Chronic Coronary Syndrome: Diagnosis and Initial Evaluation

Definition and Pathophysiology

Chronic coronary syndromes (CCS) comprise the clinical manifestations of chronic structural and/or functional disease involving the epicardial coronary arteries and/or the coronary microcirculation. These abnormalities may produce a transient mismatch between myocardial oxygen demand and coronary blood supply, resulting in myocardial hypoperfusion or ischaemia. Ischaemia is commonly precipitated by exertion, emotional stress, or another form of physiological stress, but it may also occur at rest or remain clinically silent.

The underlying coronary disease may be obstructive or non-obstructive. Atherosclerotic plaque accumulation in the epicardial arteries is a major pathological substrate, but ischaemia may also result from epicardial vasomotor abnormalities or structural and functional microvascular disease. Thus, the presence of non-obstructive epicardial arteries does not exclude a coronary cause of symptoms.

CCS is a clinical syndrome rather than a permanently stable state. Patients may remain stable for prolonged periods, but chronic coronary disease can progress or destabilize abruptly, leading to an acute coronary syndrome (ACS). Clinical manifestations may therefore change over time, including transitions between stable angina, angina or ischaemia with non-obstructive coronary arteries (ANOCA/INOCA), post-ACS or post-revascularization states, and heart failure of ischaemic or cardiometabolic origin.

Major clinical presentations

The principal outpatient presentations include:

• Reproducible stress-induced angina or ischaemia associated with obstructive epicardial coronary disease.

• Angina or ischaemia caused by epicardial vasomotor dysfunction or microvascular abnormalities without obstructive epicardial disease.

• The non-acute phase after ACS or coronary revascularization.

• Non-acute heart failure in which an ischaemic or cardiometabolic cause is suspected.

• Selected asymptomatic individuals in whom coronary disease is detected incidentally or during cardiovascular risk assessment.

The mechanisms overlap clinically. Microvascular angina, vasospastic angina, and obstructive epicardial disease may produce similar symptoms, and symptom characteristics alone cannot reliably identify the underlying mechanism.

Clinical Presentation and Symptoms

Angina and anginal equivalents

Chest pain or discomfort remains the cardinal symptom of CCS, but presentations are frequently non-classical. Contemporary clinical populations include only a minority with symptoms having all of the traditional aggravating and relieving characteristics of angina; many patients report less characteristic symptoms, while others present primarily with exertional dyspnoea.

Symptoms should be characterized systematically, including:

• Onset and duration.

• Location and radiation.

• Quality and intensity.

• Precipitating factors, including exertion, emotional stress, meals, or exposure to cold.

• Relieving factors, including rest or medication.

• Time of day and temporal pattern.

• Change in frequency, severity, or exercise threshold.

Potential anginal equivalents include:

• Dyspnoea on exertion.

• Fatigue.

• Dizziness during exertion.

• Discomfort in the arm, jaw, neck, or upper back.

• Chest discomfort triggered by emotional stress.

• Palpitations associated with physical activity, a large meal, emotional upset, or cold exposure.

The absence of chest pain does not exclude clinically important CCS. Silent or minimally symptomatic disease may occur in patients with diabetes and autonomic neuropathy, as well as in older adults with markedly limited physical activity.

Traditional labels such as “typical” and “atypical” angina have limited value, particularly in patients with microvascular dysfunction or vasospasm. Angina associated with microvascular disease or vasomotor abnormalities may not be predictably exertional or relieved by rest or nitroglycerine. Symptoms should therefore be described in detail, followed by objective evaluation for obstructive disease, microvascular dysfunction, and coronary vasospasm before being designated non-cardiac.

Variation according to age and sex

Symptoms may vary with age, sex, race, socioeconomic circumstances, and geographical location. Women with suspected angina are often older, have a greater burden of cardiovascular risk factors and comorbidity, and more frequently report dyspnoea and fatigue rather than classic anginal discomfort. Microvascular angina is also more prevalent among women in this setting. Nonetheless, anginal chest pain occurs in both women and men, and symptom classification alone should not determine the diagnostic strategy.

Differential diagnosis and acute coronary syndrome

Chest pain is not synonymous with myocardial ischaemia. Pericardial and other non-coronary cardiovascular conditions, as well as non-cardiovascular disorders, may produce similar symptoms. Initial evaluation must distinguish suspected CCS from ACS and consider pulmonary, musculoskeletal, neuromuscular, joint, and other relevant causes.

