Clinical Pathway for Coronary Atherosclerosis in Patients Without Conventional Modifiable Risk Factors: JACC State-of-the-Art Review

Our multidisciplinary, international team was awarded a National Health & Medical Research Council (Australia) Centre for Research Excellence (CRE) grant to develop evidence-based clinical pathways to improve the care of people with CAD without SMuRFs (grant number GNT1196629, “CRE for Better Outcomes in CAD”). Translation of research into outcomes within the CRE is based on the Promoting Action on Research Implementation in Health Services theoretical framework. 11 The framework has been used by many international studies to guide the application of research evidence into practice and proposes that implementation is dependent on the interplay between the robustness of evidence, context (culture, leadership, and collaboration), and process facilitation. An expert panel composed of 17 internationally recognized cardiovascular disease (CVD) leaders was asked to consider the design of the SMuRFless CAD clinical pathway. The panel included clinicians, researchers, health economic and policy experts, and patient representatives. The expert panel was convened electronically (email and digital survey) 5 times between September 2020 and January 2021. Panel members were invited to contribute diagnostic investigations potentially relevant in this patient population to either: 1) confirm SMuRFless status; or 2) identify less frequent risk factors for coronary atherosclerosis initiation or progression ( Central Illustration ). Proposals for specific therapeutic decisions were also encouraged. The central team collated these suggestions into a database for future workshops. Central Illustration Diagnostic Considerations to Confirm No Standard Modifiable Cardiovascular Risk Factors, and to Screen for Nonstandard Factors Less common risk factors for consideration in patients with coronary artery disease (CAD) in the absence of standard modifiable cardiovascular risk factors (SMuRFS) (hypertension, hypercholesterolemia, diabetes, and smoking) were identified by an international and multidisciplinary panel of cardiovascular disease experts. Dedicated clinical pathways and specialized clinics will ensure comprehensive investigation and evaluation of these factors in patients with SMuRFless atherosclerotic CAD as a novel strategy to optimize disease management and secondary prevention in this overlooked subgroup of the CAD population. Diagnostic Considerations to Confirm No Standard Modifiable Cardiovascular Risk Factors, and to Screen for Nonstandard Factors Less common risk factors for consideration in patients with coronary artery disease (CAD) in the absence of standard modifiable cardiovascular risk factors (SMuRFS) (hypertension, hypercholesterolemia, diabetes, and smoking) were identified by an international and multidisciplinary panel of cardiovascular disease experts. Dedicated clinical pathways and specialized clinics will ensure comprehensive investigation and evaluation of these factors in patients with SMuRFless atherosclerotic CAD as a novel strategy to optimize disease management and secondary prevention in this overlooked subgroup of the CAD population. Initially, a total of 46 items were proposed and considered by the expert panel. A 2-step modified Delphi method was then used to establish agreement on investigations to include in the clinical pathway and for whom. In round 1, expert panel members were asked to indicate whether each investigation was appropriate in the following categories: 1) clinically for all SMuRFless CAD patients; 2) clinically indicated in a moderate proportion; or 3) as a research tool only. Investigations that did not receive a majority of experts voting in 1 of the 3 categories were included in 2 additional electronic voting rounds after adjustment within the proposed pathway. Investigations considered to be research-only tools were removed from this clinical pathway.

After review of existing evidence, as well as considering expert opinion where published evidence was unavailable, a clinical pathway was developed that outlines additional investigations and management that will be considered in patients with CAD without SMuRFs. Eighty-six percent of the components included in the final SMuRFless CAD clinical pathway received at least 75% support for their inclusion in the pathway. Nine components—including vitamin D, calcium/magnesium/phosphate, Self-Reported Oral Health Questionnaire, rheumatoid factor, anti-CCP antibody, PAI-1, ankle-brachial index, heart rate variability, and tick immunoglobulin (Ig) E sensitivity to α-galactose-1,3-galactose (α-gal)—received between 66.7% and 74.9% approval and were ultimately included in the final clinical pathway. This diagnostic pathway will be implemented in National Health & Medical Research Council SMuRFless CAD specialty clinics, initially in 3 Australian states (New South Wales, Victoria, and South Australia) and incorporated into additional dedicated or broader CAD clinics where SMuRFless patients may be found, including in Singapore and Mount Sinai Health System, New York. It is encouraged for any physician managing a patient with CAD in the absence of SMuRFs. A schematic representing the steps and their components is shown in Figure 2 , with further details provided in the following sections. Figure 2 SMuRFless CAD Clinical Pathway A novel, evidence-based pathway for investigating the potential causes of atherosclerotic CAD in patients with no SMuRFs for improved clinical management and secondary prevention. A 2-step, modified Delphi