(ENGELS) Atrial fibrillation causes DNA damage and energy depletion in the heart

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 is available via open access of Nature Communications.

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Comments 2

  1. MICHAEL J.A.McGrath

    I am interested in the clinical trial with Nicotinamide Riboside(NR) to treat atrial fibrillation in patients with heart failure.

    I have the congenital condition of hypogonadotropic hypogonadism (c.HH)

    I am unable to accept testosterone replacement therapy and am currently being treated for AF and systolic heart failure with standard medication: candesartan, bisoprolol, aspirin, and folic acid

    I have been advised by Professor Johan Auwerx, (Lausanne, Switzerland) based on his group’s preclinical findings that NR supplementation may be beneficial for my cHH.

    Although preclinical findings to treat heart failure were positive, the results of clinical trial NCT03423342 see: http://www.clinicaltrials.gov “Treatment of Systolic Heart Failure with NR have not been published.

    I have not been able to find any preclinical studies with NR to treat AF

    NR (“TRU-NIAGEN”) is available to buy as a supplement in NEW ZEALAND.

    However I am not going to initiate NR supplementation to treat my AF and systolic heart failure until I know it will be safe and produce additive benefits to my current medication.

    I would be grateful if you could tell me if interim results of the clinical trial treating patients with AF

    associated with systolic heart failure supervised by Professor Brundel and Professor De Groot , are

    positive?

    Do you think based on the interim results of the above clinical trial to treat AF associated with heart failure

    with NR , it would safe to initiate supplementation of my medication with NR to treat my AF and systolic

    heart failure with monitoring by doctors in Dunedin, NEW ZEALAND?

    I would be grateful if you could forward my email to Professor Brundel and/or Professoe De Groot.

    Thank you, Michael McGrath (Ph.D chemistry, University of Otago, Dunedin, NEW ZEALAND)

    Address: 366P Bay View Road,
    St.Clair,
    Dunedin, 9012,
    NEW ZEALAND

    Telephone: 64-03-455-8290

    My general practitioner is: Dr Alan Walker

    email address: alan.walker@xtra.co.nz

    Address: Pitt Street Medical Centre,
    2 Pitt Street,
    Dunedin. NEW ZEALAND

    Telephone: 64-03-474-0288

  2. Dear Michael McGrath

    We published in Circulation 2014 and Nature communications 2019 research findings indicating that nicotinamide may protect against experimental AF. This compound also may protect against HFpEF. As nicotinamide conserves the mitochondrial function, supplementation with this compound may reveal beneficial effects on heart (HFpEF and AF) function.

    We did not start with a NR clinical trial, so we have no data to share.

    You may start using nicotinamide riboside (1000 mg/day) and you can read more on our research findings via Nature Communications. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428932/

    You can also share your opinion on this topic by leaving a reply on our website.

    Kind regards

    Bianca Brundel

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