Kareema A. Dakhil (1), Zahraa Ali Nashoor Alnawas (2)
General Background: Ischemic heart disease (IHD) remains a major global health burden, primarily driven by atherosclerosis, thrombosis, and chronic inflammation. Specific Background: Emerging evidence implicates amino acid metabolism, particularly the tryptophan (Trp)–kynurenine pathway, in cardiovascular pathogenesis through its interplay with inflammation and energy homeostasis. Knowledge Gap: While the kynurenine pathway has been linked to cardiovascular disease, the specific role of Trp degradation in IHD, especially regarding NAD+ metabolism and SIRT1 regulation, is not well established. Aims: This study examined the association between Trp catabolism, NAD+ availability, SIRT1 expression, and inflammatory markers in IHD patients. Results: Compared with healthy controls, IHD patients exhibited significantly reduced serum Trp and NAD+ levels, while SIRT1 expression was markedly elevated. In parallel, inflammatory markers including CRP and Troponin were consistently higher across myocardial infarction, angina, and heart failure groups. Novelty: These findings highlight a distinct metabolic-inflammatory axis in IHD, where enhanced Trp degradation coincides with disrupted NAD+ homeostasis and compensatory SIRT1 elevation. Implications: Targeting Trp metabolism, NAD+ pathways, and SIRT1 regulation may offer novel diagnostic biomarkers and therapeutic strategies for IHD and related cardiovascular conditions.Highlight :
Serum tryptophan and NAD+ levels are lower in IHD patients.
SIRT1 levels are significantly higher compared to controls.
CRP and troponin confirm inflammation and heart damage.
Keywords : Ischemic Heart Disease, Tryptophan, NAD+, SIRT1, CRP, Troponin
Ischemic heart disease (IHD) is one of the most common cardiovascular diseases and a major threat to public health worldwide. IHD includes acute myocardial infarction, chronic stable angina, chronic IHD and associated heart failure [1]. Ischemic heart disease refers to a category of heart disease wherein the coronary arteries do not get an adequate amount of blood supply and is very closely associated with a pathological process such as atherosclerosis, thrombosis, and myocardial ischemia [2]. These processes contribute to the narrowing of the coronary arteries, which impairs blood flow and exacerbates the risk of ischemic events [3].
Amino acid metabolism has been reported to be an important participant in the development of CVD [4][5]. For instance, by increased production of reactive oxygen species and inflammation, branched chain AAs cause endothelial cell dysfunction [6]. Additionally, aromatic amino acids have a significant impact on how cardiovascular disease develops naturally [7]. Likewise, metabolites of tryptophan (Trp) have been linked to inflammation and are thus thought to play a role in CVD [8][9].
Tryptophan (TRP) is an essential exogenous amino acid that intermediates in human protein synthesis and has critical metabolic functions as a substrate for crucial molecules such as serotonin (the neurotransmitter), nicotinamide adenine dinucleotide (NAD), and nicotinic acid [10]. TRP has been the object of numerous research because of its metabolism in a series of bioactive metabolites with the ability to influence many metabolic pathways of numerous cells in mammalian species. The kynurenine pathway (KP) is the hub of metabolism of peripheral TRP (95%) in humans and animals [11]. Furthermore, it results in NAD’s biosynthesis, as NAD functions as a crucial cofactor [12]. Also In the heart, >99% of NAD+ is synthesized via the salvage pathway [13]. NAD+ supplies in the cells are replenished by either de novo synthesis from dietary tryptophan or via salvage pathways from precursors including nicotinamide, nicotinamide riboside (NR), and nicotinic acid [14].
Moreover, Sirtuins deacetylate proteins or enzymes utilizing NAD+ as a co-substrate. Sirtuins initially catalyze the cleavage of NAD+, yielding nicotinamide (NAM) and 2’-O-acetyl-ADP-ribose. NAM is then converted back into NAD+ by the action of several enzymes [15].
