The prevalence and prognostic importance of possible familial hypercholesterolemia in patients with myocardial infarction

doi:10.1016/j.ahj.2016.08.001

American Heart Journal

Volume 181, November 2016, Pages 35-42

https://doi.org/10.1016/j.ahj.2016.08.001 Get rights and content

Aims

Familial hypercholesterolemia (FH) is a common genetic disorder causing accelerated atherosclerosis and premature cardiovascular disease. The aim of this study was to examine the prevalence and prognostic significance of possible FH in patients with myocardial infarction (MI).

Methods and results

By individual-level linkage of data from the Eastern Danish Heart Registry and national administrative registries, a study population of patients referred for coronary angiography due to MI was selected. The study population was divided into “unlikely FH” and “possible FH” based on the Dutch Lipid Clinic Network criteria, which included a plasma low-density lipoprotein cholesterol (LDL-C) and age for onset of cardiac disease. A score of ≥3 points was used as the cutpoint between the 2 groups.

Among the study population of 13,174 MI patients, 1,281 (9.7%) had possible FH. These patients were younger (59.1 vs 65.7 years, P ≤ .0001), had similar levels of comorbidities, and were treated more aggressively with cholesterol-lowering drugs compared with patients with unlikely FH. During a median of 3.3 years of follow-up, the unadjusted and adjusted event rates of recurrent MI were higher in patients with possible FH compared with unlikely FH (16% vs 11%, adjusted hazard ratio 1.28, 95% CI 1.09-1.51, P = .003.). Differences in adjusted all-cause mortality were not statistically significant (17% vs 23%, adjusted hazard ratio 0.89 [0.74-1.04], P = .1).

Conclusion

We found that MI patients with possible FH have higher risk of recurrent MI but similar risk of mortality compared with unlikely FH patients. Further studies on secondary prevention are warranted.

Section snippets

Data sources

The data used in this study were gathered from multiple Danish registries and linked on individual-level by the unique civil registration number that every citizen in Denmark is given by birth or immigration to the country. Information on cardiac procedures was obtained through the Eastern Danish Heart Registry, which is a quality improvement registry that has been collecting data from all patients in eastern Denmark undergoing coronary angiography and percutaneous coronary intervention since

Baseline characteristics

Figure 1 shows the selection of patients for this study. We included 13,174 consecutive patients who were all referred for coronary angiography due to STEMI or NSTEMI. Most patients were included after 2005. Based on data obtained from the Eastern Danish Heart Registry, 1,281 had a DLCN score ≥3 points and hence a possible diagnosis of FH. The median LDL-C in the possible FH group was 5.3 mmol/L (IQR 5.0-5.9; corresponding to 205 mg/dL [IQR 193-228]), whereas it was 3.0 mmol/L (IQR 2.4-3.7;

Discussion

This study examined the prevalence, characteristics, and longitudinal outcomes of patients with MI and possible FH. The main findings included the following: approximately 9.7% of the consecutive acute MI patients had possible FH, probable FH, or definite FH. These patients were characterized by lower age and similar levels of comorbidity, yet similar severity and distribution of CAD. Patients with possible FH were treated more aggressively with cholesterol-lowering pharmacotherapy both before

Conclusions

In this study, we found that possible FH in individuals with MI was associated with a higher risk of recurrent MI compared with unlikely FH. A prevalence of 9.7% of possible FH was obtained in this large cohort of consecutive MI patients, but further research is needed to strengthen this estimate. Future studies on the effect of screening for FH and optimization of secondary prevention are warranted.

The following are the supplementary data related to this article.

Disclosures

Ms Rerup and Drs Bang, Engstrøm, Jørgensen, Pedersen, Gislason, James, Køber, and Fosbøl have no relevant disclosures to report. Dr Mogensen reports personal fees for lectures for Novo Nordisk and MSD. Dr Torp-Pedersen reports grant support from Cardiome, Merck, Sanofi, Daiichi-Sankyo, and BMS and personal fees from Cardiome, Merck, Sanofi, and Daiichi-Sankyo. Dr Hagström reports grant support from AstraZeneca, Amgen, and Zanofi.

