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An Alternative, Simple Approach to Confirming Subclinical Cardiovascular Disease

Published:December 21, 2022DOI:https://doi.org/10.1016/j.amjmed.2022.12.010

      Keywords

      Introduction

      The utilization of internet cardiovascular risk calculators (i.e., pooled cohort equations) has been useful since their introduction over a decade ago. However, more recent clinical investigations have demonstrated their loss of accurate predictive ten-year risk in several large populations including obesity
      • Khera R
      • Pandey A
      • Ayers CR
      • Carnethon MR
      • Greenland P
      • Ndumele CE
      • et al.
      Performance of the pooled cohort equations to estimate atherosclerotic cardiovascular disease risk by body mass index.
      , young men
      • Cook NR
      • Ridker PM.
      Calibration of the Pooled Cohort Equations for Atherosclerotic Cardiovascular Disease.
      , asymptomatic women
      • Michos ED
      • Nasir K
      • Braunstein JB
      • Rumberger JA
      • Budoff MJ
      • Post WS
      • et al.
      Framingham risk equation underestimates subclinical atherosclerosis risk in asymptomatic women.
      , and different ethnic groups
      • Jung KJ
      • Jang Y
      • Oh DJ
      • Oh BH
      • Lee SH
      • Park SW
      • et al.
      The ACC/AHA 2013 pooled cohort equations compared to a Korean Risk Prediction Model for atherosclerotic cardiovascular disease.
      . The efforts to improve mathematical calculations by the American Heart Association, the Framingham Study, the Reynolds equations and others, have been met with confusion for patients and healthcare professionals because of their differing input variables and output recommendations
      • deGoma EM
      • Dunbar RL
      • Jacoby D
      • French B
      Differences in absolute risk of cardiovascular events using risk-refinement tests: A systematic analysis of four cardiovascular risk equations.
      . Their inherent limitations leading to inaccurate predictions include risk assessment at only one point in time and their inability to accurately input more or less (i.e., intermittent) exposure to major risk factors over the lifetime of the individual.

      Risk Parameters

      New investigations into cardiovascular pathophysiology have demonstrated that all major risks can be expressed by at least one of the following blood tests: 1) lipid profile, 2) Apolipoprotein B (Apo B), 3) Apolipoprotein (a) (Lp[a]), and 4) high sensitivity C-reactive protein (hsCRP). Because atherosclerosis is a chronic disease developing over the lifetime of the individual starting in infancy, an abnormality in any of these variables requires follow-up evaluation independent of that already necessitated by traditional clinical risk factors.
      The prevalence of cardiovascular disease is increasing. Prevention of heart attacks and strokes requires identification of all individuals with an increased risk profile, and subsequent preventive therapy when indicated. The knowledge of the atherosclerotic plaque burden can support the clinical justification for introducing improved lifestyle and pharmacological therapy. This approach avoids introducing unnecessary therapeutic interventions or frequent evaluations if no vessel atherosclerotic plaque is present.
      Traditional risk calculator equations can be superseded by assessment of proven clinical risk factors and measurement of their mediators. In place of the traditional risk equations, the physician should identify a patient's family history of atherosclerosis, the past or current presence of hypertension, smoking, and diabetes, and order the four baseline blood tests listed above to assess cardiovascular risk. If any of these parameters are abnormal, then a coronary artery calcium scan (CAC scan) should be obtained if the patient's age is appropriate for subclinical atherosclerosis. Coronary artery calcium scanning has permitted the reclassification of individuals evaluated by a risk equation score (e.g., Framingham risk score) throughout the risk categories ranging from 12% to 15% in the low-risk category, 52% to 66% in the intermediate-risk category, and 34% to 36% in the high-risk category
      • Hecht HS
      • Narula J.
      Coronary artery calcium scanning in asymptomatic patients with diabetes mellitus: a paradigm shift.
      . In a recent change in policy, the American Heart Association now supports calcium scanning in most individuals with proven risk factors
      American Heart Association
      Policy Guidance: Expanding Coverage of Cardiac Computed Tomography for Calcium Screening.
      . Furthermore, coronary artery calcium heart scanning has become widely available at relatively minimal cost. Preventive treatment is not only inexpensive and safe but is effective in the clinical population
      • Giannini J
      • Padilla J
      • Eaton RP
      • Gonzales K
      • Schade DS.
      Prevention of coronary heart disease: A translational clinical challenge.
      .

      Informative blood testing

      (table 1) A lipid profile provides the following useful risk information – a total cholesterol, an HDL cholesterol, a triglyceride level, and a calculated LDL cholesterol. An HDL cholesterol concentration assesses the reverse cholesterol transport capability of the individual; a triglyceride level assesses the risk of elevated triglycerides (cardiovascular and pancreatitis), and an LDL cholesterol assesses the potential atherosclerotic hazard of this lipoprotein remnant to atherosclerotic plaque formation. In addition, a non-HDL cholesterol level can be calculated from these lipids to provide an estimate of the total quantity of cholesterol contained in atherogenic particles.
      Table 1Important Risk Parameters to be Assessed to Categorize CVD Risk
      TestNormal ValueKey PointsWhat is assessedApproximate Quest CostLimitations
      Lp (a)

      Ref #

      9
      <30 mg/dlGenetically determined.

