A 33-year-old male patient of Lebanese origin has been diagnosed with Familial Hypercholesterolemia (FH) since 2001 (clinical diagnosis at that time and with confirmed molecular diagnosis in 2010). His father and uncle both suffered a myocardial infarction at the age of 30 years. The patient also was a former smoker (10 pack-years, stopped at the age 26 years) and sedentary. Despite the FH diagnosis and other risk factors, he was a poorly adherent patient and many times stopped taking lipid-lowering drugs. In June 2008, on treatment with atorvastatin 80 mg and ezetimibe 10 mg, he presented with the following lipid profile: total cholesterol 275 mg/dL, HDL-C 16 mg/dL, LDL-C 200 mg/dL and triglycerides 295 mg/dL.
In July 2008, despite being asymptomatic, he had a computed tomography coronary angiography (CTCA) after a positive treadmill test. The CTCA showed a calcified plaque in the left main coronary artery without luminal reduction, a mixed plaque in the left anterior descending artery (LAD) with low-grade luminal reduction, a non-calcified plaque in the distal right coronary artery (RCA) with moderate/important luminal reduction and a coronary calcium score of 96.
At this time, it was decided to continue medical treatment. He improved treatment adherence. Nicotinic acid 1g and aspirin were also prescribed. The next lipid profile showed an important reduction in LDL-C to 54 mg/dL. He remained asymptomatic with LDL-C levels maintained below 70 mg/dL.
In 2013, a routine repeat CTCA showed progression in his coronary disease with a 70% luminal reduction in the LAD and appearance of a non-calcified plaque in the posterior descending artery with important luminal reduction. There was also an increase in the coronary calcium score to 258. Subsequently, due to the CTCA findings and strong family history of early myocardial infarction, he was referred directly for invasive coronary angiography showing moderate lesions in LAD and diagonal artery. Additionally, there were significant lesions in the left marginal and RCA, which were treated with percutaneous transluminal coronary angioplasty with stent implantation.
The patient remains asymptomatic up to the present date. Current daily medications are rosuvastatin 40 mg, ezetimibe 10 mg, aspirin 100 mg, atenolol 50 mg, nicotinic acid 2 grams and clopidogrel 75 mg. The last lipid profile was: total cholesterol 87 mg/dL, HDL-C 28 mg/dL, LDL-C 48 mg/dL and triglycerides 55 mg/dL.
Regarding cardiovascular risk stratification for this patient, what should be the best response?
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The correct answer is: 4. FH patients should have their cardiovascular risk assessed using clinical and laboratory parameters; however, computed tomography coronary angiography could be used to optimize risk stratification and treatment in selected cases.
Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder characterized by high plasma low-density lipoprotein-cholesterol (LDL-C) levels and premature coronary heart disease (CHD) onset. Even with the advent of statins to lower LDL-C levels, the rates of cardiovascular events in primary prevention HeFH men and women, at age 15 to 66 years, remain high: 3% and 1.6% per year respectively.1 HeFH subjects have a high lifetime risk for CHD due to their exposure to elevated LDL-C levels since early age. Despite elevated cholesterol levels and the high relative risk of CHD, the clinical course of atherosclerosis manifestations in FH subjects is variable.2
Risk factors for CHD in HeFH individuals are similar to those for the general population. However, in the setting of high cholesterol levels, the effect of each risk factor is amplified, resulting in a greater increase in absolute risk than occurs with lower cholesterol levels. Framingham Risk Scores, or scores derived from other cardiovascular risk engines such as the new 2013 ASCVD risk score,2,3 are not reliable to guide management in FH and should not be used, particularly in younger patients, in whom a measure of long-term risk may be more appropriate.2,3 Some guidelines in FH attribute a high-risk condition for FH subjects with two or more cardiovascular risk factors. In particular for FH, high lipoprotein(a) levels and Achilles tendon xantomas also are considered important risk factors.4 The 2013 US Cholesterol Treatment Guidelines recommend aggressive lipid lowering in anyone with an LDL-C of ≥190 mg/dL3.
Subclinical atherosclerosis can be assessed by imaging methods such as computed tomography of the coronary arteries, evaluation of carotid intima media thickness and identification of possible plaques by B-mode ultrasound, and assessment of atherosclerotic plaques by magnetic resonance imaging of the carotids and aorta, among other technologies. Prospective studies in non-FH populations have shown that both coronary5 and carotid subclinical atherosclerosis6 are independent markers of clinical vascular events; however, we do not have the same studies for FH population and many indications are based on expert opinions and some case-control studies.
