Risk Factors for Coronary Artery Disease

Earn CME/CE in your profession:

Free Review Questions

Continuing Education Activity

Coronary artery disease (CAD) is the most common cause of mortality among adults in the United States. While common, it is preventable. CAD and its risk factors can be screened, identified, and treated early. Education and counseling can also help mitigate risk. This activity will review and update the current recommendations by utilizing the most recent systematic reviews and highlight the interprofessional team's role in managing patients with risk factors for CAD.

Objectives:

  • Identify the risk factors for coronary artery disease.

  • Assess screening recommendations for coronary artery disease.

  • Identify diet and exercise recommendations for coronary artery disease.

  • Communicate the importance of an interprofessional team-based approach to improve coronary artery disease outcomes.

Introduction

Coronary artery disease (CAD) accounts for approximately 610,000 deaths annually (estimated 1 in 4 deaths) and is the leading cause of mortality in the United States.[1] It is the third leading cause of mortality worldwide and is associated with 17.8 million deaths annually.[2][3][4][5] In the United States, healthcare services for CAD are estimated to cost more than 200 billion dollars annually.[6] While CAD is a significant cause of death and disability, it is preventable. 

The Framingham Heart Study enrolled its first participant in 1948 and is currently studying its third generation of participants.[7][8] This was the first study that elucidated risk factors associated with cardiovascular disease. Since then, cohort studies have continued to study the impact of different risk factors on cardiovascular disease. The FINRISK study is an ongoing Finnish population-based observational study that began in 1972.[9] The ULSAM, PIVUS, POEM, EpiHealth, and SCAPIS were cohort studies completed at Uppsala University in Sweden. The PREDICT Cardiovascular Disease Cohort study was another study completed in New Zealand.[10] These studies classify CAD into 2 broad categories: non-modifiable and modifiable risk factors. Non-modifiable risk factors include age, gender, ethnicity, and family history of CAD. Modifiable risk factors include hypertension, hyperlipidemia, diabetes, obesity, smoking, poor diet, sedentary lifestyle, and stress.[7][11]

Given the immense healthcare burden of CAD, modifiable and non-modifiable risk factors were identified to mitigate the resulting economic and disease-related burden. Risk factor identification, combined with advances in medical technology, has significantly decreased CAD mortality rates over the past forty years in Western countries. One public health study that gathered mortality data from 1969 to 2014 concluded that by 2020, the number of heart disease-related deaths would decrease by 21.3 percent for men and 13.4 percent for women.[12] This topic reviews the impact and management of these risk factors. Ever since the Framingham Heart Study, there has been a plethora of data on CAD risk factors. This topic concisely summarizes the most recent systemic reviews and evidence.

Issues of Concern

Risk factors for CAD are classified into modifiable and non-modifiable risk factors. 

A 2019 article indicated that age, sex, and race captured 63% to 80% of predictive performance, while modifiable risk factors contributed only modestly. Yet, controlling modifiable risk factors led to substantial reductions in CAD events.[11] Non-modifiable risk factors are discussed first:  

  • Age: CAD prevalence increases after 35 years of age in both men and women. The lifetime risk of developing CAD in men and women after 40 years of age is 49% and 32%, respectively.[13]
  • Gender: Men are at increased risk compared to women.
  • Ethnicity: Blacks, Hispanics, Latinos, and Southeast Asians are ethnic groups with an increased risk of CAD morbidity and mortality.[14][15][16]
  • Family history: Family history is also a significant risk factor. Patients with a family history of premature cardiac disease younger than 50 years of age have an increased CAD mortality risk.[17] A separate article indicated that a father or brother diagnosed with CAD before 55 years of age and a mother or sister diagnosed before 65 years of age are considered risk factors.[7]

Modifiable risk factors have a smaller but still significant role.[11] Yet, only two-thirds of patients receive optimal medication interventions.[18] If this were achieved, there would be a substantial reduction in CAD events.[11] One study observed that those with optimal risk factor profiles had a substantially lower rate of death from cardiovascular events.[19]

  • Hypertension: 
    • About 1 out of every 3 patients have hypertension. Hypertension and smoking were responsible for the largest number of deaths in a 2009 review comparing twelve modifiable risk factors.[20] Yet, only 54% of these patients achieve adequate blood pressure control.[21]
    • Hypertension has long been a major risk factor for heart disease through both oxidative and mechanical stress it places on the arterial wall.[22][23]
    • A 1996 article reported that in the Framingham cohort, a systolic of 20 mmHg and diastolic of 10 mmHg increase was observed from age 30 to 65 years.[24]
  • Hyperlipidemia:
    • Hyperlipidemia is considered the second most common risk factor for ischemic heart disease.[18]
    • According to the World Health Organization, raised cholesterol caused an estimated 2.6 million deaths.[18]   
    • A recent cross-sectional study utilizing the coronary calcium score indicated a 55%, 41%, and 20% higher prevalence of hypercholesterolemia, combined hyperlipidemia, and low HDL-c, respectively.[25]
    • Elevated triglycerides have also been implicated in CAD; however, the relationship is more complicated as the association becomes attenuated when adjusted for other risk factors such as central adiposity, insulin resistance, and poor diet. Thus, it is challenging to determine an isolated effect of triglycerides on CAD.[26]
  • Diabetes mellitus:  
    • The Centers for Disease Control (CDC) reports that more than 1 out of every 3 adult patients in the United States have prediabetes, which puts one at risk of developing type 2 diabetes, heart disease, and stroke. 
    • The heart disease rate is 2.5 times higher in men and 2.4 times higher in women in adult patients with diabetes compared to those without diabetes.[18]
    • A 2017 meta-analysis indicated that patients with diabetes with an A1C > 7.0 had an 85% higher likelihood (hazard ratio 1.85, 95% CI 1.14-2.55) of cardiovascular mortality compared to those with an A1C < 7.0%. It also revealed that non-diabetic patients with an A1C > 6.0% had a 50% higher likelihood (hazard ratio, 1.50, 95% CI 1.01-2.21) of cardiovascular mortality compared to those with an A1C of < 5.0%. Researchers also reported significant study heterogeneity.[27]  
    • Cardiovascular disease is the leading cause of morbidity and mortality in patients with diabetes.[28]
  • Obesity:   
    • 69% of adults in the United States are overweight or obese. 35% of adults are obese.[18]
    • Obesity is an independent risk factor for CAD and also increases the risk of developing other CAD risk factors, including hypertension, hyperlipidemia, and diabetes mellitus.[29][30][31] 
    • One recent study indicated that obese patients were twice as likely to have coronary heart disease (hazard ratio 2.00, 95% CI 1.67-2.40) after adjustment for demographics, smoking, physical activity, and alcohol intake.[32]
    • A 1998 research study and 2016 review article conferred that obesity is associated with more complex, raised, and hi-grade atherosclerotic coronary artery lesions.[33][34]
    • The "obesity paradox" has also been reported. Despite evidence pointing to obesity as an independent risk factor for cardiovascular morbidity, some authors have described better outcomes in overweight and obese patients. There is an ongoing debate in light of this conflicting data.[35]
  • Smoking:
    • The Food & Drug Administration (FDA) estimates that cardiovascular disease causes 800,000 deaths and 400,000 premature deaths per year. About one-fifth and one-third of these result from smoking, respectively. 
    • A 2015 meta-analysis revealed that smoking resulted in a 51% increased risk (21 studies, RR 1.51, 95% CI 1.41.1-62) of coronary heart disease in patients with diabetes.[36]
    • A separate 2015 meta-analysis revealed that smoking resulted in twice the risk of cardiovascular disease for current smokers and a 37% increase in risk with former smokers among patients > 60 years old.[37] 
    • Nonsmokers regularly exposed to second-hand smoke also have a 25% to 30% increased risk of coronary heart disease compared to those not exposed.[38]
  • Poor diet: 
    • The association between saturated fat and coronary heart disease has been a journey. Initially thought to be a significant causative factor in the development of coronary heart disease, more recent reviews have cast more doubt on this association, placing more of an emphasis on the re-emergence of refined sugars as the main risk factor.[39][40]
    • Research has more clearly shown that trans fat increases the risk of cardiovascular disease through adverse effects on lipids, endothelial function, insulin resistance, and inflammation.[41] Every 2% of calories consumed from trans fat was associated with a 23% higher CAD risk (RR 1.23, 95% CI 1.11-1.37).[18][42]  
    • A 2016 systemic review revealed that soft drinks and sweetened beverages were associated with a 22% higher risk of myocardial infarction.[43]
    • A 2014 prospective cohort study revealed a 30% and 175% higher chance of cardiovascular disease mortality in the groups who consumed 10% to 24.9% (adjusted hazard ratio 1.30, 95% CI 1.09-1.55) and 25% (adjusted hazard ratio 2.75, 95% CI 1.40-5.42) more calories from added sugar compared with those who consumed less than 10% calories from added sugar.[44] High fructose corn syrup, sucrose, and table sugar have also been reported to be significant in CAD.[45]
    • Recent studies and systematic review articles have focused on red and processed meat consumption. These articles have revealed a consistently higher risk of coronary heart disease and cardiovascular events, ranging from 15% to 29% higher risk with red meat and 23% to 42% higher risk with processed meat consumption. Most studies included approximately 50 to 100 grams per day of consumption.[46][47][48][49][50][51] Only 1 of these review articles revealed no significant association between red meat and coronary heart disease (4 studies, RR 1.00 per 100 gram serving per day, 95% CI 0.92-1.46, P=0.25).[46] One article indicated no significant association between processed meats and overall mortality, however, added that the combined intake of red and processed meats was associated with a 23% higher risk (HR 1.23, 95% ci 1.11-1.36) of overall mortality.[51]
  • Sedentary lifestyle: 
    • Exercise is a protective factor in preventing the development of CAD. A 2004 case-control study performed in 52 countries, representing all continents, and involving 15,152 cases and 14,820 controls revealed a population-attributable risk of 12.2% that physical inactivity has on myocardial infarction.[52]
    • Several observational studies have shown that individuals who self-select for exercise have lower morbidity and mortality. Mechanisms for this include enhanced endothelial nitrous oxide production, more effective reactive oxygen species deactivation, and improved vasculogenesis. 

