Role of mitochondrial ribosomal protein L7/L12 (MRPL12) in diabetic ischemic heart disease.

BACKGROUND: Myocardial infarction (MI) is a significant cause of death in diabetic patients. Growing evidence suggests that mitochondrial dysfunction contributes to heart failure in diabetes. However, the molecular mechanisms of mitochondrial dysfunction mediating heart failure in diabetes are still poorly understood. METHODS: We examined MRPL12 levels in right atrial appendage tissues from diabetic patients undergoing coronary artery bypass graft (CABG) surgery. Using AC-16 cells overexpressing MRPL12 under normal and hyperglycemic conditions we performed mitochondrial functional assays OXPHOS, bioenergetics, mitochondrial membrane potential, ATP production and cell death. RESULTS: We observed elevated MRPL12 levels in heart tissue samples from diabetic patients with ischemic heart disease compared to non-diabetic patients. Overexpression of MRPL12 under hyperglycemic conditions did not affect oxidative phosphorylation (OXPHOS) levels, cellular ATP levels, or cardiomyocyte cell death. However, notable impairment in mitochondrial membrane potential (MMP) was observed under hyperglycemic conditions, along with alterations in both basal respiration oxygen consumption rate (OCR) and maximal respiratory capacity OCR. CONCLUSIONS: Overall, our results suggest that MRPL12 may have a compensatory role in the diabetic myocardium with ischemic heart disease, suggesting that MRPL12 may implicate in the pathophysiology of MI in diabetes.

A rare case of left atrial appendage aneurysm.

BACKGROUND: Left atrial appendage aneurysm is a rare cardiac mass, with only a few cases reported. There are usually no specific symptoms, and a few patients visit the doctor with symptoms. CASE PRESENTATION: A 20-year-old male presented to our hospital with a "pericardial cyst found by medical evaluation in another hospital for 2 years." Cardiac ultrasound performed at clinics of our hospital suggested a cystic dark area in the left ventricular lateral wall and the anterior lateral wall, consistent with a pericardial cyst and mild mitral regurgitation. After further relevant examinations and ruling out contraindications, an excision of the left atrial appendage aneurysm was performed under general anesthesia and cardiopulmonary bypass with beating-heart. The postoperative pathological results identified that: (left atrial appendage) fibrocystic wall-like tissue with a focal lining of the flat epithelium, consistent with a benign cyst. CONCLUSION: Left atrial appendage aneurysms are rare and insidious. They are usually found by chance during medical evaluations. If the location is not good or the volume is too large, then compression symptoms or arrhythmia, thrombosis and other concomitant symptoms will occur. Surgical resection is presently the only effective radical cure for a left atrial appendage aneurysm.

Unusual cardiac aneurysms: a surgical pathology experience.

Among the cardiac outpouchings, left ventricular aneurysms or pseudo-aneurysms that develop secondary to myocardial infarctions are the most common. On the other hand, atrial appendageal and valvular aneurysms are uncommon occurrences. The appendageal aneurysms develop possibly due to congenital dysplasia of atrial pectinate muscles, while valvular aneurysms result from infective endocarditis, mechanical injury or degenerative changes. Despite their unusual locations, they are prone to life-threatening complications. We present our experience of unusual cardiac aneurysms in surgical cardiovascular material.

Activated factor X stimulates atrial endothelial cells and tissues to promote remodelling responses through AT1R/NADPH oxidases/SGLT1/2.

