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Mundal LJ, Hovland A, Igland J, et al. Association of Low-Density Lipoprotein Cholesterol With Risk of Aortic Valve Stenosis in Familial Hypercholesterolemia. JAMA Cardiol. 2019;4(11):1156–1159. doi:10.1001/jamacardio.2019.3903
Are patients with genetically proven familial hypercholesterolemia at risk of aortic valve stenosis compared with the general population?
In this registry-based cohort study of all Norwegian genotyped patients with familial hypercholesteremia, during 18 300 person-years of follow-up, an increased incidence of aortic valve stenosis was observed compared with the total Norwegian population stratified by sex and age.
A significantly higher incidence of aortic valve stenosis was observed in patients with familial hypercholesterolemia compared with the total Norwegian population.
Aortic valve stenosis (AS) is the most common valve disease. Elevated levels of low-density lipoprotein (LDL) cholesterol are a risk factor; however, lipid-lowering treatment seems not to prevent progression of AS. The importance of LDL cholesterol in the development of AS thus remains unclear. People with familial hypercholesterolemia (FH) have elevated LDL cholesterol levels from birth and until lipid-lowering treatment starts. Thus, FH may serve as a model disease to study the importance of LDL cholesterol for the development of AS.
To compare the incidence of AS per year in all genetically proven patients with FH in Norway with the incidence of these diseases in the total Norwegian population of about 5 million people.
Design, Setting, and Participants
This is a registry-based prospective cohort study of all Norwegian patients with FH with regard to first-time AS between 2001 and 2009. All genotyped patients with FH in Norway were compared with the total Norwegian populations through linkage with the Cardiovascular Disease in Norway project and the Norwegian Cause of Death Registry regarding occurrence of first-time AS. Data were analyzed between January 1, 2018, and December 31, 2018.
Main Outcomes and Measures
Standardized incidence ratios.
In total, 53 cases of AS occurred among 3161 persons (1473 men [46.6%]) with FH during 18 300 person-years of follow-up. Mean age at inclusion and at time of AS were 39.9 years (range, 8-91 years) and 65 years (range, 44-88 years), respectively. Total standardized incidence ratios were 7.9 (95% CI, 6.1-10.4) for men and women combined, 8.5 (95% CI, 5.8-12.4) in women, and 7.4 (95% CI, 5.0-10.9) in men, respectively, indicating marked increased risk of AS compared with the general Norwegian population.
Conclusions and Relevance
In this prospective registry study, we demonstrate a marked increase in risk of AS in persons with FH.
Aortic valve stenosis (AS) is the most common valvular disease in the western world. The underlying pathophysiology of AS is divided into an initiation phase resembling atherosclerosis, including lipid infiltration, oxidation, and inflammation, and a propagation phase characterized by fibrosis and calcification.1 Even if low-density lipoprotein (LDL) cholesterol may be important in the initiation phase, lipid-lowering therapy with statins and ezetimibe has been unsuccessful in halting the disease.2
Familial hypercholesterolemia (FH) is a disorder with increased levels of LDL cholesterol and increasing the risk of atherosclerotic diseases, particularly coronary heart disease.3 In the severe homozygous form of FH, AS is seen frequently and more often in null mutations, with even higher LDL cholesterol than in defective mutations.4 The risk of AS in heterozygous FH mutation carriers is not known. This study was designed as a prospective registry study to assess the risk of AS in a large cohort of genetically verified heterozygous patients with FH compared with the total Norwegian population.
The study was approved by the Regional Committee for Medical and Health Research Ethics, and the cohort, study design, and methods have been described previously.3 In brief, this is a registry-based prospective cohort study of all genotyped patients with FH in Norway. Characteristics of 714 of 3161 patients in the FH cohort have been reported previously in a retrospective study on collection of data from medical records.5 These patients had been followed up at a lipid clinic for a mean (SD) of 11.1 (7.9) years, and 89% of the patients were treated with statin (n = 635 of 714) and 58% received ezetimibe (n = 411 of 714), with a mean (SD) achieved LDL cholesterol level of 131 (50) mg/dL (to convert to millimoles per liter, multiply by 0.0259).
All patients with genetically diagnosed FH in Norway are included in the National Unit for Cardiac and Cardiovascular Genetics (UCCG) Registry after written informed consent. This registry was coupled with all hospitalizations in Norway from 1994 to 2009 for AS from the Cardiovascular Disease in Norway project (http://www.cvdnor.no), a collaborative project between the University of Bergen and the Norwegian Knowledge Centre for the Health Services. We obtained data regarding death from the Norwegian Cause of Death Registry containing information on date and cause of death (underlying, contributing, and immediate causes) for all deaths among Norwegian residents.
