Background: Mutations in the Lamin A/C (LMNA) gene are responsible for about 6% of all familial dilated cardiomyopathy (DCM) cases which tend to present at a young age and follow a fulminant course. Methods: We report a 47-year-old DCM patient with severely impaired left ventricular ejection fraction and NYHA functional class IV despite optimal heart failure treatment. Whole-exome sequencing revealed an LMNA E161K missense mutation as the pathogenetic cause for DCM in this patient. We generated a patient-specific LMNA-knock in (LMNA-KI) in vitro model using mES cells. Results: Beta adrenergic stimulation of cardiomyocytes derived from LMNA-KI mES cells resulted in augmented mTOR signaling and increased dysregulation of action potentials, which could be effectively prevented by the mTOR-inhibitor rapamycin. A cardiac biopsy confirmed strong activation of the mTOR-signaling pathway in the patient. An off-label treatment with oral rapamycin was initiated and resulted in an improvement in left ventricular ejection fraction (27.8% to 44.5%), NT-BNP (8120 ng/L to 2210 ng/L) and NYHA functional class. Conclusion: We have successfully generated the first in vitro model to recapitulate a patient-specific LMNA E161K mutation which leads to a severe form of DCM. The model may serve as a template for individualized and specific treatment of heart failure.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia with a massive burden on global health. The prevalence of AF increases dramatically with age and can be up to 18% in patients older than 80 years. Telomeres, which are short, repeated DNA sequences at the end of chromosomes, are known to act as a biological aging marker. In this study, we investigated the relation of telomere shortening and AF in the context of atrial remodeling. Furthermore, we assessed changes in the gene expression profiles of patients with AF according to telomere length (TL) and left atrial fibrosis. Methods: We included 72 patients undergoing catheter ablation for AF. Bipolar voltage maps were obtained to determine left atrial low voltage areas as a surrogate for atrial fibrosis. TL was quantified and correlated to low voltage areas. 3′ mRNA sequencing was performed for gene expression profiling. Clonal hematopoiesis of indeterminate potential was assessed by next generation sequencing. Telomerase reverse transcriptase knockout ( Tert ^−/− ) and telomerase RNA component knockout ( Terc ^−/− ) mice were used to investigate the mechanistic impact of telomere shortening on atrial remodeling. Results: Patients with advanced left atrial fibrosis had shorter telomeres compared with patients with healthy left atria. Furthermore, there was a strong correlation between the extent of left atrial low voltage areas, TL, and outcome after catheter ablation of AF. 24 months after ablation, only 26.5% of patients with advanced fibrosis and short TL were in sinus rhythm compared with 62.5% of patients with no/low fibrosis and long TL. Gene expression profiles and clonal hematopoiesis of indeterminate potential frequency differed in patients with AF with short and long telomeres. Finally, atrial tissue of mouse models with shortened telomeres showed marked left atrial fibrosis and over‐expression of fibrosis‐related genes. Conclusions: Telomere shortening is correlated with left atrial remodeling. Shorter telomeres are associated with a series of molecular events which could eventually lead to cardiac fibrosis and perpetuate AF.

Atrial fibrillation is the most prevalent sustained cardiac arrhythmia, characterized by limited therapeutic options because of incompletely understood mechanisms of its development. The key underlying pathogenetic mechanisms involve atrial myocardial inflammation and fibrosis in response to pressure or volume overload, myocardial infarction, as well as metabolic alterations. Recent studies have highlighted the crucial role of osteopontin in diverse cardiovascular diseases, including atrial fibrillation. Osteopontin is a multifunctional extracellular matrix protein that has recently emerged as a potential mediator of atrial remodeling and arrhythmogenesis. Human studies have revealed that circulating osteopontin levels can serve as a valuable biomarker for atrial fibrillation and its progression. Furthermore, in vitro studies have demonstrated that osteopontin modulates several key cellular processes involved in atrial inflammation and fibrosis, including fibroblast activation, extracellular matrix remodeling, and proinflammatory cytokine production. This review critically examines the available evidence on the role of osteopontin in atrial remodeling and arrhythmia starting from the molecular mechanisms by which osteopontin contributes to structural and electrical remodeling of the atria, to its potential as a biomarker for atrial fibrillation.