Atrial Enlargement Research Articles

The Predictive Value of Global Longitudinal and Circumferential Strains in Hypertensive Patients: 10-Year Follow-Up

Background: The aim of the current study was to investigate the predictive value of a multidirectional LV strain on adverse outcomes in a large population of uncomplicated hypertensive patients who were followed for a mean period of 10 years. Methods: This retrospective study included 591 recently diagnosed hypertensive patients who underwent clinically indicated echocardiography between January 2010 and December 2014 and were followed for a mean period of 10 years. Global longitudinal, circumferential and radial strains (GLS, GCS and GRS) were measured by 2D speckle tracking imaging. The primary outcome was a MACE occurrence defined by all-cause mortality, cardiovascular mortality, myocardial infarction, coronary artery by-pass, coronary stent implantation, stroke, development of heart failure and the occurrence of atrial fibrillation during follow-up. Results: Our results showed that GLS, GCS and GRS were significantly lower in patients who experienced MACE. Age, male gender, systolic blood pressure, left ventricular hypertrophy (LVH) and left atrial enlargement (LAE) were associated with MACE occurrence. Reduced GLS [OR 1.15; 95%CI: 1.01–1.30] and reduced GCS [OR 1.1; 95%CI: 1.02–1.22] were related with MACE independently of clinical characteristics, LV systolic and diastolic function, as well as LVH. Reduced GRS was not independently associated with adverse outcomes. Conclusions: Reduced GLS and GCS were independently associated with adverse outcomes during 10-year follow-up in patients who were recently diagnosed and uncomplicated hypertensive patients at the baseline.

Degenerative mitral stenosis by echocardiography: presentation and outcome

Abstract Aims Degenerative mitral stenosis (DMS) is due to degenerative mitral annular calcification (MAC) and valvular calcification. However, DMS impacts on the outcome, and therefore, potential treatment needs are poorly known. We aimed at evaluating survival after DMS diagnosis by Doppler echocardiography in routine practice. Methods and results A cohort of 2937 (75 ± 12 years, 67% women) consecutive patients were diagnosed between 2003 and 2014 with DMS (diastolic mean gradient ≥ 5 mmHg), with analysis of short- and long-term survival. All patients had overt mitral annular/valvular degenerative calcification without rheumatic involvement. Mean gradient was 6.5 ± 2.4 mmHg, and DMS was considered mild in 50%, moderate in 44%, and severe in 6%. DMS was associated with left atrial enlargement (52 ± 23 mL/m2) and elevated pulmonary pressure (49 ± 16 mmHg) despite generally normal ejection fraction (61 ± 13%). DMS was associated with frequent comorbid conditions (74% hypertension, 58% coronary disease, and 52% heart failure) and humoural alterations (haemoglobin 11.3 ± 1.8 g/dL and creatinine 1.5 ± 1.4 mg/dL). One-year mortality was 22%, most strongly related to older age, higher comorbidity, and abnormal haemoglobin/creatinine but only weakly to DMS severity (with anaemia 42% irrespective of DMS severity, P = 0.99; without anaemia 18, 23, and 28% with mild, moderate, and severe DMS, respectively, P < 0.0004). Long-term mortality was high (56% at 5 years) also mostly linked to aging and weakly to DMS severity [with anaemia P = 0.90; without anaemia: adjusted-hazard ratio: 1.30 (1.19–1.42), P < 0.0001, for moderate vs. mild DMS and 1.63 (1.34–1.98), P < 0.0001, for severe vs. mild DMS]. Conclusion DMS is a condition of the elderly potentially resulting in severe mitral obstruction and haemodynamic alterations. However, DMS is frequently associated with severe comorbidities imparting considerable mortality following diagnosis, whereas DMS severity is a weak (albeit independent) determinant of mortality. Hence, patients with DMS should be carefully evaluated and interventional/surgical treatment prudently considered in those with limited comorbidity burden, particularly without anaemia. Keywords: Degenerative Mitral Stenosis; Outcome; Natural history; Ecocardiography; Mitral Stenosis.

