1309

emergency surgery in similar patients, the superiority ofemergency endoscopic drainage over urgent surgery has tobe confirmed by a randomised controlled study.The nasobiliary catheters (’ENBD-6 5-LEUNG 7’) were provided by

Wilson-Cooke Medical Inc, USA.

Correspondence should be addressed to J. W. C. L., Department ofMedicme, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.

REFERENCES

1 Li AKC, Chung SCS, Leung JWC, Mok SD Recurrent pyogenic cholangitis—anupdate. Trop Gastroenterol 1985; 6: 119-31.

2 Reynold BM, Dargan El. Acute obstructive cholangitis—a distinct clinical syndromeAnn Surg 1958; 150: 229.

3 Boey JH, Way LW. Acute cholangitis Ann Surg 1980, 191: 264-704 Lam SK. A study of endoscopic sphincterotomy in recurrent pyogenic cholangitis.

Br J Surg 1984; 71: 262-66.5. Ong GB Recurrent pyogenic cholangitis. In. Rob C, Smith R, eds. Operative surgery,

vol 4. London: Butterworth 1969. 356-74.6. Ong GB. A study of recurrent pyogenic cholangitis. Arch Surg 1962, 84: 63-89.7 Huang T, Bass TA, William RD The significance of biliary pressure in cholangitis

Arch Surg 1969, 98: 629-32.8 Lygidakis NJ, Brummelkamp WH The significance of intrabiliary pressure in acute

cholangitis Surg Gynecol Obstet 1985; 161: 465-69

9. Leung JWC, Chan RCY, Ling TKW, Chung SCS, French GL The role of antibioticprophylaxis in biliary obstruction. Gastrointest Endosc 1987; 33: 181.

10. Thompson JE, Tompkins RK, Longmire WP. Factors in management of acutecholangitis. Ann Surg 1982; 195: 137-45.

11. Pitt HA, Cameron JL, Postier RG, Gadaez TR. Factors affecting mortality in biliarytract surgery. An J Surg 1981; 141: 66-72.

12. Chew RKH, Lim S, Cheng C, Foong WC. Acute cholangitis in Singapore. Ann AcadMed 1986; 15: 172-75.

13. Gould RJ, Vogelzang RL, Neiman HL, Pearl GJ, Poticha SM. Percutaneous biliarydrainage as an initial therapy in the sepsis of the biliary tract. Surg Gynecol Obstet1985; 160: 523-27.

14 Kadir S, Baassiri A, Barth KH, Kaufman SL, Cameron JL, White RI. Percutaneousbiliary drainage in the management of biliary sepsis. AJR 1982; 138: 2-29.

15. Jan YY, Chan SC, Chan MF, Lee TY. Percutaneous transhepatic billiary drainage asinitial therapy of acute cholangitis. Proceedings of the 6th Biennial GeneralScientific Meeting of the Association of Surgeons of SE Asia. Bangkok: BangkokMedical Publishers, 1987. 181.

16. Cotton PB. Endoscopic management of bile duct stones (apples and oranges). Gut1984; 25: 587-97.

17 Safrany L. Endoscopic treatment of biliary tract diseases. Lancet 1978; ii: 983-8518 Escourrou J, Cordova JA, Lazorthes F, Frexmos J, Ribet A. Early and late

complications after endoscopic sphincterotomy for biliary lithiasis with andwithout the gallbladder in situ. Gut 1984; 25: 598-602.

19 Leese T. Neoptolemos JR, Bake AR, Carr-Locke DL. Management of acutecholangitis and the impact of endoscopic sphincterotomy. Br J Surg 1986; 73:988-92.

20. Gogel HK, Runyon BA, Volpicelli NA, Palmer RC. Acute suppurative obstructivecholangiotis due to stones: treatment by urgent endoscopic sphincterotomy.Gastroinrest Endosc 1987; 33: 210-13.

21. Cotton PB, Bumey PG, Mason RR. Transnasal bile duct catheterization afterendoscopic sphincterotomy, method for biliary drainage, perfusion and sequentialcholangiography. Gut 1979; 20: 285-87.

Occasional Survey

ARRHYTHMIA IN HEART FAILURE: ROLE OFMECHANICALLY INDUCED CHANGES IN

ELECTROPHYSIOLOGY

JOHN W. DEAN* MAX J. LAB

Department of Physiology, Charing Cross and Westminster MedicalSchool, London W6

Department of Physiology, Charing Cross and Westminster MedicalSchool, London W6

Summary Various mechanisms have been suggestedto explain the high prevalence of

ventricular arrhythmia in patients with heart failure, but asyet there is no unifying theory. There is growing evidencethat changes in myocardial mechanical properties maydirectly alter cardiac electrophysiology by a process ofmechanoelectric feedback. Moreover, when changes incardiac loading similar to those seen in heart failure areproduced experimentally in normal heart, there is a greatertendency to arrhythmogenesis. The intimate relationbetween changes in mechanical function and arrhythmia inheart failure could account for the lack of effect of mostconventional antiarrhythmic drugs on arrhythmogenesis,and the beneficial effect of peripheral vasodilators. Thispaper argues that mechanically induced changes in

electrophysiology are very important in the development ofarrhythmia in cardiac failure; there may be no need toimplicate other mechanisms, such as relative ischaemia,metabolic changes, or changes in sympathetic tone.

