nach oben

American Journal of Cardiovascular Drugs

20.12.2024 | Review Article

The Role of NAD⁺ Metabolism in Cardiovascular Diseases: Mechanisms and Prospects

verfasst von: Huimin Li, Qingxun Hu, Deqiu Zhu, Dan Wu

Erschienen in: American Journal of Cardiovascular Drugs

Einloggen, um Zugang zu erhalten

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) is a promising anti-aging molecule that plays a role in cellular energy metabolism and maintains redox homeostasis. Additionally, NAD⁺ is involved in regulating deacetylases, DNA repair enzymes, inflammation, and epigenetics, making it indispensable in maintaining the basic functions of cells. Research on NAD⁺ has become a hotspot, particularly regarding its potential in cardiovascular disease (CVD). Many studies have demonstrated that NAD⁺ plays a crucial role in the occurrence and development of CVD. This review summarizes the biosynthesis and consumption of NAD⁺, along with its precursors and their effects on raising NAD⁺ levels. We also discuss new mechanisms of NAD⁺ regulation in cardiovascular risk factors and its effects of NAD⁺ on atherosclerosis, aortic aneurysm, heart failure, hypertension, myocardial ischemia–reperfusion injury, diabetic cardiomyopathy, and dilated cardiomyopathy, elucidating different mechanisms and potential treatments. NAD⁺-centered therapy holds promising advantages and prospects in the field of CVD.

Navas LE, Carnero A. NAD(+) metabolism, stemness, the immune response, and cancer. Signal Transduct Target Ther. 2021;6(1):2. https://doi.org/10.1038/s41392-020-00354-w.CrossRefPubMedPubMedCentral

Lautrup S, Hou Y, Fang EF, et al. Roles of NAD(+) in health and aging. Cold Spring Harb Perspect Med. 2024;14(1): a041193. https://doi.org/10.1101/cshperspect.a041193.CrossRefPubMed

Abdellatif M, Sedej S, Kroemer G. NAD(+) metabolism in cardiac health, aging, and disease. Circulation. 2021;144(22):1795–817. https://doi.org/10.1161/circulationaha.121.056589.CrossRefPubMed

Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 2018;27(3):529–47. https://doi.org/10.1016/j.cmet.2018.02.011.CrossRefPubMedPubMedCentral

Lee CF, Chavez JD, Garcia-Menendez L, et al. Normalization of NAD+ redox balance as a therapy for heart failure. Circulation. 2016;134(12):883–94. https://doi.org/10.1161/CIRCULATIONAHA.116.022495.CrossRefPubMedPubMedCentral

Tong D, Schiattarella GG, Jiang N, et al. Female sex is protective in a preclinical model of heart failure with preserved ejection fraction. Circulation. 2019;140(21):1769–71. https://doi.org/10.1161/circulationaha.119.042267.CrossRefPubMedPubMedCentral

Li X, Yang H, Jin H, et al. The acute effect of different NAD(+) precursors included in the combined metabolic activators. Free Radic Biol Med. 2023;205:77–89. https://doi.org/10.1016/j.freeradbiomed.2023.05.032.CrossRefPubMed

Kremer JI, Gömpel K, Bakuradze T, et al. Urinary excretion of niacin metabolites in humans after coffee consumption. Mol Nutr Food Res. 2018;62(7): e1700735. https://doi.org/10.1002/mnfr.201700735.CrossRefPubMed

Feng D, Xu D, Murakoshi N, et al. Nicotinamide phosphoribosyltransferase (Nampt)/nicotinamide adenine dinucleotide (NAD) axis suppresses atrial fibrillation by modulating the calcium handling pathway. Int J Mol Sci. 2020;21(13):4655. https://doi.org/10.3390/ijms21134655.CrossRefPubMedPubMedCentral

10.

Bermudez B, Dahl TB, Medina I, et al. Leukocyte overexpression of intracellular NAMPT attenuates atherosclerosis by regulating PPARγ-dependent monocyte differentiation and function. Arterioscler Thromb Vasc Biol. 2017;37(6):1157–67. https://doi.org/10.1161/atvbaha.116.308187.CrossRefPubMed

11.

Byun J, Oka S-I, Imai N, et al. Both gain and loss of Nampt function promote pressure overload-induced heart failure. Am J Physiol Heart Circ Physiol. 2019;317(4):H711–25. https://doi.org/10.1152/ajpheart.00222.2019.CrossRefPubMedPubMedCentral

12.

Sun X, Sun BL, Babicheva A, et al. Direct Extracellular NAMPT involvement in pulmonary hypertension and vascular remodelling. Transcriptional regulation by SOX and HIF-2α. Am J Respir Cell Mol Biol. 2020;63(1):92–103. https://doi.org/10.1165/rcmb.2019-0164OC.CrossRefPubMedPubMedCentral

13.

Ratajczak J, Joffraud M, Trammell SA, et al. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun. 2016;7:13103. https://doi.org/10.1038/ncomms13103.CrossRefPubMedPubMedCentral

14.

Ahmad F, Tomar D, Aryal ACS, et al. Nicotinamide riboside kinase-2 alleviates ischemia-induced heart failure through P38 signaling. Biochim Biophys Acta Mol Basis Dis. 2020;1866(3): 165609. https://doi.org/10.1016/j.bbadis.2019.165609.CrossRefPubMed

15.

Marzook H, Gupta A, Tomar D, et al. Nicotinamide riboside kinase-2 regulates metabolic adaptation in the ischemic heart. J Mol Med (Berl). 2023;101(3):311–26. https://doi.org/10.1007/s00109-023-02296-6.CrossRefPubMed

16.

McReynolds MR, Chellappa K, Chiles E, et al. NAD(+) flux is maintained in aged mice despite lower tissue concentrations. Cell Syst. 2021;12(12):1160-1172.e4. https://doi.org/10.1016/j.cels.2021.09.001.CrossRefPubMedPubMedCentral

17.