The value of computed tomography angiography for evaluation of left atrial enlargement in patients with persistent atrial fibrillation

BackgroundThe post-processing technology of CTA offers significant advantages in evaluating left atrial enlargement (LAE) in patients with persistent atrial fibrillation (PAF). This study aims to identify parameters for rapidly and accurately diagnosing LAE in patients with PAF using CT cross-sections.MethodsLeft atrial pulmonary venous (PV) CT was performed to 300 PAF patients with dual-source CT, and left atrial volume (LAV), left atrial anteroposterior diameter (LAD1), left atrial transverse diameter (LAD2), and left atrial area (LAA) were measured in the ventricular end systolic (ES) and middle diastolic (MD). LA index (LAI) = LA parameter/body surface area (BSA). Left atrial volume index (LAVIES) > 77.7 ml/m2 was used as the reference standard for the LAE diagnosis.Results227 patients were enrolled in the group, 101 (44.5%) of whom had LAE. LAVES and LAVMD (r = 0.983), LAVIES and LAVIMD (r = 0.984), LAAES and LAVIES (r = 0.817), LAAMD and LAVIES (r = 0.814) had strong positive correlations. The area under curve (AUC) showed that all measured parameters were suitable for diagnosing LAE, and the diagnostic efficacy was compared as follows: LAA/LAAI> LAD> the relative value index of LAD, LAD2> LAD1. LAA and LAAI demonstrated comparable diagnostic efficacy, with LAA being more readily available than LAAI.ConclusionsThe axial LAA measured by CTA can be served as a parameter for the rapid and accurate diagnosis of LAE in patients with PAF.

Pathways to precision medicine: deciphering the secrets of physiological and pathological atrial enlargement.

Cardiac functional, morphological, and histological analysis, coupled with liquid chromatography and mass spectrometry, of two transgenic mouse models with cardiomyocyte-specific overexpression of insulin-like growth factor 1 receptor (IGF1R) or a dominant-negative PI3K mutant (DCM-dnPI3K) revealed distinctive functional and molecular profiles during physiological (driven by IGF1R overexpression) and pathological (driven by dn-PI3K overexpression) atrial remodeling. The current study confirmed previously reported findings, including ventricular dilatation and enhanced systolic function with no evidence of arrhythmia in IGF1R model, as well as ventricular hypertrophy and decreased systolic function with intermittent atrial fibrillation in DCM-dnPI3K model. Novel findings obtained from the left atrial (LA) characterization of female mice revealed that physiological atrial enlargement resulted from increased atrial myocyte size and was associated with preserved atrial function, as determined by maintained LA ejection fraction (EF). The proteomic profile of IGF1R transgenic (Tg) mice was enriched for metabolic remodeling and showed a protein expression pattern similar to that of healthy human atria; on the other hand, pathological atrial enlargement resulted from increased atrial fibrosis with normal myocyte size and was associated with impaired atrial function due to a reduced LA EF. The proteomic profile of DCM-dnPI3K mice was enriched to both metabolic and structural remodeling and showed a protein expression pattern similar to that of human AF atria.

A Case Report: Myxomatous Mitral Valve Disease in a Shih Tzu

Myxomatous Mitral Valve Disease (MMVD) is a degenerative condition of the mitral valve where it weakens and causes regurgitation, eventually leading to cardiac remodeling. Jason, a seven-year-old male Shih Tzu weighing 7.5 kg, was presented with a persistent cough and exercise intolerance lasting over a month. A physical examination revealed a Grade II/VI heart murmur. Radiography and echocardiography were performed as part of the laboratory examinations. Radiography demonstrated cardiac remodeling, with a VHS of 10.3 viscerocranial, an intercostal space of 3, and a VLAS of 2.3. Echocardiography unveiled left atrial enlargement, mitral valve regurgitation, and a reduction in heart function. The dog was treated with Pimobendan (Cardisure® 10mg, Dechra, England) as an inodilatator at 0.25mg, Enalapril Maleate 0.5mg/kg (Tenace® 5mg, Combiphar, Indonesia), and furosemide (Farsix® 40mg, Fahrenheit, Indonesia) at 2 mg/kg via oral route twice a day over the course of seven days. Thereafter, the dose was reduced to 1.5 mg/kg PO twice a day for seven days, and eventually once a day for the remainder of the seven days. Following the three-week treatment, there was a significant reduction in the frequency and intensity of coughing.

Aldosterone Robustly Promotes Atrial Fibrillation in the Presence of Chronic Volume Overload in Rats.

