© 2000 American Heart Association, Inc.
Clinical Research |
Polymorphisms of the ß2-Adrenergic Receptor Determine Exercise Capacity in Patients With Heart Failure
From the Department of Medicine, Divisions of Cardiology (L.E.W., L.L.C., B.S., D.P.S., P.W.Z., N.M., W.T.A., G.W.D.) and Pulmonary Medicine (S.B.L.), and the Institute for Health Policy and Health Services Research (T.C.C.), University of Cincinnati College of Medicine, Cincinnati, Ohio.
Correspondence to Lynne E. Wagoner, MD, University of Cincinnati College of Medicine, 231 Bethesda Ave, PO Box 670542, Cincinnati, OH 45267-0542. E-mail Wagonele{at}ucmail.uc.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract—The ß2-adrenergic receptor (ß2AR) exists in multiple polymorphic forms with different characteristics. Their relevance to heart failure (HF) physiology is unknown. Cardiopulmonary exercise testing was performed on 232 compensated HF patients with a defined ß2AR genotype. Patients with the uncommon Ile164 polymorphism had a lower peak
O2 (15.0±0.9 mL
· kg-1 · min-1) than did patients
with Thr164 (17.9±0.9 mL · kg-1 ·
min-1, P<0.0001). The percentage achieved
of predicted peak O2 was also lower in
patients with Ile164 (62.3±4.5% versus 71.5±5.1%,
P=0.045). The relative risk of a patient having a
O2 
14 mL ·
kg-1 · min-1 who had Ile164 was 8.0
(P=0.009). Catheterization-based
invasive exercise testing revealed depressed changes in the
exercise-induced cardiac index, systemic vascular resistance, stroke
volume, and O2 in patients with Ile164.
The polymorphisms at position 16 also impacted exercise capacity:
peak O2 for Arg16 versus Gly16 was
17.0±0.8 versus 15.6±0.5
mL · kg-1 · min-1, respectively
(P=0.03). Because the polymorphisms at loci 16 and
27 can occur together, 4 homozygous combinations exist. Patients with
Arg16/Glu27 had the highest percentage achieved of predicted peak
O2 (75.7±6.4%), whereas those with
Gly16/Gln27 had the lowest (55.3±2.8%, P=0.0032). The
above findings were not confounded by baseline clinical
characteristics, including ß-blocker usage. We conclude that the
ß2AR polymorphisms Ile164, Gly16, and the combination
of Gly16 and Gln27 are associated with depressed exercise
performance in HF and represent a genetically
determined factor in the pathophysiology of HF.
Key Words: exercise • heart failure • ß-adrenergic receptors • genetics
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The sequence of the human ß2-adrenergic receptor (ß2AR) gene is highly variable, giving rise to a coding region with numerous genetic polymorphisms (Figure 1
).1 2 3 Of particular
interest, 3 polymorphic ß2ARs exhibit
altered receptor function in in vitro expression assays. As a common
frame of reference, the ß2AR containing Arg16,
Gln27, and Thr164 is considered to be a "wild type" (although Gly
at position 16 appears to be more frequent than Arg).1
Compared with the wild types, ß2ARs with the
following substitutions exhibit abnormal receptor-effector coupling or
patterns of desensitization: Gly versus Arg at amino acid position 16,
Glu versus Gln at position 27, and Ile versus Thr at position 164.