A change in symptom pattern, a marked reduction in the level of exertion required to provoke symptoms, or symptoms suggestive of an acute event should prompt assessment for ACS rather than a routine stable-syndrome pathway.

Evaluation and Physical Examination

The initial assessment consists of a directed clinical history, cardiovascular risk assessment, physical examination, resting 12-lead ECG, and basic laboratory testing. The clinical examination should also account for the patient’s broader health trajectory and associated pulmonary, neurological, cognitive, hepatic, and renal disease.

Medical and family history

The history should review:

• Known CAD, previous myocardial infarction, and prior PCI or CABG.

• Arrhythmias, syncope, or presyncope.

• Pulmonary disease, including asthma, emphysema, bronchitis, and recent pulmonary embolism.

• Cerebrovascular disease and peripheral arterial disease.

• Hypertension, diabetes, obesity, dyslipidaemia, and smoking.

• Current pregnancy where relevant.

• Recent illness, hospitalization, or surgery.

• Current medication names, doses, schedules, tolerability, and adherence.

• Functional capacity and ability to undertake physical activity.

• Family history, particularly premature coronary disease or familial hypercholesterolaemia.

• Exposure to treatments that may provoke or accelerate coronary disease, including selected anticancer therapies.

A careful interview also identifies the patient’s understanding of illness, concerns, motivations, preferences, and attitudes toward testing and treatment. These factors are important when diagnostic procedures or revascularization are being considered.

Physical examination

Physical examination may help identify cardiovascular risk, alternative diagnoses, and consequences of established disease. Particular attention should be directed to:

• Blood pressure, heart rate, rhythm, and general haemodynamic status.

• Peripheral arterial pulses and evidence of peripheral arterial disease.

• Signs of heart failure, including elevated jugular venous pressure and pulmonary congestion.

• Cardiac murmurs and other findings suggesting valvular disease.

• Evidence of systemic disease that may affect interpretation of symptoms or test selection.

• Findings relevant to planned CT coronary angiography (CCTA), invasive angiography, or contrast administration.

The examination is not a substitute for objective testing. It is used to refine the estimated likelihood of obstructive CAD, identify comorbidities, and guide the choice and urgency of downstream investigations. Point-of-care ultrasound may verify selected findings, but the clinical assessment should remain integrated rather than test-driven.

Estimating clinical likelihood

The initial probability of obstructive epicardial CAD should be estimated using a Risk Factor-weighted Clinical Likelihood model. The estimate should then be adjusted using additional clinical information, such as:

• Peripheral arterial findings.

• Resting ECG abnormalities.

• Resting echocardiographic findings.

• Vascular calcification identified on previous imaging.

• Age, diabetes, chronic kidney disease, left ventricular ejection fraction, and anginal threshold.

Patients with a very low pre-test likelihood, defined as less than 5%, may be considered for deferral of further diagnostic testing. In those with an initially low likelihood above 5% but no more than 15%, coronary artery calcium scoring (CACS) may help reclassify risk and identify individuals whose calcium-weighted likelihood becomes very low. Exercise ECG or evidence of atherosclerosis in non-coronary arteries may also be considered in selected patients in this low-likelihood range.

Diagnostic Strategy

The evaluation of suspected CCS follows four broad stages:

• General clinical evaluation: characterize symptoms, identify alternative diagnoses, exclude ACS, perform ECG and basic blood testing, and use chest radiography or pulmonary function testing selectively.

• Further cardiac evaluation: perform resting echocardiography, assess ventricular function and valve disease, and estimate the likelihood of obstructive CAD.

• Diagnostic confirmation and risk assessment: select anatomical, functional, or invasive testing according to clinical likelihood and the clinical question.

• Initial management: initiate lifestyle and risk-factor intervention, disease-modifying treatment, symptom-directed therapy, and revascularization when appropriate.

The choice of test depends on the estimated likelihood of obstructive disease, the need to assess ischaemia or anatomy, local expertise, comorbidities, exercise capacity, renal function, contrast allergy, and whether revascularization is being contemplated.

Electrocardiography

Resting 12-lead ECG

A resting 12-lead ECG is part of the initial evaluation of suspected CCS. It may support the diagnosis, identify previous myocardial injury or other cardiac disease, and modify the estimated likelihood of obstructive CAD. It also contributes to risk assessment.

