A 54-Year-Old Man With "Optimal" LDL-C and a Family History of Coronary Heart Disease: Assessing CV Risk Beyond Low Density Lipoprotein Cholesterol
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History of Presenting Illness
A 54-year-old white accountant presents to cardiology clinic to establish care. He denies chest pain, shortness of breath, dyspnea on exertion, palpitations, syncope or presyncope. Several male members in his family had suffered premature cardiovascular events. He exercises two to four times a week. He has been tolerating his prescription medications well and reports no side effects. Recently his 56-year-old first cousin suffered a massive heart attack and this got him concerned regarding his "cardiovascular risk."
He is a non-smoker and drinks one glass of red wine daily. His father had his first heart attack at age 54 and his first male cousin, age 56, had a recent heart attack and coronary artery bypass grafting. He was commenced on Atorvastatin 20 mg daily by his primary care physician a few weeks ago and he also takes one multivitamin pill daily. Physical exam was significant for a blood pressure of 122/76mmHg, body mass index of 28 kg/m2, and a waist circumference of 40 inches.
Complete blood count and basic metabolic panel are within normal limits.
TC: 198 mg/dL
HDL-C: 38 mg/dL
LDL-C: 115 mg/dL
TGs – 225 mg/dl
FBG: 91 mg/dL
ALT and AST: Normal
Normal sinus rhythm with no abnormality
All the following additional laboratory tests are reasonable and can help guide further management of his cardiovascular risk except:
The correct answer is: 5. Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass
Low density lipoprotein cholesterol (LDL-C) remains central to the risk of atherosclerotic cardiovascular disease (ASCVD);1 however, many statin treated individuals with "optimal" LDL-C levels may continue to experience ASCVD events due to a "residual" risk.2, 3 It is important to identify these patients with "residual risk" as they can be targeted with intensive preventive strategies for ASCVD events. Several lipid parameters as well as serum and imaging biomarkers have been associated with elevated ASCVD risk in these patients, who are otherwise low risk based on their traditional risk factor profile.
Non-High Density Lipoprotein cholesterol (Non HDL-c)
Non HDL-c is easily calculated from a standard lipid profile in the office and is simply total cholesterol (TC) minus HDL-c (TC-Non HDL-c). It is a good marker for atherogenecity as it represents the cholesterol content of all atherogenic lipoprotein particles (i.e., LDL, very low-density lipoprotein [VLDL], intermediate density lipoprotein [IDL] and lipoprotein (a) [Lp (a)]) in the plasma.4 Non-HDL-C has also shown to be a stronger predictor of future ASCVD events compared to LDL-c in statin treated individuals.5 Also, non-HDL-c is a better surrogate for atherogenic particles than LDL-c in patients with diabetes and metabolic syndrome.6
The advantage of non-HDL-c lies in the fact that it does not entail ordering another test and is cost effective, while at the same time offering additional information. However, few physicians routinely calculate non-HDL-c in their office as part of ASCVD risk assessment per recent surveys.7, 8 Although neither LDL-c nor non-HDL-c is currently recommended as the targets of therapy as per the recently released American College of Cardiology American Heart Association (ACC/AHA) guidelines on cholesterol management, most recent guidelines of the IAS recommend non- HDL-c as the primary focus of therapy.9 In our patient, non HDL-c is 198-38=160 mg/dL, which is elevated and may serve as a surrogate for quantification of his residual risk.
