Standard and Non-standard Cardiovascular Risk Factors in Ischemic Heart Disease and Atherosclerotic Cardiovascular Disease: A Clinical Review

Abstract

Atherosclerotic cardiovascular diseases, including ischemic heart disease (IHD), remain the leading cause of morbidity and mortality worldwide and are typically induced by the detrimental effects of risk factors on the cardiovascular system. Although some risk factors, such as age and sex, are non-modifiable, the identification and therapeutic interventions against standard modifiable cardiovascular risk factors (SMuRFs), namely hypertension, dyslipidemia, diabetes, smoking, and obesity, contribute to improved cardiovascular outcomes. Beyond SMuRFs, non-traditional, potentially modifiable risk factors for IHD have been identified, such as inflammation, lipoprotein(a), and air pollution. This review article summarizes recent clinical evidence regarding SMuRFs and non-traditional risk factors for IHD and atherosclerotic cardiovascular diseases.

Introduction

Atherosclerotic (obstructive) coronary artery disease is a major phenotype of ischemic heart disease (IHD) and is a leading cause of morbidity and mortality worldwide (1,2). It is well known that standard modifiable cardiovascular risk factors (SMuRFs), namely hypertension, dyslipidemia, diabetes, smoking, and obesity, play a crucial role in the development of atherosclerotic cardiovascular disease (ASCVD) including IHD, and the targeted interventions as primary and secondary prevention strategies against SMuRFs improve clinical outcomes.

Recent international individual-level pooled data from 34 countries and 8 geographic regions by the Global Cardiovascular Risk Consortium (n=1,518,028) demonstrated that nearly 60% of cases of incident ASCVD are attributable to the 5 SMuRFs and that the modification of the SMuRFs resulted in longer life-years free of cardiovascular disease and mortality (3,4). These findings highlight the clinical relevance of SMuRF identification and interventions.

In current clinical practice, achieving appropriate management of SMuRFs is an important quality indicator for IHD (5). However, it is conceivable that a sizable proportion of ASCVD, including IHD, is also attributable to non-traditional risk factors such as inflammation, lipoprotein(a), air pollution, and many others. Recently, cases of “no SMuRFs” have garnered significant attention in the field of IHD, particularly in patients with acute myocardial infarction (MI), because of the poor prognosis compared to cases with at least one SMuRF (6-10).

Although some risk factors (e.g. age, sex, ethnicity, and genetics) are non-modifiable (Fig. 1), non-traditional risk factors can be treated, potentially leading to better care and clinical outcomes. This narrative review article summarizes recent clinical evidence concerning SMuRFs and nontraditional, potentially modifiable risk factors for IHD and ASCVD (Fig. 1).

Figure 1.

Non-modifiable, standard modifiable, and non-traditional risk factors for ischemic heart disease. CSID: chronic systemic inflammatory disease, CVD: cardiovascular disease, SDOH: social determinants of health, SMuRF: standard modifiable cardiovascular risk factor

SMuRFs

Hypertension

Hypertension is prevalent worldwide, affecting 30-50% of the population in developed countries (11,12). Notably, less than a quarter of patients with hypertension are well treated (13). An elevated blood pressure (BP) is one of the strongest risks for ASCVD (2,14). Indeed, the Global Cardiovascular Risk Consortium showed that persons with modified hypertension in their midlife had the most additional life-years free from ASCVD (4). Although BP-lowering therapy can improve ASCVD outcomes, the clinical benefit of intensive treatment and the optimal target BP have been debated. In this context, randomized control trials (RCTs) from Western and Eastern countries (the SPRINT and STEP trials) demonstrated that intensive treatment with a systolic BP target of ＜130 mmHg resulted in a lower incidence of ASCVD than standard care (15,16). More recently, other RCTs from China (the ESPRIT and BPROAD trials) have confirmed the benefits of intensive BP management irrespective of diabetes and previous stroke (17,18). Accordingly, current international guidelines recommend a target BP of ＜130/80 mmHg (19,20). Because the proportional effects of BP lowering on cardiovascular outcomes are believed to be similar between patients with and without previous ASCVD (21), a target BP ＜130/80 mmHg is also applicable to patients with IHD, although complications such as renal impairment and syncope should be carefully managed.