In addition to these traditional cardiovascular risk factors, novel risk factors have also been subject to research. These include:

  • Non-alcoholic fatty liver disease (NAFLD):
    • NAFLD has links to cardiovascular disease. It is also the most common chronic liver disease in developed countries.[53]
    • A 2017 meta-analysis revealed a 77% higher risk (RR 1.77, 95% CI 1.26-2.48) of cardiovascular events and over double the risk (RR 2.26, 95% CI 1.04-4.92) for CAD in patients with NAFLD.[54]
    • A more recent prospective study revealed that patients with NAFLD had greater than double the risk of cardiovascular events. Patients with liver fibrosis had a 4-fold increase.[55]
  • Chronic kidney disease (CKD):
    • CKD has been reported as an independent risk factor for CAD. Pro-inflammatory mediators, oxidative stress, and decreased nitric oxide production leading to endothelial dysfunction have been reported as possible mechanisms. Silent myocardial infarctions occur more commonly, likely due to the higher incidence of diabetic and uremic neuropathy in patients with CKD.[56]
    • With a GFR of 15-59, CKD is a risk-enhancing factor in the American Heart Association Guideline for the Primary Prevention of Cardiovascular Disease.[57]
  • Systemic lupus erythematosus (SLE): 
    • The most common cause of mortality in SLE is cardiovascular disease. There is also a higher prevalence of atherosclerotic cardiovascular disease in these patients. The mechanism is likely a pro-inflammatory effect on coronary microcirculation.[58][59] 
    • Pericarditis is a common manifestation of SLE.[60] One case report stated that pericarditis is the most common cardiac manifestation of SLE.[61]
  • Rheumatoid arthritis (RA):
    • Estimates are that patients with RA have a 1.5 to 2.0-fold increased risk of CAD. Traditional risk factors such as body mass and lipoprotein levels also showed more unpredictable patterns in their predictive accuracy. The mechanism behind this associated risk is likely through a pro-inflammatory effect.[62]
    • Rheumatoid arthritis is also listed among the risk-enhancing factors in the American Heart Association Guideline for the Primary Prevention of Cardiovascular Disease.[57]
  • Inflammatory bowel disease (IBD):
    • A 2017 meta-analysis noted that IBD is associated with a higher risk of CAD. However, the results were interpreted with caution due to the heterogeneity of the studies. The risk mechanism was uncertain, but it was thought to be due to a chronic inflammatory state.[63]
  • Human immunodeficiency virus (HIV):
    • HIV is understood to come with a higher risk of cardiovascular disease and its associated sequelae.[64]   
    • A 2018 expert analysis from the American College of Cardiology noted that patients with HIV showed a 1.5 to 2-fold increased risk of CAD. The mechanism, again, was based on a pro-inflammatory state.
  • Thyroid disease:
    • The thyroid gland intricately links to cardiovascular function. Proposed mechanisms include the effect of thyroid hormone on dyslipidemia, cardiac function, atherosclerosis, vascular compliance, and cardiac arrhythmias; this area is still under study.[65] Guidelines also vary in their screening recommendations for thyroid disease, hypothyroidism, and subclinical hypothyroidism.[66][67]
  • Testosterone:
    • In 2014, the FDA released a required labeling change for low testosterone products for the use of low testosterone due to aging due to a possible increased risk of heart attack and stroke. Subsequent studies and reviews have not been consistent in this correlation. Some reviews have even indicated a potential beneficial cardiovascular effect when treating low testosterone with testosterone supplementation. Further study is needed to provide more clarity on this specific topic.[68][69][70][71][72]
  • Vitamin D
    • Vitamin D has been increasingly studied and debated over the past decade. Vitamin D deficiency is linked to an increased risk of CAD.[73][74][75][76] Further studies, however, have not confirmed a beneficial effect on Vitamin D supplementation. Further studies are needed to clarify whether vitamin D supplementation benefits CAD prevention.[77][78][79]

Socioeconomic Status

  • Socioeconomic status is a significant risk factor for cardiovascular disease. Upstream determinants include financial strain, lack of affordable and nutritious food, exposure to domestic violence, and inadequate housing; this is an important consideration to consider, given existing cardiovascular disease risk equations do not capture this.[41]  

Women and Coronary Artery Disease

  • Although men are at higher risk than women of CAD, it is still the leading cause of death among women. Among women, only 54% were aware of this in 2009. Cardiovascular disease caused approximately 1 in 3 female deaths.[80] Women were found to have non-obstructive CAD in 57% of cases, in contrast to men who more commonly had obstructive CAD. Proposed mechanisms for this include coronary microvascular dysfunction (CMD), altered endothelial tone, structural changes, and altered response to vasodilator stimuli.[81] Estrogen is thought to have a protective role in coronary vasoreactivity and is also theorized to promote plaque stabilization via an anti-inflammatory effect on atherosclerosis.[82] 
  • Lack of awareness and understanding of CAD in women has also led to a disparity in health outcomes. There has been more focus on obstructive CAD in men than in women.[80][83] One 2012 article reported a decrease in CAD mortality across all age groups in men and an increase in CAD mortality among young women (< 55 years old).[81]

Clinical Significance

CAD remains the number 1 cause of death in the United States. Given the prevalence of CAD and its risk factors, interprofessional, team-based care may result in significantly improved patient outcomes.[41] Clinicians should be aware of screening recommendations and the impact of risk factor mitigation on CAD outcomes. Nurses play a central role in routine screening and education. Clinical pharmacists play a pivotal role in the pharmacologic management of modifiable risk factors such as hypertension, hyperlipidemia, diabetes, and smoking cessation. Nutritionists contribute by providing dietary education. Community outreach by all team members can help mitigate the complex yet crucial role that socioeconomic status can have on CAD risk and outcomes. This section covers screening recommendations, the impact of risk factor mitigation on CAD outcomes, aspirin, and new CAD screening tests. 

Hypertension

  • The United States Preventive Services Task Force (USPSTF) gives a grade A recommendation for universal screening for hypertension in patients over 18 years of age and a grade I (current evidence insufficient) recommendation for screening for children and adolescents.[84][85]
  • A systolic and diastolic blood pressure reduction of greater than 10 mmHg and 5 mmHg led to a significant absolute risk reduction in CAD-related events (NNT 91).[86]
  • A systolic blood pressure reduction to a goal of 130 mmHg reduced the incidence of CAD (NNT 27).[11]
  • A 2002 meta-analysis revealed that systolic blood pressure reduction of 20 mmHg and diastolic blood pressure reduction of 10 mmHg decreases the risk of death from coronary heart disease by about 50% between ages 40 to 49 and about 1/3 between ages 80 to 89.[41][87][88]

Hyperlipidemia

  • The USPSTF recommends evaluation for statin use for the primary prevention of cardiovascular disease between 40 and 75 years of age.[89] The USPSTF gives a grade I (current evidence insufficient) recommendation for routine screening for lipid disorders in children and adolescents.[90]
  • In 2011, the National Heart, Lung, and Blood Institute (NHLBI) recommended universal screening between 9 and 11 years of age and again at 17 to 21 years of age. The American Academy of Pediatrics subsequently endorsed this. Despite the publication of these guidelines, pediatric lipid screening practice patterns have not followed suit.[91] 
  • An early 1994 review showed that a 10% reduction in serum cholesterol leads to a 50%, 40%, 30%, and 20% drop in CAD risk at ages 20, 50, 60, and 70, respectively.[92]
  • The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study demonstrated that statins reduce the risk of major cardiovascular events.[93] Treatment with a moderate-intensity statin resulted in a CAD absolute risk reduction of 2.7% (NNT 37). Treatment with a high-intensity statin resulted in a 4.1% absolute risk reduction (NNT 24).[11]

Diabetes

  • The USPSTF recommends screening for abnormal glucose in patients aged 40 to 70 years old who are overweight or obese. Early screening for diabetes can also be a consideration for patients in higher-risk groups. This risk pool includes patients with a family history of diabetes, a history of gestational diabetes or polycystic ovarian syndrome, or members of specified racial/ethnic groups (Blacks, American Indians, Alaskan natives, Asian Americans, Hispanics or Latinos, native Hawaiians, or Pacific Islanders).[94] 
  • The American Diabetes Association states that 3 years is a reasonable screening interval.
  • A 2019 meta-analysis of 12 cardiovascular outcomes trials indicated a 0.5% reduction in A1C conferred a 20% hazard risk reduction (95% CI 4-33%) for major cardiovascular events. This analysis included patients on peptidase-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors.[95]

