CARDIAC FAILURE RESPONDING TO GROWTH HORMONE

838 CARDIAC CATHETERISATION DATA

COMPARISON OF EXERCISE TEST RESPONSES IN SURVIVORS AND NON-SURVIVORS

Normal values: stroke volume 30-65 ml, systemic vascular resistance 10-20 units, vascular resistance 0 25—1-5 units. To convert mm Hg to kPa multiply by 0,133.

pulmonary

as means (SD). NS =not significant. Stepwise regression analysis based on Cox proportional hazards model indicates that depth of ST segment depression, decision to perform coronary angiography, and age of the patient are significant predictors of survival (when coronary artery score is excluded).

Results

(48%) of patients. These had several indicators of functional impairment on exercise testing: they had had significantly lower heart rates, peak systolic blood pressures and peak work loads than the other 226 patients; they had more angina; and they tended to be After coronary angiography, 125 (60%) younger (all p<0’01). had coronary bypass surgery. The severity of coronary patients artery disease was the major association with bypass surgery (p < 0-001). Depth of ST segment depression and older age were less strongly associated with the decision to advise surgery (p < 005). 51 (11-8%) of the 434 patients died over 6 years. One factor associated with death was non-performance of coronary angiography; another was non-performance of cardiac surgery (though this is not independent), others were severity of coronary artery disease, depth of ST segment depression, and age (table). Despite the greater disability from angina in patients undergoing coronary angiography 95% of these patients were alive at 5 years compared with 86% of patients not having coronary angiography (p < 001). In this study, derived from an exercise test data base, we did not measure other major determinants of survival-ie, left-ventricular 208

narrowing

in the left anterior

descendmg

coronary artery.

Endomyocardial biopsy showed no signs of myocarditis and serological studies for viral infection, blood cultures, and other laboratory tests were negative, apart from a serum angiotensin converting enzyme (ACE) level of 56 U/ml (normal 16-53).3 weeks after the introduction of captopril the patient was still very ill, and cardiac transplantation was considered. In view of his wasted state ( — 16 kg) and panhypopituitarism recombinant-DNA human GH (12 units daily, subcutaneously at 2200 hours) was tried. Within days, he said he felt better; peripheral perfusion increased and mobility improved over the next few months until he could walk indefinitely on the flat and climb two flights of stairs with only minor dyspnoea. In March, 1988, after 3 months of hGH treatment, postural syncopal episodes occurred; clinically he had become sodium

depleted. Frusemide was withdrawn and no further episodes occurred, suggesting that the dose of diuretic, which had previously been essential, had become excessive. The dose of ACE inhibitor was reduced to enalapril 5 mg daily, and hGH was reduced to 4 units daily. The clinical improvement was supported by treadmill exercise testing (Bruce protocol) and measurement of skeletal muscle

function, coronary artery disease risk factors or social class. Nevertheless, we feel that the improved survival in patients

undergoing coronary angiography can be explained by the procedure’s ability to provide a better assessment of risk of dying and by the benefits of bypass surgery in patients selected for this procedure on the basis of angiographic findings. We recommend that all patients with effort angina be evaluated by coronary angiography. St Vincent’s Hospital, Fitzroy, 3065 Victoria, Australia

MICHAEL V. JELINEK NIELS G. BECKER WILLIAM F. RYAN ALEXIA CLEMENS

CARDIAC FAILURE RESPONDING TO GROWTH HORMONE

SIR,--Growth hormone (GH) is a potent anabolic agent. In rats with hypopituitarism GH increases cardiac mass, in keeping with the increase in total body weight,’ but the action of GH on adult cardiac muscle in man is unknown. A 53-year-old man presented in September, 1986, for investigation of Cushing’s syndrome. He had a history of insulin dependent diabetes mellitus. Hypertension had been controlled with atenolol since 1980. Cushing’s disease was confirmed and a total hypophysectomy was done in November, 1986. After major postoperative complications he was discharged on Jan 1, 1987. Heart failure developed in August, 1987, and echocardiography revealed a dilated, diffusely hypokinetic left ventricle and an apical mural thrombus (figure). Despite frusemide and warfarin therapy cardiac function deteriorated. Haemodynamic data are shown in the table. Coronary angiography was normal, apart from a 50%

