, etc.). Atrial fibrillation therapy could have a protective effect on dementia through diversified actions: (i) prevention of left atrial remodelling; (ii) prevention of cardio-embolism and silent (and not) cerebral infarcts; (iii) improvement of cardiac output and cerebral perfusion. Randomized trials will be needed to clarify the links between left atrium and dementia and to identify the most appropriate therapeutic strategies.

Effect of Weight Loss on Early Left Atrial Myopathy in People With Obesity But No Established Cardiovascular Disease.

Background Obesity is associated with left atrial (LA) remodeling (ie, dilatation and dysfunction) which is an independent determinant of future cardiovascular events. We aimed to assess whether LA remodeling is present in obesity even in individuals without established cardiovascular disease and whether it can be improved by intentional weight loss. Methods and Results Forty-five individuals with severe obesity without established cardiovascular disease (age, 45±11 years; body mass index; 39.1±6.7 kg/m2; excess body weight, 51±18 kg) underwent cardiac magnetic resonance for quantification of LA and left ventricular size and function before and at a median of 373 days following either a low glycemic index diet (n=28) or bariatric surgery (n=17). Results were compared with those obtained in 27 normal-weight controls with similar age and sex. At baseline, individuals with obesity displayed reduced LA reservoir function (a marker of atrial distensibility), and a higher mass and LA maximum volume (all P<0.05 controls) but normal LA emptying fraction. On average, weight loss led to a significant reduction of LA maximum volume and left ventricular mass (both P<0.01); however, significant improvement of the LA reservoir function was only observed in those at the upper tertile of weight loss (≥47% excess body weight loss). Following weight loss, we found an average residual increase in left ventricular mass compared with controls but no residual significant differences in LA maximum volume and strain function (all P>0.05). Conclusions Obesity is linked to subtle LA myopathy in the absence of overt cardiovascular disease. Only larger volumes of weight loss can completely reverse the LA myopathic phenotype.

Abstract 15227: Decreased Left Atrial Emptying Fraction is Associated With Increased Odds of Diagnosing Atrial Fibrillation Within 1 Year of ESUS

Introduction: A significant proportion of patients with embolic stroke of unknown source (ESUS) are subsequently diagnosed with atrial fibrillation (AF). Left atrial myopathy characterized by mechanical left atrial dysfunction has been associated with development of AF. Hypothesis: Decreased left atrial emptying fraction (LAEF) is independently associated with AF in patients with ESUS. Methods: Patients admitted at a tertiary care medical center for ESUS treated with implantable loop recorders from 2015-2022 were included. Patients were excluded for lack of an interpretable transthoracic echocardiogram during sinus rhythm and electrocardiogram with 6 months of ESUS. Patients were also excluded for lack of clinical follow-up. Co-variates (table) were ascertained from chart review. LAEF was calculated by Simpson’s method of discs. Results: 153 patients were included. The mean(standard deviation) LAEF of patients who developed and did not develop AF within 1 year post ESUS was 48.0%(17.0%) and 57.6%(13.1%), respectively (P&lt;0.001). The odds of diagnosing atrial fibrillation within 1 year post ESUS were 7.18-fold greater in patients with LAEF&lt;40%. Conclusions: LAEF is independently associated with increased odds of AF within 1 year post ESUS. Future research is needed to validate these findings.

Pragmatic analysis of ECG classification models &amp; architectures from a statistical perspective