Diet

  • The DASH, Mediterranean, and vegetarian diets have the most evidence for cardiovascular disease prevention.[96] 
  • The DASH diet can reduce systolic blood pressure up to 11.5 mmHg in adults with hypertension.[18][97] A 2013 meta-analysis and systematic review revealed a 21% CAD risk reduction (RR 0.79, 95% CI 0.71-0.88) with the DASH diet.[98]
  • A 2017 meta-analysis and systematic review revealed an 8% risk reduction (15 studies, RR 0.92, 95% CI 0.90-0.95) of CAD for every 200 grams of fruits and vegetables per day. This effect was observable at up to 800 grams per day.[99]
  • A 2016 meta-analysis and systematic review revealed a 29% risk reduction (29 studies, RR 0.71, 95% CI 0.63-0.80) of CAD for every 28 grams per day of nut consumption.[100]
  • A 2017 narrative review revealed a decreased risk of about 20% to 25% with the Mediterranean diet on cardiovascular disease. It also showed positive effects on endothelin function, arterial stiffness, and cardiac function.[101]
  • The American Heart Association recommends the replacement of saturated fat with polyunsaturated and monounsaturated fats.[102] A 5% exchange in saturated fat consumption with polyunsaturated fat is associated with a 10% lower CAD risk (RR 0.90, 95% CI 0.83-0.97).[18][103] As noted above, a 2018 review, however, challenged the strength of the traditional link between saturated fat and higher CAD risk compared to other nutrients.[39] In a separate review, there was a lack of a significant association between saturated fat and cardiovascular disease due to studies replacing saturated fat with highly refined carbohydrates. Coronary heart disease would be reduced if polyunsaturated fats replaced saturated fats.[40]
  • While it is challenging to research diet practices and CAD, much research has been done in the past.[39] The AHA/ACC guidelines recommend a diet consisting mostly of vegetables, fruits, legumes, nuts, whole grains, and fish. Dietary intake of processed meats, refined carbohydrates, and sweetened beverages should be reduced while avoiding trans fats altogether. Saturated fats should be replaced with polyunsaturated and monounsaturated fats.[102]
  • The USPSTF recommends offering or referring adults who are obese/overweight and have 1 additional cardiovascular risk factor intensive behavioral counseling to promote a healthful diet and physical activity (Grade B). The USPSTF also recommends individualizing the decision to offer or refer patients without obesity or other cardiovascular risk factors for behavioral counseling.

Smoking

  • The USPSTF recommends screening for tobacco use in all adults with each clinical encounter and provides behavioral and pharmacologic smoking cessation interventions.[104] The USPSTF also recommends educating children and adolescents about the risks of smoking to prevent the initiation of tobacco use.[105]
  • The American Heart Association recommends combining behavioral and pharmacologic approaches to maximize quit rates.[41]
  • The risk of CAD drops to a level of lifetime nonsmokers within 4 years of quitting, according to the FDA, and within 10 years, according to the CDC.[106][107]
  • Behavioral interventions include motivational interviewing (Ask, Advise, Assess, Assist, Arrange for follow-up). 
  • Pharmacologic interventions such as nicotine replacement therapy, varenicline, and bupropion reduce cravings and withdrawal symptoms. 
  • A 2014 Cochrane review revealed that nicotine replacement therapies, such as nicotine gum and the nicotine patch, increased the chances of smoking cessation by 49% (55 trials, RR 1.49, 95% CI 1.40-1.60) and 64% (43 trials, RR 1.64, 95% CI 1.52-1.78), respectively. The nicotine oral tablets/lozenges (6 trials, RR 1.95, 95% CI 1.61-2.36), inhaler (4 trials, RR 1.90, 95% CI 1.36-2.67), and nasal sprays (4 trials, RR 2.02, 95% CI 1.49-2.73) approximately doubled the chances of success. The combination of bupropion and nicotine replacement therapy increased the likelihood of success by 24% compared to bupropion alone (4 trials, RR 1.24, 95% CI 1.06-1.45).[108]
  • Varenicline doubled the chances of smoking cessation.[109] There have been rare reports of neuropsychiatric adverse effects with varenicline. The FDA removed this black box warning in 2016 after noting that the risk was lower than expected. 
  • A 2014 Cochrane review showed that bupropion increases the chances of smoking cessation by 62% (44 trials, N=13,728, RR 1.62, 95% CI 1.48-2.78).[102][110]
  • A 2016 Cochrane review indicated that combined behavioral support and pharmacotherapy had a higher chance of success.[111]

Obesity

  • A patient's body mass index (BMI) should be measured at each clinical encounter. The USPSTF recommends that practitioners offer obese adults a referral to a multicomponent behavioral interventionist.[112]
  • There is a large amount of evidence showing that in obese or overweight patients, even just a modest 5% body weight loss can lead to clinically significant health benefits.[113]

Exercise

  • The USPSTF recommends patients who are overweight, obese or have CAD risk factors to intensive behavioral counseling for interventions to promote physical activity for the prevention of CAD.[18][114][115]
  • According to the National Health Interview Survey, only 20.9% of adults met the 2008 federal physical activity guidelines for aerobic and strengthening activity.[18]
  • Approximately 150 minutes per week of moderate-intensity aerobic activity reduces the risk of cardiovascular disease (CAD).[116] Moderate-intensity aerobic exercise is defined as 50 to 70 percent of the patient's maximum heart rate (220 beats per minute minus the patient's age). Any amount of physical activity has been shown to have benefits in reducing CAD risk.[102][117] The most active patients have an approximately 35 to 40 percent risk reduction for CAD. 
  • The AHA/ACC guidelines also recommend incorporating resistance strength training into regular physical activity, as this can help improve physical function and ability to exercise.[102][118]

Aspirin in Primary Prevention

  • Aspirin has long played a role in atherosclerotic cardiovascular disease prevention. Although still established for secondary prevention, its use in primary prevention has recently become questioned due to a less favorable risk-benefit ratio.[57] Recent evidence suggested a more tailored approach to the use of aspirin.[119]
  • The USPSTF recommends aspirin for patients aged 50 to 59 years of age, with a 10-year atherosclerotic cardiovascular disease risk, and who do not have bleeding risk factors. Aspirin may be considered for those 60 to 69 but may have less overall benefit and higher bleeding risk.[120]

New CAD Screening Tests

Coronary Artery Calcium (CAC) Score

  • CAC is an established noninvasive screening test for CAD. It involves a non-contrast CT of the heart, which totals identified coronary artery calcium, a component of atherosclerosis. 
  • A large prospective cohort study found that CAC improved the detection of at-risk patients for coronary events to match statin therapy with appropriate patients better.[121]
  • The 2019 AHA/ACC primary prevention guideline recommends CAC for those who are at intermediate-risk (10-year >/=7.5% to <20%) or selected borderline risk (10-year ASCVD risk 5-<7.5%) patients. The CAC score can help patients who desire more information before starting pharmacotherapy. If the CAC score is zero, then the patient does not require a statin as long as the patient does not smoke, has diabetes mellitus, or has a family history of premature clinical ASCVD. If CAC is 1 to 99, a statin is favored in patients aged 55 and above. If the CAC is 100 or in the 75th percentile or higher, then statin treatment is favored.[57]
  • The 2017 SCCT (Society of Cardiovascular Computed Tomography) guideline recommends shared and CAC consideration for those who are 5% to 20% 10-year ASCVD risk or < 5% 10-year ASCVD risk who have another strong indication, such as those with a family history of premature CAD.[122]

Carotid Intimal Medial Thickness (CIMT)

  • CIMT is another proposed tool for non-invasive risk stratification for CAD. This assessment is accomplished predominantly by ultrasound but may also use MRI. There has been conflicting data from several large studies regarding this modality, most likely due to differences in non-standard image acquisition and analysis and study design.[123]
  • A 2012 meta-analysis combining CIMT and Framingham Risk Score (FRS) did not substantially improve risk prediction.[124]
  • The AHA/ACC changed its stance from a class IIa recommendation for its use in intermediate-risk patients in 2010 to recommend against its use in a 2013 update.[125][126]
  • More recently, a 2017 observational multi-ethnic study of atherosclerosis (MESA) found that combining CIMT and positive CAC improved cardiovascular risk prediction.[127]

Flow-Mediated Dilation (FMD) and Endothelin Function 

  • FMD is another proposed test that can potentially predict cardiovascular risk by measuring the health of blood vessel endothelial function. Physiologic and pharmacologic stress, such as hypertension, smoking, or certain medications, can alter this. 
  • There are different methods to measure FMD. Protocols involving vasoactive agents via coronary catheterization is a more direct measurement of the coronary artery endothelial function, specifically referred to as coronary flow reserve (CFR).[128]
  • Brachial artery flow-mediated dilation and reactive hyperemia-peripheral arterial tonometry (RH-PAT) are more peripheral measurements. A 2015 meta-analysis conferred that these 2 methods demonstrated similar prognostic value on cardiovascular outcomes. Additional research is necessary to determine whether this screening strategy can improve cardiovascular outcomes.[129]

Novel biomarkers

  • A 2017 article reviewed novel potential biomarkers for CAD, such as fibrinogen, hs-CRP, lipoprotein-associated PA2, lipoprotein A, hs-troponin, NT-proBNP, and cystatin C. None met all necessary criteria to be considered an ideal biomarker.[130]

Enhancing Healthcare Team Outcomes

CAD is the leading cause of death in the United States and many countries worldwide. Given the prevalence of CAD and its risk factors, interprofessional, team-based care may significantly improve patient outcomes. Clinicians, nurses, and pharmacists must remain abreast of current research and work together as an interprofessional team to encourage long-term treatment recommendations and regular exercise to obtain the best patient outcomes.