We investigated the modulatory effects of aldosterone on atrial remodeling induced by an abdominal aorto-venocaval shunt (AVS) in rats, as patients with primary hyperaldosteronism are suggested to have a higher risk of developing atrial fibrillation (AF). The rats were divided into four groups based on the basis of whether they underwent AVS surgery, received aldosterone using an intraperitoneally implanted osmotic minipump, or both. Aldosterone was started at 0.5 µg/h during the AVS surgery, and morphological and electrophysiological assessments were performed four weeks after AVS creation. The atrial structural changes induced by AVS, including atrial cell hypertrophy and fibrosis, were not modulated by aldosterone, whereas P-wave duration was longer in aldosterone-treated AVS rats than in non-treated rats. Although the average AF duration induced by burst pacing was 10-25 s in the untreated, aldosterone-treated, and AVS rats, the AF duration was approximately 100 s in the aldosterone-treated AVS rats. Meanwhile, there was no significant difference in the atrial effective refractory period among the four experimental groups. Notably, premature atrial contractions (PAC) were frequently observed in aldosterone-treated sham rats, while paroxysmal AF, in addition to PAC, was detected in aldosterone-treated AVS rats, which was not induced in non-treated AVS rats. These findings suggest that aldosterone robustly promotes AF, particularly in the presence of chronic volume overload.

Impact of changes in left heart geometry on predicting new-onset atrial fibrillation in patients with hypertension.

Hypertension-induced left ventricular hypertrophy (LVH) increases end-diastolic LV pressure and contributes to left atrial enlargement (LAE), which are associated with development of atrial fibrillation. However, the impact of LVH and LAE and their regression following antihypertensive therapy on atrial fibrillation incidence remains unclear. This retrospective analysis included consecutive patients with sinus rhythm who underwent echocardiography at hypertension diagnosis and after 6-18 months between 2006 and 2021 at tertiary care centres in Korea. LVH was defined as LV mass index greater than 115 g/m2 (men) and greater than 95 g/m2 (women), and LAE was defined as LA volume index greater than 42 ml/m2. The occurrence of new-onset atrial fibrillation (NOAF) was assessed in relation to changes in LVH and LAE status. Among the 1464 patients included, 163 (11.1%) developed NOAF during a median 63.8 [interquartile range (IQR) 35.9-128.5] months of surveillance period. New-onset LVH [adjusted hazard ratio (aHR) 1.88, 95% confidence interval (CI) 1.20-2.94, P = 0.006] and LAE (aHR 1.89, 95% CI 1.05-3.40, P = 0.034) were significant predictors of NOAF. Conversely, regression of LVH (aHR 0.51, 95% CI 0.28-0.91, P = 0.022) or LAE (aHR 0.30, 95% CI 0.15-0.63, P = 0.001) was associated with a reduced risk for developing NOAF. Patients with both LVH and LAE at follow-up echocardiography had a higher risk for NOAF (aHR 4.30, 95% CI 2.81-6.56, P < 0.001) than those with either LVH or LAE or those with neither. The changes in left heart geometry can serve as a predictive marker for NOAF in patients with hypertension.

Updates on the Association Between Anemia and Heart Failure: A Systematic Review.

This systematic review aims to investigate the potential relationship between anemia and heart failure (HF) by summarizing existing literature on the topic. A comprehensive search was performed using four major databases, PubMed, Scopus, Web of Science, and ScienceDirect, to find the relevant literature. Ten studies, including a total of 2,828 participants, with 1,451 (51.3%) males, were included in this review.Iron deficiency anemia was the most prevalent type in the included studies; however, two studies included megaloblastic anemia. The prevalence of anemia in patients diagnosed with HF ranged from 33.3% to 69.8%, with a total prevalence of 1,643 (58.1%). Hypertension, diabetes mellitus, chronic kidney disease, and atrial fibrillation were the most commonly associated comorbidities in patients with HF. Anemia patients had a considerably higher risk of mortality than those without anemia. Anemia served as a marker of disease severity rather than an independent predictor of death in congestive individuals. Anemia was substantially correlated with elevated serum creatinine, left ventricular hypertrophy, and left atrial enlargement. According to the findings of this review, anemia has a significant impact on the prognosis of HF. In patients with HF, anemia may be a reliable indicator of both short- and long-term all-cause mortality as well as the rates of all-cause HF events. Future and ongoing research may provide vital information that may help guide clinical judgments in the future.

Evaluation of the effectiveness of two neural networks (Resnet50v2 and Inception V3) in identifying left atrial enlargement in adult dogs.