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Cited by (35)

Prevalence of familial hypercholesterolaemia in patients presenting with premature acute coronary syndrome
2022, Archives of Cardiovascular Diseases
Familial hypercholesterolaemia (FH) is responsible for severe hypercholesterolaemia and premature cardiovascular morbidity and mortality. The first clinical event is typically an acute coronary syndrome. Unfortunately, FH is largely underdiagnosed in the general population.
To assess the prevalence of clinical FH among patients with premature (aged ≤ 50 years) acute myocardial infarction (MI) and compare it with FH prevalence in a control population.
We reviewed in our database all patients with premature MI (aged ≤ 50 years) referred to Ambroise Paré Hospital from 2014 to 2018. FH prevalence was estimated via the Dutch Lipid Clinic Network score, based on personal and family history of premature cardiovascular disease and low-density lipoprotein cholesterol concentrations. FH was “possible” with a score between 3 and 5 points, “probable” with a score between 6 and 8 and “definite” with a score above 8. FH prevalence in young patients with MI was then compared with FH prevalence in a general population of the same age from the CARVAR 92 prospective cohort.
Of the 457 patients with premature MI, 29 (6%) had “probable” or “definite” FH. In the CARVAR 92 cohort, 16 (0.16%) of 9900 subjects aged ≤ 50 years had “probable” or “definite” FH. FH prevalence was 39 times greater among patients with premature MI than in the control population (P < 0.0001). In multivariable analysis, FH was strongly associated with MI (adjusted odds ratio 38.4, 95% confidence interval 19.1–79.4).
FH is > 30-fold more common in patients referred for premature MI than in the general population; this highlights the need for FH screening after a first MI to enhance lipid-lowering therapy and allow early identification of family members.
L’hypercholestérolémie familiale est responsable d’une hypercholestérolémie sévère et d’une morbi-mortalité cardiovasculaire prématurée. Malheureusement, l’hypercholestérolémie est largement sous-diagnostiquée.
L’objectif était de calculer la prévalence de l’hypercholestérolémie familiale (HF) clinique parmi des patients ayant fait un infarctus du myocarde (IDM) avant 50 ans et de la comparer à la prévalence de l’HF dans la population générale.
Les patients < 50 ans admis pour un IDM au CHU Ambroise Paré entre 2014 et 2018 ont été inclus. La prévalence de l’HF a été calculée en utilisant le score de Dutch incluant les antécédents personnels et familiaux de maladie cardiovasculaire prématurée et le taux de LDL cholestérol. L’HF était « possible » avec un score entre 3 et 5, « probable » avec un score entre 6 et 8 et « certaine » avec un score supérieur à 8. La prévalence de l’HF chez ces jeunes coronariens était ensuite comparée à la prévalence dans une population contrôle du même âge, issue de la cohorte CARVAR 92.
Parmi les 457 patients admis pour un IDM précoce, 29 (6 %) avaient une HF « probable » ou « certaine ». Dans la cohorte CARVAR 92, 16 (0,16 %) parmi 9900 sujets < 50 ans avaient une HF « probable » ou « certaine ». La prévalence de l’HF était 39 fois plus grande chez les jeunes coronariens que dans la population contrôle (p < 0,0001). En analyse multivariée, l’HF était fortement associée à la survenue d’un IDM précoce (aOR 38,4, IC95 % 19,1–79,4).
L’HF est > 30 fois plus fréquente chez les patients admis pour un IDM prématuré qu’en population générale.
Outcomes of Acute Myocardial Infarction in Patients with Familial Hypercholesteremia
2021, American Journal of Medicine
There is a paucity of contemporary data regarding the outcomes of acute myocardial infarction among patients with familial hypercholesteremia.
We queried the Nationwide Readmissions Database (2016-2018) for hospitalizations with acute myocardial infarction. Multivariable regression analysis was used to compare in-hospital outcomes and 30-day readmissions among patients with and without familial hypercholesteremia.
The analysis included 1,363,488 hospitalizations with acute myocardial infarction. The prevalence of familial hypercholesteremia was 0.07% among acute myocardial infarction admissions. Compared with those without familial hypercholesteremia, admissions with familial hypercholesteremia were younger and had less comorbidities but were more likely to have had prior infarct and revascularization. Admissions with familial hypercholesteremia were more likely to present with ST-elevation myocardial infarction and undergo revascularization. After multivariable adjustment, there was no difference in in-hospital case fatality among patients with hypercholesteremia compared with those without it (adjusted odds ratio [aOR] = 0.76; 95% confidence interval [CI] 0.41-1.39). Admissions with acute myocardial infarction and familial hypercholesteremia had higher adjusted rates of cardiac arrest and utilization of mechanical support. There were no group differences in overall 30-day readmission (aOR 0.75; 95% CI 0.51-1.10) or 30-day readmission for acute myocardial infarction. However, a nonsignificant trend toward higher readmission for percutaneous coronary intervention was observed among patients with familial hypercholesteremia (aOR 1.89; 95% CI 0.98-3.64).