|
When recombinantly expressed in Chinese hamster fibroblasts or studied as the endogenous polymorphic receptor in human airway smooth muscle cells, Gly16 ß2ARs show enhanced agonist-promoted receptor downregulation.3 In contrast, the Glu27 polymorphic receptor undergoes little or no downregulation under similar conditions.3 Although the mechanism of altered downregulation imposed by these variations is not entirely clear, our studies have indicated that modified receptor degradation after internalization is the basis of these phenotypes.3 As predicted from their location in the extracellular terminus, coupling of these polymorphic receptors to stimulation of adenylyl cyclase is not modified. However, evidence suggests that endogenous catecholamines are sufficient to induce the different downregulation phenotypes4 ; thus, receptor function is, in fact, altered by the amino-terminal polymorphism (Gly16 has depressed and Glu27 has enhanced function compared with wild-type function). In contrast to these amino-terminal polymorphisms, the Ile164 receptor has decreased basal and agonist-stimulated adenylyl cyclase activities and decreased affinity for agonists and some antagonists.2 This receptor also downregulates, so it has the potential to have the most severe phenotype of the 3 polymorphisms. Transgenic mice overexpressing this polymorphic ß2AR in the heart exhibit depressed inotropy and chronotropy.5
In considering the pathophysiological consequences of polymorphic ß2ARs, it is important to note that ß2ARs are highly expressed throughout the cardiovascular system, in which they mediate increased myocardial inotropy and chronotropy6 and arterial vasodilation. Downregulation of the myocardial ß1-adrenergic receptor in heart failure (HF) and the resulting increase in relative cardiac ß2AR expression suggest that cardiac ß2AR expression and function are of particular importance in this condition.6 Consistent with this notion, our prior studies in HF have demonstrated that genetic variability of ß2ARs is one determinant of disease progression. Patients with Ile164 progress more rapidly to death or transplantation than those with Thr164.7 Strong trends were also seen with Gly16 or Gln27 (both of which have increased downregulation compared with their counterparts).7
Exercise capacity is a critical determinant of prognosis in HF
patients. Indeed, exercise capacity measured by peak
O2 during
cardiopulmonary exercise testing (CPX) with respiratory gas
analysis predicts survival in patients with HF.8
Moreover, a significant deterioration of maximal exercise
performance frequently precedes clinical
decompensation.9 Also, peak
O2 and exercise duration are
correlated with overall cardiac ß-adrenergic receptor density in
patients with mild to moderately severe HF due to idiopathic dilated
cardiomyopathy.10 Thus, we considered
that if ß2AR polymorphisms are disease
modifiers in congestive HF, clinically compensated patients bearing
these polymorphisms should exhibit different
cardiovascular responses to exercise. Specifically, we
hypothesized that the patients with the polymorphism Ile164 would
have significantly depressed responsiveness to exercise and that, to a
lesser extent, those with Gly16 and/or Gln27 would have depressed
responsiveness compared with those with Arg16 and/or Glu27. In the
present study, we describe the effect of these
ß2AR polymorphisms on the outcome of CPX in
232 clinically compensated congestive HF patients with idiopathic
dilated or ischemic cardiomyopathies.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Patients
The study was approved by the Institutional Review Board of the University of Cincinnati. Two hundred thirty-two unrelated sequential patients (73% male, 80% white and 20% African American, aged 49.5±0.6 years) with ischemic cardiomyopathy (n=84) or idiopathic dilated cardiomyopathy (n=148), New York Heart Association functional class (NYHA FC) II to IV, and left ventricular ejection fraction (LVEF) 26.7±0.9% were genotyped for ß2AR polymorphism, with genomic DNA used as a template. All patients were stable on HF therapy and were ambulatory. Pertinent medications and frequency of use at the time of the exercise test included digoxin (93.9%), diuretics (92.1%), ß-blockers (24.9%), angiotensin-converting enzyme inhibitors (90.0%), angiotensin II receptor blockers (9.6%), and amiodarone (17.5%).
ß2AR Genotyping
Genomic DNA was isolated from peripheral blood.
ß2AR genotyping was carried out with the use of
the genetic bit analysis method.7
Cardiopulmonary Exercise Testing
Patients underwent CPX on a treadmill (Medgraphics); a Modified
Naughton protocol was used.
O2 (mL/min),
CO2 (mL/min), and minute
ventilation (L/min) were measured continuously.
O2 was normalized for body
mass (O2, mL ·
kg-1 · min-1).
Pertinent exercise parameters included peak
O2,
O2 at anaerobic
threshold, O2 at a respiratory
exchange ratio (RER) of 1, O2
divided by the predicted maximum (%Max
O2), metabolic
equivalents at peak exercise, and exercise time.
Invasive Exercise Hemodynamic Testing
Twelve patients (6 with Ile164 and 6 with Thr164) were enrolled
in an invasive assessment of exercise hemodynamics.
Angiotensin-converting enzyme inhibitors,
angiotensin II receptor blockers, ß-blockers, and
calcium channel blockers were held for 48 hours. A Swan-Ganz catheter
(Baxter CCO/sVO2) was positioned in the
pulmonary artery (PA). A catheter was inserted into the radial
artery. Thirty minutes later, baseline hemodynamic
measurements were made of PA pressure, pulmonary capillary
wedge pressure (PCWP), central venous pressure, and systemic pressures.
Cardiac output was calculated by using the Fick equation with
arterial saturation obtained from pulse oximetry and PA
saturation from the sVO2 catheter. Patients
exercised to symptomatic maximum with use of a bicycle
ergometry protocol. Respiratory gas and heart rate measurements were
made continuously; hemodynamic measurements and
arterial and PA saturations were recorded at every 2
minutes of exercise, at peak exercise, and at 1, 3, and 5 minutes of
recovery.
