Insulin-Like Growth Factor IAn Attractive Option for Chronic Heart Failure?

Marc Y. Donath and Jürgen Zapf

Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, Zürich, Switzerland

Abstract Chronic congestive heart failure is a syndrome with a poor prognosis. Currently,the only therapy providing the possibility of long term survival is heart transplan-tation. Therefore, new therapeutic strategies continue to be investigated.One suchnew approach may be the application of recombinant human insulin-like growthfactor (IGF)-1. IGF-1 has both acute and long term cardiovascular effects. Acuteadministration of IGF-1 resulted in a reduction in afterload and positive inotropiceffects in patients with heart failure. In vitro and animal studies have demon-strated that IGF-1 can stimulate myofibril formation. In addition, IGF-1 adminis-tration has beneficial metabolic effects. The benefits of prolonged IGF-1 therapyhave yet to be investigated.

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Chronic congestive heart failure (CHF) is a syn-drome with a poor prognosis and a limited numberof treatment options. Heart transplantation, the onlytherapy with long term survival possibility, is anoptionwhich is limited by a shortage of donor organs.Therefore, other therapeutic strategies continue tobe investigated. A new approach may become theapplication of recombinant human insulin-likegrowth factor (IGF)-I. It iswell established that IGF-Imediates the effects of growth hormone (GH) ongrowth. The main site of IGF-I production is theliver, but other cells and organs also produce IGF-Iwhere this hormone acts more like a cytokine in anauto/paracrine fashion. IGF-I is a growth and dif-ferentiation factor with metabolic effects.[1] Further-more IGF-I exerts specific cardiovascular effects. Inthis article, the acute cardiovascular effects of IGF-Iare distinguished from its long term cardiac effects.

1. Long Term Cardiac Effects

In vitro, IGF-I induces hypertrophy of culturedneonatal rat cardiac cells by inducing the synthesis

of cardio-specific proteins.[2,3] In cultured adult ratcardiomyocytes, IGF-I, but not GH, increases the ex-pression of contractile elements (myofibrils).[4,5] Invivo, IGF-I selectively stimulates heart but not skel-etal muscle growth in rats, whereas GH stimulatesboth.[6,7] Moreover, IGF-I stimulates major compo-nents (such as β-myosin heavy chain) of the myo-fibrils in rat heart.[7]Although early coronary artery reperfusion of the

ischaemic myocardium is a desired therapeutic goal,reperfusion itself may contribute to additional myo-cardial cell injury (i.e. reperfusion injury).[8] Akeyfactor for this phenomenon includes programmedcell death (apoptosis) of cardiac myocytes.[9] IGF-Ihas been shown to inhibit apoptosis both in vitroand in vivo.[10-18] Buerke et al.[19] showed that IGF-Ilimited myocardial reperfusion injury in rats, pos-sibly by the inhibition of apoptosis and of leucocyte-induced cardiac necrosis.[19] Further investigationshave demonstrated a cardioprotective effect of IGF-Iin doxorubicin-treated rats[20] and improved myo-cardial function in rats aftermyocardial infarction.[21]

2. Acute Cardiovascular Effects

IGF-I increases contractility of cultured neona-tal rat cardiomyocytes,[22] and has positive inotro-pic effects on the isolated rat heart.[23,24] The limiteddata available on the acute cardiovascular effectsof IGF-I in humans show that IGF-I has vasodilatoryeffects.[25-27] Furthermore, Russell-Jones et al.[28]have demonstrated that an intravenous infusion ofIGF-I increases the cardiac output and stroke vol-ume in healthy volunteers, as assessed by imped-ance cardiography.We have investigated the systemic cardiovascu-