Another recently evolved topic is the impact of salt intake on cardiovascular outcomes. It has long been recognized that a reduction in salt intake leads to a reduction in BP (22). In recent years, scientifically robust RCTs have been reported. The BP-lowering effect of a low-sodium diet (1.3 g/day) was confirmed in a study with a crossover design (23). A stepped-wedge cluster RCT in Peru showed that a reduction in the salt intake with a salt substitution strategy resulted in a lower risk of developing hypertension (24). Furthermore, the landmark SSaSS trial, an open-label, cluster-randomized trial involving persons from 600 villages in rural China, demonstrated fewer cardiovascular events in villages where participants used a salt substitute than in others without such intervention (25). These findings indicate that salt reduction is fundamental to the management of hypertension. Notably, however, salt reduction and potassium supplementation have been included in the experimental arms of recent RCTs. Therefore, the RCT results can be explained, at least partly, by the additional potassium intake. Salt substitution with additional potassium may be an important therapeutic option for the management of hypertension. Recent guidelines recommend the restriction of salt intake (19,20) with a limit of ＜6 g daily in Japan (26).

In summary, in patients with hypertension, BP should be targeted at ＜130/80 mmHg, with a target salt reduction of ＜6 g/day, and a salt substitute may be considered (Fig. 2). Upcoming pharmacological approaches (e.g. angiotensinogen suppression) and interventions (e.g. renal denervation) may aid in better BP management (27,28).

Figure 2.

Secondary prevention strategies for modifiable risk factors in ischemic heart disease. ACS: acute coronary syndrome, ASCVD: atherosclerotic cardiovascular disease, BMI: body mass index, BP: blood pressure, CCS: chronic coronary syndrome, CKD: chronic kidney disease, DAPT: dual antiplatelet therapy, GIP: glucose-dependent insulinotropic polypeptide, GLP-1: glucagon-like peptide-1, HF: heart failure, IHD: ischemic heart disease, LDL-C: low-density lipoprotein cholesterol, OAC: oral anticoagulation, P2Y12-i: P2Y12 inhibitor, PCSK9: proprotein convertase subtilisin kexin 9, RA: receptor agonist, SAPT: single antiplatelet therapy, SGLT2-i: sodium-glucose cotransporter 2 inhibitor, SSB: sugar-sweetened beverage

Dyslipidemia

Although the term “dyslipidemia” includes several conditions involving abnormal lipid profiles in the blood, an elevated level of low-density lipoprotein cholesterol (LDL-C) shows a robust cause-and-effect relationship with ASCVD and is thus a major therapeutic target in patients with ASCVD. In settings of both primary and secondary prevention, achieved LDL-C levels are linearly associated with the development of cardiovascular disease (29). Unlike sodium in the management of hypertension, it is challenging to reduce the level of LDL-C using dietary approaches alone, even with vegetarian or vegan diets (30). LDL-C lowering with any intervention reportedly reduces cardiovascular risks (29), but statins are a fundamental prevention drug and should be prescribed in all patients with IHD unless contraindicated (31,32). From a mechanistic perspective, a reduction in LDL-C levels results in coronary plaque regression and stabilization (33), and a meta-analysis showed that the regression of atherosclerotic plaques can be translated into a reduction in ASCVD events (34).

The LDL-C level in IHD is usually targeted at ＜55 mg/dL in patients with acute coronary syndrome (ACS) and ＜70 mg in those with chronic coronary syndrome, although the cutoff values vary among international guidelines (31,35,36). To achieve lower levels of LDL-C, ezetimibe- and proprotein convertase subtilisin kexin 9 (PCSK9)-targeted therapies secondary to statins may be considered. The landmark IMPROVE-IT trial showed that ezetimibe resulted in incremental lowering of LDL-C levels and improved cardiovascular outcomes in patients with ACS when added to statin therapy (37). The RACING trial from Korea demonstrated that, among patients with ASCVD, moderate-intensity statin with ezetimibe combination therapy was superior to high-intensity statin monotherapy in the proportion of achieved target LDL-C levels with a lower drug discontinuation rate (38). Another LDL-C-lowering approach includes PCSK9 inhibition with a monoclonal antibody, small-interfering ribonucleic acid, macrocyclic peptide, and genome editing (39). In current clinical practice, subcutaneous PCSK9-targeted drugs (e.g. evolocumab and inclisiran) are the available treatment options. Although the cost-effectiveness is uncertain (40,41), PCSK9 inhibitors can reduce ASCVD events in secondary prevention (42).

In summary, statins should be prescribed to patients with IHD irrespective of their baseline LDL-C levels. To achieve the target levels of LDL-C (＜55 or 70 mg/dL), ezetimibe and PCSK9-therapies should be considered (Fig. 2). Other treatment options, such as bempedoic acid and obicetrapib, are also promising (43,44).

