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J Am Coll Cardiol, 2003; 41:190-194
© 2003 by the American College of Cardiology Foundation
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CLINICAL STUDY: CARDIAC ARREST AND PULMONARY EDEMA

Variation in the alpha2B-adrenoceptorgene as a risk factor for prehospitalfatal myocardial infarction and sudden cardiac death

Amir Snapir, MD*,*, Jussi Mikkelsson, MD, PhD{dagger}, Markus Perola, MD, PhD{ddagger}, Antti Penttilä, MD, PhD§, Mika Scheinin, MD, PhD* and Pekka J. Karhunen, MD, PhD{dagger}

* Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland
{dagger} Medical School, University of Tampere and Tampere University Hospital, Tampere, Finland
{ddagger} UCLA Department of Human Genetics, Gonda Neuroscience and Genetics Research Center, Los Angeles, California, USA
§ Department of Forensic Medicine, University of Helsinki, Helsinki, Finland

Manuscript received June 5, 2002; revised manuscript received September 23, 2002, accepted October 4, 2002.

* Reprint requests and correspondence: Dr. Amir Snapir, Department of Pharmacology and Clinical Pharmacology, University of Turku, Itäinen Pitkäkatu 4, FIN-20520 Turku, Finland.
snapir{at}utu.fi


   Abstract
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 Abstract
Methods
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 Discussion
 References
 
OBJECTIVES: Our aim was to corroborate the observed association between the deletion/deletion (DD) genotype of the insertion/deletion polymorphism in the alpha2B-adrenoceptor (AR) and increased risk for acute myocardial infarction (AMI), and to study whether this genotype also confers an increased risk for sudden cardiac death (SCD).

BACKGROUND: Vasospasm has been suggested to play a role in AMI. Alpha2-AR mediate coronary vasoconstriction in humans, and studies on mice suggest the involvement of the alpha2-AR subtype B in vasoconstriction. A deletion variant of the human alpha2B-AR has been associated with impaired receptor desensitization in vitro. In a population-based prospective study of 912 middle-aged men, the DD genotype of the alpha2B-AR conferred an increased risk for AMI.

METHODS: A series of 700 unselected sudden out-of-hospital deaths of middle-aged white men subjected to medico-legal autopsy was analyzed.

RESULTS: Genotype information was obtained for 683 men (DD = 22%, insertion/deletion = 51%, insertion/insertion = 27%). Carriers of the DD genotype had an increased risk for SCD (n = 278, odds ratio [OR] = 2.0, p = 0.01) and fatal AMI (n = 84, OR = 2.1, p = 0.04) compared with the other two genotypes combined. The risks for SCD and fatal AMI were higher in carriers of the DD genotype who died before the age of 55 years (OR = 4.5 and 5.0, p < 0.001 for both).

CONCLUSIONS: Middle-aged white men carrying the DD genotype of the alpha2B-AR have a significantly increased risk for SCD and AMI, especially before the age of 55 years.

Abbreviations and Acronyms
  AMI
  acute myocardial infarction
  AR
  adrenoceptor
  CHD
  coronary heart disease
  CI
  confidence interval
  DD
  deletion/deletion
  DNA
  deoxyribonucleic acid
  HSDS
  Helsinki Sudden Death Study
  ID
  insertion/deletion
  II
  insertion/insertion
  MI
  myocardial infarction
  OR
  odds ratio
  SCD
  sudden cardiac death

Sudden death is often the first symptom of coronary heart disease (CHD). In early middle age, when event mortality of acute myocardial infarction (AMI) is 40% to 45% and occurs mainly in the prehospital phase (1), sudden cardiac death (SCD) is often caused by coronary thrombosis (2). Vasoconstriction, occurring in normal coronary arteries or locally around a coronary plaque, has been suggested to trigger an acute coronary event (3). In vivo studies in humans have shown that alpha2-adrenoceptors (ARs) mediate constriction of large and small coronary arteries (4), an effect augmented by atherosclerosis (5). For a broader perspective on the role of alpha2-AR in coronary vasoconstriction and myocardial ischemia, and genetic determinants of coronary vasomotor tone in humans, review the studies by Heusch et al. (6,7). As the available pharmacologic ligands lack alpha2-AR subtype selectivity, it has been impossible to assign coronary vasoconstriction to an alpha2-AR subtype. As an alternative, molecular genetic techniques have been used to inactivate alpha2-AR subtype genes to establish mouse lines that are deficient in individual receptor subtypes. Results of these studies suggest that the alpha2A-AR mediates the central hypotensive effect of clonidine-like alpha2-AR agonists, and that the alpha2B-AR mediates peripheral vasoconstriction (8).

