Cardiovascular disease is a serious threat to human health. Most of the existing interventions focus on secondary prevention, although it is not too late to mend the fold. However, as the front line of cardiovascular disease prevention and treatment moves forward, primary prevention, which is “prevention before it is too late”, is receiving more and more attention. While the incidence of cardiovascular disease in Western countries has been declining at an inflection point, the incidence of cardiovascular disease in China continues to soar. Early screening and risk assessment of asymptomatic people, and thus early intervention, are essential to reduce the incidence of cardiovascular disease.
Screening of asymptomatic individuals for cardiovascular disease is done for the primary purpose of detecting disease rather than excluding it. The need for screening lies in the fact that clinically asymptomatic individuals do not mean disease-free individuals. In fact, about half of all myocardial infarctions and strokes occur in apparently healthy individuals with no significant elevation in LDL-C.1 Therefore, the WHO has made recommendations for screening for disease.2 However, screening tests may have some shortcomings, such as false exclusion of a disease due to low sensitivity of the test and anxiety due to false positives. Some specific tests, such as coronary CT, can increase radiation exposure and lead to anxiety and additional medical expenses and interventions due to unexpected detection of certain lesions. The technical aspects of screening tests also have some problems, such as dependence on the examiner, errors and errors in the reader, lack of uniform standards for most measurements, and lack of uniformity in measuring instruments. There is also a lack of agreement on the interval between reviews and on the significance of changes in measurements. When to begin screening is also an issue, and existing risk scores are usually aimed at those over 40 years of age. However, while young people may be at low risk for 10-year cardiovascular risk, many may be at high risk for lifetime cardiovascular risk. With the current prevalence of obesity and physical inactivity lifestyles, they may benefit more from risk factor control. A recent study showed a high incidence of subclinical atherosclerotic lesions including increased intima-media thickness in the carotid arteries and coronary calcification for those under 50 years of age with low 10-year cardiovascular risk (<10%) and high lifetime cardiovascular risk (≥39%), and a 3% increase in the rate of progression of coronary calcification was also found in this group at follow-up.
I. Methods for assessing cardiovascular risk in asymptomatic adults
There are many methods to assess cardiovascular risk in asymptomatic adults, including risk scores, genetic background (including family history and genetic testing), biomarkers, direct evaluation of the heart (including electrocardiogram, echocardiogram, composite electrocardiogram and echocardiogram, myocardial perfusion imaging, etc.), and noninvasive atherosclerosis testing methods. Non-invasive atherosclerosis testing mainly includes the following two parts i.e. the assessment of arterial function and structure. There are three main methods for arterial function: 1) Pulse Wave Velocity (PWV); 2) Augmentation Index (AI); and 3) Direct measurement of dilatability and compliance of specific arterial walls using ultrasound imaging. There are two main methods to detect arterial structure: 1) Intima-Media Thickness (IMT), atheromatous plaque formation, and coronary artery calcification score using ultrasound, EBCT, spiral CT, and MRI; 2) Ankle-Brachial Index (ABI), which assesses the opening of arterial vessels in the lower extremities.
1.Risk score
At present, the cardiovascular risk assessment of asymptomatic people is mainly based on known cardiovascular risk factors, and the risk score (Table 1) is used to determine the cardiovascular risk based on these risk factors, such as Framingham score (FRS) and SCORE score. The “Study on Comprehensive Risk Assessment and Intervention Program for Coronary Heart Disease and Stroke” has also developed a 10-year risk of ischemic cardiovascular disease in China based on the epidemiological results of the national population.4 Although many cardiovascular risk scoring systems have been developed, the use of these scoring systems is still low at this stage in the actual clinical process. The use of these scoring systems is still very low. On the one hand, we advocate the use of these scoring systems, and in the 2010 ACCF/AHA guidelines for the evaluation of cardiovascular risk in asymptomatic adults (hereafter referred to as the 2010 guidelines)5, the risk score is classified as a category IB indication. On the other hand we should consider using some more concise and intuitive methods to determine the cardiovascular risk of patients. When using the risk score we should be aware of its relative nature, for example, for two different patients with a 10-year cardiovascular risk of 9.8% and 10.2%, although the risk ratings are low and intermediate risk, there is no essential difference in their cardiovascular risk, which should be further determined based on the patient’s clinical situation. For the individual patient, high risk indicates a higher risk of cardiovascular disease and requires intensive intervention. However, for population cardiovascular disease risk, low and intermediate risk groups are more important. Because of their high numbers, there is a need to evaluate individual lifetime cardiovascular risk as well as to use other methods within the low and intermediate risk groups to further distinguish those at relatively high risk for intervention. Because of the different characteristics of cardiovascular disease development in different populations, such as high prevalence of stroke in Chinese and coronary heart disease in Westerners, differences in genetic background, lifestyle habits and susceptibility to risk factors in different populations, a risk scoring system for different populations should be considered. For example, the use of FRS may overestimate the cardiovascular risk in the national population, and it may be possible to better assess the cardiovascular risk if other indicators are available to complement it.
