Portal de Periódicos da CAPES

NAD Repletion Therapy: A Silver Bullet for HFpEF?

2021; Lippincott Williams & Wilkins; Volume: 128; Issue: 11 Linguagem: Inglês

10.1161/circresaha.121.319308

1524-4571

Fadi G. Akar, Lawrence H. Young,

Silicon Carbide Semiconductor Technologies

HomeCirculation ResearchVol. 128, No. 11NAD Repletion Therapy: A Silver Bullet for HFpEF? Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessResearch ArticlePDF/EPUBNAD Repletion Therapy: A Silver Bullet for HFpEF? Fadi G. Akar, Lawrence H. Young Fadi G. AkarFadi G. Akar https://orcid.org/0000-0001-9146-8407 Internal Medicine (Cardiovascular) (F.G.A., L.H.Y.), Yale School of Medicine, New Haven, CT. Department of Biomedical Engineering (F.G.A.), Yale School of Medicine, New Haven, CT. , Lawrence H. YoungLawrence H. Young Correspondence to: Lawrence H. Young, MD, Section of Cardiovascular Medicine, Yale University School of Medicine, Medicine and Physiology, 323 FMP, 333 Cedar St, New Haven, CT 06520-8017. Email E-mail Address: [email protected] https://orcid.org/0000-0003-0295-7298 Internal Medicine (Cardiovascular) (F.G.A., L.H.Y.), Yale School of Medicine, New Haven, CT. Cellular & Molecular Physiology (LH.Y.), Yale School of Medicine, New Haven, CT. Originally published27 May 2021https://doi.org/10.1161/CIRCRESAHA.121.319308Circulation Research. 2021;128:1642–1645is related toNAD+ Repletion Reverses Heart Failure With Preserved Ejection FractionArticle, see p 1629Patients with heart failure (HF) are classified as having HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF). These subtypes, although not entirely distinct, reflect different underlying pathogenic mechanisms and treatments that are effective in HFrEF often fail to impart similar benefits in HFpEF. Because HFrEF is easier to recognize clinically and model experimentally, it has received the lion's share of attention, culminating in many effective approaches for its treatment. In contrast, there remains no evidence-based therapy that prolongs survival in patients with HFpEF, at a time when its incidence is outpacing that of HFrEF.Ongoing clinical research is defining distinct phenotypic clusters (so-called phenomes) of HFpEF that include hypertension, aging, diabetes, obesity, renal dysfunction, hypertrophy, and diastolic dysfunction. Hampering the development of mechanism-based therapies has been the lack of animal models that faithfully recapitulate the multifactorial causes and phenotypic heterogeneity of clinical HFpEF. In this context, the Hill laboratory has addressed this challenge by developing a reproducible experimental model that mimics key features of HFpEF.1 Specifically, they produced a murine model that incorporates metabolic and mechanical stressors, by combining high-fat diet with pharmacological inhibition of nitric oxide synthase using N[w]-nitro-l-arginine methyl ester. This two-hit model recapitulates many features of human HFpEF, including left ventricular hypertrophy, diastolic dysfunction, oxidative stress, and fibrosis. Importantly, this model also manifests extra-cardiac pathogenic alterations that are common in clinical HFpEF, including vascular dysfunction (hypertension) and impaired metabolism (obesity and glucose intolerance).1 As such, it provides a platform for discovering disease mechanisms and testing next-generation therapeutic approaches in proof-of-concept studies.NAD and the Quest for a Silver BulletIn this issue of Circulation Research,2 the authors identify NAD depletion as a central feature of HFpEF while also providing evidence of the therapeutic efficacy of NAD repletion. NAD is a critical cofactor that is synthesized de novo or via a salvage pathway from its nicotinamide-derived precursors. Oxidized (NAD+) and reduced (NADH) forms of NAD control cellular redox status, bioenergetics, substrate metabolism, mitochondrial biogenesis, and dynamics. Because NAD content and the ratio of its oxidized-to-reduced forms regulate metabolic flux, ensuring homeostasis within a physiological range is critical in diverse cardiac, metabolic, and neurological disease models.3The extent of NAD depletion, the efficacy of NAD repletion, and whether this approach reverses diastolic dysfunction in advanced HFpEF, have remained largely unknown. Tong et al2 report that NAD content was reduced in HFpEF and repleted with oral nicotinamide riboside (NR) therapy. Despite ongoing stress (high-fat diet+N[w]-nitro-l-arginine