N-acetyl-cysteine (NAC) & Cardiovascular Health

Cardiovascular Health — scientific infographic poster

NAC has been studied in cardiovascular medicine in two main ways. The older work paired it with nitroglycerin: a continuous nitroglycerin infusion loses much of its effect over 48 hours (nitrate tolerance), and in heart failure oral NAC partially reversed this in eight patients (Packer 1987); in 46 patients with unstable angina, NAC plus nitroglycerin was followed by fewer heart attacks than nitroglycerin alone (3 versus 10) but more symptomatic hypotension (7 versus 0) (Horowitz 1988). The newer work is the NACIAM trial (Pasupathy 2017, Circulation), in which high-dose intravenous NAC given with low-dose nitroglycerin to STEMI patients undergoing primary PCI was associated with an absolute 5.5% reduction in MRI-measured infarct size (median 11.0% versus 16.5%) and approximately doubled myocardial salvage; its authors called for a larger trial of clinical outcomes. Smaller studies have measured homocysteine, endothelial function, blood pressure and lipids, with mixed results, and two large trials, ACT and PRESERVE, found no benefit of NAC for preventing kidney injury after angiography. The best-documented hazard in this area is symptomatic hypotension when NAC is combined with nitroglycerin.

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Table of Contents

  1. Cardiovascular Mechanism: Thiols, Nitric Oxide, and Homocysteine
  2. Homocysteine Lowering
  3. Hypertension and Endothelial Function
  4. Atherosclerosis and Oxidized LDL
  5. Acute Myocardial Infarction — the NACIAM Trial
  6. Heart Failure
  7. Nitrate Tolerance
  8. Type 2 Diabetes and Metabolic Syndrome
  9. Blood Lipids and Lipoprotein(a)
  10. Peripheral Artery Disease
  11. Doses Used in the Studies
  12. Safety and the Nitroglycerin Interaction
  13. Key Research Papers
  14. Connections
  15. Featured Videos

Cardiovascular Mechanism: Thiols, Nitric Oxide, and Homocysteine

Reactive oxygen species and inflammation are considered important in the development of atherosclerosis (Zhu 2022), and oxidized LDL, rather than native LDL, is regarded as the atherogenic form (Cui 2015). Nitric oxide is thought to lose its beneficial effects on blood vessels in the presence of oxygen radicals, which is the rationale researchers have given for testing antioxidants such as NAC in people with diabetes and high blood pressure (Martina 2008).

The mechanisms proposed for NAC in the cardiovascular studies are:

Homocysteine Lowering

Elevated total plasma homocysteine is considered an independent cardiovascular risk factor, although lowering it with B vitamins has improved only certain clinical endpoints (Hildebrandt 2015). The NAC studies measured homocysteine levels; none measured heart attacks or strokes.

Hypertension and Endothelial Function

The blood pressure data come from small trials, two of which combined NAC with another active treatment.

Atherosclerosis and Oxidized LDL

No trial measuring atherosclerosis progression in people taking NAC was among the papers checked for this page.

Acute Myocardial Infarction — the NACIAM Trial

NACIAM (Pasupathy 2017, Circulation)

A randomized, double-blind, placebo-controlled, multicenter trial in 112 STEMI patients undergoing primary PCI. Intravenous high-dose NAC (29 g over 2 days) plus background low-dose nitroglycerin (7.2 mg over 2 days) was compared with placebo plus the same nitroglycerin. Of the 112 patients, 75 had the early cardiac MRI used for the primary endpoint.

Other Acute MI and Reperfusion Data

Cardiac Surgery and Postoperative Atrial Fibrillation

The meta-analyses of NAC around heart surgery disagree on atrial fibrillation:

Heart Failure

Nitrate Tolerance

Continuous nitroglycerin infusion loses much of its effect over 48 hours, a phenomenon called nitrate tolerance. Depletion of sulfhydryl groups is one proposed cause, which led researchers to test the sulfhydryl donor NAC.

Type 2 Diabetes and Metabolic Syndrome

The results on blood sugar are mixed and come from small, short studies.

