Myocardial Gene Expression in Dilated Cardiomyopathy Treated with Beta-Blocking Agents
Brian D. Lowes, M.D., Edward M. Gilbert, M.D., William T. Abraham, M.D., Wayne A. Minobe, B.S., Patti Larrabee, B.S., Debra Ferguson, M.S., Eugene E. Wolfel, M.D., JoAnn Lindenfeld, M.D., Tatiana Tsvetkova, M.D., Alastair D. Robertson, Ph.D., Robert A. Quaife, M.D., and Michael R. Bristow, M.D., Ph.D.
Background Beta-blocker therapy may improve cardiac functionin patients with idiopathic dilated cardiomyopathy. We testedthe hypothesis that beta-blocker therapy produces favorablefunctional effects in dilated cardiomyopathy by altering theexpression of myocardial genes that regulate contractility andpathologic hypertrophy.
Methods We randomly assigned 53 patients with idiopathic dilatedcardiomyopathy to treatment with a -adrenergic–receptorblocking agent (metoprolol or carvedilol) or placebo. The amountof messenger RNA (mRNA) for contractility-regulating genes (thoseencoding 1- and 2-adrenergic receptors, calcium ATPase in thesarcoplasmic reticulum, and - and -myosin heavy-chain isoforms)and of genes associated with pathologic hypertrophy (-myosinheavy chain and atrial natriuretic peptide) was measured witha quantitative reverse-transcription polymerase chain reactionin total RNA extracted from biopsy specimens of the right ventricularseptal endomyocardium. Myocardial levels of -adrenergic receptorswere also measured. Measurements were conducted at base lineand after six months of treatment, and changes in gene expressionwere compared with changes in the left ventricular ejectionfraction as measured by radionuclide ventriculography.
Results Twenty-six of 32 beta-blocker–treated patients(those with complete mRNA measurements) had an improvement inleft ventricular ejection fraction of at least 5 ejection-fraction(EF) units (mean [±SE] increase, 18.8±1.8). Ascompared with the six beta-blocker–treated patients whodid not have a response (mean change, a decrease of 2.5±1.8EF units), those who did have a response had an increase insarcoplasmic-reticulum calcium ATPase mRNA and -myosin heavychain mRNA and a decrease in -myosin heavy chain mRNA. The changein sarcoplasmic-reticulum calcium ATPase was not present inthe patients in the placebo group who had a spontaneous response.There were no differences between those who had a response andthose who did not in terms of the change in mRNA or proteinexpression of -adrenergic receptors.
Conclusions In idiopathic dilated cardiomyopathy, functionalimprovement related to treatment with beta-blockers is associatedwith changes in myocardial gene expression.
In dilated cardiomyopathy, -adrenergic–receptor blockingagents improve systolic function and reverse cardiac remodelingby a process that may result from changes in gene expression.1Several categories of contractility- and hypertrophy-modifyinggenes may be involved in producing structural and functionalchanges in dilated cardiomyopathy (which is characterized byincreases in end-systolic and end-diastolic volumes along withdecreases in systolic function)2; changes prompted by such genesinclude alterations in the expression of -adrenergic receptors,calcium-handling proteins, and myosin heavy-chain isoforms.3These categories of genes would therefore be candidates forfavorable modification by beta-blocking agents.
It is now possible to quantify the levels of messenger RNA (mRNA)in RNA extracted from endomyocardial-biopsy specimens.4,5,6,7Using this approach and measurements of -adrenergic–receptorprotein,7 we tested the hypothesis that functional improvementin dilated cardiomyopathy due to beta-blocker therapy,1,8 includingpotential quantitative differences in the response to individualagents,9,10 is related to favorable changes in the expressionof genes that regulate contractile function and pathologic hypertrophy.
Methods
Clinical Protocol
The study was conducted between July 1993 and April 2000. Patientsof either sex between 18 and 80 years of age who had chronicsymptomatic heart failure due to idiopathic dilated cardiomyopathyand a clinical indication for endomyocardial biopsy were eligiblefor enrollment. At our two institutions, endomyocardial biopsyis performed routinely in patients with idiopathic dilated cardiomyopathyto rule out inflammation or other infiltrative processes. Tobe eligible for randomization, patients could not have a lymphocyticinfiltrate or other infiltrate in the biopsy specimen, and theyhad to have a base-line left ventricular ejection fraction,as measured by radionuclide ventriculography, of no more than0.35 and an increase in the size of the left ventricle, as assessedby two-dimensional echocardiography. Mandatory background therapyconsisted of an angiotensin-converting–enzyme inhibitorand digoxin, with diuretics as needed.