INTRODUCTION

VENTRICULAR arrhythmia is common in patients withheart failure1,2 but the mechanism is unclear. The frequencyand severity of arrhythmias are related to the degree ofmyocardial dysfunction but seem to be independent of

*Present address: National Heart and Lung Institute, London SW3.

aetiology.3,4 The presence of ventricular tachycardia onprolonged electrocardiographic (ECG) monitoring seems tobe a poor prognostic sign in these patients2,5,6 and suddendeath, presumably due to arrhythmia, is common.5,7,8There is growing evidence that changes in the stress/

strain relation within the myocardium may lead directly toarrhythmia. Thus the mechanical dysfunction associatedwith heart failure may have a major role in the developmentof arrhythmia by a process known as mechanoelectricfeedback or contraction-excitation feedback9 (seeaccompanying figure).

In the normal heart (inner circle on figure) an electricalstimulus leads to contraction of heart muscle by the processof excitation-contraction (E-C) coupling. However,conversely, the morphology of the recorded electrical signalmay vary according to the mechanical status of the heartowing to mechanoelectric (M-E) feedback. In heart failure(outer broken circle on figure) the abnormal mechanics ofcontraction may directly initiate an arrhythmia bymechanoelectric feedback. The maintenance of such an

arrhythmia is favoured by the further deterioration inmechanical function caused by the arrhythmia.

EXPERIMENTAL EVIDENCE

The mechanical changes that occur in the failing heartinclude ventricular dilatation, myocardial hypertrophy, andincreased preload (left ventricular end-diastolic pressure)and afterload (peripheral resistance). These changes can beimposed under experimental conditions in the presence orabsence of external neurohumoral influences.

Animal Experiments

Experiments on isolated cardiac muscle, in-vitro wholehearts, and in-situ preparations have shown that mechanicalmanoeuvres, similar to those found in the failing heart, caninfluence the cardiac action potential, by changing its

duration and/or inducing abnormal depolarisations, to

produce ventricular arrhythmia. When healthy heart muscleis continuously stretched, shortening of the duration of the

1310

Mechanism of mechanoelectric (M-E) feedback.

E-C = excitation-contraction.

action potential (equivalent to the QT interval of the ECG)and spontaneous depolarisations can be recorded. Stepwiseincreases in length produce more pronounceddepolarisations until spontaneous activity occurs.1o-18 Anincrease in afterload by aortic clamping causes shortening ofthe action potential in pigs’ hearts. 19 In dogs, occlusion of thepulmonary artery, sufficient to raise right ventricular

pressure, leads to the appearance of transient depolarisationswhich grow progressively until an apparent threshold isreached to produce right ventricular extrasystoles.18 Thesechanges are related to disturbances of segment motionwithin the ventricular wall. Similar electrical disturbancesare seen within the left ventricle after aortic occlusion in

pigs9,16,20 and dogs,21 and the electrophysiological changesthat occur during load manipulation in these animals parallelthe mechanical events.21-23These changes in action potential seem to be independent

of external neurohumoral influences24 and reflect changes inmyocardial refractoriness and excitability. For instance,when the action potential duration was reduced in isolated,intact canine hearts by means of an increase in preload, therewas proportional shortening of both relative and absoluterefractory periods.25 Likewise, changes in the absolute

refractory period of the in-situ pig heart parallel those of theaction potential duration during load manipulation.23

Hurnan Heart

There is now evidence that mechanoelectric feedback

operates in the human heart. Ford and Campbell26 usedamyl nitrate to reduce afterload in volunteers; thismanoeuvre speeded wall shortening, reduced duration ofsystole, and prolonged the Q-T interval of the ECG.Taggart et ap7 reported shortening of the action potential asmyocardial wall stress increased in patients coming offcardiopulmonary bypass. Levine et al28have shown similar

changes in the action potential during balloon valvuloplastyin children and young adults. Since changes in cardiac actionpotential duration have consequences on ventricular

excitability, changes in load by way of mechanoelectricfeedback may thus effect the development of arrhythmia.

MECHANICAL LOADING AND ELECTROPHYSIOLOGICAL

INHOMOGENEITY

Repolarisation in normal myocardium is inhomogeneousin both the transverse (endo-epicardium) and longitudinal(apex-base) planes, which gives rise to the anomalous

"upright" T-wave of the ECG.29 A disturbance that

changes the normal dispersion of repolarisation and

excitability may potentiate the likelihood of re-entrant

arrhythmia, since re-entry depends on non-uniform

recovery of excitability and repolarisation.3O Similarly,regional differences exist in electrical restitution31 such thatchanges in loading status may possibly exaggerate theelectrical inhomogeneity32 that normally exists, owing toasymmetry of ventricular geometry and wall stress, and thuspredispose to re-entrant arrhythmia. Ventricular dilatationof the isolated rabbit heart leads to increased dispersion ofrefractoriness independent of coronary perfusion pressureand cycle length .33