Statistical Methods
Because of the low frequency of the Ile164 allele in the
population,7 we paired in a blinded fashion all 18
patients exhibiting Ile164 with 18 randomly assigned patients with
similar characteristics homozygous for Thr164, matching for NYHA FC,
sex, age, race, and cause of HF. CPX parameters were
analyzed by paired t tests. Potential confounders,
including ß2AR genotype at positions 16
and 27, LVEF, right ventricular ejection fraction, and
medication use, were examined by using multiple regression models.
Pertinent hemodynamic and exercise variables of
patients tested with invasive exercise testing were analyzed by
paired t tests using percent change from baseline.
The polymorphisms at positions 16 and 27 were analyzed in isolation and in combination: patients homozygous for Arg16 were compared with those homozygous for Gly16, homozygous Gln27 was compared with homozygous Glu27, and the 4 combinations of homozygous genotypes at positions 16 and 27 were compared. Multiple regression models were applied as described above.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
From our cell-based and transgenic mouse studies and our previous observation that patients with the Ile164 receptor appear to progress more rapidly to death or transplantation, we hypothesized that individuals bearing this substantially impaired Ile164 receptor would have a lower peak
O2 than
individuals with Thr164. Eighteen patients in the cohort were found to
be heterozygous for this polymorphism. No homozygous Ile164
individuals were found, as has been previously reported.7
The characteristics of patients with the Ile164 versus the Thr164
receptor are shown in Table 1.
|
Table 2 shows the exercise
parameters of patients with Ile164 compared with Thr164. As
predicted, patients with Ile164 had a lower peak
O2 (15.0±0.9 mL ·
kg-1 · min-1) than
patients with Thr164 (17.9±0.9 mL ·
kg-1 · min-1;
P=0.0004, unadjusted). Potential confounders were added into
the statistical model as indicated above. The only factor found to be a
significant confounder was the genotype of the
ß2AR at position 16 (P=0.003), and
after adjustment, the difference in the peak
O2 was even more
statistically significant (P<0.0001). Importantly,
ß-blocker usage, which was similar in both groups, was not a
confounder. Also, %Max
O2 was significantly
lower in the patients with Ile164 compared with those with Thr164
(62.3±4.5% versus 71.5±5.1%; P=0.045, adjusted) as was
O2 at RER 1
(12.1±0.8 versus 13.8±0.8 mL ·
kg-1 · min-1;
P=0.045, adjusted). These significant differences did not
result from differing exercise levels or motivation; the patients in
both groups achieved equivalent maximum RER and maximum heart rate at
peak exercise. Identical peak heart rates occurred in the 2 groups. No
differences were found in baseline or maximum systolic or
diastolic blood pressure. Furthermore, we calculated the
relative risk of having a peak
O2 14 mL ·
kg-1 · min-1 (a
clinically accepted value that indicates a lower 1-year survival
rate8 ) if the Ile164 receptor is present. We
found the risk to be 8.0 (P=0.009).
|
Six patients with the Ile164 receptor (aged 57.7±3.6 years, LVEF
20.0±3.7%) and 6 patients with the Thr164 receptor (aged 52.8±3.9
years, LVEF 25.5±4.1%) underwent invasive exercise
hemodynamic testing. Consistent with the
noninvasive studies (Tables 1
and 2), baseline cardiac
output, cardiac index, heart rate, stroke volume, and systemic vascular
resistance (SVR) were not different between the 2 groups (data not
shown). Exercise-induced changes were significantly lower in patients
with the polymorphisms at position 164 for
O2, stroke volume, cardiac
index, and SVR (Figure 2). No differences
in heart rate, PA systolic or diastolic pressures,
PCWP, or systemic systolic or diastolic pressures
were noted.
|
On the basis of our previous in vitro studies in which Gly16
ß2ARs show enhanced receptor downregulation, we
hypothesized that individuals bearing the homozygous Gly16 receptor
would have reduced exercise capacity compared with individuals with
homozygous Arg16. We excluded patients who were heterozygous at
position 16 and patients with Ile164 from this analysis. Thus,
the results from 74 patients bearing the Gly16 receptor and 44 patients
with Arg16 were analyzed. The characteristics of patients
homozygous for Gly16 and Arg16 are shown in Table 1.