Also SIRT1 has several roles in maintaining cardiac function and has been suggested as a predictive indicator for myocardial infarction occurrence [16]. The highest rates of global morbidity are associated with cardiovascular disease (CVD), and atherosclerosis is the primary etiological factor leading to various manifestations of CVD, including coronary heart disease and stroke [17]. One of the critical factors in CVD pathogenesis is the immune response, and a clinical solution remains to be identified [18]. Scholars in recent years have directed significant energy towards the examination of the Kyn pathway and the role it plays in CVD pathogenesis, and because several hypotheses have suggested that various factors, including oxidative stress, immune activation, and inflammation, are central to the pathogenesis of atherosclerosis and CVD, a critical area of future investigation is to examine to potential part played by the Kyn pathway in CVD regarding these factors [19].
The study aimed to investigate whether the inflammatory processes involved in IHD pathogenesis is linked with increased tryptophan degradation.
90 patients were participated in the study and were divided into three groups: In the first group, 30 patients with myocardial infraction (MI) with mean age (63.7 ±11.4 years), The second group involved 30 patients with angina (AN), with mean age of (59.93 ±11.8 years). The third group 30 with heart failure (HF) patients with mean age (58.23±9.7 yr). After being diagnosed with IHD by expert physician, patients were gathered from the cardiac center in the Thi-Qar Governorate between October 2024 and January 2025.
The healthy control group consisted of 60 samples of healthy individuals with a mean age of 54.18±12.3 years who did not have CAD, diabetes mellitus, hypertension, renal disease, endocrine problems, metabolic abnormalities, infections, or acute or chronic diseases. These healthy subjects visited the hospital for routine check-ups matched for age, sex, and other relevant demographic characteristics. Information like family history of the disease, living situation, treatment type, and sex was collected using structured questionnaires and medical records. Written informed consent was obtained from all subjects.
A 3 milliliters of venous blood were collected and placed in a gel tube and allowed to clot for a few minutes at room temperature. Then serum was obtained after centrifugation at 300 g for 15-20 minutes at room temperature. The resulting serum was transferred into Eppendorf tube and stored at -40°C for further analysis. Serum Tryptophan was detected by using Fluorescence HPLC in accordance with the instructions provided by the Shimadzu/Japan kit, while serum KMO and 3HAAO was identified by the enzyme-linked immunosorbent assay (ELISA) according to procedures of kit (Bioassay/China) respectively.
The statistical analysis was conducted using SPSS, or Version 23 of the Social Sciences Statistical Software. Categorical variables were represented using percentages and frequencies. For continuous variables, Means ± SD was used.
The Shapiro-Wilk test was used to determine if the data distribution was normal. The Student's t-test was used to see if there was a significant difference between the patient and control groups. A one-way analysis of variance (ANOVA) was used to compare significant differences between multiple groups. A P-value of less than 0.05 was considered statistically significant for all analyses. Receive operating curve (ROC) was applied to test the sensitivity and specifity for biomarkers.
The frequency distribution of control individuals and patients by age, sex and BMI, was shown in table 1. The group of patients with type MI consisted of 4 (13.3) females and 26 (86.67%) males. Of the patients in the second group, 10 (33.33%) were male and 20 (66.67%) were female (Angina).As the third group was patients with HF included 19(63.33%) males and11(36.67%) females, whereas, control group included 47(78.33%) males and 13(21.67%) females.
The mean BMI of patients (MI, Angina , HF) was (25.29±3.8, 26.57±4.06, 25.41± 3.82) respectively and that of control subjects was (25.35±4.89) .
n: number of cases; SD: standard deviation; S: significant at P > 0.05: NS: not significant at P > 0.05
The comparison of serum Troponin and CRP levels between IHD patients and healthy control groups has been carried out and the results were demonstrated in (Table 2). Levels of serum Troponin in patients with IHD were highly significantly higher than the levels of serum Troponin in healthy control subject (P < 0.01). In same table shown comparison of CRP levels were higher in patients with IHD in comparison with healthy control subject and the difference was higher significant (P < 0.01).
n: number of subjects NS: not significant ** P < 0.01
The findings of this study demonstrated a significant lower in the serum levels of the Tryptophan in MI, AN, and HF patient groups compared to healthy individuals (P < 0.01, Figure 1,2).