Wu QJ, Zhang TN, Chen HH, et al. The sirtuin family in health and disease. Signal Transduct Target Ther. 2022;7(1):402. https://doi.org/10.1038/s41392-022-01257-8.CrossRefPubMedPubMedCentral

18.

Wątroba M, Dudek I, Skoda M, et al. Sirtuins, epigenetics and longevity. Ageing Res Rev. 2017;40:11–9. https://doi.org/10.1016/j.arr.2017.08.001.CrossRefPubMed

19.

Covarrubias AJ, Kale A, Perrone R, et al. Senescent cells promote tissue NAD(+) decline during ageing via the activation of CD38(+) macrophages. Nat Metab. 2020;2(11):1265–83. https://doi.org/10.1038/s42255-020-00305-3.CrossRefPubMedPubMedCentral

20.

Chini CCS, Peclat TR, Warner GM, et al. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD(+) and NMN levels. Nat Metab. 2020;2(11):1284–304. https://doi.org/10.1038/s42255-020-00298-z.CrossRefPubMedPubMedCentral

21.

Lindskog C, Linné J, Fagerberg L, et al. The human cardiac and skeletal muscle proteomes defined by transcriptomics and antibody-based profiling. BMC Genom. 2015;16(1):475. https://doi.org/10.1186/s12864-015-1686-y.CrossRef

22.

Uhlén M, Fagerberg L, Hallström BM, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. https://doi.org/10.1126/science.1260419.CrossRefPubMed

23.

Gan L, Liu D, Liu J, et al. CD38 deficiency alleviates Ang II-induced vascular remodeling by inhibiting small extracellular vesicle-mediated vascular smooth muscle cell senescence in mice. Signal Transduct Target Ther. 2021;6(1):223. https://doi.org/10.1038/s41392-021-00625-0.CrossRefPubMedPubMedCentral

24.

Zuo W, Liu N, Zeng Y, et al. CD38: a potential therapeutic target in cardiovascular disease. Cardiovasc Drugs Ther. 2020;35(4):815–28. https://doi.org/10.1007/s10557-020-07007-8.CrossRef

25.

Li S, Wang L, Wang Y, et al. The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment. J Hematol Oncol. 2022;15(1):147. https://doi.org/10.1186/s13045-022-01360-x.CrossRefPubMedPubMedCentral

26.

Padella A, Ghelli Luserna Di Rorà A, Marconi G, et al. Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies. J Hematol Oncol. 2022;15(1):10. https://doi.org/10.1186/s13045-022-01228-0.CrossRefPubMedPubMedCentral

27.

Watson A, Nong Z, Yin H, et al. Nicotinamide phosphoribosyltransferase in smooth muscle cells maintains genome integrity, resists aortic medial degeneration, and is suppressed in human thoracic aortic aneurysm disease. Circ Res. 2017;120(12):1889–902. https://doi.org/10.1161/circresaha.116.310022.CrossRefPubMed

28.

Korski KI, Kubli DA, Wang BJ, et al. Hypoxia prevents mitochondrial dysfunction and senescence in human c-Kit(+) cardiac progenitor cells. Stem Cells. 2019;37(4):555–67. https://doi.org/10.1002/stem.2970.CrossRefPubMed

29.

Fukamizu Y, Uchida Y, Shigekawa A, et al. Safety evaluation of beta-nicotinamide mononucleotide oral administration in healthy adult men and women. Sci Rep. 2022;12(1):14442. https://doi.org/10.1038/s41598-022-18272-y.CrossRefPubMedPubMedCentral

30.

Yaku K, Nakagawa T. NAD(+) precursors in human health and disease: current status and future prospects. Antioxid Redox Signal. 2023;39(16–18):1133–49. https://doi.org/10.1089/ars.2023.0354.CrossRefPubMed

31.

Airhart SE, Shireman LM, Risler LJ, et al. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS ONE. 2017;12(12): e0186459. https://doi.org/10.1371/journal.pone.0186459.CrossRefPubMedPubMedCentral

32.

Xiao Y, Phelp P, Wang Q, et al. Cardioprotecive properties of known agents in rat ischemia-reperfusion model under clinically relevant conditions: only the NAD precursor nicotinamide riboside reduces infarct size in presence of fentanyl, midazolam and cangrelor, but not propofol. Front Cardiovasc Med. 2021;8: 712478. https://doi.org/10.3389/fcvm.2021.712478.CrossRefPubMedPubMedCentral

33.

Lauritzen KH, Olsen MB, Ahmed MS, et al. Instability in NAD(+) metabolism leads to impaired cardiac mitochondrial function and communication. Elife. 2021;10: e59828. https://doi.org/10.7554/eLife.59828.CrossRefPubMedPubMedCentral

34.

Damgaard MV, Treebak JT. What is really known about the effects of nicotinamide riboside supplementation in humans. Sci Adv. 2023;9(29):eadi4862. https://doi.org/10.1126/sciadv.adi4862.CrossRefPubMedPubMedCentral

35.

Sharma A, Chabloz S, Lapides RA, et al. Potential synergistic supplementation of NAD+ promoting compounds as a strategy for increasing healthspan. Nutrients. 2023;15(2):445. https://doi.org/10.3390/nu15020445.CrossRefPubMedPubMedCentral

36.

Wang P, Chen M, Hou Y, et al. Fingerstick blood assay maps real-world NAD(+) disparity across gender and age. Aging Cell. 2023;22(10): e13965. https://doi.org/10.1111/acel.13965.CrossRefPubMedPubMedCentral

37.

Luongo TS, Eller JM, Lu MJ, et al. SLC25A51 is a mammalian mitochondrial NAD(+) transporter. Nature. 2020;588(7836):174–9. https://doi.org/10.1038/s41586-020-2741-7.CrossRefPubMedPubMedCentral

38.

Schaefer PM, Huang J, Butic A, et al. Nicotinamide riboside alleviates exercise intolerance in ANT1-deficient mice. Mol Metab. 2022;64: 101560. https://doi.org/10.1016/j.molmet.2022.101560.CrossRefPubMedPubMedCentral

39.