method was applied to generate the pathway. Following confirmation of SMuRFless atherosclerotic CAD, historic and/or additional investigations (step 4) are required for all patients (outlined in red) or if clinically indicated (outlined in purple) . Created with BioRender.com. Ab = antibody; ACEI = angiotensin-converting enzyme inhibitor; ACS = acute coronary syndrome; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibodies; APTT = activated partial thromboplastin clotting time; ARB = angiotensin receptor blocker; BP = blood pressure; CAD = coronary artery disease; CCP = cyclic citrullinated protein; CM = cardiomyopathy; CCTA = coronary computed tomography angiography; CVD = cardiovascular disease; DAPT = dual antiplatelet therapy; HbA1c = glycosylated hemoglobin; HDL-C = high-density lipoprotein cholesterol; HOMA = homeostatic model assessment for insulin resistance; Hs-CRP = high-sensitivity C-reactive protein; IgE = immunoglobulin E; IL = interleukin; LDL-C = low-density lipoprotein cholesterol; LV = left ventricle; PAI = plasminogen activator inhibitor; PT = prothrombin time; SCAD = spontaneous coronary artery dissection; SMuRF = standard modifiable cardiovascular risk factor; TC = total cholesterol; U/S = ultrasound; Vit D = vitamin D. SMuRFless CAD Clinical Pathway A novel, evidence-based pathway for investigating the potential causes of atherosclerotic CAD in patients with no SMuRFs for improved clinical management and secondary prevention. A 2-step, modified Delphi method was applied to generate the pathway. Following confirmation of SMuRFless atherosclerotic CAD, historic and/or additional investigations (step 4) are required for all patients (outlined in red) or if clinically indicated (outlined in purple) . Created with BioRender.com. Ab = antibody; ACEI = angiotensin-converting enzyme inhibitor; ACS = acute coronary syndrome; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibodies; APTT = activated partial thromboplastin clotting time; ARB = angiotensin receptor blocker; BP = blood pressure; CAD = coronary artery disease; CCP = cyclic citrullinated protein; CM = cardiomyopathy; CCTA = coronary computed tomography angiography; CVD = cardiovascular disease; DAPT = dual antiplatelet therapy; HbA1c = glycosylated hemoglobin; HDL-C = high-density lipoprotein cholesterol; HOMA = homeostatic model assessment for insulin resistance; Hs-CRP = high-sensitivity C-reactive protein; IgE = immunoglobulin E; IL = interleukin; LDL-C = low-density lipoprotein cholesterol; LV = left ventricle; PAI = plasminogen activator inhibitor; PT = prothrombin time; SCAD = spontaneous coronary artery dissection; SMuRF = standard modifiable cardiovascular risk factor; TC = total cholesterol; U/S = ultrasound; Vit D = vitamin D. First, the diagnosis of atherosclerotic CAD will be confirmed. In the case of a prior acute MI presentation, nonatherosclerotic etiologies—such as spontaneous coronary artery dissection, coronary artery embolism, and takotsubo cardiomyopathy—will be excluded because they each mandate a different diagnostic and treatment pathway. In patients with stable CAD, coronary computed tomography angiography (CCTA), or coronary artery calcium scoring can be used. After atherosclerotic CAD is confirmed, an assessment of potentially missed or multiple subthreshold SMuRFs will occur. This allows for the identification of people in whom CAD is considered to have developed truly in the absence of SMuRFs or where the development of CAD is not clearly attributable or is out of proportion to mild elevation of SMuRFs and where there is likely benefit in investigating for additional modifiable factors. Pragmatic and conservative cutoffs for the 4 risk factors are presented in Table 1 . Multiple resting blood pressure (BP) measurements will be performed as well as a review of prior medical records. In most cases, unless the patient has a long-term record of low normal BP readings, a 24-hour ambulatory BP monitor is recommended. A diagnosis of hypertension will be established by: 1) an average reading of systolic BP of ≥140 mm Hg or diastolic BP of ≥90 mm Hg recorded from at least 2 readings obtained on separate days; 2) hypertension diagnosed by 24-hour ambulatory BP; or 3) ongoing treatment of hypertension. A standard fasting lipid panel will be obtained in all patients, including LDL-C. The use of LDL-C of >3.5 mmol/L for the SMuRF definition of hyperlipidemia is based on the cutoffs used in primary prevention guidelines for the commencement of lipid-lowering therapy. Fasting glucose and glycosylated hemoglobin levels will be measured in all patients. Diabetes mellitus is defined as a fasting blood glucose level of ≥7.0 mmol/L or glycosylated hemoglobin of ≥6.5% (48 mmol/L), as per the World Health Organization. 12 Table 1 Thresholds Used for the Definition of SMuRF/SMuRFless Status Risk Factor Definition for SMuRF Positive Hypertension SBP ≥140 mm Hg or DBP ≥90 mm Hg Diabetes mellitus HbA1c ≥ 6.5% or fasting BGL ≥7.0 mmol/L or OGTT 2-h BGL >11.1 mmol/L Hypercholesterolemia TC >5.5 mmol/L LDL-C >3.5 mmol/L Cigarette smoking Current smoker (smoking within 12 months) BGL = blood glucose level; DBP = diastolic blood pressure; HbA1c = glycosylated hemoglobin; LDL-C = low-density lipoprotein cholesterol; OGTT = oral glucose tolerance test; SBP = systolic blood pressure; SMuRF = standard modifiable risk factor; TC = total cholesterol. Thresholds Used for the Definition of SMuRF/SMuRFless Status BGL = blood glucose level; DBP = diastolic blood pressure; HbA1c = glycosylated hemoglobin; LDL-C = low-density lipoprotein cholesterol; OGTT = oral glucose tolerance test; SBP = systolic blood pressure; SMuRF = standard modifiable risk factor; TC = total cholesterol. Given the limitation of single binary thresholds for risk factors with linear associations with CVD risk, interactions among risk factors, and the potential for multiple risk factors at subthreshold levels to contribute to heightened CAD risk, the pooled cohort equation will be calculated during the clinic visit and contribute to the clinician’s confirmation of SMuRFless atherosclerotic CAD. Obesity has not been included as 1 of the 4 SMuRFs in the definition of SMuRFless CAD, but it is documented and is a potential modifiable factor that will be addressed in the clinical pathway. 