methyl ester), they also showed that NR improved diastolic function, left ventricular hypertrophy, exercise capacity, and pulmonary congestion after 8-weeks of treatment. Their findings coincide with another recent study, which documented the efficacy of a second NAD precursor (nicotinamide), in ameliorating impaired myocyte relaxation and diastolic dysfunction in rodent models, including aging (2-year-old C57BL/6J mice), hypertension (Dahl salt–sensitive rats), and cardiometabolic syndrome (Zucker Diabetic Fatty [ZDF] rats).4 Together, these studies provide support for the strategy of reversing HFpEF-related cardiac dysfunction with NAD repletion therapy.Sirtuin-Dependent and Independent Effects of NAD RepletionMechanisms underlying the therapeutic effects of NAD repletion are complex. Tong et al2 highlight the potential importance of NAD+-mediated Sirt3 (sirtuin 3)-dependent deacetylation of mitochondrial proteins. Sirt3 is localized in the mitochondria, and they found decreased Sirt3 content and increased mitochondrial protein acetylation in HFpEF, including those involved in fatty acid oxidation, such as VLCAD (very long-chain acyl-coenzyme A dehydrogenase). In mitochondria, Sirt3-dependent lysine deacetylation of target proteins regulates fundamental bioenergetic processes, substrate metabolism, mitochondrial dynamics, and the unfolded protein response. Sirt3 dysregulation has been implicated in cardiac hypertrophy, fibrosis, and oxidative stress, all hallmark features of HFpEF. Interestingly, Tong et al2 found that NR-mediated NAD repletion successfully improved myocardial function in HFpEF and reversed VLCAD hyperacetylation without correcting overall bulk mitochondrial protein acetylation. It is worth noting that the premise of protein hyperacetylation as a causal event in the pathogenesis of HF has been questioned recently by findings in a mouse model, which develops extreme hyperacetylation of its mitochondrial proteome without exhibiting altered myocardial bioenergetics or a predisposition to HF.5 In addition, the stoichiometry of protein acetylation warrants consideration. Although a relatively minor increase in the percent of residues with activating modifications can significantly augment enzymatic activity, the result of minor increases in inhibitory modifications is less predictable. Also, the impact of acetylation depends on its interaction with other post-translational protein modifications. Thus, additional investigation is needed to elucidate the role of acetylation/deacetylation in regulating fatty acid oxidation and other bioenergetic processes in this and other models of HFpEF.Although Tong et al2 focus on Sirt3, and mitochondria contain much of the cardiomyocyte NAD pool, cytosolic sirtuins have also been implicated in HFpEF pathophysiology and may in part mediate the therapeutic efficacy of NAD precursor therapy. Nicotinamide improved cardiomyocyte passive stiffness and calcium-dependent relaxation through deacetylation of Titin and SERCA2a (sarco[endo]plasmic reticulum Ca2+ ATPase2a), likely via a Sirt1-dependent mechanism.4 A clinical correlate of Sirt1-related benefits was reported in patients with HFpEF who underwent exercise training for cardiac rehabilitation and demonstrated concomitant increases in NAD+ and Sirt1 coincided with improved metabolic status and decreased oxidized LDL (low-density lipoprotein).6Systemic Effects of NAD Repletion on Cardiac FunctionNAD precursor therapy exerts a multiplicity of systemic actions, which likely play a major role in determining its ultimate efficacy as an HFpEF therapeutic, by impacting blood pressure, obesity, inflammation, and both skeletal muscle and liver metabolism. As the authors note, their two-hit model exhibited whole-body characteristics that are common in patients with HFpEF, including hypertension, obesity, and altered metabolism. They also found that NR treatment improved glucose tolerance despite no apparent change in food intake, obesity, or hypertension. Recognizing the pleiotropic effects of in vivo NR administration, they treated a separate cohort of HFpEF mice with P7C3-A20, an agent that restores NAD+ levels by activating NAMPT (nicotinamide phosphoribosyltransferase), a key enzyme in the salvage pathway. Unlike NR, P73C3-A20 did not impact glucose tolerance but still reversed diastolic dysfunction. Although NAMPT activators no doubt have other systemic actions, the latter results corroborated the