Table 1 Characteristics of different risk scores
Scoring system
Indicator
Endpoint
Study population
Validation population
ROC value
Limitations
Framingham
Risk score
Age, sex, smoking, antihypertensive therapy, TC and HDL
Coronary heart disease (angina pectoris, myocardial infarction, and sudden death)
White American men and women
Age: 30-62 years
Males, females, blacks, Europeans, Mediterranean, and Asians
0.7744 (females)
0.7598 (male)
Age <30 and >65 years, Japanese American males, Hispanic males, Indian females, females, left ventricular hypertrophy, severe hypertension, diabetes mellitus
Overall cardiovascular risk
Age, sex, SBP, smoking, TC, HDL, diabetes, antihypertensive therapy
Coronary heart disease, stroke, heart failure, peripheral vascular disease
White American men and women
Age: 30-74 years
Framingham offspring
0.793 (female) 0.763 (male)
Mainly for whites
SCORE score
Age, sex, smoking, TC or TC/HDL, high- or low-risk areas
Fatal cardiovascular events
European men and women
Age: 45-64 years
Europeans
0.71C0.84
No non-fatal cardiovascular events, risk factors determined by single measurement rather than usual levels
ASSIGN score
Age, sex, SBP, TC, HDL, family history, social deprivation
Cardiovascular death, coronary heart disease admission, PTCA or CABG
Scottish men and women
Age: 30-74 years
Scottish
0.7841 (female) 0.7644 (male)
Slightly better than Framingham risk score, but still overestimates risk
Reynolds score
Age, SBP, smoking, TC, HDL, Hs-CRP, family history, diabetics plus HbA1c
Myocardial infarction, stroke, coronary revascularization, cardiovascular death
US women.
Age >45 years
U.S. women
0.808
Predominantly white, all female, relatively homogeneous socioeconomic status, blood pressure, weight and family history obtained from self-reported study subjects
QRISK score
Age, sex, SBP, smoking, TC/HDL, family history, antihypertensive treatment, BMI, social deprivation
Myocardial infarction, coronary artery disease, stroke and TIA
UK men and women
Age: 35-74 years
British
0.7879 (female) 0.7674 (male)
”Home field advantage” validated with the same population
Reynolds male scores
Age, sex, SBP, smoking, TC, HDL, Hs-CRP, family history, diabetics plus HbA1c
Myocardial infarction, stroke, coronary revascularization, cardiovascular death
American men.
Age: 50-80 years
US males
0.7-0.714
Primarily middle-aged whites, relatively homogeneous socioeconomic status and access to care, family history obtained from self-reported study subjects
National 10-year fatal and nonfatal ischemic cardiovascular disease scores
Age, BMI, smoking, SBP, TC, diabetes mellitus
Coronary heart disease, ischemic stroke
Chinese men and women
Age: 35-59 years
Chinese
0.791 (female)
0.796 (men) Relatively low age of study population, mainly applicable to mainland Chinese population, more applicable to those without cardiovascular disease at baseline, possible underestimation of overall ischemic cardiovascular disease
2 Carotid IMT
Carotid artery IMT (CIMT) thickness and plaque are currently more certain indicators of atherosclerosis. cIMT is associated with cardiovascular risk factors, FRS, coronary atherosclerosis confirmed by arteriography, and intravascular ultrasound confirmed plaque burden, coronary calcification, and cardiovascular disease. Several studies suggest that CIMT thickening predicts cardiovascular events in asymptomatic populations and event recurrence in those with prior cardiovascular events. In the ARIC study, a 4-7 year follow-up of 7289 women and 5552 men aged 45-64 years with non-coronary heart disease in four US communities, the risk of coronary heart disease was 5.07 times (95% CI: 3.08-8.36) and 1.85 times (95% CI: 1.28-2.69) higher in women and men with CIMT ≥1 mm than in women with CIMT <1 mm, respectively.6 Subsequently, the risk of coronary heart disease in women and men with CIMT ≥1 mm was 1.85 times (95% CI: 1.28-2.69) higher than in women with CIMT <1 mm. Subsequent follow-up of this cohort for up to 15 years found that CIMT measurement did provide additional prognostic information for cardiovascular disease beyond traditional risk factors, particularly in patients with intermediate risk scores.7 In the 5858 patients aged 65 years or older enrolled in the Cardiovascular Health Study, the risk of heart attack and stroke increased linearly with IMT thickening, with individuals with baseline IMT in the upper 1/4 of the range compared with those in the lower 1/4. The relative risk was 3.15 (95% CI: 2.19, 4.52) for individuals in the upper 1/4 compared with those in the lower 1/4.8
