The risk of various types of cardiovascular diseases in mutation positive familial hypercholesterolemia; a review.

Familial hypercholesterolemia (FH) is a common, inherited disease characterized by high levels of low-density lipoprotein Cholesterol (LDL-C) from birth. Any diseases associated with increased LDL-C levels including atherosclerotic cardiovascular diseases (ASCVDs) would be expected to be overrepresented among FH patients. There are several clinical scoring systems aiming to diagnose FH, however; most individuals who meet the clinical criteria for a FH diagnosis do not have a mutation causing FH. In this review, we aim to summarize the literature on the risk for the various forms of ASCVD in subjects with a proven FH-mutation (FH+). We searched for studies on FH+ and cardiovascular diseases and also included our and other groups published papers on FH + on a wide range of cardiovascular and other diseases of the heart and vessels. FH + patients are at a markedly increased risk of a broad range of ASCVD. Acute myocardial infarction (AMI) is the most common in absolute numbers, but also aortic valve stenosis is by far associated with the highest excess risk. Per thousand patients, we observed 3.6 incident AMI per year compared to 1.9 incident aortic valve stenosis, however, standardized incidence ratio (SIR) for incident AMI was 2.3 compared to 7.9 for incident aortic valve stenosis. Further, occurrence of ischemic stroke seems not to be associated with increased risk in FH+. Clinicians should be aware of the excess risk of almost all kind of ASCVD in FH+, and the neutral risk of stroke need to be studied further in FH + patients.

Risk of stroke in genetically verified familial hypercholesterolemia: A prospective matched cohort study.

BACKGROUND AND AIMS: Individuals with familial hypercholesterolemia (FH), causing severely elevated LDL-C, are expected to have a higher risk of ischemic stroke. The risk of hemorrhagic stroke and impact of statin use are, however, not known. We aimed to investigate the risk of incident total, ischemic and hemorrhagic stroke in individuals with FH compared to controls, and to explore the association between cumulative statin use and risk of total stroke in FH. METHODS: This prospective cohort study consists of 4186 individuals with genetically verified FH and 82 180 age and sex matched controls followed from 2008 to 2018 for incident stroke. Daily defined doses (DDD) described cumulative statin exposure: 0-5000 DDD ("low"), 5000-10,000 DDD ("intermediate"), and >10 000 DDD ("high"). Results were presented as hazard ratio (95% CI) derived from Cox proportional hazards models. RESULTS: Individuals with FH did not have a higher risk of total stroke (1.16 (0.95-1.43) nor ischemic stroke (1.11 (0.88-1.38). Excess risk of hemorrhagic stroke was observed (1.63 (1.07, 2.48) but attenuated after adjusting for antithrombotic medication (1.25 (0.81, 1.93). Among individuals with FH, there was no association between statin use and total stroke for intermediate vs. low DDD [0.69 (0.32, 1.48)] or for high vs. low DDD [0.83 (0.41, 1.67)]. CONCLUSIONS: No significant excess risk of incident total and ischemic stroke in FH, and no difference in total stroke risk among the FH population with low, intermediate, and high statin exposure were observed. The observed relationship between FH and hemorrhagic stroke was no longer significant after adjusting for use of anti-thrombotic medication.

Association of Familial Hypercholesterolemia and Statin Use With Risk of Dementia in Norway.

