Lack of available resources needed to conduct study.

Atherosclerosis and diabetes are related to coronary artery disease and peripheral artery disease. The mechanisms are related to increased reactive oxygen species (ROS) formation and inflammatory cytokine secretion. However, simply using antioxidant or anti-inflammatory therapies has no optimal outcomes. On the other hand, N-acetylcysteine (NAC) which has both antioxidant and anti-inflammatory effects could effectively attenuate ROS production and reduce vascular inflammation. Hence, we will investigate the effect of NAC treatment on the outcomes in patients with advanced atherosclerotic heart diseases and patients with diabetes combined with significant peripheral artery disease.

Atherosclerosis is a chronic inflammatory disease and remains one of the major causes of death globally, despite aggressive risk stratifications including smoking cessation, optimal control of lipid, blood pressure, and diabetes. Antioxidant therapies with vitamin E and C or β-carotene failed to achieve significant clinical benefits in patients with cardiovascular diseases (CVD) including atherosclerosis. New therapies including interleukin-1β monoclonal antibody canakinumab and anti-inflammatory drug colchicine could significantly reduce the rate of major adverse cardiovascular events (MACE) including nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. However, canakinumab therapy did not decrease all-cause mortality, and was associated with a significant increase in the incidence of fatal infection (including sepsis), and high cost. While colchicine is a generic drug and decreases the rate of MACE, colchicine therapy is associated with a significant increase in death from non-cardiovascular causes5. Thus, alternative options are needed to attenuate atherosclerosis. N-acetylcysteine (NAC) has been traditionally considered an antioxidant although it is more like an anti-inflammatory agent, and could effectively attenuate reactive oxygen species (ROS) production, and reduce vascular inflammation. NAC significantly decreases the progression of atherosclerosis in young apolipoprotein E-deficient mice and low-density lipoprotein receptor deficient (LDLR-/-) mice with an atherogenic high fat diet (HFD). NAC treatment delays cellular senescence in endothelial cells from atherosclerotic patients, and improves coronary and peripheral endothelium-dependent vasodilation in human subjects with or without atherosclerosis. NAC treatment also inhibits oxidized LDL-induced foam cell formation and suppresses matrix-degrading capacity of foam cells. However, it is unclear if NAC could attenuate the progression of atherosclerosis or reverse the course of atherosclerosis in aging mice. Diabetes mellitus (DM) significantly increases the risk of developing severe peripheral artery disease (PAD) with critical limb ischemia (CLI) and chronic ulcers. Due to poor healing, patients with diabetic CLI may need limb amputation that accounts for about 60% of all non-traumatic amputations in the U. S. After a two decade reduction in diabetes-related non-traumatic lower-extremity amputation, recent data show an increase in amputation, particularly in young and middle-aged adults. In addition, major randomized clinical trials have shown that blood glucose-lowering or anti-hypertensive therapies have very limited effects on reducing macrovascular complications, and no benefit on amputation rates in diabetic patients. These highlight an urgent need for alterative effective approaches to promoting the recovery of diabetic ischemic limb to reduce lower-extremity amputation in DM. It is known that reactive oxygen species (ROS) production and oxidative stress are significantly increased in DM, and excessive oxidative stress is closely involved in the development of diabetic complications, including cardiovascular diseases, nephropathy, and retinopathy. Although low levels of ROS function as signaling molecules to mediate various biological responses such as gene expression, cell proliferation, migration, angiogenesis, apoptosis, and senescence in endothelial cells (ECs), high levels of ROS could contribute to a variety of pathologic conditions, including reduced nitric oxide (NO) bioavailability, impairment of vascular function and other endothelial phenotypic abnormalities. The metabolic abnormalities in DM could cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. Increased glucose levels could stimulate ROS production, leading to further glucose uptake and triggering cell toxicity and death. In addition, increased formation of advanced glycation end-products (AGEs) could enhance the activity of ROS-generating enzymes including NADPH oxidase, exacerbating oxidative stress and mitochondrial superoxide production. Thus, the objectives of the proposed study are: 1) to investigate the effect of NAC treatment on the outcomes in patients with advanced atherosclerotic heart diseases and not a candidate for revascularization; and 2) to investigate the effect of NAC treatment on the outcomes in diabetic patients with significant peripheral artery disease.

Inclusion Criteria:

• 1) significant coronary artery disease (CAD) and not a candidate for revascularization (CABG or PCI), or 2) significant peripheral artery disease (PAD) with or without critical limb ischemia (CLI) or chronic ulcers.

Exclusion Criteria:

• 1) Pregnant or nursing (lactating) women, confirmed by a positive hCG laboratory test 2). Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are a. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone or partial or total hysterectomy, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

  3). Planned coronary revascularization (PCI or CABG) or any other major surgical procedure.

  4). Major non-cardiac surgical or major endoscopic procedure within the past 6 months prior to the initial visit (Visit 1) 5). Multi-vessel CABG surgery within the past 3 years 6). Symptomatic patients with Class IV heart failure (HF) (New York Heart Association).

  7). Uncontrolled hypertension (defined as an average SBP >180 mmHg or an average diastolic blood pressure (DBP) >110 mmHg at Visit 1. Patients are allowed to be re-evaluated, at the discretion of investigator for this criterion if anti-hypertensive therapy has been started or increased as a result of initial screening blood pressure above these limits.

  8). Uncontrolled diabetes with persistent fasting blood glucose level of 300 or A1C of 7.5 for 3 months or defined by the investigator 9). Kidney or other organ transplant (due to anti-immune therapy) at Visit 1 10). Prior malignancy other than basal cell skin carcinoma. 11). A history of alcohol and/or substance abuse that could interfere with the conduct of the trial.

  12). History of ongoing, chronic or recurrent infectious disease except hepatitis.

  13). History of hypersensitivity to NAC. 14). Patients who have received an investigational drug or device within 30 days (inclusive) of Visit 1, or who are expected to participate in any other investigational drug or device study during the conduct of this trial, except for patients who have an investigational drug eluting stent (DES), provided that they have completed the DES trial. FDA/country-specific drug regulatory authority approved DES devices are permitted.

  15). Any life threatening condition with life expectancy < 3 years, other than vascular disease that might prevent the patient from completing the study.

Due to the confidential information included in this study, all data won't be shared for now.

We will use double blind for this study. Neither the participants nor the researcher knows which treatment or intervention participants are receiving until the clinical trial is over.