Borsky P, Holmannova D, Andrys C, et al. Evaluation of potential aging biomarkers in healthy individuals: telomerase, AGEs, GDF11/15, sirtuin 1, NAD+, NLRP3, DNA/RNA damage, and klotho. Biogerontology. 2023;24(6):937–55. https://doi.org/10.1007/s10522-023-10054-x.CrossRefPubMedPubMedCentral

40.

Yang F, Deng X, Yu Y, et al. Association of human whole blood NAD(+) contents with aging. Front Endocrinol (Lausanne). 2022;13:829658. https://doi.org/10.3389/fendo.2022.829658.CrossRefPubMed

41.

Schwarzmann L, Pliquett RU, Simm A, et al. Sex-related differences in human plasma NAD+/NADH levels depend on age. Biosci Rep. 2021;41(1):BSR20200340. https://doi.org/10.1042/BSR20200340.CrossRefPubMedPubMedCentral

42.

Walli-Attaei M, Rosengren A, Rangarajan S, et al. Metabolic, behavioural, and psychosocial risk factors and cardiovascular disease in women compared with men in 21 high-income, middle-income, and low-income countries: an analysis of the PURE study. Lancet. 2022;400(10355):811–21. https://doi.org/10.1016/s0140-6736(22)01441-6.CrossRefPubMed

43.

Nizami HL, Minor KE, Chiao YA, et al. Sexually dimorphic effects of SARM1 deletion on cardiac NAD(+) metabolism and function. Am J Physiol Heart Circ Physiol. 2022;323(4):H774-h781. https://doi.org/10.1152/ajpheart.00370.2022.CrossRefPubMedPubMedCentral

44.

van der Velpen V, Rosenberg N, Maillard V, et al. Sex-specific alterations in NAD+ metabolism in 3xTg Alzheimer’s disease mouse brain assessed by quantitative targeted LC-MS. J Neurochem. 2021;159(2):378–88. https://doi.org/10.1111/jnc.15362.CrossRefPubMedPubMedCentral

45.

Marques-Carvalho A, Sardão VA, Kim HN, et al. ECSIT is essential for RANKL-induced stimulation of mitochondria in osteoclasts and a target for the anti-osteoclastogenic effects of estrogens. Front Endocrinol (Lausanne). 2023;14:1110369. https://doi.org/10.3389/fendo.2023.1110369.CrossRefPubMed

46.

Koay YC, Liu RP, McIntosh B, et al. The efficacy of risk factor modification compared to NAD(+) repletion in diastolic heart failure. JACC Basic Transl Sci. 2024;9(6):733–50. https://doi.org/10.1016/j.jacbts.2024.01.011.CrossRefPubMedPubMedCentral

47.

Kane AE, Chellappa K, Schultz MB, et al. Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner. bioRxiv. 2024. https://doi.org/10.1101/2024.06.21.599604.CrossRefPubMedPubMedCentral

48.

Murashige D, Jang C, Neinast M, et al. Comprehensive quantification of fuel use by the failing and nonfailing human heart. Science. 2020;370(6514):364–8. https://doi.org/10.1126/science.abc8861.CrossRefPubMedPubMedCentral

49.

Nolfi-Donegan D, Braganza A, Shiva S. Mitochondrial electron transport chain: oxidative phosphorylation, oxidant production, and methods of measurement. Redox Biol. 2020;37: 101674. https://doi.org/10.1016/j.redox.2020.101674.CrossRefPubMedPubMedCentral

50.

Vranas M, Wohlwend D, Qiu D, et al. Structural basis for inhibition of ROS-producing respiratory complex I by NADH-OH. Angew Chem Int Ed Engl. 2021;60(52):27277–81. https://doi.org/10.1002/anie.202112165.CrossRefPubMedPubMedCentral

51.

Zhang Y, Murugesan P, Huang K, et al. NADPH oxidases and oxidase crosstalk in cardiovascular diseases: novel therapeutic targets. Nat Rev Cardiol. 2020;17(3):170–94. https://doi.org/10.1038/s41569-019-0260-8.CrossRefPubMed

52.

Luengo A, Li Z, Gui DY, et al. Increased demand for NAD(+) relative to ATP drives aerobic glycolysis. Mol Cell. 2021;81(4):691-707.e696. https://doi.org/10.1016/j.molcel.2020.12.012.CrossRefPubMed

53.

Chornyi S, Costa CF, Li J, et al. Human peroxisomal NAD(+)/NADH homeostasis is regulated by two independent NAD(H) shuttle systems. Free Radic Biol Med. 2023;206:22–32. https://doi.org/10.1016/j.freeradbiomed.2023.06.020.CrossRefPubMed

54.

Tian H, Zhao X, Zhang Y, et al. Abnormalities of glucose and lipid metabolism in myocardial ischemia-reperfusion injury. Biomed Pharmacother. 2023;163: 114827. https://doi.org/10.1016/j.biopha.2023.114827.CrossRefPubMed

55.

Patgiri A, Skinner OS, Miyazaki Y, et al. An engineered enzyme that targets circulating lactate to alleviate intracellular NADH:NAD(+) imbalance. Nat Biotechnol. 2020;38(3):309–13. https://doi.org/10.1038/s41587-019-0377-7.CrossRefPubMedPubMedCentral

56.

Rimal S, Tantray I, Li Y, et al. Reverse electron transfer is activated during aging and contributes to aging and age-related disease. EMBO Rep. 2023;24(4):e55548. https://doi.org/10.15252/embr.202255548.CrossRefPubMedPubMedCentral

57.

Haythorne E, Rohm M, van de Bunt M, et al. Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells. Nat Commun. 2019;10(1):2474. https://doi.org/10.1038/s41467-019-10189-x.CrossRefPubMedPubMedCentral

58.

Higgins CB, Mayer AL, Zhang Y, et al. SIRT1 selectively exerts the metabolic protective effects of hepatocyte nicotinamide phosphoribosyltransferase. Nat Commun. 2022;13(1):1074. https://doi.org/10.1038/s41467-022-28717-7.CrossRefPubMedPubMedCentral

59.

