Screening for coronary heart disease

INTRODUCTION — Coronary heart disease (CHD) is a leading cause of death around the world. Although there is interest in screening for CHD, questions persist regarding the appropriateness, cost-effectiveness, and optimal approach to such screening.

Screening for CHD should be distinguished from estimation of risk for CHD. By definition, both are performed in asymptomatic persons, and both aim to improve outcomes with interventions, if indicated. However, screening for CHD identifies existing disease rather the likelihood of future events related to CHD. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)

The issues surrounding screening for CHD will be reviewed here, with particular emphasis on the effectiveness of available screening methodologies. Screening for CHD in patients with diabetes, generally a higher-risk population, is discussed in detail separately. (See "Screening for coronary heart disease in patients with diabetes mellitus".)

RATIONALE FOR SCREENING — Advanced obstructive coronary heart disease (CHD) can exist with minimal or no symptoms, with manifestations that can progress suddenly and/or rapidly. The first clinical manifestations of CHD (eg, acute myocardial infarction, unstable angina, or sudden cardiac death) are often associated with significant morbidity and/or mortality [1].

The rationale for screening and subsequent detection of CHD during the subclinical stages of disease is the hope that appropriate treatment (medical therapy or coronary revascularization) may improve prognosis [2].

Screening may be appropriate for persons in certain high-risk occupations (eg, pilots, bus drivers) where an acute cardiac event could endanger large numbers of people, or for individuals with higher perceived risk of CHD who are beginning an exercise program. However, although screening can identify patients with CHD at increased risk, there is a paucity of evidence that such screening actually improves outcomes. (See 'Treatment' below.)

Bayesian considerations — Understanding the theory of conditional probability (Bayes' theorem) as applied to medical decision-making is useful in understanding the utility of screening tests for CHD [3]. Diagnostic test performance is discussed in detail elsewhere. (See "Glossary of common biostatistical and epidemiological terms", section on 'Measures of diagnostic test performance'.)

The pretest likelihood of CHD in a population influences the posttest risk of having CHD. A positive result is likely to be a true positive result (ie, a low false-positive rate) in a population with a high pretest risk for CHD, while a negative test is likely to be falsely negative (figure 1). Conversely, in a population with a low pretest risk for CHD, a positive test is only weakly correlated with the presence of CHD (ie, a high false-positive rate), while a negative test is highly predictive of the absence of CHD. Thus, when performing a screening test, the result (positive versus negative) has the greatest impact to differentiate high versus low posttest probability of disease in a population with an intermediate pretest probability of disease.

In the case of CHD, as in other diseases, testing in low-risk subjects can add to the costs of care without significant benefit, as positive screening results can lead to unnecessary tests and procedures. Conversely, in persons with a high estimated CHD risk, testing should be approached keeping in mind the higher likelihood of false negatives.

The pretest probability of CHD has, for decades, been based on patient age, sex, and typicality of anginal symptoms, as validated using invasive coronary angiography [4,5]. However, since subsequent studies have found symptom-based pretest probabilities to be overestimated, especially in patients with symptoms of atypical angina, a clinician-patient discussion for shared decision-making is warranted before ordering a screening study [6].

OUR APPROACH — By definition, screening for a medical condition takes place in asymptomatic persons without a history of the disease in question. Therefore, our approach to screening starts with determining coronary heart disease (CHD) disease status (see 'Bayesian considerations' above). All patients aged 20 years or older without established cardiovascular disease (CVD) should undergo periodic cardiovascular risk assessment every three to five years. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach", section on 'Our approach to ASCVD risk assessment'.)

History and physical examination — We do not perform screening tests to evaluate for CHD on the basis of cardiovascular risk factors alone. Estimation of cardiovascular risk requires both a history identifying risk factors and a formal or informal risk score calculation. Our approach to estimation and mitigation of cardiovascular risk in an asymptomatic patient is presented in detail separately. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)

●History – Questions should focus on detection of angina or angina equivalent symptoms as well as an assessment of lifestyle factors, including the level of physical activity and overall fitness, dietary choices, smoking, intake of alcohol, use of illicit drugs, emotional stress, and quality of sleep, all of which impact cardiovascular risk.