Nursing, Allied Health, and Interprofessional Team Interventions

The first portion of the encounter identifies the patient's age, gender, ethnicity, and past medical history. CAD risk factors can be detected within the first 5 minutes of the clinical encounter. Vital signs detect elevated blood pressure and excessive weight. Diet and physical activity can also be discussed. Early education on lifestyle modifications can improve outcomes and mitigate risk factors. Screening recommendations can also be provided. 

"The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army, Department of the Air Force, Department of Defense, or the U.S. government. This document was created free of branding or market affiliations. The author is operating solely as a contributor."

Details

Author

Jonathan C. Brown

Author

Thomas E. Gerhardt

Editor:

Edward Kwon

Updated:

1/23/2023 12:55:36 PM

Feedback:

Send Us Your Comments

References

[1]

Friede A, O'Carroll PW, Thralls RB, Reid JA. CDC WONDER on the Web. Proceedings : a conference of the American Medical Informatics Association. AMIA Fall Symposium. 1996:():408-12     [PubMed PMID: 8947698]

[2]

GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet (London, England). 2018 Nov 10:392(10159):1736-1788. doi: 10.1016/S0140-6736(18)32203-7. Epub 2018 Nov 8     [PubMed PMID: 30496103]

Level 1 (high-level) evidence

[3]

Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in Europe 2014: epidemiological update. European heart journal. 2014 Nov 7:35(42):2929. doi: 10.1093/eurheartj/ehu378. Epub     [PubMed PMID: 25381246]

Level 2 (mid-level) evidence

[4]

Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O'Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y, American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008 Jan 29:117(4):e25-146     [PubMed PMID: 18086926]

[5]

Lloyd-Jones D,Adams RJ,Brown TM,Carnethon M,Dai S,De Simone G,Ferguson TB,Ford E,Furie K,Gillespie C,Go A,Greenlund K,Haase N,Hailpern S,Ho PM,Howard V,Kissela B,Kittner S,Lackland D,Lisabeth L,Marelli A,McDermott MM,Meigs J,Mozaffarian D,Mussolino M,Nichol G,Roger VL,Rosamond W,Sacco R,Sorlie P,Stafford R,Thom T,Wasserthiel-Smoller S,Wong ND,Wylie-Rosett J, Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation. 2010 Feb 23;     [PubMed PMID: 20177011]

[6]

Johnson NB, Hayes LD, Brown K, Hoo EC, Ethier KA, Centers for Disease Control and Prevention (CDC). CDC National Health Report: leading causes of morbidity and mortality and associated behavioral risk and protective factors--United States, 2005-2013. MMWR supplements. 2014 Oct 31:63(4):3-27     [PubMed PMID: 25356673]

[7]

Hajar R. Risk Factors for Coronary Artery Disease: Historical Perspectives. Heart views : the official journal of the Gulf Heart Association. 2017 Jul-Sep:18(3):109-114. doi: 10.4103/HEARTVIEWS.HEARTVIEWS_106_17. Epub     [PubMed PMID: 29184622]

Level 3 (low-level) evidence

[8]

Mahmood SS, Levy D, Vasan RS, Wang TJ. The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet (London, England). 2014 Mar 15:383(9921):999-1008. doi: 10.1016/S0140-6736(13)61752-3. Epub 2013 Sep 29     [PubMed PMID: 24084292]

Level 3 (low-level) evidence

[9]

Jousilahti P,Laatikainen T,Peltonen M,Borodulin K,Männistö S,Jula A,Salomaa V,Harald K,Puska P,Vartiainen E, Primary prevention and risk factor reduction in coronary heart disease mortality among working aged men and women in eastern Finland over 40 years: population based observational study. BMJ (Clinical research ed.). 2016 Mar 1;     [PubMed PMID: 26932978]

Level 2 (mid-level) evidence

[10]

Lind L. Population-based cardiovascular cohort studies in Uppsala. Upsala journal of medical sciences. 2019 Jan:124(1):16-20. doi: 10.1080/03009734.2018.1515282. Epub 2018 Oct 3     [PubMed PMID: 30278808]

[11]

Pencina MJ, Navar AM, Wojdyla D, Sanchez RJ, Khan I, Elassal J, D'Agostino RB Sr, Peterson ED, Sniderman AD. Quantifying Importance of Major Risk Factors for Coronary Heart Disease. Circulation. 2019 Mar 26:139(13):1603-1611. doi: 10.1161/CIRCULATIONAHA.117.031855. Epub     [PubMed PMID: 30586759]

[12]

Weir HK, Anderson RN, Coleman King SM, Soman A, Thompson TD, Hong Y, Moller B, Leadbetter S. Heart Disease and Cancer Deaths - Trends and Projections in the United States, 1969-2020. Preventing chronic disease. 2016 Nov 17:13():E157. doi: 10.5888/pcd13.160211. Epub 2016 Nov 17     [PubMed PMID: 27854420]

[13]

Sanchis-Gomar F,Perez-Quilis C,Leischik R,Lucia A, Epidemiology of coronary heart disease and acute coronary syndrome. Annals of translational medicine. 2016 Jul;     [PubMed PMID: 27500157]

[14]

Carnethon MR, Pu J, Howard G, Albert MA, Anderson CAM, Bertoni AG, Mujahid MS, Palaniappan L, Taylor HA Jr, Willis M, Yancy CW, American Heart Association Council on Epidemiology and Prevention; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Functional Genomics and Translational Biology; and Stroke Council. Cardiovascular Health in African Americans: A Scientific Statement From the American Heart Association. Circulation. 2017 Nov 21:136(21):e393-e423. doi: 10.1161/CIR.0000000000000534. Epub 2017 Oct 23     [PubMed PMID: 29061565]

[15]

Rodriguez CJ, Allison M, Daviglus ML, Isasi CR, Keller C, Leira EC, Palaniappan L, Piña IL, Ramirez SM, Rodriguez B, Sims M, American Heart Association Council on Epidemiology and Prevention, American Heart Association Council on Clinical Cardiology, American Heart Association Council on Cardiovascular and Stroke Nursing. Status of cardiovascular disease and stroke in Hispanics/Latinos in the United States: a science advisory from the American Heart Association. Circulation. 2014 Aug 12:130(7):593-625. doi: 10.1161/CIR.0000000000000071. Epub 2014 Jul 14     [PubMed PMID: 25098323]

[16]

Volgman AS, Palaniappan LS, Aggarwal NT, Gupta M, Khandelwal A, Krishnan AV, Lichtman JH, Mehta LS, Patel HN, Shah KS, Shah SH, Watson KE, American Heart Association Council on Epidemiology and Prevention; Cardiovascular Disease and Stroke in Women and Special Populations Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Quality of Care and Outcomes Research; and Stroke Council. Atherosclerotic Cardiovascular Disease in South Asians in the United States: Epidemiology, Risk Factors, and Treatments: A Scientific Statement From the American Heart Association. Circulation. 2018 Jul 3:138(1):e1-e34. doi: 10.1161/CIR.0000000000000580. Epub 2018 May 24     [PubMed PMID: 29794080]

[17]

Bachmann JM,Willis BL,Ayers CR,Khera A,Berry JD, Association between family history and coronary heart disease death across long-term follow-up in men: the Cooper Center Longitudinal Study. Circulation. 2012 Jun 26;     [PubMed PMID: 22623718]

[18]

Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB, American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 2015 Jan 27:131(4):e29-322. doi: 10.1161/CIR.0000000000000152. Epub 2014 Dec 17     [PubMed PMID: 25520374]

[19]

Berry JD, Dyer A, Cai X, Garside DB, Ning H, Thomas A, Greenland P, Van Horn L, Tracy RP, Lloyd-Jones DM. Lifetime risks of cardiovascular disease. The New England journal of medicine. 2012 Jan 26:366(4):321-9. doi: 10.1056/NEJMoa1012848. Epub     [PubMed PMID: 22276822]

[20]

Danaei G, Ding EL, Mozaffarian D, Taylor B, Rehm J, Murray CJ, Ezzati M. The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors. PLoS medicine. 2009 Apr 28:6(4):e1000058. doi: 10.1371/journal.pmed.1000058. Epub 2009 Apr 28     [PubMed PMID: 19399161]

Level 2 (mid-level) evidence

[21]

Merai R,Siegel C,Rakotz M,Basch P,Wright J,Wong B,Thorpe P, CDC Grand Rounds: A Public Health Approach to Detect and Control Hypertension. MMWR. Morbidity and mortality weekly report. 2016 Nov 18;     [PubMed PMID: 27855138]

[22]

Malakar AK, Choudhury D, Halder B, Paul P, Uddin A, Chakraborty S. A review on coronary artery disease, its risk factors, and therapeutics. Journal of cellular physiology. 2019 Aug:234(10):16812-16823. doi: 10.1002/jcp.28350. Epub 2019 Feb 20     [PubMed PMID: 30790284]