Eligible patients gave their written informed consent on formsthat had been approved by the institutional review boards ofthe University of Colorado Health Sciences Center or Universityof Utah Health Sciences Center. They then underwent base-linetests designed to measure the expression of myocardial genes,left and right ventricular function, hemodynamics, and the levelof cardiac adrenergic activity as estimated by coronary sinusnorepinephrine levels. The patients were then randomly assignedin a double-blind manner to treatment with placebo, metoprololtartrate, or carvedilol. The initial dose of carvedilol was3.125 mg twice daily, and the initial dose of metoprolol was6.25 mg twice daily. The dose of study medication was doubledweekly until target doses were reached or until limiting sideeffects occurred. Target doses were 50 mg of carvedilol twicedaily and 100 mg of metoprolol twice daily for patients weighing85 kg or more and 25 mg of carvedilol twice daily and 50 mgof metoprolol twice daily for patients weighing less than 85kg. After six months of treatment, all the tests performed atbase line were repeated.
Random assignment to placebo was stopped on January 13, 1998,when the estimated sample size had been reached for the detectionof differences in -adrenergic–receptor mRNA expressionand protein levels; 44 patients had been enrolled. Nine additionalpatients were then enrolled and randomly assigned to treatmentwith metoprolol or carvedilol. In these additional patients,the analysis of mRNA expression was expanded to include gene-chiptechnology,11 which took the place of measurement of -adrenergic–receptorproteins. A total of 53 patients participated in the study:15 were randomly assigned to placebo, 17 to metoprolol, and21 to carvedilol.
Base-line measurements of mRNA and receptor protein in these53 patients with idiopathic dilated cardiomyopathy were comparedwith measurements in 8 patients with normal left ventricularfunction who underwent endomyocardial biopsy to rule out inflammatoryor infiltrative myocardial disease or as part of a chemotherapyprotocol.7
Measurements of Gene Expression and -Adrenergic– Receptor Proteins
Right-sided heart catheterization and biopsy of right ventricularseptal endomyocardium were performed from the right internaljugular vein with the use of combined fluoroscopic and echocardiographicguidance, as previously described.7 Total RNA was extractedfrom two, three, or four endomyocardial-biopsy specimens, aspreviously described.7 In the extracted RNA, the amount of mRNAthat encoded 1- and 2-adrenergic receptors, - and -myosin heavychain, atrial natriuretic peptide, and sarcoplasmic reticulumcalcium ATPase was measured by the reverse-transcription quantitativepolymerase chain reaction with the use of previously describedmethods and primers for each reverse-transcribed complementaryDNA.7
The total density of -adrenergic–receptor and 1- and 2-adrenergic–receptorsubtypes was measured in biopsy specimens as previously described,7after extensive washing (three washes with a buffer composedof 20 mM TRIS, 150 mM sodium chloride, and 1 mM ascorbate atpH 7.8 and 4°C) to remove bound therapeutically administeredbeta-blockers. Plasma norepinephrine was measured in coronary-sinusand arterial blood by a radioenzymatic method.12
Measurements of Ejection Fraction
Left ventricular and right ventricular ejection fractions weremeasured by in vitro red-cell labeling and radionuclide ventriculography,as previously described.13,14 The results were expressed interms of ejection-fraction (EF) units, calculated by dividingthe stroke volume by the end-diastolic volume and multiplyingby 100.
Statistical Analysis
The investigators had full access to the data and performedthe analyses independently of the sponsor. Ejection fractionswere measured at base line and on completion of the six-monthstudy in a total of 49 patients, who were divided into thosewho had a response (predefined as an increase in left ventricularejection fraction by at least 5 EF units) during this periodand those who did not have such a response. Potential differenceswithin subgroups of patients with a response and subgroups ofthose without a response were assessed by paired t-tests performedon base-line measurements and end-of-study measurements. Unpairedt-tests and Mann–Whitney tests were used to assess differencesbetween controls and patients with cardiomyopathy, between theplacebo group and the combined beta-blocker groups, and betweenthe patients with a response and those without a response. Analysisof variance with the Bonferroni adjustment was used to assessdifferences among the three treatment groups (placebo, metoprolol,and carvedilol). A test for interaction was used to examinechanges in gene expression and -adrenergic–receptor proteinlevel in patients with a response and those without a responsein the combined beta-blocker group as compared with changesin the corresponding subgroups in the placebo group. A testfor interaction was also used to assess potential differencesbetween the metoprolol group and the carvedilol group. Contingency-tableanalysis was used to detect differences in binary variablesamong treatment groups. All the tests were two-sided, and aP value of less than 0.05 was considered to indicate statisticalsignificance.
Results
Base-Line Characteristics and General Outcomes
Table 1 presents the base-line characteristics of the 49 patientswho completed the trial. There were no significant differencesamong the treatment groups with respect to demographic characteristics,ventricular function, or hemodynamic variables. The patientswith dilated cardiomyopathy were relatively young (50 to 56years), with moderate-to-severe left ventricular dysfunction(left ventricular ejection fraction, 19 to 25 EF units), andhad high levels of cardiac adrenergic activity (coronary-sinusnorepinephrine level, >800 pg per milliliter). All the patientstolerated the initiation of treatment and the initial increasein the dose of study medication. All 15 of the patients whoreceived placebo, 14 of the 17 patients who received metoprolol,and 20 of the 21 patients who received carvedilol completedthe six-month treatment period. Of the patients who receivedmetoprolol, one underwent cardiac transplantation and two withdrewfor other reasons. One patient who received carvedilol diedsuddenly, six weeks after enrollment. The mean (±SD)total daily doses of metoprolol and carvedilol in the groupsof patients who received those drugs and who completed the studywere 125±47 mg and 70±29 mg, respectively. Noneof the patients had complications of endomyocardial biopsy orright-sided heart catheterization. No infiltrative or inflammatoryprocesses were identified by light microscopy, which revealedevidence of hypertrophy and variable amounts of interstitialfibrosis in all the patients.
Table 1. Base-Line Characteristics of the Patients with Idiopathic Dilated Cardiomyopathy Who Completed the Study.
Base-line mRNA expression in the 45 patients with idiopathicdilated cardiomyopathy and complete data for this variable aregiven in Table 2, as are base-line -adrenergic–receptorprotein levels in the 36 patients with complete data for thatvariable. The patients with idiopathic dilated cardiomyopathyhad lower levels of mRNA for 1-adrenergic–receptor, -myosinheavy chain, and sarcoplasmic-reticulum calcium ATPase thanthe eight control patients, and they had higher levels of atrialnatriuretic peptide mRNA and somewhat (but not significantly)higher levels of -myosin heavy chain mRNA. In addition, thelevel of 1-adrenergic–receptor proteins and its proportionof the total level of -adrenergic–receptor proteins werelower in the patients with idiopathic dilated cardiomyopathythan in the controls, as was (to a marginal degree) the total-adrenergic–receptor protein level (P=0.057). Among thethree treatment groups, the only base-line difference in mRNAexpression or receptor-protein levels was a lower level of 2-adrenergic–receptorprotein in the carvedilol group (15.0±6.4 fmol per milligram)than in the placebo group (27.1±14.5 fmol per milligram,P=0.02).
Table 2. Base-Line mRNA Expression and Protein Level in the Control Patients and the Patients with Idiopathic Dilated Cardiomyopathy.
Effect of Treatment with Placebo, Metoprolol, or Carvedilol
Of the measurements listed in Table 1 and Table 2, there werestatistically significant differences among treatment groupsin the change in left ventricular ejection fraction, in whichboth the metoprolol group and the carvedilol group had greatermean (±SE) increases (13.9±2.5 and 15.5±2.9EF units, respectively) than the placebo group (4.2±2.8EF units, P=0.015 by analysis of variance); the change in leftventricular stroke-work index, in which the carvedilol grouphad a greater increase than the placebo group (11.7±3.6vs. 0.0±2.6 ml per beat per square meter of body-surfacearea, P=0.04); and the change in peak heart rate during exercise,in which both beta-blocker groups had greater decreases (29.3±5.8beats per minute in the metoprolol group and 28.6±4.7beats per minute in the carvedilol group) than the placebo group(2.8±5.3 beats per minute, P=0.005). When the beta-blockergroups were combined, changes in these variables were significantlydifferent from changes in the placebo group; there was alsoa greater reduction in the heart rate at rest in the combinedbeta-blocker group.
Changes in Functional Class, Hemodynamic Variables, Functional Capacity, Ventricular Function, and Coronary-Sinus Norepinephrine
To determine what changes are specifically associated with improvementin left ventricular function and reversal of remodeling, wedivided the placebo, metoprolol, and carvedilol groups intosubgroups according to the presence or absence of a response(an increase in left ventricular ejection fraction of at least5 EF units) after six months of treatment. In the placebo group,there were 5 patients with a response and 10 without a response;in the metoprolol group, there were 12 with a response and 2without a response; and in the carvedilol group, there were16 patients with a response and 4 without a response (P=0.003by contingency-table analysis). In a test for interaction, changesin left ventricular ejection fraction, hemodynamic variables,and gene expression did not differ among the four response ornonresponse subgroups of patients who were taking metoprololor carvedilol. In subsequent analyses the patients who had aresponse with either beta-blocker were combined, as were thosewho did not have a response with either beta-blocker.
There were differences between patients with a response andthose without a response in both the placebo group and the combinedbeta-blocker groups with respect to left ventricular ejectionfraction and right ventricular ejection fraction, but with respectto no other variables (Table 3). According to peak heart rateduring exercise, the response and nonresponse subgroups amongthe patients who received beta-blockers had nearly identicaldegrees of beta-blockade; their decreases in heart rate duringexercise were 28.9 and 28.8 beats per minute, respectively.
Table 3. Changes in Ventricular Function, Hemodynamic Variables, Functional Capacity, and Cardiac Adrenergic Drive during the Six-Month Study, According to the Presence or Absence of an Increase in Left Ventricular Ejection Fraction with Treatment.
Placebo-treated patients who had a response (in terms of leftventricular ejection fraction) also had an improvement in rightventricular ejection fraction, but they had no statisticallysignificant change in any other variable during the six-monthstudy (Table 3). There were no significant changes in the subgroupof placebo-treated patients who did not have a response. Patientsin the beta-blocker group who had an improvement in left ventricularejection fraction also had increases in right ventricular ejectionfraction, stroke-volume index, and left ventricular stroke-workindex and decreases in New York Heart Association class, heartrate at rest, peak heart rate during exercise, mean pulmonary-arterypressure, and mean pulmonary-capillary wedge pressure. In contrast,the only change in the subgroup of beta-blocker–treatedpatients who did not have a response was a reduction in peakheart rate during exercise.
Changes in Gene Expression and Receptor Density
Figure 1 shows data for changes in the quantity of mRNA andin -adrenergic–receptor protein levels in the subgroupsof patients with or without a response in the placebo groupand the combined beta-blocker groups. In the placebo group,there were no significant differences between patients witha response and those without a response in either the amountof any mRNA or the levels of -adrenergic–receptor proteins.In contrast, among the beta-blocker–treated patients,those with a response had an increase in the amount of -myosinheavy chain mRNA and sarcoplasmic-reticulum calcium ATPase mRNA,as well as a decrease in -myosin heavy chain mRNA (Figure 1B).In a test for interaction, the difference between the responseand nonresponse subgroups in the change in sarcoplasmic-reticulumcalcium ATPase mRNA was significant (P=0.046), but the changesin mRNA for myosin heavy-chain isoforms were not significant,in the placebo group as compared with the beta-blocker group.Among the beta-blocker–treated patients, there were nosignificant differences or trends between those with a responseand those without a response with respect to changes in 1- or2-adrenergic–receptor mRNA or protein levels (Figure 1Band Figure 1D, respectively).
Figure 1. Changes in Myocardial Messenger RNA (mRNA) Expression and -Adrenergic–Receptor Protein Levels.
Panels A and B show changes between base line and the end of the six-month study in the abundance of myocardial mRNA for six contractility-regulating or hypertrophy-regulating proteins in patients who received placebo or a beta-blocker. The changes in patients who had an improvement in left ventricular ejection fraction (a "response," defined as an increase by at least 5 ejection fraction [EF] units) were compared with the changes in patients who did not have such a response. Gene expression is shown as molecules of mRNA per microgram of total RNA on a logarithmic scale; I bars represent standard errors, plotted within the unit scales of the nominal absolute changes. Panels C and D show changes in the levels of -adrenergic–receptor proteins in patients given placebo or a beta-blocker. Changes in patients who had a response were compared with changes in patients who did not have a response. I bars represent standard errors. The asterisk indicates P<0.10 for the change between the base-line value and the value measured at six months, by the paired t-test; the daggers P<0.05 for the comparison with the placebo group by the test for interaction; the double daggers P<0.05 for the change between the base-line value and the value measured at six months, by the paired t-test; and the section marks P<0.05 for the comparison with patients who did not have a response. Each panel shows results for patients with complete data for the indicated mRNA and receptor-protein measurements.
For changes within the subgroups shown in Figure 1, among thesmall number of patients in the placebo group who had a response,there were no significant changes in mRNA expression or -adrenergic–receptorprotein levels during the treatment period (Figure 1A and Figure 1C,respectively); the increase in -myosin heavy chain mRNAreached a significance level of P=0.15. Among the patients inthe placebo group who did not have a response, there were increasesover time in total -adrenergic–receptor level, 1-adrenergic–receptorlevel, and the percentage of 1-adrenergic receptor (Figure 1C),and there was a trend toward a decrease in the expression ofatrial natriuretic peptide mRNA (Figure 1A).
Among the patients in the combined beta-blocker groups who hada response, there were increases over time in the amount ofmRNA for 2-adrenergic–receptor, sarcoplasmic-reticulumcalcium ATPase, and -myosin heavy chain (Figure 1B) and in total-adrenergic–receptor and 1-adrenergic–receptor proteinlevels (Figure 1D). The subgroup of beta-blocker–treatedpatients with a response also had a decrease in the expressionof atrial natriuretic peptide mRNA (Figure 1B). Among the beta-blocker–treatedpatients without a response, there was a trend toward an increasein the expression of -myosin heavy chain mRNA and no significantchange in any other mRNA or receptor measurement (Figure 1Band Figure 1D).
Discussion
Treatment of patients with dilated cardiomyopathy results inimproved intrinsic systolic function (assessed in terms of ejectionfraction or more load-independent indexes1) and a reversal ofcardiac remodeling (assessed in terms of ejection fraction,1,8,15ventricular volume13,14 or dimension,16,17,18 or left ventricularmass and chamber shape17,18). According to the definition ofa "response" as an increase in left ventricular ejection fractionof at least 5 EF units, these favorable changes occur in 50to 70 percent of beta-blocker–treated patients19,20,21,22(62 percent in the Multicenter Oral Carvedilol Heart FailureAssessment [MOCHA] Trial22 [unpublished data]). Use of the leftventricular ejection fraction to measure the response to a beta-blockerallows assessment of both intrinsic systolic function23 andthe degree of cardiac remodeling,15 the two fundamental physiologicalprocesses that characterize dilated cardiomyopathy,8,24 becausethe calculation incorporates end-systolic volume in the numeratorand end-diastolic volume in the denominator. Moreover, in dilatedcardiomyopathy, left ventricular ejection fraction is a majordeterminant of clinical outcome,25,26 and improvement in thisvariable is probably related to the substantial clinical benefitproduced by beta-blocking agents.1,8,27
We reasoned that time-dependent improvement in idiopathic dilatedcardiomyopathy with beta-blocker therapy would be accompaniedby changes in myocardial gene expression, defined as the quantityof mRNA or proteins in the steady state. Three different categoriesof genes involved in the regulation of contractility3 were assessed:-adrenergic receptors, sarcoplasmic-reticulum calcium ATPase(which is involved in calcium handling), and the contractile-proteinisoforms -myosin and -myosin heavy chain. In addition, the mRNAexpression of one protein directly involved in pathologic hypertrophy(-myosin heavy chain) and of one molecular marker of hypertrophy(atrial natriuretic peptide) was measured. Gene expression inall three categories of contractility-regulating genes was initiallyabnormal in the patients with idiopathic dilated cardiomyopathy,as compared with the controls. The investigational strategywas to study changes in gene expression in biopsy specimensfrom ventricles that showed phenotypic improvement as comparedwith those that did not show improvement, in beta-blocker–treatedas compared with placebo-treated patients. Right ventricularseptal specimens were used for gene-expression measurementsand were related to changes in left ventricular ejection fractionfor three reasons: the ventricular septum is a shared wall;in idiopathic dilated cardiomyopathy, changes in gene expressionin the septum reflect those in both the right ventricular andleft ventricular free walls7; and the left ventricular ejectionfraction is more reliably measured than the right ventricularejection fraction.28
The main finding was that in idiopathic dilated cardiomyopathy,improvement in left ventricular ejection fraction by beta-blockingagents is specifically associated with favorable changes inthe expression of genes encoding sarcoplasmic-reticulum calciumATPase and the and isoforms of myosin heavy chain, but notthe genes encoding -adrenergic receptors. The changes in sarcoplasmic-reticulumcalcium ATPase and the myosin heavy chains, coupled with a statisticallysignificant reduction in the expression of atrial natriureticpeptide mRNA, indicate that beta-blocker therapy is associatedwith molecular remodeling in the form of reversal of inductionof elements of the "fetal" gene program29,30 in patients whohave a favorable myocardial response to treatment. There wereno differences in mean pulmonary capillary-wedge pressure ormean systemic arterial pressure between the beta-blocker–treatedpatients with a response and those without a response, indicatingthat regression of the fetal-gene program was not the resultof changes in loading conditions.