Mitral valve endocardiosis is a heart disease that is present in approximately 75% of cases of canine heart disease. Currently, the gold standard for diagnosis is echocardiography, but radiography provides us with valuable information for clinical staging of the disease, such as detecting left atrial enlargement, the presence or absence of pulmonary congestion and cardiogenic pulmonary edema more quickly. The aim of this study was to evaluate the effectiveness of two neural networks, Resnet50v2 and Inception V3, in detecting left atrial enlargement. A database was built with 1052 lateral images. The images were then separated into three distinct groups: 198 images with left atrial enlargement (LAA), 124 images with left atrial enlargement simultaneously with pulmonary edema (LAA_EP), totaling 322 images with left atrial enlargement and 580 images considered normal (N). As a result, all the models were &gt; 90% accurate; Resnet50V2: 94.77%; Inception V3: 92.84%. In conclusion, the use of artificial neural networks to classify left atrial enlargement in radiographs of dogs is a viable approach that can help veterinary radiologists screen patients for left atrial enlargement.

Clinical characteristics and prognostic impact of atrial fibrillation among older patients with heart failure with preserved ejection fraction hospitalized for acute heart failure.

Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are often coexisting conditions, but their interrelationship has not yet been clarified. This study investigated the clinical characteristics and prognostic impact of AF among older patients with HFpEF hospitalized for acute HF (AHF). The study included patients 65years of age and older who were admitted to the Emergency Department due to AHF from 1 January 2016 to 31 December 2019. Patients were divided into two groups according to the presence of AF. The primary endpoint was all-cause, in-hospital mortality. Overall, 770 patients with HFpEF were included, mean age 82years, 53% were females. Nearly, a third (30%) of these patients had a concomitant AF and they were significantly older and had higher N-Terminal pro-B-type natriuretic peptide (NT-proBNP) values. Overall, the in-hospital mortality rate was much higher among HFpEF patients with AF compared to those without AF (11.4% vs 6.9%, respectively; p = 0.037). At multivariate analysis, AF emerged as an independent risk factor for death (OR 1.73 [1.03-2.92]; p = 0.038). Among older patients with HFpEF admitted for AHF, the coexistence of AF was associated with a nearly twofold increased risk of all-cause in-hospital mortality. Patients with HFpEF and AF describe a phenotype of older and more symptomatic patients, with higher NT-proBNP, left atrial enlargement, right ventricular dysfunction, and higher CV mortality.

Atrial Adaptations in Athletes Heart.

Intensive training efforts are associated with hemodynamic changes accompanied by increases in cardiac output and stroke volume related to higher peak oxygen consumption and better athletic performance during exercise. These hemodynamic changes induce an enlargement of cardiac chambers, but also of the atria and may result in an athletes' heart (AH). Data from large studies about atrial enlargement in AH are sparse. Competitive athletes aged ≥18years, who presented for pre-participation screening 04/2020-10/2021 were included in this study and stratified for AH (defined as physiologically increased heart volume >13.0 in males and >12.0mL/kg in females). Overall, 646 athletes aged ≥18years (median age 24.0 [20.0/31.0]years; 206 [31.9%] females) were included in our study 04/2020-10/2021; among these, 118 (18.3%) had an AH. The computed absolute heart volume was 969.4 (853.1/1083.0)mL in athletes with AH and 841.3 (707.4/966.3)mL in those without AH (p<0.001). AH was associated with larger left ventricular mass (206.6±39.0vs. 182.7±44.2g, p<0.001). LA area (15.4 [13.7/18.2] vs. 14.3 [12.0/16.3]cm2, p<0.001) and RA area (15.8 [13.8/18.6] vs. 14.5 [12.3/17.0]cm2, p<0.001) were enlarged in AH versus those athletes without AH. The logistic regressions confirmed an independent association of AH on LV mass (OR 1.05 [95% CI 1.04-1.06], p<0.001). LA area (OR 1.29 [95% CI 1.19-1.39], p<0.001) as well as RA area (OR 1.28 [95% CI 1.19-1.38], p<0.001) were afflicted by AH. An AH is accompanied by significant enlargement of the atria as well as increased cardiac muscle mass.

Atrial functional mitral regurgitation in cardiology and cardiac surgery.