Cross-sectional studies with asymptomatic FH individuals show a higher plaque burden assessed by computed coronary angiography (CTCA) compared to control subjects. Martinez et al.7 showed a higher prevalence and severity of coronary calcium scores (CAC) in FH subjects compared to normolipidemic controls. The authors included 89 HeFH patients (39±14 years, mean LDL-C 279 mg/dL) and 31 normal subjects. Nearly three times as many FH subjects had detectable CAC compared to the normolipidemic controls (34% vs. 12%, p=0.024), had almost six times more subjects with CAC>75th % for age and gender (23% vs. 4%, p=0.041) and higher CAC scores than controls (p=0.026).
Miname et al.8 studied 102 asymptomatic FH subjects (36% male, 45±13 years, mean LDL-C 280 mg/dL) and 35 age and gender normolipidemic matched controls (mean LDL-C 103 mg/dL). HeFH subjects had a greater atherosclerotic burden represented by higher numbers of patients with plaques (48% vs. 14%, p=0.0005), coronary stenosis (19% vs. 3%, p=0.015), segments with plaques (2.05 ± 2.85 vs. 0.43 ±1.33, p=0.0016), and higher calcium score (55±129 vs.38±140, p=0.0028).
Some argue that FH subjects are definitely high-risk patients, so there is no reason for further cardiovascular risk stratification, as they all should be aggressively treated.2 Indeed the recently published ACC/AHA guidelines3 recommend high intensity statin treatment to individuals older than 21 years-old presenting LDL-C ≥190 mg/dL, independently of the presence of other risk factors. These cholesterol values are usually found in FH populations. However, some FH subjects have early coronary events while others will develop it very late or will not develop cardiovascular disease at all. Thus, risk stratification in this population is important given the implications related to treatment cost-effectiveness and safety. Currently, there is no indication for routine CTCA in asymptomatic patients with FH.2
The unanswered question regarding the clinical utility of subclinical atherosclerosis screening in FH is if these imaging modalities would substantially change patient clinical management and improve clinical outcomes. Substantial clinical judgment is necessary and these modalities are most appropriate in the hands of clinicians with expertise in FH. Early and sustained LDL-C lowering therapy, aggressive control of other present risk factors and possibly preventive aspirin use in those with elevated plaque burden are imperative for CVD prevention in FH. Despite the current benefits of early and intensive pharmacological treatment there are still challenges on the care of FH individuals. Many of them still persist with very elevated LDL-C levels and are at increased cardiovascular disease risk as is the case for severe heterozygous FH9 and homozygous FH.2
Important new horizons for pharmacological treatment are being opened for FH patients. Recently mipomersen10 and lomitapide11 were approved for the treatment of homozygous FH. Also, phase III studies of antibodies against PCSK9 (proprotein convertase subtilisin/kexin type 9) have shown very important reductions in LDL-C in heterozygous FH12 and might also be useful for homozygous patients.
In the case discussion, the patient is a young male with FH and three additional risk factors: family history for premature CHD, smoking and low HDL-C. The latter can be low in FH and HDL might also be dysfunctional.13 CTCA was used to improve cardiovascular risk stratification. The test results helped to improve treatment adherence; however, diffuse atherosclerosis was already present. It is hoped that long-term adherence to lipid lowering with combination therapy will help to stabilize plaques so that the patient can avoid the same fate suffered by his father and uncle.
References
Mohrschladt MF, Westendorp RG, Gevers Leuven JA, Smelt AH. Cardiovascular disease and mortality in statin-treated patients with familial hypercholesterolemia. Atherosclerosis 2004;172:329-35.
Nordestgaard BG, Chapman MJ, Humphries SE et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-90.
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].
Civeira F; International Panel on Management of Familial Hypercholesterolemia. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis 2004;173:55-68.
Detrano R, Guerci AD, Carr JJ et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008; 358:1336–45.
Lorenz MW, Polak JF, Kavousi M, et al. PROG-IMT Study Group. Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. Lancet 2012;379:2053-62.
Martinez LR, Miname MH, Bortolotto LA et al. No correlation and low agreement of imaging and inflammatory atherosclerosis' markers in familial hypercholesterolemia. Atherosclerosis 2008;200:83-8.
Miname MH, Ribeiro MS 2nd, Parga Filho J, et al. Evaluation of subclinical atherosclerosis by computed tomography coronary angiography and its association with risk factors in familial hypercholesterolemia. Atherosclerosis 2010;213:486-91.
Besseling J, Kindt I, Hof M, Kastelein JJ, Hutten BA, Hovingh GK. Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14,000 mutation carriers. Atherosclerosis 2014;233:219-23.
Santos RD, Duell PB, East C, Guyton JR, Moriarty PM, Chin W, Mittleman RS. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J 2013; [Epub ahead of print].
Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013;381:40-6.
Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, Stein EA. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 2012;126:2408-17.
Guerin M. Reverse cholesterol transport in familial hypercholesterolemia. Curr Opin Lipidol 2012;23:377–85.
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