AIMS: Atrial fibrillation (AF), the most common cardiac arrhythmia favouring ischemic stroke and heart failure involves left atrial remodelling, fibrosis and a complex interplay between cardiovascular risk factors. This study examined whether activated factor X (FXa) induces pro-remodelling and pro-fibrotic responses in atrial endothelial cells (AECs) and human atrial tissues and determined the underlying mechanisms. METHODS AND RESULTS: AECs collected from porcine hearts and human right atrial appendages (RAA) from patients undergoing heart surgery. Protein expression levels were assessed by Western blot and immunofluorescence staining, mRNA levels by RT-qPCR, formation of reactive oxygen species (ROS) and NO using fluorescent probes, thrombin and angiotensin II generation by specific assays, fibrosis by Sirius red staining and senescence by senescence-associated beta-galactosidase (SA-ß-gal) activity. In AECs, FXa increased ROS formation, senescence (SA-ß-gal activity, p53, p21), angiotensin II generation and the expression of pro-inflammatory (VCAM-1, MCP-1), pro-thrombotic (tissue factor), pro-fibrotic (TGF-ß and collagen-1/3a) and pro-remodelling (MMP-2/9) markers whereas eNOS levels and NO formation were reduced. These effects were prevented by inhibitors of FXa but not thrombin, protease-activated receptors antagonists (PAR-1/2) and inhibitors of NADPH oxidases, ACE, AT1R, SGLT1/SGLT2. FXa also increased expression levels of ACE1, AT1R, SGLT1/2 proteins which were prevented by SGLT1/2 inhibitors. Human RAA showed tissue factor mRNA levels that correlated with markers of endothelial activation, pro-remodelling and pro-fibrotic responses and SGLT1/2 mRNA levels. They also showed protein expression levels of ACE1, AT1R, p22phox, SGLT1/2, and immunofluorescence signals of nitrotyrosine and SGLT1/2 colocalized with those of CD31. FXa increased oxidative stress levels which were prevented by inhibitors of the AT1R/NADPH oxidases/SGLT1/2 pathway. CONCLUSION: FXa promotes oxidative stress triggering premature endothelial senescence and dysfunction associated with pro-thrombotic, pro-remodelling and pro-fibrotic responses in AECs and human RAA involving the AT1R/NADPH oxidases/SGLT1/2 pro-oxidant pathway. Targeting this pathway may be of interest to prevent atrial remodelling and the progression of atrial fibrillation substrate.

Complex left appendage morphology is associated with Embolic Stroke of Undetermined Source.

INTRODUCTION: Variations in the left atrial appendage (LAA) morphology are associated with different embolic risk in patients with atrial fibrillation (AF). Data are scarce regarding the association between LAA morphology and Embolic stroke of undetermined source (ESUS). PATIENTS AND METHODS: Using cardiac computed tomography (CCT) scans, LAA morphology was categorized as either chicken wing (CW), cactus, windsock, or cauliflower. Furthermore, we examined the presence of large secondary lobes arising from the main lobe, considering their existence as indicative of a complex LAA morphology. LAA morphologies were compared between ESUS (n = 134) and AF patients (n = 120); and between ESUS patients with (n = 24) and without (n = 110) subsequent AF diagnosis during long-term follow-up. RESULTS: ESUS patients had a significantly higher prevalence of cauliflower morphology compared to AF group (52% vs 34%, respectively, p = 0.01); however, no significant difference was found between the groups when categorizing LAA morphology to either CW or non-CW. ESUS patients had significantly higher prevalence of large secondary lobes compared with AF patients (50% vs 29%, respectively, p = 0.001). When comparing ESUS patients with and without AF diagnosis during follow-up (20-48 months of follow-up, median 31 months), there were no significant differences in the prevalence of the "classical" morphologies, but large secondary lobes were significantly more prevalent among those without subsequent AF diagnosis. CONCLUSION: ESUS patients have a high prevalence of complex LAA morphology, which might be associated with an increased risk for thrombus formation even in the absence of AF.

From the archives of MD Anderson Cancer Center. Mesothelial/monocytic incidental cardiac excrescence with a review of the literature.