Chiao YA, Chakraborty AD, Light CM, et al. NAD(+) redox imbalance in the heart exacerbates diabetic cardiomyopathy. Circ Heart Fail. 2021;14(8): e008170. https://doi.org/10.1161/CIRCHEARTFAILURE.120.008170.CrossRefPubMedPubMedCentral

60.

Tur J, Badole SL, Manickam R, et al. Cardioprotective effects of 1-(3,6-dibromo-carbazol-9-yl)-3-phenylamino-Propan-2-Ol in diabetic hearts via nicotinamide phosphoribosyltransferase activation. J Pharmacol Exp Ther. 2022;382(2):233–45. https://doi.org/10.1124/jpet.122.001122.CrossRefPubMedPubMedCentral

61.

Karamanlidis G, Lee CF, Garcia-Menendez L, et al. Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab. 2013;18(2):239–50. https://doi.org/10.1016/j.cmet.2013.07.002.CrossRefPubMedPubMedCentral

62.

Yoon JY, Daneshgar N, Chu Y, et al. Metabolic rescue ameliorates mitochondrial encephalo-cardiomyopathy in murine and human iPSC models of Leigh syndrome. Clin Transl Med. 2022;12(7): e954. https://doi.org/10.1002/ctm2.954.CrossRefPubMedPubMedCentral

63.

Matasic DS, Yoon JY, McLendon JM, et al. Modulation of the cardiac sodium channel Na(V)1.5 peak and late currents by NAD(+) precursors. J Mol Cell Cardiol. 2020;141:70–81. https://doi.org/10.1016/j.yjmcc.2020.01.013.CrossRefPubMedPubMedCentral

64.

Lopaschuk GD, Karwi QG, Tian R, et al. Cardiac energy metabolism in heart failure. Circ Res. 2021;128(10):1487–513. https://doi.org/10.1161/circresaha.121.318241.CrossRefPubMedPubMedCentral

65.

Ajoolabady A, Chiong M, Lavandero S, et al. Mitophagy in cardiovascular diseases: molecular mechanisms, pathogenesis, and treatment. Trends Mol Med. 2022;28(10):836–49. https://doi.org/10.1016/j.molmed.2022.06.007.CrossRefPubMedPubMedCentral

66.

Abdellatif M, Rainer PP, Sedej S, et al. Hallmarks of cardiovascular ageing. Nat Rev Cardiol. 2023;20(11):754–77. https://doi.org/10.1038/s41569-023-00881-3.CrossRefPubMed

67.

Deng Y, Xie M, Li Q, et al. Targeting mitochondria-inflammation circuit by β-hydroxybutyrate mitigates HFpEF. Circ Res. 2021;128(2):232–45. https://doi.org/10.1161/circresaha.120.317933.CrossRefPubMed

68.

Dikalova AE, Pandey A, Xiao L, et al. Mitochondrial deacetylase Sirt3 reduces vascular dysfunction and hypertension while Sirt3 depletion in essential hypertension is linked to vascular inflammation and oxidative stress. Circ Res. 2020;126(4):439–52. https://doi.org/10.1161/circresaha.119.315767.CrossRefPubMed

69.

Sanz-Alcázar A, Britti E, Delaspre F, et al. Mitochondrial impairment, decreased sirtuin activity and protein acetylation in dorsal root ganglia in Friedreich Ataxia models. Cell Mol Life Sci. 2023;81(1):12. https://doi.org/10.1007/s00018-023-05064-4.CrossRefPubMedPubMedCentral

70.

Jin L, Geng L, Ying L, et al. FGF21-sirtuin 3 axis confers the protective effects of exercise against diabetic cardiomyopathy by governing mitochondrial integrity. Circulation. 2022;146(20):1537–57. https://doi.org/10.1161/CIRCULATIONAHA.122.059631.CrossRefPubMed

71.

Ma S, Feng J, Lin X, et al. Nicotinamide riboside alleviates cardiac dysfunction and remodeling in pressure overload cardiac hypertrophy. Oxid Med Cell Longev. 2021;2021:5546867. https://doi.org/10.1155/2021/5546867.CrossRefPubMedPubMedCentral

72.

Liu X, Zhang Y, Deng Y, et al. Mitochondrial protein hyperacetylation underpins heart failure with preserved ejection fraction in mice. J Mol Cell Cardiol. 2022;165:76–85. https://doi.org/10.1016/j.yjmcc.2021.12.015.CrossRefPubMed

73.

Yamamura S, Izumiya Y, Araki S, et al. Cardiomyocyte Sirt (Sirtuin) 7 ameliorates stress-induced cardiac hypertrophy by interacting with and deacetylating GATA4. Hypertension. 2020;75(1):98–108. https://doi.org/10.1161/hypertensionaha.119.13357.CrossRefPubMed

74.

Prola A, Pires Da Silva J, Guilbert A, et al. SIRT1 protects the heart from ER stress-induced cell death through eIF2alpha deacetylation. Cell Death Differ. 2017;24(2):343–56. https://doi.org/10.1038/cdd.2016.138.CrossRefPubMed

75.

Gorski PA, Jang SP, Jeong D, et al. Role of SIRT1 in modulating acetylation of the sarco-endoplasmic reticulum Ca(2+)-ATPase in heart failure. Circ Res. 2019;124(9):e63–80. https://doi.org/10.1161/CIRCRESAHA.118.313865.CrossRefPubMedPubMedCentral

76.

Luo C, Ding W, Zhu S, et al. Nicotinamide mononucleotide administration amends protein acetylome of aged mouse liver. Cells. 2022;11(10):1654. https://doi.org/10.3390/cells11101654.CrossRefPubMedPubMedCentral

77.

Tong D, Schiattarella GG, Jiang N, et al. NAD(+) repletion reverses heart failure with preserved ejection fraction. Circ Res. 2021;128(11):1629–41. https://doi.org/10.1161/CIRCRESAHA.120.317046.CrossRefPubMedPubMedCentral

78.

Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–31. https://doi.org/10.1056/NEJMoa1707914.CrossRefPubMed

79.

Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381(26):2497–505. https://doi.org/10.1056/NEJMoa1912388.CrossRefPubMed

80.

Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020;383(19):1838–47. https://doi.org/10.1056/NEJMoa2021372.CrossRefPubMed

81.

He M, Chiang H-H, Luo H, et al. An acetylation switch of the NLRP3 inflammasome regulates aging-associated chronic inflammation and insulin resistance. Cell Metab. 2020;31(3):580-591.e585. https://doi.org/10.1016/j.cmet.2020.01.009.CrossRefPubMedPubMedCentral

82.

Marín-Aguilar F, Lechuga-Vieco AV, Alcocer-Gómez E, et al. NLRP3 inflammasome suppression improves longevity and prevents cardiac aging in male mice. Aging Cell. 2020;19(1): e13050. https://doi.org/10.1111/acel.13050.CrossRefPubMed

83.

Opstad TB, Papotti B, Åkra S, et al. Sirtuin1, not NAMPT, possesses anti-inflammatory effects in epicardial, pericardial and subcutaneous adipose tissue in patients with CHD. J Transl Med. 2023;21(1):644. https://doi.org/10.1186/s12967-023-04518-4.CrossRefPubMedPubMedCentral

84.

Gallí M, Van Gool F, Leo O. Sirtuins and inflammation: friends or foes? Biochem Pharmacol. 2011;81(5):569–76. https://doi.org/10.1016/j.bcp.2010.12.010.CrossRefPubMed

85.

Walker MA, Chen H, Yadav A, et al. Raising NAD(+) level stimulates short-chain dehydrogenase/reductase proteins to alleviate heart failure independent of mitochondrial protein deacetylation. Circulation. 2023;148(25):2038–57. https://doi.org/10.1161/circulationaha.123.066039.CrossRefPubMedPubMedCentral

86.

Zhang S, Weinberg S, DeBerge M, et al. Efferocytosis fuels requirements of fatty acid oxidation and the electron transport chain to polarize macrophages for tissue repair. Cell Metab. 2019;29(2):443-456.e445. https://doi.org/10.1016/j.cmet.2018.12.004.CrossRefPubMed

87.

Guo Q, Jin Y, Chen X, et al. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther. 2024;9(1):53. https://doi.org/10.1038/s41392-024-01757-9.CrossRefPubMedPubMedCentral

88.

Fang C, Liu J, Feng M, et al. Shengyu decoction treating vascular cognitive impairment by promoting AKT/HIF-1α/VEGF related cerebrovascular generation and ameliorating MAPK/NF-κB mediated neuroinflammation. J Ethnopharmacol. 2022;296: 115441. https://doi.org/10.1016/j.jep.2022.115441.CrossRefPubMed

89.

Sivandzade F, Prasad S, Bhalerao A, et al. NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible therapeutic approaches. Redox Biol. 2019;21: 101059. https://doi.org/10.1016/j.redox.2018.11.017.CrossRefPubMed

90.

Yu P, Li Y, Fu W, et al. Panax quinquefolius L. saponins protect myocardial ischemia reperfusion no-reflow through inhibiting the activation of nlrp3 inflammasome via TLR4/MyD88/NF-κB signaling pathway. Front Pharmacol. 2020;11:607813. https://doi.org/10.3389/fphar.2020.607813.CrossRefPubMed

91.

Zhou B, Wang DD, Qiu Y, et al. Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure. J Clin Investig. 2020;130(11):6054–63. https://doi.org/10.1172/jci138538.CrossRefPubMedPubMedCentral

92.

Elhassan YS, Kluckova K, Fletcher RS, et al. Nicotinamide riboside augments the aged human skeletal muscle NAD(+) metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Rep. 2019;28(7):1717-1728.e1716. https://doi.org/10.1016/j.celrep.2019.07.043.CrossRefPubMedPubMedCentral

93.

Wu K, Li B, Ma Y, et al. Nicotinamide mononucleotide attenuates HIF-1α activation and fibrosis in hypoxic adipose tissue via NAD+/SIRT1 axis. Front Endocrinol. 2023;14:1099134. https://doi.org/10.3389/fendo.2023.1099134.CrossRef

94.

Nacarelli T, Lau L, Fukumoto T, et al. NAD(+) metabolism governs the proinflammatory senescence-associated secretome. Nat Cell Biol. 2019;21(3):397–407. https://doi.org/10.1038/s41556-019-0287-4.CrossRefPubMedPubMedCentral

95.

Wang DX, Qing SL, Miao ZW, et al. Hepatic Nampt deficiency aggravates dyslipidemia and fatty liver in high fat diet fed mice. Cells. 2023;12(4):568. https://doi.org/10.3390/cells12040568.CrossRefPubMedPubMedCentral

96.

Kong YY, Li GQ, Zhang WJ, et al. Nicotinamide phosphoribosyltransferase aggravates inflammation and promotes atherosclerosis in ApoE knockout mice. Acta Pharmacol Sin. 2019;40(9):1184–92. https://doi.org/10.1038/s41401-018-0207-3.CrossRefPubMedPubMedCentral

97.

Kiss T, Giles CB, Tarantini S, et al. Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects. GeroScience. 2019;41(4):419–39. https://doi.org/10.1007/s11357-019-00095-x.CrossRefPubMedPubMedCentral

98.

Ronsein GE, Vaisar T, Davidson WS, et al. Niacin increases atherogenic proteins in high-density lipoprotein of statin-treated subjects. Arterioscler Thromb Vasc Biol. 2021;41(8):2330–41. https://doi.org/10.1161/atvbaha.121.316278.CrossRefPubMedPubMedCentral

99.

Razavi AC, Jain V, Grandhi GR, et al. Does elevated high-density lipoprotein cholesterol protect against cardiovascular disease? J Clin Endocrinol Metab. 2023;109(2):321–32. https://doi.org/10.1210/clinem/dgad406.CrossRefPubMedCentral

100.

