Growth Hormone Replacement Delays the Progression of Chronic Heart Failure Combined With Growth Hormone Deficiency

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JACC: Heart Failure Vol. 1, No. 4, 2013� 2013 by the American College of Cardiology Foundation ISSN 2213-1779/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jchf.2013.04.003

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Growth Hormone Replacement Delays theProgression of Chronic Heart Failure CombinedWith Growth Hormone Deficiency

An Extension of a Randomized Controlled Single-Blind Study

Antonio Cittadini, MD,* Alberto M. Marra, MD,* Michele Arcopinto, MD,* Emanuele Bobbio, MD,*

Andrea Salzano, MD,* Domenico Sirico, MD,* Raffaele Napoli, MD,* Annamaria Colao, MD,ySalvatore Longobardi, MD,z Ragavendra R. Baliga, MD,x Eduardo Bossone, MD,k Luigi Saccà, MD*

Naples, Rome, and Salerno, Italy; and Columbus, Ohio

From the *

Sciences, U

Clinical En

zMedical L

vascular Me

Division, Ca

Salerno, Sal

from Merck

authors repo

to disclose.

Manuscri

ded From

Objectives T

Department of Internal

niversity “Federico II,” N

docrinology and Oncolo

iaison Office, Merck Sero

dicine, The Ohio State Un

va dei Tirreni-Amalfi Co

erno, Italy. This study ha

Serono and Ipsen. Dr. Lo

rted that they have no rel

pt received March 23, 201

: http://heartfailure.o

his study sought to evaluate the efficacy and safety of long-term growth hormone (GH) replacement therapy inGH-deficient patients with chronic heart failure (CHF).

Background R

ecent evidence indicates that growth hormone deficiency (GHD) affects as many as 40% of patients with CHF, andshort-term GH replacement causes functional benefit. Whether long-term GH replacement also affects CHFprogression is unknown.

Methods T

he study is an extension of a previous randomized, controlled single-blind trial that screened 158 consecutive CHFpatients (New York Heart Association classes II to IV) and identified 63 who had GHD by the growth hormonereleasing hormone plus arginine test. Fifty-six patients were randomized to receive either GH therapy or standardCHF therapy. Patients were evaluated at baseline and after a 4-year follow-up. The primary endpoint was peakoxygen consumption (VO2). Secondary endpoints included left ventricular (LV) ejection fraction and volumes, serumamino terminal fragment of the pro-hormone brain-type natriuretic peptide, quality of life, and safety.

Results S

eventeen patients in the GH group and 14 in the control group completed the study. In the GH group, peak VO2

improved over the 4-year follow-up. The treatment effect was 7.1 � 0.7 ml/kg/min versus �1.8 � 0.5 ml/kg/minin the GH and control groups, respectively. At 4 years, LV ejection fraction increased by 10 � 3% in the GH group,whereas it decreased by 2 � 5% in control patients. The treatment effect on LV end-systolic volume index was�22 � 6 ml and 8 � 3 ml/m2 in the GH and control groups, respectively (all p < 0.001). No major adverse eventswere reported in the patients who received GH.

Conclusions A

lthough this is a preliminary study, the finding suggests a new therapeutic approach to a large proportion of GHDpatients with CHF. (J AmColl Cardiol HF 2013;1:325–30)ª 2013 by the American College of Cardiology Foundation

A recent model of chronic heart failure (CHF) predicts thatdeficiency of the main anabolic forces plays a central role,not only with regard to the functional abnormalities, but alsoin terms of disease progression and mortality (1). In thiscontext, the growth hormone (GH)/insulin-like growthfactor (IGF)-1 axis is of the utmost importance because: 1) it

Medicine, Cardiovascular and Immunological

aples, Italy; yDepartment of Molecular and

gy, University “Federico II,” Naples, Italy;

no S.p.A., Rome, Italy; xDivision of Cardio-

iversity, Columbus, Ohio; and the kCardiologyast Hospital, Heart Department, University of

s been supported in part by unrestricted grants

ngobardi is a Merck Serono employee. All other

ationships relevant to the contents of this paper

3; accepted April 1, 2013.

nlinejacc.org/ by Andrea Salzano on 08/16/2

is the most effective anabolic system in nature; 2) betweenone-third and two-thirds of CHF patients are also affectedby GH or IGF-1 deficiency (1,2); and 3) GH and IGF-1play an essential physiological role in supporting cardiacgrowth and performance (3). On this ground, it is reasonableto ask whether correction of growth hormone deficiency(GHD) in CHF patients improves their functional capacity,and more importantly, whether it delays CHF progression.