Mesothelial/monocytic incidental cardiac excrescence (MICE) is a rare benign lesion composed of monocytes and mesothelial cells that is most often encountered during cardiothoracic surgery. We describe a case in a 71-year-old man with known aortic valve stenosis who presented with gradual onset dyspnea over a few weeks, made worse with minimal exertion. A transesophageal echocardiogram revealed severe aortic stenosis and mild pericardial effusion. The patient underwent aortic valve replacement, coronary artery bypass, and amputation of the left atrial appendage. Histological examination of a 0.8 cm blood clot received along with the atrial appendage showed an aggregation of bland cells with features of monocytes associated with small strands and nodules of mesothelial cells, fat cells, fibrin and a minute fragment of bone. Immunohistochemical analysis showed that the monocytic cells were positive for CD4 and CD68 (strong) and negative for calretinin and keratin. By contrast, the mesothelial cells were positive for calretinin and keratin and negative for all other markers. In sum, the morphologic and immunohistochemical findings support the diagnosis of MICE. Based on our review of the literature, about 60 cases of MICE have been reported previously which we have tabulated. We also discuss the differential diagnosis.

Fluid-structure interaction analysis of the thromboembolic risk in the left atrial appendage under atrial fibrillation: Effect of hemodynamics and morphological features.

BACKGROUND: Complications of atrial fibrillation (AF) include ischemic events originating within the left atrial appendage (LAA), a protrusion of the left atrium with variable morphological characteristics. The role of the patient specific morphology and pathological haemodynamics on the risk of ischemia remains unclear. METHODS: This work performs a comparative assessment of the hemodynamic parameters among patient-specific LAA morphologies through fluid-structure interaction computational analyses. Three LAA models per each of the four commons patient-specific morphological families (chicken wing, cactus, windsock, and cauliflower) were analysed. Mechanical properties of the tissue were based on experimental uniaxial tests on a young pig's heart. Boundary conditions were imposed based on clinical assessments of filling and emptying volumes. Sinus rhythm and atrial fibrillation operative conditions were simulated and analysed. RESULTS: For each model, the effect of morphological and functional parameters, such as the number of trabeculae and LAA stroke volume, over the hemodynamics established into the appendage was analysed. Comparison between results obtained in healthy and diseased conditions suggested the introduction of a new parameter to quantify the risk of thrombosis, here called blood stasis factor (BSF). This is defined as the LAA surface area which permanently experiences levels of shear strain rate inferior to a threshold value, set to 5 s-1 (BSF5). CONCLUSIONS: This work suggests that the current morphological classification is unsuitable to evaluate the probability of thrombus formation. However, hemodynamic parameters easy to determine from clinical examinations, such as normalised stroke volume, LAA orifice flow rate and presence of extensive trabeculations can identify departures from healthy hemodynamics in AF and support a more systematic stratification of the thromboembolic risk.

Late overlooked intraluminal right atrial metastasis in endometrial carcinoma.

We report the case of an 83-year-old woman that presented with progressive dyspnoea due to an intraluminal right atrial metastasis of an endometrial carcinoma that had been diagnosed 4 years earlier. Treatment up to that point consisted of an hysterectomy and resection and radiation of local recurrences. Follow-up had been interpreted as negative, despite a PET-CT 8 months before presentation which had shown increased FDG uptake in the right atrium, but was unfortunately considered benign. After confirmation of metastasis, first-line chemotherapy was started. However, due to poor tolerance and rapid symptom progression, chemotherapy had to be stopped early. She died 2 months later. Cardiac metastasis in endometrial carcinoma is rare. However, the incidence is increasing simultaneously with prolonged cancer survival. Because advances in systemic and radiotherapy now allow curative treatment, more focus should be put on early detection, for example by PET-CT. This way aggressive combined therapy can be started before the burden of cardiac metastasis does not allow it any longer.

Intensity-modulated radiotherapy and chemotherapy for canine right atrial tumors: A retrospective study of seven dogs.