[23]

Alexander RW. Theodore Cooper Memorial Lecture. Hypertension and the pathogenesis of atherosclerosis. Oxidative stress and the mediation of arterial inflammatory response: a new perspective. Hypertension (Dallas, Tex. : 1979). 1995 Feb:25(2):155-61     [PubMed PMID: 7843763]

Level 3 (low-level) evidence

[24]

Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA. 1996 May 22-29:275(20):1571-6     [PubMed PMID: 8622248]

[25]

Abd Alamir M,Goyfman M,Chaus A,Dabbous F,Tamura L,Sandfort V,Brown A,Budoff M, The Correlation of Dyslipidemia with the Extent of Coronary Artery Disease in the Multiethnic Study of Atherosclerosis. Journal of lipids. 2018     [PubMed PMID: 29785308]

[26]

Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Jordan LC, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, O'Flaherty M, Pandey A, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Spartano NL, Stokes A, Tirschwell DL, Tsao CW, Turakhia MP, VanWagner LB, Wilkins JT, Wong SS, Virani SS, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation. 2019 Mar 5:139(10):e56-e528. doi: 10.1161/CIR.0000000000000659. Epub     [PubMed PMID: 30700139]

[27]

Cavero-Redondo I, Peleteiro B, Álvarez-Bueno C, Rodriguez-Artalejo F, Martínez-Vizcaíno V. Glycated haemoglobin A1c as a risk factor of cardiovascular outcomes and all-cause mortality in diabetic and non-diabetic populations: a systematic review and meta-analysis. BMJ open. 2017 Jul 31:7(7):e015949. doi: 10.1136/bmjopen-2017-015949. Epub 2017 Jul 31     [PubMed PMID: 28760792]

Level 1 (high-level) evidence

[28]

American Diabetes Association. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes-2019. Diabetes care. 2019 Jan:42(Suppl 1):S103-S123. doi: 10.2337/dc19-S010. Epub     [PubMed PMID: 30559236]

[29]

Wilson PW,D'Agostino RB,Sullivan L,Parise H,Kannel WB, Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Archives of internal medicine. 2002 Sep 9;     [PubMed PMID: 12196085]

[30]

Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F, American Heart Association, National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005 Oct 25:112(17):2735-52     [PubMed PMID: 16157765]

[31]

Ades PA, Savage PD. Obesity in coronary heart disease: An unaddressed behavioral risk factor. Preventive medicine. 2017 Nov:104():117-119. doi: 10.1016/j.ypmed.2017.04.013. Epub 2017 Apr 13     [PubMed PMID: 28414064]

[32]

Ndumele CE, Matsushita K, Lazo M, Bello N, Blumenthal RS, Gerstenblith G, Nambi V, Ballantyne CM, Solomon SD, Selvin E, Folsom AR, Coresh J. Obesity and Subtypes of Incident Cardiovascular Disease. Journal of the American Heart Association. 2016 Jul 28:5(8):. doi: 10.1161/JAHA.116.003921. Epub 2016 Jul 28     [PubMed PMID: 27468925]

[33]

Garcia-Labbé D,Ruka E,Bertrand OF,Voisine P,Costerousse O,Poirier P, Obesity and coronary artery disease: evaluation and treatment. The Canadian journal of cardiology. 2015 Feb     [PubMed PMID: 25661553]

[34]

McGill HC Jr, McMahan CA. Determinants of atherosclerosis in the young. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. The American journal of cardiology. 1998 Nov 26:82(10B):30T-36T     [PubMed PMID: 9860371]

[35]

Akin I, Nienaber CA. "Obesity paradox" in coronary artery disease. World journal of cardiology. 2015 Oct 26:7(10):603-8. doi: 10.4330/wjc.v7.i10.603. Epub     [PubMed PMID: 26516414]

[36]

Pan A, Wang Y, Talaei M, Hu FB. Relation of Smoking With Total Mortality and Cardiovascular Events Among Patients With Diabetes Mellitus: A Meta-Analysis and Systematic Review. Circulation. 2015 Nov 10:132(19):1795-804. doi: 10.1161/CIRCULATIONAHA.115.017926. Epub 2015 Aug 26     [PubMed PMID: 26311724]

Level 1 (high-level) evidence

[37]

Mons U,Müezzinler A,Gellert C,Schöttker B,Abnet CC,Bobak M,de Groot L,Freedman ND,Jansen E,Kee F,Kromhout D,Kuulasmaa K,Laatikainen T,O'Doherty MG,Bueno-de-Mesquita B,Orfanos P,Peters A,van der Schouw YT,Wilsgaard T,Wolk A,Trichopoulou A,Boffetta P,Brenner H, Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults: meta-analysis of individual participant data from prospective cohort studies of the CHANCES consortium. BMJ (Clinical research ed.). 2015 Apr 20     [PubMed PMID: 25896935]

Level 1 (high-level) evidence

[38]

Japuntich SJ, Eilers MA, Shenhav S, Park ER, Winickoff JP, Benowitz NL, Rigotti NA. Secondhand tobacco smoke exposure among hospitalized nonsmokers with coronary heart disease. JAMA internal medicine. 2015 Jan:175(1):133-6. doi: 10.1001/jamainternmed.2014.5476. Epub     [PubMed PMID: 25383761]

[39]

Temple NJ. Fat, Sugar, Whole Grains and Heart Disease: 50 Years of Confusion. Nutrients. 2018 Jan 4:10(1):. doi: 10.3390/nu10010039. Epub 2018 Jan 4     [PubMed PMID: 29300309]

[40]

Anand SS, Hawkes C, de Souza RJ, Mente A, Dehghan M, Nugent R, Zulyniak MA, Weis T, Bernstein AM, Krauss RM, Kromhout D, Jenkins DJA, Malik V, Martinez-Gonzalez MA, Mozaffarian D, Yusuf S, Willett WC, Popkin BM. Food Consumption and its Impact on Cardiovascular Disease: Importance of Solutions Focused on the Globalized Food System: A Report From the Workshop Convened by the World Heart Federation. Journal of the American College of Cardiology. 2015 Oct 6:66(14):1590-1614. doi: 10.1016/j.jacc.2015.07.050. Epub     [PubMed PMID: 26429085]

[41]

Correction to: 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Sep 10     [PubMed PMID: 31498691]

Level 1 (high-level) evidence

[42]

Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Trans fatty acids and cardiovascular disease. The New England journal of medicine. 2006 Apr 13:354(15):1601-13     [PubMed PMID: 16611951]

[43]

Narain A, Kwok CS, Mamas MA. Soft drinks and sweetened beverages and the risk of cardiovascular disease and mortality: a systematic review and meta-analysis. International journal of clinical practice. 2016 Oct:70(10):791-805. doi: 10.1111/ijcp.12841. Epub 2016 Jul 25     [PubMed PMID: 27456347]

Level 1 (high-level) evidence

[44]

Yang Q, Zhang Z, Gregg EW, Flanders WD, Merritt R, Hu FB. Added sugar intake and cardiovascular diseases mortality among US adults. JAMA internal medicine. 2014 Apr:174(4):516-24. doi: 10.1001/jamainternmed.2013.13563. Epub     [PubMed PMID: 24493081]

[45]

DiNicolantonio JJ, OKeefe JH. Added sugars drive coronary heart disease via insulin resistance and hyperinsulinaemia: a new paradigm. Open heart. 2017:4(2):e000729. doi: 10.1136/openhrt-2017-000729. Epub 2017 Nov 29     [PubMed PMID: 29225905]

[46]

Micha R, Wallace SK, Mozaffarian D. Red and processed meat consumption and risk of incident coronary heart disease, stroke, and diabetes mellitus: a systematic review and meta-analysis. Circulation. 2010 Jun 1:121(21):2271-83. doi: 10.1161/CIRCULATIONAHA.109.924977. Epub 2010 May 17     [PubMed PMID: 20479151]

Level 1 (high-level) evidence

[47]

Rohrmann S, Overvad K, Bueno-de-Mesquita HB, Jakobsen MU, Egeberg R, Tjønneland A, Nailler L, Boutron-Ruault MC, Clavel-Chapelon F, Krogh V, Palli D, Panico S, Tumino R, Ricceri F, Bergmann MM, Boeing H, Li K, Kaaks R, Khaw KT, Wareham NJ, Crowe FL, Key TJ, Naska A, Trichopoulou A, Trichopoulos D, Leenders M, Peeters PH, Engeset D, Parr CL, Skeie G, Jakszyn P, Sánchez MJ, Huerta JM, Redondo ML, Barricarte A, Amiano P, Drake I, Sonestedt E, Hallmans G, Johansson I, Fedirko V, Romieux I, Ferrari P, Norat T, Vergnaud AC, Riboli E, Linseisen J. Meat consumption and mortality--results from the European Prospective Investigation into Cancer and Nutrition. BMC medicine. 2013 Mar 7:11():63. doi: 10.1186/1741-7015-11-63. Epub 2013 Mar 7     [PubMed PMID: 23497300]

[48]

Larsson SC, Orsini N. Red meat and processed meat consumption and all-cause mortality: a meta-analysis. American journal of epidemiology. 2014 Feb 1:179(3):282-9. doi: 10.1093/aje/kwt261. Epub 2013 Oct 22     [PubMed PMID: 24148709]

Level 1 (high-level) evidence

[49]