IMT increases ≤0.03 mm per year in asymptomatic individuals, but increases at an increased rate in those with cardiovascular risk factors, and this increase is associated with an increased risk of myocardial infarction as well as stroke, with serial measurements providing more prognostic information. However, for individuals, serial measurements are of limited significance due to the presence of measurer error. Carotid plaque may be more predictive of preexisting cardiovascular disease while CIMT is more prognostic in asymptomatic individuals. It has also been shown that common carotid artery IMT is strongly associated with hypertension, while carotid sinus and internal carotid arteries are more strongly associated with atherosclerosis. The Bugalusa Heart Study in the United States showed that LDL-C and BMI levels in childhood and adolescence predicted CIMT thickness in early adulthood, suggesting the importance of early intervention for cardiovascular risk factors.9 In the 2010 guidelines, measurement of carotid IMT in asymptomatic intermediate-risk patients is listed as a Class IIa indication, but is advocated in experienced centers.
3. ABI
ABI is a simple and cost-effective tool for the diagnosis of lower extremity peripheral vascular disease. The relative risk of cardiovascular death was 2.52 (95% CI: 1.34-2.14) and 1.77 (95% CI: 1.48-2.13) for ABI <0.9 and ABI >1.4, respectively, and the relative risk of all-cause death was 1.69 (95% CI: 1.69) for ABI >1.4 and 1.77 (95% CI: 1.48-2.13), respectively, in the Strong heart study. 1.69 (95% CI: 1.74-3.64) and 2.09 (95% CI: 1.49-2.94), respectively.10 And a meta-analysis showed that even after adjustment for FRS, the risk of total mortality and cardiovascular death was significantly increased in those with a decreased ABI (≤0.9), thus requiring the addition of ABI.11 And the significance of ABI addition to the risk score differs between men and women, with men judged to be at high risk on the basis of the FRS having their risk reduced to intermediate risk if their ABI is normal. In women who are low risk by FRS score, an abnormal ABI suggests that these patients are at high risk. In the 2010 guidelines, measurement of ABI in asymptomatic intermediate-risk patients is listed as a Class IIa indication.
4. PWV
IMT reflects changes in arterial structure and PWV reflects arterial stiffness. Studies have shown that PWV can provide additional information on cardiovascular disease beyond traditional risk factors. The Rotterdam study in a healthy population showed that PWV can predict coronary heart disease and stroke after adjusting for traditional cardiovascular risk factors, CIMT, ABI and pulse pressure.12 The correlation between PWV and atherosclerosis was previously thought to be mainly in the middle-aged and elderly, but the Bugalusa series in the United States found that PWV can also be used as a predictor of vascular damage in younger people with multiple cardiovascular risk factors. However, in the 2010 guidelines, PWV testing is not recommended for asymptomatic patients beyond the study.
5. Biomarkers
In addition to the noninvasive indicators of atherosclerosis described above, there are several biomarkers used to predict the development of cardiovascular disease in asymptomatic patients. Examples include blood homocysteine, LP(a), tPA, PAI-1, fibrinogen, microalbuminuria, BNP, HbA1c, Hs-CRP, etc. However, the evaluation of genetic testing, BNP, lipoproteins and apolipoproteins in asymptomatic patients is not recommended in the 2010 guidelines. Due to the results of the Jupiter study, testing for Hs-CRP was designated as a Class IIa indication in this guideline for asymptomatic patients aged 50 years or older in men and 60 years or older in women with LDL <130 mg/dl. In addition HbA1c, detection of microalbuminuria in patients without diabetes and at intermediate risk for hypertension, and lipoprotein-associated phospholipase A2 (Lp-PLA2) for prediction of cardiovascular disease need further investigation.