Baman JR, Eskandari MK. What is an abdominal aortic aneurysm? JAMA. 2022;328(22):2280. https://doi.org/10.1001/jama.2022.18638.CrossRefPubMed

101.

Emeto TI, Moxon JV, Au M, et al. Oxidative stress and abdominal aortic aneurysm: potential treatment targets. Clin Sci (Lond). 2016;130(5):301–15. https://doi.org/10.1042/cs20150547.CrossRefPubMed

102.

Sharma N, Dev R, Ruiz-Rosado JD, et al. Pharmacological inhibition of Notch signaling regresses pre-established abdominal aortic aneurysm. Sci Rep. 2019;9(1):13458. https://doi.org/10.1038/s41598-019-49682-0.CrossRefPubMedPubMedCentral

103.

Horimatsu T, Blomkalns AL, Ogbi M, et al. Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide. Cardiovasc Res. 2020;116(14):2226–38. https://doi.org/10.1093/cvr/cvz303.CrossRefPubMed

104.

Ungvari Z, Tarantini S, Donato AJ, et al. Mechanisms of vascular aging. Circ Res. 2018;123(7):849–67. https://doi.org/10.1161/circresaha.118.311378.CrossRefPubMedPubMedCentral

105.

Raucci A, Macrì F, Castiglione S, et al. MicroRNA-34a: the bad guy in age-related vascular diseases. Cell Mol Life Sci. 2021;78(23):7355–78. https://doi.org/10.1007/s00018-021-03979-4.CrossRefPubMedPubMedCentral

106.

Zhang W, Shang T, Huang C, et al. Plasma microRNAs serve as potential biomarkers for abdominal aortic aneurysm. Clin Biochem. 2015;48(15):988–92. https://doi.org/10.1016/j.clinbiochem.2015.04.016.CrossRefPubMed

107.

Kin K, Miyagawa S, Fukushima S, et al. Tissue- and plasma-specific MicroRNA signatures for atherosclerotic abdominal aortic aneurysm. J Am Heart Assoc. 2012;1(5): e000745. https://doi.org/10.1161/jaha.112.000745.CrossRefPubMedPubMedCentral

108.

Oller J, Gabande-Rodriguez E, Ruiz-Rodriguez MJ, et al. Extracellular tuning of mitochondrial respiration leads to aortic aneurysm. Circulation. 2021;143(21):2091–109. https://doi.org/10.1161/CIRCULATIONAHA.120.051171.CrossRefPubMedPubMedCentral

109.

Bozkurt B, Coats AJS, Tsutsui H, et al. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur J Heart Fail. 2021;23(3):352–80. https://doi.org/10.1002/ejhf.2115.CrossRefPubMed

110.

Summer G, Kuhn AR, Munts C, et al. A directed network analysis of the cardiome identifies molecular pathways contributing to the development of HFpEF. J Mol Cell Cardiol. 2020;144:66–75. https://doi.org/10.1016/j.yjmcc.2020.05.008.CrossRefPubMed

111.

Abdellatif M, Trummer-Herbst V, Koser F, et al. Nicotinamide for the treatment of heart failure with preserved ejection fraction. Sci Transl Med. 2021;13(580):eabd7064. https://doi.org/10.1126/scitranslmed.abd7064.CrossRefPubMedPubMedCentral

112.

Wang YC, Koay YC, Pan C, et al. Indole-3-propionic acid protects against heart failure with preserved ejection fraction. Circ Res. 2024;134(4):371–89. https://doi.org/10.1161/circresaha.123.322381.CrossRefPubMed

113.

Li H, Zhang M, Wang Y, et al. Daidzein alleviates doxorubicin-induced heart failure via the SIRT3/FOXO3a signaling pathway. Food Funct. 2022;13(18):9576–88. https://doi.org/10.1039/d2fo00772j.CrossRefPubMed

114.

Hu J, Liu T, Fu F, et al. Omentin1 ameliorates myocardial ischemia-induced heart failure via SIRT3/FOXO3a-dependent mitochondrial dynamical homeostasis and mitophagy. J Transl Med. 2022;20(1):447. https://doi.org/10.1186/s12967-022-03642-x.CrossRefPubMedPubMedCentral

115.

Wang DD, Airhart SE, Zhou B, et al. Safety and tolerability of nicotinamide riboside in heart failure with reduced ejection fraction. JACC Basic Transl Sci. 2022;7(12):1183–96. https://doi.org/10.1016/j.jacbts.2022.06.012.CrossRefPubMedPubMedCentral

116.

Zhou L, Zhang S, Bolor-Erdene E, et al. NAMPT/SIRT1 attenuate ang ii-induced vascular remodeling and vulnerability to hypertension by inhibiting the ROS/MAPK pathway. Oxid Med Cell Longev. 2020;2020:1974265. https://doi.org/10.1155/2020/1974265.CrossRefPubMedPubMedCentral

117.

Forte M, Bianchi F, Cotugno M, et al. Pharmacological restoration of autophagy reduces hypertension-related stroke occurrence. Autophagy. 2020;16(8):1468–81. https://doi.org/10.1080/15548627.2019.1687215.CrossRefPubMed

118.

Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults. Nat Commun. 2018;9(1):1286. https://doi.org/10.1038/s41467-018-03421-7.CrossRefPubMedPubMedCentral

119.

Qiu Y, Xu S, Chen X, et al. NAD(+) exhaustion by CD38 upregulation contributes to blood pressure elevation and vascular damage in hypertension. Signal Transduct Target Ther. 2023;8(1):353. https://doi.org/10.1038/s41392-023-01577-3.CrossRefPubMedPubMedCentral

120.

Wang LF, Li Q, Wen K, et al. CD38 deficiency alleviates diabetic cardiomyopathy by coordinately inhibiting pyroptosis and apoptosis. Int J Mol Sci. 2023;24(21):16008. https://doi.org/10.3390/ijms242116008.CrossRefPubMedPubMedCentral

121.

Oka SI, Byun J, Huang CY, et al. Nampt potentiates antioxidant defense in diabetic cardiomyopathy. Circ Res. 2021;129(1):114–30. https://doi.org/10.1161/circresaha.120.317943.CrossRefPubMedPubMedCentral

122.