Figure 1. Serum Tryptophan levels in patients with MI, AN and HF and the control group. The data were shown as mean ± SD. ** indicated a statistically significant difference between the patient and control groups (P < 0.01).
Figure 2. HPLC peaks for serum Tryptophan in patients with MI, AN and HF and the control groups.
The results showed that serum NAD+ level were significantly decreased in IHD compared to control groups (P <0.01, Figure 3 ).
Figure 3. Serum NAD+ levels in patients with MI, AN, HF, and the control. Data are expressed as mean ± SD. **indicates a significant difference between the patient and control groups (P ≤0.01).
Serum SIRT1 level were declared a significant increase in IHD patients as compared to control groups (P < 0.01, Figure 4).
Figure 4. Serum SIRT1 levels in patients with MI, AN, and HF as well as the control group .The data is shown as means ± SD.**indicates a significant difference between the patient and control groups (P < 0.01).
Recent research has indicated a possible connection between CVD and tryptophan (Trp) metabolism [20]. Where TRP is mainly degraded into N-formylkynurenine leading to the generation of several active metabolites known as Kynurenine (Kyn) metabolites. Tryptophan (Trp) metabolites have been shown to be closely related to inflammation and thereby suggested to be involved in CVD, providing a comprehensive and quantitative value for human cardiac fuel using in IHD [21][22]. Downstream Trp metabolites from the kynurenine pathway may serve as CVD biomarkers or causative risk factors.
In this study, Table 1 provides a summary of all clinical and hemodynamic variables. And with the increasing prevalence of risk factors, it has become essential to study the relationship between variables biochemical factors and the risk of developing heart disease. Levels of serum C-reactive protein (CRP) were increased significantly in patients with IHD in comparison with healthy control subject (P < 0.01). Where CRP reflects disease progression and predicts the prognosis of recurrent cardiovascular events, this result agreed with other studies,which found that CRP levels increased in patients with CAD. CRP has been shown to affect CAD development through various mechanisms, including activating the complement system, being involved in LDL-C uptake by macrophages and platelets, inhibiting fibrinolysis, and promoting smooth muscle cell proliferation polarization and lipid deposition [23][24][25]. Researchers believe CRP causes inflammation, platelet aggregation, and thrombosis [26]. Also troponin levels in the IHD patient group were significantly elevated than in the control group.as shown by the presence in( table 2) (P ≤ 0.01). These agreed with previous studies [27][28]. The biomarker of choice for detecting myocardial ischemia/necrosis is cardiac troponin (cTn), which is produced in three isoforms (I, T, and C) [29]. The breakdown products of cardiac troponin are released into the circulation, as there are myocytes' apoptotic and necrotic cells [30]. Additionally, it was shown that membranous blebs respond to ischemia without necrosis by releasing cardiac troponin [31].
Moreover, this study found that serum tryptophan levels were considerably lower in IHD patients than in healthy controls (P < 0.01) (Figure 1). It is consistent with research demonstrating the link between Trp and CVD. This implies that the plasma Trp concentration is lower in individuals with CVD, suggesting that inflammation may possibly be a contributing cause to lower Trp levels in these patients [32]. The Th1-type cytokine IFN-γ in CVD patients, causes increased 2,3-dioxygenase activity, which ultimately decreases the serum levels of Trp [33]. Moreover, plasma Trp is negatively associated with cardiovascular events. A reduction in circulating Trp levels may serve as a significant predictor of adverse outcomes in patients with CVD.
Also it was found a significant lower in the mean levels of serum NAD+ in patients in comparison with healthy control group (P < 0.01).The result of this study is in agreement with the results of many studies have demonstrated that NAD+ plays a crucial role in the occurrence and development of CVD [34][35].Where low-grade chronic inflammation is the basic trigger of vascular dysfunction and related diseases, and a systemic decline in NAD+ is associated with inflammation [36]. Where NAD+, is one of the most essential small molecules in mammalian cells. NAD+ interacts with over 500 enzymes and plays important roles in almost every vital aspect in cell biology and human physiologs [37][38]. Dysregulation of NAD+ homeostasis is associated with a number of diseases including CVD. Importantly, imbalanced NAD+ metabolism has also been observed in vascular pathologies, including atherosclerosis [39].