Wolk A. Potential health hazards of eating red meat. Journal of internal medicine. 2017 Feb:281(2):106-122. doi: 10.1111/joim.12543. Epub 2016 Sep 6     [PubMed PMID: 27597529]

[50]

Bechthold A, Boeing H, Schwedhelm C, Hoffmann G, Knüppel S, Iqbal K, De Henauw S, Michels N, Devleesschauwer B, Schlesinger S, Schwingshackl L. Food groups and risk of coronary heart disease, stroke and heart failure: A systematic review and dose-response meta-analysis of prospective studies. Critical reviews in food science and nutrition. 2019:59(7):1071-1090. doi: 10.1080/10408398.2017.1392288. Epub 2017 Nov 7     [PubMed PMID: 29039970]

Level 1 (high-level) evidence

[51]

Alshahrani SM, Fraser GE, Sabaté J, Knutsen R, Shavlik D, Mashchak A, Lloren JI, Orlich MJ. Red and Processed Meat and Mortality in a Low Meat Intake Population. Nutrients. 2019 Mar 14:11(3):. doi: 10.3390/nu11030622. Epub 2019 Mar 14     [PubMed PMID: 30875776]

[52]

Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L, INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet (London, England). 2004 Sep 11-17:364(9438):937-52     [PubMed PMID: 15364185]

Level 2 (mid-level) evidence

[53]

Tana C, Ballestri S, Ricci F, Di Vincenzo A, Ticinesi A, Gallina S, Giamberardino MA, Cipollone F, Sutton R, Vettor R, Fedorowski A, Meschi T. Cardiovascular Risk in Non-Alcoholic Fatty Liver Disease: Mechanisms and Therapeutic Implications. International journal of environmental research and public health. 2019 Aug 26:16(17):. doi: 10.3390/ijerph16173104. Epub 2019 Aug 26     [PubMed PMID: 31455011]

[54]

Mahfood Haddad T, Hamdeh S, Kanmanthareddy A, Alla VM. Nonalcoholic fatty liver disease and the risk of clinical cardiovascular events: A systematic review and meta-analysis. Diabetes & metabolic syndrome. 2017 Nov:11 Suppl 1():S209-S216. doi: 10.1016/j.dsx.2016.12.033. Epub 2016 Dec 15     [PubMed PMID: 28017631]

[55]

Baratta F, Pastori D, Angelico F, Balla A, Paganini AM, Cocomello N, Ferro D, Violi F, Sanyal AJ, Del Ben M. Nonalcoholic Fatty Liver Disease and Fibrosis Associated With Increased Risk of Cardiovascular Events in a Prospective Study. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2020 Sep:18(10):2324-2331.e4. doi: 10.1016/j.cgh.2019.12.026. Epub 2019 Dec 27     [PubMed PMID: 31887443]

[56]

Cai Q, Mukku VK, Ahmad M. Coronary artery disease in patients with chronic kidney disease: a clinical update. Current cardiology reviews. 2013 Nov:9(4):331-9     [PubMed PMID: 24527682]

[57]

. Correction to: 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Sep 10:140(11):e647-e648. doi: 10.1161/CIR.0000000000000724. Epub 2019 Sep 9     [PubMed PMID: 31498692]

Level 1 (high-level) evidence

[58]

Zeller CB, Appenzeller S. Cardiovascular disease in systemic lupus erythematosus: the role of traditional and lupus related risk factors. Current cardiology reviews. 2008 May:4(2):116-22. doi: 10.2174/157340308784245775. Epub     [PubMed PMID: 19936286]

[59]

Fors Nieves CE, Izmirly PM. Mortality in Systemic Lupus Erythematosus: an Updated Review. Current rheumatology reports. 2016 Apr:18(4):21. doi: 10.1007/s11926-016-0571-2. Epub     [PubMed PMID: 26984805]

[60]

Dein E, Douglas H, Petri M, Law G, Timlin H. Pericarditis in Lupus. Cureus. 2019 Mar 1:11(3):e4166. doi: 10.7759/cureus.4166. Epub 2019 Mar 1     [PubMed PMID: 31086751]

[61]

Bezwada P, Quadri A, Shaikh A, Ayala-Rodriguez C, Green S. Myopericarditis and Pericardial Effusion as the Initial Presentation of Systemic Lupus Erythematosus. Case reports in medicine. 2017:2017():6912020. doi: 10.1155/2017/6912020. Epub 2017 Feb 5     [PubMed PMID: 28261271]

Level 3 (low-level) evidence

[62]

Crowson CS, Liao KP, Davis JM 3rd, Solomon DH, Matteson EL, Knutson KL, Hlatky MA, Gabriel SE. Rheumatoid arthritis and cardiovascular disease. American heart journal. 2013 Oct:166(4):622-628.e1. doi: 10.1016/j.ahj.2013.07.010. Epub 2013 Aug 29     [PubMed PMID: 24093840]

[63]

Feng W, Chen G, Cai D, Zhao S, Cheng J, Shen H. Inflammatory Bowel Disease and Risk of Ischemic Heart Disease: An Updated Meta-Analysis of Cohort Studies. Journal of the American Heart Association. 2017 Aug 2:6(8):. doi: 10.1161/JAHA.117.005892. Epub 2017 Aug 2     [PubMed PMID: 28768646]

[64]

Sinha A, Feinstein MJ. Coronary Artery Disease Manifestations in HIV: What, How, and Why. The Canadian journal of cardiology. 2019 Mar:35(3):270-279. doi: 10.1016/j.cjca.2018.11.029. Epub 2018 Dec 4     [PubMed PMID: 30825949]

[65]

Cappola AR, Desai AS, Medici M, Cooper LS, Egan D, Sopko G, Fishman GI, Goldman S, Cooper DS, Mora S, Kudenchuk PJ, Hollenberg AN, McDonald CL, Ladenson PW. Thyroid and Cardiovascular Disease: Research Agenda for Enhancing Knowledge, Prevention, and Treatment. Circulation. 2019 Jun 18:139(25):2892-2909. doi: 10.1161/CIRCULATIONAHA.118.036859. Epub 2019 May 13     [PubMed PMID: 31081673]

[66]

Central action of nomifensine., Maj J,Kapturkiewicz Z,Michaluk J,, Polish journal of pharmacology and pharmacy, 1976 Nov-Dec     [PubMed PMID: 23246686]

[67]

LeFevre ML, U.S. Preventive Services Task Force. Screening for thyroid dysfunction: U.S. Preventive Services Task Force recommendation statement. Annals of internal medicine. 2015 May 5:162(9):641-50. doi: 10.7326/M15-0483. Epub     [PubMed PMID: 25798805]

[68]

Bianchi VE. Testosterone, myocardial function, and mortality. Heart failure reviews. 2018 Sep:23(5):773-788. doi: 10.1007/s10741-018-9721-0. Epub     [PubMed PMID: 29978359]

[69]

[Energy transfer in photosynthetic units (author's transl)]., Frackowiak D,Fiksiński K,, Postepy biochemii, 1976     [PubMed PMID: 29275030]

[70]

Goodale T, Sadhu A, Petak S, Robbins R. Testosterone and the Heart. Methodist DeBakey cardiovascular journal. 2017 Apr-Jun:13(2):68-72. doi: 10.14797/mdcj-13-2-68. Epub     [PubMed PMID: 28740585]

[71]

The missed menstrual period., deProsse CA,Keettel WC,, Postgraduate medicine, 1977 Jan     [PubMed PMID: 26846952]

[72]

Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clinic proceedings. 2015 Feb:90(2):224-51     [PubMed PMID: 25636998]

Level 3 (low-level) evidence

[73]

Modarresi-Ghazani F, Hejazi ME, Gharekhani A, Entezari-Maleki T. Role of Vitamin D in Cardiovascular Disease. Archives of Iranian medicine. 2016 May:19(5):359-62     [PubMed PMID: 27179169]

[74]

Aggarwal R, Akhthar T, Jain SK. Coronary artery disease and its association with Vitamin D deficiency. Journal of mid-life health. 2016 Apr-Jun:7(2):56-60. doi: 10.4103/0976-7800.185334. Epub     [PubMed PMID: 27499590]

[75]

Siadat ZD, Kiani K, Sadeghi M, Shariat AS, Farajzadegan Z, Kheirmand M. Association of vitamin D deficiency and coronary artery disease with cardiovascular risk factors. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences. 2012 Nov:17(11):1052-5     [PubMed PMID: 23833580]

Level 3 (low-level) evidence

[76]

Kheiri B, Abdalla A, Osman M, Ahmed S, Hassan M, Bachuwa G. Vitamin D deficiency and risk of cardiovascular diseases: a narrative review. Clinical hypertension. 2018:24():9. doi: 10.1186/s40885-018-0094-4. Epub 2018 Jun 22     [PubMed PMID: 29977597]

[77]

Rai V, Agrawal DK. Role of Vitamin D in Cardiovascular Diseases. Endocrinology and metabolism clinics of North America. 2017 Dec:46(4):1039-1059. doi: 10.1016/j.ecl.2017.07.009. Epub 2017 Sep 29     [PubMed PMID: 29080634]

[78]

Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ, D'Agostino RB, Wolf M, Vasan RS. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008 Jan 29:117(4):503-11. doi: 10.1161/CIRCULATIONAHA.107.706127. Epub 2008 Jan 7     [PubMed PMID: 18180395]