Importance: Hypercholesterolemia, which is a cardiovascular risk factor, may also be associated with dementia risk. The benefit of statin treatment on dementia risk is controversial. Objective: To determine whether individuals with familial hypercholesterolemia (FH), who have been exposed to lifelong hypercholesterolemia, have an excess risk of dementia and whether statin use is associated with dementia risk. Design, Setting, and Participants: This was a prospective cohort study performed from 2008 to 2018 in Norway. Statistical analysis was performed from January 2021 to February 2022. This study included individuals with genetically verified FH and age-matched and sex-matched controls obtained from the general Norwegian population. Exposures: Dementia was defined according to International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes F00-03 and G30. Main Outcomes and Measures: Incident cases of total dementia, vascular dementia, Alzheimer disease-dementia in Alzheimer disease, and data on lipid-lowering medication were obtained from the Norwegian Patient Registry, Cause of Death Registry, and the Norwegian Prescription Database. Hazard ratios (HRs) for risk of dementia for individuals with FH vs matched controls were calculated using Cox regression. The cumulative sum of defined daily doses (DDDs) of statins prescribed during study follow-up was calculated for individuals with FH and was analyzed as a time-varying covariate with 3 levels: 1 to 4999 DDDs, 5000 to 10 000 DDDs, and more than 10 000 DDDs. Results: Among the 3520 individuals with FH (1863 women [52.9%]; mean [SD] age at the start of follow-up, 51.8 [11.5] years) and the 69 713 controls (36 958 women [53.0%]; mean [SD] age at the start of follow-up, 51.7 [11.5] years), 62 patients with FH (39 women [62.9%]) and 1294 controls (801 women [61.9%]) had developed dementia over the course of 10 years of follow-up. Most dementia cases occurred among individuals aged 70 years and older (39 patients with FH [62.9%] and 870 patients [67.2%] in the control group). We found no excess risk of dementia in patients with FH vs matched controls (HR for total dementia, 0.9; 95% CI, 0.7-1.2). There was no association between cumulative DDDs of statins and total dementia in patients with FH with HRs of 1.2 (95% CI, 0.4-3.8) for cumulative DDDs of 5000 to 10 000 and 1.9 (95% CI, 0.7-5.0) for cumulative DDDs greater than 10 000. Conclusions and Relevance: These findings suggest that individuals with FH have no excess risk of dementia compared with age-matched and sex-matched controls and that there is no association between use of statins and risk of dementia in patients with FH.

2.5-fold increased risk of recurrent acute myocardial infarction with familial hypercholesterolemia.

BACKGROUND AND AIMS: A first-time acute myocardial infarction (AMI) is a severe diagnosis that leads to initiation or intensification of lipid-lowering medication to prevent recurrent events. Individuals with familial hypercholesterolemia (FH) already use high-intensity lipid-lowering medication at the time of an incident AMI due to their diagnosis. Hence, we hypothesized that compared with matched non-FH controls, individuals with genetically verified FH have increased mortality and risk of recurrent AMI after their first event. METHODS: The study population comprised 4871 persons with genetically verified FH, and 96,251 age and sex matched controls randomly selected from the Norwegian population. Data were obtained from the Cardiovascular Disease in Norway Project, the Norwegian Patient Registry and the Norwegian Cause of Death Registry. Incidence of AMI, all-cause mortality and recurrent AMI after incident AMI were analyzed for the period 2001-2017. Incidence and mortality were compared using hazard ratios (HR) from Cox regression. Risk of recurrent AMI was compared using sub-hazard ratios (SHR) from competing risk regression with death as a competing event. RESULTS: We identified 232 individuals with FH and 2118 controls with an incident AMI [HR 2.10 (95% CI 1.83-2.41)]. Among survivors ≥29 days after the incident AMI, both mortality [HR = 1.45 (95% CI: 1.07-1.95)] and recurrent AMI [SHR = 2.53 (95% CI: 1.88-3.41)] were significantly increased among individuals with FH compared with non-FH controls. CONCLUSIONS: Individuals with FH have increased mortality and increased risk of recurrent AMI after the first AMI event compared with controls. These findings call for intensive follow-up of individuals with FH following an AMI.

Lower risk of smoking-related cancer in individuals with familial hypercholesterolemia compared with controls: a prospective matched cohort study.

According to guidelines, individuals with familial hypercholesterolemia (FH) shall receive lifestyle intervention and intensive lipid-lowering treatment from early in life to reduce the risk of coronary heart disease. Our aim was to study if treatment of FH also could affect risk of lifestyle-related cancer. We presented cumulative incidence of total cancer and lifestyle-related cancer sites in individuals with genetically verified FH (n = 5531) compared with age and sex matched controls (n = 108354). Individuals with FH had 20% lower risk of smoking-related cancer compared with the control population [HR 0.80 (95% CI, 0.65-0.98)], in particular men with FH at 40-69 years at age of diagnosis with HR 0.69 (95% CI, 0.49-0.97). The FH population and controls had similar rates of total cancer [HR 0.97 (95% CI, 0.86-1.09)], cancer related to poor diet [HR 0.82 (95% CI, 0.59-1.15)], cancer related to physical inactivity [HR 0.93 (95% CI, 0.73-1.18)], alcohol-related cancer [HR 0.98 (95% CI, 0.80-1.22)] and cancer related to obesity [HR 1.03 (95% CI, 0.89-1.21)]. In summary, we found reduced risk of smoking-related cancer in individuals with FH, most likely due to a lower prevalence of smoking. Implications of these findings can be increased motivation and thus compliance to treatment of hypercholesterolemia.