As shown in Table 3, patients expressing
Gly16 had a lower peak O2
(15.6±0.5 versus 17.0±0.8 mL ·
kg-1 · min-1;
P=0.045, unadjusted). Again, no significant difference was
noted in the maximum RER and maximum heart rate at peak exercise,
indicating no difference in exercise effort during the tests. Potential
confounders were added into the statistical model; age
(P=0.0001), sex (P=0.002), and race
(P=0.02) were significant confounders, whereas ß-blocker
usage was not. When the data were reanalyzed with these
confounders taken into account, the difference in peak
O2 between Arg16 and
Gly16 was significant (P=0.03, adjusted). The %Max
O2 was also lower with Gly16 compared with
Arg16 (62.2±2.1% versus 69.1±2.7%, P=0.045). The results
were unchanged after deleting those patients on ß-blocker therapy at
the time of the exercise test, consistent with medication use
not being a confounder in the whole population analysis. No
statistically significant differences in exercise
parameters were noted for the individuals homozygous for
the Gln27 receptor, which undergoes some degree of downregulation
compared with the Glu27 polymorphism, which does not (data not
shown).
|
Because the polymorphisms at loci 16 and 27 frequently occur
together, 4 different homozygous combinations are possible. To examine
the effects that the polymorphisms at positions 16 and 27 would
have in combination, we analyzed the exercise
parameters for the 76 patients with homozygous
combinations. We hypothesized that patients expressing receptors in
which both have less downregulation (Arg16/Glu27) would demonstrate an
exercise capacity higher than that in patients expressing receptors in
which both are highly sensitive to downregulation (Gly16/Gln27). The
patients with a heterozygous receptor at either position 16 or 27 were
excluded because of the potential for intermediate effects. The
clinical characteristics of patients with the combinations for loci 16
and 27 were not significantly different between groups (data not
shown). The exercise parameters were analyzed by
use of a multiple regression model. Significant confounders included
age (P=0.0001), dilated cardiomyopathy
(P=0.0041), sex (P=0.0002), and race
(P=0.0072). Figure 3
demonstrates the %Max
O2 for all 4
combinations. The patients with Arg16/Glu27, which is the rarest
combination, had the highest %Max
O2 (75.7±6.4%),
whereas the patients with Gly16/Gln27 had the lowest %Max
O2 (55.3±2.8%;
P=0.0032 by ANOVA, adjusted). The patients with Arg16/Gln27
and Gly16/Glu27 demonstrated %Max
O2 values that were
intermediate to the other 2 groups. A similar pattern was noted for
maximum O2
(18.6±1.7 mL · kg-1 ·
min-1 for Arg16/Glu27 compared with 16.3±1.1
mL · kg-1 ·
min-1 for Gly16/Gln27), but this did not reach
statistical significance (P=0.09, adjusted).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The present study demonstrates that HF patients with the hypofunctional ß2AR adrenergic receptor caused by the fourth transmembrane domain Ile164 polymorphism have a significantly lower peak
O2
during treadmill exercise testing, ie, diminished exercise capacity,
than do patients with Thr164. With invasive studies, these individuals
were found to have depressed inotropic and vascular responses to
exercise. A relationship between the Ile164 receptor and increased risk
of death or need for transplantation previously delineated a possible
genetic mechanism for individual heterogeneity in the
disease progression of end-stage HF.7 The present
results establish an association between disease-modifying
ß2AR polymorphisms and clinical outcome in
clinically compensated HF. Furthermore, because exercise capacity is
directly related to length of survival in HF,8 these
findings provide a link between our survival results, in vitro and
transgenic studies, and physiological responses in
patients. To our knowledge, this is the first study to do so with any
G-protein–coupled receptor polymorphism and HF.
The basis for interindividual variability in the severity or
progression of HF is largely unexplained but may relate to the fact
that clinical "heart failure" is the common end point for numerous
diverse disease processes, each with distinct characteristic
pathophysiologies. Genetic variability in disease-related genes, such
as ß2AR, further act as disease modifiers.