A family history of premature atherosclerotic disease or sudden cardiac death is often associated with an increased risk of CHD. (See "Overview of established risk factors for cardiovascular disease", section on 'Family history'.)

●Risk score calculation – A variety of cardiovascular risk scores have been developed and validated in different populations, with no single risk score being optimal for every patient. (See "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)

Who should be screened? — Candidates for CHD screening are generally members of one or more "special populations" in which a CHD event may pose unique or additional risks beyond those in the average population, including competitive athletes and persons with high-risk occupations, avocations, or public safety occupations. In these populations, the decision to screen may be driven by a need to satisfy regulatory or other requirements rather than by traditional medical decision-making.

Screening for CHD in asymptomatic patients with diabetes mellitus, generally a population at higher risk of CVD, is discussed separately. (See "Screening for coronary heart disease in patients with diabetes mellitus".)

Pre-participation testing for athletes — Pre-participation evaluation of asymptomatic patients differs slightly depending on whether the goal of the athlete is recreation or competition:

●Recreational athletes – For asymptomatic patients who have been fairly sedentary and who plan to begin a recreational exercise program, no pre-participation testing is mandatory prior to beginning an exercise program [7-9]. Some patients, however, may request reassurance that they will be able to actively exercise; in such cases, medical clearance is appropriate, with exercise testing being at the discretion of the provider per the American College of Sports Medicine [8,9]. This is discussed in detail elsewhere. (See "Exercise for adults: Terminology, patient assessment, and medical clearance", section on 'Medical assessment and clearance for exercise'.)

Screening in this population is of limited value as both the prevalence of CHD and the sensitivity of testing is low. For example, only 2 percent of 3617 asymptomatic, hypercholesterolemic men who underwent exercise electrocardiogram (ECG) testing at baseline prior to an exercise program experienced an activity-related acute cardiac event during follow-up (average of 7.4 years) [10]. Although the risk of a cardiac event was increased 2.6-fold in patients with clinically silent, exercised-induced ST-segment changes during submaximal exercise treadmill test (ETT) at study entry, only 11 of the 62 men who experienced an activity-related event had a positive ETT at entry (sensitivity 18 percent).

●Competitive athletes – Professional societies in both North America and Europe have published recommendations for pre-participation screening for young competitive athletes (those younger than 35 years of age). A full discussion of screening prior to participation in competitive athletics is presented separately. (See "Screening to prevent sudden cardiac death in competitive athletes".)

Public safety occupations, high-risk occupations, and high-risk avocations — Some asymptomatic patients who have an occupation associated with public safety (eg, airline pilots, bus drivers, truck drivers) or a high-risk occupation or avocation (eg, scuba divers) are required by regulatory agencies or governing bodies to have routine testing as part of a periodic health assessment. In such patients, our experts typically proceed with the requested testing. In the absence of any mandated testing, our experts do not perform regular screening or routine pre-participation testing in these otherwise asymptomatic patients.

Other patients — Outside of the specific situations mentioned above, CHD screening tests are generally not recommended for asymptomatic patients, and cardiac stress testing should not be part of a routine annual physical or health screening examination. However, there are other patients in whom we perform stress testing: patients who need reassurance that it is safe for them to be active, in which a stress test can help providers delineate an activity program with specific levels of exercise to achieve; and patients who have an occupation in which high levels of exertion may be routinely required (eg, farmer).

Persons in whom screening to detect CHD is not indicated — Screening does not apply to individuals with established CVD or CVD risk equivalents. Such patients should be treated with appropriate secondary prevention measures. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

Screening does not apply to patients with symptoms suggestive of CHD. Such patients should be evaluated for CHD or with appropriate diagnostic testing. (See "Outpatient evaluation of the adult with chest pain" and "Stress testing for the diagnosis of obstructive coronary heart disease".)