M-mode

echocardiographic studies. Cushing’s disease diagnosed in September, 1986, cardiac failure developed in August, 1987; institution of captopril in early December, 1987; and hGH treatment between December, 1987, and August, 1988 Normal values: left ventncular (LV) end-diastolic 3-5-5 6 and end-systolic dtmension 2-3-3-7 cm; ejection fraction >40%; septum < 1-2 cm; posterior wall < I’l cm.

839

strength, and psychological assessments. Treatment with hGH was discontinued, in part due to the patient’s wish for fewer injections and also to assess the need for long-term medication. 3 months later there were no changes in cardiorespiratory or locomotor symptoms. This man probably had biventricular failure as a result of several factors resulting in a diminution in cardiac mass. There was an element of hypertensive heart disease; his hypercortisolism would have been catabolic; the hypophysectomy and the postoperative complications would have resulted in negative protein balance; and the total pituitary clearance would have led to the loss of endogenous GH secretion with its potent anabolic actions. Echocardiography suggested significant loss of ventricular mass, a factor indicative of a poor prognosis in

idiopathic cardiomyopathy. responded to hGH but not to diuretics or captopril. The improvement in cardiac output was associated with a reduction in He

radius: wall thickness ratio from 3 16 to 2 52 at the end of GH suggesting an increased left-ventricular mass. An echocardiographic study2 has suggested that GH has a positive inotropic effect in normal adults; the increase in cardiac output may have also been due to peripheral factors. We have no direct proof of an increase in myocardial contractility, but our patient’s skeletal force/cross-sectional area of the quadriceps increased from 2 7 to 46 N/cm2 (normal 5-5-10-5), and hence there may have been an increase in both cardiac mass and contractility. Long-term follow-up is necessary before all treatment responses can be ascribed to hGH. However, continuation of ACE inhibitor therapy and the interruption of the cardiac-cachexia cycle may allow maintenance of his current functional state. The response is in keeping with other observations2,4 that hGH has a major role in catabolic states in adults. treatment,

We thank KabiVitrum for supplying the recombinant-DNA hGH.

R. C. CUNEO P. WILMSHURST C. LOWY G. MCGAULEY P. H. SÖNKSEN

Departments of Medicine and Cardiology, UMDS, St Thomas’ Hospital, London SE1 7EH

Kostyo JL, Nutting DF. Growth hormone and protein metabolism. In: Knobil E, Sawyer WH, eds. Handbook of physiology: vol IV, section 7. Washington, DC: American Physiology Society 1974 195-96. 2. Thuesen L, Christiansen JS, Sorensen KE, Jorgensen JOL, Orskov H, Henningsen P Increased myocardial contractility following growth hormone administration m 1

normal man Dan Med Bull 1988; 35: 193-96. DR, Snyder DK, Williams R, Underwood LE. Growth hormone administration conserves lean body mass during dietary restriction in obese subjects J Clin Endocrinol Metab 1987, 64: 878-83 4. Ponting GA, Halliday D, Teale JD, Sim ALW. Postoperative nitrogen balance with intravenous hyponutrition and growth hormone Lancet 1988; i: 438-40 3. Clemmons

EMBRYO BIOPSY

SIR,—Dr Jarmulowicz (March 11, p 547) suggests that our discussion on preimplantation diagnosis of the sex of human embryos is misleading. He says that cleavage stage biopsy may damage a zygote, implying that we gloss over risks. He correctly suggests that morphological study of cultured embryos is inadequate alone, pointing out that apparently normal embryos may have chromosomal defects. However, this ignores the fact that transfer of such embryos has not increased the incidence of chromosomal anomalies in many thousands of live births. Our cytogenetic studies clearly show that biopsy does not cause embryonic chromosomal defects. Jarmulowicz also cites work in rabbit blastocytes, published in 1968, which produced a single anencephalic fetus. Much animal work in many species, including primates, has been done in the past twenty years. The isolated occurrence of an anenecephalic rabbit in a species peculiarly liable to this defect (and, incidentally, after biopsy at a much later stage of pregnancy) is not relevant. We need to establish the safety of cleavage stage biopsy but such studies, which are going on in our laboratory, were not relevant to our Lancet paper. Assessment of embryonic hatching, embryonic cell numbers, inner and outer cell mass, embryonic glucose and pyruvate uptake, embryonic gene expression, and detailed animal