An exercise ECG should not be used diagnostically in patients with:

• At least 0.1 mV of ST-segment depression on the resting ECG.

• Left bundle branch block.

• Treatment with digitalis.

Exercise ECG

Exercise ECG may be used selectively to assess:

• Exercise tolerance.

• Reproduction of symptoms.

• Exercise-associated arrhythmias.

• Blood pressure response.

• Event risk.

It is not recommended as the test for ruling out CAD in patients with a low or moderate likelihood when CCTA or functional imaging is available. In patients with established CCS, a Duke Treadmill Score below −10 is considered a high-risk exercise finding.

Ambulatory ECG monitoring

Ambulatory ECG monitoring may be considered when vasospastic angina is suspected. It is also relevant when symptoms suggest an intermittent rhythm disturbance, although the source material provides no further diagnostic protocol or duration specification.

Resting Echocardiography and Cardiac Magnetic Resonance

Resting transthoracic echocardiography

Resting echocardiography is recommended during the further evaluation of suspected CCS to:

• Assess left ventricular systolic function.

• Identify regional wall-motion abnormalities.

• Detect valvular heart disease.

• Support risk assessment.

• Provide an alternative explanation for symptoms such as dyspnoea.

In patients with heart failure, resting imaging forms part of the evaluation for underlying CAD and helps determine whether further anatomical or functional testing is appropriate.

Cardiac magnetic resonance

Cardiac magnetic resonance (CMR) is useful for myocardial characterization and for identifying ischaemia, scar, and fibrosis. Late gadolinium enhancement, T1 mapping, and extracellular volume assessment can contribute to the distinction between ischaemic and non-ischaemic myocardial disease. Ischaemic injury typically produces subendocardial scarring, whereas mid-wall scar is characteristic of dilated cardiomyopathy.

Stress CMR perfusion imaging is recommended in patients with a moderate or high likelihood of obstructive CAD to diagnose and quantify myocardial ischaemia and/or scar and to estimate the risk of major adverse cardiovascular events (MACE).

CMR is also relevant in patients with heart failure, particularly when the underlying diagnosis is uncertain or when myocardial viability, scar, or alternative cardiomyopathic processes require assessment.

Coronary Computed Tomography Angiography

CCTA is the preferred non-invasive anatomical test for ruling out obstructive CAD in patients with a low or moderate pre-test likelihood, defined as greater than 5% to 50%. It is also recommended when functional imaging is non-diagnostic in this probability range. CCTA can diagnose obstructive disease and estimate the risk of MACE.

Technical prerequisites

Good image quality generally requires:

• A slow and regular heart rate.

• Ability to comply with breath-holding instructions.

• Suitability for premedication, commonly with oral or intravenous beta-blockers when required.

• Adequate kidney function.

• No prohibitive allergy to contrast agents.

• Contemporary CT technology, described in the source material as 64-slice technology or above.

• An appropriately trained imaging team.

Temporal and spatial resolution can limit assessment of stenosis severity, especially in older patients with extensive coronary calcification. In such patients, functional testing may be more appropriate.

For patients with an intermediate stenosis in a proximal or mid-coronary segment identified by CCTA, CT-derived fractional flow reserve may be considered.

Functional Myocardial Imaging

Stress echocardiography

Stress echocardiography is recommended for patients with a moderate or high pre-test likelihood of obstructive CAD, greater than 15% and up to 85%, to diagnose inducible myocardial ischaemia and estimate MACE risk.

When two or more contiguous myocardial segments are inadequately visualized, intravenous ultrasound contrast agents consisting of microbubbles are recommended to improve diagnostic accuracy. Contrast myocardial perfusion assessment may further refine risk stratification beyond wall motion. Doppler assessment of left anterior descending coronary flow reserve may be considered to improve risk stratification and evaluate microvascular function.

High-risk stress echocardiographic findings include stress-induced hypokinesia or akinesia in at least 3 of 16 myocardial segments.

SPECT and PET perfusion imaging

SPECT, or preferably PET where available and supported by local expertise, is recommended in patients with a moderate or high likelihood of obstructive CAD. These techniques can:

• Detect and quantify myocardial ischaemia.

• Identify myocardial scar.

• Estimate MACE risk.