A variant form of the human alpha2B-AR gene encodes a receptor protein with deletion of three glutamate residues (9). Studies on transfected cells have revealed that this deletion variant manifests significantly impaired agonist-promoted receptor desensitization (10). In a recent population-based, prospective study of 912 middle-aged men, the deletion/deletion (DD) genotype was associated with an increased incidence of AMI in comparison to the other two genotypes (the adjusted risk ratio was 2.2) (11). Therefore, we hypothesized that the DD genotype of the alpha2B-AR confers an increased risk for SCD and prehospital fatal AMI in an unselected autopsy material representing out-of-hospital sudden deaths, and that the relative risk may be higher in younger men.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
To test this hypothesis, we carried out an analysis of 700 out-of-hospital deaths of white men between the ages of 33 and 70 years, who were subjected to medico-legal autopsy.

Study population.   The Helsinki Sudden Death Study (HSDS) is comprised of two consecutive series collected in 1981 to 1982, and 10 years later, in 1991 to 1992 (12). Medico-legal autopsy was conducted on all unexpected sudden deaths occurring outside of a hospital, often unwitnessed—unless the deceased had a clinically diagnosed condition with a high probability of causing an untimely and sudden demise, such as severe chronic heart failure. Thus, nearly all men age 33 to 70 years who suffered SCD outside hospital, and all prehospital first-attack AMI deaths in the population of the city of Helsinki during the study period are included in this study. Causes of death were cardiac causes in 41% (n = 288), of which 80% (n = 230) were due to CHD without critical valvular disease, significant non-ischemic cardiomyopathy, or other cardiac diseases; other diseases in 20% (n = 140); and suicides or accidents in 39% (n = 272). Characteristics of the study population are presented in Table 1. The study was approved by the Ethics Committee of the Department of Forensic Medicine, University of Helsinki.


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  		Table 1 Characteristics of the Deceased in Relation to Causes of Death

 
Characterization of cardiac pathology
The presence of myocardial infarction (MI) was confirmed by macroscopic and histologic examination of the myocardium. The presence of neutrophil granulocytes was considered diagnostic of an AMI and the presence of fibrous scar tissue diagnostic of an old MI. Based on autopsy findings and nitro blue tetrazolium staining, MI was classified as either transmural or nontransmural. Of the entire series of 700 men, 184 were found to have had MI. Eighty-five men were determined to have died of AMI with or without an old MI. Of the AMI deaths, 39 were associated with coronary thrombosis, of which 24 were acute. Old nonfatal MI scars without AMI were found in an additional 99 cases, of which a macroscopic organizing thrombus was observed in 14 cases. The AMI was transmural in 52% of the men under 55 years of age (n = 29) and in 42% of men older than 55 years of age (n = 55). Macroscopic coronary thrombosis was found in 89% of cases with transmural AMI, whereas the corresponding figure in nontransmural AMI was only 11%. The methods used in measuring coronary narrowing in silicone rubber casts (n = 670), direct measuring of areas of coronary atherosclerosis by morphometry (n = 512), and assessment of risk factors for CHD and SCD (n = 500) have been described in detail elsewhere (12).

Deoxyribonucleic acid (DNA) extraction and alpha2B-AR insertion/deletion genotyping
In the 1981 to 1982 series, DNA was extracted from paraffin-embedded samples of cardiac muscle, and in the 1991 to 1992 series DNA was isolated from frozen (–70°C) cardiac muscle samples. The method used to genotype the alpha2B-AR insertion/deletion polymorphism was based on polymerase chain reaction amplification and DNA electrophoresis, and has been described elsewhere (11).