Zeng F, Zhou P, Wang M, et al. ACMSD mediated de novo NAD(+) biosynthetic impairment in cardiac endothelial cells as a potential therapeutic target for diabetic cardiomyopathy. Diabetes Res Clin Pract. 2023;206: 111014. https://doi.org/10.1016/j.diabres.2023.111014.CrossRefPubMed

123.

Hu L, Guo Y, Song L, et al. Nicotinamide riboside promotes Mfn2-mediated mitochondrial fusion in diabetic hearts through the SIRT1-PGC1α-PPARα pathway. Free Radic Biol Med. 2022;183:75–88. https://doi.org/10.1016/j.freeradbiomed.2022.03.012.CrossRefPubMed

124.

Zhang YJ, Zhang M, Zhao X, et al. NAD(+) administration decreases microvascular damage following cardiac ischemia/reperfusion by restoring autophagic flux. Basic Res Cardiol. 2020;115(5):57. https://doi.org/10.1007/s00395-020-0817-z.CrossRefPubMed

125.

Cai WB, Zhao YJ, Liu L, et al. Redox environment metabolomic evaluation (REME) of the heart after myocardial ischemia/reperfusion injury. Free Radic Biol Med. 2021;173:7–18. https://doi.org/10.1016/j.freeradbiomed.2021.06.033.CrossRefPubMed

126.

Lagu B, Wu X, Kulkarni S, et al. Orally bioavailable enzymatic inhibitor of CD38, MK-0159, protects against ischemia/reperfusion injury in the murine heart. J Med Chem. 2022;65(13):9418–46. https://doi.org/10.1021/acs.jmedchem.2c00688.CrossRefPubMed

127.

Guan XH, Liu XH, Hong X, et al. CD38 deficiency protects the heart from ischemia/reperfusion injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway. Oxid Med Cell Longev. 2016;2016:7410257. https://doi.org/10.1155/2016/7410257.CrossRefPubMedPubMedCentral

128.

Wang XX, Wang XL, Tong MM, et al. SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3α-dependent antioxidant defense mechanisms. Basic Res Cardiol. 2016;111(2):13. https://doi.org/10.1007/s00395-016-0531-z.CrossRefPubMed

129.

Jafari-Azad A, Hosseini L, Rajabi M, et al. Nicotinamide mononucleotide and melatonin counteract myocardial ischemia–reperfusion injury by activating SIRT3/FOXO1 and reducing apoptosis in aged male rats. Mol Biol Rep. 2021;48(4):3089–96. https://doi.org/10.1007/s11033-021-06351-8.CrossRefPubMed

130.

Hosseini L, Vafaee MS, Badalzadeh R. Melatonin and nicotinamide mononucleotide attenuate myocardial ischemia/reperfusion injury via modulation of mitochondrial function and hemodynamic parameters in aged rats. J Cardiovasc Pharmacol Ther. 2020;25(3):240–50. https://doi.org/10.1177/1074248419882002.CrossRefPubMed

131.

Nie H, Zhang Y, Yu H, et al. Oral delivery of carrier-free dual-drug nanocrystal self-assembled microspheres improved NAD(+) bioavailability and attenuated cardiac ischemia/reperfusion injury in mice. Drug Deliv. 2021;28(1):433–44. https://doi.org/10.1080/10717544.2021.1886198.CrossRefPubMedPubMedCentral

132.

Tannous C, Deloux R, Karoui A, et al. NMRK2 gene is upregulated in dilated cardiomyopathy and required for cardiac function and NAD levels during aging. Int J Mol Sci. 2021;22(7):3534. https://doi.org/10.3390/ijms22073534.CrossRefPubMedPubMedCentral

133.

Shahzadi SK, Marzook H, Qaisar R, et al. Nicotinamide riboside kinase-2 inhibits JNK pathway and limits dilated cardiomyopathy in mice with chronic pressure overload. Clin Sci (Lond). 2022;136(2):181–96. https://doi.org/10.1042/cs20210964.CrossRefPubMed

134.

Diguet N, Trammell SAJ, Tannous C, et al. Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy. Circulation. 2018;137(21):2256–73. https://doi.org/10.1161/CIRCULATIONAHA.116.026099.CrossRefPubMed

135.

Wu K, Li B, Lin Q, et al. Nicotinamide mononucleotide attenuates isoproterenol-induced cardiac fibrosis by regulating oxidative stress and Smad3 acetylation. Life Sci. 2021;274: 119299. https://doi.org/10.1016/j.lfs.2021.119299.CrossRefPubMed

136.

Zhang R, Shen Y, Zhou L, et al. Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure. J Mol Cell Cardiol. 2017;112:64–73. https://doi.org/10.1016/j.yjmcc.2017.09.001.CrossRefPubMedPubMedCentral

137.

Yamamoto T, Endo J, Kataoka M, et al. Sirt1 counteracts decrease in membrane phospholipid unsaturation and diastolic dysfunction during saturated fatty acid overload. J Mol Cell Cardiol. 2019;133:1–11. https://doi.org/10.1016/j.yjmcc.2019.05.019.CrossRefPubMed

138.

Zhang Q, Li Z, Li Q, et al. Control of NAD(+) homeostasis by autophagic flux modulates mitochondrial and cardiac function. EMBO J. 2024;43(3):362–90. https://doi.org/10.1038/s44318-023-00009-w.CrossRefPubMedPubMedCentral

139.

Vignier N, Chatzifrangkeskou M, Morales Rodriguez B, et al. Rescue of biosynthesis of nicotinamide adenine dinucleotide protects the heart in cardiomyopathy caused by lamin A/C gene mutation. Hum Mol Genet. 2018;27(22):3870–80. https://doi.org/10.1093/hmg/ddy278.CrossRefPubMed

140.

Dierickx P, Carpenter BJ, Celwyn I, et al. Nicotinamide riboside improves cardiac function and prolongs survival after disruption of the cardiomyocyte clock. Front Mol Med. 2022;2: 887733. https://doi.org/10.3389/fmmed.2022.887733.CrossRefPubMedPubMedCentral

141.

