Myocardial infarction, familial

Last update: December 4, 2018

Recommended panel testing at Breda Genetics for this condition:

Myocardial Infarction, familial (ABCG5, ABCG8, APOE, LRP6, LDLR, APOB, PCSK9, ACTC1, CALR3, CAV3, CSRP3, GLA, JPH2, LAMP2, LIPA, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, NEXN, PLN, PRKAG2, SLC25A4, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL)

blue heart with blue DNA pills

Summary

Cardiovascular disease is the leading cause of death in both developed and developing countries, with an yearly incidence rate of myocardial infarction (heart attack) of approximately 300-600 cases per 100,000 people. The causes of myocardial infarction may be subdivided in two large groups: (1) atherosclerosis and (2) non-atherosclerotic causes. Genetically determined conditions with clear mendelian inheritance may be found in both groups (although most cases of myocardial infarction are not attributable to a genetic disease). In this review we’ll consider just those non-syndromic genetic conditions where myocardial infarction (and its underlying predisposing factors like, for instance, ventricular hypertrophy or dyslipidemia) may be the sole clinical features in patients otherwise healthy and asymptomatic and in whom a genetic mutation might therefore not be initially suspected. The presence of such mutations should be considered especially in families where early-onset myocardial infarction is recurrent accross generations. As both autosomic dominant (with or without incomplete penetrance) and autosomic recessive phenotypes may appear, it is worth to consider pedigrees with any type of segregation.

 

Artery clogged with red cells due to cholesterol plaques

Detailed clinical description

Atherosclerotic causes

Atherosclerosis is the primary cause of most acute coronary syndrome cases. Approximately 90% of myocardial infarctions result from an acute thrombus that obstructs an atherosclerotic coronary artery. Plaque rupture and erosion are considered to be the major triggers for coronary thrombosis.

Certain factors contribute to the unwanted buildup of fatty deposits (atherosclerosis) that narrows arteries throughout the body: age (men age 45 or older and women age 55 or older are more likely to have a heart attack than are younger men and women), tobacco, high blood pressure, hypercholesterolemia and hypertriglyceridemia, diabetes, family history of early heart attack (by age 55 for male relatives and by age 65 for female relatives), lack of physical activity, obesity (losing just 10 percent of the body weight can lower this risk), stress, illegal drug use (cocaine and amphetamines), history of preeclampsia (high blood pressure during pregnancy), and  autoimmune conditions (rheumatoid arthritis or lupus).

Non-syndromic or pauci-syndromic genetic diseases that cause atherosclerosis typically involve lipoprotein metabolism (inherited lipoprotein disorders): familial hypercholesterolemia (caused by mutation in the LDLR, APOB, or PCSK9 gene), APOE p.Leu167del-related lipid disorders, autosomal dominant coronary artery disease 2 (LRP6 gene) and sitosterolemia (ABCG5 and ABCG8 mutation). Cholesteryl Ester Storage Disease (CESD) is at the milder of the LIPA gene mutation phenotypic spectrum and shows a very wide clinical variability, ranging from early onset involvement with severe cirrhosis to later onset manifestations with more slowly progressive hepatic disease and survival into adulthood. Accumulation of neutral fats and cholesterol esters in the arteries predispose CESD affected persons to atherosclerosis. Hepatic lipase deficiency (LIPC gene mutations) is characterized by abnormally triglyceride-rich low and high density lipoproteins as well as beta-migrating very low density lipoproteins. Patients with hepatic lipase deficiency have been found to possibly develop angina pectoris in their forties. They also may have eruptive and palmar xanthomas. Some LIPC common polymorphisms have also been associated to variation in high density lipoprotein cholesterol levels (in particular with elevation of LDL or lower levels of HDL).

Also some other genetic syndromes can be characterized by lipoprotein disorders and atherosclerosis, although the presence of major particular features (e.g. dysmorphisms and/or onset of cardiac disease in infancy) makes such syndromes more readily recognizable.

Nonatherosclerotic causes

normal heart anatomyNonatherosclerotic causes of myocardial infarction include the following: coronary occlusion secondary to vasculitis, ventricular hypertrophy (e.g., left ventricular hypertrophy, idiopathic hypertrophic subaortic stenosis [IHSS], underlying valve disease), coronary artery emboli, secondary to cholesterol, air, or the products of sepsis, congenital coronary anomalies (like coronary artery tortuosity), aneurysms of coronary arteries, coronary trauma, primary coronary vasospasm, drug use (eg, cocaine, amphetamines, ephedrine), arteritis, factors that increase oxygen requirement, such as heavy exertion, fever, or hyperthyroidism, factors that decrease oxygen delivery, such as hypoxemia of severe anemia, aortic dissection, with retrograde involvement of the coronary arteries, infected cardiac valve through a patent foramen ovale (PFO), significant gastrointestinal bleed. Amongst all above causes, ventricular hypertrophy may be genetic in some cases (hereditary hypertrophic cardiomyopathy: ACTC1, CALR3, CAV3, CSRP3, GLA, JPH2, LAMP2, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, NEXN, PLN, PRKAG2, SLC25A4, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, or VCL gene mutation).

Summarizing, in some families with recurrent myocardial infarction in early adulthood or youth it may be worth to consider the presence of a genetic mutation as the cause of an atheroschelrotic or non-atherosclerotic condition which has favoured the buildup of fatty deposits or triggered myocardium hypoxia. Preliminary investigations should include a biochemical screening of lipid blood levels as well as cardiac imaging (echocardiography). Molecular genetic testing for familial recurrent myocardial infarction may include a panel with a following genes: the ABCG5, ABCG8, APOE, LRP6, LDLR, APOB, PCSK9, ACTC1, CALR3, CAV3, CSRP3, GLA, JPH2, LAMP2, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, NEXN, PLN, PRKAG2, SLC25A4, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, and VCL.

Recommended testing workflow

To test for genetic conditions which may predispose to myocardial infarction, testing an extended panel of genes based on clinical exome sequencing (6,000 genes) is recommended. Recommended panel testing at Breda Genetics for this condition:

Myocardial Infarction, familial (ABCG5, ABCG8, APOE, LRP6, LDLR, APOB, PCSK9, ACTC1, CALR3, CAV3, CSRP3, GLA, JPH2, LAMP2, LIPA, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, NEXN, PLN, PRKAG2, SLC25A4, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL)

References

Familial Hypercholesterolemia. Youngblom E, Pariani M, Knowles JW. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2014 Jan 2 [updated 2016 Dec 8]. PMID: 24404629

Genetics of coronary artery disease and myocardial infarction. Dai X, Wiernek S, Evans JP, Runge MS. World J Cardiol. 2016 Jan 26;8(1):1-23. PMID: 26839654

Sitosterolemia. Merkens LS, Myrie SB, Steiner RD, Mymin D. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2013 Apr 4 [updated 2018 May 17]. PMID: 23556150

APOE p.Leu167del-Related Lipid Disorders. Greyshock N1, Guyton JR1, Sebastian S2, Okorodudu D1. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2014 Jun 12. PMID: 24921113

The diagnosis and treatment of hypertrophic cardiomyopathy. Prinz C, Farr M, Hering D, Horstkotte D, Faber L. Dtsch Arztebl Int. 2011 Apr;108(13):209-15. PMID: 21505608

Lysosomal Acid Lipase Deficiency. Hoffman EP, Barr ML, Giovanni MA, Murray MF. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2015 Jul 30 [updated 2016 Sep 1]. PMID: 26225414

 

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