Background Cardiac hypertrophy is a physiologic response thatallows the heart to adapt to an excess hemodynamic load. Wehypothesized that inducing cardiac hypertrophy with recombinanthuman growth hormone might be an effective approach to the treatmentof idiopathic dilated cardiomyopathy, a condition in which compensatorycardiac hypertrophy is believed to be deficient.
Methods Seven patients with idiopathic dilated cardiomyopathyand moderate-to-severe heart failure were studied at base line,after three months of therapy with human growth hormone, andthree months after the discontinuation of growth hormone. Standardtherapy for heart failure was continued throughout the study.Cardiac function was evaluated with Doppler echocardiography,right-heart catheterization, and exercise testing.
Results When administered at a dose of 14 IU per week, growthhormone doubled the serum concentrations of insulin-like growthfactor I. Growth hormone increased left-ventricular-wall thicknessand reduced chamber size significantly. Consequently, end-systolicwall stress (a function of both wall thickness and chamber size)fell markedly (from a mean [±SE] of 144±11 to85±8 dyn per square centimeter, P<0.001). Growth hormoneimproved cardiac output, particularly during exercise (from7.4±0.7 to 9.7±0.9 liters per minute, P = 0.003),and enhanced ventricular work, despite reductions in myocardialoxygen consumption (from 56±6 to 39±5 ml per minute,P = 0.005) and energy production (from 1014±100 to 701±80J per minute, P = 0.002). Thus, ventricular mechanical efficiencyrose from 9±2 to 21±5 percent (P = 0.006). Growthhormone also improved clinical symptoms, exercise capacity,and the patients' quality of life. The changes in cardiac sizeand shape, systolic function, and exercise tolerance were partiallyreversed three months after growth hormone was discontinued.
Conclusions Recombinant human growth hormone administered forthree months to patients with idiopathic dilated cardiomyopathyincreased myocardial mass and reduced the size of the left ventricularchamber, resulting in improvement in hemodynamics, myocardialenergy metabolism, and clinical status.
Idiopathic dilated cardiomyopathy is a common cause of cardiacdysfunction.1,2 It is characterized by progressive dilatationof the left ventricle (and sometimes the right ventricle aswell), unaccompanied by compensatory wall thickening. This accountsfor the marked elevation of left ventricular systolic wall stress,which is a function of both wall thickness and chamber size.3There is no specific therapy for dilated cardiomyopathy. Medicaltreatment is aimed at alleviating the symptoms of heart failure,and only cardiac transplantation offers lasting benefit to patientswith this condition.
Evidence is accumulating that growth hormone is a physiologicregulator of myocardial growth and performance.4,5 In patientswith congenital deficiency of growth hormone, cardiac growthand function are impaired.6,7 Administering growth hormone tosuch patients increases wall thickness and normalizes cardiacperformance.7,8 Conversely, a long-term excess of growth hormonecauses cardiac hypertrophy and a hyperkinetic syndrome, withincreased cardiac output and reduced vascular resistance.9,10In an experimental model of heart failure, insulin-like growthfactor I induced additional myocyte growth, which was associatedwith significant improvement of cardiac function.11 More recently,growth hormone itself was shown to improve cardiac functionin experimental heart failure.12
These observations provide a rationale for testing the effectof growth hormone in patients with heart failure due to dilatedcardiomyopathy. Growth hormone activates cardiac cell growth,without changing the collagen content of the myocardium or thecapillary density.11,12,13 It also induces physiologic ventricularremodeling, in which the growth response is not detrimentalbut instead is associated with enhanced contractile performance.11,12In addition, in models of long-term excess of growth hormonethe force of cardiac contraction is increased despite a redistributionof the myosin heavy-chain isoforms toward the V3 isoform, onethat is characterized by a low shortening velocity and ATPaseactivity.14,15 This finding has led to the hypothesis that byreducing the energy cost, growth hormone may improve the thermodynamicefficiency of the contractile apparatus.14 Consequently, growthhormone may be effective in the treatment of dilated cardiomyopathy,in which the high-energy phosphate reserve is depleted16,17and the ability to convert metabolic energy to mechanical workis impaired.18,19,20
In this preliminary study, we examined the effect of therapywith recombinant human growth hormone in seven patients withidiopathic dilated cardiomyopathy.