We followed up patients for end points through linkage with the Norwegian Cause of Death Registry and the Cardiovascular Disease in Norway project by using the unique personal identification number for each Norwegian resident. Data were given according to the International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) (AS: ICD-9: 424.1 and ICD-10: I35.0 and I35.2). Aortic valve replacements were coded according to Nordic Medico-Statistical Committee classification for medical procedures: FMD00, FMD10, FMD12, FMD13, FMD20, and FMD96.
Persons were followed up from time of FH diagnosis until the first occurrence of AS, death from other causes, or December 31, 2009, whichever occurred first. Similarly, we also calculated time to the first occurrence of valve replacement. To analyze the first-time events only, we required 7 years of observation free of events prior to the start of follow-up. Incidence rates were thus calculated for the period of 2001 to 2009 among persons with FH aged 25 years and older. We calculated unadjusted incidence rates for each end point (AS diagnosis and valve replacement) in 2001 to 2009, stratified by sex and age. For each age stratum, the incidence rates were calculated as the number of events per 1000 person-years of follow-up for patients with FH and the entire Norwegian population. We calculated standardized incidence ratios (SIRs) for each end point using indirect standardization, with incidence rates for the total Norwegian population as reference rates.6 Expected number of incident events was calculated for each combination of 1-year age group and calendar year in the UCCG registry as time spent in the cohort multiplied by the incidence rate for the same combination of birth year and calendar year in the total Norwegian population. Calculations were performed for men and women separately and in combination. Total expected number of incident events were obtained by summing expected number of events over 1-year age groups and calendar years. The SIR was calculated as the observed number of events divided by the expected number of events. Confidence limits were obtained using the normal approximation to the Poisson distribution. All statistical tests were 2-sided, and .05 was used as the level of significance in all analyses.
In total, 53 cases of AS occurred among 3161 persons (1473 men [46.6%]) with FH during 18 300 person-years of follow-up. Mean ages at inclusion (date of genetic FH diagnosis) and AS (date of first AS diagnosis) were 39.9 years (range, 8-91 years) and 65.0 years (range, 44-88 years), respectively. Total SIR was 7.9 (95% CI, 6.1-10.4) in women and men combined, 8.5 (95% CI, 5.8-12.4) in women, and 7.4 (95% CI, 5.0-10.9) in men, respectively, indicating marked increased risk of AS compared with the general Norwegian population (Table 1). In the FH group, the total SIR for aortic valve replacements was 7.7 (95% CI, 5.2-11.5), and SIR was significant for both women and men (Table 2).
To our knowledge, this is the largest prospective registry study to date demonstrating increased risk of AS in persons with FH compared with the general population. The estimated SIR of 7.9 is higher than we previously have demonstrated for coronary artery disease, heart failure, atrial fibrillation, and cerebrovascular disease.3,7,8 Furthermore, the significant increased risk of aortic valve replacements in the FH group indicates that the AS are severe and in need of surgical treatment.
Acknowledging the contribution of age to the risk of AS, mean age at hospitalization for AS was 65 years in our cohort of FH mutation carriers. In an epidemiologic study from Norway, the prevalence of AS was 0.2% in the cohort aged 50 to 59 years, 1.3% in the cohort aged 60 to 69 years, and 3.9% in the cohort aged 70 to 79 years.9 Previously, Ten Kate et al10 have demonstrated increased aortic valve calcification assessed by cardiac computed tomography in asymptomatic, heterozygous patients with FH (mean age, 52 years) when compared with control individuals. A large mendelian randomization study found that genetic predisposition of high LDL cholesterol increased the risk of aortic valve calcification and AS.11 Our data support that increased LDL cholesterol owing to FH may indeed increase the risk of AS. Although LDL cholesterol–lowering therapy has failed to reduce the risk in established AS, the importance of LDL cholesterol in AS development suggests that early initiation of LDL cholesterol–lowering therapy could prevent development of AS. Persons with FH with increased incidence of AS could be an ideal group to test this hypothesis in prospective studies. Whether other patient groups with increased risk of AS, including those with bicuspid aortic valves, would benefit from lipid-lowering therapy remains unknown. A European consensus on FH states that one could screen for asymptomatic coronary artery disease; however, AS is not mentioned.12 Our finding of increased risk of AS in heterozygous FH might indicate a need for some form of echocardiographic evaluation in this large patient group.
