Aortic stenosis in homozygous familial hypercholesterolaemia: a paradigm shift over a century

Abstract

Aims Homozygous familial hypercholesterolaemia (HoFH) is an orphan disease defined by extreme elevations in low-density lipoprotein cholesterol, cutaneous xanthomas, and pre-mature atherosclerotic cardiovascular disease. Survival has more than doubled over the past three decades. Aortic stenosis (AS) [supravalvular aortic stenosis (SVAS) or valvular aortic stenosis (VAS)] is commonly encountered. There are no medical treatments available and complex high-risk surgeries represent the only available option in severe cases. A systematic review was performed to summarize the current evidence on AS in HoFH and to determine whether pharmacological treatment (statins) have had an impact on clinical presentation, phenotype and clinical course over the past nine decades (PROSPERO CRD42021250565). Methods and results MEDLINE, Embase Classic + Embase, Cochrane Central Register of Controlled Trials, PubMed, AfricaWide, and Scopus were searched from inception to 10 November 2021. Searches identified 381 publications, of which 19 were retained; they were cross-sectional or retrospective studies. Separately, 108 individual case reports were described. Within the 424 HoFH cases, AS was identified in 57% of patients in the pre-statin era vs. 35% in patients reported more recently (>2000, long-term statin period). With an increase in longevity due to statins and lipoprotein apheresis, a change in the proportion of patients with SVAS and VAS with a SVAS:VAS ratio of 47:53 and 10:90 for HoFH patients not on statin and on long-term statin, respectively, was noted. Conclusion These data suggest that SVAS and VAS are frequent in HoFH and that the phenotype has shifted towards calcific VAS as statins and lipoprotein apheresis improve survival in these patients.

Familial hypercholesterolemia is related to cardiovascular disease, heart failure and atrial fibrillation. Results from a population‐based study

“…17 Secondly, it has been shown that FH is associated with some of the valvular diseases, especially with aortic valve stenosis. 18,19 Recent Mendelian randomization studies have suggested that LDL cholesterol as well as lipoprotein (a) [Lp(a)] both of which are elevated in patients with FH appear to be causally associated with developing aortic valve stenosis. 20 Thus, FH status may lead to increased HF and AF via increased risk for valvular diseases.…”

“…Firstly, it is reasonable to think that one of the major causes of HF and AF is ASCVD, and thus FH is associated with HF and AF because FH is strongly associated with ASCVD 17 . Secondly, it has been shown that FH is associated with some of the valvular diseases, especially with aortic valve stenosis 18,19 . Recent Mendelian randomization studies have suggested that LDL cholesterol as well as lipoprotein (a) [Lp(a)] both of which are elevated in patients with FH appear to be causally associated with developing aortic valve stenosis 20 .…”

Lipoprotein(a) and calcific aortic valve disease: current evidence and future directions

“…Inclisiran, a small interfering RNA that inhibits hepatic synthesis of PCSK9, is being evaluated in ASCVD outcome trials (NCT03705234, NCT05030428) but not in the prevention of AS [56]. The impact of lipoprotein apheresis on CAVD is unclear; current data are limited to observational studies of individuals with homozygous FH [48].…”

“…Initial efforts at preventing AS focused on reducing atherogenic lipoproteins, particularly LDL-cholesterol [47]. Additionally, individuals with homozygous FH have a high prevalence of supravalvular and valvular AS [48,49]. However, statins have not been demonstrated to slow the progression of AS [10 ▪ ,13].…”

Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolemia: an expert consensus statement from ERKNet and ESPN

“…46 AS is mainly evaluated by echocardiography, and seldom by invasive cardiac catheterization, contrast angiography or cardiac magnetic resonance imaging (MRI). 53, 54 Presence of (non-) calcified plaques, perivascular inflammation and hemodynamic obstructive lesions can be evaluated by prospective ECG-triggered CT coronary angiography (CTCA). Potential ischemia due to obstructive coronary artery stenoses should be primarily evaluated by non-invasive functional tests, such as exercise ECG, stress perfusion with PET-CT, cardiac MRI or Single Photon Emission CT Myocardial Perfusion (SPECT).…”