Methods
Study Patients
The study involved seven patients — five men and two women— with chronic heart failure caused by dilated cardiomyopathy.The mean (±SD) clinical duration of their condition was3.5±1.5 years, and their mean age was 46±9 years(range, 36 to 57). The criteria for enrollment in the studywere clinical evidence of heart failure despite conventionaltherapy; a left ventricular end-diastolic dimension greaterthan 60 mm, as measured by M-mode echocardiography; a left ventricularejection fraction below 40 percent, as assessed by two-dimensionalechocardiography; the ability to exercise for at least fiveminutes on a bicycle ergometer at 75 percent of the maximalcapacity; a stable hemodynamic condition for the previous sixmonths, as indicated by the absence of changes in the left ventricularejection fraction of more than 5 percent; and a normal sinusrhythm. The exclusion criteria were the presence of active myocarditis,substantial coronary-artery stenosis, valvular heart disease(except mild mitral regurgitation), systemic hypertension, hypertrophiccardiomyopathy, diabetes mellitus, and chronic alcoholism. Heartfailure was treated with digoxin, an angiotensin-converting–enzymeinhibitor (2.5 mg of ramipril per day), and a diuretic. Duringthis therapeutic regimen, five patients were in New York HeartAssociation functional class III and two were in class II. Writteninformed consent was obtained from each patient, and the studyprotocol was approved by the Ethics Committee of the Universityof Naples Federico II.
Study Protocol
All the patients were studied at three times: at base line,immediately after a three-month course of treatment with recombinanthuman growth hormone (Genotropin [potency, 3 IU per milligram],Pharmacia, Stockholm, Sweden), and three months after treatmentwas discontinued. Growth hormone was administered subcutaneouslyat a dose of 4 IU every other day (0.15 to 0.20 IU per kilogramof body weight per week), which is a low replacement dose forpatients with growth hormone deficiency.4 Standard medical therapyfor heart failure was continued throughout the study. Patientswere observed closely during the first week of therapy becauseof the potential sodium-retaining effect of growth hormone,which could aggravate congestive heart failure.21
Procedures
M-mode, two-dimensional, and Doppler echocardiographic measurementswere performed with an ultrasonographic system equipped witha 3.5-mHz transducer (Apogee Cx, Interspec, Ambler, Pa.), accordingto the recommendations of the American Society of Echocardiography.22Details of the procedure and variability coefficients of themeasurements are reported elsewhere.23 Left ventricular end-systolicstress, calculated according to Reichek et al.,24 served asan index of afterload. The patients' maximal exercise capacitywas determined before and after growth hormone treatment byupright bicycle ergometry, beginning with a workload of 25 watts,which was increased by 25 watts every two minutes. The testwas stopped when severe fatigue or dyspnea developed. The effectof growth hormone treatment on the quality of the patients'lives was assessed on the Patient's Self-rating Scale.25
Right-heart catheterization was performed in the morning afterthe patients had fasted overnight and had received no therapyfor 24 hours; no premedication was given. Pulmonary-artery andpulmonary-capillary wedge pressures were measured with a Swan–Ganzcatheter introduced through the right jugular vein. Cardiacoutput was determined in triplicate by the thermodilution techniquewith the use of the same catheter. The coronary sinus was cannulatedwith a double-thermistor catheter (Wilton-Webster Laboratories,Baldwin Park, Calif.), introduced through the brachial vein.This catheter was used to measure coronary blood flow by theconstant-infusion thermodilution technique26 and to obtain bloodsamples from the coronary sinus. The possibility of substantialcoronary-sinus reflux was excluded by monitoring the coronaryblood temperature after injecting cold saline into the rightatrium. A brachial artery was cannulated percutaneously withan 18-g catheter to record arterial blood pressure and to obtainarterial blood samples. After a stabilization period of 20 to30 minutes, the resting hemodynamic measurements were taken,and two consecutive pairs of blood samples from the artery andfrom the coronary sinus were withdrawn simultaneously. The patientsthen performed submaximal physical exercise with a bicycle ergometerthat was attached to the catheterization table. The workloadwas gradually increased to a level corresponding to 75 percentof the peak workload reached in the maximal-exercise test atbase line. This workload was kept constant to allow the variousmeasurements to be taken under similar conditions before andafter growth hormone treatment. After at least five minutesof exercise at the final workload level, two pairs of arterialand coronary-sinus blood samples were withdrawn for the assayof blood gases, and the hemodynamic measurements were repeated.Blood oxygen and carbon dioxide were measured by an automatedblood gas analyzer (ABL 520, Radiometer, Copenhagen, Denmark).Serum growth hormone, insulin-like growth factor I, thyroidhormone, and thyrotropin were measured before and during growthhormone treatment with the use of commercially available radioimmunoassaykits.