All AS hospitalizations and the corresponding reported AS-related deaths from the Norwegian Cause of Death Registry for the entire Norwegian population from 2001 to 2009 were included. Data on all registered AS hospitalizations in Norway were included in the analyses, but there is always a risk of misclassification owing to errors in diagnostic coding at the hospitals. We do not know about any validation studies on the accuracy of the AS diagnosis in Norwegian hospital data. However, we do not expect the rate of misclassification to differ between persons with and without FH. Important risk factors for AS were not accounted for, that is, smoking habits, body mass index, LDL cholesterol values, lipoprotein(a) values, statin treatment, other lipid-lowering treatment, and dietary habits. There might be a detection bias because patients with FH may have closer monitoring possible, leading to detection of murmurs and hence echocardiography, leading to detection of AS. Patients with homozygous FH are well known for having an increased risk of AS. Three of 3161 patients in our total FH population were homozygous. We were not able to exclude them from the analyses because they were not flagged in the anonymized data file. In a sensitivity analysis where we excluded the 3 AS cases with shortest time from baseline to AS diagnosis (as a worst-case scenario), the total SIR was reduced from 7.9 to 7.5. Because all 3 homozygous patients probably do not have AS, the true bias caused by inclusion of the 3 homozygous patients with FH is even smaller.
Selection bias is important in registry studies. Participants in the present study account for almost one-third of the total number of patients with FH in Norway, given a prevalence of 1:300. This large proportion of the total number reduces the possibility of any major selection bias. Testing is free of charge for physicians and patients in Norway, probably reducing the risk of bias owing to economic reasons.
In this prospective registry study, spanning more than 18 000 person-years, we demonstrated a marked increase in risk of AS in persons with FH.
Corresponding Author: Anders Hovland, MD, PhD, Division of Internal Medicine, Nordland Hospital, N-8092 Bodø, Norway (firstname.lastname@example.org).
Accepted for Publication: August 20, 2019.
Correction: This article was corrected on November 20, 2019, to correct and error in the text.
Published Online: October 16, 2019. doi:10.1001/jamacardio.2019.3903
Author Contributions: Dr Igland had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Mundal, Hovland, Bogsrud, Retterstøl.
Acquisition, analysis, or interpretation of data: Mundal, Hovland, Igland, Veierød, Holven, Tell, Leren, Retterstøl.
Drafting of the manuscript: Mundal, Hovland, Retterstøl.
Critical revision of the manuscript for important intellectual content: Hovland, Igland, Veierød, Holven, Bogsrud, Tell, Leren, Retterstøl.
Statistical analysis: Igland, Retterstøl.
Obtained funding: Retterstøl.
Administrative, technical, or material support: Mundal, Hovland, Holven, Bogsrud, Leren, Retterstøl.
Supervision: Hovland, Veierød, Bogsrud, Retterstøl.
Conflict of Interest Disclosures: Dr Holven reported grants from Mills SA, TINE, Kaneka, and Olympic Seafood; grants and personal fees from Amgen; and personal fees from Sanofi and Pronova outside the submitted work. Dr Bogsrud reported personal fees from Sanofi, Amgen, and Boehringer outside the submitted work. Dr Retterstøl reported grants from Oslo Economics through Amgen and personal fees from Amgen, Mills DA, Norwegian Medical Association, Sanofi, Chiesi, and Sunovion outside the submitted work. No other disclosures were reported.
Funding/Support: This work was funded by the South-Eastern Norway Regional Health Authority, Oslo, Norway, and Throne Holst Foundation for Nutrition Research, Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank the patients for allowing us to study the data presented here and in particular Margaretha Hamrin for the important contribution in leading the patient organization FH Norway (FH-Norge) and for being editor of the biannual FH magazine (http://www.f-h.no/). We thank referring physicians for many years of shipping samples for testing and the staff at the UCCG and at the Lipid Clinic in Oslo. We thank Tomislav Dimoski, MBA, at the Norwegian Institute of Public Health, Oslo, Norway, for developing the software necessary for obtaining data from Norwegian hospitals, conducting the data collection, and quality assurance of data in this project. We thank Dr Leiv Ose, MD, PhD, who established the Lipid Clinic in Oslo and headed the clinic for more than 30 years. Without his great efforts in the field of FH, this article would not have been possible. No compensation was received from a funding sponsor for these contributions.