Abstract Body: Localized rupture of the nuclear envelope has recently been reported in various pathologies, including myocardial infarction, neurodegenerative disease, cancer, as well as dilated cardiomyopathy caused by Lamin A/C gene mutations (LMNA-DCM). Whether and how nuclear rupture contributes to disease remains unknown. Here, we report that nuclear rupture causes global transcriptional deficiency in a mouse model of LMNA-DCM. We observed that ruptured nuclei lost RNA polymerase II, leading to downregulation of numerous genes essential for cardiomyocyte structure and function. We identified endogenous resealing of nuclear envelopes as a cardioprotective mechanism in LMNA-DCM mouse hearts. Resealing involved the ESCRT-III membrane remodeling complex recruited to nuclear rupture sites. Resealed nuclei restored transcription while inhibiting ESCRT-III activity accelerated cardiomyopathy. However, live imaging showed that resealed nuclei were short-lived. They re-ruptured at a rate twice that of resealing, and this re-rupture rate was tenfold higher than the de novo rupture rate. A kinetic model predicted progressive accumulation of ruptured nuclei despite ongoing resealing. Consistently, a human LMNA-mutant heart contained numerous ruptured nuclei at disease presentation. These findings linked nuclear rupture to organ deterioration through global transcriptional deficiency and suggested rupture resealing as a critical modifier of nuclear rupture-associated conditions.