Additional risk factors influence excess mortality in heterozygous familial hypercholesterolaemia

doi:10.1016/S0021-9150(99)00336-6

Atherosclerosis

Volume 149, Issue 2, April 2000, Pages 421-425

https://doi.org/10.1016/S0021-9150(99)00336-6 Get rights and content

Abstract

Life expectancy of patients with familial hypercholesterolaemia is decreased. Some untreated patients reach a normal life span and, therefore, additional risk factors and the type of mutation in the low-density lipoprotein (LDL) receptor gene are likely to influence the clinical outcome. We determined all cause mortality in kindreds with the disorder, who were untreated, in order to study (a) additional risk factors for coronary artery disease (CAD) and (b) the types of LDL receptor gene mutations that may contribute to a poor prognosis. The mortality in all 855 first-degree relatives of 113 unrelated patients was compared to the Dutch population after standardisation for age, gender, and calendar period. Analyses restricted to affected relatives could have underestimated the mortality risk due to lack of information about severe cases, who died prematurely. Therefore, all first-degree relatives were analysed and as a result the standardised mortality ratios (SMRs) exhibit only 50% of the excess mortality from familial hypercholesterolaemia. We observed 190 deaths in 32048 person-years leading to an overall SMR of 1.34 (95% confidence interval (CI) 1.16–1.55, P=0.001). High excess mortality occurred in males between age 40 and 54 (SMR 2.34, 95% CI 1.60–3.31, P<0.001). The excess mortality decreased during the last decades. This change of mortality over calendar time shows that additional risk factors modulate the mortality from the disorder. The SMR of 62 families referred with premature CAD was 1.62 (95% CI 1.32–1.93, P<0.001) and the SMR was 1.10 (95% CI 0.86–1.34, P=0.4) in 51 families without premature CAD. The mortality risk of kindreds with null alleles was similar to that of kindreds with other mutations. In conclusion, the burden of the untreated disorder occurred mainly among middle-aged males and was not influenced by the type of mutation. Additional risk factors increased excess mortality significantly and are highlighted by the presence of premature CAD among first-degree relatives. This underscores the need for active identification of all hypercholesterolaemic relatives of such patients.

Introduction

Familial hypercholesterolaemia is caused by mutations in the low-density lipoprotein receptor gene and has an autosomal dominant mode of inheritance with full penetrance from birth onwards [1], [2]. Mortality varies to a large extent among patients with heterozygous familial hypercholesterolaemia, even among carriers of an identical mutation [3], [4]. This suggests that additional risk factors contribute to excess mortality among patients with familial hypercholesterolaemia. Familial hypercholesterolaemia is strongly associated with coronary artery disease (CAD) [5], [6], [7], [8] and decreased life expectancy [3], [7], [9], [10], [11] in kindreds where family members presented with premature CAD. Routine measurement of serum cholesterol has facilitated the detection of familial hypercholesterolaemia in patients, irrespective of the onset of CAD. The present day mortality risk of these patients is, therefore, expected to vary with the origin of referral, i.e. hypercholesterolaemic patients with or without multiple familial risk factors for CAD [12].

Besides classical risk factors, the specific underlying molecular defect of the low-density lipoprotein receptor gene may also contribute to the variance of the susceptibility to CAD [13], [14]. About 700 different sequence variations in the low-density lipoprotein receptor gene have been identified [2], [15] and mutations that underlie null alleles produce a lipoprotein profile that is considered more atherogenic [14], [16], [17].

In the present study, we determined all cause mortality (standardised for age, gender and calendar time) in 113 kindreds with untreated familial hypercholesterolaemia in order to study whether additional risk factors for CAD and the presence of null alleles associate with the prognosis.

Section snippets

Probands

At an outpatients lipid clinic between July 1988 and December 1990, 51 patients with familial hypercholesterolaemia were referred by general practitioners, 39 by cardiologists, 19 by other specialists, and four patients were detected by examination at the request of insurance companies. In these 113 unrelated and untreated patients, familial hypercholesterolaemia was clinically diagnosed after twelve weeks of eucaloric dietary intervention [18], based on mean fasting total serum cholesterol ≥8

Results

The mean fasting total serum concentration of cholesterol was 11.04 mmol/l (range, 8.09–17.78 mmol/l) and triglycerides 1.72 mmol/l (range, 0.69–2.98 mmol/l) and tendon xanthomas were found in 66 (58%) of the index patients.