Most primary cardiac tumors in dogs are located in the right atrium/atrial appendage, with hemangiosarcoma being the most common. The aims of this retrospective, case series were to describe outcomes for seven dogs with right atrial tumors treated with hypofractionated intensity-modulated radiotherapy and concurrent vinblastine and propranolol. One dog had a complete response, four dogs had partial responses and two dogs had stable disease after treatment. Effusions resolved in all dogs. Median progression-free survival was 290 days. Five dogs died from metastatic disease, one dog from unrelated neoplasia, and one dog is alive. Median overall survival was 326 days. Three dogs with confirmed hemangiosarcoma survived 244, 326, and 445 days. Two dogs developed clinically significant, but nonfatal, cardiac arrhythmias. One dog that received three courses of radiation had subclinical myocardial and arterial fibrosis at necropsy. Hypofractionated chemoradiotherapy was well tolerated and may provide clinical benefit in dogs with right atrial tumors.

Relationship Between Fibrosis, Endocardial Endothelial Damage, and Thrombosis of Left Atrial Appendage in Atrial Fibrillation.

BACKGROUND: Left atrial appendage (LAA) thrombus (LAAT) and ischemic stroke are considered important in atrial cardiomyopathy with progressive atrial fibrosis and endocardial endothelial damage. OBJECTIVES: This study aimed to obtain histological evidence to clarify the association between LAA fibrosis and endocardial endothelial damage with LAAT, ischemic stroke, and clinical risk factors. METHODS: Ninety-six patients with atrial fibrillation (AF) scheduled to undergo LAA excision during surgery were enrolled. They underwent transesophageal echocardiography before the surgery to validate the LAA function/morphology and LAAT presence or absence. The resected LAAs were subjected to Azan-Mallory staining and CD31 immunohistochemistry to quantify the degree of fibrosis and endocardial endothelial damage staged as F1-F4 and E1-E4 per the quantiles. RESULTS: Patients with an LAAT and/or ischemic stroke history had higher fibrosis degrees (18.4% ± 9.9% vs 10.4% ± 7.0%, P < 0.0001) and lower CD31 expressions (0.27 [IQR: 0.05-0.57] vs 1.02 [IQR: 0.49-1.65]; P < 0.0001). Also, higher CHADS2 was associated with a higher degree of fibrosis and lower CD31 expression. Multivariate logistic regression analysis revealed that endothelial damage (E4) was associated with an LAAT and/or ischemic stroke history independent of AF type (paroxysmal or nonparoxysmal) with an OR of 3.47. Among patients with nonparoxysmal AF, fibrosis (F4, OR: 3.66), endothelial damage (E4, OR: 4.62), and LAA morphology (non-chicken-wing, OR: 3.79) were independently associated with LAAT and/or stroke. The degree of fibrosis correlated significantly with endothelial damage (R = -0.38, P = 0.0001). CONCLUSIONS: These histological findings may be essential in considering the pathophysiology of LAAT and stroke within the atrial cardiomyopathy context.

Left atrial appendage dimension predicts elevated brain natriuretic peptide in nonvalvular atrial fibrillation.

INTRODUCTION: BNP elevation in patients with AF is observed in the absence of heart failure; however, prior mechanistic studies have not included direct left atrial pressure measurements. This study sought to understand how emptying function of the left atrial appendage (LAA) and LAA dimension contributes to brain-natriuretic peptide elevations (BNP) in atrial fibrillation (AF) accounting for left atrial pressure (LAP). METHODS: 132 patients referredfor left atrial appendage occlusion (LAAO) were prospectively enrolled in this study. BNP levels and LAP were measured just before LAAO. Statistical analysis considered BNP, rhythm at time of procedure, LAP, LAA morphology, LAA size (ostial diameter, depth, volume), LAA emptying velocity, CHADS2-VASc score, body mass index (BMI), left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (eGFR), and obstructive sleep apnea (OSA) diagnosis as covariates. RESULTS: Bivariate statistical analysis demonstrated positive associations with age, LAA ostial diameter, depth, and volume, LAP, AF status at time of measurement, OSA, and CHADS2-VASc score. BNP was negatively associated with LVEF, eGFR, LAA emptying velocity and BMI. With multivariate logistic regression including LAP as covariate, significant relationships between BNP and AF/AFL(OR 1.99 [1.03, 3.85]), LAP (OR 1.13 [1.06, 1.20]), LAA diameter (OR 1.14 [1.03, 1.27]), LAA depth (OR 1.14 [1.07, 1.22]), and LAA emptying velocity (OR 0.97 [0.96,0.99]) were observed; however, no significant associations were seen with LAA morphology or CHADS2-VASc score. CONCLUSIONS: BNP elevations in AF are associated with LAA size and function, but not CHADS2-VASc score or appendage morphology after accounting for changes in LAP.