Calculations
Systemic vascular resistance (dyn · sec · cm-5)was calculated with the following formula: 80 x (mean arterialpressure - right atrial pressure) ÷ cardiac output. Pulmonaryvascular resistance was calculated as follows: 80 x (mean pulmonarypressure - capillary wedge pressure) ÷ cardiac output.Left ventricular mechanical work (LVW, measured in kilogram-metersper minute) was calculated as follows: cardiac output x (meansystolic pressure - pulmonary wedge pressure) x 0.0136, in which0.0136 is a factor used to convert units of pressure and volumeto kilogram-meters.
Myocardial oxygen uptake (MVO2) and carbon-dioxide production(MVCO2) were calculated as the product of coronary blood flowand the arterial–coronary-sinus blood-concentration gradientof each gas. The myocardial respiratory quotient was calculatedas MVCO2 ÷ MVO2. Myocardial energy production (MEP,measured in joules per minute) was calculated as 0.33 MVO2 +0.14 MVCO2.27 The oxidation rates of carbohydrates and lipidswere calculated with classic calorimetric equations27 and expressedas percent contributions to total energy production. Ventricularmechanical efficiency, defined as the fraction of chemical energythat is converted to external mechanical work, was calculatedin two ways: by the equation LVW ÷ (MVO2 x 2.059), inwhich 2.059 is the conversion factor representing the energyequivalent per unit of oxygen metabolized (1 ml of oxygen =20.18 J), under the assumption that the metabolic substratesare oxidized by the myocardium in a fixed ratio; and by theequation LVW ÷ MEP, taking into account that 1 kg-m =9.8 J. The latter approach is based on actual metabolic energygenerated in the myocardium and takes into account any shiftthat may occur in the oxidative pattern of metabolic substratesas a consequence of physical exercise, growth hormone treatment,or both. Both measures of mechanical efficiency are dimensionlessand are expressed as percentages.
All data are presented as means ±SE. The effects of growthhormone on hemodynamic and metabolic measures were evaluatedby the paired t-test or the two-way analysis of variance withDuncan's multiple-range test28 when the comparison includedthe effects of discontinuing growth hormone therapy.
Results
Clinical Effects of Growth Hormone Therapy
All the patients completed the three-month course of growthhormone treatment with no reported side effects. The clinicaleffects of the treatment are shown in Table 1. During growthhormone treatment, the patients reported a feeling of well-beingand an improved quality of life. The patients' maximal exercisecapacity increased after they received growth hormone, as shownby the significantly greater duration of exercise and peak workloadthan at base line. Arterial blood pressure was not affectedby the treatment. Heart rates were lower at rest and slightlyhigher during peak exercise after treatment with growth hormone.The clinical improvement, although attenuated, persisted, interms of both symptoms and maximal exercise capacity, threemonths after growth hormone treatment had been discontinued.
Table 1. Clinical Variables and Maximal Exercise Capacity before, Immediately after, and Three Months after Growth Hormone Treatment.
Left Ventricular Size and Shape
Doppler echocardiographic data are shown in Table 2. Growthhormone induced a significant increase in left ventricular massand wall thickness. Despite the increased myocardial mass, bothend-systolic and end-diastolic left ventricular dimensions weresignificantly reduced by growth hormone treatment. Overall,growth hormone improved left ventricular dimensions, as reflectedin the significant increase in relative wall thickness (wallthickness ÷ ventricular radius). Cardiac mass and wallthickness were still significantly increased three months afterthe completion of growth hormone therapy, although there wasa partial reversal of the effect of growth hormone on thesevariables.
Table 2. Doppler Echocardiographic Data before, Immediately after, and Three Months after Growth Hormone Treatment.
Growth hormone consistently improved the indexes of systolicperformance at rest — that is, ejection fraction, shorteningvelocity, and aortic acceleration (Table 2). The fall in theend-systolic wall stress was especially pronounced, probablyas a consequence of the changes in left ventricular size andshape since arterial blood pressure did not change. Growth hormonealso improved the isovolumic relaxation time. The other diastolicindexes were only marginally affected; therefore, the ratioof early to late diastolic-flow velocity was slightly but notsignificantly increased. The beneficial effect of growth hormoneon the systolic performance was reduced but still significantthree months after the withdrawal of therapy, whereas the relaxationtime returned to base-line levels.