A total of 190 deaths was observed in 32 048 person-years (Table 1); 97% of the deaths took place after 1945. The lifelong standardised mortality ratio of the relatives was 1.34 (95% CI 1.16–1.55, P=0.001). The standardised mortality ratio between 1935 and 1964 was 2.09 (95%

Discussion

In the present study, mortality was highest in families which were ascertained through cases with a premature onset of CAD. These families — in particular the male patients in middle age — had high excess mortality. This high excess mortality underscores that our results do not detract from the older finding of increased mortality in families in whom the disorder was clinically recognised. These old studies described a decreased life expectancy in families with familial hypercholesterolaemia

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Cited by (63)

Why patients with familial hypercholesterolemia are at high cardiovascular risk? Beyond LDL-C levels
2021, Trends in Cardiovascular Medicine
Citation Excerpt :
Available evidence indicates that a family history of CVD event in first-degree or second-degree relatives of FH patients and a personal history of previous CVD events in FH patients may confer a higher CVD risk. In a family-based study of CVD risk and its predictors in HeFH, the standardized mortality ratio in patients with a family history of premature coronary artery disease was significantly higher than that of patients with a negative family history [35]. In a recent time-dependent analysis assessing CVD risk in a cohort of 821 HeFH patients on lipid-lowering therapy, patients who developed a CVD event more often had a family history or a personal history of premature CVD [6].
Familial hypercholesterolemia (FH) is a common genetic cause of elevated low-density lipoprotein cholesterol (LDL-C) due to defective clearance of circulating LDL particles. All FH patients are at high risk for premature cardiovascular disease (CVD) events due to their genetically determined lifelong exposure to high LDL-C levels. However, different rates of CVD events have been reported in FH patients, even among those with the same genetic mutations and comparable LDL-C levels. Hence, additional CVD risk modifiers, beyond LDL-C, may contribute to increase CVD risk in the FH population. In this review, we discuss the overall CVD risk burden of the FH population. Additionally, we revise the prognostic impact of several traditional and emerging predictors of CVD risk and we provide an overview of the role of specific tools to stratify CVD risk in FH patients in order to ensure them a more personalized treatment approach.
Efficiency and problems of statin therapy in patients with heterozygous familial hypercholesterolemia
2019, Atherosclerosis Supplements
Familial hypercholesterolemia (FH) is associated with a very high risk of cardiovascular complications and the need for an early aggressive lipid-lowering therapy. The achievement of lipid target levels is often an extremely difficult task in these patients.
to analyze sex and age structure of ischemic heart disease (IHD) in patients with a definite, possible and probable FH. to assess the degree of achievement of low density lipoprotein cholesterol (LDL-C) target levels in FH patients on statin therapy and complications that occur during therapy; to analyze the adherence of FH patients to statin therapy and reveal the factors which have an influence on it.
The analysis of IHD clinical characteristics was performed in 253 FH patients from Karelian register, mean age 52.5 years (confidence interval, CI 22.0; 78.0). Using Dutch Lipid Clinic Network Criteria (DLCN), we established the diagnosis of FH as “definite” if the total number of points was more than eight, “probable” – if the number of points was 6–8, “possible” if the number of points was 3–5. The diagnosis was considered to be excluded if the score was less than three. A definite FH was diagnosed in 96 patients.
For the evaluation of target LDL-C levels achievement on statin therapy we analyzed data from 191 FH patients (75 males). For the evaluation of adherence to statin therapy Morisky-Green questionnaire was used in 93 definite FH patients.
In the group with a definite FH the incidence of IHD in the age range from 39 to 60 years was higher in women than in men (50% and 39.4%, p > 0.05), in patients older than 60 years IHD was observed in 66.7% of women and 50% of men (p > 0.05). In general, in the group with a definite FH, the frequency of IHD was more than three times higher in the age group over 40 years compared with patients under 40 years.
57% of patients with a definite FH were adherent to lipid-lowering therapy, 16% had partial adherence and no adherence to therapy was documented in 27% of patients. The achievement of LDL-C target levels was 19.2%: 22.6% in definite FH group and 12.5% in possible FH.
Smoking and gender were not associated with adherence to statin therapy. Associated factors with increased adherence to statin therapy were age (p = 0.000003), arterial hypertension (OR = 1.90 (1.02; to 3.55), p = 0.044), the history of IHD (OR = 2.99 (1.50; of 5.97) p = 0.002), myocardial infarction (OR = 5.26 (2.03; 13.60), p = 0.0006), myocardial revascularization (OR = 20.3 (2.64; 156.11), p = 0.004) and the fact of target LDL-cholesterol levels achievement (OR = 19.93 (7.03; 56.50), p < 0.0001).