Lipoprotein (a) (Lp [a]) consists of an apolipoprotein B100 (apo B100) molecule, much like LDL, but covalently linked to a very large glycoprotein, apolipoprotein (a) (Apo[a]). 10 The inactive protease domain of components of Lp (a) is structurally similar to the corresponding part of plasminogen. Therefore, Lp (a) may interfere with plasminogen activation, leading to thrombosis and anti-fibrinolytic effect by competitive activation. 10 The plasma levels of Lp (a) are mostly determined by the gene, LPA, which encodes apo (a). Both plasma levels and proatherogenic mechanism are related to copy-number variation of kringle repeats.10 Many studies have reported independent associations of baseline Lp(a) concentration with coronary heart ASCVD risk11, 12, 13, 14 independent of other lipid parameters and is additive to traditional risk factors for ASCVD.10 In a recent study looking at a subset of patients from Justification for the Use of Statins in Primary Prevention: an intervention Trial Evaluating Rosuvastatin (JUPITER) Study on-statin, Lp(a) concentrations were associated with residual risk of ASCVD, independent of LDL-C.15 In terms of therapy directed at elevated Lp (a) levels, the options currently are limited. These levels are less affected by therapeutic lifestyle changes and use of statins than the traditional lipid markers. Statins, in general, have little impact on the level of Lp (a). Nicotinic acid and estrogen hormone replacement have shown some benefit in Lp (a) reduction, but these findings have not translated to improved cardiovascular outcomes.16, 17 LDL apheresis reduces Lp (a) as do mipomerson and lomitapide but these therapies are used only in severe cases of familial hypercholesterolemia. The investigational therapies such PCSK9 inhibitors and CETP inhibitors also reduce Lp (a) but their cardiovascular benefits remain undetermined.18 In the Women's Health Study,19 the subset of patients with elevated Lp(a) levels had reduction in ASCVD events with aspirin use. Overall, Lp (a) can be considered as a risk marker measured in the office in patients with or without prior ASCVD with strong family history for further guiding intensity of lipid management. High efficacy statins may be reasonable for patients with particularly high Lp (a) level. In this patient, the Lp (a) level was 140 nmol/L. (Normal <10mg/dL/35nmol/L)
High sensitivity C-reactive protein (hs-CRP)
High sensitivity C-reactive protein (hs-CRP) is a marker of systemic burden of inflammation and is the most studied novel risk prediction marker for ASCVD.20 The Justification for the Use of Statins in Primary Prevention: an intervention Trial Evaluating Rosuvastatin (JUPITER) 21 showed benefits of high potency statin therapy in patients with average LDL-C levels but elevated hs-CRP levels, giving support to hs CRP as ASCVD risk marker. Individuals who achieved LDL-c levels less than 70 mg/dl and hs CRP levels of less than 2 mg/dl had the lowest CVD event rates in JUPITER and the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE- IT) 22 study 22 The major drawback of the use of hs-CRP for risk stratification of asymptomatic patients for ASCVD is the non-specific elevation in any inflammatory condition. Overall, hs-CRP is a widely available biomarker that can help guide intensity of preventive measures and most useful in helping refine the ASCVD risk estimation in patients with an intermediate risk.20 The Reynolds Risk Score (www.reynoldsriskscore.org) is a risk prediction score which includes hs-CRP and a parental history of premature ASCVD in addition to traditional risk factors. 23 This risk score was successfully able to reclassify 30% initially healthy women in the "intermediate" risk category into either a "low" or a "high" risk tier, in the process improving global risk prediction. The new ACC-AHA 2013 recommendations on Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines give a ACC/AHA COR II B, level of Evidence B for use of hs-CRP for quantitative risk assessment in ASCVD 24. Though hs-CRP has been predominantly used as a pre-statin treatment risk prediction tool, recent studies have also depicted that on-treatment level of hs-CRP in patients with "optimal" LDL-C are independently associated with ASCVD events.25
Apolipoprotein B (Apo-B)
Apolipoprotein B (ApoB) is contained in all atherogenic lipids in circulation.26 Measurement of ApoB may be superior to that of LDL-c in some situations as the amount of cholesterol carried per LDL particle does vary.27 ApoB levels in such cases provide a more accurate assessment of atherogenic burden and ultimately the ASCVD risk. 27 Patients with diabetes, metabolic syndrome and hypertriglyceridemia, and low HDL-c and normal LDL-c 27 have increased LDL particles with a small dense pattern that is associated with increased ASCVD risk .These patients may have normal LDL-c levels but a higher concentration of ApoB which more accurately mirrors their atherogenic burden. ApoB measurement does entail extra cost as it is a separate test. Non-HDL-c may provide similar information and can be calculated from a standard lipid panel with no extra cost. Whether one measurement is superior remains to be determined.28 The role of ApoB in patients with increased discordance between LDL-C and non-HDL-C is clearly present, and ApoB measurement might be useful for refining lipid lowering therapy in these individuals. Use of ApoB for risk estimation, however, is currently not endorsed by the guidelines. The ApoB level in this patient was 105 mg/dl, which is elevated. (Normal <60mg/dL)
Lipoprotein-associated phospholipase A2 (Lp-PLA2)
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a novel biomarker of vascular inflammation and has recently being investigated for its role in primary and secondary prevention in population based studies. 29 Evidence suggests that Lp-PLA2 is an ASCVD risk marker independent of traditional risk factors like lipids 30; furthermore, studies also suggest that risk prediction by Lp-PLA2 is complementary to that of hs- CRP. Lp-PLA2 may be considered for reclassification in intermediate risk patients and some patients with known ASCVD with high risk, to guide intensification of therapy. Lp-PLA2 testing should generally not be performed in low-risk patients for the purpose of reclassification. On the other hand, there is lack of evidence on the predictive value of Lp-PLA2 after treatment with statin therapy. Thus, Lp-PLA2 testing is currently not recommended for patients who are already receiving statin therapy.
In addition to these biomarkers for risk stratification Coronary Artery Calcium (CAC) score or Ankle Brachial Index (ABI) can also be used as risk markers for ASCVD.24 He has a striking family history, his on-treatment LDL-c level is 115 mg/dl, non-HDL-c is 160 mg/dL and his Lp (a) was also found to be elevated.
Although the new ACC/AHA guidelines do not designate any specific target levels for LDL-c or non HDL-c, they do state that one should follow the lipid profile to assess response to therapy and compliance with medication. The patient states that he is compliant with medications. In high risk patients, such as those with baseline LDL-c over 190 mg/dl, the guidelines state that in general, one should treat to achieve a reduction in LDL-c of greater than or equal to 50%. The guidelines also state that in general, one would expect to achieve an LDL-c of less than 100 mg/dl because the vast majority of patients will have a baseline LDL-c of less than or equal to 200 mg/dl. If one has not achieved the desired response, the recommendation is to intensify statin therapy and/or consider additional therapy depending upon the response.
Issues to discuss with the patient
He has a high lifetime risk for ASCVD event and may still benefit from more intensive therapy. He remains overweight with a BMI of 28 and a 40 inch waist and both diet and exercise could be intensified. His statin therapy should be increased to the high efficacy range (either 40mg or 80mg of Atorvastatin or 20mg or 40mg of rosuvastatin). He should take ASA 81 mg daily. His other siblings and children should get lipid profiles measured as well as levels of Lp (a) evaluated. He should be educated on the importance of any symptoms of chest discomfort with exercise, shortness of breath, etc.
After discussing with the patient, the dose of Atorvastatin was increased to 40 mg daily. He agreed to exercise for five to six times weekly with a goal of at least three hours of exercise per week. He also agreed to reduce simple carbohydrates and saturated fat and set a weight loss goal of 10 lbs over the next four to six months.
- Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106:3143-3421.
- Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statins. Lancet 2005; 366(9493):1267-78.
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- Kastelein JJ, van der Steeg WA, Holme I, Gaffney M, Cater NB, Barter P, Deedwania P, Olsson AG, Boekholdt SM, Demicco DA, Szarek M, LaRosa JC, Pedersen TR, Grundy SM; TNT Study Group; IDEAL Study Group. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation 2008;117(23):3002-3009.
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- Negi SI, Steinberg L, Polsani VR, et al. Non-high-density lipoprotein cholesterol calculation and goal awareness among physicians-in-training. J Clin Lipidol 2012;6(1):50-57.
- Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013. [Epub Ahead of Print].
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