work gives excellent evidence of the safety of biopsy; and many of our results will shortly be published. Jarmulowicz argues that results with in vitro fertilisation are so poor that preimplantation diagnosis will not be feasible. Perhaps, instead of citing (incorrectly) results from other units he should examine those at Hammersmith Hospital, where 40% of embryo transfers result in pregnancy. These results may be even better in

inherently infertile. In suggesting that "human subjects" (ie, cleavage embryos) should not be used for experimentation, Jarmulowicz reveals his true outlook. We respect his view on when human life starts but neither we nor our patients agree with it. Many of our patients have had up to five pregnancies terminated; they eagerly await preimplantation diagnosis. We have been painstakingly establishing the safety of these techniques and, as clinicians or scientists, are working with the sole aim of helping our patients have healthy children. women not

Institute of Obstetrics and Gynaecology, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 0HS

R. M. L. WINSTON A. H. HANDYSIDE R. J. A. PENKETH

FETAL BRAIN TISSUE

SIR,-We were interested in Dr Gustavii’s letter (March 11, p 565) on a technique used to obtain donor brain tissue in Sweden. In the UK the Peel code prevents modification of the termination of pregnancy to obtain donor tissue. Although Gustavii’s procedure is advantageous in obtaining easily identifiable "fetal fragment" for transplantation it is a variation on normal practice because the opening of the cannula is directed towards the fetus under ultrasonic guidance. The UK brain implantation team, in obtaining fetal cells, has carried out implantation under strict adherence to the Peel code. The method and timing of abortion is not influenced at all by the possibility of neural implantation. We too experienced difficulty in gathering and identifying donor tissue for transplantation in our experiments before our first stereotactic implantation of fetal mesencephalon in 1988.’ Rather than use first trimester abortion material we now use older fetuses from 12-18 weeks’ gestation. These larger fetuses are delivered intact and dissection results in bigger cell blocks. We think that the cells from the older fetuses are still immature and are capable of growth as long as mechanical dispersion of cells is used rather than enzymatic separation. Thus the use of the older fetus may provide a better source of brain cells for transplantation, without recourse to changing the abortion technique as in the Swedish experiments. Department of Neurosurgery, University of Birmingham, Midland Centre for Neurosurgery and Neurology, Smethwick, Warley, West Midlands B67 7JX

1. Hitchcock ER, Clough CG, Hughes RC, Lancet 1988; i: 1274

E. R. HITCHCOCK C. G. CLOUGH R. C. HUGHES B. KENNY

Kenny B Embryos and Parkinson’s disease

99mTc-HMPAO WASHOUT IN PROGNOSIS

OF

STROKE

SIR,-Dr Costa and Professor Ell suggest (Jan 28, p 213) that increased retention of tracer followed by reduced washout after an ischaemic stroke might indicate good prognosis. They report a regional cerebral blood flow (rCBF) study with single photon emission tomography (SPET) 10 days after a supratentorial cortical brain infarction. An area of hyperactivity washed out partly, in contrast to normal brain with no washout. Costa and Ell state that incomplete washout is due to the presence of viable tissue within the infarcted area. We do not agree for the following reasons. The "natural history" of rCBF/SPET in acute brain infarction is of deficit, which decreases in size after 2 weeks and later becomes visible again. We have studied prospectively 26 patients who had acute supratentorial cortical brain infarction by rCBF/SPET with thallium-201 diethyldithiocarbamate, within 24 hours and after 2