SCREENING TESTS

Choice of test — The choice of screening test depends on the patient and the circumstances in which the test is being ordered. In general, if a patient can exercise, it is best to have them exercise rather than to perform a pharmacologic stress test.

It is best to begin with a physiologic assessment using an exercise stress test in patients who are able to exercise to an anticipated workload of 5 Mets and have an interpretable ECG. In particular, persons who require screening because they wish to begin an exercise program should be screened with an exercise stress test. This will also allow the clinician to outline specific exercise level goals based on their test. In addition, an exercise test is the most appropriate and useful test for persons who require screening and who are at high risk of coronary heart disease (CHD). In symptomatic individuals, an exercise stress test is favored for baseline assessment because a negative test generally avoids any downstream testing.

In asymptomatic individuals at intermediate or high risk who are able to exercise, an exercise stress test is also the first preferred test. For patients who develop a positive stress test at a low workload or >20 percent of the myocardium showing ischemia, invasive coronary angiography is indicated. A positive test at higher workloads may warrant treatment or further workup with additional imaging modalities, and CT angiography would be favored given the advantage of anatomic coronary assessment. However, in those with a higher baseline risk, CT angiography would provide the advantage of an anatomic assessment to help assess extent of underlying disease and deciding next steps in invasive testing.

The anticipated quality of the study in the particular patient should be considered. In patients with anatomical issues such as obesity, quality radionuclide perfusion or echocardiographic images may be difficult to obtain; in patients of advanced age with high incidence of coronary calcium, CT angiography may not be the best option.

Coronary artery calcium (CAC) scoring is most helpful in patients who require screening and who are at intermediate or borderline risk with the presence of risk-enhancing factors, such as a family history of very early coronary artery disease [11]. However, CAC scoring should not be used in high-risk patients due to the likelihood of a false-negative test. For example, a negative scan can frequently occur in patients with familial hypercholesterolemia, especially when young, and gives a false sense of the patient being low risk [11]. High-risk patients with a negative computed tomography (CT) scan for CAC still have an event rate of 15 to 20 percent over the next few years [12]. CAC scoring should be used judiciously in the young (<50 years for females, <40 years for males), because these patients may have a negative scan due to noncalcified plaque, and in older patients (>70 years for females, >60 years for a males), since calcium is frequently present in these age groups.

Exercise stress testing — In patients who will undergo screening, exercise stress testing can indirectly identify the presence or absence of underlying obstructive CHD by assessing for myocardial ischemia [9]. Although exercise electrocardiogram (ECG) testing is a part of the diagnostic evaluation of patients with known or suspected CHD and provides prognostic information in patients with CHD, there is controversy regarding its use in screening asymptomatic individuals [2]. While asymptomatic ischemia detected during exercise ECG testing has predicted increased risk of coronary events and cardiac death at later follow-up [13-19], there are concerns about the predictive value of exercise ECG testing and its relation to the prior probability of disease in the population being tested. (See 'Bayesian considerations' above and "Evaluating diagnostic tests", section on 'Disease prevalence'.)

●Screening exercise ECG testing was performed in more than 10,000 subjects who participated in the Multiple Risk Factor Intervention Trial (MRFIT) and the Lipid Research Clinic's Coronary Primary Prevention Trial (LRCPPT); asymptomatic ischemia detected during baseline treadmill exercise testing predicted an increased risk of coronary events and cardiac death at 7- to 10-year follow-up [13,14].

●In a study of 2994 asymptomatic women who underwent exercise ECG testing and were followed for 20 years, exercise-induced ST segment depression (≥1.0 mm) did not increase the risk of cardiovascular death (age-adjusted hazard ratio [HR] 1.02) [20]. By contrast, women who were below the median for both exercise capacity and heart rate recovery, which were considered measures of fitness, had a 3.5-fold increased risk of cardiovascular death (95% CI, 1.57-7.86) compared with those above the median for both variables.