13 This is because of the mixed evidence for diet-based weight loss as a therapy. Emerging evidence regarding the benefits of bariatric surgery on major adverse cardiovascular events (MACE) may shift this. 14 Of interest, studies have demonstrated lower body mass index (BMI) in SMuRFless ACS patients compared to their counterparts with SMuRFs, which may suggest that adiposity is not the main driver of advanced atherosclerosis in the SMuRFless cohort. 5 Ethnicity-based thresholds for BMI will be used, recognizing the inaccuracy and poor sensitivity of this measure correlating to high-risk body fat distribution across racially diverse populations. 15 , 16 , 17 , 18 , 19 Step 2 will likely reveal a proportion of patients in whom SMuRFs had been “missed” or with results that are borderline and require further investigation. Additional commonly measured lipid parameters such as triglyceride/high-density lipoprotein cholesterol (HDL-C) will also be considered. In this scenario, appropriate diagnosis and management of the newly diagnosed risk factor will be pursued and is described, as appropriate, in step 4. In accordance with treatment guidelines for patients with manifest atherosclerotic CAD, every effort will be made to ensure that patients receive guideline-based and evidence-based secondary prevention therapies, irrespective of their cholesterol and BP measures. 20 , 21 , 22 As more specific evidence evolves, including metadata from previous clinical trials, specific guidelines may emerge that particularly focus on the heightened susceptibility to disease and the vascular inflammatory response. Additionally, given the prevalence of SMuRFless ACS patients and their heightened early mortality, we advocate for intentional inclusion of SMuRFless CAD patients in interventional and secondary prevention trials because they are likely risk enhancers. In the absence of any specific contraindications, appropriate antiplatelet therapy considering revascularization status, angiotensin-converting enzyme inhibitors/angiotensin receptor blocker, beta-blockers, and maximally tolerated statin therapy—with or without other lipid-lowering therapies—should all be prescribed according to guidelines. 20 , 23 Additional heart failure–targeted therapies (including mineralocorticoid receptor antagonists, sacubitril/valsartan, sodium-glucose cotransporter-2 inhibitors, and/or device therapy) will be considered when indicated. 24 , 25 Recent evidence suggests potential benefits of anti-inflammatory agents, such as colchicine for patients with both ACS and stable CAD, though more evidence is needed. 26 , 27 Further studies are required; however, the development of CAD in the absence of traditional cardiovascular risk factors may suggest an inflammatory process, and the use of anti-inflammatory agents may be particularly relevant to SMuRFless CAD patients. Although the primary intention of the experts in developing this clinical pathway is to address potential modifiable components driving susceptibility to atherosclerosis and to ensure that secondary prevention is optimized, residual ischemia should also be considered and addressed according to current international guidelines, 28 taking into consideration the acute vs chronic nature of presentation, patient symptoms, and left ventricular function. The SMuRFless CAD clinical pathway has been designed to systematically screen for additional factors known to be associated with atherosclerosis, increased CVD morbidity, and mortality. A comprehensive clinical history that screens for cardiovascular and specific noncardiovascular comorbidities (including liver, lung, or kidney disease; inflammatory disorders; endocrinopathies; hormonal or sex-specific factors; neurologic disorders; malignancy; chronic infections; and mental health disorders) as well as physical and hemodynamic factors (including BP, heart rate, height, weight, and waist and hip circumference) will be assessed. Details of evidence and recommended investigations are outlined in the following sections. Abnormal results from these investigations will precipitate referral to appropriate specialist physicians. There is currently no hierarchy for these potential drivers; however, evidence from the proposed registry will be used to assess prevalence and impact of treatment and, thus, will guide prioritization of these factors in the future. Emerging evidence of new potential contributors or new assays will be considered by the CRE for CAD investigators for incorporation into the pathway on a biennial basis. The hypoxemic and sleep fragmentation consequences of OSA are associated with altered cardiac and pulmonary vascular hemodynamics and have been shown to drive sympathetic activation, systemic inflammation (via a nuclear factor κB pathway), endothelial dysfunction, and generation of reactive oxygen species, which promote the development of atherosclerosis. 