lar effects of IGF-I at rest and during exercise in 8healthy adults.[29] Individuals were randomised toreceive recombinant human IGF-I 60 μg/kg or salinesubcutaneously in a crossover, double-blind trial,with an interval of 6 days between the 2 injections.Cardiac function and performance were evaluated byechocardiography and exercise tests. IGF-I treat-ment improved cardiac performance, with a 14%increase in stroke volume and an 18% increase incardiac output compared with untreated controls.Left ventricular ejection fraction increased by 9%following IGF-I administration (68 vs 62%). Leftventricular diastolic function was not affected byIGF-I compared with controls. Exercise was un-eventful, with no pathological changes observed onelectrocardiogram. No changes in heart rate orblood pressure were found during rest or exercise.Neither maximal exercise duration nor peak oxygenconsumption were influenced by IGF-I treatment.The acute haemodynamic effects of IGF-I were

then evaluated in patients with CHFNewYork HeartAssociation Stage II and III.[30] Eight patients wererandomised to receive recombinant human IGF-I60 μg/kg or placebo intravenously over 4 hours ina crossover, double-blind study on 2 consecutivedays. Using heart catheterisation, IGF-I treatmentwas shown to increase cardiac index and stroke vol-ume index, and to decrease systemic vascular resis-tance, right atrial pressure and pulmonary arterywedged pressure. Mean systemic and pulmonary ar-tery pressure, as well as heart rate and pulmonaryvascular resistance were not significantly influencedby IGF-I.Urinary levels of noradrenaline (norepineph-

rine) decreased significantly during IGF-I infusion,which may indicate a beneficial effect of IGF-I onneurohumoral activation in patientswithCHF. IGF-Iwas well tolerated in all patients, and no pathologicalelectrocardiogramchangeswere recordedduring treat-ment.The increase in cardiac output following IGF-I

treatment could be caused by a direct cardiac effector it could reflect peripheral vasodilatation. In theabsence of direct measurements of myocardial ino-tropy, it is not possible to differentiate between these2 mechanisms.

3. Growth Hormone or Insulin-LikeGrowth Factor I?

IGF-I mediates many of the effects of pituitaryGH.[31,32] The relationship between GH and the car-diovascular system has been extensively investi-gated. Patients with acromegaly have an increasedincidence of cardiovascular disease.[33,34] On theother hand, individuals with GH deficiency tend toexhibit impaired cardiac performance.[35-37] Bene-ficial effects of GH in the treatment of idiopathicdilated cardiomyopathy[38] and of ischaemic cardio-myopathy have been reported.[39] Part of these GH-induced cardiovascular effects may be promotedby GH stimulation of circulating IGF-I levels and/or of locally produced IGF-I in the heart.[40-42] In linewith this explanation, we[4] did not observe directGH effects on cultured cardiomyocytes and nor didother investigators.[3] On the other hand, IGF-I in-duces cardiomyocyte hypertrophy and myofibrildevelopment in vitro[2-4] and in vivo.[6,7] Neverthe-less, sequelae of GH excess such as hypertension,hyperinsulinaemia, insulin resistance and hyper-lipidaemia[43-46] are not mediated by GH-inducedIGF-I. On the contrary, IGF-I administration dimin-ishes GH secretion, and lowers plasma levels of insu-lin, very low density lipoprotein (VLDL) and lowdensity lipoprotein (LDL) cholesterol, and increasesinsulin sensitivity,[47-51] thereby reducing risk fac-tors of cardiovascular disease.

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4. Conclusions

These data demonstrate that IGF-I administrationelicits significant cardiovascular effects. In pa-tients with heart failure, IGF-I may act in 2 ways:(i) acutely by a reduction of afterload, and possiblyby positive inotropic effects; and (ii) long term bystimulation of myofibril formation, which couldlead to a prolonged improvement of the pump func-tion of the heart. Furthermore, IGF-I administrationexerts beneficial metabolic effects: it lowers insu-lin levels and increases insulin sensitivity,[47-50]and it improves the lipid profile.[51] Thus, IGF-Ihas an attractive therapeutic potential for the treat-ment of cardiac conditions, such as heart failure. Itremains to be investigated whether the observedacute effects of IGF-I prove to be beneficial duringprolonged IGF-I therapy.

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Correspondence and reprints: Dr Marc Donath, Division ofEndocrinology and Diabetes, Department of Medicine,University Hospital, CH-8091 Zurich, Switzerland.E-mail: marc.donath@dim.usz.ch

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