Statistical analysis
Logistic regression was used to analyze interactions between the alpha2B-AR insertion/deletion variation and known risk factors for CHD. Analyses of the effect of genotype on the odds of AMI with and without thrombosis, and comparisons between acute thrombosis cases and other SCD victims, were based on logistic regression with and without the risk factor data. Analyses of atherosclerotic variables and stenosis percentage were based on one-way or multiple analysis of variance with covariates and with Bonferroni adjustments. The computations were carried out with STATISTICA/WIN (StatSoft Inc., Tulsa, Oklahoma) version 5.0 and SPSS (SPSS Inc., Chicago, Illinois) version 10 for Windows.


   Results
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 Methods
 Results
Discussion
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Genotype information was obtained for 683 men (98%). Of these, 152 (22%) carried the DD genotype, 186 (27%) had the insertion/insertion (II) genotype, and 345 (51%) were heterozygous. The genotype distribution was in Hardy-Weinberg equilibrium (p = 0.7) and is similar to the alpha2B-AR insertion/deletion variation genotype distribution that was observed previously in the Finnish population (11). No differences (p > 0.1) in major risk factors for CHD were found between the alpha2B-AR insertion/deletion variation genotype groups (Table 2). Multivariate analyses revealed that coronary narrowing percentages and areas of atherosclerotic lesions were similar in the DD and in the II + ID genotype groups (Table 3), suggesting that variation in this genetic locus was not involved in the development of coronary atherosclerosis.


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  		Table 2 Distribution of Conventional Risk Factors by Causes of Death and Genotype

 

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  		Table 3 Extent of Coronary Narrowing and Atherosclerotic Lesion Areas (Mean ± SD) in the Most Affected Artery Among Men With SCD and Men Who Died From Other Causes

 
The DD genotype was associated with an increased risk for SCD in logistic regression analysis: the adjusted odds ratio (OR) versus ID was 2.0 (95% confidence interval [CI] 1.1 to 3.7, p = 0.033), and the OR versus II was 2.1 (95% CI 1.1 to 4.0, p = 0.050). The DD genotype was also associated with an increased risk for prehospital fatal AMI: the OR versus ID was 2.4 (95% CI 1.1 to 5.1, p = 0.035), and the OR versus II was 1.8 (95% CI 1.0 to 3.7, p = 0.048). The ID and the II genotypes were not different with respect to odds of SCD (p = 0.74) and AMI (p = 0.95). Based on the ORs of SCD and AMI for the DD genotype in comparison with the II or the ID genotype groups, the similarity of the ID and II genotypes with respect to SCD and AMI, and the previously published findings (11), we also analyzed the data assuming a recessive inheritance model, now comparing the DD genotype with the ID + II genotypes combined. Also when this model was used, the DD genotype conferred an increased risk for SCD and AMI, especially for AMI without macroscopic thrombus (Table 4). The DD genotype conferred a considerably higher risk for SCD and AMI in a subpopulation of men who died suddenly before the age of 55 years (Table 4). This finding was similar when the data were analyzed with and without the risk factors, and in both HSDS cohorts, collected 10 years apart (12).


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  		Table 4 Alpha2B-Adrenoceptor Genotype Frequencies Among Men Who Died of Cardiac Diseases or Other Causes and the Corresponding Odds Ratios

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This study indicates that the DD genotype of the alpha2B-AR insertion/deletion variation confers an increased risk for SCD in white men, especially in men who died before the age of 55 years. This association seemed to be due mainly to the association of the DD genotype with nonthrombotic fatal prehospital AMI. This result confirms and extends our previous observation of an increased incidence of AMI in middle-aged men with the DD genotype (11).

Analysis of the coronary arteries revealed similar narrowing and other indices of atherosclerosis in the alpha2B-AR insertion/deletion variation genotype groups. Thus, our results suggest that the alpha2B-AR insertion/deletion polymorphism does not confer its increased risk for SCD and AMI through mechanisms related to progression of atheromatous coronary wall lesions.

The prognosis of prehospital cardiac arrest is currently relatively poor. Identification of factors predisposing to fatal arrhythmias in the acute phase of MI may help in preventing cardiac arrest and reducing early AMI mortality. Because no differences have been found in the anatomy and pathology of fatal and nonfatal AMI, factors that affect microvascular obstruction and ionic instability of the ischemic myocardium are likely to be important in predicting the fatality of an acute coronary event. Knowledge on these factors may help to improve our ability to lower the risk of SCD in high-risk individuals.

