Lipoprotein(a) as a risk factor for calcific aortic valvulopathy in heterozygous familial hypercholesterolemia

A large number of epidemiological studies in ethnically diverse populations show that lipoprotein(a) [Lp(a)] levels above 30-50 mg/dL are significantly associated with calcific aortic valve stenosis, although less so in African Americans. Patients with heterozygous familial hypercholesterolemia (he-FH) have a marked lifelong elevation of serum low-density lipoprotein cholesterol (LDL-C) level, and the prevalence of aortic valve calcification (AVC) is at least two-fold higher among adult he-FH patients compared with healthy controls. Additionally, Lp(a) levels above 50 mg/dL were recently found to be an independent risk factor for AVC among asymptomatic statin-treated he-FH patients. Given that worldwide an estimated 1.4 billion people have an Lp(a) level over 50 mg/dL, and that one out of 250 individuals has he-FH, then globally about 5 million he-FH patients should have an Lp(a) level higher than 50 mg/dL. However, because Lp(a) levels are, on average, significantly higher in he-FH patients than the general population, the actual number of he-FH patients with such high Lp(a) levels must be even higher. We proposed recently that Lp(a) life-years is a useful metric of cumulative burden of risk for atherosclerotic cardiovascular disease (ASCVD), and now posit that this metric may be extended to the development of AVC. The Lp(a) life-years illustrates the age-dependent exposure to a given Lp(a) level (years x mg/dL). Effective novel pharmacotherapies using apo(a) antisense oligonucleotides (ASOs) or small interfering RNA (siRNA)-based therapies targeting the hepatic expression of apo(a) offer unprecedented potential for significant reduction in the cumulative exposure of the aortic valves to Lp(a), and need to be tested in controlled clinical trials on the progression of AVC.Peer reviewe

Aorta of young and middle-aged heterozygous familial hypercholesterolemia patients shows no functional or morphological impairment assessed by MRI

In familial hypercholesterolemia (FH) the level of LDL cholesterol is 2–3 times that of the normal population and leads to accelerated atherosclerosis. Improved care for risk factors has decreased cardiovascular mortality of these patients. We studied subclinical atherosclerotic changes with morphologic and functional aortic magnetic resonance imaging (MRI) in FH patients under the age of 50. 39 DNA test-verified heterozygous FH-North Karelia patients, aged 6–48, 28 of them treated with statins, and 25 healthy controls, aged 12 to 50, underwent aortic MRI, carotid ultrasound (US), and risk-factor assessment. No differences in any of the morphologic or functional aortic parameters appeared between patients and controls. Age and gender were independent predictors of the majority of the morphologic and functional measures. Carotid intima-media thickness assessed by US was greater in patients (0.57 mm ± 0.13 vs 0.48 ± 0.13 mm, p = 0.005) as was cholesterol-years score (243 ± 122 vs 137 ± 74, p < 0.001). Patients had thicker intima-media of the common carotid artery and higher cholesterol burden as indicated by their cholesterol-years score. Despite this, no differences existed in morphologic or functional aortic parameters assessed with MRI. The improved care of cardiovascular risk factors, especially statin treatment, may protect the aorta of FH patients. However, larger confirmatory studies are needed

Compliance of the aorta in two diseases affecting vascular elasticity, familial hypercholesterolemia and diabetes: a MRI study

Sami Soljanlahti1, Taina Autti1, Laura Hyttinen2, Alpo F Vuorio3, Pekka Keto1, Kirsi Lauerma11Helsinki Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland; 2Department of Internal Medicine, North Karelia Central Hospital, Joensuu, Finland; 3Division of Internal Medicine, Department of Medicine, University of Helsinki, Helsinki, FinlandAbstract: Arterial elasticity changes in familial hypercholesterolemia (FH) and diabetes mellitus (DM) with different but overlapping mechanisms. We compared aortic elasticity between 19 FH patients with the same mutation, 18 type 2 DM patients, and 30 controls, all aged 48 to 64. They underwent aortic magnetic resonance imaging, risk-factor assessment, and carotid and femoral ultrasound measurements. All patients were on adequate cardiovascular medication including statins and had established coronary heart disease (CHD). FH patients had longer-duration CHD (13.3 &plusmn; 7.7 years) than did DM patients (5.0 &plusmn; 3.1). Aortic compliance in the descending thoracic (DM 0.38 &plusmn; 0.14 vs control 0.53 &plusmn; 0.19, P = 0.032) and abdominal aorta (DM 0.45 &plusmn; 0.20 vs control 0.66 &plusmn; 0.25, P = 0.011) was lower in DM patients than in controls, whereas no significant difference existed between FH patients and controls. Carotid and femoral intima-media thickness was greater in FH and DM patients than in controls with no difference between patient groups. Carotid or femoral plaques appeared in 15 (79%) FH and in 10 (56%) DM patients. One control had a femoral plaque. Five FH patients showed stenosis, occlusion or both in carotid arteries. In our opinion, DM patients&rsquo; lower compliance reflect mainly arterial media affecting arteriosclerosis, while FH patients&rsquo; plaque status and longer duration of CHD suggest more advanced atherosclerosis. The FH patients may therefore be at increased risk for atherothrombotic events. However, due to small patient material, larger confirmatory studies are needed.Keywords: MRI, ultrasound, familial hypercholesterolemia, diabetes mellitus, elasticity, intima-media thicknes

Statin treatment of children with familial hypercholesterolemia – trying to balance incomplete evidence of long-term safety and clinical accountability: are we approaching a consensus?

In the heterozygous form of familial hypercholesterolemia (FH), blood concentrations of low-density lipoprotein cholesterol (LDL-C) are elevated two to three times above the normal range since birth, and cause strongly elevated risk of premature coronary artery disease (CAD). There is no evidence that statin therapy is unsafe in FH children, and it has not been associated with clinically significant changes in measures of growth or maturation, liver enzymes, serum creatine kinase, or incidence of myopathy. However, the opinions among clinicians, and between countries, about the age at which statin therapy should be initiated in FH children vary. This review attempts to critically examine the available data, so that clinically the most appropriate age of initiating statin treatment in FH children as a preventive measure for future CAD could be established