Overview of possible risk factors for cardiovascular disease

INTRODUCTION — An overview of the possible emerging cardiovascular risk disease (CVD) risk factors is presented here. An overview of the established risk factors for CVD, data supporting the importance of the individual risk factors (eg, hyperlipidemia, hypertension, smoking), coronary risk factors of particular importance in women and in young patients, and estimation of coronary risk in an individual patient are discussed elsewhere.

●(See "Overview of established risk factors for cardiovascular disease".)

●(See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)

●(See "Overview of hypertension in adults", section on 'Treatment'.)

●(See "Overview of atherosclerotic cardiovascular risk factors in females".)

●(See "Coronary artery disease and myocardial infarction in young people".)

DEFINITIONS AND BACKGROUND — CVD is common in the general population, affecting the majority of adults past the age of 60 years. As a diagnostic category, CVD includes four major areas:

●Coronary heart disease (CHD), manifested by myocardial infarction (MI), angina pectoris, heart failure, and coronary death

●Cerebrovascular disease, manifested by stroke and transient ischemic attack

●Peripheral artery disease, manifested by intermittent claudication

●Aortic atherosclerosis and thoracic or abdominal aortic aneurysm

CHD accounts for approximately one-third to one-half of the total cases of CVD. The lifetime risk of CHD was illustrated in the Framingham Heart Study of 7733 participants, ages 40 to 94, who were initially free of CHD [1]. The lifetime risk for individuals at age 40 was 49 percent in men and 32 percent in women. Even those who were free from CHD at age 70 had a non-trivial lifetime risk of developing CHD (35 and 24 percent in males and females, respectively).

Death rates from CVD, CHD, and stroke have declined in the United States since 1975, and evidence from 2000 to 2008 shows a decline in CHD mortality (figure 1). CVD and its related complications remain highly prevalent and expensive to treat [2]. CVD is the leading cause of death in most developed countries, with approximately one million Americans dying annually from CVD [3]. The prevalence of CVD is rapidly increasing in resource-limited countries as well.

Many risk factors for CVD are modifiable by specific preventive measures. In the worldwide INTERHEART study of patients from 52 countries, nine potentially modifiable factors accounted for over 90 percent of the population-attributable risk of a first MI: smoking, dyslipidemia, hypertension, diabetes, abdominal obesity, psychosocial factors, lack of daily consumption of fruits and vegetables, regular alcohol consumption, and lack of regular physical activity [4].

Most patients with CVD have at least one established or borderline risk factor other than age and sex [5-7]. However, it is clear that there are other risk factors, not all treatable, that may be important. The additive value of screening for these risk factors has not been firmly established, and there is only limited evidence that targeted therapeutic intervention will reduce the risk associated with these factors [8].

EVALUATION OF PUTATIVE CVD RISK FACTORS — Prospective observational studies are typically used to assess whether a risk factor contributes to risk. The starting point in the analyses are often the variables used to predict the CVD outcome of interest. For instance, for three-point major adverse cardiovascular events, the factors are typically age, sex, blood pressure, cholesterol (or low-density lipoprotein [LDL] cholesterol), high-density lipoprotein (HDL) cholesterol, diabetes mellitus, and cigarette smoking. Robust analyses include use of the key factors in a Cox proportional hazards model followed by assessment of the effects of adding the newer factor(s) to the prediction, with evaluation of the incremental effect on the C-statistic or on reclassification. Analyses that do not include this strategy and simply assess the impact of adding a new putative risk factor to national risk factor prediction algorithms such as the pooled cohort equations published in 2014 are generally not a satisfactory assessment to establish utility for a potential new CVD risk factor [9].

CARDIOVASCULAR FACTORS

Arterial intima-media thickness — Carotid artery intima-media thickness (IMT) is linked to the atherosclerotic process because of its association with known cardiovascular risk factors [10-13]. A more extensive discussion of carotid IMT with CVD risk is presented separately. (See "Carotid intima-media thickness".)

Arterial stiffness — Arterial stiffness, measured as the aortic pulse wave velocity (PWV) between the carotid and femoral arteries, is a predictor of cardiovascular events [14,15]. This was demonstrated in a meta-analysis of 17 studies that included over 15,000 patients in whom aortic PWV had been correlated to clinical outcome [14]. The pooled relative risks for total cardiovascular events, cardiovascular mortality, and all-cause mortality were significantly increased comparing high versus low aortic PWV groups: 2.26 (95% CI 1.89-2.70), 2.02 (95% CI 1.68-2.42), and 1.90 (95% CI 1.61-2.24) respectively.

Arterial calcification — Calcium deposits in extracoronary arteries, particularly the aortic arch and abdominal aorta, may be a marker for CVD and an increase in cardiovascular events and overall mortality [16]. However, it is not certain if the predictive value of calcification is independent of other coronary risk factors [17].

●Aortic arch – Calcification of the aortic arch is associated with a greater risk of CVD and total mortality.

•In one study of 139,849 members of a health maintenance organization followed for a median of 28 years, aortic arch calcification identified on a chest radiograph was independently associated with an increased risk of coronary heart disease (CHD) in men (relative risk [RR] 1.3) and women (RR 1.2), as well as a 1.5-fold increased risk of ischemic stroke in women [18].

•In a subset of 2408 patients from the Rotterdam Study who underwent computed tomography (CT) to quantify arterial calcification in the coronary arteries, intracranial and extracranial carotid arteries, and the aortic arch, increasing amounts of calcification in any vascular territory were associated with increases in mortality [16]. The largest associated increase in both total and cardiovascular mortality was seen with calcification in the aortic arch.

Ischemic strokes in such patients may reflect embolic as well as thrombotic events. (See "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)" and "Thromboembolism from aortic plaque".)

●Abdominal aorta – In addition to thoracic aortic calcification, calcification of the abdominal aorta is also associated with an increased risk of CVD. In a meta-analysis of 10 studies (22,170 patients), calcification of the abdominal aorta was associated with significantly higher risks of four major endpoints [19]:

•CHD events (five studies with 11,250 patients; RR 1.81, 95% CI 1.54-2.14)

•Cerebrovascular disease events (four studies with 9736 patients; RR 1.37, 95% CI 1.22-3.54)

•Combined CVD events (four studies with 4960 patients; RR 1.64, 95% CI 1.24-2.17)

•CVD death (three studies with 4986 patients; RR 1.72, 95% CI 1.03-2.86)

Another method for establishing the presence and severity of aortic calcification and atherosclerotic plaque burden is measurement of aortic elastic properties, based on the biomechanics of pulse wave-vessel wall interaction determined by transesophageal echocardiography [20]. The specific elastance is of incremental value to other clinical variables.

