European Heart Journal Advance Access originally published online on February 9, 2008
European Heart Journal 2008 29(6):827-828; doi:10.1093/eurheartj/ehn014
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Familial aggregation of left main coronary artery disease and future risk of coronary events in asymptomatic siblings of affected patients: reply
Klinik und Poliklinik für Innere Medizin II
Universität Regensburg
Franz-Josef-Strauss Allee 11
93053 Regensburg
Germany
Email: marcus.fischer{at}klinik.uni-regensburg.de
Medizinische Klinik II
Universität Schleswig-Holstein, Campus Lübeck
Ratzeburger Allee 160
23538 Lübeck
Germany
Email: heribert.schunkert{at}innere2.uni-regensburg.de
We thank Dr Patel et al. for their kind interest in our manuscript. Indeed, we agree with the authors that manifestation of atherosclerosis is anatomically diffuse and as such modulated by several, including heritable, risk factors. Also, their notion that left main disease (LMD) is rarely an isolated phenomenon but rather occurs in addition to disease manifestation at other branches of the coronary tree is concordant with our results. Based on their clinical observations, Dr Patel et al. argue that the heritability of LMD is a surrogate of heritability of severe coronary artery disease (CAD) rather than a result from distinct heritable predisposition. They further conclude that coincidence of LMD and severe CAD may explain our finding that relatives of LMD patients have a higher risk of developing incident cardiovascular events, as they might have inherited a more severe underlying atherosclerotic process.1
In fact, we considered such line of thoughts in our initial analysis.2 However, in contrast to LMD, we did not find significant heritability estimates for the existence of 1-, 2-, or 3-vessel CAD.2 Moreover, surrogate phenotypes of CAD severity, like the number of stenoses or the Gensini index seemed not to be markedly influenced by genetic factors.2 Interestingly, similar observations come from analyses of other traditional risk factors, as it is generally well perceived that they may affect one or the other vascular bed with specific preference.3 Unfortunately, our subgroup of subjects with LMD is too small to allow meaningful statistical analysis considering further coronary phenotypes as covariates particularly in terms of estimating heritability.1
Also, we believe that the mechanism proposed by Dr Patel et al. falls short explaining the higher event rates in relatives of LMD. Indeed, the group used for comparison consisted of individuals who had at least two siblings with evidence of CAD including one with myocardial infarction—but no family history of LMD.1 Moreover, with the exception of LMD, there was no difference in the distribution of the number of vessels involved in relatives of siblings with known coronary morphology, who experienced myocardial infarctions during follow-up when compared with those relatives of siblings who remained asymptomatic (data not shown). Regrettably, we have no evidence of disease localization in prospectively observed, initially unaffected siblings of CAD patients, of whom many died suddenly.
Finally, Dr Patel et al. consider alternative explanations for the heritability of LMD including flow mechanics in the development of lesions, i.e. arterial wall shear stress. Indeed, it may be plausible that low shear stress in anatomically identical vascular regions would lead to plaque development in such sites. Our previous analysis revealed low if not absent concordance rates for the predominance of coronary blood supply even in monozygotic twins.4 Thus, as already mentioned by Dr Patel et al., this theory does not explain the relatively high LMD inheritance. Of interest in this regard might be the particular ontogenetic determination of this proximal site that is distinct from more distal parts of the coronary artery.2
Future studies including genome-wide associations may shed further light on the inherited factors for CAD in general and LMD in particular. From our perspective, we kindly invite Dr Patel and coworkers for combining their and our respective analyses for addressing these pertinent questions.5
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] - Espinola-Klein C, Rupprecht HJ, Blankenberg S, Bickel C, Peth S, Kopp H, Victor A, Hafner G, Meyer J. Manifestations of atherosclerosis in various vascular regions. Similarities and differences regarding epidemiology, etiology and prognosis. Med Klin (2002) 97:221–228.[CrossRef][Web of Science]
- Frings AM, Mayer B, Böcker 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] - Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, Dixon RJ, Meitinger T, Braund P, Wichmann HE, Barrett JH, König IR, Stevens SE, Szymczak S, Tregouet DA, Iles MM, Pahlke F, Pollard H, Lieb W, Cambien F, Fischer M, Ouwehand W, Blankenberg S, Balmforth AJ, Baessler A, Ball SG, Strom TM, Braenne I, Gieger C, Deloukas P, Tobin MD, Ziegler A, Thompson JR, Schunkert H., WTCCC and the Cardiogenics Consortium. Genomewide association analysis of coronary artery disease. N Engl J Med (2007) 357:443–453.
[Abstract/Free Full Text]
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