Key findings:

Key findings indicate cardiovascular disease (CVD) as the primary contributor to global non-communicable disease (NCD)-related morbidity and mortality. Variability in CVD incidence and risk factors is observed across geographical regions, genders, and ethnicities. Longitudinal epidemiological studies offer crucial insights into CVD's natural progression and associated risk factors, informing risk factor assessment strategies for effective disease management and prevention.

 What is known and what is new?

The abstract underscores cardiovascular disease (CVD) as the leading cause of non-communicable disease (NCD)-related morbidity and mortality globally. It highlights the significant variability in CVD incidence, risk factors, and outcomes based on geographical region, gender, and ethnicity. Moreover, it emphasizes the contribution of longitudinal epidemiological studies in providing insights into CVD's natural history, risk factors, and prognosis.

What is the implication, and what should change now?

The significance of comprehensive risk factor assessment for cardiovascular diseases (CVD) is emphasized, considering its global burden and variability across populations. There's a critical need for tailored preventive strategies addressing regional, gender-specific, and ethnic disparities in CVD risk factors. Implementing targeted interventions based on longitudinal epidemiological studies can enhance prevention efforts and reduce the growing burden of CVD-related morbidity and mortality worldwide.

Randomized clinical trials have demonstrated the value of management of several key risk factors for both the primary and secondary prevention of CVD [1]. In order to understand an individual’s risk of CVD or CHD, it is important to understand an individual’s ‘global risk’ of developing the condition. Most typically, this involves determination of the future risk of developing CHD in the next 10 years. This can be done by various ‘risk assessment’ algorithms. Most commonly used for this purpose are the Framingham Risk Algorithms that are recommended to assess an individual’s 10-year risk of CHD [2] for the purposes of appropriate stratification for risk factor management, especially for the initiation or intensification of lipid management. From knowing an individual’s age, gen- der, systolic blood pressure (and treatment status), current smoking status, total cholesterol, and HDL-C, for which each factor is assigned a certain number of points according to its presence (and degree) or absence, a total score is obtained which corresponds to a probability of suffering a hard CHD event in the next 10 years based on Framingham follow-up data. If the projected 10-year risk of CHD is less than 10 per cent, the individual is generally considered to be at low risk of CHD, 10–20 per cent intermediate risk, and if greater than 20 per cent is judged to be at high risk, and in fact, a CHD risk-equivalent (a condition or combination of risk factors conferring a future risk or prognosis similar to that of diagnosed CHD). Use of these algorithms have been recommended for those with at least two major risk factors out of the following: family his- tory of premature CHD (< 45 years in male or < 55 years in female first-degree relative), low HDL-C, hypertension, cigarette smoking, and advanced age (male 55 years or older or female 65 years or older). Those with fewer than two risk factors are felt to be generally at lower risk where treatment would not typically be warranted. Those with diabetes, CHD, or other atherosclerotic disease would also be designated at high risk for aggressive treatment, so such a calculation has not been recommended for such individuals. [3]

There is, however, great heterogeneity in the end point predicted by various risk scores. For example, the 10-year CHD risk score recommended by the Third Adult Treatment Panel of the National Cholesterol Education Program includes only hard CHD (myocardial infarction and CHD death) as its end point, thus does not include other forms of CHD (such as angina or revascularization) as well as other forms of CVD such as stroke, heart failure, and peripheral arterial dis- ease, which are also important CVD manifestations of concern which should be included in such risk scores. Other algorithms such as the European SCORE or German PROCAMM risk scores are utilized mainly outside the United States. More recently, algorithms for total CVD risk from Framingham have been developed, which are more global as they incorporate the combined risk for CHD, stroke, heart failure, and peripheral arterial disease [4]. Most recently, the American College of Cardiology (ACC) and American Heart Association (AHA) released new guidelines for cardiovascular risk assessment which call for the use of a pooled cohort risk score [5]. These new risk scores are based on 4 major US population-based cohort studies comprising over 25,000 black and white adults with at least 10 years of follow-up for atherosclerotic cardiovascular disease (ASCVD) events. The risk calculator provides both 10-year and lifetime risk estimates for ASCVD consisting of nonfatal myocardial infarction, CHD death, and stroke [6].

In those where a global risk estimate is obtained, depending on the risk status, the appropriate intensity of treatment for given risk factors is considered. For instance, if an individual is found to be at high risk or to have a CHD risk equivalent, treatment for dyslipidemia would be recommended to reduce the LDL-C level to less than 100 mg/dL. If at intermediate risk or low risk, however, these goals would be less than 130 mg/dL and less than 160 mg/dL, respectively. 