In these studies, NAC alone did not change glucose tolerance in two weeks of use, while the platelet and endothelial findings come from small trials of laboratory markers.

Blood Lipids and Lipoprotein(a)

Peripheral Artery Disease

The evidence is limited to vascular-function measurements:

No trial of NAC in people with peripheral artery disease was among the papers checked for this page.

Doses Used in the Studies

The doses below are those reported by the studies cited on this page, not dosing guidance.

Oral

Intravenous (hospital studies)

In a study of six healthy volunteers, the oral bioavailability of NAC was 4.0% for reduced NAC and 9.1% for total NAC (Olsson 1988).

Safety and the Nitroglycerin Interaction

The Nitroglycerin Interaction

NAC potentiates the vasodilator effects of nitroglycerin. In the Horowitz 1988 unstable-angina trial, symptomatic hypotension occurred in 7 of 24 patients given intravenous NAC with intravenous nitroglycerin versus none of 22 given nitroglycerin alone. In the Ardissino 1997 trial, side effects, mainly intolerable headache, occurred in 35% of patients on transdermal nitroglycerin plus oral NAC, almost twice the rate with nitroglycerin alone. These findings matter most for people who use nitrates; decisions about medicines and supplements belong with a clinician.

Other Safety Findings

Key Research Papers

  1. Hildebrandt W, Sauer R, Bonaterra G, Dugi KA, Edler L, Kinscherf R. Oral N-acetylcysteine reduces plasma homocysteine concentrations regardless of lipid or smoking status. Am J Clin Nutr 2015;102(5):1014–1024. PubMed PMID: 26447155
  2. Wiklund O, Fager G, Andersson A, Lundstam U, Masson P, Hultberg B. N-acetylcysteine treatment lowers plasma homocysteine but not serum lipoprotein(a) levels. Atherosclerosis 1996;119(1):99–106. PubMed PMID: 8929261
  3. Friedman AN, Bostom AG, Laliberty P, Selhub J, Shemin D. The effect of N-acetylcysteine on plasma total homocysteine levels in hemodialysis: a randomized, controlled study. Am J Kidney Dis 2003;41(2):442–446. PubMed PMID: 12552508
  4. Ventura P, Panini R, Pasini MC, Scarpetta G, Salvioli G. N-Acetyl-cysteine reduces homocysteine plasma levels after single intravenous administration by increasing thiols urinary excretion. Pharmacol Res 1999;40(4):345–350. PubMed PMID: 10527647
  5. Martina V, Masha A, Gigliardi VR, Brocato L, Manzato E, Berchio A, et al. Long-term N-acetylcysteine and L-arginine administration reduces endothelial activation and systolic blood pressure in hypertensive patients with type 2 diabetes. Diabetes Care 2008;31(5):940–944. PubMed PMID: 18268065
  6. Andrews NP, Prasad A, Quyyumi AA. N-acetylcysteine improves coronary and peripheral vascular function. J Am Coll Cardiol 2001;37(1):117–123. PubMed PMID: 11153725
  7. Packer M, Lee WH, Kessler PD, Gottlieb SS, Medina N, Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Engl J Med 1987;317(13):799–804. PubMed PMID: 3114637
  8. Horowitz JD, Henry CA, Syrjanen ML, Louis WJ, Fish RD, Smith TW, et al. Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris. Circulation 1988;77(4):787–794. PubMed PMID: 3127076
  9. Ardissino D, Merlini PA, Savonitto S, Demicheli G, Zanini P, Bertocchi F, et al. Effect of transdermal nitroglycerin or N-acetylcysteine, or both, in the long-term treatment of unstable angina pectoris. J Am Coll Cardiol 1997;29(5):941–947. PubMed PMID: 9120179
  10. Pasupathy S, Tavella R, Grover S, Raman B, Procter NEK, Du YT, et al. Early use of N-acetylcysteine with nitrate therapy in patients undergoing primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction reduces myocardial infarct size (the NACIAM trial [N-acetylcysteine in Acute Myocardial Infarction]). Circulation 2017;136(10):894–903. PubMed PMID: 28634219