• Quantify myocardial blood flow with PET.

When SPECT or PET is performed, CACS should be measured from the unenhanced chest CT acquired for attenuation correction because this improves detection of both non-obstructive and obstructive CAD.

An ischaemic burden involving at least 10% of the left ventricular myocardium on stress SPECT or PET is considered a high-risk finding.

Stress CMR

Stress CMR perfusion imaging is recommended for patients with a moderate or high likelihood of obstructive CAD. It can identify and quantify ischaemia and scar and estimate MACE risk. High-risk findings include stress perfusion defects in at least 2 of 16 segments or at least 3 dobutamine-induced dysfunctional segments.

Invasive Coronary Angiography and Coronary Physiology

Indications

Invasive coronary angiography (ICA) is used when non-invasive testing is inconclusive, when the clinical diagnosis remains uncertain, or when the initial presentation is highly suggestive of obstructive disease at a low level of exertion and revascularization is being considered. In that latter situation, ICA with a view toward revascularization is recommended as the first diagnostic test after specialist clinical assessment.

ICA with access to invasive functional assessment is recommended to confirm or exclude obstructive CAD or ANOCA/INOCA when non-invasive testing leaves the diagnosis uncertain.

In patients with heart failure and angina or an anginal equivalent despite pharmacological treatment, coronary angiography is recommended to establish the presence and severity of CAD. In heart failure with reduced ejection fraction and an intermediate-to-high likelihood of CAD, angiography may also be considered when revascularization is potentially appropriate. In patients with LVEF below 35% and suspected obstructive CAD, ICA is recommended when CABG may improve prognosis, subject to procedural risk and expected benefit.

Radial access is the preferred access site when ICA is undertaken.

Functional assessment of epicardial stenoses

Intermediate non-left-main coronary stenoses should undergo selective physiological assessment before revascularization. The recommended thresholds are:

Coronary flow reserve, hyperaemic stenosis resistance, and coronary flow capacity may be used as complementary investigations. Resting indices such as Pd/Pa, diastolic pressure ratio, resting full-cycle ratio, or angiography-derived vessel FFR may be considered as alternatives.

Routine wire-based pressure assessment of every coronary vessel is not recommended.

Microvascular dysfunction and vasospasm

When symptoms persist despite non-obstructive epicardial arteries, the evaluation should consider microvascular dysfunction and coronary vasospasm. In patients with heart failure with preserved ejection fraction, angina or an anginal equivalent, and normal or non-obstructive epicardial arteries, PET or CMR perfusion imaging, or invasive functional coronary testing, should be considered to detect or exclude coronary microvascular dysfunction.

Invasive coronary functional testing is recommended in patients with refractory angina, poor quality of life, and documented or suspected ANOCA/INOCA, because identifying the endotype can guide treatment.

Biomarkers and Laboratory Findings

Basic blood testing forms part of the initial evaluation, although the source material does not provide a complete laboratory panel or specific routine thresholds. Relevant considerations include:

• Renal function, particularly before contrast-enhanced CCTA or ICA.

• Cardiovascular risk assessment, including diabetes and dyslipidaemia.

• Left ventricular function as part of clinical risk stratification.

• High-sensitivity C-reactive protein and/or fibrinogen, which may be considered in the initial assessment.

• HbA1c and other metabolic measures where diabetes and cardiometabolic risk are being assessed, although specific testing schedules are not stated.

Laboratory evaluation should also identify comorbidities that affect test selection, treatment tolerance, bleeding risk, or procedural planning.

Risk Stratification

Initial risk assessment should integrate clinical information and test results. Important clinical variables include:

• Age.

• Resting ECG findings.

• Anginal threshold.

• Diabetes.

• Chronic kidney disease.

• LVEF.

High-risk test findings include:

The finding of a high-risk anatomical or functional pattern influences the need for invasive assessment, revascularization, and intensity of follow-up.

Initial Management After Diagnosis

Initial management combines symptom control, prevention of cardiovascular events, lifestyle intervention, and revascularization when indicated.

Patient education and lifestyle

An individualized discussion should explain cardiovascular risk, expected treatment benefits, symptoms requiring reassessment, and the rationale for diagnostic and therapeutic decisions. Multidisciplinary behavioural support should accompany pharmacological treatment.