The main reason for the non-acceptance of statin therapy for FH patients was the fear of side effects in 87%. The main reasons for stopping current statin intake were myalgia in 12%, an increase in transaminases in 35%, skin rashes in 12%, and high cost in 6%. 29% of patients had made the decision to stop therapy themselves.
the frequency of IHD in FH patients was more than three times higher in the age group over 40 years and was higher in women. In clinical practice statin therapy in FH patients rarely reaches target lipid values, one of the reasons was low adherence to statin therapy.
Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia
2018, Medical Hypotheses
High low-density-lipoprotein cholesterol (LDL-C) is routinely described as the main cause of cardiovascular disease (CVD) in familial hypercholesterolemia (FH). However, numerous observations are in conflict with Bradford Hill’s criteria for causality: a) degree of atherosclerosis is not associated with LDL-C; b) on average the life span of people with FH is about the same as for other people; c) LDL-C of people with FH without CVD is almost as high as in FH patients of the same age with CVD; and d) questionable benefit or none at all have been achieved in the controlled, randomized cholesterol-lowering trials that have included FH individuals only. Obviously, those individuals with FH who suffer from CVD may have inherited other and more important risk factors of CVD than high LDL-C. In accordance, several studies of FH individuals have shown that various coagulation factors may cause CVD. Equally, some non-FH members of an FH kindred with early CVD, have been found to suffer from early CVD as well. Cholesterol-lowering has only been successful in an animal experiment by using probucol, which has anticoagulant effects as well.
We conclude that systematic studies of all kinds of risk factors among FH individuals are urgently required, because today millions of people with FH are treated with statins, the benefit of which in FH is unproven, and which have many serious side effects.
We predict that treatment of FH individuals with elevated coagulation factors with anticoagulative drugs is more effective than statin treatment alone.
Indications for the use of PCSK9 inhibitors
2017, Revista Colombiana de Cardiologia
Los anticuerpos monoclonales anti PCSK9, evolocumab y alirocumab, representan un nuevo grupo de hipolipemiantes no-estatinas, destinados a conseguir reducciones significativas en el cLDL, específicamente en pacientes de alto riesgo cardiovascular que no logran las metas en el cLDL propuestas en la actualidad a pesar de cambios en el estilo de vida, tratamiento máximo tolerado de estatinas en monoterapia o combinadas con ezetimibe, así como en aquellos que son intolerantes o tienen contraindicación para el uso de estatinas pero que igualmente tienen alto riesgo de eventos cardiovasculares. La evidencia clínica demuestra que los i. PCSK9 son fármacos eficaces y seguros, que reducen los eventos cardiovasculares.
The anti-PCSK9 monoclonal antibodies evolocumab and alirocumab represent a new group of non-statin hypolipidemic medications targeted at achieving significant reductions in LDLc, specifically in patients with high cardiovascular risk who do not attain the currently recommended LDLc goals, despite lifestyle changes and a maximum tolerated dose of statins in monotherapy or combined with ezetimibe. They are also directed to patients with intolerance, or a contraindication, to the use of statins, but who also have a high risk of cardiovascular events. The clinical evidence shows that the PCSK9 inhibitors are effective and safe medications, and that they reduce cardiovascular events.
Cardiovascular Disease Risk Associated With Familial Hypercholesterolemia: A Systematic Review of the Literature
2016, Clinical Therapeutics
Citation Excerpt :
These articles are limited by ascertainment bias and a lack of generalizability. In the first study,25 the investigators evaluated 855 first-degree relatives of 113 patients who have a 50% probability of being affected, and they found that these patients are at increased risk of premature CVD. In the second study, Sijbrands et al examined the genealogy of 3 probands to a single pair of ancestors in the 19th century, then all first-degree relatives on the transmission line, finding 412 descendants, with 250 surviving ≥20 years.
The goal of this study was to determine cardiovascular disease (CVD) risk associated with familial hypercholesterolemia (FH).
A systematic review of the published literature was conducted. All publications describing FH risk from PubMed (“cardiovascular disease risk + familial hypercholesterolaemia,” 2004–2015), Internet and Medline search of FH registries, and associated references were screened for FH-related CVD risk in titles, abstracts, and study methods. CVD risk expressed as rates, odds, or ratios of mortality and morbidity were extracted. Each article was reviewed for bias by 2 reviewers within 17 items in 7 categories; a modified Newcastle-Ottawa assessment scale was used for nonrandomized studies.