  11. Arstall MA, Yang J, Stafford I, Betts WH, Horowitz JD. N-acetylcysteine in combination with nitroglycerin and streptokinase for the treatment of evolving acute myocardial infarction. Safety and biochemical effects. Circulation 1995;92(10):2855–2862. PubMed PMID: 7586252
  12. Koramaz I, Pulathan Z, Usta S, Karahan SC, Alver A, Yaris E, et al. Cardioprotective effect of cold-blood cardioplegia enriched with N-acetylcysteine during coronary artery bypass grafting. Ann Thorac Surg 2006;81(2):613–618. PubMed PMID: 16427861
  13. Wang G, Bainbridge D, Martin J, Cheng D. N-acetylcysteine in cardiac surgery: do the benefits outweigh the risks? A meta-analytic reappraisal. J Cardiothorac Vasc Anesth 2011;25(2):268–275. PubMed PMID: 20638862
  14. Yazdi A, Khansari N, Mehrpooya M, Mohammadi Y, Zareie S. Oral N-acetylcysteine as an adjunct to standard medical therapy improved heart function in cases with stable class II and III systolic heart failure. Ir J Med Sci 2022;191(5):2063–2075. PubMed PMID: 34727343
  15. Giam B, Chu PY, Kuruppu S, Smith AI, Horlock D, Kiriazis H, et al. N-acetylcysteine attenuates the development of cardiac fibrosis and remodeling in a mouse model of heart failure. Physiol Rep 2016;4(7):e12757. PubMed PMID: 27081162
  16. Cui Y, Narasimhulu CA, Liu L, Zhang Q, Liu PZ, Li X, et al. N-acetylcysteine inhibits in vivo oxidation of native low-density lipoprotein. Sci Rep 2015;5:16339. PubMed PMID: 26536834
  17. Franceschini G, Werba JP, Safa O, Gikalov I, Sirtori CR. Dose-related increase of HDL-cholesterol levels after N-acetylcysteine in man. Pharmacol Res 1993;28(3):213–218. PubMed PMID: 8108311
  18. Szkudlinska MA, von Frankenberg AD, Utzschneider KM. The antioxidant N-Acetylcysteine does not improve glucose tolerance or β-cell function in type 2 diabetes. J Diabetes Complications 2016;30(4):618–622. PubMed PMID: 26922582
  19. Treweeke AT, Winterburn TJ, Mackenzie I, Barrett F, Barr C, Rushworth GF, et al. N-Acetylcysteine inhibits platelet-monocyte conjugation in patients with type 2 diabetes with depleted intraplatelet glutathione: a randomised controlled trial. Diabetologia 2012;55(11):2920–2928. PubMed PMID: 22935960
  20. Hosseini H, Naderi-Behdani F, Zarghami N, et al. NAC effects on metabolic syndrome: RCT. Complement Ther Med 2022;71:102898. — Editorial note: this reference could not be found in PubMed or Crossref (checked 2026-10-14); no statement on this page relies on it.
  21. Zhu Q, Xiao Y, Jiang M, Liu X, Cui Y, Hao H, et al. N-acetylcysteine attenuates atherosclerosis progression in aging LDL receptor deficient mice with preserved M2 macrophages and increased CD146. Atherosclerosis 2022;357:41–50. PubMed PMID: 36041358
  22. Wilmink HW, Stroes ES, Erkelens WD, et al. NAC prevents post-methionine endothelial dysfunction. Arterioscler Thromb Vasc Biol 1999;19(12):2862–2866. Search PubMed — Editorial note: this reference could not be found in PubMed or Crossref (checked 2026-10-14); no statement on this page relies on it.
  23. Pizzulli L, Hagendorff A, Zirbes M, Jung W, Lüderitz B. N-acetylcysteine attenuates nitroglycerin tolerance in patients with angina pectoris and normal left ventricular function. Am J Cardiol 1997;79(1):28–33. PubMed PMID: 9024731
  24. Barrios V, Calderón A, Navarro-Cid J, Lahera V, Ruilope LM. N-acetylcysteine potentiates the antihypertensive effect of ACE inhibitors in hypertensive patients. Blood Press 2002;11(4):235–239. PubMed PMID: 12361192