Diabetes

Diabetes is a rapidly growing global health concern. In 2021, 529 million people were living with diabetes worldwide, and this number is projected to increase to 1.3 billion by 2050 (45). In contrast to LDL-C-lowering therapy, lifestyle interventions and modification of diet and physical activity are believed to be fundamental in the management of diabetes (46). Although the pivotal Look AHEAD trial failed to demonstrate the superiority of an intensive lifestyle intervention in reducing ASCVD events (47), a sub-analysis of the RCT indicated that maintaining weight loss and higher physical activity volume were associated with lower cardiovascular risks in patients with diabetes (48). In addition to lifestyle modifications, pharmacological therapies have been evolving, particularly with sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Although the underlying mechanisms are unclear, pivotal RCTs have demonstrated that SGLT2 inhibitors can improve clinical outcomes in patients with and without diabetes, particularly in reducing heart failure (HF) and renal events (49). GLP-1 receptor agonists are also reportedly associated with a lower risk of ASCVD events (50).

Notably, the effect of GLP-1 receptor agonists on weight loss is clinically relevant (51). Recently, the FLOW trial demonstrated that subcutaneous semaglutide improved renal outcomes in patients with type 2 diabetes and chronic kidney disease (CKD), as SGLT2 inhibitors showed (52). In addition, the SOUL trial indicated that oral semaglutide also reduced cardiovascular risk in diabetic patients with ASCVD, CKD, or both (53). In the management of diabetes, given the RCT results, SGLT2 inhibitors may be preferable in patients with or at risk of developing HF and CKD, whereas GLP-1 receptor agonists can be prioritized in patients with ASCVD and obesity and have the potential to improve renal outcomes. A recent network meta-analysis suggested that SGLT2 inhibitors were more cardioprotective in the elderly, while GLP-1 receptor agonists were more beneficial in younger people (54). Although drug-specific complications, such as genital infection and ketoacidosis for SGLT2 inhibitors and severe gastrointestinal events for GLP-1 receptor agonists, should be carefully managed (51), these two drugs should be considered for better outcomes when treating patients with ASCVD, including IHD and/or CKD. The dual agonist of GLP-1 and glucose-dependent insulinotropic polypeptide receptors (e.g. tirzepatide) may be another promising pharmacological therapy for patients with diabetes and obesity, and clinical evidence has been accumulating (55,56). In addition, nonsteroidal mineralocorticoid receptor antagonists may be beneficial in patients with diabetes and CKD (57). Recent advancements in insulin treatment (e.g. once-weekly formulations and automated insulin delivery systems) are remarkable (58,59).

In summary, in addition to lifestyle modifications, SGLT2 inhibitors, GLP-1 receptor agonists, or both may offer better outcomes in high-risk patients with ASCVD and CKD (Fig. 2). Multiple molecules with different mechanisms of action are currently under development for diabetes, obesity, and other metabolic complications (60).

Obesity, an unhealthy diet, and physical inactivity

The global obesity epidemic has been well established, with an increasing prevalence in most countries since the 1980s. Obesity directly contributes to incident SMuRFs and other risk factors and independently leads to the development of cardiovascular diseases, including ASCVD, HF, atrial fibrillation, and mortality (61). Obesity was included among SMuRFs in some previous studies and not in others (3,4,6); it should be treated to prevent the development of cardiovascular risk factors and events.

Although some other variables (e.g. waist-to-height ratio) can be useful metrics (62), obesity is usually defined by the body mass index (BMI). The universal criteria of the World Health Organization (WHO) define overweight as BMI 25 to ＜30 kg/m² and obese as a BMI ≥30 kg/m² (61). However, given that Asians have higher morbidity and mortality even with a lower BMI and smaller waist circumference than people in Western countries, the WHO Asia-Pacific region defines BMI 23 to ＜25 kg/m² as overweight and ≥25 kg/m² as obese (63). Of note, an underweight status, represented as frailty, is also a health concern; the targeted BMI may range from 18.5 to 23.0 kg/m² in East Asian countries, including Japan (64).