In this contemporary nationwide observational analysis, patients with familial hypercholesteremia represent a small proportion of the overall population with acute myocardial infarction and have a distinctive clinical profile but do not appear to have worse in-hospital case fatality compared with those without familial hypercholesteremia.
2.5-fold increased risk of recurrent acute myocardial infarction with familial hypercholesterolemia
2021, Atherosclerosis
Citation Excerpt :
In this large prospective cohort study, we found that after an incident AMI, the long-term mortality was increased by 45%, and the risk of recurrent AMI was 2.5-fold increased during 17 years of follow-up in individuals with genetically verified FH compared with controls. These results in 232 individuals with genetically verified FH who had experienced a first-time AMI support and extend (with 17 years of follow-up) previous results in individuals with probable FH [7,8,14–19]. Rerup and co-workers found that individuals with probable FH had a 1.28-fold increased risk of recurrent AMI after a median of 3.3 years of follow-up [8], whereas Danchin and co-workers found a 2.2-fold increased risk of the combined outcome death or recurrent major cardiovascular events after 5 years of follow-up in probable FH [7].
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.
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.
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.
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.
Estimating the Prevalence of Familial Hypercholesterolemia in Acute Coronary Syndrome: A Systematic Review and Meta-analysis
2019, Canadian Journal of Cardiology
Citation Excerpt :
Notably, the cohorts with the 2 highest reported prevalence values out of the 17 studies were those in which the eligibility criteria included patients ≤ 35 years.26,34 For comparison, we assessed the pooled prevalence of all studies for which no upper age limit was specified in the eligibility criteria.20,23-25,28-31,35 Based on these 9 studies, the pooled prevalence in the absence of an upper age restriction was 2.7% (95% CI, 1.6-4.6; range 0.4% to 6.9%) (Supplemental Fig. S4), significantly lower than the value for cohorts that were limited to patients aged ≤ 45 years.
Heterozygous familial hypercholesterolemia (FH) is one of the most common monogenic conditions but remains substantially underdiagnosed. One method for increasing the diagnosis is via opportunistic screening of individuals presenting with acute coronary syndrome (ACS). The prevalence of FH in the ACS population has been assessed in numerous studies using various diagnostic criteria, resulting in wide variability of prevalence estimates. The purpose of this study was to perform a systematic review and meta-analysis to provide a more robust estimate.
We searched MEDLINE, EMBASE, Pubmed, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews to identify peer-reviewed articles reporting the prevalence of FH in ACS. We calculated pooled prevalence using a random-effects model. When multiple diagnostic criteria were used in a single study, we gave priority to DNA-based criteria, followed by Dutch Lipid Clinic Network (DLCN) criteria. We also investigated the prevalence in subanalyses according to age and diagnostic criteria.
The overall pooled prevalence of FH in ACS, derived from 22 studies, was 4.7% (95% confidence interval [CI], 3.0-7.3). DNA-based criteria and DLCN criteria provided similar estimates of 5.0% (95% CI, 2.6-9.3) and 5.5% (95% CI, 3.0-10.0), respectively. The prevalence was 7.3% (95% CI, 5.3-10.0) for patients aged ≤ 60 years and increased to 13.7% (95% CI, 8.2-22.1) for those aged ≤45 years.
Approximately 1 in 21 patients with ACS has FH, and this increases to 1 in 7 among those ≤45 years. These results reinforce the importance of screening for FH in the ACS population.
L’hypercholestérolémie familiale hétérozygote est l’une des affections monogéniques les plus fréquentes, mais elle demeure nettement sous-diagnostiquée. L’une des méthodes permettant de favoriser son diagnostic est le dépistage opportuniste des personnes consultant pour un syndrome coronarien aigu (SCA). La prévalence de l’hypercholestérolémie familiale hétérozygote chez la population présentant un SCA a été évaluée dans de nombreuses études à l’aide de divers critères diagnostiques, donnant lieu à une importante variabilité de la prévalence estimée. L’objectif de cette étude était de réaliser un examen systématique et une méta-analyse afin d’obtenir une estimation plus solide.
Nous avons mené des recherches dans les bases de données MEDLINE, EMBASE, Pubmed, Cochrane Central Register of Controlled Trials et Cochrane Database of Systematic Reviews afin d’y trouver des articles révisés par des pairs indiquant la prévalence de l’hypercholestérolémie familiale hétérozygote en présence d’un SCA. À l’aide d’un modèle à effets aléatoires, nous avons calculé la prévalence à partir des données groupées. Lorsque plusieurs critères diagnostiques étaient utilisés dans la même étude, nous avons privilégié les critères fondés sur l’ADN, puis les critères du Dutch Lipid Clinic Network (DLCN). Nous avons aussi évalué la prévalence dans des sous-analyses effectuées en fonction de l’âge et des critères diagnostiques.