Functional or secondary mitral regurgitation (MR) is a clear and present danger to cardiovascular health, with heightened morbidity and mortality rates. Secondary MR is caused by an imbalance between two sets of forces. There are two forces at play here. One keeps the mitral leaflets tethered, while the other closes them. The evidence clearly shows inadequate coaptation. Functional MR (FMR) is the typical form of MR. It is almost always caused by dysfunction and alterations of the left ventricle (LV) geometry. It occurs in both ischemic and non-ischemic disease states. Atrial FMR (AFMR) is a disease that has only recently come to be acknowledged. This phenomenon arises when mitral annular enlargement is caused by left atrial enlargement. This preserves the geometry and function of the LV. AFMR is most frequently encountered in individuals with chronic atrial fibrillation or heart failure, in whom a normal ejection fraction is present. Published studies and ongoing research vary in their definition of AFMR, but there is no doubt that AFMR exists. This review definitively explains the pathophysiology of AFMR and demonstrates the necessity of a common working standard for the definition of AFMR. This is essential to warrant cohesiveness in the data reported and to drive forward the much-needed research into the outcomes and treatment strategies in this critical field. A number of high-quality studies have demonstrated that restrictive mitral annuloplasty and transcatheter procedure based on edge-to-edge repair are effective in reducing MR and alleviating symptoms. The pathophysiology, echocardiographic diagnosis, and treatment of AFMR are thoroughly reviewed in this comprehensive review.

Prevalence and associated factors of atrial fibrillation among patients with rheumatic heart disease attending public referral hospitals in Bahir Dar city, Northwest Ethiopia, 2023

BackgroundAtrial fibrillation (AF) is a supraventricular arrhythmia associated with uncoordinated atrial activation. Atrial fibrillation is complication of rheumatic heart disease and is associated with substantial morbidity and mortality. It is a growing public health problem and economic and social burden. Studies investigating the prevalence and factors associated with atrial fibrillation among chronic rheumatic heart disease patients in Ethiopia are scarce. Therefore, this study aimed to determine the prevalence and factors associated with atrial fibrillation in patients with chronic rheumatic heart disease.Methods and materialsA hospital-based cross-sectional study was conducted. A total of 410 patients were selected using a systematic random sampling method. The data were entered into Epi-Data version 4.6 and subsequently exported to SPSS version 26 software for analysis. A binary logistic regression model was applied to identify significant variables related to AF.ResultsIn this study, 410 patient charts were reviewed. The prevalence of atrial fibrillation was 43% (95% CI of 38% up to 48%). Male (AOR = 3.81, 95% CI 2.00-7.26), age greater than 30 years (AOR = 7.26, 95% CI 3.93–13.41), heart failure (AOR = 4.65, 95% CI 2.39–9.04), mitral valve stenosis (AOR = 6.36, 95% CI 2.92–13.87), and left atrial diameter enlargement (AOR = 3.41, 95% CI 1.64–7.09) were associated with atrial fibrillation.Conclusions and recommendationsAtrial fibrillation leads patients to frequent hospital admission and increases hospital mortality. As a result, health care professionals need to pay more attention to and apply more clinical treatment for older patients, those with heart failure, those with mitral valve stenosis, and those with left atrial diameter enlargement-associated causes of atrial fibrillation.

Presentation of mitral valve cleft with concurrent atrial septal defect and ventricular septal defect detected by three-dimensional transesophageal echocardiography: a case report

BackgroundCleft in the mitral valve leaflet is a primary cause of congenital mitral regurgitation, stemming from developmental anomalies in the mitral valve and frequently associated with other congenital heart defects. Concurrent presence of cleft in mitral valve leaflet with atrial septal defect and ventricular septal defect is relatively rare. Echocardiography, especially transesophageal echocardiography, is essential in diagnosing cleft mitral valve leaflet and related congenital heart defects, providing critical, detailed imagery for accurate assessment. This study presents a young female patient whose anterior mitral cleft, along with atrial septal defect and ventricular septal defect, was revealed through three-dimensional transesophageal echocardiography.Case presentationA 25-year-old Iranian female, experiencing progressive dyspnea and diminished physical capacity over 3 months, was referred to our hospital. Initial examination and transthoracic echocardiography indicated severe mitral regurgitation. Further evaluation with transesophageal echocardiography corroborated these findings and identified a cleft in the anterior mitral valve leaflet, coupled with mild left ventricular enlargement and significant left atrial enlargement. The complexity of the patient’s condition was heightened by the diagnosis of cleft mitral valve leaflet in conjunction with atrial septal defect and ventricular septal defect, showing the complex nature of congenital defects.ConclusionThis case emphasizes the critical role of transthoracic echocardiography in diagnosing cleft of mitral valve leaflet and associated cardiac anomalies, showcasing its superiority over transthoracic echocardiography for detailed visualization of cardiac structures. The identification of multiple congenital defects highlights the necessity for a comprehensive diagnostic approach to manage and treat patients with complex congenital heart diseases effectively. Future research should aim to refine diagnostic methodologies to enhance patient outcomes for cleft of mitral valve leaflets and related congenital conditions.

