DNA Damage, an Innocent Bystander in Atrial Fibrillation and Other Cardiovascular Diseases?

Abstract

Atrial Fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time. AF is difficult to treat and therefore there is a great need to dissect root causes of AF with the ultimate goal to develop mechanism-based (drug) therapies. New findings related to mechanisms driving AF progression indicate a prime role for DNA damage-induced metabolic remodeling. A recent study uncovered that AF results in oxidative DNA damage and consequently excessive poly-ADP-ribose polymerase 1 (PARP1) activation and nicotinamide adenine dinucleotide (NAD +) depletion and finally atrial cardiomyocyte electrical and contractile dysfunction. This newly elucidated role of DNA damage in AF opens opportunities for novel therapeutic strategies. Recently developed PARP inhibitors, such as ABT-888 and olaparib, provide beneficial effects in limiting experimental AF, and are also found to limit atherosclerotic coronary artery disease and heart failure. Another therapeutic option to protect against AF is to replenish the NAD + pool by supplementation with NAD + or its precursors, such as nicotinamide and nicotinamide riboside. In this review, we describe the role of DNA damage-mediated metabolic remodeling in AF and other cardiovascular diseases, discuss novel druggable targets for AF and highlight future directions for clinical trials with drugs directed at PARP1-NAD + pathway with the ultimate aim to preserve quality of life and to attenuate severe complications such as heart failure or stroke in patients with AF.

Blood-based 8-hydroxy-2′-deoxyguanosine level: A potential diagnostic biomarker for atrial fibrillation

“…12 PARP1mediated synthesis of ADP ribose chains, in turn, depletes NAD 1 levels, thereby inducing further oxidative DNA damage and electrical and contractile dysfunction, which drives AF progression. 12,13 Consistent with these findings, cardiomyocytes of patients with persistent AF show significant oxidative DNA damage in atrial tissue, characterized by an elevated level of phosphorylated histone 2A family member X (H2AX), forming g-H2AX, which is an early response to the induction of DNA double-strand breaks. 12,14,15 Based on these findings, we hypothesize that oxidative DNA damage represents a potential biomarker for staging AF and predicting AF recurrence.…”

The Inverse Correlation Between the Duration of Lifetime Occupational Radiation Exposure and the Prevalence of Atrial Arrhythmia

“…A recent mechanism implicated in AA progression, especially in AF, is DNA damage induced metabolic remodeling of cardiac tissue ( 39 ). Considering this finding, the cytogenetic adaptive response can elucidate the benefits of low-dose radiation in protection against DNA damage ( 40 – 43 ).…”

Cytoskeletal Protein Variants Driving Atrial Fibrillation: Potential Mechanisms of Action

“…In DCM, all these effects were ameliorated by supplementation with a precursor of NAD + , nicotinamide [39], or conservation of the cytoskeletal network with geranylgeranylacetone (GGA), a heat shock protein (HSP)inducer [77]. Importantly, the activation of the DNA damage-PARP1-NAD + depetion axis has also been found to drive 'wear and tear' AF [90,91], a potential key pathway in LMNA mutation-induced AF.…”