●Renal arteries – Calcification of the renal arteries has also been reported to be associated with greater overall mortality. Among a cohort of 4450 persons without known CVD who underwent whole-body CT, 622 (14 percent) were found to have calcification of one or both renal arteries [21]. Following adjustment for age, sex, and traditional cardiac risk factors, those with renal artery calcification had a significantly greater overall mortality (risk-adjusted hazard ratio [HR] 1.63, 95% CI 1.17-2.29).

●Breast arteries – Breast arterial calcification (BAC) can be an incidental finding on mammography. in one cohort study, over 5000 women aged 60-79 years were recruited after attending mammography screening [22]. Over 6.5 years of followup, BAC presence was associated with increased incidence of atherosclerotic CVD (ASCVD) (HR 1.51 (95% CI, 1.08–2.11). Independent confirmation of these findings and analyses that follow the methods described above (see 'Evaluation of putative CVD risk factors' above) may help to support the use of BAC as a risk-enhancing factor for ASCVD. (See "Cardiovascular disease risk assessment for primary prevention: Risk calculators", section on 'ACC/AHA pooled cohort hard ASCVD risk calculator (2013), updated algorithm 2018'.)

Coronary artery calcification — Coronary artery calcification (CAC) detected by electron-beam CT or multidetector-row CT can be used to quantify the amount of calcium present in the coronary arteries of a given patient. The coronary calcium score correlates with the risk of cardiovascular events in both asymptomatic and symptomatic patients. Issues related to the possible utility of CAC scanning are discussed separately. (See "Coronary artery calcium scoring (CAC): Overview and clinical utilization".)

Electrocardiographic abnormalities

ECG changes — Asymptomatic persons with resting electrocardiogram (ECG) abnormalities such as ST depression, T-wave inversion, left ventricular hypertrophy (LVH) or strain, and premature ventricular contractions have a 2 to 10-fold increased risk of CHD compared with those with a normal ECG [23-26]. As examples:

●Among a cohort of 6991 persons aged 65 years or older who participated in the Copenhagen Heart Study and had a baseline resting ECG, 30.6 percent had baseline ECG abnormalities [26]. Over a median follow-up of 12 years, during which 2236 participants developed a fatal CVD event, the risk of fatal CVD was significantly greater in persons with an abnormal baseline ECG (HR 1.33 compared with normal baseline ECG, 95% CI 1.29-1.36).

●Among 2192 adults aged 70 to 79 without known CVD who were followed for eight years, persons with minor (defined as minor ST-T abnormalities) and major (defined as Q waves, LVH, bundle branch block, atrial fibrillation or flutter, Wolff-Parkinson-White (WPW) syndrome, or major ST-T changes) ECG abnormalities were more likely to develop CVD than those with normal baseline ECGs (HR 1.35, 95% CI 1.02-1.81 and HR 1.51, 95% CI 1.20-1.90, respectively) [25].

The usual transition zone, where the R and S wave are equal in amplitude in the precordial leads, usually occurs between V3 and V4. In a cohort of 9067 persons (44 percent male) followed for 24 years, clockwise rotation (also called "late transition") was associated with increased risk of CVD (HR 1.49, 95% CI 1.12-1.98), while counterclockwise rotation (also called "early transition") was inversely associated with CVD (HR 0.74, 95% CI 0.59-0.94) [27]. While these data are easily identified from the surface ECG, the exact mechanism by which cardiac rotation on ECG alters the risk of CVD remains undetermined. (See "ECG tutorial: Miscellaneous diagnoses", section on 'Early or late transition'.)

Left ventricular hypertrophy — LVH, which is associated with hypertension as well as with age and obesity, is a risk factor for CHD [28-31]. This has been identified in several large cohorts, as illustrated by the following examples:

●Electrocardiographic and anatomic LVH, based upon the finding of an enlarged cardiac silhouette on a chest radiograph, each independently increased the risk of CVD in the Framingham study [29]. Manifestations of atherosclerosis occurred at two to three times the general population rate in persons with LVH.

●Among more than 15,000 patients in the Atherosclerosis Risk in Communities Study who were followed for 15 years, both women and men with baseline ECG-identified LVH were significantly more likely to die from CVD than from non-CVD causes (HR in women 8.4, 95% CI 4.5-15.6, HR in men 4.9, 95% CI 3.0-7.8) [30].

Echocardiographic evidence of LVH (eccentric or concentric), which is more sensitive than the ECG, also is predictive of cardiovascular risk.

Endothelial dysfunction — Endothelial dysfunction induced by dyslipidemia and oxidative stress is an initial step in atherosclerosis. Several studies have found that coronary artery endothelial dysfunction and increased vascular oxidative stress predict long-term progression of atherosclerosis and an increased incidence of cardiovascular events [32-34]. (See "Coronary endothelial dysfunction: Clinical aspects".)

Endothelial progenitor cells — Endothelial progenitor cells (EPCs) are derived from the bone marrow and are thought to support the vascular endothelium and prevent the development of atherosclerosis. (See "Coronary endothelial dysfunction: Clinical aspects".)

Decreased numbers of circulation EPCs have been associated with endothelial dysfunction and a higher Framingham risk factor score in patients without established CVD and more frequent atherosclerotic events including death at 10 to 12-month follow-up of patients with established CVD [35-37].

The mechanisms by which EPCs might be reduced in patients with or at risk for CVD are not well understood. Two possible contributing factors are selective functional exhaustion of hematopoietic progenitor cells in bone marrow and peripheral blood in ischemic cardiomyopathy and an increased plasma concentration of asymmetrical dimethylarginine (ADMA) [38,39].

Asymmetrical dimethylarginine — ADMA is an endogenous nitric oxide synthase inhibitor that may be an independent risk factor for endothelial dysfunction and CVD [40]. Patients with and without established CHD and elevated levels of serum ADMA have an increased risk of acute coronary events compared with individuals with lower ADMA levels [41-43]. In a systematic review and meta-analysis which included 19,842 patients from 22 studies (mean follow-up 7.1 years), individuals in the top tertile of ADMA levels were at significantly greater risk of CVD (RR 1.42, 95% CI 1.29-1.56), CHD (RR 1.39, 95% CI 1.19-1.62), and stroke (RR 1.60, 95% CI 1.33-1.91) compared with patients with ADMA levels in the lowest tertile.