29 , 30 There is evidence for higher rates of incident CAD and excess MACE in patients with severe untreated OSA, 31 although OSA treatment has been disappointing with regard to protecting against MACE. 32 The prevalence of OSA in people with CAD without SMuRFs is not yet known but should be considered. All SMuRFless CAD clinic patients will initially be screened for OSA utilizing the OSA-50 questionnaire. 33 Patients with a significant OSA-50 score will be screened with a second tool, the Epworth Sleepiness Scale (ESS). 34 Patients will be referred directly for a home-based sleep study, according to Australian guidelines, 35 if OSA-50 and ESS screening results are both significant. Patients will additionally be referred to a sleep physician if indicated, with recognition of the development of the OSA-50 and ESS tools outside of CVD cohorts. Dietary intake of fruit, vegetables, and fish will be considered along with measures of iron. Patients with poor diet should be provided recommendations, as per guidelines, 20 , 36 and potentially referred to a dietician. Counseling should include information about the benefits of consuming a Mediterranean or similar diet, replacement of saturated with unsaturated fat, increased consumption of plant-based foods rich in fiber, restricted consumption of processed meats, and consumption of fish. 37 Advice to reduce the consumption of sugary beverages and other forms of free sugar to <10% of total daily energy intake is recommended. 38 Guidance on daily sodium targets and reduction strategies will be provided. Counseling regarding optimal weight and calorie restriction approaches will be provided. A detailed history of physical activity and sedentary time will be recorded for all patients using the International Physical Activity Questionnaire, 39 with continuous and categorical outcomes provided. Patients will be encouraged to adhere to a minimum amount of exercise, as per World Health Organization guidelines. 40 This includes at least 150 to 300 minutes of moderate-intensity aerobic activity or 75 to 150 minutes of vigorous-intensity aerobic physical activity throughout the week in addition to limiting the amount of sedentary time. Education programs, counseling, and the use of wearable devices to track and prompt activity will be considered to help optimize physical activity. Systematic reviews and meta-analyses support the benefit of increased physical activity with activity monitoring and prompts. 41 , 42 , 43 , 44 , 45 , 46 Poor oral health has been associated with atherosclerotic CVD in several observational cohort studies 47 , 48 , 49 and will be considered. Periodontal disease is observed in 42% of the adult U.S. population. 50 An analysis of the 45 and Up study—a cohort of 267,153 men and women randomly sampled from the general population of New South Wales, Australia—revealed a relationship between increased risk of CAD and tooth loss, self-reported health of teeth and gums, and all-cause mortality. 51 A meta-analysis of 22 studies, including 129,630 participants, added further evidence, showing an approximately 2-fold increased odds of MI in those with periodontal disease after adjustment for traditional CVD risk factors. 52 Although causality is not certain and confounders may include lower education and socioeconomic status, a detailed history and examination are advised. All SMuRFless CAD clinic patients will be screened for periodontal disease using the 5-part Self-Reported Oral Health questionnaire 53 and referred to a dentist for further assessment if indicated. Maintenance strategies to ensure long-term improvements of oral hygiene 54 should be implemented in all patients as a cheap and accessible intervention strategy. Mental health and psychosocial risk factors have long been recognized for their association with risk of developing CAD and worse clinical outcomes, both via direct biological mechanisms and indirectly through common risk factors, environmental exposures, medication and substance exposures, and health behaviours. 55 Lower socioeconomic status 56 , 57 and tools measuring social isolation 58 , 59 have been associated with incident CAD and worse clinical outcomes, with varying degrees of interactions with traditional risk factors. Patients with depression have worse outcomes following a CVD event compared to nondepressed individuals, potentially in a dose-response relationship. 60 , 61 All SMuRFless CAD clinic patients will be screened to identify a depressive disorder with the Patient Health Questionnaire screening tool. 62 This questionnaire relies on self-report and needs to be verified by a qualified clinician. There is a well-established increased risk of CVD in those with systemic inflammatory conditions. These include systemic lupus erythematosus, 63 rheumatoid arthritis, 64 psoriasis, 65 and inflammatory bowel diseases. 66 Optimizing the treatment of inflammatory conditions, including using disease-modifying agents and targeted immunotherapy (eg, monoclonal antibodies), may reduce the incidence of CVD events in patients with inflammatory disorders. 