NR findings in this model. Nonetheless, further elucidating the systemic in vivo actions of each NAD repletion strategy is critically important, particularly focusing on the concentrations of circulating substrates and hormones, vascular function, inflammation, and metabolism in skeletal muscle and liver, which may also vary between various strategies.Distinguishing Between Causal and Coincidental Metabolic RemodelingTong et al2 demonstrate that HFpEF mice had PDK4 upregulation and impaired mitochondrial pyruvate oxidation capacity, both signatures of high-fat diet and metabolic disease. However, NR treatment did not improve these abnormalities, suggesting that impaired carbohydrate oxidation is not a causal determinant of their HFpEF cardiac phenotype. In contrast, therapy was associated with a reduction in VLCAD hyperacetylation and improvement in palmitoyl-carnitine oxidation capacity in isolated mitochondria from HFpEF mice. These parameters showed a good association with functional recovery, but the extent to which they are causal and whether the mitochondrial abnormalities translate into altered metabolism in the intact heart will require further examination. Rates of metabolism are multi-determined by circulating substrates and hormones, tissue perfusion, and hemodynamic load. In addition, a comprehensive understanding of HFpEF will also require additional investigation into the metabolism of ketones, amino acids, and additional fatty acid species, as well as a systematic analysis of cardiac bioenergetics.NAD depletion appears to be a common finding in experimental and clinical studies of heart failure regardless of cause. For example, Tong et al2 showed a similar reduction in NAMPT transcripts in myocardial samples from patients with HFpEF and HFrEF. A treatment that potentially addresses a common pathogenic mechanism is appealing from a clinical standpoint. However, the parallel reduction in NAD content also indicates that NAD depletion is not a differentiating feature of HFpEF versus HFrEF. Rather, it suggests that other mechanisms underlie these distinct phenotypes. Conceivably, the degree of NAD depletion in specific subcellular microdomains and the localization and function of NAD-dependent proteins might also differentiate these distinct phenotypes. Moreover, mechanisms underlying NAD depletion that focus on upstream pathways will be important to sort out. For one, AMPK (5' adenosine monophosphate-activated protein kinase), which controls substrate and energy metabolism, increases cellular NAD+ levels and enhances Sirt1 activity in skeletal muscle.7 To what extent alterations in a cardiac AMPK-NAD-Sirt1 axis are involved in HFpEF remains to be elucidated. Moreover, mechanisms responsible for NAMPT downregulation including miRNA (microRNA)-regulated transcription warrant examination.ConclusionsAs with any good study, we are left with unanswered questions that need to be addressed as we consider the potential clinical utility of NAD repletion therapy. Will findings in mice translate to large animals and ultimately humans? We are just learning about the clinical pharmacokinetics and diverse physiological effects of NAD replacement treatment. In older men, NR has had limited impact thus far on insulin sensitivity,8 a beneficial effect which was readily observed in rodents. Do the effects of NR treatment depend on HFpEF phenotype? The benefit of NR in these young male mice with HFpEF was striking, but female mice were less susceptible to HFpEF in this model9 and were not included in this treatment study. Whether women and older patients with HFpEF will respond to NAD replacement will need to be addressed, although recent clinical research is encouraging in suggesting improvement in insulin sensitivity in postmenopausal women treated with nicotinamide mononucleotide.10NAD-targeted therapy is gaining momentum with ongoing clinical trials testing NAD precursors in a variety of conditions. This is driven by emerging experimental work as well as the premise that as commercially available nutritional supplements, they will be well-tolerated. Initial short-term studies with NAD precursors are encouraging in this regard, but the adverse experience with the use of vitamin therapy in lung cancer prevention is a reminder that long-term studies will be needed to confirm safety of NAD precursors in HFpEF.While awaiting the results of the ongoing trial of nicotinamide in HFrEF (ClinicalTrials.gov) and