[79]

Kunadian V, Ford GA, Bawamia B, Qiu W, Manson JE. Vitamin D deficiency and coronary artery disease: a review of the evidence. American heart journal. 2014 Mar:167(3):283-91. doi: 10.1016/j.ahj.2013.11.012. Epub 2013 Dec 19     [PubMed PMID: 24576510]

[80]

Nuclear coupling of 33S and the nature of free radicals in irradiated crystals of N-acetyl-L-cysteine., Hadley JH Jr,Gordy W,, Proceedings of the National Academy of Sciences of the United States of America, 1977 Jan     [PubMed PMID: 27081110]

[81]

Gulati M, Shaw LJ, Bairey Merz CN. Myocardial ischemia in women: lessons from the NHLBI WISE study. Clinical cardiology. 2012 Mar:35(3):141-8. doi: 10.1002/clc.21966. Epub     [PubMed PMID: 22389117]

Level 3 (low-level) evidence

[82]

Burke AP, Farb A, Malcom G, Virmani R. Effect of menopause on plaque morphologic characteristics in coronary atherosclerosis. American heart journal. 2001 Feb:141(2 Suppl):S58-62     [PubMed PMID: 11174360]

[83]

Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. Journal of the American College of Cardiology. 2009 Oct 20:54(17):1561-75. doi: 10.1016/j.jacc.2009.04.098. Epub     [PubMed PMID: 19833255]

[84]

Siu AL, Screening for high blood pressure in adults: U.S. Preventive Services Task Force recommendation statement. Annals of internal medicine. 2015 Nov 17;     [PubMed PMID: 26458123]

[85]

Moyer VA, U.S. Preventive Services Task Force. Screening for primary hypertension in children and adolescents: U.S. Preventive Services Task Force recommendation statement. Pediatrics. 2013 Nov:132(5):907-14. doi: 10.1542/peds.2013-2864. Epub 2013 Oct 7     [PubMed PMID: 24101758]

[86]

Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 7. Effects of more vs. less intensive blood pressure lowering and different achieved blood pressure levels - updated overview and meta-analyses of randomized trials. Journal of hypertension. 2016 Apr:34(4):613-22. doi: 10.1097/HJH.0000000000000881. Epub     [PubMed PMID: 26848994]

Level 3 (low-level) evidence

[87]

Lewington S, Clarke R, Qizilbash N, Peto R, Collins R, Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet (London, England). 2002 Dec 14:360(9349):1903-13     [PubMed PMID: 12493255]

Level 2 (mid-level) evidence

[88]

Kannel WB. Hypertension: reflections on risks and prognostication. The Medical clinics of North America. 2009 May:93(3):541-58, Table of Contents. doi: 10.1016/j.mcna.2009.02.006. Epub     [PubMed PMID: 19427490]

[89]

US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW Jr, García FAR, Gillman MW, Kemper AR, Krist AH, Kurth AE, Landefeld CS, LeFevre ML, Mangione CM, Phillips WR, Owens DK, Phipps MG, Pignone MP. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2016 Nov 15:316(19):1997-2007. doi: 10.1001/jama.2016.15450. Epub     [PubMed PMID: 27838723]

[90]

US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW Jr, García FA, Gillman MW, Kemper AR, Krist AH, Kurth AE, Landefeld CS, LeFevre M, Mangione CM, Owens DK, Phillips WR, Phipps MG, Pignone MP, Siu AL. Screening for Lipid Disorders in Children and Adolescents: US Preventive Services Task Force Recommendation Statement. JAMA. 2016 Aug 9:316(6):625-33. doi: 10.1001/jama.2016.9852. Epub     [PubMed PMID: 27532917]

[91]

de Ferranti SD, Rodday AM, Parsons SK, Cull WL, O'Connor KG, Daniels SR, Leslie LK. Cholesterol Screening and Treatment Practices and Preferences: A Survey of United States Pediatricians. The Journal of pediatrics. 2017 Jun:185():99-105.e2. doi: 10.1016/j.jpeds.2016.12.078. Epub 2017 Feb 13     [PubMed PMID: 28209292]

[92]

Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ (Clinical research ed.). 1994 Feb 5:308(6925):367-72     [PubMed PMID: 8043072]

[93]

Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. The New England journal of medicine. 2008 Nov 20:359(21):2195-207. doi: 10.1056/NEJMoa0807646. Epub 2008 Nov 9     [PubMed PMID: 18997196]

[94]

Siu AL, Screening for Abnormal Blood Glucose and Type 2 Diabetes Mellitus: U.S. Preventive Services Task Force Recommendation Statement. Annals of internal medicine. 2015 Dec 1;     [PubMed PMID: 26501513]

[95]

Giugliano D, Chiodini P, Maiorino MI, Bellastella G, Esposito K. Cardiovascular outcome trials and major cardiovascular events: does glucose matter? A systematic review with meta-analysis. Journal of endocrinological investigation. 2019 Oct:42(10):1165-1169. doi: 10.1007/s40618-019-01047-0. Epub 2019 Apr 6     [PubMed PMID: 30955180]

[96]

Pallazola VA,Davis DM,Whelton SP,Cardoso R,Latina JM,Michos ED,Sarkar S,Blumenthal RS,Arnett DK,Stone NJ,Welty FK, A Clinician's Guide to Healthy Eating for Cardiovascular Disease Prevention. Mayo Clinic proceedings. Innovations, quality & outcomes. 2019 Sep     [PubMed PMID: 31485563]

Level 2 (mid-level) evidence

[97]

Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER 3rd, Simons-Morton DG, Karanja N, Lin PH, DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. The New England journal of medicine. 2001 Jan 4:344(1):3-10     [PubMed PMID: 11136953]

[98]

Salehi-Abargouei A, Maghsoudi Z, Shirani F, Azadbakht L. Effects of Dietary Approaches to Stop Hypertension (DASH)-style diet on fatal or nonfatal cardiovascular diseases--incidence: a systematic review and meta-analysis on observational prospective studies. Nutrition (Burbank, Los Angeles County, Calif.). 2013 Apr:29(4):611-8. doi: 10.1016/j.nut.2012.12.018. Epub     [PubMed PMID: 23466047]

[99]

Aune D, Giovannucci E, Boffetta P, Fadnes LT, Keum N, Norat T, Greenwood DC, Riboli E, Vatten LJ, Tonstad S. Fruit and vegetable intake and the risk of cardiovascular disease, total cancer and all-cause mortality-a systematic review and dose-response meta-analysis of prospective studies. International journal of epidemiology. 2017 Jun 1:46(3):1029-1056. doi: 10.1093/ije/dyw319. Epub     [PubMed PMID: 28338764]

Level 1 (high-level) evidence

[100]

Aune D, Keum N, Giovannucci E, Fadnes LT, Boffetta P, Greenwood DC, Tonstad S, Vatten LJ, Riboli E, Norat T. Nut consumption and risk of cardiovascular disease, total cancer, all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis of prospective studies. BMC medicine. 2016 Dec 5:14(1):207     [PubMed PMID: 27916000]

[101]

Mattioli AV, Palmiero P, Manfrini O, Puddu PE, Nodari S, Dei Cas A, Mercuro G, Scrutinio D, Palermo P, Sciomer S, Di Francesco S, Novo G, Novo S, Pedretti RFE, Zito A, Parati G, Pedrinelli R, Farinetti A, Maiello M, Moscucci F, Tenaglia RL, Sucato V, Triggiani M, Cugusi L, Scicchitano P, Saba PS, Ciccone MM. Mediterranean diet impact on cardiovascular diseases: a narrative review. Journal of cardiovascular medicine (Hagerstown, Md.). 2017 Dec:18(12):925-935. doi: 10.2459/JCM.0000000000000573. Epub     [PubMed PMID: 28914660]

Level 3 (low-level) evidence

[102]

Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Himmelfarb CD, Khera A, Lloyd-Jones D, McEvoy JW, Michos ED, Miedema MD, Muñoz D, Smith SC Jr, Virani SS, Williams KA Sr, Yeboah J, Ziaeian B. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. 2019 Sep 10:74(10):e177-e232. doi: 10.1016/j.jacc.2019.03.010. Epub 2019 Mar 17     [PubMed PMID: 30894318]

Level 1 (high-level) evidence

[103]

Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. PLoS medicine. 2010 Mar 23:7(3):e1000252. doi: 10.1371/journal.pmed.1000252. Epub 2010 Mar 23     [PubMed PMID: 20351774]

Level 1 (high-level) evidence

[104]

Siu AL, U.S. Preventive Services Task Force. Behavioral and Pharmacotherapy Interventions for Tobacco Smoking Cessation in Adults, Including Pregnant Women: U.S. Preventive Services Task Force Recommendation Statement. Annals of internal medicine. 2015 Oct 20:163(8):622-34. doi: 10.7326/M15-2023. Epub 2015 Sep 22     [PubMed PMID: 26389730]

[105]

Moyer VA, U.S. Preventive Services Task Force. Primary care interventions to prevent tobacco use in children and adolescents: U.S. preventive services task force recommendation statement. Pediatrics. 2013 Sep:132(3):560-5. doi: 10.1542/peds.2013-2079. Epub 2013 Aug 26     [PubMed PMID: 23979083]

[106]