Proton pump inhibitors (PPIs), commonly used to reduce gastric acid secretion in a variety of gastrointestinal disorders, increase ADMA levels by inhibiting the enzymatic degradation of ADMA, a result which has been shown ex vivo in cultured human endothelial cells and saphenous vein segments, and in vivo in a mouse model [44]. This suggests a potential mechanism for the increased number of cardiac events following coronary artery intervention among patients taking both clopidogrel and a PPI. (See "Clopidogrel resistance and clopidogrel treatment failure".)

Because the elevation of ADMA in patients taking PPIs is not specific to those also taking clopidogrel, it stands to reason that an increased risk for cardiovascular events may also extend to the general population of PPI users. However, there are no published data to support or refute this.

Heart rate — Resting and peak exercise heart rate may be predictive of cardiovascular and CHD mortality [45-51]. This has been studied in several population-based cohorts, the largest of which involved 53,322 persons (24.5 percent women) who were followed for an average of 15 years (but some as long as 30 years) [49]. Compared with persons with a resting heart rate <60 beats per minute, those with a resting heart rate of 80 or more beats per minutes had significantly higher all-cause (HR 1.66, 95% CI 1.45-1.89) and cardiovascular (HR 1.87, 95% CI 1.52-2.30) mortality.

Changes in resting heart rate over time also correlate with an increased risk of CHD death. In a prospective cohort study of 29,325 Norwegians (46 percent men) without known CHD, resting heart rate was measured on two occasions approximately 10 years apart, after which the group was followed for an average for 12 years [52]. Persons with a resting heart rate <70 bpm at the initial but >85 bpm at second visit had a significantly high risk of CHD death (adjusted HR 1.9 compared with persons with resting heart rate <70 bpm at both visits, 95% CI 1.0-3.6). Similar results were noted for persons with a resting heart rate of 70 to 85 bpm at the initial but >85 bpm at second visit (adjusted HR 1.8, 95% CI 1.2-2.8).

A lower-than-expected peak heart rate during exercise, known as chronotropic incompetence, is also predictive of CHD and all-cause mortality [53]. (See "Prognostic features of stress testing in patients with known or suspected coronary disease", section on 'Heart rate response to exercise'.)

Reduced heart rate variability is also associated with a greater risk of CHD. (See "Evaluation of heart rate variability".)

Retinal vessel caliber — Retinal arteriolar narrowing or retinal venous dilation is associated with an increased risk for the development of CHD [54,55]. A meta-analysis of over 22,000 patients in six studies suggested that this relationship is present only in women [55].

OTHER SYSTEMIC CONDITIONS

Autoimmune disease — Autoimmune diseases, and inflammatory conditions in general, are associated with an increased risk of CVD, likely due to chronic and systemic inflammation disease processes attributed to proinflammatory cytokines and autoantibodies.

In a 2022 population-based matched cohort study of over 440,000 persons with a new diagnosis of an autoimmune disease who were free from CVD in the following 12 months, 15.3 percent of people with an autoimmune disease developed incident CVD during a median follow-up of 6.2 years compared with 11.0 percent of controls [56]. Among the autoimmune diseases, the risk of CVD was highest for systemic sclerosis (hazard ratio [HR] 3.59, 95% CI 2.81-4.59), Addison’s disease (HR 2.83 95% CI 1.96-4.09]), systemic lupus erythematosus (HR 2.82, 95% CI 2.38-3.33), and type 1 diabetes (HR 2.36, 95% CI 2.21-2.52). The risk was also higher among adults under the age of 45 years (HR 2.33, 95% CI 2.16-2.51) than in those 55 to 64 years (HR 1.76, 95% CI 1.67-1.85) or ≥75 years (HR 1.30, 95% CI 1.24-1.36). The risk of CVD increased with the number of autoimmune diseases present (one disease: HR 1.41, 95% CI 1.37-1.45; two diseases: 2.63, 95% CI 2.49-2.78; three or more diseases: 3.79, 95% CI 3.36-4.27).

A discussion of CVD in several autoimmune diseases is discussed elsewhere. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications" and "Coronary artery disease in systemic lupus erythematosus" and "Cardiac manifestations of systemic sclerosis (scleroderma)".)

Androgen deficiency — Epidemiologic studies have shown that reduced serum testosterone concentrations are associated with the subsequent development of metabolic syndrome, diabetes mellitus, and elevated C-reactive protein levels in addition to higher overall mortality [57]. Among a cohort of 930 British men with angiographically documented coronary heart disease (CHD) prospectively observed for a mean of seven years, those with low testosterone levels (bio-available testosterone <2.6 nmol/L, 21 percent of the group) had significantly greater mortality (21 versus 12 percent in those with normal testosterone levels) [58].

Additionally, several observational studies and retrospective analyses of randomized trials have shown an association between therapeutically reduced androgen levels (ie, as treatment for prostate cancer) and higher rates of CVD and mortality. However, a systematic review and meta-analysis of randomized trials of androgen deprivation therapy (ADT) showed that ADT was not associated with increased risk of cardiovascular death [59]. Detailed discussions of these data are presented elsewhere. (See "Approach to older males with low testosterone" and "Side effects of androgen deprivation therapy", section on 'Potential cardiovascular harm'.)

Testosterone therapy — Normalization of testosterone levels with testosterone replacement therapy (TRT) may affect the risk of CVD in men. Also, the effects of testosterone therapy on cardiovascular risk in post-menopausal women are not clear. These issues are discussed separately (See "Testosterone treatment of male hypogonadism", section on 'Cardiovascular risks' and "Overview of androgen deficiency and therapy in females", section on 'Risks and side effects of androgen therapy'.)

Collagen vascular disease — Patients with collagen vascular disease, especially those with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), have a significantly increased incidence of CVD. In the Nurses' Health Study, those with RA for more than 10 years, compared with those without RA, had an increased risk of CVD (relative risk [RR] 3.1, 95% CI 1.64-5.87) [60]. An even higher RR has been demonstrated for patients with SLE, especially among young women [61]. This is discussed in greater detail elsewhere (see "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications" and "Coronary artery disease in systemic lupus erythematosus" and "Overview of established risk factors for cardiovascular disease").

