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

Snapir, Amir; Mikkelsson, Jussi; Perola, Markus; Penttilä, Antti; Scheinin, Mika; Karhunen, Pekka J.

doi:10.1016/s0735-1097(02)02702-x

Cited by 102 publications

(64 citation statements)

References 11 publications

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“…19 Because our study was designed to assess sympathetic activation through ␣ 2 -AR blockade, individuals with cardiac morbidity, such as myocardial infarction, were excluded. Consistent with the results of Snapir et al, 15,16 our initial analysis of the 173 individuals who underwent testing with yohimbine revealed a decrease in Del/Del individuals aged 40 and older, suggesting a selection "bias" caused by the lack of healthy older individuals with that genotype, because individuals with Del/Del might have experienced premature mortality or been excluded because of previous cardiovascular disease. However, subsequent analysis in 2 larger groups of subjects, including those drawn from a large populationbased cohort with extreme values for BP, failed to confirm our initial conclusions from the smaller-sized population.…”

Section: Discussionsupporting

confidence: 87%

“…Evidence has been reported in a Finnish population that the deletion polymorphism, particularly Del/Del homozygosity, increases the risk for acute coronary events and sudden cardiac death. 15,16 Other data have provided possible mechanistic explanations for the impact of the Del/Del genotype on cardiovascular risk through increased vasoconstriction of the coronary vasculature, 17 endothelial dysfunction as defined by decreased flow Etzel et al Genetic Variation of the ␣ 2B -Adrenergic Receptormediated dilatation, 18 and association with obesity. 19 Because our study was designed to assess sympathetic activation through ␣ 2 -AR blockade, individuals with cardiac morbidity, such as myocardial infarction, were excluded.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…12 Common genetic variants in the ␣ 2 -ARs have been associated with cardiovascular pathology. 13 Homozygosity for a 9-bp in-frame deletion (Del) of 3 glutamic acid residues (Glu 301 to Glu 303 ) in the third intracellular loop of the ␣ 2B receptor, which leads to decreased agonist-stimulated desensitization, 14 has been associated with increased risk of myocardial infarction and sudden cardiac death, 15,16 vasoconstriction of the coronary vasculature, 17 endothelial dysfunction (as defined by decreased flow-mediated dilation) 18 and obesity. 19 Although some studies have found no association between this genotype and hypertension, 15,20 individuals homozygous for the deletion were reported to have increased risk for early-onset hypertension.…”

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confidence: 99%

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Genetic Variation at the Human α _2B -Adrenergic Receptor Locus

Etzel

Rana²,

Wen³

et al. 2005

Hypertension

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Abstract-Exaggerated response to ␣ 2 -adrenergic receptor (␣ 2 -AR) blockade by yohimbine in normotensive subjects is an intermediate phenotype that predicts increased risk for development of hypertension. Here, we assessed the 3 ␣ 2 -AR loci (␣ 2A, ␣ 2B, ␣ 2C ) as candidate genes for their influence on baseline and yohimbine-mediated increase in mean arterial pressure. Because initial results with 173 individuals implicated a possible association of yohimbine response with genetic variation at a site in the ␣ 2B -AR gene, but not at sites in the other 2 ␣ 2 -AR, we sequenced the ␣ 2B -AR gene (4.4 kb, including 1.2 kb upstream and 1.9 kb distal to the coding sequence) in those subjects and an additional 81 individuals to search for other ␣ 2B -AR variants. We identified 25 polymorphisms, of which 14 are previously unreported, and 2 major haplotypes that differ by the presence/absence of a 9-bp in-frame deletion that encodes Glu 301 to Glu 303 . Frequency differences in haplotypes were observed between blacks and whites but did not predict response to yohimbine. Genotyping of 2 additional white cohorts, including 1269 individuals with extremes in blood pressure selected from Ͼ50 000 subjects, also failed to reveal an association of the 2 major ␣ 2B -AR haplotypes with differences in blood pressure. Thus, despite considerable polymorphism in ␣ 2 -AR genes, such variation is not a major determinant of variability in yohimbine response and by inference, in susceptibility to essential hypertension. he sympathetic nervous system regulates cardiovascular physiology primarily by the release of catecholamines and activation of adrenergic receptors (AR). Multiple subtypes of ␣ 1 -, ␣ 2 -, and ␤-AR regulate cardiovascular cells and contribute to the pathophysiology of cardiovascular disease. 1 For example, heritable differences in ␣ 2 -AR subtypes have been implicated in human 2 and rodent 3 hypertension. The 3 ␣ 2 -AR subtypes in the human genome, ␣ 2A , ␣ 2B , and ␣ 2C , are located on separate chromosomes, expressed in different locations, and regulate different functional responses. 1,4 ␣ 2 -AR agonists have an antihypertensive effect that is primarily attributed to stimulation of central presynaptic receptors and a decrease in sympathetic activity 5 as a consequence predominantly of central ␣ 2A -AR. 6,7 ␣ 2C -AR also contributes to this response, especially at low levels of stimulation of nerve activity. 6 Although central inhibition of sympathetic outflow not does involve ␣ 2B -AR, the receptor may have a role in blood pressure (BP) through peripheral effects. Mice with a knockout of 1 copy of the ␣ 2B -AR are resistant to the development of salt-induced hypertension. 8 Moreover, the latter form of hypertension is partially dependent on neural mechanisms and expression of ␣ 2B -AR, because it can be treated by injection of antisense ␣ 2B receptor DNA into the cerebrospinal fluid. 9 It is unclear whether this salt-induced hypertensive effect is mediated by central ␣ 2B -AR or receptors in the periphery. Acti...