Association of Low-Density Lipoprotein Cholesterol With Risk of Aortic Valve Stenosis in Familial Hypercholesterolemia.

Importance: 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. Objective: 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. Results: 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.

Economic evaluation of lipid lowering with PCSK9 inhibitors in patients with familial hypercholesterolemia: Methodological aspects.

BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have proved to reduce low density lipoprotein cholesterol levels in numerous clinical trials. In two large clinical trials, PCSK9 inhibitor treatment reduced the risk of cardiovascular disease. Our aim was to explore the impact of varying assumptions about clinical effectiveness on health and economic outcomes for patients with familial hypercholesterolemia. METHODS: We used a previously published and validated Norwegian model for cardiovascular disease. The model was updated with recent data from the world's second largest registry of patients with genetically confirmed familial hypercholesterolemia. We performed analyses for 24 different subgroups of patients based on age, gender, statin tolerance and previous history of cardiovascular disease. RESULTS: In 1 out of 24 subgroups, PCSK9 inhibitors were cost-effective when effectiveness was modelled using direct relative efficacy as reported in the FOURIER trial. When using assumptions, as suggested in a recent consensus statement from the European Atherosclerosis Society, 14 subgroups were cost-effective. CONCLUSIONS: Cost-effectiveness of PCSK9 inhibitors depends highly on assumptions regarding effectiveness. Basing assumptions only on randomised controlled trials, and not taking into account varying effects based on baseline cholesterol level, results in much fewer groups being cost-effective.

LDL-cholesterol goal achievement, cardiovascular disease, and attributed risk of Lp(a) in a large cohort of predominantly genetically verified familial hypercholesterolemia.

BACKGROUND: Current treatment goals for familial hypercholesterolemia (FH) recommended by the European Atherosclerosis Society (EAS) are LDL-C ≤2.5 mmol/L (∼100 mg/dL) or ≤1.8 mmol/L (∼70 mg/dL) in very high-risk subjects. OBJECTIVE: The objective of the present study was to investigate characteristics and treatment status in subjects with genetically verified FH followed at specialized lipid clinics in Norway. METHODS: Data from treatment registries of 714 adult (>18 years) subjects with FH. RESULTS: Fifty-seven percent were female. Mean age (SD) at last visit was 44 (16.3) years, and the subjects had been followed at a lipid clinic for 11.1 (7.9) years. Two hundred forty-five (34%) were classified as very-high-risk, and 44% of these had established coronary heart disease. Very-high-risk FH subjects more often received maximal statin dose (54% vs 33%, P < .001), ezetimibe (76% vs 48%, P < .001) or resins (23% vs 9%, P < .001), and achieved LDL-C was lower (3.2 vs 3.5 mmol/L [124 vs 135 mg/dL], P = .003) than normal-risk FH. LDL-C treatment goal was achieved in 25% and 8% of subjects with normal-risk and very-high-risk FH, respectively. Lp(a) levels were available in 599 subjects, and they were divided into 2 groups: ≥90 mg/dL (n = 96) and <90 mg/dL (n = 503). Despite similar lipid levels, body mass index, smoking status, presence of diabetes, and blood pressure, prevalence of coronary heart disease was doubled in the high- compared to low-Lp(a) group (30% vs 14%, P < .001). CONCLUSION: Very few FH subjects achieve their LDL-C treatment goal. New treatment modalities are needed. Independent of LDL-C and other risk factors, high Lp(a) seem to be an important additional risk factor in genetically verified FH.

Risk of Ischemic Stroke and Total Cerebrovascular Disease in Familial Hypercholesterolemia: A Register Study From Norway.