NR4A3 prevents diabetes induced atrial cardiomyopathy by maintaining mitochondrial energy metabolism and reducing oxidative stress

Atrial cardiomyopathy (ACM) is responsible for atrial fibrillation (AF) and thromboembolic events. Diabetes mellitus (DM) is an important risk factor for ACM. However, the potential mechanism between ACM and DM remains elusive. Atrial tissue samples were obtained from patients diagnosed with AF or sinus rhythm (SR) to assess alterations in NR4A3 expression, and then two distinct animal models were generated by subjecting Nr4a3-/- mice and WT mice to a high-fat diet (HFD) and Streptozotocin (STZ), while db/db mice were administered AAV9-Nr4a3 or AAV9-ctrl. Subsequently, invivo and invitro experiments were conducted to assess the impact of NR4A3 on diabetes-induced atrial remodeling through electrophysiological, biological, and histological analyses. RNA sequencing (RNA-seq) and metabolomics analysis were employed to unravel the downstream mechanisms. The expression of NR4A3 was significantly decreased in atrial tissues of both AF patients and diabetic mice compared to their respective control groups. NR4A3 deficiency exacerbated atrial hypertrophy and atrial fibrosis, and increased susceptibility to pacing-induced AF. Conversely, overexpression of NR4A3 alleviated atrial structural remodeling and reduced AF induction rate. Mechanistically, we confirmed that NR4A3 improves mitochondrial energy metabolism and reduces oxidative stress injury by preserving the transcriptional expression of Sdha, thereby exerting a protective influence on atrial remodeling induced by diabetes. Our data confirm that NR4A3 plays a protective role in atrial remodeling caused by diabetes, so it may be a new target for treating ACM. This study was supported by the major research program of National Natural Science Foundation of China (NSFC) No: 82370316 (to Q-S. W.), No. 81974041 (to Y-P. W.), and No. 82270447 (to Y-P. W.) and Fundation of Shanghai Hospital Development Center (No. SHDC2022CRD044 to Q-S. W.).

Abstract Or107: MyBP-HL nonsense mutations fail in sarcomere incorporation leads to modifications in myocyte contraction trough calcium modifications.

Introduction: Heart function depends on the cardiomyocyte contractile apparatus and proper sarcomere protein expression. Mutations in sarcomere genes cause inherited forms of cardiomyopathy and arrhythmias, including atrial fibrillation. AF is the most common cardiac arrhythmia and is associated with ischemic stroke, heart failure, and substantial morbidity and mortality. Recently, our group described a novel sarcomere component, myosin binding protein-H like (MyBP-HL), that is mainly expressed in the cardiac atria. MyBP-HL is composed of two immunoglobulin domains and one fibronectin domain, with homology to last three C-terminal domains of cardiac myosin binding protein-C (cMyBP-C). cMyBP-C nonsense mutations prevent his incorporation into the sarcomere. C-MyBP-C truncated peptides are identified by cells as poisoning peptides, and they are rapidly degraded. cMyBP-C nonsense mutations are causative of hypertrophic cardiomyopathy (HCM). The MyBP-HL Arg255stop variant has been described in humans and has been linked to ventricular conduction system abnormalities, atrial enlargement, dilated cardiomyopathy, and atrial and ventricular arrhythmias. The gnomAD database reports 9 nonsense mutations for MYBPHL in humans (Gln29, Trp54, Arg113, Tyr123, Trp158, Trp192, Lys250, Arg255, and Tyr307). Hypothesis: MYBPHL nonsense mutations fail to incorporate into the sarcomere will lead to contractile disfunction. Results: We demonstrated that MyBP-HL overexpression showed to be able to incorporate in a similar pattern to cMyBP-C C-zone doublets. Nevertheless, nonsense mutations disrupt normal sarcomere localization. MyBP-HL nonsense mutations promote an increase in contraction amplitude and slower relaxation kinetics. Also, we observed an increase in sarcomere length. Similarly, MyBP-HL nonsense mutations lead to increase in amplitude peak of calcium transients, and reduction in velocity to maximal calcium peak. In accordance with calcium modifications, we observed through mass spectrometry an increase in calpain 6 abundance promoted by MyBP-HL nonsense mutations. Conclusion: Based on these data, we demonstrated that MYBPHL nonsense mutations prevent MyBP-HL incorporation into the thick filament. The failure of MyBP-HL truncating peptides to incorporate into the sarcomere leads to a deficiencies in myocytes contraction patterns, changes in calcium patterns and increase in degradation proteins abundance, which are related to AF prevalence.