Stress radionuclide myocardial perfusion imaging and stress echocardiography are alternative approaches to exercise ECG testing [21]. These studies may be particularly useful in patients who are unable to exercise or have uninterpretable ECGs. However, they are expensive and their utility as screening tests has not been well studied. (See "Overview of stress radionuclide myocardial perfusion imaging" and "Overview of stress echocardiography".)

CAC score and CT angiography — Screening can also be performed with CT to obtain a CAC score or to perform noninvasive coronary CT angiography. In the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for cholesterol management (2018) and primary prevention (2019) for those adults at intermediate 10-year risk of atherosclerotic cardiovascular disease (ASCVD; 7.5 to 20 percent) if statin therapy decision remains uncertain, a CAC score to screen for underlying CHD is considered reasonable to help with risk stratification [11]. CAC scoring should not be used in high-risk patients, including those with familial hypercholesterolemia. (See 'Choice of test' above.)

CT angiography is useful in patients with an uninterpretable ECG and in those who cannot exercise [9]. CAC scoring is discussed in detail elsewhere. (See "Coronary artery calcium scoring (CAC): Overview and clinical utilization".)

Ineffective or non-recommended screening tests

Blood tests — We do not perform screening for CHD with blood tests as there are no available blood markers which can diagnose asymptomatic atherosclerosis and CHD.

Measurement of serum cholesterol levels is well-established as part of the assessment of cardiovascular risk but not as a screening test. Similarly, although gene expression testing has been shown to have a relatively high sensitivity and negative predictive value for CHD in symptomatic patients referred for stress testing, it has not been evaluated in asymptomatic patients as a screening tool [22-25]. (See "Overview of possible risk factors for cardiovascular disease", section on 'Genetic markers'.)

Measurement of other markers such as high-sensitivity C-reactive protein is more controversial [7]. The approach to biomarker measurement in assessment of cardiovascular risk is discussed in greater detail in other topics. (See "Overview of established risk factors for cardiovascular disease", section on 'Inflammation' and "Natriuretic peptide measurement in non-heart failure settings", section on 'Predictor of cardiovascular events' and "C-reactive protein in cardiovascular disease" and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Indications for statin therapy'.)

Resting ECG and ambulatory ECG monitoring — We do not perform screening for CHD with resting 12-lead ECG or 24-hour ambulatory ECG monitoring due to their poor sensitivity and specificity [26,27].

Asymptomatic persons with resting ECG abnormalities such as ST depression, T-wave inversion, left ventricular hypertrophy or strain, and premature ventricular contractions have a 2- to 10-fold increased risk of CHD compared with those with a normal ECG [28-30]. In different epidemiologic studies, the presence of variably defined ECG abnormalities has increased the adjusted relative risk for cardiovascular mortality and morbidity by 1.5- to 2.5-fold (figure 2) [28,29]. However, the utility of these findings for screening is limited for the following reasons:

●Approximately 30 to 50 percent of individuals with a normal coronary arteriogram have ECG abnormalities.

●Approximately 30 percent of individuals with angiographically proven CHD have a normal resting ECG [31].

●Most coronary events occur in individuals without resting ECG abnormalities [32].

Ambulatory ECG monitoring is insensitive for detecting the presence of CHD in persons without a prior diagnosis. Although it may be useful for detecting periods of silent ischemia in persons with known obstructive CHD, such periods of ischemia do not necessarily correlate with the presence and extent of ischemia as determined by radionuclide myocardial perfusion imaging [33]. (See "Silent myocardial ischemia: Epidemiology, diagnosis, treatment, and prognosis".)

Invasive coronary angiography — We do not recommend screening with invasive coronary angiography [34]. Although coronary angiography has long been considered the "gold standard" test for the detection of CHD, the risks of performing an invasive procedure in a patient who is otherwise asymptomatic are generally perceived to outweigh any potential benefits. Additionally, the clinical usefulness of identifying high-grade obstructive CHD lesions in predicting the future risk of coronary events is uncertain because arteriography does not assess the morphological and cellular characteristics of a lesion or its functional significance.