67 , 68 A higher rate of ACS has been reported in people a year after recovery from COVID-19, and we await data on the extent to which this can be explained by standard risk factors 69 ; a clinical history will include COVID-19 infection and vaccination status, which may be valuable for registry purposes, although this currently will not influence management. All patients attending the clinic will be screened for chronic inflammatory disorders by taking a comprehensive medical history to identify inflammatory arthritides, connective tissue disorders, and inflammatory bowel disease, as well as the use of disease-modifying therapies. In addition, a limited set of screening tests targeting biological markers for disease activity or diagnosis of certain inflammatory conditions will be obtained, including high-sensitivity C-reactive protein, rheumatoid factor, anti-cyclic citrullinated protein antibodies, antinuclear antibody, and antineutrophil cytoplasmic antibodies. A more comprehensive panel of inflammatory markers should be undertaken if the clinical suspicion for an underlying chronic inflammatory disorder is high (based on history and clinical examination) or if the result of the initial biomarker screen described earlier is abnormal, with referral to a specialist physician if positive. A history of previous malignancy and management will be assessed and documented in all SMuRFless CAD clinic patients, with a particular focus on childhood malignancy; mediastinal radiation; and chemotherapy agents, immunotherapies, and biologics. 70 , 71 , 72 There is growing evidence in support of assessment for sex-specific factors associated with increased CVD risk in women and men. 73 Factors that will be considered in the SMuRFless CAD clinic include features of pregnancy (pre-eclampsia, small for gestational age, preterm birth, gestational hypertension, gestational diabetes, maternal pre-existent type 1 or type 2 diabetes), 74 , 75 , 76 , 77 sex hormones (endometriosis, polycystic ovary syndrome, ovarian insufficiency), 78 , 79 menopause/hormonal status, and use of hormone contraceptives. Male-specific factors that are associated with increased risk of CAD include androgen deficiency, 80 erectile dysfunction, 81 and use of anabolic or synthetic steroids. 82 All participants will be screened for such potential sex-specific contributors through history, examination, and potential additional investigations where relevant. If the standard measures of metabolic health in step 2 detect any abnormality or are borderline, fasting insulin and glucose levels will be measured in people attending the SMuRFless CAD clinic, and homeostatic model assessment for insulin resistance and homeostatic model assessment of beta-cell function scores will be calculated. The use of glucose tolerance tests (>4 weeks post-ACS, to avoid false-positive results) will also be considered by the clinician, with referral to endocrinology specialists as relevant. In addition to standard fasting lipid levels, lipoprotein(a) will be measured in all patients. Non–HDL-C will be calculated and reviewed as an alternative marker, with consideration of the role of atherogenic particles in complex settings, such as hypertriglyceridemia and diabetes, chronic kidney disease, and metabolic syndrome. 83 Abnormalities in clotting and fibrinolysis may contribute to both the development of atherosclerosis and risk of an acute arterial thrombotic event, although specific management may not be clear if abnormalities are identified. Such measures should be taken >4 weeks post-ACS (and in the absence of acute infections) to assess baseline levels rather than acute phase reactants. Fibrinogen binds to platelets via glycoprotein IIb/IIIa receptors, promoting platelet aggregation in addition to contributing to blood viscosity, and it is an independent risk factor for CVD. 84 , 85 , 86 Fibrinogen levels and activity may mediate the effect of some traditional CVD risk factors, with higher fibrinogen antigen and activity seen in association with age, smoking, diabetes, BMI, total cholesterol and triglyceride levels, and lower levels with increasing HDL-C. 87 Plasminogen activator inhibitor (PAI)-1 is the main physiologic inhibitor of tissue-type and urokinase-type plasminogen activator, which are responsible for the enzymatic activation of plasminogen and, thus, are required for the dissolution of insoluble fibrin in clots. Polymorphisms in the promoter are associated with altered plasma PAI-1 concentrations and are associated with CAD. 88 PAI-1 antigen levels, but not activity, are associated with increased MACE. 89 Homocysteine is an intermediary molecule in the biosynthesis of methionine and cysteine, predominantly found in the circulation bound to plasma proteins. Hyperhomocysteinemia, which may arise from genetic mutations to enzymes including cystathionine-β-synthase and homozygous mutations in methylenetetrahydrofolate reductase, have been associated with premature CVD events. 90 Hyperhomocysteinemia can also result from nutritional deficiencies in folate, vitamin B12, and vitamin B6 and with metformin therapy (via reduction in B12 levels). Homocysteine is renally cleared and is elevated in patients with chronic renal impairment, which provides one of several potential mechanisms for increased rates of CVD in patients with renal disease. Several observational studies have shown an association between homocysteine levels and coronary events. 91 Measuring homocysteine levels, along with other nutritional factors, such as B12 and folate, may provide additional insights into mechanisms, with the caveat that a systematic review and meta-analysis of intervention studies reducing homocysteine levels did not show a reduction in MI, stroke, or mortality. The potential role of homocysteine in SMuRFless CAD patients remains unknown and will be reconsidered as additional data become available. 