Imaging of left heart intracardiac thrombus: clinical needs, current imaging, and emerging cardiac magnetic resonance techniques.

Intracardiac thrombus in the left atrium and atrial appendage (LA/LAA) and left ventricle (LV) increases the risk of systemic thromboembolism and causes potentially devastating diseases such as ischemic stroke and acute ischemia in abdominal organs and lower extremities. Detecting the presence and monitoring the resolution of left heart intracardiac thrombus are of vital importance for stratifying patients and guiding treatment decisions. Currently, echocardiography is the most frequently used method for the above clinical needs, followed by computed tomography. An increasing number of studies have been performed to investigate the value of cardiac magnetic resonance (CMR) as an alternative imaging modality given its several unique strengths. This article provides an overview of the clinical relevance of the LA/LAA and LV thrombus as well as the diagnostic performance of the current imaging modalities and emerging CMR techniques.

Autopsy findings of left atrial appendage closure device.

We report an autopsy case of an 80-year-old woman who underwent left atrial appendage closure with a WATCHMAN (Boston Scientific, St. Paul, MN, USA) device. This is the first report of histologic assessment following left atrial appendage closure with a WATCHMAN device at 3 months. Gross and histopathological examinations revealed neoendocardial coverage of the WATCHMAN device. Partial endothelialization was verified by CD34 staining; however, it remains unclear when complete endothelialization is likely to occur.

Left atrial appendage orifice area and morphology is closely associated with flow velocity in patients with nonvalvular atrial fibrillation.

BACKGROUND: Thromboembolic events are the most serious complication of atrial fibrillation (AF), and the left atrial appendage (LAA) is the most important site of thrombosis in patients with AF. During the period of COVID-19, a non-invasive left atrial appendage detection method is particularly important in order to reduce the exposure of the virus. This study used CT three-dimensional reconstruction methods to explore the relationship between LAA morphology, LAA orifice area and its mechanical function in patients with non-valvular atrial fibrillation (NVAF). METHODS: A total of 81 consecutive patients with NVAF (36 cases of paroxysmal atrial fibrillation and 45 cases of persistent atrial fibrillation) who were planned to undergo catheter radiofrequency ablation were enrolled. All patients were examined by transthoracic echocardiography (TTE), TEE, and computed tomography angiography (CTA) before surgery. The LAA orifice area was obtained according to the images of CTA. According to the left atrial appendage morphology, it was divided into chicken wing type and non-chicken wing type. At the same time, TEE was performed to determine left atrial appendage flow velocity (LAAFV), and the relationship between the left atrial appendage orifice area and LAAFV was analyzed. RESULTS: The LAAFV in Non-chicken wing group was lower than that in Chicken wing group (36.2 ± 15.0 cm/s vs. 49.1 ± 22.0 cm/s, p-value < 0.05). In the subgroup analysis, the LAAFV in Non-chicken wing group was lower than that in Chicken wing group in the paroxysmal AF (44.0 ± 14.3 cm/s vs. 60.2 ± 22.8 cm/s, p-value < 0.05). In the persistent AF, similar results were observed (29.7 ± 12.4 cm/s vs. 40.8 ± 17.7 cm/s, p-value < 0.05). The LAAFV in persistent AF group was lower than that in paroxysmal AF group (34.6 ± 15.8 cm/s vs. 49.9 ± 20.0 cm/s, p-value < 0.001). The LAAFV was negatively correlated with left atrial dimension (R = - 0.451, p-value < 0.001), LAA orifice area (R= - 0.438, p-value < 0.001) and left ventricular mass index (LVMI) (R= - 0.624, p-value < 0.001), while it was positively correlated with LVEF (R = 0.271, p-value = 0.014). Multiple linear regression analysis showed that LAA morphology (ß = - 0.335, p-value < 0.001), LAA orifice area (ß = - 0.185, p-value = 0.033), AF type (ß = - 0.167, p-value = 0.043) and LVMI (ß = - 0.465, p-value < 0.001) were independent factors of LAAFV. CONCLUSIONS: The LAA orifice area is closely related to the mechanical function of the LAA in patients with NVAF. The larger LAA orifice area and LVMI, Non-chicken wing LAA and persistent AF are independent predictors of decreased mechanical function of LAA, and these parameters might be helpful for better management of LA thrombosis.