Infection — Acute infectious illnesses may be associated with a transient increase in the risk of cardiovascular events [62-64]. In addition, it has been proposed that certain types of infections may play a role in the pathogenesis of atherosclerosis by establishing a low-grade persistent inflammatory process; acute or chronic inflammation may result in endothelial dysfunction and may be responsible for a cardiac event.

●Specific infectious organisms – The major organisms that have been studied with respect to chronic inflammation are Chlamydia pneumoniae, cytomegalovirus, and Helicobacter pylori; however, enterovirus (coxsackie viral infection), hepatitis A virus, and herpes simplex virus type 1 and type 2 have also been implicated.

Large randomized trials do not support benefit from antibiotic therapy against C. pneumoniae to reduce coronary events. (See "Pathogenesis of atherosclerosis", section on 'Infection'.)

●Influenza – Several studies have shown an association between influenza infection and increased risk of acute MI within seven days after respiratory infection. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis", section on 'Cardiac complications'.)

●SARS-CoV-2 – The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the coronavirus disease 2019 (COVID-19) pandemic, has been associated with myocardial injury and potential increased risk for MI and other vascular disease events [65,66]. This is discussed in detail elsewhere. (See "COVID-19: Evaluation and management of cardiac disease in adults" and "COVID-19: Myocardial infarction and other coronary artery disease issues".)

●Endotoxin – It has been proposed that exposure to sustained high levels of endotoxin constitutes a risk factor for atherosclerosis [67].

●Periodontitis – The potential association between chronic periodontitis and CHD is discussed elsewhere. (See "Epidemiology, pathogenesis, and clinical manifestations of odontogenic infections", section on 'Association with cardiovascular risk'.)

Iron overload — Heart disease is a manifestation of iron overload in hereditary hemochromatosis (HH). Whether minimal degrees of iron overload in HH heterozygotes increases cardiovascular risk remains controversial. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Cardiac iron overload'.)

Nonalcoholic fatty liver disease — Nonalcoholic fatty liver disease (also referred to as nonalcoholic steatohepatitis) is a clinico-histopathological entity with features that resemble alcohol-induced liver injury that occurs in patients with little or no history of alcohol consumption. Although its etiology is unknown, it is frequently associated with obesity, type 2 diabetes mellitus, and hyperlipidemia.

While patients with nonalcoholic fatty liver disease often meet the diagnostic criteria for the metabolic syndrome, there is evidence for an increased risk of incident CVD that is independent of the risk conferred by traditional risk factors and components of the metabolic syndrome [68,69]. (See "Overview of established risk factors for cardiovascular disease", section on 'Metabolic syndrome' and "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Associated disorders'.)

Abnormal sleep — Abnormal sleep duration, both too little and too much, has been associated with an increased risk of CVD [70-72]. Obstructive sleep apnea is associated with an increased risk for coronary artery disease, cardiac arrhythmias, systemic hypertension, and pulmonary hypertension. These relationships are discussed elsewhere. (See "Insufficient sleep: Definition, epidemiology, and adverse outcomes", section on 'Cardiovascular morbidity' and "Obstructive sleep apnea and cardiovascular disease in adults".)

Small for gestational age — Adults who were small-for-gestational-age infants are at increased risk for ischemic heart disease and related disorders including hypertension, stroke, diabetes, and hypercholesterolemia [73-76]. It is possible that the association between small-for-gestational-age and CVD can be explained by other maternal or socioeconomic factors [75]. (See "Possible role of low birth weight in the pathogenesis of primary (essential) hypertension".)

CIRCULATING SERUM OR PLASMA MARKERS

Aldosterone — Elevated plasma aldosterone levels are seen in numerous clinical conditions, including hypertension and heart failure, with evidence suggesting that increased aldosterone levels are associated with greater CVD mortality [77,78]. Results from one prospective cohort study of 3153 patients (average follow-up 7.7 years) in whom plasma aldosterone levels were measured at the time of coronary angiography suggested greater all-cause and cardiovascular mortality among patients in the top three quartiles of plasma aldosterone concentration (most of whom had an aldosterone concentration considered to be in the normal range for this assay) compared with those in the lowest quartile, even after adjusting for traditional coronary heart disease (CHD) risk factors [77]. Further studies are needed before recommending this test in the general population.

Antibodies against oxidized LDL — In healthy men aged 50 years, circulating immune complexes and autoantibodies against oxidized low-density lipoproteins (LDL) and cardiolipin predict the occurrence of a myocardial infarction (MI) within the subsequent 20 years; the predictive power was independent of that of other risk factors [79]. In patients with CHD an elevated titer of antibodies against oxidized LDL independently predicts the progression of atherosclerosis over six months [80].

BNP and N-terminal pro-BNP — Brain natriuretic peptide (BNP) is a natriuretic hormone released from myocardial cells in response to volume expansion and possibly increased wall stress. The N-terminal fragment, N-pro-BNP, is also released into the circulation. Serum BNP and N-pro-BNP are increased in patients with heart failure and are predictors of death and cardiovascular events in asymptomatic patients without heart failure [81]. (See "Natriuretic peptide measurement in heart failure".)

Coagulation factors — The following coagulation factors may be related to cardiovascular risk:

●Plasma fibrinogen levels – Fibrinogen levels are independent risk factors for CVD [82,83]. In a 2005 meta-analysis of over 150,000 healthy, middle-aged adults in 31 prospective studies, there was an approximately log-linear relationship between plasma fibrinogen and any CHD, any stroke, and mortality due to other cardiovascular events [84]. However, in a 2013 meta-analysis of 28 genome-wide association studies involving over 90,000 persons, none of the genetic polymorphisms associated with variations in circulating fibrinogen levels was associated with any increased risk of coronary artery disease or stroke, which raises questions about any genetic component to circulating fibrinogen levels [85].

It is not known whether elevated plasma fibrinogen plays a causal role in CVD progression. Animal experiments have shown that an increase in plasma fibrinogen can accelerate thrombus formation and increase blood vessel intimal thickness [86,87]. However, elevated plasma fibrinogen could simply be a marker of chronic vascular inflammation that in itself does not contribute to CVD progression. A meta-analysis of genetic fibrin variants associated with hyperfibrinogenemia found no increased risk of CVD, suggesting that elevated fibrinogen alone does not cause atherosclerosis [88]. Additional studies are necessary to determine if true causal relationships exist between hyperfibrinogenemia and CVD in humans and to determine if therapeutic interventions that lower plasma fibrinogen (or improve fibrinolysis) could reduce CVD.