92 Haptoglobin is a glycoprotein produced by the liver that binds to free hemoglobin in blood, thereby mediating its removal from the circulation and preventing oxidative damage to tissues. Haptoglobin has 2 alleles (Hp-1 and Hp-2). The Hp-2/Hp-2 homozygous phenotype is associated with an increased risk of MI, stroke, and CVD mortality, 93 , 94 , 95 possibly through differences in antioxidant potential. In addition, haptoglobin appears to directly inhibit the oxidation of LDL-C, a key step in the pathogenesis of atherosclerosis. Fibrinogen, PAI-1, and homocysteine will be measured in all SMuRFless CAD clinic patients. Haptoglobin may be considered in some patients. Screening for clinically significant atherosclerosis in other vascular territories will be considered in all SMuRFless CAD clinic patients, including carotid and vertebral artery atheroma using duplex Doppler ultrasound and peripheral artery disease in the lower limbs using ankle-brachial index if symptoms are suggestive of clinically relevant disease. Patients may be referred for lower limb arterial ultrasound assessment and referred to a vascular surgeon when appropriate. The burden of atherosclerotic CVD in noncoronary vessels in the absence of standard modifiable risk factors is currently unknown. The increased proportion of people post-STEMI without SMuRFs may be linked to increased exposure to environmental factors with a known or potential association with CAD. 4 Though patients will have been screened for history of tobacco smoking, significant exposure to passive tobacco smoke is a potential factor for the development of premature atherosclerosis 96 , 97 and will be considered in all SMuRFless CAD clinic patients. Population-level data have pointed to an association between heavy metal exposure and atherosclerotic CVD. 98 Heavy metal chelator treatment has been shown to reduce CVD events in those with prior events, 99 which strengthens the level of evidence for a causal association. Exposure to common tick bites may sensitize the bite recipient to the development of IgE antibodies to mammalian α-gal. 100 At high levels, this leads to a hypersensitivity reaction to mammalian red meat. At more moderate levels, elevated α-gal IgE levels are associated with >2-fold risk of obstructive CAD 101 and are more pronounced in patients presenting with ACS than those with stable CAD. 101 Potential environmental contributors to be investigated in all patients include exposure to heavy metals (lead, cadmium, mercury, and arsenic) and particulate air pollution, 102 collected by a history and/or direct measure. IgE sensitivity to α-gal will be considered in some patients with potential tick exposure history. Genetic testing will likely be of limited direct benefit to those with known CAD based on the present evidence because guideline-directed medical therapy should be offered regardless. Because of recent advances in biotechnology and high-throughput sequencing platforms, several options for genetic testing are available; however, they currently remain at a direct cost to the consumer. These including whole-genome sequencing (WGS), whole-exome sequencing (WES), single-nucleotide polymorphism array, with derivation of a polygenic risk score (PRS). Several studies have shown that PRS performs well compared to traditional risk factors in univariate prediction of risk and augments the C-statistics of traditional risk factors taken as a whole. It can be implemented at minimal cost. 103 , 104 An index patient with SMuRFless CAD with high PRS may lead to the identification of family members where a high PRS may guide the individual’s choices regarding lifestyle and behaviors associated with improved CVD health as well as heighten adherence to primary prevention pharmacotherapy (particularly statins). 105 The identification of family members with high PRS may additionally allow the clinician to recommend a coronary artery calcium study to delineate coronary atherosclerotic burden or to establish more aggressive treatment targets or personalize secondary prevention approaches, given that PRS predicts relative and absolute benefit of LDL-C lowering. 106 , 107 , 108 , 109 It is important for interpretation and action with regard to PRS to consider patient ethnicity and the population in which the specific algorithm was developed. All SMuRFless CAD clinic patients will be screened for a family history of CAD, which is typically defined as an MI, stroke/transient ischemic attack, or peripheral artery disease in a first-degree relative who had an event before the age of 55 years if male or 65 years if female. A family pedigree will be obtained, including second-degree relatives, which will help to guide consideration of genetic testing for inherited risk. In cases where a strong family history of premature and SMuRFless CAD is evident, screening for rare variants will be considered using whole-genome sequencing, WES, or single-nucleotide polymorphism array. 110 It is important to note that in the SMuRFless CAD setting where severe hypercholesterolemia is not present, genomics studies are not the clinical standard of care and would be performed on a research basis. Appropriate genetic counseling will be provided because of the implications of genetic testing on inherited risk in family members. WES or targeted sequencing provides an opportunity to identify patients attending the SMuRFless CAD clinic with clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood cell clone in persons without other hematologic abnormalities. 111 , 112 This relatively common finding has been associated with nearly a 2-fold increase in CAD in humans. 113 Strategies interrupting key inflammatory pathways may mitigate CHIP-associated CAD risk. 114 , 115 , 116 , 117 , 118 This may become increasingly relevant as clinical trials examine the efficacy of targeting CHIP with novel therapies.