La prévalence globale de l’hypercholestérolémie familiale hétérozygote en présence d’un SCA selon les données groupées de 22 études a été de 4,7 % (intervalle de confiance [IC] à 95 % : de 3,0 à 7,3). Les critères fondés sur l’ADN et les critères du DLCN ont donné des estimations similaires, soit 5,0 % (IC à 95 % : de 2,6 à 9,3) et 5,5 % (IC à 95 % : de 3,0 à 10,0), respectivement. La prévalence était de 7,3 % (IC à 95 % : de 5,3 à 10,0) chez les patients âgés de ≤ 60 ans et passait à 13,7 % (IC à 95 % : de 8,2 à 22,1) chez les patients âgés de ≤ 45 ans.
Environ 1 patient sur 21 présentant un SCA était atteint d’hypercholestérolémie familiale hétérozygote, cette prévalence passait à 1 sur 7 chez les patients de ≤ 45 ans. Ces résultats soulignent l’importance du dépistage de l’hypercholestérolémie familiale hétérozygote chez la population présentant un SCA.
The prevalence and management of familial hypercholesterolemia in patients with acute coronary syndrome in the Polish tertiary centre: Results from the TERCET registry with 19,781 individuals
2019, Atherosclerosis
The prevalence of familial hypercholesterolemia (FH) is high among patients with stable coronary artery disease (CAD). However, data on FH on admission among patients with acute coronary syndrome (ACS) are still relatively scarce. Therefore, we aimed to assess the prevalence, lipid-lowering therapy and short- and long-term outcomes in patients with FH among ACS patients.
The investigation was performed in a cohort of 19,781 consecutive patients from the TERCET Registry. There were 7319 patients admitted with ACS: 3085 due to STEMI, 2256 due to NSTEMI, and 1978 due to UA. The stable CAD group (n = 12,462) was considered the reference group. Based on the personal and familial history of premature cardiovascular disease and LDL cholesterol concentration, the Dutch Lipid Clinic Network (DLCN) algorithm was used for FH diagnosis.
The overall occurrence of probable/definite FH and possible FH was 1.2% and 13.5% respectively. Among patients with ACS, 1.6% had probable/definite FH and 17.0% possible FH. The highest occurrence of FH was observed in the STEMI subgroup (20.6%). Patients with definite and probable FH had higher 30-day mortality than patients without FH (8.2% and 3.8% vs. 2.0%, respectively; p = 0.0052). No significant differences were observed between the FH groups in the 12-, 36- and 60-month follow-up. Propensity-score matching analysis showed that definite/probable FH patients had significantly higher all-cause mortality at 36- and 60-month follow-up in comparison to non-FH subjects (11.4% vs. 4.8% and 19.2% vs. 7.2%, respectively; p ≤ 0.021 for both).
The prevalence of FH according to the DLCN criteria in the Polish very high-risk population is significantly higher in patients with ACS than in patients with sCAD. FH is a cause of increased all-cause mortality in the long-term follow-up.
High burden of recurrent cardiovascular events in heterozygous familial hypercholesterolemia: The French Familial Hypercholesterolemia Registry
2018, Atherosclerosis
Cardiovascular risk is high in heterozygous familial hypercholesterolemia (HeFH). The objective of this study was to describe recurrent cardiovascular events in selected patients with HeFH attending lipid clinics in France.
We included 781 patients with a clinical (Dutch Lipid Clinic Network score ≥ 6) or genetic diagnosis of HeFH who had experienced a first cardiovascular event (myocardial infarction, percutaneous coronary intervention or coronary bypass, unstable angina, stroke, peripheral arterial revascularization or cardiovascular death) and were enrolled in the French Familial Hypercholesterolemia Registry (November 2015 to March 2018).
The first cardiovascular event occurred at the mean age of 47 years (interquartile range 39–55) in a predominantly male population (72%); 48% of patients were on statin therapy. Overall, 37% of patients had at least one recurrent cardiovascular event (mean of 1.8 events per patient), of which 32% occurred in the 12 months after the index event; 55% of events occurred >3 years after the first event. Mean LDL-C at the last clinic visit was 144 ± 75 mg/dL (132 ± 69 mg/dL for patients on high-potency statin therapy and 223 ± 85 mg/dL for untreated patients).
The rate of recurrent cardiovascular events was high in French patients with HeFH in secondary prevention. The detection of FH during childhood is crucial to prevent CV events at a young age by early initiating statin therapy. There is a clear urgent need to expand the actual very small target population which can be treated with the PCSK9 inhibitor in France.

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Clinical InvestigationThe prevalence and prognostic importance of possible familial hypercholesterolemia in patients with myocardial infarction

Aims

Methods and results

Conclusion

Section snippets

Data sources

Baseline characteristics

Discussion

Conclusions

Disclosures

Am J Cardiol

Atherosclerosis

Am J Cardiol

J Am Coll Cardiol

Atherosclerosis

Eur J Intern Med

Atherosclerosis

Am Heart J

Familial hypercholesterolemia and coronary heart disease: a HuGE association review

Am J Epidemiol

Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review

Am J Epidemiol

Clinical Investigation
The prevalence and prognostic importance of possible familial hypercholesterolemia in patients with myocardial infarction