●Fibrin turnover – Preliminary data suggest an association between CHD and elevated levels of fibrin D-dimer, which reflects fibrin turnover in the circulation [89,90].

●Thrombomodulin – This is an integral membrane glycoprotein that has a major role in the regulation of intravascular coagulation. It has anticoagulant activity since, in concert with thrombin, it activates protein C (see "Overview of hemostasis"). Soluble thrombomodulin showed a strong, graded, inverse association with coronary artery disease in one study [91], and one polymorphism of thrombomodulin was associated with an increased risk of CHD in Black persons.

●von Willebrand factor – There are conflicting data as to whether elevated plasma von Willebrand factor (vWF) concentrations predict an increased risk of CVD [83,90,92-94]. A report from the Framingham Offspring Study found the higher levels of vWF were associated with an increased risk of CVD only in patients with diabetes mellitus [95].

●Hemophilia – Patients with hemophilia and carriers of hemophilia appear to have a reduced risk of CHD mortality [96,97]. The protective effect against CHD appears to be less in carriers of hemophilia [98].

●Coagulation factors – The relationship between the activity of coagulation factors XI, XII, VIII and IX, and the risk of a first MI in men was increased with higher levels of factor XI activity and lower levels of factor XII activity, and the highest risk was found among men with both high levels of factor XI and low factor XII activities [99]. Higher levels of factor VIII and IX activity were also associated with an increased risk of MI in men.

Homoarginine — Homoarginine, an amino acid derived from lysine that serves as a precursor of the vasodilator nitric oxide (NO), may enhance endothelial function, thereby lowering cardiovascular risk. In a cohort of 3305 patients with angiographically proven CHD (78 percent) or at high risk for CHD who were prospectively followed for nearly eight years, those in the lowest quartile of homoarginine levels had a fourfold higher risk of death from CVD (adjusted hazard ratio [HR] 4.1 compared with highest quartile, 95% CI 3.0-5.7) [100]. Further studies are needed before recommending this test in the general population.

Leptin — Leptin plays a role in fat metabolism and correlates with insulin resistance and other markers of the metabolic syndrome and was shown in the WOSCOPS trial of primary prevention to be predictive of CHD events after adjusting for body mass index (BMI) and other classic risk factors [101].

Serum phosphate — In patients with chronic kidney disease (CKD) or established CHD, a higher serum phosphate or calcium-phosphate product is associated with increased cardiovascular mortality. (See "Risk factors and epidemiology of coronary heart disease in end-stage kidney disease (dialysis)", section on 'Risk factors unique to chronic kidney disease' and "Vascular calcification in chronic kidney disease".)

There is also evidence that a higher serum phosphate level is associated with an increased risk of CVD in persons without known CHD or CKD [102,103].

Trimethylamine-N-oxide — Trimethylamine-N-oxide (TMAO), produced through intestinal microbial metabolism of dietary lecithin, appears to contribute to the development of atherosclerotic plaques through its interactions with macrophages and foam cells [104]. Plasma TMAO levels have been shown to decline following the suppression of intestinal microorganisms with oral broad-spectrum antibiotics and then return to near previous levels following the withdrawal of antibiotics [105].

●TMAO levels were measured in a cohort of 4007 patients (mean age 63 years, 64 percent male) who underwent elective coronary angiography (74 percent of patients had one or more coronary artery with 50 percent or greater stenosis) and were followed for an average of three years [105]. After adjusting for standard cardiac risk factors, increased levels of plasma TMAO were associated with significantly greater risk of death, MI, or stroke (adjusted HR for highest versus lowest quartile 1.88, 95% CI 1.44-2.44).

●In a systematic review and meta-analysis of 26,167 patients from 17 studies, with a mean follow-up of 4.3 years, high TMAO levels were associated with increased risk of all-cause death (HR 1.9, 95% CI 1.4-2.6), albeit with a high degree of heterogeneity between the studies (I² = 94 percent) [106]. The risk of major adverse cardiac events was also significantly greater among patients with high TMAO levels (HR 1.7, 95% CI 1.3-2.1, I² = 46 percent).

●Increasing TMAO levels have also been correlated with increased atherosclerotic plaque burden [107].

Given the association between TMAO levels and atherosclerotic events as well as the potential for modification of TMAO levels based on intestinal microbiota, TMAO levels may be a future target for therapies aimed at lowering the risk of atherosclerotic events. Prior to this, however, these findings will need to be replicated in other populations.

TMAO levels have also been investigated as prognostic markers in patients with heart failure and possible acute coronary syndromes.

●In a single-center cohort of 720 patients with heart failure who underwent coronary angiography and were followed for five years, median TMAO levels were higher in the heart failure cohort than in a healthy control cohort [108]. Within the heart failure cohort, 207 deaths occurred during the five-year follow-up; patients with TMAO levels in the highest quartile had significantly higher mortality (HR 3.4 compared with lowest quartile, 95% CI 2.2-5.2). As with TMAO levels and atherosclerotic events, TMAO levels in heart failure patients may be a future target for therapies aimed at lowering the risk of heart failure events, but additional data are needed that replicate these findings in other populations. (See "Epidemiology of heart failure".)

●In a single-center cohort of 530 consecutive patients who presented with chest pain suspected to be cardiac in nature, elevated TMAO levels at presentation were associated with greater risk of major adverse cardiac events (MI, stroke, revascularization, and death) at 30 days (odds ratio [OR] 6.3, 95% CI 1.9-21.0) and six months (OR 5.7, 95% CI 1.9-16.7) as well as an increased risk of long-term mortality (OR 1.81 at 7 years, 95% CI 1.04-3.15) [109]. (See "Risk factors for adverse outcomes after non-ST elevation acute coronary syndromes", section on 'Biomarkers'.)

Urate — Large epidemiologic studies have shown that hyperuricemia is associated with an increased incidence of CHD and increased mortality in those with and without preexisting CHD [110-114]. Proposed mechanisms for such an increase in risk include the development of hypertension and oxidative stress [115,116]. It is unclear if hyperuricemia has a causal effect or, as has been more often suggested, is simply a marker for other risk factors such as hypertension, dyslipidemia, and diabetes [117-121].