To study and improve the potential utility and scalability of the SMuRFless CAD clinical pathway, a multicenter, prospective, observational patient registry has been established ( ACTRN12622000452796 ). All patients receiving care in the SMuRFless CAD clinics across international sites will be invited to participate. In Australia, patients will be invited to provide informed consent for Medicare Benefits Schedule/Pharmaceutical Benefits Scheme data linkage, providing 5-year clinical outcomes data and facilitating analyses of the cost-effectiveness of the specialty clinic design. Patient-reported outcome measures and experience have also been incorporated. SMuRFless CAD clinic patients will be offered the opportunity to participate in the BioHEART (Cardiology Biobanking for Biomarker Discovery; ACTRN12618001322224 ) cohort study. 119 The BioHEART study invites participants to provide blood samples, clinical and imaging data, and permission for linked outcome data collection. Here, deep molecular phenotyping with candidate and multiomic technologies will be performed, with machine learning efforts used to identify residual mechanisms of CAD susceptibility and resilience. As evidence emerges regarding novel risk factors, treatment patterns, and biomarkers in this population, testing in controlled interventional study settings will be required. The SMuRFless CAD Registry is planned to serve as a mechanism to efficiently engage well-phenotyped, appropriate individuals who have indicated that they wish to be contacted for future research opportunities regarding new interventional studies or itself as a platform for embedded implementation studies and clinical trials. This may be particularly relevant to pathways involved in individual susceptibility to atherosclerosis, such as inflammatory and redox pathways, and novel targets that emerge from unbiased discovery “omic” studies. There is currently insufficient data available to assess the cost-effectiveness of recommendations within this clinical pathway to screen for the nonstandard risk factors. To begin to address this important issue, we plan to perform health economic analyses incorporating prevalence and outcome data collected in the proposed national registry, together with data from randomized trials when available. This document presents an expert opinion consensus clinical pathway for the evidence-based management of patients with atherosclerotic CAD in the absence of SMuRFs. We considered all of the levels of evidence available and acknowledge that, in many cases, high-level evidence is lacking. There is much opportunity to refine this pathway as more evidence becomes available. We advocate for the implementation of a multicenter global registry to provide further insights into the appropriate management of SMuRFless CAD patients and a platform for embedded implementation studies and clinical trials.

Patients with SMuRFless CAD are being increasingly recognized for their prevalence and their specific unmet needs. They are, as a subgroup, not visible in clinical trials or guidelines. Here, we have provided a comprehensive review of current evidence and, where evidence is not available, expert opinion regarding the management of CAD in patients without SMuRFs. Adherence to current guidelines for acute MI management and secondary prevention is recommended but is currently suboptimal according to large registry data. This disparity in guideline-based care for SMuRFless MI patients is a significant contributor to their heightened early mortality. Dedicated clinical pathways and specialized clinics will ensure that people with CAD without SMuRFs receive personalized, evidence-based secondary prevention, agnostic to SMuRFless status, and, in some cases, specialized diagnostic tests for potential modifiable contributors to CAD. The related SMuRFless CAD Registry will provide ongoing data to improve practice and will provide a platform for embedded clinical trials of novel therapeutic strategies targeted at these individuals.

The Centre for Research Excellence is supported by National Health & Medical Research Council of Australia (grant number GNT1196629). Dr Figtree is funded by a National Health & Medical Research Council Practitioner Fellowship (GNT1135920). Dr Ellinor is supported by grants from the National Institutes of Health (1RO1HL092577, 1R01HL157635, 1R01HL157635), by a grant from the American Heart Association Strategically Focused Research Networks (18SFRN34110082), and by a grant from the European Union (MAESTRIA 965286). Dr Psaltis is funded by a National Heart Foundation Level 3 Future Leader Fellowship (106656). Dr Redfern is supported by grants from the National Health & Medical Research Council of Australia (GNT2007946 and GNT1182301). Dr Wilson is supported by grants from the National Health & Medical Research Council of Australia (GNT119600, GNT9100001, GNT1153479). Dr Guzik is funded by the British Heart Foundation and European Research Council (ERC-InflammaTENSION 726318). Dr Arnott has received honoraria from Amgen and AstraZeneca. Dr Brown has received consulting fees from Novartis. Dr Bhatt has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, Cincor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Pharmaceuticals, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer Inc, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89bio; has received royalties from Elsevier; has received consulting fees from Broadview Ventures, Hims, and McKinsey; has received payment or honoraria from the American College of Cardiology, Baim Institute for Clinical Research, Belvoir Publications, Boston Scientific, Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, Population Health Research Institute, Rutgers University, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, HMP Global, Journal of the American College of Cardiology , K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Slack Publications, WebMD, Wiley, and Society of Cardiovascular Patient Care; has received payment for expert testimony from Arnold and Porter law firm; has received travel or meeting support from the American College of Cardiology, Society of Cardiovascular Patient Care, and American Heart Association; has been named (no income) on a patent application for sotagliflozin, assigned to Brigham