II. Interventions after cardiovascular risk assessment in asymptomatic adults
Screening for cardiovascular disease in asymptomatic patients is performed to screen for those at relatively high risk for interventions to reduce the incidence of cardiovascular disease in these individuals. Risk assessment, which traditionally relies on risk factors, correlates well with the presence of atherosclerotic lesions in individuals, but is limited by the fact that it does not directly detect atherosclerotic lesions.Akosah et al. found that 75% of 229 (men <55 years and women <65 years) coronary patients with acute myocardial infarction as their first symptom did not require a statin before the infarction according to ATP III guidelines did not require a statin prior to the infarction.14 Similarly, Khurram et al. found that among 546 asymptomatic Brazilian men, approximately half of those with significant coronary calcification did not require medication according to the guidelines, thus potentially resulting in a lost opportunity for intervention in this population.15 However, no firm conclusions have been reached on how to intervene in screened high-risk patients. Although some studies have suggested that making patients aware of their carotid lesions may facilitate lifestyle changes in patients. However, a study of asymptomatic middle-aged US military personnel showed that screening for coronary artery calcification did not lead to a change in risk factors for cardiovascular disease within a year.16 This suggests that we cannot wishfully assume that screening is beneficial simply because we can perform certain tests and that such tests do have certain pathophysiological or anatomical implications, but that further research is needed to clarify.
For primary prevention of cardiovascular disease, lifestyle changes are certainly the cornerstone. There is a lack of agreement on when to initiate drug therapy. In general, low-risk patients benefit less from pharmacotherapy and the health economics are inconclusive, so lifestyle interventions are usually used. For high-risk patients, pharmacologic interventions should be used. For intermediate-risk patients, further means should be taken to distinguish between relatively high-risk and low-risk patients for different levels of intervention, and relatively high-risk individuals may be considered for pharmacologic interventions, for which the health economics are not clearly studied. However, most such distinctions consider 10-year cardiovascular risk and may need to be reconsidered in terms of lifetime cardiovascular risk.
Aspirin has played a very important role in the secondary prevention of cardiovascular disease. However, its use in primary prevention remains controversial and is recommended for people at high risk of cardiovascular disease, while balancing the bleeding and cardiovascular benefits.17 The current use of statins may weaken the role of aspirin in primary prevention of cardiovascular disease.18 Various antihypertensive drugs and statins are available for primary prevention of cardiovascular disease, but previous studies have mostly been based on risk factors. The positive results of the Jupiter study suggest that statins can reduce cardiovascular events in asymptomatic patients, but the study was conducted in people with increased Hs-CRP, and the observed endpoints did not involve changes in Hs-CRP, so whether statins work by affecting The METEOR study evaluated the effect of 40 mg of Rosuvastatin on CIMT in middle-aged patients (mean age 57 years) with a Framingham risk score of low risk but an IMT of 1.2 mm-3.5 mm, with the aim of evaluating whether two years of statin therapy could slow or even reverse the progression of CIMT. progression of the disease. The randomized, double-blind, placebo-controlled clinical study enrolled 984 individuals, with the primary endpoint being the annual rate of change in maximum CIMT. The results showed that although no reversal of CIMT by reseruvastatin was found, it did reduce the annual rate of change in maximal CIMT, which continued to increase in the placebo group.19 A recent meta-analysis showed that although active drug therapy, did reduce cardiovascular events, reversal or slowing of IMT progression due to drug therapy was not associated with a reduction in cardiovascular events.20 This suggests that further research is needed to determine whether the mechanism by which drugs reduce cardiovascular events is through their effect on these intermediate indicators.
A sub-topic similar to the METEOR study is currently underway in the National Eleventh Five-Year Plan project “Research on Early Diagnosis and Comprehensive Treatment Technology System for Coronary Heart Disease”. We will not only observe the effect of statins on CIMT in asymptomatic people, but also observe the effect of intensive lifestyle interventions and the combination of both on CIMT, and evaluate the effect of these interventions on other two non-invasive atherosclerosis indicators, PWV and ABI. It is believed that this study will provide a strong basis for the intervention modalities for the asymptomatic CVD population in China.
With the rapid increase in the incidence of cardiovascular disease in China, the importance of primary prevention of cardiovascular disease is self-evident. The transition from dealing with patients who have already developed the disease to interventions targeting the early asymptomatic population is of great significance for both the nation and the individual. From existing clinical studies and guidelines, it appears that risk scores combined with certain noninvasive evaluation indicators can screen for a relatively high-risk population for cardiovascular disease. Lifestyle changes and risk factor control in this population are important, and further studies are needed to clarify whether pharmacological interventions without risk factors should be performed.