The level of growth differentiation factor 15 as a predictor of left atrial thrombosis in patients with nonvalvular atrial fibrillation.

Aim    To study the role of blood concentration of growth differentiation factor 15 (GDF-15) as a predictor of left atrial/left atrial appendage (LA/LAA) thrombosis in patients with nonvalvular atrial fibrillation (AF).Material and methods    538 patients with nonvalvular AF were admitted to the Tyumen Cardiology Research Center in 2019-2020 for radiofrequency ablation and elective cardioversion. According to findings of transesophageal echocardiography (EcoCG), 42 (7.8%) of these patients had LA/LAA thrombosis and 79 (14.7%) of them had the effect of spontaneous echo contrast (SEC). This comparative, cross-sectional, cohort study included at the initial stage 158 successively hospitalized patients with nonvalvular AF: group 1 (with LA/LAA thrombosis, n=42) and group 2 (without LA/LAA thrombosis and without SEC, n=116). To eliminate significant differences in age between the groups, an additional inclusion criterium was introduced, age from 45 to 75 years. Finally, 144 patients were included into the study: group 1 (with LA/LAA thrombosis, n=42, mean age 60.9±7.2 years) and group 2 (without LA/LAA thrombosis and without SEC, n=116, mean age 59.5±6.0 years). 93 (91%) patients in group 1 and 40 (95%) patients in group 2 had arterial hypertension (p=0.4168); 53 (52%) and 29 (^(%), respectively, had ischemic heart disease (p=0.0611). The groups did not differ in sex, profile of major cardiovascular diseases, or frequency and range of oral anticoagulant treatment. General clinical evaluation, EchoCG, and laboratory tests, including measurements of blood concentrations of GDF-15 and NT-proBNP, were performed.Results    In the group with LA/LAA thrombosis, 1) persistent AF prevailed whereas paroxysmal AF was more frequently observed in patients without thrombosis; 2) a tendency toward more pronounced chronic heart failure was observed; 3) tendencies toward a high median CHA2DS2­VASc score and toward a greater proportion of patients with scores ≥3 were observed. According to EchoCG findings, group 1 had higher values of sizes and volumes of both atria and the right ventricle, left ventricular (LV) end-systolic volume and size, pulmonary artery systolic blood pressure, and LV myocardial mass index. LV ejection fraction (EF) was in the normal range in both groups but it was significantly lower for patients with LA/LAA thrombosis, 59.1±5.1 and 64.0±7.3, respectively (p=0.00006). Concentrations of GDF-15 (p=0.00025) and NT-proBNP were significantly higher in group 1 than in group 2 (p=0.000001). After determining the threshold values for both biomarkers using the ROC analysis, two independent predictors of LA/LAA thrombosis were obtained by the stepwise multiple regression analysis: GDF-15 >935.0 pg/ml (OR=4.132, 95 % CI 1.305-13.084) and LV EF (OR=0.859, 95 % CI 0.776-0.951). The ROC analysis assessed the model quality as good: AUC=0.776 (p<0.001), sensitivity 78.3 %, specificity 78.3 %.Conclusion    For patients with nonvalvular AF, both increased GDF-15 (>935.0 pg/ml) and LV EF are independent predictors for LA/LAA thrombosis.