  25. Camuglia AC, Maeder MT, Starr J, Farrington C, Kaye DM. Impact of N-acetylcysteine on endothelial function, B-type natriuretic peptide and renal function in patients with the cardiorenal syndrome: a pilot cross over randomised controlled trial. Heart Lung Circ 2013;22(4):256–259. PubMed PMID: 23219310
  26. Sekhar RV. GlyNAC (glycine and N-acetylcysteine) supplementation improves impaired mitochondrial fuel oxidation and lowers insulin resistance in patients with type 2 diabetes: results of a pilot study. Antioxidants (Basel) 2022;11(1):154. PubMed PMID: 35052658
  27. Faghfouri AH, Zarezadeh M, Tavakoli-Rouzbehani OM, Radkhah N, Faghfuri E, Kord-Varkaneh H, et al. The effects of N-acetylcysteine on inflammatory and oxidative stress biomarkers: a systematic review and meta-analysis of controlled clinical trials. Eur J Pharmacol 2020;884:173368. PubMed PMID: 32726657
  28. Gu WJ, Wu ZJ, Wang PF, Aung LH, Yin RX. N-Acetylcysteine supplementation for the prevention of atrial fibrillation after cardiac surgery: a meta-analysis of eight randomized controlled trials. BMC Cardiovasc Disord 2012;12:10. PubMed PMID: 22364379
  29. Liu XH, Xu CY, Fan GH. Efficacy of N-acetylcysteine in preventing atrial fibrillation after cardiac surgery: a meta-analysis of published randomized controlled trials. BMC Cardiovasc Disord 2014;14:52. PubMed PMID: 24739515
  30. Hassan AA, Ismail NR, Rezk AE, Elfeky HM, Mady AM, Allam AG, et al. Efficacy of N-acetylcysteine in reducing the risk of postoperative atrial fibrillation in cardiothoracic surgery: a systematic review and meta-analysis of randomized controlled trials. Minerva Cardiol Angiol 2025;73(3):387–396. PubMed PMID: 38842239
  31. Pereira JEG, El Dib R, Braz LG, Escudero J, Hayes J, Johnston BC. N-acetylcysteine use among patients undergoing cardiac surgery: a systematic review and meta-analysis of randomized trials. PLoS One 2019;14(5):e0213862. PubMed PMID: 31071081
  32. ACT Investigators. Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: main results from the randomized Acetylcysteine for Contrast-induced nephropathy Trial (ACT). Circulation 2011;124(11):1250–1259. PubMed PMID: 21859972
  33. Weisbord SD, Gallagher M, Jneid H, Garcia S, Cass A, Thwin SS, et al. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med 2018;378(7):603–614. PubMed PMID: 29130810
  34. Bateman DN, Dear JW, Thanacoody HK, Thomas SH, Eddleston M, Sandilands EA, et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial. Lancet 2014;383(9918):697–704. PubMed PMID: 24290406
  35. Olsson B, Johansson M, Gabrielsson J, Bolme P. Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine. Eur J Clin Pharmacol 1988;34(1):77–82. PubMed PMID: 3360052

PubMed Topic Searches

Selected PubMed topic searches relevant to N-acetylcysteine in cardiovascular medicine, including nitrate tolerance, homocysteine, and endothelial function.

  1. PubMed: NAC and nitrate tolerance
  2. PubMed: NAC and homocysteine reduction
  3. PubMed: NAC and endothelial function
  4. PubMed: NAC in STEMI (NACIAM trial)
  5. PubMed: NAC and cardiac ischemia-reperfusion
  6. PubMed: NAC and atrial fibrillation prevention
  7. PubMed: NAC in heart failure
  8. PubMed: NAC and contrast nephropathy
  9. PubMed: NAC and platelet aggregation
  10. PubMed: Glutathione and cardiovascular disease
  11. PubMed: Homocysteine and cardiovascular risk
  12. PubMed: Nitric oxide and vascular function

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Connections

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