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Brain, heart, and sudden death.

ABSTRACT: During the past 30 years, rate of coronary artery disease (CAD), as the main cause of sudden death (SD), has decreased more than rate of SD. Likewise, cause of SD remains elusive in not a trivial portion of its victims. One possible reason is attention to only one organ, the heart, as the cause of SD. In fact, SD literature focuses more on the heart, less on the brain, and seldom on both. A change is required. In this paper, we first review the pathological findings seen in heart autopsies of SD victims after psychological stressors such as physical assault victims without internal injuries. Then, we summarize new studies investigating brain areas, like the insula, whose malfunctions and injuries are related to SD. Next, we review prototypes of neurological diseases and psychological stressors associated with SD and look at heart failure (HF)-related SD providing evidence for the brain-heart connection. Finally, we propose a new look at SD risk factors considering both brain and heart in their association with SD, and review strategies for prevention of SD from this perspective.

SUBMITTER: Oveisgharan S

PROVIDER: S-EPMC9527862 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Brain, heart, and sudden death.

Oveisgharan Shahram S Ghaffarpasand Fariborz F Sörös Peter P Toma Mustafa M Sarrafzadegan Nizal N Hachinski Vladimir V

Current journal of neurology 20220101 1

During the past 30 years, rate of coronary artery disease (CAD), as the main cause of sudden death (SD), has decreased more than rate of SD. Likewise, cause of SD remains elusive in not a trivial portion of its victims. One possible reason is attention to only one organ, the heart, as the cause of SD. In fact, SD literature focuses more on the heart, less on the brain, and seldom on both. A change is required. In this paper, we first review the pathological findings seen in heart autopsies of SD ...[more]

PMID: 38011455

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Project description:BackgroundHeart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension, and diabetes. O-GlcNAcylation (the attachment of O-linked β-N-acetylglucosamine [O-GlcNAc] moieties to cytoplasmic, nuclear, and mitochondrial proteins) is a posttranslational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. Total levels of O-GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of 2 enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Failing myocardium is marked by increased O-GlcNAcylation, but whether excessive O-GlcNAcylation contributes to cardiomyopathy and heart failure is unknown.MethodsWe developed 2 new transgenic mouse models with myocardial overexpression of OGT and OGA to control O-GlcNAcylation independent of pathologic stress.ResultsWe found that OGT transgenic hearts showed increased O-GlcNAcylation and developed severe dilated cardiomyopathy, ventricular arrhythmias, and premature death. In contrast, OGA transgenic hearts had lower O-GlcNAcylation but identical cardiac function to wild-type littermate controls. OGA transgenic hearts were resistant to pathologic stress induced by pressure overload with attenuated myocardial O-GlcNAcylation levels after stress and decreased pathologic hypertrophy compared with wild-type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O-GlcNAc-mediated cardiac pathology.ConclusionsOur data provide evidence that excessive O-GlcNAcylation causes cardiomyopathy, at least in part, attributable to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O-GlcNAcylation is beneficial against pressure overload-induced pathologic remodeling and heart failure. These findings suggest that attenuation of excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.

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Brain, heart, and sudden death.

Publications

Brain, heart, and sudden death.

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