Liao B, Zhao Y, Wang D, et al. Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study. J Int Soc Sports Nutr. 2021;18(1):54. https://doi.org/10.1186/s12970-021-00442-4.CrossRefPubMedPubMedCentral

142.

Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224–9. https://doi.org/10.1126/science.abe9985.CrossRefPubMedPubMedCentral

143.

Remie CME, Roumans KHM, Moonen MPB, et al. Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans. Am J Clin Nutr. 2020;112(2):413–26. https://doi.org/10.1093/ajcn/nqaa072.CrossRefPubMedPubMedCentral

144.

Pool L, Knops P, Manintveld OC, et al. The HF-AF ENERGY trial: nicotinamide riboside for the treatment of atrial fibrillation in heart failure patients. Cardiovasc Drugs Ther. 2022;37(6):1243–8. https://doi.org/10.1007/s10557-022-07382-4.CrossRefPubMedPubMedCentral

145.

Solier S, Müller S, Cañeque T, et al. A druggable copper-signalling pathway that drives inflammation. Nature. 2023;617(7960):386–94. https://doi.org/10.1038/s41586-023-06017-4.CrossRefPubMedPubMedCentral

146.

Ju J, Li XM, Zhao XM, et al. Circular RNA FEACR inhibits ferroptosis and alleviates myocardial ischemia/reperfusion injury by interacting with NAMPT. J Biomed Sci. 2023;30(1):45. https://doi.org/10.1186/s12929-023-00927-1.CrossRefPubMedPubMedCentral

147.

Hwang E, Song S. Possible adverse effects of high-dose nicotinamide: mechanisms and safety assessment. Biomolecules. 2020;10(5):687. https://doi.org/10.3390/biom10050687.CrossRefPubMedPubMedCentral

148.

Li T, Garcia-Gomez A, Morante-Palacios O, et al. SIRT1/2 orchestrate acquisition of DNA methylation and loss of histone H3 activating marks to prevent premature activation of inflammatory genes in macrophages. Nucleic Acids Res. 2020;48(2):665–81. https://doi.org/10.1093/nar/gkz1127.CrossRefPubMed

Titel: The Role of NAD+ Metabolism in Cardiovascular Diseases: Mechanisms and Prospects
verfasst von: Huimin Li
Qingxun Hu
Deqiu Zhu
Dan Wu
Publikationsdatum: 20.12.2024
Verlag: Springer International Publishing
Erschienen in: American Journal of Cardiovascular Drugs
Print ISSN: 1175-3277
Elektronische ISSN: 1179-187X
DOI: https://doi.org/10.1007/s40256-024-00711-y

Kompaktes Leitlinien-Wissen Innere Medizin (Link öffnet in neuem Fenster)

Mit medbee Pocketcards schnell und sicher entscheiden.
Leitlinien-Wissen kostenlos und immer griffbereit auf ihrem Desktop, Handy oder Tablet.

Kostenlos registrieren

Neu im Fachgebiet Kardiologie

Erhöhte Hypoglykämie-Gefahr nach Beginn einer Betablockertherapie

26.03.2025
Typ-2-Diabetes
Nachrichten

Beginnen Diabetiker eine Behandlung mit Betablockern, verdoppelt sich in den ersten Wochen fast das Hypoglykämie-Risiko, normalisiert sich mit der Zeit aber wieder. Besondere Vorsicht ist unter einer Therapie mit nichtselektiven Wirkstoffen geboten.

Vom Wert der Ernährung bei neurodegenerativen Erkrankungen

25.03.2025
Parkinson-Krankheit
Podcast

Am Beispiel Parkinson zeigt sich, dass Ernährung nicht nur präventiv förderlich ist, sondern auch die Wirkung von Medikamenten und den Krankheitsverlauf beeinflusst. Prof. Dr. Andrés Ceballos-Baumann, München, fasst die aktuelle Studienlage zusammen, nennt die bestehenden Probleme und veranschaulicht seine Vorgehensweise.

ePA: Entlastung oder Mehrarbeit?

25.03.2025
FOKO 2025
Kongressbericht

Die elektronische Patientenakte (ePA) soll das Gesundheitswesen revolutionieren. Mit über 2000 Krankenhäusern und mehr als 100.000 ärztlichen Praxen ist sie eines der größten Digitalisierungsprojekte Europas. Während die Politik die ePA als „Gamechanger“ feiert, zeigt sich in der Praxis ein anderes Bild.

Herzkongress ACC 2025: Diese neuen Studien stehen im Brennpunkt

21.03.2025
ACC 2025
Kongressbericht

Vom 29. bis 31. März findet in Chicago der Herzkongress ACC 2025 statt. Die Liste der als „Late-breaking Trials“ in den Blickpunkt gerückten neuen Studien zu wichtigen kardiologischen Themen ist wieder einmal lang.

EKG Essentials: EKG befunden mit System (Link öffnet in neuem Fenster)

In diesem CME-Kurs können Sie Ihr Wissen zur EKG-Befundung anhand von zwölf Video-Tutorials auffrischen und 10 CME-Punkte sammeln.
Praxisnah, relevant und mit vielen Tipps & Tricks vom Profi.

Jetzt 10 CME-Punkte sammeln

Update Kardiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Bildnachweise

Die Leitlinien für Ärztinnen und Ärzte, Ältere Dame nimmt Tabletten ein/© Satjawat / stock.adobe.com (Symbolbild mit Fotomodell), Springer Medizin Podcast - Ernährung bei neurodegenerativen Erkrankungen/© Bild: oscargutzo / Stock.adobe.com | Logo: Springer Medizin, MFA am Computer/© Gorodenkoff / stock.adobe.com (Symbolbild mit Fotomodell), Ärztin mit Befunden und einem Herzmodell/© H_Ko / stock.adobe.com (Symbolbild mit Fotomodell), EKG befunden mit System - EKG Essential/© Springer Medizin Verlag GmbH

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten