The correct answer is: 5. Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass

Discussion

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)

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 risk^{11, 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.

References

1. 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.
2. 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.
3. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999; 282(24):2340-6.
4. 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.
5. Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ, Simes RJ, Durrington P, Hitman GA, Welch KM, DeMicco DA, Zwinderman AH, Clearfield MB, Downs JR, Tonkin AM, Colhoun HM, Gotto AM Jr, Ridker PM, Kastelein JJ. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 2012;307(12):1302-1309.
6. Williams K, Sniderman AD, Sattar N, D'Agostino R, Jr., Wagenknecht LE, Haffner SM. Comparison of the associations of apolipoprotein B and low-density lipoprotein cholesterol with other cardiovascular risk factors in the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2003;108(19):2312-2316.
7. Virani SS, Steinberg L, Murray T, Negi S, Nambi V, Woodard LD, Bozkurt B, Petersen LA, Ballantyne CM. Barriers to non-HDL cholesterol goal attainment by providers. The Am J Med 2011;124(9):876-80.
8. 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.
9. 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].
10. Kamstrup PR, Tybjærg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein (a) and increased risk of myocardial infarction. JAMA 2009; 301:2331–2339.
11. Danesh J, Collins R, Peto R. Lipoprotein (a) and coronary heart disease. A Meta-analysis of prospective studies. Circulation 2000; 102:1082-5.
12. Bennet A, Di Angelantonio E, Erqou S, Eiriksdottir G, Sigurdsson G, Woodward M, Rumley A, Lowe GD, Danesh J, Gudnason V. Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data. Arch Intern Med 2008;168:598–608.
13. Nordestgaard BG, Chapman MJ, Ray K, Borén J, Andreotti F, Watts GF, Ginsberg H, Amarenco P, Catapano A, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Reiner Z, Taskinen MR, Tokgözoglu L, Tybjærg-Hansen A; European Atherosclerosis Society Consensus Panel. Lipoprotein (a) as a cardiovascular risk factor. Eur Heart J 2010 Dec; 31 (23):2844-53.
14. Kronenberg F, Kronenberg MF, Kiechl S, Trenkwalder E, Santer P, Oberhollenzer F, Egger G, Utermann G, Willeit J.Role of lipoprotein (a) and apolipoprotein (a) phenotype in atherogenesis: prospective results from the Bruneck study. Circulation 1999; 100:1154-60.
15. Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth J, Ridker PM, Mora S. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin).Circulation 2014; 129:635-42.
16. Shlipak MG, Simon JA, Vittinghoff E, Lin F, Barrett-Connor E, Knopp RH, Levy RI, Hulley SB. Estrogen and progestin, lipoprotein(a) and the risk of recurrent coronary heart disease events after menopause. JAMA 2000; 283:1845–52.
17. Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis 2010; 210:353–61.
18. Lippi G, Targher G. Optimal therapy for reduction of lipoprotein (a). J Clin Pharm Therap 2012; 37:1-3.
19. Chasman DI, Shiffman D, Zee RY, Louie JZ, Luke MM, Rowland CM, Catanese JJ, Buring JE, Devlin JJ, Ridker PM. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis 2009; 203:371-6.
20. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342: 836–43.
21. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, Macfadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373:1175-82.
22. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald E; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352:20-8.
23. Ridker PM, Buring JE, Rifai N, Cook NR. Reynolds risk score: calculating heart and stroke risk for women and men [Internet]. Bethesda, MD: National Heart Lung and Blood Institute; 2007 [cited 2010 Jul 19]. Available from: http://www.reynoldsriskscore.org.
24. Goff DC Jr, Lloyd-Jones DM, Bennett G, O'Donnell CJ, Coady S, Robinson J, D'Agostino RB Sr, Schwartz JS, Gibbons R, Shero ST, Greenland P, Smith SC Jr, Lackland DT, Sorlie P, Levy D, Stone NJ, Wilson PW. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: 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].
25. Puri R, Nissen SE, Libby P, Shao M, Ballantyne CM, Barter PJ, Chapman MJ, Erbel R, Raichlen JS, Uno K, Kataoka Y, Nicholls SJ. C-reactive protein, but not low-density lipoprotein cholesterol levels, associate with coronary atheroma regression and cardiovascular events after maximally intensive statin therapy. Circulation 2013;128:2395-403.
26. Ingelsson E, Schaefer EJ, Contois JH, McNamara JR, Sullivan L, Keyes MJ, Pencina MJ, Schoonmaker C, Wilson PW, D'Agostino RB, Vasan RS. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 2007; 298:776–85.
27. Sniderman AD, Scantlebury T, Cianflone K. Hypertriglyceridemic hyperapob: the unappreciated atherogenic dyslipoproteinemia in type 2 diabetes mellitus. Ann Intern Med 2001; 135:447–59.
28. Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302:1993–2000.
29. Madjid M, Awan I, Willerson JT, Casscells SW. Leukocyte count and coronary heart disease: implications for risk assessment. J Am Coll Cardiol 2004;44:1945-56.
30. Sabatine MS, Morrow DA, O'Donoghue M, Jablonksi KA, Rice MM, Solomon S, Rosenberg Y, Domanski MJ, Hsia J; PEACE Investigators. Prognostic utility of lipoprotein associated phospholipase A2 for cardiovascular outcomes in patients with stable coronary artery disease. Arterioscler Thromb Vasc Biol 2007; 27:2463-9.