Histopathological changes in the right atrial appendages triggering atrial fibrillation: A tertiary care center study.

BACKGROUND: Atrial fibrillation(AF) is as an abnormal irregular rhythm with chaotic generation of electrical signals in the atria of the heart. Various studies in the West have proved that atrial substrates, like isolated atrial amyloidosis can trigger the development of atrial fibrillation. In India, these structural changes have been analyzed on autopsied hearts. AIM: To determine the role of Atrial Amyloid as a substrate for Atrial fibrillation in ante mortem hearts. METHODS AND RESULTS: Atrial appendages were obtained from seventy five patients undergoing open heart surgery at a tertiary care hospital in south India. They were stained with Hematoxylin &Eosin, Masson's Trichrome and Congo red stains and were examined for myocarditis, fibrosis and amyloidosis, respectively. 30 (40%) patients were in AF. Amyloid deposits were seen in 3 cases. All the three were in AF and had undergone mitral valve replacement (MVR) (P<0.05). 2 out of the 3 amyloid-positive cases showed active myocarditis and severe scarring but there was no statistically significant correlation between these factors. CONCLUSION: Amyloid and myocarditis, independently act as an arrythmogenic substrates in the development of atrial fibrillation and are also increasingly associated with female gender and MVR. We hypothesize that the amyloid deposits are due to isolated atrial amyloidosis as they were seen only in young individuals. Some patients in sinus rhythm (SR) had large left atria and myocarditis and probably are at a higher risk for developing AF. Hence, follow-up of these patients is required for prevention of severe organ damage and timely therapeutic intervention.

Extracellular matrix remodeling precedes atrial fibrillation: Results of the PREDICT-AF trial.

BACKGROUND: To which extent atrial remodeling occurs before atrial fibrillation (AF) is unknown. OBJECTIVE: The PREventive left atrial appenDage resection for the predICtion of fuTure Atrial Fibrillation (PREDICT-AF) study investigated such subclinical remodeling, which may be used for risk stratification and AF prevention. METHODS: Patients (N = 150) without a history of AF with a CHA2DS2-VASc score of ≥2 at an increased risk of developing AF were included. The left atrial appendage was excised and blood samples were collected during elective cardiothoracic surgery for biomarker discovery. Participants were followed for 2 years with Holter monitoring to determine any atrial tachyarrhythmia after a 50-day blanking period. RESULTS: Eighteen patients (12%) developed incident AF, which was associated with increased tissue gene expression of collagen I (COL1A1), collagen III (COL3A1), and collagen VIII (COL8A2), tenascin-C (TNC), thrombospondin-2 (THBS2), and biglycan (BGN). Furthermore, the fibroblast activating endothelin-1 (EDN1) and sodium voltage-gated channel ß subunit 2 (SCN2B) were associated with incident AF whereas the Kir2.1 channel (KCNJ2) tended to downregulate. The plasma levels of COL8A2 and TNC correlated with tissue expression and predicted incident AF. A gene panel including tissue KCNJ2, COL1A1, COL8A2, and EDN1 outperformed clinical prediction models in discriminating incident AF. CONCLUSION: The PREDICT-AF study demonstrates that atrial remodeling occurs long before incident AF and implies future potential for early patient identification and therapies to prevent AF (ClinicalTrials.gov identifier NCT03130985).

