Abstract Body: Localized rupture of the nuclear envelope has been observed in myocardial infarction, neurodegenerative disorders, cancer, and senescence, as well as familial cardiomyopathy caused by Lamin A/C mutations, a critical nuclear envelope structural protein. However, its pathogenic significance remains unclear. We recently reported that cardiomyocyte-specific Lamin A/C knockout mice (Lmna^CKO) – a model for Lamin A/C-associated cardiomyopathy – develop pervasive nuclear envelope rupture in cardiomyocytes. Here, we show that global transcriptional arrest is a direct consequence of nuclear envelope rupture in Lmna^CKO mice. Ruptured nuclei in Lmna^CKO cardiomyocytes lost RNA Polymerase II (Pol II), accompanied by a reduction of Ser5-phosphorylated, transcriptionally initiating Pol II. This resulted in global transcriptional arrest with downregulation of sarcomeric and metabolic genes. Surprisingly, 40% of ruptured nuclei eventually restored nuclear compartmentalization, suggesting an endogenous repair mechanism. Indeed, the ESCRT-III membrane remodeling machinery, which mediates mitotic nuclear membrane sealing, accumulated at rupture sites in Lmna^CKO cardiomyocytes. Repaired nuclei regained Pol II and resumed transcription, indicating that transcriptional arrest resulted from rupture, not Lamin A/C deficiency itself. Inhibiting ESCRT-III accelerated cardiomyopathy in Lmna^CKO mice, suggesting that endogenous rupture repair counteracts disease progression. This study implicates rupture-associated transcriptional arrest in the pathogenesis of Lamin A/C-associated cardiomyopathy and suggests enhancing rupture repair as a potential therapeutic strategy.