      Not decreased by statins
      A specific atherosclerotic particle

      that inhibits plasminogen
      $50Normal range is lab assay specific
      Apo B

      Ref #

      10
      <90 mg/dlProvides an accurate number of atherosclerotic particlesIdentifies # of small LDL particles for improved risk assessment$35None
      hsCRP

      Ref #

      12
      <1.0 mg/LAssesses the degree of systemic inflammation (specify “high sensitivity”)Measures low values of CRP

      Major risk for coronary artery atherosclerosis
      $79Also Increased during acute illness
      LDL chol

      Ref #

      8,10
      < 70 mg/dl

      Lower is desirable
      Accounts for 80% of total cholesterol in plasmaUsually calculated

      but if TG direct assay available
      $156 for entire lipid panelDoes not include all atherogenic particles
      CAC scan

      Ref # 6,

      7,13,14
      Zero

      (No calcified plaques)
      Excellent noninvasive predictor of future CVD riskHighly correlated with atherosclerotic plaque burden$50 - $200

      Widely available
      Identifies only calcified plaques
      Measuring Lp(a) provides an assessment of a very important independent risk factor
      • Wilson DP
      • Jacobson TA
      • Jone PH
      • Koschinsky ML
      • McNeal CJ
      • Nordestgaard BG
      • Orringer CE
      Use of lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association.
      . Lp(a) is genetically determined and minimally changes over the lifetime of the individual. It tends to be elevated in certain ethnic groups such as African Americans. Not only does it contain an atherogenic LDL particle but it also contains amino acid kringles (amino acid folds held together by disulfide bonds) that share homology with kringles on plasminogen. Their interaction results in an inhibition of thrombolysis and an increased risk of a coronary thrombosis. Lp(a) is highly susceptible to oxidation, making it available to macrophages that initiate atherosclerotic plaque formation. At autopsy, Lp(a) has been identified in atherosclerotic plaques. It has the undesirable properties of being proatherosclerotic, proinflammatory, and prothrombotic.
      Apolipoprotein B (Apo B) is a constituent of all atherogenic particles. Since there is only one Apo B per particle, its quantification provides a precise assessment of the number of total atherogenic particles. This is important since many studies have shown that small, dense LDL cholesterol particles are more atherogenic than large LDL particles, even with the same total cholesterol particle content
      • Sniderman AD
      • Lamarche B
      • Contois JH
      • de Graaf J.
      Discordance analysis and the Gordian Knot of LDL and non-HDL cholesterol versus apoB.
      . Non HDL cholesterol does not provide this important information, since it only measures total particle cholesterol content. Recent data suggest that apo B must be reduced to reduce cardiovascular disease
      • Virani S.
      The Fibrates Story – a tepid end to a prominent drug.
      .
      HsCRP is a surrogate marker for the severity of systemic inflammation
      • Ridker PM.
      High-Sensitivity C-Reactive Protein: Potential Adjunct for Global Risk Assessment in the Primary Prevention of Cardiovascular Disease.
      . Inflammation is a critical component of the atherosclerotic process. It damages the arterial endothelium and thereby permits additional LDL cholesterol particles to enter the subendothelial space. It also stimulates the endothelial secretion of specific cytokines (e.g., VCAM-1) that increase the adherence of monocytes to the arterial wall. These monocytes then pass through the endothelium by diapedisis, internalize the oxidized LDL-cholesterol particle, and form fatty streaks, the precursor to atherosclerotic plaques.
      Recent studies now demonstrate the value of atherosclerotic plaque burden as quantified by the coronary artery calcium scan's ten-year cardiovascular event prediction
      • Erbel R
      • Mohlenkamp S
      • Moebus S
      • Schmermund A
      • Lehmann N
      • Stang A
      • et al.
      Coronary Risk Stratification, Discrimination, and Reclassification Improvement Based on Quantification of Subclinical Coronary Atherosclerosis: The Heinz Nixdorf Recall Study.
      . The quantity of calcium is an excellent predictor of total atherosclerotic plaque. Alternatively, a zero calcium score provides assurance of protection from an atherosclerotic event for at least five years. A coronary calcium scan is noninvasive, requires approximately 10 minutes, and costs approximately $100. Guidelines for the appropriate use of CAC scanning have been published
      • Schade DS
      • Obenshain S
      • Hickey M
      • Febbo J
      • Wann S
      • Eaton RP.
      Guidelines for the prevention of symptomatic cardiovascular disease, based upon the presence of coronary artery calcified plaque - Provided by the Society for the Prevention of Symptomatic Heart Disease.
      .

      Summary

      In contrast to placing a patient in a specific risk category by risk equations, (e.g., low, intermediate, high, very high), just two categories are necessary: 1) very low risk and 2) significant potential risk. This categorization is easily determined from the assessment of the above evaluation. If all above measurements are within a normal range with no hypertension, smoking, diabetes, nor family history of atherosclerosis, then cardiovascular risk is minimal. However, if any of the tests are abnormal, then a coronary artery calcium scan should be obtained after considering the age of the individual and the severity of the risk factor. Treatment should be individualized for each patient. Identifying individuals at risk, documenting early coronary atherosclerosis, and treating them aggressively will reduce the number one cause of death in the U.S., i.e., atherosclerotic cardiovascular disease
      • Giannini J
      • Padilla J
      • Eaton RP
      • Gonzales K
      • Schade DS.
      Prevention of coronary heart disease: A translational clinical challenge.
      .

      Financial Support

      The authors received no external funding support for this manuscript.

      Declaration of Competing Interest

      All authors had access to the data and a role in writing the manuscript.

      Acknowledgements

      none

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