Thus, progression and therapeutic response in HF are likely determined
by a complex interplay of intrinsic genetic characteristics and
extrinsic pathogenic factors. In the present study, we have focused
on the ß2AR, which has 3 polymorphic loci
in its coding region.3 These 3
ß2AR polymorphisms have previously
undergone detailed characterization as to their signaling
phenotypes, providing both a structural and functional basis
for clinical studies of these particular receptor variants. The Gly16
"polymorphism" is actually more common (allele frequency of
0.60) than the "wild-type" receptor, which is so designated
because of the original cloning of the receptor. Site-directed
mutagenesis was used to create, in vitro, this and other
polymorphisms and to generate plasmid constructs for permanent
expression in transfected Chinese hamster fibroblasts. As expected from
its position in the amino-terminus, the Gly16 receptor had normal
agonist- and antagonist-binding affinities, coupling to
Gs, and stimulation of adenylyl
cyclase.3 11 However, compared with the wild-type
receptor, this receptor exhibited enhanced sensitivity to
agonist-promoted downregulation because of increased degradation after
apparently normal receptor internalization. These functional
characteristics were confirmed in human airway smooth muscle cells
naturally expressing the Arg16 or Gly16 alleles.11
Similar studies have also established the characteristics of the Glu27
variant, the allelic frequency of which is 0.40. This
polymorphic receptor has impaired homologous downregulation in
either transfected or endogenously expressing
cells.3 11 In asthma, airway ß2AR
polymorphisms at 16 and 27 confer differences in airway
reactivity12 and in the response to
ß2-agonists13 in the absence of
pretreatment with agonists. This indicates that the receptors have the
capacity to be differentially regulated by endogenous
catecholamines.
Compared with the amino-terminal polymorphisms, the Ile164 receptor
is uncommon, with a frequency of the heterozygous polymorphism of
0.05. In vitro expression of Ile164 has shown that compared with the
wild-type receptor, the polymorphic receptor has decreased
agonist-binding affinities but normal affinities for most
ß-adrenergic receptor antagonists.2 The
Ile164 receptor has a substantially impaired basal and
agonist-stimulated coupling to adenylyl cyclase, which we have found is
due to an altered receptor conformation that results in a loss of
high-affinity receptor–Gs
interaction.2 In vivo cardiomyocyte-specific
expression of this receptor in transgenic mice confirmed lower basal
and isoproterenol stimulated adenylyl cyclase activity for this
receptor, resulting in lower resting heart rates and inotropic and
lusitropic indices.5
These ß2AR polymorphisms have been studied within the context of disease modification of asthma4 and hypertension.14 15 In asthma, a disease in which these polymorphisms have been the most extensively studied, most, but not all, studies have shown a disease-modifying effect. The differences in the study designs and, in some studies, relatively small patient numbers may be the basis for some of this inconsistency. In regard to cardiovascular disease, the polymorphism at position 16 has been associated with hypertension.14 15 However, in African Caribbeans, hypertension was associated with the Gly16 variant,15 whereas in Norwegians, an association was found with Arg16.14 The designs of these 2 studies were quite different; thus, the association of hypertension with ß2AR polymorphisms remains unclear.
In the present study, we have focused on the potential modifying
roles of the genetic variants at position 164 on exercise
performance because of its clinical relevance in HF and its
relationship to catecholamine responsiveness. Peak
O2 and/or percentage achieved
of predicted peak oxygen uptake (%Max
O2) are excellent predictors
of survival in patients with HF.8 16 Patients with a peak
O2 of 14 mL ·
kg-1 · min-1
obtained by CPX have a reduced survival rate at 1 year (70%) compared
with patients with a peak O2
>14 mL · kg-1 ·
min-1 (94%); thus, peak
O2 has become an established
parameter for cardiac transplant listing.8 On
the basis of the aforementioned in vitro and human data, we postulated
that patients with the hypofunctional Ile164
ß2AR would have substantially lower peak
O2 with exercise than patients
with Thr164. Markedly lower peak
O2 was demonstrated in HF
patients with Ile164 than in matched controls (15.0 versus 17.9 mL
· kg-1 · min-1),
leading us to a potential mechanism for decompensation in patients with
this polymorphism of the ß2AR. This
difference in peak O2 could
not be explained on the basis of age, sex, NYHA FC, medication usage,
exercise effort levels, or peak exercise heart rates. An equal number
of patients in each group were being treated with ß-blockers (4 of 18
in the Ile164 group [3 treated with carvedilol and 1 with metoprolol]
and 3 of 18 in the Thr164 group [2 treated with carvedilol and 1 with
metoprolol]), and ß-blocker use was not a confounder in the
analysis. Furthermore, our invasive exercise
hemodynamics demonstrating a lower exercise-induced
cardiac index, stroke volume, and SVR in patients with Ile164 confirm
that the difference in exercise parameters observed with
noninvasive CPX are indeed cardiovascular effects. Of
note, in these invasive studies, the patients had been withdrawn from
ß-blockers before the study.
This significant impact on cardiac physiology was present in individuals who are heterozygous for the Ile164 receptor. We would predict that the impairment would be of even greater magnitude in individuals homozygous for the polymorphism. However, we have not, to date, identified an individual (patient or normal) who is homozygous. Of note, the altered responses of the heterozygous patients averaged 53% of the response of those with the homozygous wild-type receptor, consistent with the notion that those with homozygous Ile164 would display little responsiveness.