Recommended physical activity is:

• 150–300 minutes per week of moderate-intensity aerobic activity; or

• 75–150 minutes per week of vigorous-intensity activity,

together with reduction of sedentary time.

Home-based cardiac rehabilitation and mobile-health interventions may improve adherence to healthy behaviours and reduce hospitalization or cardiac events. Behavioural interventions, family and multiprofessional involvement, simplified medication regimens, and digital tools such as text messaging, applications, and wearable devices are recommended strategies for improving adherence.

Antianginal treatment

Antianginal treatment should be selected according to:

• Symptom pattern and underlying pathophysiology.

• Heart rate and blood pressure.

• Left ventricular function.

• Comorbidities.

• Concomitant medications.

• Tolerability.

• Local availability and cost.

Combination treatment is frequently required when symptoms are not controlled with a single agent, although the source material does not provide a complete drug-by-drug dosing schedule.

Ivabradine may be added in patients with LVEF below 40% and inadequate symptom control, or used initially in appropriately selected patients. It is not recommended as add-on therapy in patients with LVEF above 40% who have no clinical heart failure. Ivabradine should not be combined with a non-dihydropyridine calcium-channel blocker or another strong CYP3A4 inhibitor.

Prevention of cardiovascular events

Antithrombotic therapy

For patients with previous myocardial infarction or PCI, clopidogrel 75 mg once daily is a recommended alternative to aspirin monotherapy.

Aspirin 75–100 mg once daily is recommended lifelong:

• After CABG.

• In patients without previous myocardial infarction or revascularization who have significant obstructive CAD.

The overall antithrombotic regimen must account for bleeding risk and any indication for oral anticoagulation. Bleeding risk assessment should use PRECISE-DAPT, the ARC-HBR tool, or another validated method. Specific dual-antiplatelet or anticoagulant regimens are not detailed in the source material.

Lipid lowering

Lipid-lowering treatment should target:

• LDL cholesterol below 1.4 mmol/L, or 55 mg/dL; and

• At least a 50% reduction from baseline.

For patients who are statin-intolerant and remain above target on ezetimibe, adding bempedoic acid is recommended. Bempedoic acid may also be considered in patients who do not reach target despite the maximum tolerated statin dose and ezetimibe.

Diabetes, overweight, and obesity

Sodium-glucose cotransporter 2 inhibitors with proven cardiovascular benefit are recommended in patients with type 2 diabetes and CCS to reduce cardiovascular events, independently of baseline or target HbA1c and independently of concurrent glucose-lowering treatment.

Semaglutide should be considered in patients with CCS without diabetes who are overweight or obese, defined in the guideline table as BMI ≥27 kg/m2, to reduce cardiovascular death, myocardial infarction, or stroke.

Anti-inflammatory therapy

Low-dose colchicine 0.5 mg once daily should be considered in patients with atherosclerotic CAD to reduce myocardial infarction, stroke, and the need for revascularization.

Revascularization

Revascularization is considered when symptoms remain limiting despite medical treatment or when anatomy and/or functional testing indicate a high-risk coronary pattern. The decision should be individualized and patient-centred.

A Heart Team discussion is recommended for complex cases, particularly when PCI and CABG have comparable guideline recommendations. The decision should incorporate:

• Coronary anatomy and anatomical complexity.

• Clinical risk and comorbidities.

• LVEF.

• Procedural risk.

• Life expectancy.

• Expected completeness of revascularization.

• Patient preferences, health literacy, cultural circumstances, and social support.

For patients with LVEF ≤35%, the choice between revascularization and medical therapy alone should follow careful evaluation of coronary anatomy, the relationship between CAD and LV dysfunction, comorbidities, life expectancy, risk–benefit balance, and patient perspectives.

In significant left-main disease and low surgical risk, CABG is recommended over medical therapy alone to improve survival and is generally preferred to PCI because of lower risks of spontaneous myocardial infarction and repeat revascularization. When left-main disease is of low complexity, defined as SYNTAX score ≤22, and PCI can achieve a completeness of revascularization equivalent to CABG, PCI is an alternative because of its lower invasiveness and non-inferior survival.

For anatomically complex PCI, including left-main disease, true bifurcations, and long lesions, intravascular ultrasound or optical coherence tomography guidance is recommended. In multivessel disease, FFR, iFR, or QFR should guide lesion selection for intervention.