However, coronary angiography may be considered in select patients who require CHD screening if other screening modalities (ie, stress testing and/or coronary CT angiography) have yielded nondiagnostic results.

FOLLOW-UP OF A POSITIVE SCREENING TEST — Subsequent evaluation and treatment of those with positive findings on a screening test should be based upon consideration of the patient's risk factors, occupation, cost-effectiveness, and clinical justification for any intervention that might be recommended as a result of the findings on further testing.

Further testing — Patients with indirect evidence of coronary heart disease (CHD) following screening with exercise electrocardiogram (ECG) may or may not have atherosclerotic CHD depending upon the diagnostic accuracy of the test performed and the pretest likelihood of CHD in the individual patient. Since positive exercise ECG tests in asymptomatic patients are often false positives, subsequent testing is generally necessary. The choice of the second test (CT angiography, stress echocardiography, exercise myocardial perfusion imaging) varies on a case-by-case basis, taking into consideration the individual risk and prior stress test modality used. Some general guidelines are below:

●The 2002 American College of Cardiology/American Heart Association (ACC/AHA) guidelines suggested that exercise radionuclide myocardial perfusion imaging or exercise echocardiography has potential use as a second test in asymptomatic patients who have an intermediate- or high-risk Duke treadmill score on a non-imaging exercise ECG testing (even though the score has not been evaluated in asymptomatic patients) [35]. (See "Silent myocardial ischemia: Epidemiology, diagnosis, treatment, and prognosis".)

●Coronary artery calcium (CAC) scoring or coronary CT angiography can also be used as a second test following a positive exercise ECG or positive stress imaging study in cases where we have an abnormal result or an equivocal result, as supported by the 2012 ACC/AHA guidelines for stable ischemic heart disease [36].

●Patients at intermediate or high pretest probability of CHD, and who have a positive result on stress radionuclide myocardial perfusion imaging or stress echocardiography, should be considered for optimization of antiischemic medical therapy with follow-up evaluation versus proceeding with coronary angiography depending on baseline medical therapy, the extent of ischemia, and/or stress workload achieved.

Patients with direct evidence of CHD based on abnormal anatomic findings on CAC score or coronary CT angiography should be considered to have atherosclerotic disease and be treated with appropriate secondary preventive measures. (See 'Treatment' below and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

Treatment — Patients who undergo screening and are found to have evidence of CHD should be treated with appropriate secondary prevention measures (eg, aspirin, blood pressure control, statin therapy, etc) or revascularization. The approach to secondary prevention is discussed in detail separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

Revascularization in patients with silent myocardial ischemia may be appropriate and are discussed in the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) guideline on percutaneous coronary intervention (PCI) and the ACC/AHA guideline on coronary artery bypass graft (CABG) in patients with asymptomatic myocardial ischemia [37,38]. (See "Silent myocardial ischemia: Epidemiology, diagnosis, treatment, and prognosis".)

RECOMMENDATIONS FROM MAJOR SOCIETIES — While recommendations vary regarding the optimal approach to screening for coronary heart disease (CHD), no professional society guideline or consensus statement advocates for universal screening. The following examples of recommendations from major groups are illustrative of the variable recommendations that have been proposed:

●The United States Preventive Services Task Force (USPSTF) made two recommendations in 2018 regarding the use of the resting or exercise electrocardiography (ECG) testing for screening for CHD [27]:

•They recommended against routine screening in adults at low risk for CHD events.

•They concluded that there was insufficient evidence to recommend for or against routine screening in adults at increased risk for CHD events.

●The 2002 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for exercise testing reached a similar conclusion that there is little evidence to support routine exercise testing in asymptomatic adults [39]. They did identify subgroups that might benefit from screening:

•The guidelines concluded that the weight of evidence favors evaluation of asymptomatic patients with diabetes who plan to begin a vigorous exercise program. (See "Screening for coronary heart disease in patients with diabetes mellitus".)