Hyperuricemia has also been identified as a risk factor for mortality in patients with heart failure, where it may be a reflection of decreased tissue perfusion. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Hyperuricemia'.)

Ceramides — Serum ceramides (the combination of sphingosine and a fatty acid) are being investigated as potential cardiovascular risk factors due to their role in atherosclerosis, diabetes, and inflammation [122]. Greater plasma ceramide levels are associated with an increased risk of cardiovascular death [123] and major adverse cardiac events [124] in patients with stable coronary artery disease, independent of traditional risk factors including lipid and C-reactive protein levels. Simvastatin has been reported to lower ceramide concentrations by approximately 25 percent [125]. However, measurement of serum ceramides is not widely available outside of research settings.

Angiotensin-converting enzyme 2 — In a global, community-based, case-cohort analysis of over 10,000 persons, analyzing data from the Prospective Urban Rural Epidemiology (PURE) study with a nine-year follow-up, higher plasma levels of angiotensin-converting enzyme (ACE) 2 were associated with greater risk of cardiovascular death (hazard ratio 1.40, 95% CI 1.27-1.54) as well as stroke and myocardial infarction, independent of age, sex, ancestry, systolic pressure, non-high-density lipoprotein (HDL) cholesterol, smoking, and diabetes [126].

MISCELLANEOUS FACTORS

Air pollution — In the early 21^st century, air pollution emerged as a potentially modifiable risk factor for the development of CVD. Multiple observational studies have demonstrated an association between fine particulate air pollution (primarily from the use of fossil fuels in automobiles, power plants, and for heating purposes) and cardiovascular and cardiopulmonary outcomes, including mortality and acute coronary syndromes [102,127-136].

Specific components of air pollution that have been associated with CVD include fine particulate matter (eg, PM2.5), ozone, carbon monoxide, and sulfur oxides.

Both the American Heart Association (2020) and the European Society of Cardiology (2015) have issued official statements discussing the association between long-term exposure to air pollution and increased risk of developing CVD [137,138].

Short-term exposure to ozone and fine particulate matter have been associated with total mortality [139] and acute coronary ischemic events [132,140-142]. Conversely, regulation of pollution has been associated with short-term reductions in CVD events [143].

We summarize representative evidence on short-term air pollution exposure and risk of CVD:

●Increased risk of myocardial infarction – In a systematic review and meta-analysis of data from 34 studies, exposure to carbon monoxide, nitrogen dioxide, sulfur dioxide, and small particulate matter (less than 10 microns and less than 2.5 microns) were all associated with an increased risk of myocardial infarction (MI), with the overall population attributable risk ranging from 1 to 5 percent [144].

●Increased mortality at levels of air pollution that are lower than suggested air quality standards – In a case-crossover study of more than 22 million deaths between 2000 and 2012 from a United States Medicare database, short-term increases in two different types of air pollution were associated with an increased risk of all-cause mortality (fine particulate matter [RR increase 1.05 percent for each 10 mcg/m³ increase] and ozone [RR increase 0.51 percent for each 10 part-per-billion increase]) [139].

●Exposure to air pollution immediately increases risk of acute coronary syndrome – A separate case-crossover study of 1.3 million people in China showed that an interquartile range increase in concentrations of fine particulate matter (PM2.5), nitric oxide, sulfur dioxide, and carbon monoxide in the 24 hours before onset of acute coronary syndrome were associated with 1.32, 3.89, 0.67, and 1.55 percent higher risks of acute coronary syndrome, respectively [145]. In this study, acute exposure to ozone was not associated with acute coronary syndrome. The association between PM2.5 and acute coronary syndrome was strongest in the concurrent hour of exposure and was then attenuated; the weakest effects were observed 15 to 29 hours after exposure.

●Air pollution bans reduce CVD mortality – Further support for the significance of air pollution comes from a study of death rates in Dublin, Ireland before and after a ban on coal sales that led to a 70 percent reduction in black smoke concentrations [143]. Adjusted cardiovascular deaths fell by 10.3 percent in the six years after the ban.

In addition to short-term effects, there is evidence for an association between long-term air pollution exposure and CVD. We summarize representative evidence for long-term air pollution exposure and CVD:

●Higher mortality from long-term exposure to air pollution – Fine particulate matter in the size 2.5 microns (known as PM2.5) is associated with cardiovascular mortality. Mortality data from nearly 450,000 patients in the American Cancer Society Cancer Prevention Study II database were correlated to geocoded air pollution data, including average concentrations of fine particulate matter (≤2.5 micrometers in diameter [PM2.5]) [133]. In multivariate analysis, PM2.5 (but not ozone) concentration was significantly associated with the risk of death from cardiovascular causes (RR 1.2, 95% CI 1.15-1.26).

●Dose response relationship – Fine particulate matter (PM2.5) is associated with CVD and subclinical atherosclerosis in a dose response fashion. In the Women's Health Initiative Observational study of >65,000 postmenopausal women without prior CVD, the association between residential geocoded air pollution and a first cardiovascular event was evaluated [127]. Unlike prior studies, potential confounding factors such as age and other cardiovascular risk factors were taken into account. A participant’s exposure to a 10 mcg/m³ increase in pollution concentration was associated with an increased risk of any cardiovascular event (hazard ratio [HR] 1.24), death from CVD (HR 1.76), and cerebrovascular events (HR 1.35).

In the prospective MESA Air cohort study involving 6795 participants in six United States metropolitan areas, each increase in PM2.5 of 5 mcg/m³ was associated with 4.8 Agatston units per year progression of coronary calcification [146].

Possible mechanisms by which fine particulate air pollution may increase the risk of CVD include [137]:

●An increase in mean resting arterial blood pressure through an increase in sympathetic tone and/or the modulation of basal systemic vascular tone [147]

●An increase in the likelihood of intravascular thrombosis through transient increases in plasma viscosity and impaired endothelial dysfunction [148]

●The initiation and promotion of atherosclerosis [146,149,150]

The impact of air pollution of the respiratory tract is discussed elsewhere. (See "Chronic obstructive pulmonary disease: Risk factors and risk reduction", section on 'Pollution, biomass, and occupational exposures'.)