While estimation of global risk as described earlier is recommended, it may be best considered a starting point in risk assessment. The presence of other risk factors not included in the risk algorithms, such as abdominal obesity, elevated triglycerides (if severe enough), impaired fasting glucose, or a strong positive pre- mature family history, if present, however, could be used by the clinician to stratify an individual’s risk or required intensity of treatment upward. Others have also recommended novel risk factors, such as C-reactive protein, a measure of systemic inflammation, or the presence of subclinical atherosclerosis, such as coronary artery calcium or carotid intimal media thicknesses, to aid in risk stratification. If these are present to a significant degree, they are being suggested as indicators for stratifying an individual’s required intensity of treatment upward. The most recent American College of Cardiology/American Heart Association risk assessment guide- line notes that when the treatment decision is uncertain, evaluation of premature family history of CHD, hs-C-reactive protein, ankle brachial index, or coronary calcium scoring may be considered for further risk stratification [7]. 

Inflammatory Measures for Cardiovascular Disease Risk:

High levels of inflammatory markers, including high-sensitivity C-reactive protein (hs-CRP), a marker of systemic inflammation, as well as lipoprotein phospholipase associated A2 (LpPla2), a measure of vascular inflammation, have been shown in numerous studies to be independently related to the risk of future cardiovascular events. Interleukin-6, other interleukins, myeloperoxidase, and tumour necrosis factor-alpha (TNF-alpha) also have inflammatory activity and have been shown to be associated with cardiovascular events in some studies, as have other biomarkers such as brain natriuretic peptide (BNP) and troponin levels. Levels of C-reactive protein exceeding 3 mg/L have been designated to be associated with increased CVD risk, levels in the range of 1–3 mg/L with intermediate risk, and low risk levels have been designated as less than 1 mg/L [8]. Modest recommendations have been provided for the measurement of hs-CRP in older adults (men ≥ 50 years or women ≥ 60 years) with LDL-C less than 130 mg/dL (class IIa) or in those below these ages who are at intermediate risk (class IIb), for the purposes of guiding the initiation or intensification of therapy. A similar class IIb recommendation is given for the measurement of LpPla2 in asymptomatic intermediate risk adults. There are no recommendations for the measurement of other inflammatory markers or biomarkers for the assessment of CVD risk in asymptomatic adults, however. [9]

Subclinical Cardiovascular Disease Assessment: 

The ability to image or directly measure the atherosclerotic burden has been of great interest but whether these measures provide added value over less expensive and easier traditional office-based risk factor measures (including global risk assessment scores) has been an important question in cardiovascular epidemiology and prevention over the past 15 years. Such measures must have a high level of sensitivity and specificity for detection of the disease, must be reproducible and cost-effective, and should provide added clinical utility over current office-based risk assessment. 

Increased carotid intima media thickness (CIMT) as measured from carotid B-mode ultrasound, has been shown to be related to the risk of future CVD events from numerous prospective epidemiological studies over the past 25 years, including the Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), and the Multiethnic Study of Atherosclerosis (MESA). CIMT has also been used as a surrogate end point in numerous clinical trials involving lipid-lowering and other interventions. Moreover, the presence of carotid plaques provides additional information and together with CIMT measurements have modest clinical utility for reclassification of risk in asymptomatic intermediate risk adults. Individuals with CIMT levels of 1 mm or higher or in the highest quartile for age-specific values are generally considered to be at increased risk. While persons at intermediate risk were previously given a class IIa recommendation for the measurement of CIMT, more recent guidelines no longer recommend CIMT measurement for risk assessment. [10]

ABI measured from ankle and arm blood pressures utilizing a Doppler, provides for an assessment of peripheral arterial disease, which is diagnosed to be present when the ABI is less than 0.9. A low ABI has also been shown to be related to increased total and CVD mortality in numerous observational studies. However, as the prevalence of a low ABI tends to be very low until after the age of 60 years, it is therefore most useful as a screening tool for peripheral arterial disease in older people. It is also a class IIa recommendation for assessment in intermediate risk individuals. [11]

Measures of coronary artery calcium (CAC) as assessed by CT, have been shown in numerous prospective studies, to be associated with the future risk of CHD and CVD events, independent of standard risk factors [12]. CAC measures also provide incremental predictive value and added reclassification of risk over global risk assessment for the prediction of cardiovascular events. In the MESA study, it has been shown to provide greater incremental risk prediction among intermediate risk individuals (from C-statistic improvement) than any other major biomarker or subclinical disease screening test [13]. CAC testing also receives a class IIa recommendation for assessment of risk in asymptomatic subjects at intermediate risk. [14]

There are also numerous other tests which have varying levels of evidence relating them to CVD event risk. These include assessments of endothelial function, pulse wave velocity, brachial artery reactivity, and imaging of soft plaque such as by CT coronary angiography. Most of these other tests, however, do not have the quantity, strength, or consistency of evidence that CIMT, ABI, or CAC assessment do, and hence there is not the same level of consensus for recommending their use for the screening of asymptomatic adults. 

Funding: No funding sources.

Conflict of interest: None declared.

Ethical approval: The study was approved by the Institutional Ethics Committee of Dr RPGMC Kangra, Himachal Pradesh. 

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6. http://tools.cardiosource.org/ASCVD-Risk-Estimator/

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