The complete literature search identified 712 potential publications: 549 from PubMed (Medline), 150 from registries, and 13 from references. Fourteen articles met the inclusion criteria: 8 from registries in the United Kingdom, the Netherlands, Norway, and Spain; 5 from single hospitals or families in Japan, Denmark, the Netherlands, and the United Kingdom; and a population survey in Denmark. Across studies, attrition bias was low in 22 (80%) of 28 items. Risk of selection bias was high in 35 (63%) of 56 items. Selection bias risk was due to low representativeness and lack of a non-FH comparator group within the same study; detection bias risk was due to variable definitions of CVD outcomes/measurement; and performance bias risk was due to long-term, intensive treatment, the most common limitations for registries. Studies from single hospitals and families lacked generalizability. In contrast, the Danish study revealed a low bias in each of the 4 selection bias criteria and 2 attrition risk criteria. Fatal and nonfatal CVD events were collected in the study. Comparing patients with FH versus non-FH patients, the odds ratios for coronary artery disease were 10.3 (95% CI, 7.8–13.8) and 13.2 (95% CI, 10.0–17.4) in subjects treated and not treated with lipid-lowering therapy, respectively. These ratios fall within the ranges of ratios reported in other studies but are generally higher than the ratios from registries and clinics, in which intensive specialized management is available.
There is a lack of available data describing CVD risk in patients with FH, and many of the existing studies have biases in their design that could affect their risk estimates. A Danish study had the highest quality based on a predefined quality check list, providing the most credible estimates of the increase in CVD risk in patients with FH. The CVD risk due to FH is high and represents unmet medical need for patients with FH. Further research is warranted to validate the magnitude of risk.
Elevated lipoprotein(a), hypertension and renal insufficiency as predictors of coronary artery disease in patients with genetically confirmed heterozygous familial hypercholesterolemia
2015, International Journal of Cardiology
Familial hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol and increased risk of premature coronary artery disease (CAD). Lipoprotein(a) [Lp(a)] increases CAD in FH, although the independence of this association relative to other CAD risk factors remains unclear. In this study, we examined the association between Lp(a) and other cardiovascular risk factors and prevalent CAD in patients with FH.
A cross-sectional study of 390 patients with genetically confirmed FH were studied. Clinical and biochemical parameters of FH patients with and without CAD were compared.
FH patients with CAD were older and more often male and had a higher prevalence of hypertension, smoking, diabetes, obesity, reduced eGFR, and elevated plasma Lp(a) and pre-treatment LDL-cholesterol and triglyceride (or low HDL-cholesterol) than FH patients without CAD (P < 0.05 for all). In univariate analyses, age, male gender, smoking, hypertension, reduced eGFR, diabetes, obesity, plasma creatinine, Lp(a) and pretreatment LDL-cholesterol, triglycerides and HDL-cholesterol levels were significant predictors of CAD in the FH patients (P < 0.05 for all). Elevated LDL-cholesterol, raised Lp(a), hypertension and reduced eGFR remained significant independent predictors of CAD (P < 0.05 for all) in FH after adjusting for other modifiable risk factors.
Elevated Lp(a), hypertension and renal insufficiency are independent risk factors beyond elevated pretreatment LDL-cholesterol which predict CAD in patients with FH. In spite of the cross-sectional design of our study, we propose the need for identifying and managing these abnormalities to reduce excess CAD risk in FH patients. However, this proposal remains to be formally tested in a prospective study.

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Additional risk factors influence excess mortality in heterozygous familial hypercholesterolaemia

Abstract

Introduction

Section snippets

Probands

Results

Discussion

Atherosclerosis

Atherosclerosis

Am. J. Kidney Dis.

Metabolism

Lancet

Familial hypercholesterolemia

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia

Hum. Mutat.

Characteristic features of long-living patients with familial hypercholesterolemia in Japan

J. Am. Geriatr. Soc.

Angina pectoris in hereditary xanthomatosis

Arch. Int. Med.

Coronary artery disease in 116 kindred with familial type II hyperlipoproteinemia

Circulation

The risk of atherosclerotic vascular disease in subjects with xanthomatosis

Acta. Med. Scand.

Coronary heart disease and xanthoma tuberosum associated with hereditary hyperlipemia

Arch. Intern. Med.

Coronary disease in familial hypercholesterolemia

Circulation