Abstract Or105: Constitutive Deletion of the Obscurin Ig58/59 Domains Induces Structural and Electrophysiological Remodeling in Atria

Introduction: Obscurin is a giant cytoskeletal protein that supports muscle development, tethers intracellular compartments and regulates contraction. In the ObscnΔIg58/59 mouse model, expressing obscurin lacking Immunoglobulin (Ig) domains 58 and 59, aging males exhibit irregular heart rhythm with prominent atrial fibrillation, atrial enlargement, and progressive remodeling of the ventricles. A mechanistic basis for the emergence of arrhythmia early on could not be identified in ObscnΔIg58/59 ventricles, suggesting that the atria are preferentially impacted by deletion of the obscurin Ig58/59 module prior to the ventricles. Hypothesis: We hypothesize that Ig58/59 deletion elicits unique structural, electrical, and functional consequences in the atria preceding ventricular maladaptation. Aims: I. Examine the structural organization of ObscnΔIg58/59 atria II. Assess Ca 2+ handling in isolated atrial cardiomyocytes and determine molecular alterations. Methods: Electron microscopy and super resolution microscopy were utilized to visualize sarcomeric ultrastructure and the transverse-axial tubule (TAT) network, respectively. Ca 2+ handling activity and synchrony were also resolved, while Phos-Tag gels were used to quantify T-cap phospho-species. Results: ObscnΔIg58/59 atria exhibited misalignment of Z-disks. Spontaneous and stimulated Ca 2+ cycling behavior were [AB1] differentially disrupted in atrial cardiomyocytes in 6- and 12-month ObscnΔIg58/59 males. Relatedly, atrial cells showed an age-dependent deterioration in TAT architecture. Finally, as a function of aging, ObscnΔIg58/59 atria displayed alterations in the expression and phosphorylation of T-cap, a Z-disk protein implicated in the integration of t-tubules with the sarcomeric cytoskeleton. Conclusions: The structural and electrical alterations that arise in ObscnΔIg58/59 atria precede ventricular dysfunction and coincide with the emergence of atrial fibrillation. Collectively, our work indicates that the atria are principally affected by Ig58/59 elimination, instigating arrhythmias and morphological alterations with age. The ObscnΔIg58/59 mouse model has thus emerged as a proxy for atrial cardiomyopathy.

Abstract Tu107: Decreased Mitochondrial Protein Expression Accompanies Atrial Hypertrophy but Precedes Atrial Fibrillation Onset in a Mouse Model of Spontaneous Atrial Fibrillation

Introduction: Atrial fibrillation (AF), characterized by episodes of rapid and irregular heart rate, increases left atrial (LA) demand for ATP. While the heart is metabolically flexible, able to use fatty acids, lactate, glucose, ketones, and amino acids to generate ATP, fatty acids are the primary fuel source. AF is associated with altered mitochondrial structure and function, but the role of energetic pathways in early stages of AF progression is not clear. Hypothesis: Decreased expression of mitochondrial proteins contributes to AF progression. Aim: Evaluate expression of proteins that influence mitochondrial structure and energetic capacity in AF onset and progression. Methods: AF burden was assessed weekly by electrocardiography (ECG) in male wild-type (WT) and cAMP responsive element modulator IbΔC-X heterozygous mice (CREM) (n=3). LA (4 - 9 mg) was obtained at 7 weeks and 16 weeks. Global proteomics was conducted, and 139,316 peptides were identified that mapped to 6000 robustly quantified proteins. Results: LA hypertrophy was evident in 7-week and 16-week CREM mice (Figure 1). We detected 2408 proteins differentially expressed in CREM compared to WT. At 7 weeks, Hallmark pathways adipogenesis, fatty acid metabolism, oxidative phosphorylation, and myogenesis were decreased in CREM (Table 1). These changes persisted at 16 weeks. We identified 740 differentially expressed mitochondrial proteins using MitoCarta 3.0 (552 decreased, 188 increased). Mitochondrial pathways associated with energy production, including branched chain amino acid metabolism, fatty acid transport and oxidation, carbohydrate metabolism, and tricarboxylic acid cycle were decreased (Table 1). Mitochondrial cristae organizing system (MICOS) and mitophagy, pathways that influence mitochondrial structure and content, were decreased. Terminal ECGs confirmed AF in 16-week CREM mice only. The coefficient of variation of RR intervals (CVRR), a measure of heart rate variability, was increased in 16-week CREM (Figure 2). These data suggest that decreased expression of mitochondrial proteins accompanies LA hypertrophy but precedes onset of AF. Conclusions: Decreased expression of proteins that regulate mitochondrial structure and energy production prior to AF onset suggests that these proteins play an important role in early LA changes that promote AF onset and progression. Future studies will examine how these changes in protein expression relate to alterations in atrial energy homeostasis.

