PITX2 deficiency leads to atrial mitochondrial dysfunction.

AIM: Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation. PITX2 is restricted to left atrial cardiomyocytes in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy and atrial fibrillation are not fully understood. METHODS AND RESULTS: To identify mechanisms linking PITX2 deficiency to atrial fibrillation, we generated and characterized PITX2-deficient human atrial cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) and their controls. PITX2-deficient hiPSC-derived atrial cardiomyocytes showed shorter and disorganised sarcomeres and increased mononucleation. Electron microscopy found an increased number of smaller mitochondria compared to the control. Mitochondrial protein expression was altered in PITX2-deficient hiPSC-derived atrial cardiomyocytes. Single-nuclear RNA-sequencing found differences in cellular respiration pathways and differentially expressed mitochondrial and ion channel genes in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2 repression in hiPSC-derived atrial cardiomyocytes replicated dysregulation of cellular respiration. Mitochondrial respiration was shifted to increased glycolysis in PITX2-deficient hiPSC-derived atrial cardiomyocytes. PITX2-deficient human hiPSC-derived atrial cardiomyocytes showed higher spontaneous beating rates. Action potential duration was more variable with an overall prolongation of early repolarization, consistent with metabolic defects. Gene expression analyses confirmed changes in mitochondrial genes in left atria from 42 patients with atrial fibrillation compared to 43 patients in sinus rhythm. Dysregulation of left atrial mitochondrial (COX7C) and metabolic (FOXO1) genes was associated with PITX2 expression in human left atria. CONCLUSIONS: In summary, PITX2 deficiency causes mitochondrial dysfunction and a metabolic shift to glycolysis in human atrial cardiomyocytes. PITX2-dependent metabolic changes can contribute to the structural and functional defects found in PITX2-deficient atria.

Atrial Cardiomyopathy Revisited - Evolution of a Concept. A Clinical Consensus Statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asian Pacific Heart Rhythm Association (APHRS), and the Latin American Heart Rhythm Society (LAHRS).

Developed in partnership with the European Heart Rhythm Association (EHRA), (a registered branch of the European Society of Cardiology (ESC)) the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin America Heart Rhythm Society (LAHRS).

Practical approach for atrial cardiomyopathy characterization in patients with atrial fibrillation.

Atrial fibrillation (AF) causes progressive structural and electrical changes in the atria that can be summarized within the general concept of atrial remodeling. In parallel, other clinical characteristics and comorbidities may also affect atrial tissue properties and make the atria susceptible to AF initiation and its long-term persistence. Overall, pathological atrial changes lead to atrial cardiomyopathy with important implications for rhythm control. Although there is general agreement on the role of the atrial substrate for successful rhythm control in AF, the current classification oversimplifies clinical management. The classification uses temporal criteria and does not establish a well-defined strategy to characterize the individual-specific degree of atrial cardiomyopathy. Better characterization of atrial cardiomyopathy may improve the decision-making process on the most appropriate therapeutic option. We review current scientific evidence and propose a practical characterization of the atrial substrate based on 3 evaluation steps starting with a clinical evaluation (step 1), then assess outpatient complementary data (step 2), and finally include information from advanced diagnostic tools (step 3). The information from each of the steps or a combination thereof can be used to classify AF patients in 4 stages of atrial cardiomyopathy, which we also use to estimate the success on effective rhythm control.

Left atrial strain: A memory of the severity of atrial myocardial stress in atrial fibrillation.

BACKGROUND: Left atrial (LA) strain is a simple marker of LA function. The aim of the study was to evaluate the determinants of atrial cardiomyopathy in AF. METHODS: In this pilot study, we prospectively evaluated clinical, biological, metabolomic and echocardiographic parameters for 85 consecutive patients hospitalized for atrial fibrillation (AF) with restoration of sinus rhythm at 6 months. Eighty-one patients with an analysable LA strain at 6 months were divided into groups according to median reservoir strain:<23.3% (n=40) versus≥23.3% (n=41). RESULTS: Compared to patients with the highest LA strain, patients with lowest LA strain had multiple differences at admission: clinical (older age; more frequent history of AF; more patterns of persistent AF); biological (higher fasting blood glucose levels, glycated haemoglobin, high-sensitivity C-reactive protein, and urea; lower glomerular filtration rate); metabolomic (higher levels of kynurenine, kynurenine/tryptophan, and urea/creatinine; lower levels of arginine and methionine/methionine sulfoxide); and echocardiographic (higher two-dimensional end-systolic LA volume [LAV] indexes; higher three-dimensional end-systolic and end-diastolic LAV and right atrial volume indexes; lower LA and right atrial emptying fractions and three-dimensional right ventricular ejection fraction) (all P<0.05). Area under the receiver operating characteristic curve to predict LA strain alteration at 6 months was highest for a combined score including clinical, biological, metabolomic and echocardiographic variables at admission (area under the receiver operating characteristic curve 0.871; P<0.0001). CONCLUSIONS: LA reservoir strain could be a memory of initial atrial myocardial stress in AF. It can be predicted using a combination of clinical, biological, metabolomic and echocardiographic admission variables.