and Women’s Hospital, who assigned to Lexicon; serves on a Data Safety Monitoring Board for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute, Boston Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, and Population Health Research Institute; has served on an Advisory Board for AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; has served on the Board of Directors for the American College of Cardiology, AngioWave, Boston VA Research Institute, Bristol Myers Squibb, DRS.LINQ, High Enroll, Society of Cardiovascular Patient Care, and TobeSoft; has stock or stock options with AngioWave, Bristol Myers Squibb, DRS.LINQ, and High Enroll; has financial or other nonfinancial interests in Clinical Cardiology, NCDR-ACTION Registry Steering Committee, Contego Medical, American Heart Association Quality Oversight Committee, VA CART Research and Publications Committee; and is a coinvestigator for Abbott, Biotronik, Boston Scientific, CSI, St Jude Medical, Phillips SpectraWAVE, Svelte, and Vascular Solutions. Dr Brieger has received research grant support from Novartis and has received honoraria from BMS/Pfizer. Dr Chong has received consulting fees from Implicit Bioscience Pty; and has a provisional patent for a cell surface marker signature for arrhythmogenic pluripotent stem cell-derived cardiomyocyte. Dr Cistulli has received research grant support from ResMed and SomnoMed; has received consulting fees from RedMed, SomnoMed, and Signifier Medical Technologies; and has received honoraria from ResMed and SomnoMed. Dr Ellinor has received sponsored research support from Bayer AG and IBM Research; and has served on Advisory Boards or consulted for Bayer AG, MyoKardia, and Novartis. Dr Figtree has received personal fees from Amgen, AstraZeneca, Bayer, CSL, and Janssen; has received grants from Abbott Diagnostic and Sanofi; is a founding director and chief medical officer of Prokardia; has a patent, “Biomarkers and Oxidative Stress,” awarded in the United States in May 2017 (US9638699B2) licensed to Northern Sydney Local Health District; has a patent, “Use of P2X7R Antagonists in Cardiovascular Disease” (PCT/AU2018/050905), licensed to Prokardia; has a patent, “Methods for Treatment and Prevention of Vascular Disease” (PCT/AU2015/000548) licensed to the University of Sydney/Northern Sydney Local Health District; and has a filed provisional patent application, “Methods for Predicting Coronary Artery Disease” (USYD Ref: 2022-009-PRO-0; 2022902660) to the University of Sydney/Northern Sydney Local Health District. Dr Hagström has received research grant support to his institution from Amgen and Pfizer; and has received honoraria from Amgen, AstraZeneca, Bayer, Novo Nordisk, Amarin, and Sanofi. Dr Jenkins has received research grant support from Abbott, Medtronic, and Mylan; and has served on Advisory Boards for Abbott Diabetes Care, Amgen, Insulet, and Medtronic. Dr Keech has received grant support from Abbott, Amgen, and Mylan; has received consulting fees from AstraZeneca, Pfizer, and Sanofi; and has participated as a Data Safety Monitoring Board member for the PROMINENT trial (Kowa Research Institute). Dr Kritharides has received research grant support from Amgen; and has received consulting fees from Seqiris. Dr Meikle has a license agreement with Juvenescence Ltd; and has received consultancy payments (made to Baker Institute) from BCAL Scientific and Juvenescence Ltd. Dr Mehran has received research grant support to her institution from Abbott, Abiomed, Alleviant Medical, AM-Pharma, Amgen, Applied Therapeutics, Arena, AstraZeneca, AtriCure, BAIM, Bayer, Beth Israel Deaconess Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CellAegis, CeloNova, CERC, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi-Sankyo, Duke University, Element Science, Faraday, Humacyte, Idorsia, Insel Gruppe AG, Magenta, Medtronic, Novartis, OrbusNeich, PhaseBio, Philips, RenalPro, RM Global, Shockwave, and Vivasure Zoll; has received consulting fees from Cine-Med Research; has served on an Advisory Board with all payments made to institution for Abbott, Janssen, Medtronic, and Novartis; and she and/or her spouse has stock or stock options in Applied Therapeutics, ControlRad, Elixir Medical, and Stel. Dr Natarajan has received research grant support from Apple, Amgen, AstraZeneca, Boston Scientific, and Novartis; has received consulting fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genetech/Roche, Invitae, Novartis, and TenSixteen Bio; has served on Advisory Boards for Esperion Therapeutics, geneXwell, and TenSixteen Bio; and holds stock or stock options in TenSixteen Bio and geneXwell. Dr Nicholls has received research grant support from AstraZeneca, Amgen, Anthera, Cerenis, Eli Lilly, Esperion, InfraReDx, LipoScience, The Medicines Company, New Amsterdam Pharma, Novartis, Resverlogix, Roche, and Sanofi-Regeneron; and has received consulting fees from Akcea, Amarin, Anthera, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Omthera, Merck, Resverlogix, Sanofi-Regeneron, Takeda, and Vaxxinity. Dr Psaltis has received consulting fees from Amgen, Esperion Therapeutics, and Novartis; has received speaker honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, and Sanofi; has received meeting travel support from Amgen and AstraZeneca; and has submitted a provisional patent for a method and composition for promoting neovascularization. Dr Sundström has stock or stock options with Anagram Kommunikation AB and Symptoms Europe AB. Dr Steg has received research grant support from Amarin, Bayer, Sanofi, and Servier Laboratories; has received consulting fees from Amgen, AstraZeneca, BMS/Myokardia, Merck, Novo Nordisk, and Regeneron; has served on Steering Committees or Critical Event Committees for Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Idorsia, Novartis, PhaseBio, Pfizer, Sanofi, and Servier; has received honoraria from AstraZeneca, Novartis, and Novo Nordisk; and has served on Data Safety Monitoring Boards for Servier, Sanofi, and PHRI. Dr Guzik has received research funding from the European Commission (ImmuneHyperCog and BrainGutCVD studies); has served as Editor-in-Chief for Cardiovascular Research ; and has served as Board Committee member for the European Society of Cardiology. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.