Results of radiographic assessment of cardiac size in dogs with progressing myxomatous mitral valve disease

Chest radiography for mitral valve endocardiosis (MMVD) is both an independent and an additional method of investigation compared to echocardiography. It allows assessment of lung tissue condition, central airways, degree of vascularization, and changes in the mediastinum and pleural cavities. This study aimed to perform a radiographic examination of dogs with mitral valve endocardiosis at different stages under previously established and new indices and to determine their informativeness. The study was conducted in the private veterinary hospital “Eurovet” and at the Department of Internal Diseases of Animals and Clinical Diagnostics clinic of the Stepan Gzhytskyi National University of Veterinary Medicine and Biotechnologies of Lviv. The subjects were 25 dogs with mitral valve endocardiosis. The diagnosis was established based on the American College of Veterinary Medicine criteria. During the study, three experimental groups of animals were formed according to their clinical-functional status and the characteristics of each stage of MMVD development: groups B1, B2, and C. In group B1, 57.1 % of the animals had a slight increase in the RLAD index. With the progression of the disease, we observed a further increase in RLAD (in 80 %), a significant increase in VLAS (P &lt; 0.01) for the first time in 40 %, as well as a decrease in RLAD-spine (P &lt; 0.05) in 40 % and Bronchus-spine (P &lt; 0.01) in 60 % of dogs, which generally indicates both local enlargement of the left atrium and cardiomegaly. The informativeness of the VHS index was noted at stage C (group C), as in 66.7 % of the experimental animals, its value exceeded (P &lt; 0.001) the reference values of the norm. At the same time, we observed an increase (P &lt; 0.05) in the mean value of RLAD by 1.3 times compared to group B1 and VLAS (P &lt; 0.001) by 1.6 times. Between the radiographic indicators, we confirmed the presence of a strong correlation. Thus, in group B2, it was positive (r = +0.779) for VHS and RLAD and negative (r = -0.831) for VHS and RLAD-spine. In group C, a further increase in the correlation (r = +0.885) was found only between VHS and RLAD. Based on the analysis of chest radiography data, it is advisable to use radiographic indices in cases of cardiomegaly, particularly with left atrial enlargement. However, this requires their group determination and mandatory comparison with echocardiographic examination results. In veterinary practice, this has diagnostic significance for establishing the stage of the disease, as well as in the selection or correction of the therapeutic support scheme for the patient.

Efficacy and Outcomes of Para-Annular Plication in Mitral Valve Repair via Right Mini-Thoracotomy.

We aim to assess the efficacy and safety of left atrial plication (LAP), particularly para-annular plication, using a right mini-thoracotomy approach. Among 90 mitral valve repair (MVr) procedures performed at our institution between 2016 and 2023, 16 left atrial plication cases for left atrial enlargement (diameter: >50 mm) were assessed; nine cases underwent median sternotomy (conventional) (Group C), and seven cases underwent minimally invasive cardiac surgery (MICS) (Group M). The surgical protocol involved mitral valve repair via a right-sided left atrial approach, incorporating para-annular plication to suture the posterior wall. The mean follow-up duration was 3.3±2.4 years. Mortality within 30 days of surgery or during hospitalization did not occur. Postoperative complications included one case in each group that required reoperation for hemorrhage originating extraneously in the left atrium. Postoperative echocardiographic assessments revealed a comparable reduction in left atrial diameter (C/M: 80.3±7.0/80.7±14.6%; p=0.94), left atrial volume index (55.6±19.3/68.3±34.1%; p=0.36), and aorto-mitral angle (AMA) enlargement (113.8±7.3/107.5±12.2%; p=0.22). The three-year survival rate (88.9%/75.0%; p=0.33) was comparable between groups. The synergistic utilization of left atrial plication with para-annular plication via right mini-thoracotomy can enhance the postoperative outcomes of mitral valve repair.