Regarding the amino-terminal polymorphisms, we postulated that
patients with Arg16 and/or Glu27 would exhibit the least degree of
downregulation and, thus, the highest peak
O2 with exercise testing;
similarly, patients with Gly16 and/or Gln27 would have a greater degree
of downregulation and, thus, lower peak
O2. When analyzed as
individual loci, those patients with Gly16 demonstrated lower peak
O2 than did patients with
Arg16. When all 4 of the genotypic combinations were considered, it was
apparent that those with Gly16/Gln27 had the lowest %Max
O2 compared with the other
combinations. The magnitude of difference observed (20 percentage
points; see Figure 2) is not only highly statistically
significant, but it is also clinically relevant, especially when
assessing a patient for listing for cardiac transplantation. On the
basis of the %Max O2, those
patients with Gly16/Gln27 with a %Max
O2 of 55% fall into a range
that would qualify them for being listed for cardiac transplantation,
whereas those with Arg16/Glu27 with a %Max
O2 of 76% would not be
listed.16
Our results indicating that genotypes including Ile164, Gly16, and Gly16/Gln27 adversely impact survival and/or exercise performance suggest that ß2AR genotyping may be a useful test in patients with HF. Potentially, then, patients identified with these genotypes during their clinical evaluation should be considered for aggressive management with pharmacological therapy even in the early stages and also considered for transplant listing. Furthermore, various pharmacological therapies for HF, such as ß-blockers, may prove to be more or less effective in patients with various ß2AR genotypes. This awaits explicit testing.
The present study is limited by the influence that numerous factors
exert on maximal exercise performance, including age, sex, the
condition of the skeletal muscles, medications, lung disease, and
patient/operator motivation.17 18 A number of these
factors, including age, sex, and medication (particular ß-blockers),
have been addressed by adding these factors to our general linear
model. Another limitation is the small size of the Ile164 and
Arg16/Glu27 groups. However, the exercise database of 232 patients is
representative of HF populations in most tertiary
referral clinical practices, and even with the smaller subgroups, the
results are both statistically and clinically significant. Finally, we
are cognizant that the inclusion of patients on ß-blockers in the
analysis might have limited the results. This did not turn out
to be the case. The use of ß-blockers in the Ile164 paired group was
nearly identical to the Thr164 group. Furthermore, in the
analysis of the invasive exercise testing of Ile164, no
patients were taking ß-blockers, and a significant difference was
again observed in peak O2.
Also, there was no confounding for ß-blocker usage in the
analysis of the polymorphisms at 16 and 27, and the results
were unchanged when patients taking ß-blockers were excluded in the
larger study with the polymorphisms at positions 16 and 27.
Nevertheless, a prospective trial assessing whether ß-blockers can
modify these genetic influences is necessary to exclude this
potential.
In conclusion, the Ile164 polymorphism of the fourth
transmembrane-spanning domain negatively impacts exercise
performance in patients with HF caused by idiopathic or
ischemic cardiomyopathies. The presence of
the heterozygous Ile164 receptor (regardless of the allele at
position 16 and 27) is associated with the most depressed cardiac and
vascular responses to exercise, even when accounting for other clinical
parameters, such as NYHA FC, cause of HF, LVEF, or
medication use. This is consistent with our recent report
showing decreased survival in patients with Ile164.7 Taken
together, then, these results point to the genotype of the
ß2AR at position 164 as being an important
genetic component in the pathophysiology of HF. Patients with Gly16 or
Gly16/Gln27 also exhibited decreased peak
O2 compared with the other
genotypic combinations. On the basis of these findings and our in vitro
and transgenic results, it appears that ß2AR
polymorphisms have a significant modifying effect in HF.
ß2AR genotyping may thus be a useful test in
the clinical evaluation of patients with HF, providing a genetic basis
for altering drug therapy or early listing for transplantation.
|
Acknowledgments |
|---|
This study was funded by National Institutes of Health grants HL-52318 (SCOR in Heart Failure) and HL-41496 (Dr Liggett) and by the American Heart Association, Ohio Affiliate (SW-9641B to Dr Wagoner). We thank Susan Forbes for technical assistance, Orchid BioSciences for genotyping assistance, and Ali Javaheri for data entry.
Received November 5, 1999; accepted February 29, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
- Reihsaus E, Innis M, MacIntyre N, Liggett SB. Mutations in the gene encoding for the ß2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol. 1993;8:334–339.