Clonal hematopoiesis of indeterminate potential (CHIP) — The term "clonal hematopoiesis of indeterminate potential" (CHIP) is used to describe individuals who have a clonal mutation associated with hematologic neoplasia yet do not meet World Health Organization (WHO) criteria for diagnosis of a hematologic neoplasm. Patients identified with CHIP are thought to be at a higher risk of CVD. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)

Environmental noise — Observational studies have reported an association between chronic exposure to increased environmental noise levels (ie, road noise, noise from low-flying airplanes, etc) and an increased risk of developing CVD or death due to MI [151,152]. This effect is hypothesized to be due to stress-related dysregulation of the autonomic nervous system, leading to increases in hypertension and subsequent CVD.

Genetic markers — Several gene loci that affect the risk for the development of coronary heart disease (CHD) have been investigated in multiple studies, with a meta-analysis of 63,746 CHD cases and 130,681 controls reporting 46 single nucleotide polymorphisms (SNPs) across the genome which are significantly associated with an increased risk of CHD [153]. Among the various implicated SNPs, those appearing on locus 9p21 have shown the strongest association with CHD risk [154-157].

●In a 2010 systematic review that evaluated 47 distinct data sets, including 35,872 cases and 95,837 controls, persons with two abnormal alleles at this locus were more likely to have CHD when compared with persons with one at-risk allele (odds ratio [OR] 1.25, 95% CI 1.21-1.29) [156].

●The association with 9p21 SNPs and an increased risk of developing CHD has also been shown in older adult patients greater than 70 years of age without known prior CHD [158].

●A 2014 systemic review and meta-analysis of 31 cohorts including 193,372 persons confirmed the association between 9p21 variants and the likelihood of a first CHD event (HR 1.19 per risk allele, 95% CI 1.17-1.22) [157]. However, 9p21 variants were not associated with an increased likelihood of subsequent CHD events among persons with known CHD (HR 1.01 per risk allele, 95% CI 0.97-1.06).

However, in spite of an apparently clear association between variants and incident CHD, locus 9p21 SNPs have not been definitively shown to significantly improve on the discrimination or classification of predicted CHD risk compared with the use of traditional risk factors [155,156,158].

A retrospective analysis evaluated the dose effect of abnormal 9p21 SNPs on the burden of CHD [159]. Among 950 non-diabetic patients with early-onset CHD (mean age 56 years) displaying at least one angiographic epicardial stenosis >50 percent seen by coronary angiography, the 9p21 genotype was associated with a risk of left main CHD (OR 2.38 per copy of risk allele, 95% CI 1.48-3.85), three-vessel CHD (OR 1.45 per copy of risk allele, 95% CI 1.18-1.79), and the need for bypass surgery (OR 1.37 per copy of risk allele, 95% CI 1.04-1.79). These data suggest more aggressive CHD occurring at a younger age in patients with abnormal 9p21 genotypes.

Different SNPs have been associated with different manifestations of CHD, with some increasing the risk of coronary atherosclerosis while others increase the risk of plaque rupture and acute MI, suggesting varying impacts of different mutations on the biology and pathophysiology of CHD [160,161]. Additionally, the pathophysiologic impact of genetic variants likely varies depending on other comorbid conditions. In a study which pooled CHD cases and controls from five large cohorts, the same SNP on chromosome 1q25 was associated with a significantly higher risk of CHD among patients with diabetes (OR 1.36 compared with diabetic patients without this SNP, 95% CI 1.22-1.51) but no change in risk of CHD among patients without diabetes (OR 0.99, 95% CI 0.87-1.13) [162]. This suggests the importance of other biologic factors in the development of CHD, and potentially different mechanisms in patients with and without diabetes.

Numerous other genetic abnormalities have been reported to be associated with the risk of CVD. As examples:

●A specific polymorphism in the gene encoding 5-lipoxygenase activating protein (FLAP) has been associated with a twofold increase in the risk of MI and stroke [163]. A FLAP inhibitor reduced both serum C-reactive protein and other biomarkers of risk in patients who sustained an MI [164].

●DAB2IP is a protein located on chromosome 9q33, which is thought to be involved in regulating cell proliferation apoptosis. In a case-control study of nearly 5000 people (1386 cases of CHD, 3532 controls), a polymorphism in this protein was associated with a great likelihood of CHD (OR 1.16, 95% CI 1.05-1.29) [165].

●In a study of 180 genetic variants associated with height among 193,449 persons (including 65,066 cases with CHD and 128,383 controls without CHD), there was a significant increase in CHD risk with decreasing height (13.5 percent for each standard deviation [6 cm] decrease in height, 95% CI 5.4-22.1 percent), with a significant decrease in CHD risk with increasing numbers of height-raising genetic variants [166].

Peripheral blood cell gene expression has also been investigated as a means of estimating the risk of CVD, specifically obstructive CHD, and based on limited data the technique may be comparable to stress testing with myocardial perfusion imaging in terms of accuracy of diagnosing CHD [167-169]. However, the test cannot be used in patients with diabetes, which significantly limits its applicability. As of November 2014, peripheral blood cell gene expression is not widely available for clinical use.

Genetic studies of other cardiac risk factors (eg, cholesterol components) are discussed separately. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia" and "HDL cholesterol: Clinical aspects of abnormal values", section on 'Low HDL cholesterol as a cause of ASCVD events'.)

Genetic risk scores — Although individual genetic markers are associated with CVD, their aggregate effect on risk beyond traditional factors has not been definitively established [170-174]. Several studies have evaluated the use of genetic risk scores as markers of cardiovascular risk:

●A genetic risk score created from 101 SNPs associated with CVD did not improve discrimination or reclassification of risk after adjustment for traditional factors in a cohort of over 19,000 White women [171].

●Using up to 50 SNPs to arrive at a polygenic risk score, the genetic risk for CHD was quantified in three prospective cohorts (ARIC, Women's Genome Health Study, and Malmo Diet and Cancer Study), along with assessment of healthy lifestyle factors (no current smoking, no obesity, regular physical activity, and healthy diet) [172]. Participants in the highest quintile of polygenic risk score had a 91 percent high risk of incident CHD events (HR 1.91, 95% CI 1.75-2.09). Participants with a favorable lifestyle (at least three of four healthy lifestyle factors) had a lower risk of CHD events at all levels of genetic risk, including a 46 percent reduction in risk among the highest quintile of polygenic risk score (HR 0.54, 95% CI 0.47-0.63), emphasizing the importance of lifestyle factors in CHD risk.