•Exercise testing can also be considered (although the weight of evidence is less clear) in the following patient populations:

-Patients with multiple risk factors for CHD as a guide to risk reduction therapy

-Men over age 45 years and women over age 55 years who are presently sedentary and plan to start a vigorous exercise program

-Patients who are involved in occupations linked to public safety

•Exercise testing can also be considered in patients who have undergone electron-beam computed tomography (EBCT) and have a coronary calcium (CAC) score above the 75^th percentile [39].

●A 2015 clinical guideline from the American College of Physicians recommends against screening low-risk, asymptomatic adults with resting ECG, stress ECG, stress echocardiography, or stress myocardial perfusion imaging [26].

●The American College of Sports Medicine recommends medical clearance prior to beginning an exercise program based on current exercise participation; history of cardiovascular, metabolic, or kidney disease or signs or symptoms suggestive of any cardiovascular metabolic or kidney disease; and desired exercise intensity. There are no specific recommendations regarding exercise treadmill testing (ETT) and pursuing such testing is at the discretion of the medical provider performing medical clearance [40].

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Coronary artery disease (The Basics)" and "Patient education: Nuclear heart testing (The Basics)" and "Patient education: Sudden cardiac arrest (The Basics)")

SUMMARY AND RECOMMENDATIONS

●All patients aged 20 years or older without established cardiovascular disease (CVD) should undergo periodic cardiovascular risk assessment every three to five years. Our approach to estimation and mitigation of cardiovascular risk in an asymptomatic patient is presented in detail separately. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)

●Patients with symptoms suggesting CVD should be evaluated. This is described separately. (See "Outpatient evaluation of the adult with chest pain" and "Stress testing for the diagnosis of obstructive coronary heart disease".)

●Screening for coronary heart disease (CHD) in asymptomatic patients with diabetes mellitus, generally a population at higher risk of CVD, is discussed separately. (See "Screening for coronary heart disease in patients with diabetes mellitus".)

●As with screening for any condition, the primary purpose of screening for CHD is to identify patients whose prognosis could be improved with an intervention (in this case, aggressive medical therapy for risk factors, or coronary revascularization). (See 'Rationale for screening' above.)

●Members of "special populations" in which a CHD event may pose unique or additional risks beyond those in the average population (eg, athletes and those in certain high risk occupations) may require a screening test because of regulatory or other requirements rather than traditional medical decision-making. (See 'Who should be screened?' above.)

●The choice of screening test depends on patient characteristics. In patients who want to begin an exercise program and are at high risk of CHD, an exercise test is the most appropriate and useful test. (See 'Choice of test' above and 'Exercise stress testing' above.)

●Coronary artery calcium (CAC) scoring is most helpful in patients who are being screened who have intermediate or borderline CHD risk, particularly those with a family history of very early coronary artery disease. CAC scoring is useful in adults at intermediate 10-year risk of atherosclerotic CVD (ASCVD; 7.5 to 20 percent) if statin therapy decision remains uncertain. CAC scoring should not be used in high-risk patients. (See 'Choice of test' above and 'CAC score and CT angiography' above.)

●We do not perform screening for CHD with blood tests, resting ECGs, or ambulatory ECG monitoring as these are not effective screening tests. Invasive coronary angiography is not used as a screening test because the risks of performing an invasive procedure in a patient who is otherwise asymptomatic are generally perceived to outweigh any potential benefits. (See 'Ineffective or non-recommended screening tests' above.)

●Subsequent evaluation, including further testing or treatment of those with positive findings on a screening test, should be based upon consideration of the patient's risk factors, occupation, cost-effectiveness, and clinical justification for any intervention that might be recommended as a result of the findings on further testing. (See 'Follow-up of a positive screening test' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Frank Yanowitz, MD, and Pamela Douglas, MD, who contributed to an earlier version of this topic review.