Similar to the management of diabetes, lifestyle interventions and modifications in diet and physical activity are essential for obesity care. Weight loss interventions may be associated with lower risks of developing type 2 diabetes and premature mortality in adults with obesity (65,66). In addition to lifestyle modifications, a network analysis of RCTs showed that GLP-1 receptor agonists, particularly subcutaneous semaglutide, effectively reduced body weight (67). Recently, in the SURPASS-2 trial, tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, was found to be superior to semaglutide with respect to reduction in glycated hemoglobin levels and weight loss in diabetic patients with BMI ≥25 kg/m² (55). Another network meta-analysis estimated the effect of tirzepatide and subcutaneous semaglutide on weight reduction as -8.6 kg and -4.6 kg in adults with type 2 diabetes (51). Bariatric surgery is another treatment option (68).

In summary, among obese patients with cardiovascular disease who are at risk, the BMI may be targeted at ＜23 kg/m² in East Asian regions and ＜25 kg/m² globally. Modifying an unhealthy diet and physical inactivity are key elements in promoting a healthy life. The intake of vegetables, fruits, legumes, and fish instead of salt, sugar-sweetened beverages, and processed foods is recommended in persons with and without obesity (61). A sedentary lifestyle should be avoided, with the implementation of moderate-intensity aerobic activity ＞90-150 minutes per week (Fig. 2). In addition, subcutaneous semaglutide and tirzepatide can be viable therapeutic options in patients with obesity in current clinical practice, irrespective of diabetes (Fig. 2). Although obesity pharmacotherapy is a rapidly moving field, the clinical inequity of access to such treatments must be improved (69).

Smoking

Tobacco use, including chewing tobacco, inhalation of secondhand smoke, and e-cigarettes, is one of the most important avoidable causes of cardiovascular diseases globally (70). Even in 2015, one in every four men worldwide was a daily smoker, with a relative increase in the number and prevalence of smokers, particularly in low- to middle-income countries (71). In general, smokers lose at least 10 years of life expectancy, compared to never-smokers, due to cardiovascular, cancer, and respiratory mortality (72-74). A clear dose-response relationship between the number of cigarettes smoked per day and the risk of ASCVD, including IHD, has been well recognized (70). Among patients with IHD undergoing percutaneous coronary intervention (PCI), current smoking is associated with an increased cardiovascular risk, and the “smoker's paradox” is unlikely (75,76). Although an RCT is ethically infeasible, previous observational studies have demonstrated that smoking cessation offers better clinical outcomes than its continuation (72-74). Even if smoking cessation leads to weight gain, it protects against ASCVD and mortality (77,78). Importantly, complete smoking cessation, but not reduction, is related to a reduced risk of stroke and MI (79,80). Although uncertain, quitting tobacco for 5-10 years may reduce cardiovascular risks close to those of never-smokers (72-74,81,82). However, cancer and respiratory mortality may still be higher in persons who have stopped smoking for ≥30 years than in never-smokers (74).

To quit smoking, several approaches are clinically available, including nicotine replacement therapy with chewing gum and varenicline, and smoking cessation programs are particularly needed in populations with lower education levels (83). The overall effects of e-cigarettes on public health are controversial, with a possible role in aiding smoking cessation. A single-center RCT suggested that switching from tobacco cigarettes to e-cigarettes was associated with improvement in peripheral endothelial function (84). In addition, a recent systematic review indicated that e-cigarettes may increase quit rates of tobacco cigarettes compared to conventional nicotine replacement therapy (85). A Korean nationwide study showed that among smokers who underwent percutaneous intervention for IHD, switching to e-cigarettes or quitting smoking was associated with a reduced risk of coronary events compared to continued tobacco cigarette use (86). Although e-cigarettes might be helpful in quitting smoking as a bridge therapy, their long-term effects are largely uncertain (87).

In summary, complete smoking cessation (not reduction) should be achieved in at-risk patients with cardiovascular disease (Fig. 2). Nicotine replacement therapy should be considered for smoking cessation. E-cigarettes might aid in smoking cessation but thus far are not recommended for cardiovascular health.