Our analysis did not disclose a mechanism by which the DD genotype confers an increased risk for SCD and AMI. However, taking into account the role of alpha2B-AR in vasoconstriction (8), and that rupture of atherosclerotic lesions can induce rapid and marked increases in distal vascular resistance due to severe microvascular constriction (13), our results may suggest that carriers of the DD genotype are particularly prone to vasoconstriction in the vicinity of preexisting stenotic lesions in the epicardial coronary arteries or spasm of small-caliber coronary branches nourishing the subendocardium. These mechanisms may then contribute to the severity and fatality of the ongoing coronary event.


   Footnotes
 
This study was supported by the Biomed 2 program of the European Union, the Academy of Finland, Turku University Hospital, the Yrjö Jahnsson Foundation, Pirkanmaa and Satakunta regional Funds of the Finnish Cultural Foundation, the Medical Research Fund of Tampere University Hospital, the Finnish Medical Society Duodecim, and the Aarne Koskelo Foundation. Dr. Perola was supported by an American Heart Association Western States Award, Ref.# 0120121Y.

Dr. Scheinin is a shareholder and board member in Juvantia Pharma Ltd., a drug discovery company. Drs. Snapir and Scheinin are coauthors on a filed patent application on the possible diagnostic and therapeutic use of the described alpha2B-AR gene variant.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Gillum RF. Sudden coronary death in the United States: 1980–1985. Circulation. 1989;79:756–765[Abstract/Free Full Text]
  2. Burke AP, Farb A, Malcom GT, Liang Yh, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997;336:1276–1282[Abstract/Free Full Text]
  3. Quyyumi AA, Panza JA, Diodati JG, Lakatos E, Epstein SE. Circadian variation in ischemic threshold: a mechanism underlying the circadian variation in ischemic events. Circulation. 1992;86:22–28[Abstract/Free Full Text]
  4. Indolfi C, Piscione F, Villari B, et al. Role of alpha 2-adrenoceptors in normal and atherosclerotic human coronary circulation. Circulation. 1992;86:1116–1124[Abstract/Free Full Text]
  5. Baumgart D, Haude M, Gorge G, et al. Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries. Circulation. 1999;99:2090–2097[Abstract/Free Full Text]
  6. Heusch G, Baumgart D, Camici P, et al. Alpha-adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation. 2000;101:689–694[Abstract/Free Full Text]
  7. Heusch G, Erbel R, Siffert W. Genetic determinants of coronary vasomotor tone in humans. Am J Physiol Heart Circ Physiol. 2001;281:H1465–1468[Free Full Text]
  8. Kable JW, Murrin LC, Bylund DB. In vivo gene modification elucidates subtype-specific functions of alpha 2-adrenergic receptors. J Pharmacol Exp Ther. 2000;293:1–7[Abstract/Free Full Text]
  9. Heinonen P, Koulu M, Pesonen U, et al. Identification of a three amino acid deletion in the alpha 2B-adrenergic receptor that is associated with reduced basal metabolic rate in obese subjects. J Clin Endocrinol Metab. 1999;84:2429–2433[Abstract/Free Full Text]
  10. Small KM, Brown KM, Forbes SL, Liggett SB. Polymorphic deletion of three intracellular acidic residues of the alpha 2B-adrenergic receptor decreases G protein-coupled receptor kinase-mediated phosphorylation and desensitization. J Biol Chem. 2001;276:4917–4922[Abstract/Free Full Text]
  11. Snapir A, Heinonen P, Tuomainen TP, et al. An insertion/deletion polymorphism in the alpha 2B-adrenergic receptor gene is a novel genetic risk factor for acute coronary events. J Am Coll Cardiol. 2001;37:1516–1522[Abstract/Free Full Text]
  12. Mikkelsson J, Perola M, Penttilä A, Karhunen PJ. Platelet glycoprotein Ibalpha HPA-2 Met/VNTR B haplotype as a genetic predictor of myocardial infarction and sudden cardiac death. Circulation. 2001;104:876–880[Abstract/Free Full Text]
  13. Taylor AJ, Bobik A, Berndt MC, Ramsay D, Jennings G. Experimental rupture of atherosclerotic lesions increases distal vascular resistance: a limiting factor to the success of infarct angioplasty. Arterioscler Thromb Vasc Biol. 2002;22:153–160[Abstract/Free Full Text]



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