Finally, mean levels of serum SIRT1 was significantly higher than in patients with IHD in comparison with healthy control (P < 0.01). the result of the current study agrees with other studies that found in relation to heart disease, where SIRT1 has drawn increasing interest as a potential biomarker for atherosclerosis due to its crucial role in various biological functions [40][41]. Alcendor have shown that SIRT1 activation can serve as a double-edged sword depending on the degree of activity increase, mild to moderately increased expression of SIRT1 reduced myocardial hypertrophy, interstitial fibrosis and senescence markers [42]. On the other hand, high levels of SIRT1 expression resulted in development of cardiomyopathy. There appears to be an emerging role for sirtuins, especially SIRT1 and SIRT3 in the pathophysiology of heart failure. SIRT1 is normally localised to the cytoplasm in normal human cardiomyocytes, where Shan et al report participation of SIRT1 in the development of congenital heart disease.[43]
Also increasing SIRT1 together with calorie restriction caused deacetylation and activation of eNOS, which ultimately increased NO, thereby dilating and protecting blood vessels [44][45].
Briefly, these findings emphasize the importance of the metabolism of an essential amino acid (tryptophan (Trp)) and its major metabolites (especially by the kynurenine pathway) during the clinical evolution of ischemic heart disease (IHD). Results Serum tryptophan and NAD+ levels were significantly lower while SIRT1 levels were significantly higher in IHD patients compared to healthy controls. ConclusionIn IHD patients; inflammatory processes change the metabolism of tryptophan and thus it can be a potential marker for early diagnosis and disease development. These findings suggest that the kynurenine pathway and SIRT1 can be potential therapeutic targets and may help in the reduction of inflammatory response in IHD. Mechanistically, more data is required to clarify the role of tryptophan metabolites in IHD and other cardiovascular diseases, and the translational aspect of the modulation of these pathways should be investigated in clinical trials.
Acknowledgments
The authors gratefully acknowledge the participants from the Heart Foundation and staff of this study.
J. Sun, Y. Qiao, M. Zhao, C. G. Magnussen, and B. Xi, “Global, Regional, and National Burden of Cardiovascular Diseases in Youths and Young Adults Aged 15–39 Years in 204 Countries/Territories, 1990–2019: A Systematic Analysis of Global Burden of Disease Study 2019,” BMC Medicine, vol. 21, no. 1, p. 222, 2023, doi: 10.1186/s12916-023-03039-9.
G. I. Fouad, “Synergistic Anti-Atherosclerotic Role of Combined Treatment of Omega-3 and Co-Enzyme Q10 in Hypercholesterolemia-Induced Obese Rats,” Heliyon, vol. 6, no. 4, 2020, doi: 10.1016/j.heliyon.2020.e03778.
E. I. Obeagu, “Red Blood Cells as Biomarkers and Mediators in Complications of Diabetes Mellitus: A Review,” Medicine, vol. 103, no. 8, p. e37265, 2024, doi: 10.1097/MD.0000000000037265.
Z.-N. Ling, Y.-F. Jiang, J.-N. Ru, J.-H. Lu, B. Ding, and J. Wu, “Amino Acid Metabolism in Health and Disease,” Signal Transduction and Targeted Therapy, vol. 8, no. 1, p. 345, 2023, doi: 10.1038/s41392-023-01587-3.
S. K. Anand, T.-A. Governale, X. Zhang, B. Razani, A. Yurdagul Jr., C. B. Pattillo, et al., “Amino Acid Metabolism and Atherosclerotic Cardiovascular Disease,” The American Journal of Pathology, vol. 194, no. 4, pp. 510–524, 2024, doi: 10.1016/j.ajpath.2023.12.003.
