European Heart Journal Advance Access originally published online on February 9, 2008
European Heart Journal 2008 29(6):826-827; doi:10.1093/eurheartj/ehn035
Familial aggregation of left main coronary artery disease and future risk of coronary events in asymptomatic siblings of affected patients
Emory University School of Medicine,
Atlanta, GA,
USA
Email: riyaz{at}doctors.org.uk
Emory University School of Medicine,
Atlanta, GA,
USA
Emory University School of Medicine,
Atlanta, GA,
USA
Emory University School of Medicine,
Atlanta, GA,
USA
We read with interest Fischer et al.'s1 recent paper on the heritability of angiographically diagnosed left main disease (LMD). They concluded that the presence of LMD in an index patient confers a three-fold increased risk of LMD in a sibling, confirming earlier findings of familial aggregation of location-specific coronary lesions.2 They further concluded that LMD, in a patient with myocardial infarction (MI), offers prognostic information on unaffected siblings over and above a family history of coronary artery disease (CAD).1
As one of the cohorts for recent genome-wide association studies, we have experienced first hand the difficulty with accurate phenotyping, especially for CAD.3,4 Atherosclerosis is a diffuse process, and coronary angiography may not always reveal the true burden of disease, especially if the vessel has undergone Glagov remodelling.5
The authors comment on and analyse LMD as a discrete entity, but clinical experience suggests that LMD is rarely an isolated phenomenon. More commonly, LMD occurs with significant CAD elsewhere in the coronary circulation. In our genetic registry of all patients passing through the catheter laboratory, we have over 2000 coronary angiograms available for analysis. Of the patients who had had an MI, we found 64 patients with LMD >50% diameter stenosis. Of these patients, those with LMD, in addition to one-vessel disease (VD), two-VD, and three-VD were 22%, 28%, and 45%, respectively (unpublished data). Only 5% had LMD alone. Fischer et al. do not address this distinction and in the absence of that data, we would argue that the heritability of LMD is actually a surrogate of heritability of severe CAD as manifested by the number of vessels involved. This would also explain the finding that relatives of LMD patients have a higher risk of developing an event, as they would have inherited a more severe underlying atherosclerotic process.
This paper raises important questions about the inheritance of CAD. The notion that disease is, in part, genetically driven to occur primarily in certain sites in families defies current evidence and our current understanding of the atherosclerotic process. Alternative explanations include the role of flow mechanics in the development of lesions especially in the proximal coronary tree.6 We know from an expanding evidence base that low-wall shear stress (WSS) contributes to plaque development in anatomically predisposed sites. It seems plausible then, that low WSS in anatomically identical vascular regions would lead to plaque development in the same sites. However, coronary anatomy is rarely identical, even in monozygotic twins7 and so this theory also fails to fully explain the rationale for site-specific coronary lesion inheritance.
In conclusion, we congratulate the authors on their important attempt to narrow the phenotype of coronary disease in order to make genetic studies more meaningful. However, we would argue from a pathophysiological perspective that a hereditary basis is more likely to explain underlying processes leading to atherosclerosis rather than a site-driven mechanism, which is difficult to link with established and accepted models of atherosclerosis.
References
- Fischer M, Mayer B, Baessler A, Riegger G, Erdmann J, Hengstenberg C, Schunkert H. Familial aggregation of left main coronary artery disease and future risk of coronary events in asymptomatic siblings of affected patients. Eur Heart J (2007) 28:2432–2437.
[Abstract/Free Full Text] - Fischer M, Broeckel U, Holmer S, Baessler A, Hengstenberg C, Mayer B, Erdmann J, Klein G, Riegger G, Jacob HJ, Schunkert H. Distinct heritable patterns of angiographic coronary artery disease in families with myocardial infarction. Circulation (2005) 111:855–862.
[Abstract/Free Full Text] - Helgadottir A, Manolescu A, Helgason A, Thorleifsson G, Thorsteinsdottir U, Gudbjartsson DF, Gretarsdottir S, Magnusson KP, Gudmundsson G, Hicks A, Jonsson T, Grant SF, Sainz J, O'Brien SJ, Sveinbjornsdottir S, Valdimarsson EM, Matthiasson SE, Levey AI, Abramson JL, Reilly MP, Vaccarino V, Wolfe ML, Gudnason V, Quyyumi AA, Topol EJ, Rader DJ, Thorgeirsson G, Gulcher JR, Hakonarson H, Kong A, Stefansson K. A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction [see comment]. Nat Genet (2006) 38:68–74.[Web of Science][Medline]
- Helgadottir A, Gretarsdottir S, St.Clair D, Manolescu A, Cheung J, Thorleifsson G, Pasdar A, Grant SF, Whalley LJ, Hakonarson H, Thorsteinsdottir U, Kong A, Gulcher J, Stefansson K, MacLeod MJ. Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet (2005) 76:505–509.[CrossRef][Web of Science][Medline]
- Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med (1987) 316:1371–1375.[Abstract]
- Soulis JV, Farmakis TM, Giannoglou GD, Louridas GE. Wall shear stress in normal left coronary artery tree. J Biomech (2006) 39:742–749.[CrossRef][Web of Science][Medline]
- Frings AM, Mayer B, Bocker W, Hengstenberg C, Willemsen D, Riegger GA, Schunkert H. Comparative coronary anatomy in six twin pairs with coronary artery disease. Heart (2000) 83:47–50.
[Abstract/Free Full Text]
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