the authors' trial of NR in HFpEF, additional investigation is needed to answer mechanistic questions about the systemic nature of this disease and its response to NAD-targeted therapeutics. How do the vascular, inflammatory, and systemic metabolic components interact to promote HFpEF? How do the individual components of this HFpEF model (high-fat diet and N[w]-nitro-l-arginine methyl ester alone) interact, are they simply additive, synergistic, or unique? What are the metabolic, bioenergetic, and molecular alterations in this and other HFpEF models?Clinical HFpEF is a complex systemic disorder rooted in multiple pathogenic mechanisms that converge to produce clinically diverse phenotypes. It remains a very challenging problem, but with a multidisciplinary approach and collaboration between scientists and clinical investigators, initial progress is finally being made in pursuit of effective therapies.Sources of FundingSupported in part by National Institutes of Health R01 HL148008, R01 HL149344, R01 HL137259.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 1644.Correspondence to: Lawrence H. Young, MD, Section of Cardiovascular Medicine, Yale University School of Medicine, Medicine and Physiology, 323 FMP, 333 Cedar St, New Haven, CT 06520-8017. Email lawrence.[email protected]eduReferences1. Schiattarella GG, Altamirano F, Tong D, French KM, Villalobos E, Kim SY, Luo X, Jiang N, May HI, Wang ZV, et al.. Nitrosative stress drives heart failure with preserved ejection fraction.Nature. 2019; 568:351–356. doi: 10.1038/s41586-019-1100-zCrossrefMedlineGoogle Scholar2. Tong D, Schiattarella GG, Jiang N, Altamirano F, Szweda PA, Elnwasany A, Lee DI, Yoo H, Kass DA, Szweda LI, et al.. NAD(+) repletion reverses heart failure with preserved ejection fraction.Circ Res2021; 128:xx–xxx. doi: 10.1161/CIRCRESAHA.120.317046LinkGoogle Scholar3. Lee CF, Chavez JD, Garcia-Menendez L, Choi Y, Roe ND, Chiao YA, Edgar JS, Goo YA, Goodlett DR, Bruce JE, et al.. Normalization of NAD+ redox balance as a therapy for heart failure.Circulation. 2016; 134:883–894. doi: 10.1161/CIRCULATIONAHA.116.022495LinkGoogle Scholar4. Abdellatif M, Trummer-Herbst V, Koser F, Durand S, Adão R, Vasques-Nóvoa F, Freundt JK, Voglhuber J, Pricolo MR, Kasa M, et al.. Nicotinamide for the treatment of heart failure with preserved ejection fraction.Sci Transl Med2021; 13:eabd7064.CrossrefMedlineGoogle Scholar5. Davidson MT, Grimsrud PA, Lai L, Draper JA, Fisher-Wellman KH, Narowski TM, Abraham DM, Koves TR, Kelly DP, Muoio DM. Extreme acetylation of the cardiac mitochondrial proteome does not promote heart failure.Circ Res. 2020; 127:1094–1108. doi: 10.1161/CIRCRESAHA.120.317293LinkGoogle Scholar6. Corbi G, Conti V, Troisi J, Colucci A, Manzo V, Di Pietro P, Calabrese MC, Carrizzo A, Vecchione C, Ferrara N, et al.. Cardiac rehabilitation increases SIRT1 activity and β-hydroxybutyrate levels and decreases oxidative stress in patients with HF with preserved ejection fraction.Oxid Med Cell Longev. 2019; 2019:7049237. doi: 10.1155/2019/7049237CrossrefMedlineGoogle Scholar7. Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity.Nature. 2009; 458:1056–1060. doi: 10.1038/nature07813CrossrefMedlineGoogle Scholar8. Elhassan YS, Kluckova K, Fletcher RS, Schmidt MS, Garten A, Doig CL, Cartwright DM, Oakey L, Burley CV, Jenkinson N, et al.. Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures.Cell Rep. 2019; 28:1717–1728.e6. doi: 10.1016/j.celrep.2019.07.043CrossrefMedlineGoogle Scholar9. Tong D, Schiattarella GG, Jiang N, May HI, Lavandero S, Gillette TG, Hill JA. Female sex is protective in a preclinical model of heart failure with preserved ejection fraction.Circulation. 2019; 140:1769–1771. doi: 10.1161/CIRCULATIONAHA.119.042267LinkGoogle Scholar10. Yoshino M, Yoshino J, Kayser BD, Patti G, Franczyk MP, Mills KF, Sindelar M, Pietka T, Patterson BW, Imai SI, et al.. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women [published online April 22, 2021].Science. doi: 10.1126/science.abe9985Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesNAD+ Repletion Reverses Heart Failure With Preserved Ejection FractionDan Tong, et al. Circulation Research. 2021;128:1629-1641 May 28, 2021Vol 128, Issue 11Article InformationMetrics Download: 295 © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.121.319308PMID: 34043421 Originally publishedMay 27, 2021 KeywordsmetabolismEditorialsmitochondriaheart failureobesityPDF download