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Genetic Variation at the Human α _2B -Adrenergic Receptor Locus

Etzel

Rana²,

Wen³

et al. 2005

Hypertension

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“…A subsequent study in the same population examined the α 2B -adrenoreceptor insertion/deletion polymorphism, previously associated with increased risk for acute MI. The deletion/deletion genotype was associated with an increased risk for SCD when compared to subjects with the insertioninsertion genotype [53]. Another study by Anvari et al [54] examined the SCD impact of the plasminogen activator inhibitor type I (PAI-I) 4G/5G polymorphism.…”

Section: Intercellular Cell-to-cell Electrical Couplingmentioning

confidence: 99%

Genomics, heart failure and sudden cardiac death

Darbar

2008

Heart Fail Rev

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Sudden cardiac death (SCD) is among the most common causes of death in developed countries throughout the world. Despite decreased overall cardiac mortality, SCD vrates appear to be increasing in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. This unfavorable trend is a consequence of our inability to identify those who will die suddenly from lethal ventricular arrhythmias and to develop effective therapies for all populations at risk. The known risk factors for SCD lack the predictive power needed to generate preventive strategies for the large number of fatal arrhythmic events that occur among lowerrisk subsets of the population. Even among recognized high-risk subsets, prediction of SCD remains challenging. With the exception of the implantable cardioverter defibrillator (ICD) there are few effective strategies for the prevention and treatment of SCD. This article discusses the prospect of genomic science as an approach to the identification of patients at high-risk for SCD. While the final common pathway for SCD is malignant ventricular arrhythmias, there are many potential contributors, pathways, and mechanisms by which common genetic variants (polymorphisms) could affect initiation and propagation of life-threatening cardiac arrhythmias. Recent advances in genomic medicine now provide us with novel approaches to both identify candidate genes/pathways and relatively common polymorphisms which may predispose patients to increased risk for SCD. Improved understanding of the relationship between common polymorphisms and SCD will not only improve risk stratification such that ICDs can be targeted to those patients most likely to benefit from them but also provide new insight into the pathophysiology of SCD. KeywordsSudden cardiac death; Genomics; Heart failure; Single nucleotide polymorphisms Heart failure and SCD Heart failure (HF) afflicts approximately 5 million people in the United States, with 550,000 new cases reported annually, but as the population ages both the incidence and prevalence is expected to rise [1]. HF is associated with high mortality and is reportedly responsible for 300,000 deaths annually in the US [1]. Prior to advent of neuro-hormonal antagonists, the mean duration of survival after onset of HF was 1.7 years for men and 3.2 years for women, with only half of patients still alive after 5 years of onset [2]. The two modes of death in patients with HF are circulatory failure due to progressive left ventricular (LV) dysfunction associated with gradual worsening of symptoms, or sudden cardiac death (SCD) in relatively clinically stable patients [3].Although the proportion of sudden deaths in published trials varies significantly, probably due to varying interpretations of reported modes of death, clinical trials data suggests that SCD accounts for approximately one-third of all HF deaths [4]. Epidemiologic evidence from the Framingham heart study suggests that about one-half of all deaths due to HF occur...

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