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ACE POLYMORPHISM LINKED TO ARDS RISK
LONDON—Because angiotensin-converting enzyme (ACE) affects pulmonary vascular tone and permeability, survival of epithelial cells, and fibroblast activation, it could play a role in the etiology of acute respiratory distress syndrome (ARDS). A recent study showed that patients homozygous for a genetic polymorphism conferring elevated ACE activity were at much higher risk for developing ARDS than were the general population or other intensive care unit (ICU) or surgical patients.[1] Furthermore, among ARDS patients, the genotype was significantly associated with mortality.
ARDS remains a major cause of death, yet factors contributing to the syndrome have not yet been clearly identified. During its early stages, ARDS may include high-permeability pulmonary edema, loss of alveolar epithelial cells, and neutrophil infiltration. This may lead to remodeling of the alveoli and interstitium.
Experimental findings suggested that activation of a renin-angiotensin system in the lung could mediate changes in vascular tone and permeability, fibroblast activity, and epithelial cell survival. Thus, variations in the renin-angiotensin system could be crucial in ARDS etiology. Furthermore, ARDS patients show increased pulmonary ACE activity. Because genotypic differences can account for 45% of the variance in plasma ACE activity, Richard P. Marshall, MD, PhD, and colleagues from the Centre for Respiratory Research at Rayne Institute in London sought to relate ACE genotype with ARDS incidence and outcome.
Previous research had shown that people with two copies of the deletion (D) allele of the ACE gene had a 75% higher plasma ACE activity than did individuals homozygous for the insertion (I) allele. This observation prompted the investigators to ask whether DD individuals were more susceptible to ARDS than those with other genotypes.
DD GENOTYPE LINKED WITH ARDS
Frequencies of the D allele (69%) and of the DD genotype (46%) were significantly higher among ARDS patients than among non-ARDS ICU patients (44% and 24%, respectively), patients undergoing bypass surgery (51% and 25%), or healthy controls (51% and 26%). In comparison, the II genotype was markedly rarer among ARDS patients than among the other three groups; all four groups had similar frequencies of the ID genotype.
Mortality was increased among patients within the ARDS group who had two D alleles: 24 of 44 (54.5%) with the DD genotype died, as compared with one of nine (11.1%) patients having the homozygous II genotype and 12 of 43 (27.9%) patients with an ID genotype.
HOW ACE MIGHT INFLUENCE ARDS
The substantial association of genetic variants of the ACE gene with elevated risk for ARDS strongly suggests involvement of the renin-angiotensin system in ARDS etiology, according to Dr. Marshall and coauthors. They cite findings from a number of laboratory studies that may lend support to this notion. Under experimental conditions, the ACE metabolite angiotensin II can alter microvascular permeability to produce pulmonary edema, and it can prompt apoptotic death of respiratory epithelial cells. ACE activity is also associated with collagen deposition and interstitial fibrosis in lung tissue, and angiotensin II has mitogenic effects on lung fibroblasts—factors that also may contribute to mortality.
Additionally, ACE is expressed in activated lymphocytes and alveolar macrophages, in which its activity is associated with free radical production. Besides converting angiotensin I to angiotensin II, ACE has been found to also degrade bradykinin, thereby also altering nitric oxide and prostaglandin output. Thus, ACE could further exacerbate inflammatory processes.
Given the likely involvement of variations in lung tissue enzyme function in determining a patient’s tendency to develop ARDS, the researchers plan to assess ACE activity in bronchoalveolar lavage fluid and recovered inflammatory cells. Such measurements would be arguably more accurate assessments of ACE activity in lung tissue than would be measurements of circulating ACE from plasma samples, Dr. Marshall and colleagues suggested.
ACE INHIBITORS MAY BE INDICATED FOR DD GENOTYPE
ACE’s putative role in ARDS etiology supports the notion that inhibitors of ACE activity might effectively reduce the propensity of individuals with a DD genotype to develop ARDS. Thus, genotyping could reveal a subpopulation who might particularly benefit from therapy with ACE inhibitors—either as prophylaxis in healthy individuals who are homozygous for the D allele or to improve outcome in a genetic subpopulation of patients with lung disease.
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ACE
Gene Variant Also Associated With Alcoholic Cardiomyopathy
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BARCELONA,
SPAIN—Alcohol abuse is implicated
in approximately 15% to 40% of all cases
of dilated cardiomyopathy, yet many chronic and heavy
alcohol abusers show little sign of myocardial impairment.
A case-control study recently found that chronic alcohol
abusers with a DD genotype for the angiotensin-converting
enzyme (ACE) gene had a 16.4-fold higher likelihood
of developing left ventricular dysfunction than did
alcohol abusers homozygous for the I allele of the
gene.[1]
Emanuel Rubin, MD, and colleagues enrolled 30 male
alcohol abusers younger than 65 who presented to the
emergency department at the Hospital Clínic in
Barcelona, Spain. All reported having consumed at
least 100 g/d of ethanol for 15 years or more and
had a left ventricular ejection fraction (LVEF) of
50% or less. The control group included 27 asymptomatic
chronic alcohol abusers with an LVEF above 60%;
these patients had alcohol abuse patterns similar
to those of the first group.
The researchers then performed polymerase chain reaction
on leukocyte DNA to establish ACE genotype. Among
alcoholic patients with an LVEF below 50%, 57%
were homozygous for the D allele, whereas only 7%
of those with normal heart function bore the DD genotype.
In the reduced-LVEF group, at least one I allele was
detected in 36% of patients and at least one
D allele was detected in 65%; by comparison,
the I and D alleles were detected in 63% and
37%, respectively, of patients with normal cardiac
function.
Seventeen of 19 (89%) patients homozygous for
the D allele had cardiomyopathy; in contrast, only
13 of 38 patients (34%) with at least one I allele
were found to have impaired cardiac function. Thus,
a single I allele reduced the excess risk for alcohol-related
cardiomyopathy associated with the D allele.
—Mimi Zucker, PhD
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Reference
1. Fernández-Solà J, Nicolás JM, Oriola
J, et al. Angiotensin-converting enzyme gene polymorphism
is associated with vulnerability to alcoholic cardiomyopathy.
Ann Intern Med. 2002;137:321-326.
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—Mimi Zucker, PhD
Reference
1. Marshall RP, Webb S, Bellingan GJ, et al. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2002;166:646-650.
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