Electrocardiograms, also known as ECGs, are capable of representing a wide range of heart conditions, such as atrial fibrillation, arrhythmia, myopathy, and heart failure. Operations such as denoising, signal enhancement, feature extraction, feature selection, stratification, and post processing are developed in order to process ECG signals. Depending on the application that is being deployed, these processes may only work in their individual components or in combination with one another. Researchers over the years have developed a wide variety of algorithms, each specifically tailored to accomplish one of these tasks. The computational complexity of these algorithms, the number of diseases they can classify, the degree of accuracy they provide, the cost of deployment, and other factors can vary. For example, models that are based on convolutional neural networks (CNNs) have a high level of accuracy; however, these models are typically slow and highly complex to deploy, and as a result, theyare not used in clinical applications that have a low cost. However, linear classification models such as support vector machines (SVMs) have acceptable accuracy, a moderate level of complexity, but are lacking in terms of precision; as a result, they are not suitable for use in applications that require real-time processing. Because there is such a wide range of algorithms that are available, it is unclear to researchers which models would be the best fit for their application, which leads to an increase in both the cost of deployment and the amount of time needed to bring the product to market. The text that lies beneath this one examines several of the recently proposed ECG classification models and assesses them based on a number of statistical parameters, including computational delay, complexity of deployment, classification accuracy, precision, number of heart diseases covered, and so on.This is done in an effort to clarify the situation and remove some of the ambiguity. After completing this analysis, the text then compares their performance and provides an estimate of the models that are the most appropriate. Researchers now have the ability to select and implement the algorithmic models that are best suited for their deployments based on this review. In addition to that, this reviwe suggests a number of different enhancements that can be made to the models that have been examined, and researchers can implement these suggestions in order to increase the effectiveness of the models.

Thrombin receptor protease-activated receptor 1 (PAR1) related cytotoxic CD8+ T cell activity is associated with atrial myopathy and pro-inflammatory immune response in early atrial fibrillation

Abstract Background and aims Cytotoxic CD8+ T cells mediate myocardial damage in patients with virus induced myocarditis, plaque erosion during acute coronary syndrome, and promote adverse post-ischemic cardiac remodeling. There is emerging evidence to support a link between inflammation and atrial fibrillation (AF). Protease-activated receptor 1 (PAR1) is the thrombin receptor expressed on platelets, but it is also expressed in endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and CD8+ T cells. The role of CD8+ T cells and PAR1 in atrial myopathy and early AF have not been studied. Methods In 80 non-anticoagulated patients with a first documented episode of AF, and 20 control subjects without AF but with a comparable cardiovascular risk profile (e.g. SCORE2, CHA2DS2-VASc, p&amp;gt;0.05), we studied PAR1-related cytotoxic T cell activity in the first hours (up to 24 h) of AF clinical manifestation. The Apolipoprotein E–knock out (ApoEko) mouse is a commonly used model of metabolic syndrome that develops atrial myopathy (structural correlate of AF). ApoEko male mice (Apoetm1Unc with a C57BL/6 genetic background) were fed for six weeks with a standard chew, western-type diet (high fat and high sucrose = WD) ± the specific PAR1 inhibitor vorapaxar. Results High levels of circulating, activated CD8+ T cells (CD8+CD57+ T cells with pro-inflammatory and high cytotoxic properties) were present in patients with early AF (flow cytometry). Stimulation of cytotoxic T cells, that expressed the thrombin receptor PAR1, that were isolated from patients with new onset of AF, released pro-inflammatory cytokines (e.g. IFN-γ, TNF-α). Enhanced cytotoxic activity of CD8+ T cells was suggested by elevated plasma levels of effector molecules (e.g. granulysin and granzyme). In ApoEko mice fed a WD, atrial myopathy as the structural correlate for AF, was paralleled by increased expression of effector molecules that were associated with CD8+ T cell activity (like perforin, granzyme A, granzyme B, IFN-γ). Cytotoxic T cell activity disrupted the release of the potective atrial natriuretic peptide, ANP, and increased signaling pathways associated with atrial fibrosis (e.g. TGF-β, cTGF, TGF-β receptor). The specific PAR1 inhibitor, vorapaxar, reduced inflammatory T cell activity, transcription of fibrotic mediators, and reconstituted ANP secretion in atria of ApoEko mice. Conclusions Targeting the FXa/FIIa-PAR1-CD8+ axis might be a promising approach to reduce atrial fibrosis and inflammation. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): BIH Charité Clinician Scientist Program