O. Zhenyukh, M. González-Amor, R. R. Rodrigues-Diez, V. Esteban, M. Ruiz-Ortega, M. Salaices, et al., “Branched-Chain Amino Acids Promote Endothelial Dysfunction Through Increased Reactive Oxygen Species Generation and Inflammation,” Journal of Cellular and Molecular Medicine, vol. 22, no. 10, pp. 4948–4962, 2018, doi: 10.1111/jcmm.13765.
J. Zhang, X. Jiang, B. Pang, D. Li, L. Kang, T. Zhou, et al., “Association Between Tryptophan Concentrations and the Risk of Developing Cardiovascular Diseases: A Systematic Review and Meta-Analysis,” Nutrition & Metabolism (London), vol. 21, no. 1, p. 82, 2024, doi: 10.1186/s12986-024-00852-w.
N. Paeslack, M. Mimmler, S. Becker, Z. Gao, M. P. Khuu, A. Mann, et al., “Microbiota-Derived Tryptophan Metabolites in Vascular Inflammation and Cardiovascular Disease,” Amino Acids, vol. 54, no. 10, pp. 1339–1356, 2022, doi: 10.1007/s00726-022-03256-8.
K. Nitz, M. Lacy, and D. Atzler, “Amino Acids and Their Metabolism in Atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 39, no. 3, pp. 319–330, 2019, doi: 10.1161/ATVBAHA.118.311577.
A. A.-B. Badawy, “Kynurenine Pathway and Human Systems,” Experimental Gerontology, vol. 129, p. 110770, 2020, doi: 10.1016/j.exger.2019.110770.
A. A. Badawy, “Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects,” International Journal of Tryptophan Research, vol. 10, p. 1178646917691938, 2017, doi: 10.1177/1178646917691938.
L. Vécsei, L. Szalárdy, F. Fülöp, and J. Toldi, “Kynurenines in the CNS: Recent Advances and New Questions,” Nature Reviews Drug Discovery, vol. 12, no. 1, pp. 64–82, 2013, doi: 10.1038/nrd3793.
V. Mori, A. Amici, F. Mazzola, M. Di Stefano, L. Conforti, G. Magni, et al., “Metabolic Profiling of Alternative NAD Biosynthetic Routes in Mouse Tissues,” PloS One, vol. 9, no. 11, p. e113939, 2014, doi: 10.1371/journal.pone.0113939.
J. R. Revollo, A. A. Grimm, and S.-i. Imai, “The Regulation of Nicotinamide Adenine Dinucleotide Biosynthesis by Nampt/PBEF/Visfatin in Mammals,” Current Opinion in Gastroenterology, vol. 23, no. 2, pp. 164–170, 2007, doi: 10.1097/MOG.0b013e32802bf6ae.
W. Kupis, J. Pałyga, E. Tomal, and E. Niewiadomska, “The Role of Sirtuins in Cellular Homeostasis,” Journal of Physiology and Biochemistry, vol. 72, no. 3, pp. 371–380, 2016, doi: 10.1007/s13105-016-0490-3.
M. Harvent, Thesis/Thèse, 2019.
M. Nichols, N. Townsend, P. Scarborough, and M. Rayner, “Cardiovascular Disease in Europe 2014: Epidemiological Update,” European Heart Journal, vol. 35, no. 42, pp. 2950–2959, 2014, doi: 10.1093/eurheartj/ehu378.
K. Miyamoto, T. Sujino, and T. Kanai, “The Tryptophan Metabolic Pathway of the Microbiome and Host Cells in Health and Disease,” International Immunology, vol. 36, no. 12, pp. 601–616, 2024, doi: 10.1093/intimm/dxae059.
P. Song, T. Ramprasath, H. Wang, and M.-H. Zou, “Abnormal Kynurenine Pathway of Tryptophan Catabolism in Cardiovascular Diseases,” Cellular and Molecular Life Sciences, vol. 74, no. 16, pp. 2899–2916, 2017, doi: 10.1007/s00018-017-2504-2.