Hemodynamic Variables
The effects of growth hormone treatment on hemodynamic variablesmeasured invasively are shown in Table 3. After treatment, themean pulmonary arterial and capillary wedge pressures decreasedsignificantly, both when the patient was at rest and in responseto physical exercise, whereas pulmonary vascular resistancewas slightly but not significantly lower. Growth hormone significantlyincreased cardiac output at rest and improved its response tophysical exercise. Stroke volume increased from 62±6to 72±8 ml per minute at rest (P = 0.05) and from 61±8to 79±9 ml per minute during exercise (P = 0.004). Similarly,growth hormone increased the resting values of cardiac workand potentiated its response to physical exercise. Systemicvascular resistance was slightly lower at rest after growthhormone treatment. The decrease was more pronounced and statisticallysignificant during physical exercise. The measurement of coronaryblood flow was technically inadequate in one patient, and thedata for coronary blood flow and myocardial energy were thereforederived from six patients. Growth hormone did not modify theresting coronary blood flow. During physical exercise, however,coronary blood flow increased to a significantly lesser extentafter growth hormone treatment.
Table 3. Effects of Growth Hormone on Hemodynamic Variables Measured Invasively with the Patient at Rest and during Submaximal Exercise.
Myocardial Energy Metabolism
The effects of growth hormone treatment on myocardial energymetabolism are shown in Table 4. In the base-line study, myocardialoxygen consumption increased threefold in response to physicalexercise. After treatment with growth hormone, the increasein oxygen consumption was significantly reduced. The differencebetween arterial and coronary-sinus oxygen volume content didnot change during exercise, either at base line or after growthhormone treatment. Myocardial energy production paralleled oxygenconsumption: the resting values were the same before and aftergrowth hormone treatment, whereas the exercise values were greatlyreduced after treatment. The myocardial respiratory quotientincreased during exercise, indicating that the myocardial relianceon fatty-acid oxidation shifted to a reliance on carbohydrateoxidation. Accordingly, the ratio of the carbohydrate componentof energy production to the lipid component rose to values above1 during exercise, both before and after growth hormone treatment.Overall, growth hormone induced beneficial changes in myocardialenergy metabolism, without, however, altering the substratepartitioning in the oxidative pathway.
Table 4. Effects of Growth Hormone on Myocardial Energy Metabolism.
In the base-line study, left ventricular mechanical efficiency(calculated from oxygen uptake) fell significantly during exercise(from 15±3 to 9±2 percent, P = 0.05) (Figure 1).Growth hormone increased mechanical efficiency at rest and preventedthe decrease observed in the base-line study during exercise.Therefore, after treatment with growth hormone, the values formechanical efficiency during exercise were more than twice ashigh as the corresponding values before treatment. Virtuallyidentical results were obtained when mechanical efficiency wascalculated from energy produced (before treatment, 18±4percent at rest and 11±3 percent during exercise; aftertreatment, 23±4 percent at rest [P = 0.04] and 23±5percent during exercise [P = 0.006]).
Figure 1. Effect of Growth Hormone on Ventricular Mechanical Efficiency at Rest and during Submaximal Bicycle Exercise in Patients with Idiopathic Dilated Cardiomyopathy.
Hormone Measurements
The serum concentrations of growth hormone, measured the dayafter injection, were not significantly different from pretreatmentvalues (0.8±0.1 vs. 1.0±0.1 ng per milliliter),whereas the concentrations of insulin-like growth factor I weredoubled (406±15 vs. 198±14 ng per milliliter,P<0.001; normal range, 90 to 210). Serum thyroid hormoneand thyrotropin concentrations did not change significantlyafter growth hormone therapy.
Discussion
Cardiac hypertrophy is an important physiologic adaptation toan excess hemodynamic load on the heart. In this study, we attemptedto induce cardiac hypertrophy with recombinant human growthhormone in an effort to improve cardiac function in patientswith idiopathic dilated cardiomyopathy. Our preliminary datademonstrated that growth hormone increased myocardial mass andimproved cardiac function and exercise performance. Althoughthese effects tended to wane three months after growth hormonewas discontinued, significant improvement in most indexes ofcardiac size, shape, and function and in maximal exercise tolerancewas still found. Our patients had moderately severe heart failure.Whether growth hormone may be beneficial in patients with moresevere heart failure remains to be determined.
Left ventricular remodeling induced by growth hormone was characterizedby increased wall thickness and reduced chamber size. This changein ventricular size and shape may benefit patients with a disordersuch as dilated cardiomyopathy, in which progressive dilatationof the ventricles is not accompanied by compensatory wall thickening.Indeed, growth hormone produced a decrease in systolic wallstress, which was probably responsible for most of the improvementin ventricular mechanics. Growth hormone also reduced peripheralvascular resistance, which allowed cardiac output to rise, particularlyduring physical exercise.
Growth hormone did not have a deleterious effect on diastolicventricular function. Some diastolic properties in fact improvedduring the administration of growth hormone, particularly theisovolumic relaxation time, which worsened again after the withdrawalof growth hormone. This finding is reassuring, given the considerableincrease in wall thickness, which could have adversely affecteddiastolic function. It is also consistent with reports thatthe growth-promoting action of growth hormone, at least in theshort term, involves primarily myocytes.11,13,29 Had the increasein cardiac mass been due to the proliferation of interstitialcells, diastolic function should not have improved and mighthave deteriorated.
This study provides insights into the way growth hormone affectscardiac performance. In dilated, failing hearts, there is animbalance between energy supply and demand, the energy reservebeing depleted and the demand increased.17,30,31 This energymismatch may limit myocardial performance, particularly underconditions of stress.16,32 Another problem with the failingmyocardium is the reduced mechanical efficiency — thatis, the process whereby metabolic energy is converted to externalwork.18,19,20 Our estimate of mechanical efficiency at restin dilated cardiomyopathy (15 percent) agrees with previousreports. Our data also show that the defect in energy conversionbecomes more pronounced during physical exercise. In our patients,a threefold increase in energy production during exercise wasaccompanied by a disproportionately lower increase in cardiacwork (from 5.4 to 9.2 kg-m per minute). This contrasts withthe physiologic response of healthy human subjects, in whomsupine exercise increases ventricular mechanical efficiency.33,34A similar pattern was recently found in studies in animals withthe use of the elastance model.35 Growth hormone treatment inducedsubstantial changes in myocardial energy metabolism in our patients,particularly during physical exercise, in which the heart generatesmore mechanical work with lower oxygen consumption and energyproduction, thus accounting for a remarkable increase in mechanicalefficiency (from 9 to 21 percent). This oxygen-sparing effectof growth hormone during physical exercise may prove particularlybeneficial in patients with heart failure due to ischemic heartdisease.
The mechanism (or mechanisms) by which growth hormone allowsthe failing myocardium to work at a lower energy cost does notappear to have a metabolic basis. After growth hormone treatment,there was no change in the preferred metabolic substrates, asexpressed by the myocardial respiratory quotient. In addition,the magnitude of the gain in efficiency induced by growth hormoneexceeded the maximal theoretical contribution of metabolic mechanisms(10 to 15 percent).36 It is conceivable that growth hormoneimproved myocardial energy metabolism indirectly through itsgrowth effect and the consequent reduction in wall stress. Indeed,wall stress is a major determinant of myocardial oxygen consumptionand energy demand. In patients with dilated cardiomyopathy andheart failure, myocardial oxygen consumption is increased37,38and correlates with the increment in wall stress.37 Consequently,it is likely that the decrease in oxygen consumption and energyproduction observed after growth hormone treatment was causallyrelated to the decrease in wall stress.
A limitation of this study is the lack of a placebo controlgroup. A placebo effect cannot be entirely ruled out in theinterpretation of some of the data, in particular those concerningthe quality of life and exercise capacity. However, given themagnitude and consistency of the changes in a wide range ofhemodynamic and metabolic variables after treatment with growthhormone, it is unlikely that the overall clinical improvementwas spontaneous and not specifically related to growth hormone.In addition, our patients were in a stable hemodynamic conditionbefore the study. It is possible that the clinical improvementwas mediated in part by indirect, extracardiac mechanisms. Forexample, growth hormone may increase skeletal-muscle mass andstrength, particularly in the elderly.39
In conclusion, administration of recombinant human growth hormoneto patients with dilated cardiomyopathy and heart failure activatedmyocardial growth, enhanced contractile performance, reducedthe myocardial oxygen requirement, and improved exercise capacity.These preliminary findings should encourage the planning oflarger clinical trials of longer duration to assess the long-termeffect of growth hormone in patients with dilated cardiomyopathyand other forms of heart failure.
Supported by a grant (95.01026.PF40) from the National ResearchCouncil and by funds from the Italian Ministry of Universityand Research.
We are indebted to Pharmacia, Peptides Hormones (Milan, Italy)for kindly providing the recombinant human growth hormone.
Source Information
From the Department of Internal Medicine, University Federico II, Naples, Italy.
Address reprint requests to Dr. Saccà at Medicina Interna, Via Pansini 5, 80131-Naples, Italy.
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