We recently reported positive effects of 6-month GHreplacement on physical and cardiac performance in CHFpatients with coexisting GHD (4). Notwithstanding theencouraging results, several critical issues remain unsettled.Because GH is an anti-insulin hormone, its long-termadministration may cause insulin resistance or clinicaldiabetes, both of which are strong predictors of CHFprogression (5,6). Another critical issue is whether the

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Abbreviationsand Acronyms

CHF = chronic heart failure

CPET = cardiopulmonary

exercise test

GH = growth hormone

GHD = growth hormone

deficiency

GHRH = growth hormone

releasing hormone

HbA1c = glycosylated

hemoglobin

IGF = insulin-like growth

factor

LV = left ventricular

MLWHFQ = Minnesota-Living

with Heart Failure

Questionnaire

NT-proBNP = serum amino

terminal fragment of the pro-

hormone brain-type

natriuretic peptide

NYHA = New York Heart

Association

VCO2 = carbon dioxide

production

VE = ventilation per minute

VO2 = oxygen consumption

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beneficial effects documentedafter a brief course of GHreplacement tend to vanish withtime or persist, or even begetfurther benefit. Consequently, wedesigned this study to determinethe effects of a very long-termreplacement therapy in patientswith CHF and concomitantGHD.

Methods

Patients. This is an extension ofa previous controlled, single-blind single-center study (4), inwhich 158 consecutive CHFpatients (New York Heart Asso-ciation [NYHA] classes II to IV)were screened with regard totheir GH/IGF-1 status by thegrowth hormone releasing hor-mone (GHRH) plus argininestimulation test. As describedelsewhere (4), according to na-tional guidelines, GHD in adultswas diagnosed if peak GH circu-lating levels were <9 mg/l afterthe GHRH plus arginine stimu-

lation test. Of the 63 patients who satisfied the criteria forGHD, 56 of them were enrolled in the trial. Twenty-eightpatients were randomly assigned to receive subcutaneoussomatropin (rDNAorigin) for injectionGH (Saizen,Merck-Serono International, Geneva, Switzerland, or NutropinAq,Ipsen, Paris, France) at a dose of 0.012 mg/kg every secondday, on top of standard therapy for CHF. GH was keptrefrigerated and administered using sterile disposablesyringes and needles. Small volume syringes were used so theprescribed dose could be drawn from the vial with reasonableaccuracy. The other 28 patients only received standardtherapy for CHF and served as a control group. The inclusioncriteria were as follows: patients of either sex affected byCHFNYHA classes II to IV secondary to ischemic or idiopathic-dilated cardiomyopathy; ages 18 to 80 years; stable medica-tions for at least 1month, including beta-blockade that had tobe started at least 5 months before entering the study; leftventricular (LV) ejection fraction 40% or less and LV end-diastolic dimension 60 mm or more; and informed consent.Exclusion criteria included active proliferative or severenonproliferative diabetic retinopathy, active malignancy, anyevidence of progression or recurrence of an underlyingintracranial tumor, unstable angina or recent myocardialinfarction, severe liver disease, and serum creatinine levels>2.5mg/dl. Racial distributionwas homogenous in our studypopulation because all patients were Caucasian, which wasstrongly representative of the epidemiological features of our

nlinejacc.org/ by Andrea Salzano on 08/16/2

region. Because this 6-month course of GH administrationexerted positive effects on exercise capacity and cardiacfunction, we hypothesized that very long-termGH treatmentcould have an effect on the progression of CHF. Therefore,we amended the initial protocol by setting a 4-yearfollow-up and peak oxygen consumption (VO2) as thestudy primary endpoint. Written informed consent was ob-tained from each patient, and the study protocol wasapproved by theEthicsCommittee of theUniversity FedericoII (NCT01576861).Measurements. Standard 12-lead electrocardiography wasperformed in each patient before and after 6 months of GHtreatment to assess heart rate, conduction, and repolarizationabnormalities. Ambulatory electrocardiographic monitoringwas performed at baseline and after 6 months. Quality of lifewas evaluated with the Minnesota-Living with Heart FailureQuestionnaire (MLHFQ) (7).

All patients underwent an incremental symptom-limitedcardiopulmonary exercise test (CPET) on a bicycle ergom-eter. After a 1-min warmup period at 0-W workload, a rampprotocol of 10 W/min was started and continued untillimiting symptoms or other indications for exercise termi-nation appeared (4,8). Respiratory gas exchange measure-ments were obtained breath-by-breath using a commerciallyavailable system (Vmax 29C, Sensormedics, Yorba Linda,California). VO2 was recorded as the mean value of VO2

during the last 20 s of the test. The ventilatory anaerobicthreshold was detected using the V-slope method. Theventilation per min (VE) versus carbon dioxide production(VCO2) relationship was measured by plotting ventilationagainst VCO2 obtained every 10 s of exercise (VE/VCO2

slope). The VE/VCO2 slope was calculated as a linearregression function, excluding the nonlinear part of therelationship after the onset of acidotic drive to ventilation (4).

An ultrasound system equipped with a 2.5-MHz multi-frequency transducer (Aplio SSA-770A, Toshiba, Japan) wasused for complete M-mode, 2-dimensional, and Dopplerechocardiographic analyses. M-mode and 2-dimensionalrecordings were made with the patients in the lateral recum-bent position, according to previously published methods (9).Intraobserver and interobserver variabilities were 9.2% and16.4% for LV mass, 2.4% and 3.1% for LV dimensions, and3.9% and 4.6% for ejection fraction, respectively. Details ofthe variability coefficients of the measurements of diastolicfunction are reported elsewhere (9).

Serum GH was assayed with an immunoradiometric assaymethod (Pharmacia & Upjohn Diagnostic AB, Uppsala,Sweden) and serum IGF-1 with a radioimmunoassay usinga monoclonal antibody after acid-ethanol extraction. Serumamino terminal fragment of the pro-hormone brain-typenatriuretic peptide (NT-proBNP) concentrations were mea-sured by an electrochemiluminescence immunoassay (RocheDiagnostics, Indianapolis, Indiana) using a Roche Elecsysanalyzer. The sensitivity of the assay was 5 pg/ml. We usedcore laboratories blinded to treatment allocation for allmeasurements.

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Statistical analysis. The results are expressed as means �SEM. Treatment effect (D changes in GH group vs. Dchanges in control group) was evaluated by an unpaired t-test.The primary variable of the studywas peakVO2. Previous datashowed that peak VO2 increased by 1.8 ml/kg/min over thecontrol group after 6-month GH replacement (4). In a recentstudy that demonstrated the beneficial effects of long-termphysical training in CHF patients, the difference in peakVO2 between treated and untreated patients at 4 years was 4 to4.5ml/kg/min (10). Based on these observations, we reasonedthat the effect of long-term GH replacement could beconsidered clinically relevant in terms of disease progression, ifthe 4-year D change in peak VO2 between GH and controlpatients was at least 4 ml/kg/min. By setting a significancelevel of 5%, a study power of 80%, and a SD of 4 U in theVO2measurements, a total sample of 34 patients was requiredto reach the endpoint. Therefore, we were confident that theinitial sample of 58 patients was adequate to test thehypothesis, even assuming a 40% dropout rate during follow-up because of adverse events or noncompliance. Consideringthe high dropout rate, the statistical plan for dealing withmissing data was a sensitivity analysis that counted missingdata as no changes in values.

Results

Baseline characteristics of the 2 groups of patients thatreached 4 years of follow-up are shown in Table 1. In theGH group, peak VO2 increased remarkably, and at 4 years,reached the value of 21 � 1 ml/kg/min, which was 2-foldhigher than the corresponding value of the control group(11.8 � 0.2 ml/kg/min) (Table 2). Comparison of the Dchanges (baseline 4 years) in peak VO2 revealed that the

Table 1Baseline Characteristics of Patients Who HaveReached 4 Years of Follow-Up

Characteristics

ControlGroup

(n ¼ 14)

TreatmentGroup

(n ¼ 17) p Value

Age (yrs) 62.5 � 2 63.2 � 2 0.98

Male/female (n) 12/2 14/3 0.99

BMI (kg/m2) 27.3 � 1 28.3 � 1 0.54

Peak GH after stimulation test 3.50.3 3.50.5 0.79

Etiology: ischemic/nonischemic (n) 11/3 13/4 0.99

Diabetes (%) 24 25 0.99

SBP/DBP (mm Hg) 126/77 127/70 0.99

ACE or ARB (%) 92 89 0.99

Beta-blockers (%) 94 92 0.99

Digoxin (%) 16 20 0.99

Diuretics (%) 100 100 1.00

Spironolactone (%) 32 35 0.99

CRT (%) 36 35 0.99

Values mean � SEM, n, or %.ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; BMI ¼ body mass

index; CRT ¼ cardiac resynchronization therapy; DBP ¼ diastolic blood pressure; GH ¼ growthhormone; NYHA¼ New York Heart Association; SBP¼ systolic blood pressure; SEM¼ standard errorof the mean.

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treatment effect was 7.1 � 0.7 ml/kg/min in the GH group(n ¼ 17) and �1.8 � 0.5 in the control group (n ¼ 14)(p < 0.001). The VE/VCO2 slope decreased in the GHgroup from 32 � 1 to 29 � 2, indicating improved venti-latory efficiency. However, the treatment effect did notreach statistical significance. GH replacement induced LVreverse remodeling, as documented by the significantreductions of both LV end-diastolic and end-systolicvolumes indexes (�23% and �37%, respectively) andcircumferential wall stress (�46%). Accordingly, LV ejec-tion fraction rose to 42 � 2% at 4 years, whereas in thecontrol group, it decreased slightly. The treatment effectwas 10 � 3% versus �2 � 5% in GH and control patients,respectively (p < 0.001). The slight reduction of LV massfollowing GH replacement therapy, although in theory incontrast to the known GH-induced, growth-promotingeffects, was accounted for by the remarkable reduction ofLV cavity size during follow-up.

The MLHF questionnaire score decreased by 26% in theGH group, and this was paralleled by a reduction of theNYHA class. Holter electrocardiography, performed every 6months, showed no significant differences between the 2groups in terms of arrhythmic events. Lown class rangedfrom 1A to 5 in all CHF patients. Specifically, in the GH-treated group, there was a reduction from Lown class 4A to1A in 2 patients, 4B to 2 in 4 patients, and in the other 11,the class remained unchanged. In the control group, 2patients had a decrease in Lown class from 4B to 4A, 7patients shifted from 2 to 4A, whereas in the other 5, Lownclass remained unchanged. The diuretic dose was decreasedin 8 patients of the GH group and increased in 3 patients ofthe control group. In the GH group, 5 patients with anejection fraction of less than 35% at the study start, in whomimplantable cardioverter-defibrillation was suggested, had anincrease in ejection fraction to more than 35% during thetreatment period; therefore, implantation was withheld.

Serum IGF-1 increased by 84% from baseline at 24months and remained stable at 48 months (77%). NT-proBNP rose from 3,940 � 1,050 pg/ml to 4,909 � 432pg/ml in the control group, whereas it decreased from3,201 � 900 pg/ml to 2,794 � 432 pg/ml in the GH group(p < 0.001 vs. control group). A significant correlation wasfound between the IGF-1 levels at 4 years and the values ofpeak VO2 (r ¼ 0.59; p < 0.05) and LV ejection fraction(r ¼ 0.55; p < 0.05).

Of the 56 patients originally enrolled, 17 and 14 patientsin the GH and control groups, respectively, completed the 4-year follow-up. Six patients in the GH group and 10 patientsin the control group died because of cardiac events. Of theremaining 5 patients in the GH group, 2 patients withdrewfrom the study because of arthralgia, 2 patients for personalreasons, and 1 patient underwent cardiac transplantation. Inthe control group, 1 patient died because of melanoma, and 2withdrew for personal reasons. Hospitalizations for wors-ening CHF were lower in the GH group than in the controlgroup (11 patients vs. 20 patients). Although the study was

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Table 2 CPET, Echocardiographic Data, Clinical Status, and Biochemical Parameters During Long-Term GH Replacement Therapy

Characteristics

Control GH D Change 0-4 yr

Baseline 4 Yrs Baseline 4 Yrs Control GH

p Value* p Valuey(n ¼ 28) (n ¼ 14) (n ¼ 28) (n ¼ 17) (n ¼ 14) (n ¼ 17)

Peak VO2 (ml/kg/min) 13.1 � 1 11.8 � 0.2 12.9 � 1 21 � 1z �1.8 � 0.5 7.1 � 0.7 0.001 0.001

VE/VCO2 slope 33 � 1 34 � 3 32 � 1 29 � 2 0.15 � 1.6 �2 � 1.3 0.21 0.23

Peak workload (W) 87 � 5 72 � 13 86 � 6 105 � 10 �7.0 � 1.6 10.3 � 7.5 0.05 0.05

RER 1.18 � 0.01 1.20 � 0.01 1.18 � 0.01 1.21 � 0.01 0.01 � 0.01 0.005 � 0.004 0.45 0.49

LV mass index (g/m2) 173 � 8 175 � 5 194 � 10 181 � 3 �7.9 � 8.8 �11.4 � 6.2 0.17 0.19

LV end-diastolic volumeindex (ml/m2)

123 � 6 136 � 8 1246 104 � 6 10 � 4 �18 � 8 0.07 0.06

LV end-systolic volumeindex (ml/m2)

86 � 6 95 � 11 85 � 5 60 � 4x 8 � 3 �22 � 6 0.005 0.001

End-systolic stress(kdynes/cm2)

409 � 8 484 � 11 398 � 34 259 � 11z 7,518 �13,221 0.01 0.01

Ejection fraction (%) 31 � 2 29 � 5 32 � 2 42 � 2z �2 � 5 10 � 3 0.001 0.001

NYHA functional class 2.7 � 0.2 3.1 � 0.3 2.6 � 0.1 1.6 � 0.2k 0.42 � 0.17 �0.38 � 0.14 0.001 0.002

MLWHFQ 47 � 7 46 � 3 46 � 4 34 � 8y 1.40.8 �9.81.2 0.001 0.001

IGF-1 (ng/ml) 97 � 11 82 � 12 94 � 8 166 � 12z �29.9 � 9.6 73.7 � 13 0.001 0.001

NT-proBNP (pg/ml) 3,940 � 1,050 4,909 � 432 3,201 � 900 2,794 � 432 1,239 � 121 �289 � 123 0.001 0.001

Values are mean � SEM. *Significance of the D changes between-group from baseline to 4 years. yadjusted significance of the D changes between-group from baseline to 4 years, after sensitivity analysis.zp < 0.001 from baseline. xp < 0.01 from baseline. kp < 0.05 from baseline.CPET ¼ cardiopulmonary exercise test; IGF ¼ insulin-like growth factor; LV ¼ left ventricular; MLWHHQ ¼ Minnesota Living With Heart Failure Questionnaire; RER: respiratory exchange rate;

SEM ¼ standard error of the mean; VCO2 ¼ carbon dioxide production; VE ¼ ventilation per min; VO2 ¼ oxygen consumption.

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not designed for hard clinical endpoints, it was noteworthythat there was a marked difference in the aggregate of deathand hospitalization for worsening CHF (17 and 31 events inthe GH and control groups, respectively).

In view of the considerable amount of missing data, weperformed a sensitivity analysis that counted the lost tofollow-up patients as no change in values. After thiscorrection, the improvements of all endpoints studiedremained statistically significant (Table 2). The finding wasnot unexpected because although the treatment effect waslower after the adjustment, this was paralleled by theconcomitant increase of the number of patients included inthe analysis. As a prototype, the final adjusted value of peakVO2 in the GH group was 17.3 � 1 ml/kg/min (p ¼ 0.008from baseline) and the adjusted treatment effect on the sameparameter was 4.3 � 0.8 ml/kg/min, whereas in the controlgroup these values were 12.2 � 0.5 ml/kg/min and �0.9 �0.3 ml/kg/min, respectively. In the active treatment group,the adjusted value of ejection fraction after 4-year follow-upwas 36 � 1.8% (p < 0.01 from baseline) and the correctedtreatment effect was 6.24 � 1.76%, whereas in the controlgroup, the values were 29.8 � 1.7% and 1.35 � 2.8%,respectively.Safety and tolerability. Except for 2 patients who com-plained of arthralgia, no other side effects of GH treatmentwere reported. GH induced no significant changes in themain biochemical and hormonal parameters. In particular,thyroid hormones, testosterone, and glycosylated hemoglobin(HbA1c) were unaffected byGH administration. Specifically,thyroid-stimulating hormone ranged from 2.2 � 1 mU/mlat baseline to 1.8 � 0.8 mU/ml after 4 years (p ¼ NS),free testosterone ranged from 435 � 12 ng/ml at baseline

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to 425 � 9 ng/ml after 4 years, and HbA1c ranged from7.3 � 0.9% at baseline to 7.5 � 1.2% after 4 years.

Discussion

The present study suggests that correction of GH deficitimproves exercise and cardiac performance of CHF patientsin an enduring way. Peak VO2, measured during CPET,was chosen as the study primary endpoint because it isa strong, independent predictor of CHF progression (11).

Against the small decrease observed in control patients,peak VO2 rose remarkably in the GH group, and thetreatment effect was well above the predicted value of 4ml/kg/min. The improvements in LV end-systolic volumeand ejection fraction were equally relevant; both areconsolidated predictors of survival. The value of peak VO2

above 20 ml/kg/min and that of ejection fraction above 40%,which was observed in the GH group at 4 years, are hardlycompatible with clinical CHF syndrome. Accordingly, theaverage NYHA class in the GH patients dropped to 1.6,which is midway between asymptomatic and mild CHF.The data on hospitalization for CHF and death, althoughinconclusive in view of the small sample size, are well inagreement with the functional response observed in the GHgroup. Altogether, the present study suggests that the sus-tained functional benefit of long-term GH replacementmust involve radical changes in the intimate mechanismsthat mediate the progression of CHF.

In this regard, several experimental and human studiesprovide the pathophysiological underpinnings for GHattenuation of pathological remodeling. Activation of theGH/IGF-1 axis promotes a unique pattern of adaptive

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myocardial growth characterized by preserved capillarydensity, absence of fibrosis and changes of calcium regulatoryproteins, and cardioprotection against ischemia-reperfusionand mechanical stretch (12–14). Furthermore, IGF-1increases myocardial contractility mainly through calciumsensitization of the myofilaments, which represent a down-stream mechanism not associated with arrhythmias (15).Reduction of apoptosis is another molecular hallmark of GH/IGF-1 activation and has been described by a number ofin vivo and in vitro studies (16,17). Endothelial nitric oxiderelease and vasodilation are further markers of the activation ofthe GH/IGF-1 pathway and may account for the salutaryvasodilatory actions of GH therapy (18). Importantly, GHalso beneficially influences respiratory and skeletal muscle,which are both impaired in CHF (19–21). Although it isdifficult to dissect the pleiotropic actions of enhanced GH/IGF-1 signaling, it is likely that the large improvements ofcardiopulmonary indexes could be accounted for by the well-described GH actions on peripheral muscle in addition to thebenefits on LV architecture and function. Taken together,GH and its mediator IGF-1 affect a broad array of relevanttargets of pathological remodeling that may have induced theremarkable reverse remodeling observed in the present study.

In the present study, we did record very few adverse effectsdue to GH replacement therapy (i.e., 2 cases of arthralgia).This is a well-known side effect of GH replacement, alsoreported by other investigators (22,23). The relatively lowprevalence of adverse effects is likely due to the replacementand not the pharmacological doses of GH employed in thepresent study, and is congruent with the largest databaseavailable, which indicates that GH replacement in adults iswell tolerated (24).

A few additional comments are warranted. First, at vari-ance with the progressive improvement of exercise capacity inthe GH group, LV volumes and ejection fraction showed thehighest response at 2 years and then tended to stabilize. Theexplanation may be that exercise capacity integratesthe multifaceted activity of GH/IGF-1 that goes beyond theheart and encompasses a variety of targets, including lung,skeletal muscle, endothelium, and energetic metabolism(3,25,26). Second, previous studies recently reviewed byArcopinto et al. (27) using pharmacological doses of GH inCHF patients have shown variable results. It must be stressedthat our data are not directly comparable to those reported bythese clinical trials because we used a relatively low replace-ment GH therapy in GHD patients with CHF, whereasprevious data were obtained from CHF patients treated withpharmacological doses of GH, independent of their GH/IGF-1 status. Although congruent with most of the 12published studies (26), our data are not congruent with the 2largest double-blind, placebo-controlled trials (28,29).Potential explanations include differences in the study design,duration of GH administration, and the lack of preliminaryassessment of the GH/IGF-1 status. In this regard, it hasbeen postulated that differences in the IGF-1 increment inresponse to GH may explain the variable results. This was

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confirmed by a meta-analysis of 12 studies in which theinvestigators showed significant relationships betweenthe IGF-1 response and GH treatment effects (30). Theoutstanding issue remains which CHF patients would displayhigher benefits after GH administration. Taken together, theresults of the present study suggest that noncachectic CHFpatients with low GH/IGF-1 activity may benefit better fromGH therapy because they display higher IGF-1 increases,paralleling improved outcome measures. We observeda significant correlation between the IGF-1 levels at 4 yearsand the values of peak VO2 (r ¼ 0.59; p < 0.05) and LVejection fraction (r ¼ 0.55; p < 0.05). These findings supportthe concept that patients with coexisting GHD and CHFrepresent a subset of patients who are highly responsive toreplacement therapy, whereas GH therapy in unselectedCHF patients yields unpredictable results.

Our population had a prevalence of GHD of almost 40%.Despite several studies that have addressed the prevalence ofIGF-1 deficiency (2,31,32), little evidence is availableregarding GHD prevalence in the CHF population. Ourdata are congruent with data reported by Broglio et al. (33),who showed a variable reduction of somatotroph respon-siveness in 53% of patients with dilated cardiomyopathy.Study limitations. Although the results of the presentstudy are encouraging, it is important to underline that thiswas a small, single-center, single-blind study. In addition tothe lack of a placebo arm, the large patient dropout repre-sents another limitation. However, care was taken that theinvestigators who performed all measurements were fullyblinded to the study protocol, and many parameters wereobjective and not easily biased. Specifically, all biochemical,imaging, and exercise tests were performed in facilitiesdifferent from the coordinating center by investigatorsunaware of the treatment protocol. Moreover, to deal withthe high dropout rate, we performed a sensitivity analysisthat counted those lost to follow-up as no change in values,and the improvements of all endpoints studied remainedstatistically significant.

Conclusions

The results from this preliminary single-blind study suggestthat more research is warranted to test the hypothesis thatlong-term GH replacement therapy could delay theprogression of CHF combined with GHD in a largemulticenter placebo-controlled double-blind trial.

Reprint requests and correspondence: Dr. Antonio Cittadini,Department of Internal Medicine, Cardiovascular and Immuno-logical Sciences, University of Naples Federico II, Via Pansini, 5,80131 Naples, Italy. E-mail: [email protected].

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Key Words: chronic heart failure - GH replacement - longterm.

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