O. Soehnlein and P. Libby, “Targeting Inflammation in Atherosclerosis—From Experimental Insights to the Clinic,” Nature Reviews Drug Discovery, vol. 20, no. 8, pp. 589–610, 2021, doi: 10.1038/s41573-021-00198-1.
S. Taleb, “Tryptophan Dietary Impacts Gut Barrier and Metabolic Diseases,” Frontiers in Immunology, vol. 10, p. 2113, 2019, doi: 10.3389/fimmu.2019.02113.
N. J. Melhem and S. Taleb, “Tryptophan: From Diet to Cardiovascular Diseases,” International Journal of Molecular Sciences, vol. 22, no. 18, p. 9904, 2021, doi: 10.3390/ijms22189904.
X. Zhao, C. Gao, H. Chen, X. Chen, T. Liu, and D. Gu, “C-Reactive Protein: An Important Inflammatory Marker of Coronary Atherosclerotic Disease,” Angiology, 2024, p. 00033197241273360, doi: 10.1177/00033197241273360.
X. Min, M. Lu, S. Tu, X. Wang, C. Zhou, S. Wang, et al., “Serum Cytokine Profile in Relation to the Severity of Coronary Artery Disease,” BioMed Research International, vol. 2017, p. 4013685, 2017, doi: 10.1155/2017/4013685.
H. A.-M. Al-Hindi, M. J. Mousa, T. A. J. Al-Kashwan, A. Sudan, and S. A. Abdul-Razzaq, “On Admission Levels of High-Sensitive C-Reactive Protein as a Biomarker in Acute Myocardial Infarction: A Case-Control Study,” Indian Journal of Public Health, vol. 10, no. 4, p. 1481, 2019.
E. A. Polyakova and E. N. Mikhaylov, “The Prognostic Role of High-Sensitivity C-Reactive Protein in Patients with Acute Myocardial Infarction,” Journal of Geriatric Cardiology, vol. 17, no. 7, pp. 379–380, 2020, doi: 10.11909/j.issn.1671-5411.2020.07.008.
M. A. Narayanan and S. Garcia, “Role of High-Sensitivity Cardiac Troponin in Acute Coronary Syndrome,” US Cardiology Review, vol. 13, no. 1, pp. 5–10, 2019, doi: 10.15420/usc.2019.3.2.
A. J. Kinsara, Z. A. Taher, A. Altalhi, M. Mahdi, A. Aldainy, A. Alqubbany, et al., “Clinical Indications for Requesting High-Sensitivity Troponin I in the Emergency Department,” International Journal of the Cardiovascular Academy, 2020, doi: 10.1016/j.ijcac.2020.04.002.
K. Thygesen, J. Mair, H. Katus, M. Plebani, P. Venge, P. Collinson, et al., “Recommendations for the Use of Cardiac Troponin Measurement in Acute Cardiac Care,” European Heart Journal, vol. 31, no. 18, pp. 2197–2204, 2010, doi: 10.1093/eurheartj/ehq251.
K. M. Eggers and B. Lindahl, “Application of Cardiac Troponin in Cardiovascular Diseases Other than Acute Coronary Syndrome,” Clinical Chemistry, vol. 63, no. 1, pp. 223–235, 2017, doi: 10.1373/clinchem.2016.255174.
P. E. Hickman, J. M. Potter, C. Aroney, G. Koerbin, E. Southcott, A. H. Wu, et al., “Cardiac Troponin May Be Released by Ischemia Alone, Without Necrosis,” Clinica Chimica Acta, vol. 411, no. 5–6, pp. 318–323, 2010, doi: 10.1016/j.cca.2009.12.009.
J. Frostegård, “Immunity, Atherosclerosis and Cardiovascular Disease,” BMC Medicine, vol. 11, p. 117, 2013, doi: 10.1186/1741-7015-11-117.
H. Mangge, I. Stelzer, E. Z. Reininghaus, D. Weghuber, T. T. Postolache, and D. Fuchs, “Disturbed Tryptophan Metabolism in Cardiovascular Disease,” Current Medicinal Chemistry, vol. 21, no. 17, pp. 1931–1937, 2014, doi: 10.2174/0929867321666131227163352.