Background and Purpose- Familial hypercholesterolemia (FH) is a common autosomal dominant disease leading to increased level of serum LDL (low-density lipoprotein) cholesterol and risk of coronary heart disease. Whether FH increases the risk of cerebrovascular disease, including ischemic stroke, is debated. Accordingly, we studied the incidence of cerebrovascular disease in a cohort of people with genetically verified FH compared with the entire Norwegian population and examined whether people in this cohort with previous cohort had increased risk of cerebrovascular disease. Methods- Incidence rates of hospitalization for cerebrovascular disease (among 3144 people with FH) and ischemic stroke (among 3166 people with FH) were estimated by linkage of FH people to Cardiovascular Disease in Norway-a nationwide database of cardiovascular disease hospitalizations (2001-2009). We calculated standardized incidence ratios and used Cox regression to estimate hazard ratios. Results- A total of 46 cases (19 women and 27 men) of cerebrovascular disease were observed in the cohort of people with FH, with no increased risk of cerebrovascular disease compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.8-1.4). Total number of ischemic strokes in the cohort of people with FH was 26 (9 women and 17 men), with no increased risk compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.7-1.5). Prior coronary heart disease significantly increased cerebrovascular disease risk in women (hazard ratio, 3.29; 95% CI, 1.20-9.00) but not in men (hazard ratio, 1.03; 95% CI, 0.45-2.37; Pinteraction=0.04). Conclusions- In a large cohort of genetically verified FH, risks of cerebrovascular disease and ischemic stroke were not increased compared with the total Norwegian population.

Impact of age on excess risk of coronary heart disease in patients with familial hypercholesterolaemia.

OBJECTIVE: The primary objective was to study the risk of acute myocardial infarction (AMI) and coronary heart disease (CHD) in patients with familial hypercholesterolaemia (FH) and compare with the risk in the general population. METHODS: Patients with an FH mutation but without prior AMI (n=3071) and without prior CHD (n=2795) were included in the study sample during 2001-2009. We obtained data on all AMI and CHD hospitalisations in Norway. We defined incident cases as first time hospitalisation or out-of-hospital death due to AMI or CHD. We estimated standardised incidence ratios (SIRs) with 95% CIs with indirect standardisation using incidence rates for the total Norwegian population stratified by sex, calendar year and 1 year age groups as reference rates. RESULTS: SIRs for AMI (95% CIs) were highest in the age group 25-39 years; 7.5 (3.7 to 14.9) in men and 13.6 (5.1 to 36.2) in women and decreased with age to 0.9 (0.4 to 2.1) in men and 1.8 (0.9 to 3.7) in women aged 70-79 years. Similarly, SIRs for CHD were highest among patients 25-39 years old; 11.1 (7.1-17.5) in men and 17.3 (9.6-31.2) in women and decreased 2.4 (1.4-4.2) in men and 3.2 (1.5-7.2) in women at age 70-79. For all age groups, combined SIRs for CHD were 4.2 (3.6-5.0) in men and 4.7 (3.9-5.7) in women. CONCLUSION: Patients with FH are at severely increased risk of AMI and CHD compared with the general population. The highest excess risk was in the youngest group aged 25-39 years, in both sexes.

Increased risk of heart failure and atrial fibrillation in heterozygous familial hypercholesterolemia.

BACKGROUND AND AIMS: Heart failure (HF) and atrial fibrillation/flutter (AF) are important causes of morbidity and mortality. Subjects with familial hypercholesterolemia (FH) carry a high risk of coronary artery disease (CAD) but it is not known if the risk of HF and AF is increased in FH. The present study investigated the incidence of hospitalization for HF and AF in a genetically verified FH cohort, age 25 years and older, compared to the general population. METHODS: Incidence rates of hospitalization for HF and AF were estimated from national registry data. Standardized incidence ratios (SIRs) were calculated. RESULTS: 4273 genotyped FH patients (51.7% women) with a total observation period of 18,300 patient years were studied. Overall, the expected number of FH patients with HF was 27.7 and the observed number of cases was 54 (SIR (95% CI) 2.0 (1.5-2.6)). The highest excess risk was observed in the age group 25-49 years, where SIRs were 3.8 (1.2-11.8) and 4.2 (2.0-8.8) in women and men, respectively. The total expected number of FH patients with AF was 39.4 while the observed number of cases was 77 (SIR 2.0 (1.6-2.4)). Among FH patients with an incident event of HF, nearly 90% had a previous diagnosis of CAD, and nearly 40% had suffered from a myocardial infarction. CONCLUSIONS: We demonstrate a doubling of the risk of hospitalization for HF or AF in patients with FH. This is could have an important prognostic impact for patients and economic impact for the society.