Non-traditional Cardiovascular Risk Factors

Inflammation

In 1973, Ross proposed that atherosclerosis is an inflammatory response to injury to the vascular endothelium (88). The landmark CANTOS trial clinically established the inflammation hypothesis, in which, among patients with previous MI and systemic inflammation, assessed with C-reactive protein ≥2 mg/L, canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, reduced the risk of cardiovascular events (89), although this anti-inflammatory drug was not approved with an indication for preventing ASCVD due to its low cost-effectiveness (90). Systemic inflammation (e.g. high C-reactive protein levels) is related to the development of cardiovascular disease independent of other SMuRFs (91), and residual inflammation, but not cholesterol risk, is associated with an increased cardiovascular risk among statin-treated patients undergoing PCI (92). Therefore, dedicated treatment options for inflammation are warranted. The subsequent CIRT trial failed to demonstrate the effect of low-dose methotrexate on the reduction in inflammatory marker levels and ASCVD events (93). Colchicine, another affordable anti-inflammatory drug, has been widely investigated in RCTs in patients with IHD and ASCVD. The placebo-controlled randomized COLCOT and LoDoCo2 trials showed that colchicine, in addition to standard pharmacological treatment, reduced ASCVD events (94,95). Thus, under current international guidelines, colchicine is recommended for patients with chronic IHD and acute MI with a Class IIa or IIb indication (31,36). While some recent RCTs failed to show a clinical benefit in patients with ST-segment elevation MI and stroke (96-98), a meta-analysis confirmed the benefit of colchicine on cardiovascular events in secondary prevention (99). Research on specific anti-inflammatory drugs (e.g. a humanized monoclonal antibody against interleukin-6 and a myeloperoxidase inhibitor) is currently ongoing in the field of ASCVD, which will shape our understanding of the fundamental mechanisms contributing to cardiovascular disease and outcomes (100).

Lipoprotein(a)

Lipoprotein(a) is a form of LDL particle with an added apolipoprotein(a) attached to the apolipoprotein(b) via a disulfide bridge and is highly atherogenic (101). The level of lipoprotein(a) is mostly genetically determined and remains stable throughout one's lifetime, regardless of lifestyle (outside of acute inflammatory states) (102). The 2022 European Atherosclerosis Society consensus statement indicates that lipoprotein(a) is likely to have a causal relationship with cardiovascular outcomes, including aortic stenosis (but not for venous thrombotic events), and recommends a lipoprotein(a) evaluation be performed at least once in adults (91,102). The cutoff value of lipoprotein(a) is 30-50 mg/dL (50-100 nmol/L), which may differ among races and ethnicities (103). Lipoprotein(a) concentration was unchanged with statin and ezetimibe but decreased with PCSK9 inhibitors by 15-30% (102). Whether or not lipoprotein(a)-lowering therapy can reduce ASCVD events is being explored in ongoing cardiovascular outcome trials (104), but novel pharmacological approaches with technologies of small interfering ribonucleic acid and antisense oligonucleotide for the management of lipoprotein(a) have been rapidly emerging (105-107).

Thrombosis management

Thrombophilia is an abnormal blood coagulation condition that leads to an increased risk of thrombotic and ischemic events. Hypercoagulable states include congenital (e.g. protein C and S deficiencies) and acquired (e.g. malignancy and antiphospholipid antibody syndrome) disorders (108). Irrespective of the hypercoagulable state, antithrombotic management is the cornerstone in patients with IHD and ASCVD. In patients with ACS and/or PCI, dual antiplatelet therapy (DAPT) has been established to reduce stent thrombosis and ischemic events (109). During the past two decades, however, the introduction of potent antithrombotic therapy, such as ticagrelor and prasugrel, as a part of DAPT has been related to a reduction in ischemic events and an increase in bleeding events (110,111). To date, numerous RCTs have been conducted to elucidate the best antithrombotic regimen in patients with IHD, and meta-analyses have shown that short-term DAPT (for one to three months) after PCI may be non-inferior in ischemic outcomes and superior in bleeding events than long-term DAPT (112). Thus, international guidelines recommend short-term DAPT, particularly in patients with chronic IHD and high bleeding risk, while in those with ACS and no high bleeding risk, a longer DAPT duration (6-12 months) may be considered (31,36,113). A no-DAPT (aspirin-free) regimen after PCI was examined in the STOPDAPT-3 trial in Japan, and the experimental regimen of single antiplatelet therapy (SAPT) with prasugrel in patients with ACS or high bleeding risk did not result in superiority in bleeding outcomes but did meet the non-inferiority in ischemic endpoints compared to standard DAPT (114). Given that the aspirin-free strategy is associated with a potential signal of excess coronary events, (short-term) DAPT remains the default antiplatelet regimen. After DAPT, lifelong SAPT with a P2Y12 inhibitor may be a preferable choice according to the results of the Korean HOST-EXAM and SMART-CHOICE 3 trials and meta-analyses (115-117). In patients with an indication for oral anticoagulation, DAPT duration should be minimized to within 1-4 weeks, and SAPT may be terminated 6-12 months after PCI (Fig. 2) (31,36,113). Several large-scale RCTs are ongoing and will offer a new standard for antithrombotic therapy in patients with IHD and ASCVD (118).

