A 58-year-old previously healthy African-American man presented to the hospital while traveling with severe abrupt onset epigastric and chest pain, diaphoresis and nausea with ST elevation in the inferior leads and diffuse reciprocal ST depressions on initial ECG. He underwent acute coronary angiography demonstrating diffuse noncritical stenosis of the left anterior decending (LAD), high grade disease in the mid left circumflex (LCx) and acutely occluded right coronary artery (RCA) with staining thrombus in the proximal third of the vessel. He was successfully treated with drug eluting stents to the RCA and LCx. He evolved a troponin I elevation to 17 ng/mL, the acute left ventricular ejection (LVEF) was 40% with inferior-posterior dense hypokinesis.
He initially did well on medical therapy for four months until presenting with two days of similar symptoms in crescendo pattern and was admitted to the hospital. There were no acute ST changes or acute changes on ECG and multiple troponin I determinations were negative. Given his history and presentation, he underwent repeat coronary arteriography showing patent stents in the RCA and LCx, but progression of disease in the mid to distal LAD now to 60-70% stenosis without evident plaque ulceration or thrombus. LVEF was 50-55% with inferior moderate hypokinesis. The LAD disease was diffuse and distal, felt unfavorable for percutaneous intervention. Medical therapy was intensified with titration of beta blocker, and addition of amlodipine and oral nitrate. Dual antiplatelet therapy and rosuvastatin 40mg were continued.
Family history was notable for a sister with coronary disease having coronary bypass surgery at age 60 without conventional risk factors. His mother, age 87, is essentially healthy but his father died in his 50’s from myocardial infarction. He has five adult children under the age of 30 who are alive and well.
His personal history is notable for the lifelong absence of conventional cardiovascular risk factors. He exercises on a rigorous schedule and has done so for his entire adult life. He is trim and athletic with normal body weight. Physical examination was entirely normal.
His initial laboratory studies showed total cholesterol 132, HDL-C 44, non-HDL-C 88, Friedewald estimated LDL-C 73 and triglycerides 73 mg/dL. Fasting glucose was 110 mg/dL. BUN and creatinine were normal. Lipoprotein(a) was elevated, 292 nmol/L (normal value <75 nmol/L); hsCRP was <0.2 mg/L.
He had no further symptoms and was discharged from the hospital.
Additional data following discharge:
Treadmill SPECT MPI: no ischemia in LAD territory at 91% age adjusted predicted heart rate.
Six months post discharge on 40 mg/day rosuvastatin:
Apolipoprotein B:
87 mg/dL (slightly less than 50th population percentile)
Apolipoprotein AI:
169 mg/dL
Two hour glucose tolerance test: normal (98 mg/dL)
Hemoglobin A1C: 5.9%
Biologic LDL-C: 48 mg/dL, distributed primarily in small dense LDL fractions
Lp(a)-C: 12 mg/dL
IDL-C: 5 mg/dL
=65 mg/dL.
What plans should be made for further management post discharge?
Show Answer
The correct answer is: 4. 2 and 3
This is a man with aggressive, arguably premature coronary disease with no conventional risk factors, well controlled conventional lipoprotein cholesterol on routine laboratory studies presenting with acute coronary syndromes which appear to be explained primarily by elevated Lp(a) in conjunction with two non-traditional other cardiometabolic risk mediators.
Lipoprotein(a) is an LDL-like core lipoprotein particle covalently bound to a large glycoprotein, apo(a), largely under genetic control by the LPA gene locus, with serum levels little affected by statins, diet or exercise. It tends to be synergistic with other atherothrombotic risk factors, both conventional and novel, when at levels exceeding the 75-80 population percentile, typically greater than 70-75 nmol/L. Without coexisting risk mediators or increased global cardiovascular risk, Lp(a) appears to carrying little or no intrinsic risk.1 Lp(a) has been shown to be causal of myocardial infarction in Mendelian randomization study.2
The biological function of Lp(a) has been debated and is not clearly known. Most of the unique characteristics of Lp(a) are mediated through the apo(a) moiety which contains domains which activate macrophages and are structurally homologous to plasminogen, known to be prothrombotic. It is known to be the primary carrier of oxidized phospholipids in the circulation which may additionally contribute to its atherogenic potential.3
Nicotinic acid typically lowers Lp(a) levels 20-30%. A recent European Atherosclerosis Society consensus statement4 endorses its use, however no conclusive data demonstrates this reduction in Lp(a) levels to be associated with reduction in risk. The primary strategy is reduction in atherogenic lipoprotein burden, which may be best assessed by non-HDL-C or particle based measures such as apolipoprotein B (apo B) although this strategy is supported by limited evidence as well.5
In the presented case, non-HDL-C was low, <10th population percentile on statin therapy. Note that the Lp(a)-C contributed about 1/5th of the Friedewald-equivalent LDL-C. At very high levels of Lp(a), particularly at low overall LDL-C levels, Lp(a) can be a major fraction of the total and resistant to reduction by statin therapy. In our patient, apo B was discordantly elevated to nearly the median population value despite very low non-HDL-C in the setting of predominantly small-dense LDL particles, contributing additional otherwise unrecognized risk. Despite being athletic and lean, he may have additional risk from insulin resistance given elevated fasting glucose and hemoglobin A1C commonly found in patients with small-dense LDL.
In this case, the patient was treated with ongoing high dose statin using 40 mg of rosuvastatin per day and ezetimibe was added for further apo B lowering. He declined addition of bile acid sequestrant for further apo B lowering.
A goal Apo B value of at least <80 mg/dL has been suggested for secondary prevention however lower values, approximating the 10th population percentile, 60 mg/dL may make sense for very high risk individuals, representing the same population percentile as the lipoprotein cholesterol goal values for LDL-C <70 mg/dL and non-HDL-C <100 mg/dL. There are no definitive data assessing outcomes vs. on-treatment apo B levels, individualized treatment decisions will be necessary considering specific coexisting risk factors and patient preferences.
Since Lp(a) is genetically determined and hence a genetically transmissible risk factor, it may be of value to screen the first degree relatives for elevated Lp(a) levels and institute more aggressive early primary prevention measures if found.
References
Eckardstein A, Schulte H, Cullen P, Assmann G. Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk. J Am Coll Cardiol 2011; 37: 434-439.
Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, et al. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009;301:2331–2339.
Taleb A, Witzum JL, Tsimikas S. Oxidized phospholipids on apoB-100-containing lipoproteins: a biomarker predicting cardiovascular disease and cardiovascular events. Biomark Med 2011;5:673–694.
Nordestgaard BG, Chapman MJ, Ray K, et al for the European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-2853.
Maher VMG, Brown, BG, MArcovina SM, et al. Effects of lowering LDL cholesterol on the cardiovascular risk of lipoprotein(a). JAMA 1995;274:1771-1774.
Log in to MyACC
