Atrial Fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time. AF progression is driven by derailment of protein homeostasis, which ultimately causes electrical conduction changes and contractile dysfunction of the atria. New research published in Nature Communications by the group of Prof. Bianca Brundel (VUmc) in collaboration with the group of Prof. Natasja de Groot (EMC), Dr. Daniel Pijnappels (LUMC), Prof. Robert Henning (UMCG) and Dr. Arie Roon (UMCG), discovered that AF causes DNA damage in atrial tissue of patients.
The DNA damage itself is not responsible for contractile dysfunction, but it results in excessive activation of the DNA repair protein poly (ADP)-ribose polymerase 1 (PARP1). PARP1 activation, in turn, depletes nicotinamide adenine dinucleotide (NAD+) levels, an important component of the energy balance of the cell, thereby inducing further DNA damage and contractile dysfunction in cardiomyocytes.
Accordingly, NAD+ replenishment with nicotinamide or PARP1 inhibition with ABT-888 protects against NAD+ depletion, oxidative stress, DNA damage and contractile dysfunction in atrial cardiomyocytes.
The findings uncover a novel mechanism by which AF impairs cardiomyocyte function and implicates PARP1 inhibitors and nicotinamide as possible therapeutic compounds that may preserve cardiomyocyte function in clinical AF.
Energy loss by DNA damage
By utilizing experimental model systems for AF, the group of Brundel revealed that rapid pacing of cardiomyocytes results in PARP1 activation as reflected by increased levels of PAR synthesis. Since PARP1 gets activated by single and double strand breaks in the DNA, the level of DNA damage was determined.
Rapid pacing increased DNA damage in the experimental model systems for AF. Upon activation, PARP1 consumes NAD+ to synthesize PAR. Therefore, progressive and excessive activation of PARP1 results in reductions in NAD+ levels, which finally results in the energy loss and functional impairment of cardiomyocytes.
Protection by PARP1 inhibition or nicotinamide replenishment
NAD+ depletion can be overcome by inhibiting PARP1 activation or by NAD+ replenishment. Accordingly, both inhibition of PARP1 and replenishment of NAD+ protect against rapid pacing-induced NAD+ depletion, oxidative DNA damage and contractile dysfunction in atrial cardiomyocytes and Drosophila.
Consistent with these findings, PARP1 is also activated in atrial tissue of (longstanding) persistent AF patients, which correlates with the level of DNA damage.
Taken together, the new study findings uncover a dominant role of PARP1 in AF-induced contractile dysfunction and disease progression, thus implicating PARP1-NAD+ as a possible therapeutic target in AF.
Novel therapeutic strategy in AF: prevention of NAD+ depletion
These research findings implicate PARP1 inhibitors as potential therapeutics in AF. Recently developed PARP inhibitors, such as ABT-888 and olaparib, exhibit increased potency and specificity relative to earlier inhibitors, and are currently in phase II and III clinical studies for the treatment of cancers.
Another therapeutic option to protect against AF is to replenish the NAD+ pool by supplementation with NAD+ or its precursors, such as nicotinamide or nicotinamide riboside. Interestingly, nicotinamide is not only a PARP1 inhibitor, but also a NAD+ precursor.
Nicotinamide can be converted into NAD+ via the salvage pathway. In heart failure, nicotinamide displayed a similar protective effect in experimental model systems, demonstrating a clear benefit of normalizing NAD+ levels in failing hearts.
The high translational potential and the applicability in humans recently prompted an open-label pharmacokinetics study with nicotinamide riboside (Niagen®, Chromadex) in healthy volunteers, showing that nicotinamide riboside stably induced circulating NAD+ and was well tolerated (even up to 2x 1000 mg/day). Therefore, nicotinamide riboside represents a potential therapy in heart failure and AF.
Novel clinical study by the AFIP team: treatment of AF with nicotinamide riboside
The AFIP team attracted sponsoring to conduct the first clinical trial with nicotinamide riboside in patients with AF in combination with heart failure. Nicotinamide Riboside (NR) is a registered form of vitamin B3 and a potent inducer of NAD+ levels in humans without causing serious side effects.
Research in mice showed that increased NAD+ levels can revitalize muscles and the heart in older mice and resemble that of much younger animals. Experimental and human studies have shown that supplementation with NR raises NAD+ levels, which may help to ameliorate some age-related conditions and heart failure.
Although we observed that nicotinamide protects against experimental AF progression by conserving the NAD+ levels, it is unknown whether nicotinamide can prevent AF onset and progression in patients with heart failure.
Therefore, in 2019 the AFIP team will conduct a clinical study to examine if NR reduces the AF burden in heart failure patients with ischemic cardiomyopathy. Hereto, patients with AF and heart failure are treated with NR (Niagen®, ChromaDex).
In addition, it is investigated whether biomarker levels of NAD+ in blood correlate with the AF burden. Are you interested in participating in this clinical trial with NR? Please check our website regularly as we will share updates on this trial and opportunities for you to participate.
The research paper on DNA damage in atrial fibrillation will soon be available via open access of Nature Communications. www.naturecommunications.com