Thun MJ, Carter BD, Feskanich D, Freedman ND, Prentice R, Lopez AD, Hartge P, Gapstur SM. 50-year trends in smoking-related mortality in the United States. The New England journal of medicine. 2013 Jan 24:368(4):351-64. doi: 10.1056/NEJMsa1211127. Epub     [PubMed PMID: 23343064]

[107]

Larzelere MM, Williams DE. Promoting smoking cessation. American family physician. 2012 Mar 15:85(6):591-8     [PubMed PMID: 22534270]

[108]

Stead LF, Perera R, Bullen C, Mant D, Hartmann-Boyce J, Cahill K, Lancaster T. Nicotine replacement therapy for smoking cessation. The Cochrane database of systematic reviews. 2012 Nov 14:11():CD000146. doi: 10.1002/14651858.CD000146.pub4. Epub 2012 Nov 14     [PubMed PMID: 23152200]

Level 1 (high-level) evidence

[109]

Cahill K,Lindson-Hawley N,Thomas KH,Fanshawe TR,Lancaster T, Nicotine receptor partial agonists for smoking cessation. The Cochrane database of systematic reviews. 2016 May 9     [PubMed PMID: 27158893]

Level 1 (high-level) evidence

[110]

Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, Lancaster T. Antidepressants for smoking cessation. The Cochrane database of systematic reviews. 2014 Jan 8:2014(1):CD000031. doi: 10.1002/14651858.CD000031.pub4. Epub 2014 Jan 8     [PubMed PMID: 24402784]

Level 1 (high-level) evidence

[111]

Stead LF,Koilpillai P,Fanshawe TR,Lancaster T, Combined pharmacotherapy and behavioural interventions for smoking cessation. The Cochrane database of systematic reviews. 2016 Mar 24;     [PubMed PMID: 27009521]

Level 1 (high-level) evidence

[112]

US Preventive Services Task Force, Curry SJ, Krist AH, Owens DK, Barry MJ, Caughey AB, Davidson KW, Doubeni CA, Epling JW Jr, Grossman DC, Kemper AR, Kubik M, Landefeld CS, Mangione CM, Phipps MG, Silverstein M, Simon MA, Tseng CW, Wong JB. Behavioral Weight Loss Interventions to Prevent Obesity-Related Morbidity and Mortality in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2018 Sep 18:320(11):1163-1171. doi: 10.1001/jama.2018.13022. Epub     [PubMed PMID: 30326502]

[113]

Cleo G, Beller E, Glasziou P, Isenring E, Thomas R. Efficacy of habit-based weight loss interventions: a systematic review and meta-analysis. Journal of behavioral medicine. 2020 Aug:43(4):519-532. doi: 10.1007/s10865-019-00100-w. Epub 2019 Sep 16     [PubMed PMID: 31529279]

Level 1 (high-level) evidence

[114]

LeFevre ML, U.S. Preventive Services Task Force. Behavioral counseling to promote a healthful diet and physical activity for cardiovascular disease prevention in adults with cardiovascular risk factors: U.S. Preventive Services Task Force Recommendation Statement. Annals of internal medicine. 2014 Oct 21:161(8):587-93. doi: 10.7326/M14-1796. Epub     [PubMed PMID: 25155419]

[115]

Shaw K,Gennat H,O'Rourke P,Del Mar C, Exercise for overweight or obesity. The Cochrane database of systematic reviews. 2006 Oct 18;     [PubMed PMID: 17054187]

Level 1 (high-level) evidence

[116]

Schoenborn CA, Stommel M. Adherence to the 2008 adult physical activity guidelines and mortality risk. American journal of preventive medicine. 2011 May:40(5):514-21. doi: 10.1016/j.amepre.2010.12.029. Epub     [PubMed PMID: 21496750]

[117]

Sattelmair J, Pertman J, Ding EL, Kohl HW 3rd, Haskell W, Lee IM. Dose response between physical activity and risk of coronary heart disease: a meta-analysis. Circulation. 2011 Aug 16:124(7):789-95. doi: 10.1161/CIRCULATIONAHA.110.010710. Epub 2011 Aug 1     [PubMed PMID: 21810663]

Level 1 (high-level) evidence

[118]

Liu CJ, Latham NK. Progressive resistance strength training for improving physical function in older adults. The Cochrane database of systematic reviews. 2009 Jul 8:2009(3):CD002759. doi: 10.1002/14651858.CD002759.pub2. Epub 2009 Jul 8     [PubMed PMID: 19588334]

Level 1 (high-level) evidence

[119]

Crowding stress and adrenal mitochondrial 11 beta-hydroxylation in vitro., Mccarthy JL,Green W,Sohal RS,, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.), 1976 Dec     [PubMed PMID: 31226053]

[120]

Lin KW, Middleton J. Rethinking Aspirin for the Primary Prevention of Cardiovascular Disease. American family physician. 2019 Jun 1:99(11):670-671     [PubMed PMID: 31150176]

[121]

Mahabadi AA, Möhlenkamp S, Lehmann N, Kälsch H, Dykun I, Pundt N, Moebus S, Jöckel KH, Erbel R, Heinz Nixdorf Recall Study Investigators. CAC Score Improves Coronary and CV Risk Assessment Above Statin Indication by ESC and AHA/ACC Primary Prevention Guidelines. JACC. Cardiovascular imaging. 2017 Feb:10(2):143-153. doi: 10.1016/j.jcmg.2016.03.022. Epub 2016 Sep 21     [PubMed PMID: 27665163]

[122]

Greenland P, Blaha MJ, Budoff MJ, Erbel R, Watson KE. Coronary Calcium Score and Cardiovascular Risk. Journal of the American College of Cardiology. 2018 Jul 24:72(4):434-447. doi: 10.1016/j.jacc.2018.05.027. Epub     [PubMed PMID: 30025580]

[123]

Naqvi TZ,Lee MS, Carotid intima-media thickness and plaque in cardiovascular risk assessment. JACC. Cardiovascular imaging. 2014 Oct     [PubMed PMID: 25051948]

[124]

Den Ruijter HM, Peters SA, Anderson TJ, Britton AR, Dekker JM, Eijkemans MJ, Engström G, Evans GW, de Graaf J, Grobbee DE, Hedblad B, Hofman A, Holewijn S, Ikeda A, Kavousi M, Kitagawa K, Kitamura A, Koffijberg H, Lonn EM, Lorenz MW, Mathiesen EB, Nijpels G, Okazaki S, O'Leary DH, Polak JF, Price JF, Robertson C, Rembold CM, Rosvall M, Rundek T, Salonen JT, Sitzer M, Stehouwer CD, Witteman JC, Moons KG, Bots ML. Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis. JAMA. 2012 Aug 22:308(8):796-803. doi: 10.1001/jama.2012.9630. Epub     [PubMed PMID: 22910757]

[125]

Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, Foster E, Hlatky MA, Hodgson JM, Kushner FG, Lauer MS, Shaw LJ, Smith SC Jr, Taylor AJ, Weintraub WS, Wenger NK, Jacobs AK, Smith SC Jr, Anderson JL, Albert N, Buller CE, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Kushner FG, Nishimura R, Ohman EM, Page RL, Stevenson WG, Tarkington LG, Yancy CW, American College of Cardiology Foundation, American Heart Association. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2010 Dec 14:56(25):e50-103. doi: 10.1016/j.jacc.2010.09.001. Epub     [PubMed PMID: 21144964]

[126]

Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB Sr, Gibbons R, Greenland P, Lackland DT, Levy D, O'Donnell CJ, Robinson JG, Schwartz JS, Shero ST, Smith SC Jr, Sorlie P, Stone NJ, Wilson PWF. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2014 Jul 1:63(25 Pt B):2935-2959. doi: 10.1016/j.jacc.2013.11.005. Epub 2013 Nov 12     [PubMed PMID: 24239921]

Level 3 (low-level) evidence

[127]

Neuropeptide MSH/ACTH 4-10 enhances attention in the mentally retarded., Sandman CA,George J,Walker BB,Nolan JD,Kastin AJ,, Pharmacology, biochemistry, and behavior, 1976     [PubMed PMID: 28110311]

[128]

Widmer RJ, Samuels B, Samady H, Price MJ, Jeremias A, Anderson RD, Jaffer FA, Escaned J, Davies J, Prasad M, Grines C, Lerman A. The functional assessment of patients with non-obstructive coronary artery disease: expert review from an international microcirculation working group. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2019 Mar 20:14(16):1694-1702. doi: 10.4244/EIJ-D-18-00982. Epub     [PubMed PMID: 30561368]

[129]

Matsuzawa Y, Kwon TG, Lennon RJ, Lerman LO, Lerman A. Prognostic Value of Flow-Mediated Vasodilation in Brachial Artery and Fingertip Artery for Cardiovascular Events: A Systematic Review and Meta-Analysis. Journal of the American Heart Association. 2015 Nov 13:4(11):. doi: 10.1161/JAHA.115.002270. Epub 2015 Nov 13     [PubMed PMID: 26567372]

Level 1 (high-level) evidence

[130]

Rusnak J, Fastner C, Behnes M, Mashayekhi K, Borggrefe M, Akin I. Biomarkers in Stable Coronary Artery Disease. Current pharmaceutical biotechnology. 2017:18(6):456-471. doi: 10.2174/1389201018666170630120805. Epub     [PubMed PMID: 28669333]