●A coronary artery disease risk score that identified 163 coronary artery disease risk loci from genome-wide association study (GWAS) analyses has been published, and the authors state that approximately 30 to 40 percent of the heritability of coronary artery disease is accounted by the aggregate information in this analysis. Gene variants of special interest were associated with PCSK9, NPC1L1, LPA, LPL, APOC3, ANGPLT4, and ANGPTL3 [175].

●In a study of over 55,000 participants, both genetic and lifestyle factors were associated coronary artery disease risk. Among participants at high genetic risk, a favorable lifestyle (defined as at least three of the four healthy lifestyle factors) was associated with a 46 percent lower relative risk of coronary events than an unfavorable lifestyle (defined as no or only one healthy lifestyle factor [172]. Other reports, based on more than 60,000 coronary artery disease cases and more than 120,000 controls, have shown that a coronary artery disease polygenic risk score is normally distributed and risk aggregates at right tail (high risk) of the distribution [176]. Investigators have begun to critically assess the relative merits of using polygenic risk scores to predict atherosclerotic CVD (ASCVD) events versus the traditional approach that uses information such as age, sex, smoking, diabetes mellitus status, lipid measures, blood pressure, and risk factors [177,178].

Socioeconomic and psychosocial factors

●Socioeconomic factors – Social determinants of health, including education, occupation, place of residence, and income, or combinations of these, have been associated with an increased risk for CVD, especially CHD, and cardiovascular mortality [179-184].

●Psychosocial factors – External situations that can potentially affect an individual's psychological health as well as the presence of mood disorders have both been linked with long term cardiovascular disease [185]. The precise role of psychological factors is difficult to delineate because of challenges in measuring, quantifying, and determining cause and effect. As an example, major depression can also be associated with established cardiovascular risk factors (such as smoking and low physical activity) [186,187].

•Mood disorders – The topics most commonly considered have been depression and anxiety. In addition, psychological stress can affect risk factor control, compliance with healthy lifestyle patterns, and adherence to medications. (See "Psychosocial factors in coronary and cerebral vascular disease".)

Vitamins, antioxidants and homocysteine — Data are available assessing the effects of numerous vitamins, antioxidants, and homocysteine on CHD risk.

●Oxidation of low-density lipoprotein (LDL) particles appears to be associated with an increased risk of atherosclerosis, suggesting that antioxidant therapy may reduce the incidence of CVD. Despite this association, randomized prospective studies of vitamin E, vitamin C, and beta-carotene have shown no clear evidence of benefit [188-190].

●Both cross-sectional and prospective studies have linked elevated levels of homocysteine to increased risk for CHD. Higher serum homocysteine concentrations are frequently accompanied by reduced levels and intake of folate and vitamin B12. However, numerous prospective randomized trials of folate supplementation to lower serum homocysteine have demonstrated no reduction in major cardiovascular outcomes (eg, death, MI, stroke).

The addition of a serum homocysteine measurement to the Framingham risk score has been shown to improve risk prediction, with net reclassification of between 13 and 20 percent of patients from two cohorts [191]. The majority of those affected were reclassified to a higher risk level. The estimation of cardiovascular risk is discussed in greater detail separately. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)

Cysteine is structurally and metabolically related to homocysteine, and the plasma total cysteine concentration is strongly related to several risk factors for CVD [192]. Although both low and high plasma total cysteine concentrations have been associated with an increased risk of peripheral vascular disease, there is no significant relationship to coronary disease after adjustment for plasma homocysteine [193].

●The effect of calcium supplementation on risk of CVD is controversial. While calcium supplementation may result in improvements in weight, blood pressure, and serum cholesterol concentrations (of approximately 5 percent) in patients with mild to moderate hypercholesterolemia, several meta-analyses have come to differing conclusions regarding CVD outcomes, with some suggesting an increased risk of CVD and others suggesting no increase in CVD risk. None of the trials (included in the meta-analyses), however, were designed to assess the effects of calcium or vitamin D on cardiovascular outcomes. As such, we do not restrict the use of calcium supplementation in patients with or at high risk for CVD and recommend optimal daily intake as discussed separately. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Side effects' and "Calcium and vitamin D supplementation in osteoporosis", section on 'Optimal intake'.)

MULTIVARIABLE RISK PROFILES — Multivariable risk models, such as the Framingham risk score and the SCORE project in Europe, have been developed in an attempt to estimate short-term (eg, 10-year) cardiovascular risk in patients without known CVD. These models and the clinical use of risk assessment are presented elsewhere. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)

Most risk-score algorithms assess risk over an intermediate follow-up interval of approximately 10 years and can help to guide interventions because categories of the risk factors are provided. Research from long-term cohort studies has also provided lifetime risk estimates.

Less detail on the individual risk factors is available with multivariable approaches to lifetime risk, but they can be used to help motivate patients to adhere to interventions. For example, the lifetime risk of CVD in a 50-year-old man with one major risk factor is approximately 10 percent by age 60 and rises to nearly 70 percent for men who live to age 90 years.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Assessment of cardiovascular risk".)

SUMMARY — An overview of the many possible emerging cardiovascular disease (CVD) risk factors that have a weak or proposed association with a greater risk of developing CVD is presented here. An overview of the established risk factors for CVD (eg, hyperlipidemia, hypertension, smoking) is discussed elsewhere. (See "Overview of established risk factors for cardiovascular disease".)

●Cardiovascular factors – Cardiovascular factors associated with CVD include arterial intima-media thickness (IMT), arterial stiffness, arterial calcification, endothelial dysfunction, higher resting heart rates, and left ventricular hypertrophy (LVH). (See 'Cardiovascular factors' above.)

●Systemic conditions – The systemic conditions associated with greater risk of CVD include collagen vascular disease, androgen deficiency, infection, iron overload, obstructive sleep apnea, and being born small for gestational age. (See 'Other systemic conditions' above.)

●Circulating serum or plasma markers – These include aldosterone, antibodies against oxidized low-density lipoprotein (LDL), brain natriuretic peptide (BNP), coagulation factors, homoarginine, leptin, phosphate, trimethylamine-N-oxide (TMAO), and urate. (See 'Circulating serum or plasma markers' above.)

●Other factors – Other factors such as genetic markers, air pollution, and socioeconomic factors have also been reported to be associated with greater risk of CVD. (See 'Miscellaneous factors' above.)