Special Considerations

Heart failure

Patients with heart failure should undergo careful clinical, family, ECG, and imaging assessment for CCS. Exercise intolerance and increased left ventricular end-diastolic pressure can make non-invasive ischaemia testing difficult.

In patients with LVEF above 35% and a low or moderate likelihood of obstructive CAD, CCTA or functional imaging is recommended. In patients with LVEF below 35% and suspected obstructive CAD, ICA should be considered with a view toward CABG when the expected prognostic benefit outweighs procedural risk.

Patients with CCS and heart failure should be enrolled in a multidisciplinary heart failure programme. In HFrEF, sacubitril/valsartan is recommended as a replacement for an ACE inhibitor or ARB to reduce heart failure hospitalization and death.

ANOCA/INOCA

ANOCA/INOCA should be considered when angina or objective ischaemia persists despite normal or non-obstructive epicardial coronary arteries. Treatment should be guided by the identified coronary functional endotype.

• ACE inhibition may be considered for symptom control in endothelial dysfunction.

• Beta-blockers should be considered for microvascular angina associated with reduced coronary or myocardial flow reserve.

• Calcium-channel blockers are recommended for isolated vasospastic angina to control symptoms and prevent ischaemia and potentially fatal complications.

• Nitrates should be considered to prevent recurrent vasospastic episodes.

• In overlapping endotypes, combined nitrates, calcium-channel blockers, and other vasodilators may be considered.

Cancer treatment

Several anticancer therapies can precipitate or accelerate coronary disease. 5-fluorouracil and capecitabine may provoke effort angina. Platinum-based chemotherapy-associated ischaemia generally occurs during one of the first three cycles and is more likely in patients with underlying CAD. Ischaemia has also been associated with antimicrotubule agents, small-molecule VEGF tyrosine-kinase inhibitors, and VEGF-inhibiting monoclonal antibodies. Nilotinib, ponatinib, and ICI335 may accelerate atherosclerosis.

New stable angina during cancer treatment warrants careful evaluation, aggressive cardiovascular risk-factor modification, and initial medical management. Management generally follows CCS recommendations, but revascularization decisions should involve a multidisciplinary team including cardio-oncology, interventional cardiology, and oncology specialists.

PCI in patients with cancer is associated with increased bleeding, readmission for acute myocardial infarction, mortality, and repeat revascularization. The excess bleeding risk should be addressed by keeping dual-antiplatelet therapy as short as possible when clinically appropriate.

Follow-up and Monitoring

Patients with established CCS require continuing assessment of symptoms, functional status, risk-factor control, comorbidities, adherence, and disease progression. Periodic review, such as annual assessment by a general practitioner or cardiovascular healthcare professional, is recommended even in asymptomatic patients.

Follow-up should evaluate:

• New or worsening angina or anginal equivalents.

• Changes in exercise tolerance.

• Cardiovascular risk-factor control.

• Medication adherence, adverse effects, and interactions.

• Bleeding risk where antithrombotic therapy is used.

• Heart failure symptoms and ventricular function when relevant.

• Progression of CAD or failure of previous revascularization.

• Psychological health, including anxiety and depression.

• Barriers related to socioeconomic, geographical, or social circumstances.

Repeated non-invasive testing should be directed by symptoms, changes in clinical risk, or concern about disease progression rather than performed indiscriminately; the source material does not provide a universal interval for repeat imaging.

Patients with recurrent or refractory angina despite treatment should be reassessed for revascularization failure, residual obstructive disease, microvascular dysfunction, or vasospasm. In refractory ANOCA/INOCA, invasive functional testing is recommended to define the coronary endotype and guide targeted treatment.

Prognosis

CCS has a variable and potentially progressive course. A prolonged stable period does not eliminate the possibility of future ACS or other adverse cardiovascular events. Prognosis is determined by the clinical profile, extent and functional significance of CAD, LV function, diabetes, chronic kidney disease, symptom threshold, ECG findings, inducible ischaemia, and anatomical complexity.

High-risk findings on exercise testing, stress imaging, CCTA, or invasive assessment identify patients requiring intensified management and consideration of revascularization. Conversely, patients with long-standing CCS who have preserved LV function and no abnormality on maximal exercise or functional imaging may be considered at low risk for exercise-induced adverse events, although ongoing surveillance and risk-factor management remain necessary.