Reduced plasma level of basic fibroblast growth factor is associated with incomplete device endothelialization at six months following left atrial appendage closure.

OBJECTIVES: To investigate whether inflammatory and growth factors (IGFs) were associated with incomplete device endothelialization (IDE) at 6 months after successful left atrial appendage closure (LAAC). BACKGROUND: IDE after LAAC is correlated with device-related thrombus (DRT) formation and subsequent thromboembolic events. However, biomarkers for early detection of IDE remain lacking. METHODS: Plasma levels of IGFs including basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF), stromal cell derived factor (SDF)-1a, transforming growth factor (TGF)-ß1, vascular growth factor receptor-1 (VEGF-R1) and von Willebrand factor (vWF) were determined using ELISA kits in 55 consecutive patients with atrial fibrillation (AF) at 6 months after LAAC with Watchman devices. The status of device endothelialization was assessed by transesophageal echocardiography and cardiac CT. RESULTS: IDE and complete device endothelialization(CDE)were detected in 38 and 17 patients, respectively. Among the six IGFs, only plasma level of bFGF was significantly lower in patients with IDE compared to those with CDE (303.49 ± 246.84 vs. 556.31 ± 197.84 pg/ml, p < 0.001). C-statistics of plasma bFGF for discriminating patients with IDE from those with CDE was 0.785 (95 % CI: 0.663-0.907, p < 0.001), with a cut-off value of 440.52pg/ml (sensitivity 0.765; specificity 0.789). Multivariate logistic regression model showed that lower bFGF was an independent factor for IDE (OR: 11.752, 95 % CI: 2.869-48.144, P = 0.001). bFGF improved the classification of patients (NRI: 0.677,95 % CI: 0.320-1.033, p = 0.004). CONCLUSIONS: Reduced plasma bFGF level confers an increased risk for IDE after LAAC. Further prospective studies are warranted to examine if bFGF could serve as a biomarker for IDE post LAAC.

Thromboembolic Risk in Atrial Fibrillation Patients With Left Atrial Scar Post-Extensive Ablation: A Single-Center Experience.

OBJECTIVES: This study evaluated the association of the post-ablation scar with stroke risk in patients undergoing atrial fibrillation (AF) ablation. BACKGROUND: Late gadolinium enhancement-cardiac magnetic resonance studies have reported a direct association between pre-ablation left atrial scar and thromboembolic events in patients with AF. METHODS: Consecutive patients with AF were classified into 2 groups based on the type of ablation performed at the first procedure. Group 1 involved limited ablation (isolation of pulmonary veins, left atrial posterior wall, and superior vena cava); and group 2 involved extensive ablation (limited ablation + ablation of nonpulmonary vein triggers from all sites except left atrial appendage). During the repeat procedure, post-ablation scar (region with bipolar voltage amplitude <0.5 mV) was identified by using 3-dimensional voltage mapping. RESULTS: A total of 6,297 patients were included: group 1, n = 1,713; group 2, n = 4,584. Group 2 patients were significantly older and had more nonparoxysmal AF. Nineteen (0.3%) thromboembolic events were reported after the first ablation procedure: 9 (1.02%) in group 1 and 10 (0.61%) in group 2 (p = 0.26). At the time of the event, all 19 patients were experiencing arrhythmia. Median time to stroke was 14 (interquartile range: 9 to 20) months in group 1 and 14.5 (interquartile range: 8 to 18) months in group 2. Post-ablation scar data were derived from 2,414 patients undergoing repeat ablation. Mean scar area was detected as 67.1 ± 4.6% in group 2 and 34.9 ± 8.8% in group 1 at the redo procedure (p < 0.001). CONCLUSIONS: Differently from the cardiac magnetic resonance-detected pre-ablation scar, scar resulting from extensive ablation was not associated with increased risk of stroke compared with that from the limited ablation.