Environmental pollution

Air, light, acoustic, chemical, and metal pollution are clinically relevant non-traditional risk factors for IHD and ASCVD (14,119). Air pollution is a heterogeneous mixture of gases and particles, including coarse particles with aerodynamic diameters ranging from 2.5 to 10 μm (PM10), fine particles (＜2.5 μm, PM2.5), and ultrafine particles (＜0.1 μm) with inorganic compounds, elemental and organic carbon, crystal materials, biological components, etc. (14). It is estimated that in 2019, nearly 7 million deaths were directly attributed to air pollution worldwide, which is also a major contributor to IHD (120). Air pollution can induce oxidative stress, inflammation, and endothelial dysfunction, leading to cardiometabolic and cardiovascular disease.

Light pollution, namely artificial nighttime illumination, is a novel environmental risk factor for ASCVD (14). A Japanese longitudinal study involving elderly individuals showed that higher levels of nighttime light intensity measured inside the bedroom were associated with the progression of carotid atherosclerosis (121). Another Chinese study demonstrated that outdoor light at night at a residential address was linked to an increased risk of hospitalization and mortality due to IHD, even after multivariable adjustment (122).

Acoustic pollution, typically associated with transportation noise exposure (e.g. road, aircraft, and railway noise), represents a growing threat to cardiovascular health. The WHO environmental noise guidelines indicate a significant association between road traffic noise and the risk of IHD, with a relative risk of 1.08 per 10 decibels (123). Light and acoustic pollution can cause endothelial dysfunction, oxidative stress, inflammation, stress hormone imbalance, and circadian rhythm disturbance (124). Other environmental risks, such as chemical and metal pollution and water contamination are also major cardiovascular risk factors often overlooked in clinical practice (119). Heat exposure is another important but underappreciated risk that contributes to the development of ASCVD (125). Policymakers, healthcare professionals, and the public should be aware of the cardiovascular risk of environmental pollution, and preventive strategies for pollution-related cardiovascular diseases through a paradigm shift to a clean environment are needed.

Other risks

Despite recent advances in pharmacological and non-pharmacological interventions (126-185), IHD and ASCVD are responsible for millions of deaths annually globally (2). Infectious diseases may be an underlying mechanism in the development of atherosclerotic diseases. In particular, influenza virus infection is well known to be associated with incident IHD (186). In a placebo-controlled RCT setting, influenza vaccination early after acute MI or in high-risk IHD was effective in reducing death and MI (187). Thus, influenza vaccination should be promoted as part of comprehensive secondary prevention of IHD. Coronavirus disease 2019 may be a risk factor for ASCVD (188). Although whether or not vaccination for coronavirus disease 2019 can mitigate the risk of acute MI remains to be established, promising results have been published (189).

Social determinants of health (SDOH) consist of five domains (economic stability, education, healthcare access and quality, social and community context, and neighborhood and built environment) and are associated with the development of ASCVD (190). The domains of SDOH have a complex interplay and often overlap. Although effective intervention for SDOH is challenging, clinicians and trained personnel (e.g. social workers) should address patients with vulnerable SDOH to link them to appropriate resources with tailored plans (190). There are numerous other non-traditional cardiovascular risk factors, including malignancy, illicit substance use, mental stress, unhealthy sleep, and chronic kidney disease (Fig. 1). The prognostic impact and therapeutic strategies for such risks remain to be established, and further research is needed to elucidate the underlying mechanisms and develop actionable interventions.

Conclusions

SMuRFs and non-traditional risk factors play a significant role in the development of IHD and ASCVD. To prevent atherosclerosis and other clinical events, lifestyle optimization and evidence-based care should be implemented for SMuRFs, and non-traditional risks should be recognized and managed as much as possible. We hope that this review article will help healthcare providers and patients appreciate the risks of atherosclerosis and the basic therapeutic strategies for secondary prevention.

Author’s disclosure of potential Conflicts of Interest (COI).

Yuichi Saito has received lecture fees from Daiichi Sankyo and Novartis Pharma. Yoshio Kobayashi received lecture fees from Abbott Medical Japan and Daiichi Sankyo, and research grants from Abbott Medical Japan, Win International, Otsuka Pharmaceutical, Boehringer Ingelheim, Nipro, and Japan Lifeline. The other authors have nothing to disclose regarding the present study.