In terms of the cognate proteins, the increase in the expressionof sarcoplasmic-reticulum calcium ATPase and the fast-contracting-myosin heavy chain, plus the decrease in the expression ofthe slow-contracting -myosin heavy chain, would improve contractilefunction, and the decreased expression of -myosin heavy chainwould diminish pathologic hypertrophy. However, since fetal-geneproteins were not measured in this study, it is not clear whetherthe observed changes at the mRNA level led to an improvementin phenotype. A variety of other gene products capable of influencingcontractile function and pathologic hypertrophy were also notmeasured in this study.
Favorable changes in the expression of -myosin heavy chain mRNAtended to occur in the small number of placebo-treated patientswith a response as well as in the more numerous beta-blocker–treatedpatients with a response. In contrast, the up-regulation ofmRNA expression of sarcoplasmic-reticulum calcium ATPase inassociation with improvement in left ventricular function wasobserved only in the beta-blocker–treated patients whohad a response. In experimental models, -adrenergic stimulationcan down-regulate the expression of the gene encoding sarcoplasmic-reticulumcalcium ATPase,31,32 as well as induce the fetal pattern ofexpression of myosin heavy chain.32 In view of the high levelsof cardiac adrenergic activity present in the study population,we speculate that -adrenergic stimulation contributed to inductionof a pathological fetal gene program, which was reversed bybeta-blockade more comprehensively and frequently than by placebotreatment.
In the current study, the degrees of beta-blockade producedby metoprolol (a selective 1-adrenergic–receptor blockingagent) and carvedilol (which blocks 1-, 2-, and 1-adrenergicreceptors)8 were substantial and nearly identical, as assessedby a reduction in peak heart rate during exercise. There wereno qualitative differences between metoprolol and carvedilolin their effects on any measurement, but a larger sample maybe required to detect such differences. In patients with a responsein left ventricular ejection fraction, treatment with eitherdrug was associated with increases in the amount of -myosinheavy chain and sarcoplasmic-reticulum calcium ATPase mRNA anddecreases in -myosin heavy chain mRNA. These findings probablyrepresent the molecular class effects of 1-adrenergic–receptorblockade.
Supported by grants from the National Institutes of Health (1R01-HL48013from the National Heart, Lung, and Blood Institute and M01-RR00051and M01-RR00064 from the National Center for Research Resources)and by Glaxo SmithKline. Drs. Gilbert, Abraham, and Bristowhave served as paid consultants to Glaxo SmithKline, and Dr.Bristow has served as a paid consultant to AstraZeneca. Dr.Bristow is a founder, officer, and stockholder in Myogen, whichowns a license to aspects of the current study that are coveredin a patent application.
We are indebted to Laurel Hunter and Jana McPherson for assistancein the preparation of the manuscript and figure.
Source Information
From the Division of Cardiology and the Cardiovascular Institute, University of Colorado Health Sciences Center, Denver (B.D.L., W.T.A., W.A.M., D.F., E.E.W., J.L., T.T., A.D.R., R.A.Q., M.R.B.); and the Division of Cardiology, University of Utah Health Sciences Center, Salt Lake City (E.M.G., P.L.).
Address reprint requests to Dr. Bristow at the Division of Cardiology, University of Colorado Health Sciences Center, 4200 E. 9th Ave., Campus Box B139, Denver, CO 80262.
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