S. Lautrup, Y. Hou, E. F. Fang, and V. A. Bohr, “Roles of NAD+ in Health and Aging,” Cold Spring Harbor Perspectives in Medicine, vol. 14, no. 1, p. a041193, 2024, doi: 10.1101/cshperspect.a041193.
R. Gao, M. Liu, H. Yang, Y. Shen, and N. Xia, “Epigenetic Regulation in Coronary Artery Disease: From Mechanisms to Emerging Therapies,” Frontiers in Molecular Biosciences, vol. 12, p. 1548355, 2025, doi: 10.3389/fmolb.2025.1548355.
L. Liaudet, Z. Yang, E.-B. Al-Affar, and C. Szabó, “Myocardial Ischemic Preconditioning in Rodents Is Dependent on Poly (ADP-Ribose) Synthetase,” Molecular Medicine, vol. 7, no. 6, pp. 406–417, 2001, doi: 10.1007/BF03401961.
R. Aarhus, R. M. Graeff, D. M. Dickey, T. F. Walseth, and C. L. Hon, “ADP-Ribosyl Cyclase and CD38 Catalyze the Synthesis of a Calcium-Mobilizing Metabolite from NADP+,” Journal of Biological Chemistry, vol. 270, no. 51, pp. 30327–30333, 1995, doi: 10.1074/jbc.270.51.30327.
E. Katsyuba, M. Romani, D. Hofer, and J. Auwerx, “NAD+ Homeostasis in Health and Disease,” Nature Metabolism, vol. 2, no. 1, pp. 9–31, 2020, doi: 10.1038/s42255-019-0161-5.
K. M. Ralto, R. P. Rhee, and S. M. Parikh, “NAD+ Homeostasis in Renal Health and Disease,” Nature Reviews Nephrology, vol. 16, no. 2, pp. 99–111, 2020, doi: 10.1038/s41581-019-0206-7.
M. O. Grootaert and M. R. Bennett, “Sirtuins in Atherosclerosis: Guardians of Healthspan and Therapeutic Targets,” Nature Reviews Cardiology, vol. 19, no. 10, pp. 668–683, 2022, doi: 10.1038/s41569-022-00773-9.
F. Biscetti, M. M. Rando, M. A. Nicolazzi, E. Rossini, M. Santoro, F. Angelini, et al., “Evaluation of Sirtuin 1 as a Predictor of Cardiovascular Outcomes in Diabetic Patients with Limb-Threatening Ischemia,” Scientific Reports, vol. 14, no. 1, p. 26940, 2024, doi: 10.1038/s41598-024-61261-1.
R. R. Alcendor, S. Gao, P. Zhai, D. Zablocki, E. Holle, X. Yu, et al., “Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart,” Circulation Research, vol. 100, no. 10, pp. 1512–1521, 2007, doi: 10.1161/01.RES.0000267723.65696.4a.
J. Shan, S. Pang, H. Wanyan, W. Xie, X. Qin, and B. Yan, “Genetic Analysis of the SIRT1 Gene Promoter in Ventricular Septal Defects,” Biochemical and Biophysical Research Communications, vol. 425, no. 4, pp. 741–745, 2012, doi: 10.1016/j.bbrc.2012.07.134.
E. Nisoli, C. Tonello, A. Cardile, V. Cozzi, R. Bracale, L. Tedesco, et al., “Calorie Restriction Promotes Mitochondrial Biogenesis by Inducing the Expression of eNOS,” Science, vol. 310, no. 5746, pp. 314–317, 2005, doi: 10.1126/science.1117728.
D. Khayatan, S. M. Razavi, Z. N. Arab, M. Khanahmadi, S. Momtaz, A. E. Butler, et al., “Regulatory Effects of Statins on SIRT1 and Other Sirtuins in Cardiovascular Diseases,” Life, vol. 12, no. 5, p. 760, 2022, doi: 10.3390/life12050760.