-
Green SA, Cole G, Jacinto M, Innis M, Liggett SB. A
polymorphism of the human
ß2-adrenergic receptor within the fourth
transmembrane domain alters ligand binding and functional properties of
the receptor. J Biol Chem. 1993;268:23116–23121.
[Abstract/Free Full Text] - Green S, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human ß2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry. 1994;33:9414–9419.[Medline] [Order article via Infotrieve]
- Liggett SB. Molecular and genetic basis of ß2-adrenergic receptor function. J Allergy Clin Immunol. 1999;103:S42–S46.
- Turki J, Lorenz JN, Green SA, Donnelly ET, Jacinto M, Liggett SB. Myocardial signalling defects and impaired cardiac function of a human ß2-adrenergic receptor polymorphism expressed in transgenic mice. Proc Natl Acad Sci U S A. 1996;10483–10488.
- Bristow MR. Why does the myocardium fail?: insights from basic science. Lancet. 1998;352(suppl I):S18–S14.
- Liggett SB, Wagoner LE, Craft LL, Hornung RW, Hoit BD, McIntosh TC, Walsh RA. The Ile164 ß2-adrenergic receptor polymorphisms adversely affects the outcome of congestive heart failure. J Clin Invest. 1998;102:1534–1539.[Medline] [Order article via Infotrieve]
-
Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH,
Wilson JR. Value of peak exercise oxygen consumption for optimal timing
of cardiac transplantation in ambulatory patients with heart failure.
Circulation. 1991;83:778–786.
[Abstract/Free Full Text] - Packer M, Pitt B. Which objective measurements parallel the course of disease progression in patients with congestive heart failure? J Am Coll Cardiol. 1988;11:202A. Abstract.
- White M, Yanowitz F, Gilbert EM, Larrabee P, O’Connell JB, Anderson JL, Renlund D, Mealey P, Abraham WT, Bristow MR. Role of beta-adrenergic receptor downregulation in the peak exercise response in patients with heart failure due to idiopathic dilated cardiomyopathy. Am J Cardiol. 1995;76:1271–1276.[Medline] [Order article via Infotrieve]
- Green SA, Turki J, Bejarano P, Hall LP, Liggett SB. Influence of ß2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol. 1995;13:25–33.[Abstract]
- Hall IP, Wheatley A, Wilding P, Liggett SB. Association of the Glu27 ß2-adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects. Lancet. 1995;345:1213–1214.[Medline] [Order article via Infotrieve]
- Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest. 1997;100:3184–3188.[Medline] [Order article via Infotrieve]
- Timmermann B, Mo R, Luft FC, Gerdts E, Busjahn A, Omvik P, Li GH, Schuster H, Wienker TF, Hoehe MR, Lund-Johansen P. Beta-2 adrenoreceptor genetic variation is associated with genetic predisposed essential hypertension: the Bergen Blood Pressure Study. Kidney Int. 1998;53:1455–1460.[Medline] [Order article via Infotrieve]
-
Kotanko P, Binder A, Tasker J, DeFreitas P, Kamdar S,
Clark AJ, Skrabal F, Caulfield M. Essential hypertension in African
Caribbeans associates with a variant of the
ß2-adrenoceptor. Hypertension. 1997;30:773–776.
[Abstract/Free Full Text] - Miller LW. Listing criteria for cardiac transplantation: results of an American Society of Transplant Physicians-National Institutes of Health Conference. Transplantation. 1998;66:947–951.[Medline] [Order article via Infotrieve]
- Moore RL, Korzick DH. Cellular adaptations of the myocardium to chronic exercise. Prog Cardiovasc Dis. 1995;37:371–396.[Medline] [Order article via Infotrieve]
- Mancini DM. Pulmonary factors limiting exercise capacity in patients with heart failure. Prog Cardiovasc Dis. 1995;37:347–370.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  E. Barbato, M. Penicka, L. Delrue, F. Van Durme, B. De Bruyne, M. Goethals, W. Wijns, M. Vanderheyden, and J. Bartunek Thr164Ile polymorphism of {beta}2-adrenergic receptor negatively modulates cardiac contractility: implications for prognosis in patients with idiopathic dilated cardiomyopathy Heart, July 1, 2007; 93(7): 856 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Iaccarino, M. Ciccarelli, D. Sorriento, G. Galasso, A. Campanile, G. Santulli, E. Cipolletta, V. Cerullo, V. Cimini, G. G. Altobelli, et al. Ischemic Neoangiogenesis Enhanced by {beta}2-Adrenergic Receptor Overexpression: A Novel Role for the Endothelial Adrenergic System Circ. Res., November 25, 2005; 97(11): 1182 - 1189. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. C. Fonarow, C. W. Yancy, J. T. Heywood, and for the ADHERE Scientific Advisory Committee, Stud Adherence to Heart Failure Quality-of-Care Indicators in US Hospitals: Analysis of the ADHERE Registry Arch Intern Med, July 11, 2005; 165(13): 1469 - 1477. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Kaye, B. Smirk, S. Finch, C. Williams, and M. D. Esler Interaction between cardiac sympathetic drive and heart rate in heart failure: Modulation by adrenergic receptor genotype J. Am. Coll. Cardiol., November 16, 2004; 44(10): 2008 - 2015. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Cascorbi, M. Paul, and H. K. Kroemer Pharmacogenomics of heart failure - focus on drug disposition and action Cardiovasc Res, October 1, 2004; 64(1): 32 - 39. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Covolo, U. Gelatti, M. Metra, S. Nodari, A. Piccichè, N. Pezzali, C. Zani, A. Alberti, F. Donato, G. Nardi, et al. Role of {beta}1- and {beta}2-adrenoceptor polymorphisms in heart failure: a case-control study Eur. Heart J., September 1, 2004; 25(17): 1534 - 1541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Kirstein and P. A. Insel Autonomic Nervous System Pharmacogenomics: A Progress Report Pharmacol. Rev., March 1, 2004; 56(1): 31 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.R. Keys and W.J. Koch The Adrenergic Pathway and Heart Failure Recent Prog. Horm. Res., January 1, 2004; 59(1): 13 - 30. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. M. Feldman The emerging role of pharmacogenomics in the treatment of patients with heart failure Ann. Thorac. Surg., December 1, 2003; 76(6): S2246 - 2253. [Full Text] [PDF]
|
|
|
|
|
|
M. J. Lohse, S. Engelhardt, and T. Eschenhagen What Is the Role of {beta}-Adrenergic Signaling in Heart Failure? Circ. Res., November 14, 2003; 93(10): 896 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Pavoine, N. Behforouz, C. Gauthier, S. Le Gouvello, F. Roudot-Thoraval, C. R. Martin, A. Pawlak, C. Feral, N. Defer, R. Houel, et al. {beta}2-Adrenergic Signaling in Human Heart: Shift from the Cyclic AMP to the Arachidonic Acid Pathway Mol. Pharmacol., November 1, 2003; 64(5): 1117 - 1125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Bruck, K. Leineweber, A. Ulrich, J. Radke, G. Heusch, T. Philipp, and O.-E. Brodde Thr164Ile polymorphism of the human {beta}2-adrenoceptor exhibits blunted desensitization of cardiac functional responses in vivo Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2034 - H2038. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. H. Au, E. M. Udris, V. S. Fan, J. R. Curtis, M. B. McDonell, and S. D. Fihn Risk of Mortality and Heart Failure Exacerbations Associated With Inhaled {beta}-Adrenoceptor Agonists Among Patients With Known Left Ventricular Systolic Dysfunction Chest, June 1, 2003; 123(6): 1964 - 1969. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Rathz, K. N. Gregory, Y. Fang, K. M. Brown, and S. B. Liggett Hierarchy of Polymorphic Variation and Desensitization Permutations Relative to beta 1- and beta 2-Adrenergic Receptor Signaling J. Biol. Chem., March 14, 2003; 278(12): 10784 - 10789. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Hajjar and C. A. MacRae Adrenergic-Receptor Polymorphisms and Heart Failure N. Engl. J. Med., October 10, 2002; 347(15): 1196 - 1199. [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Lynch, L. Wagoner, S. Li, L. Sparks, J. Molkentin, and G. W. Dorn II Novel and nondetected human signaling protein polymorphisms Physiol Genomics, September 3, 2002; 10(3): 159 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J.J. Wood Racial Differences in the Response to Drugs -- Pointers to Genetic Differences N. Engl. J. Med., May 3, 2001; 344(18): 1393 - 1396. [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Feldman Adrenergic Receptor Polymorphisms and Cardiac Function (and Dysfunction) : A Failure to Communicate? Circulation, February 27, 2001; 103(8): 1042 - 1043. [Full Text] [PDF]
|
|
|
|
|
|
O.-E. Brodde, R. Buscher, R. Tellkamp, J. Radke, S. Dhein, and P. A. Insel Blunted Cardiac Responses to Receptor Activation in Subjects With Thr164Ile {beta}2-Adrenoceptors Circulation, February 27, 2001; 103(8): 1048 - 1050. [Abstract] [Full Text] [PDF]
|
|
| |||||||||