MECHANISM

The mechanism certainly lies in the close interactionbetween membrane and mechanical events at the cellular

level, because mechanoelectric feedback is found in isolatedmyocardium. In the intact heart in situ there are

confounding changes in baroreceptor reflexes when

circulatory pressures are changed, but our study on adifferent aspect of mechanoelectric feedback24 suggests thatreflexes do not have a major role. We have proposedmolecular mechanisms for mechanically induced

potentials.9,16.34 One possibility relates the mechanicallyinduced electrical changes to changes in intracellularcalcium.35 Such changes would affect the action potentialeither by an electrogenic Na+ /Ca2+ exchange,36 or by acalcium-activated inward current,3’ to prolong the actionpotential duration. If the mechanical influence is in the latterpart of the cardiac cycle, the consequent changes inintracellular calcium could produce early after-

depolarisations.

CLINICAL RELEVANCE

About 45% of patients with heart failure die within anhour of the development of terminal symptoms.38 This highfigure has led to the speculation that many of these deaths arearrhythmic in origin. The frequency of ventricular

arrhythmias in heart failure makes this assumptionreasonable. Unsustained ventricular tachycardia has a

prevalence of about 50% on single continuous 24 h ECGrecording in patients with heart failure of New York HeartAssociation functional class III or IV,38 and the presence ofthis arrhythmia roughly doubles the mortality rate afteradjustment for the aetiology of myocardial disease and leftventricular ejection fraction.39 Moreover, conventionalantiarrhythmic drugs have little effect in controllingarrhythmia in heart failure assessed by programmedstimulation 41 or continuous 24 h ECG,41 and the lower theejection fraction the poorer the response. Amiodarone

appears the most effective antiarrhythmic agent in thisrespect, producing an impressive reduction in ventriculararrhythmias in one study.42 However, Niklos and

1311

colleagues’°3 randomised, double-blind, placebo-controlledtrial of low-dose amiodarone in patients with dilated

cardiomyopathy showed no effect on mortality or suddendeath rates at 1 year.43 Indeed, no randomised clinical trialhas yet shown improved survival after treatment with

antiarrhythmic drugs.Perhaps the difficulty lies in the aetiology of the

arrhythmia; if ventricular tachycardia is related to themechanical dysfunction of heart failure one would notexpect conventional antiarrhythmic drugs to have mucheffect. Indeed, since many of these drugs have negativeinotropic effects, they may actually worsen the mechanicalstate of the myocardium and thus exacerbate the

arrhythmia.Amiodarone is not solely an antiarrhythmic agent but is

also a powerful peripheral vasodilator with only a weaknegatively inotropic effect.44,45 If the hypothesis thatventricular arrhythmias in heart failure are due to abnormalstress/strain relations within the myocardium is correct,treatment with peripheral vasodilators, which would reducewall stress indirectly by reducing preload, afterload, or both,should have a favourable effect on arrhythmia. Such aneffect has been shown with nitrates and hydralazine39 andthe angiotensin-converting-enzyme (ACE) inhibitors

captopril46 and enalapril ’47 although the CONSENSUSstudy49 showed no effect of enalapril on arrhythmia. Inaddition, ACE inhibitors have effects other thanvasodilatation that are potentially antiarrhythmic, such asincreasing serum and total body potassium and deactivatingthe neurohumoral response to heart failure which leadsto a fall in circulating catecholamines. However, the

experimental and clinical evidence suggests that vasodilatorsmay be beneficial in heart failure not only in terms ofhaemodynamic improvement, but also as antiarrhythmicagents in their own right. Vasodilators prolong the actionpotential and absolute refractory period,23 and these

electrophysiological changes are generally antiarrhythmic.The relation between congestive heart failure and

arrhythmia is complicated by several factors, each capable ofchanging cardiac electrophysiology unfavourably and thuspotentially arrhythmogenic. Heart failure is associated withstructural (eg, hypertrophy and myocardial fibrosis) ,50metabolic (eg, diuretic-induced hypokalaemia and

hypomagnesaemia),51,52 and neurohumoral changes (eg,activation of sympathetic nervous system and renin-

angiotensin system).53 In addition, there are the

compounding arrhythmogenic effects of drug treatment,including inotropes (eg, digoxin) and antidepressants (eg,amitriptyline), and the proarrhythmic effect of

antiarrhythmic drugs (eg, quinidine, mexiletine, and

flecainide). Studies in rabbit hearts with doxorubicin-induced heart failure 54 suggest that an intrinsic mechanism,independent of any neural, humoral, or mechanical effect,may contribute to the electrophysiological changes seen inmyopathic hearts.Even if mechanically induced changes are not central to

arrhythmogenesis, they at least seem to contribute to

arrhythmia generation in the abnormal electrophysiologicalconditions of heart failure. The reduced efficacy ofconventional antiarrhythmic drugs and the apparentbeneficial effects of vasodilator compounds support thehypothesis that mechanoelectric feedback is a seriouscontender for the generation of arrhythmia in heart failure,and, if so, treatment of this disorder may have to bere-evaluated.

J. W. D. is a Wellcome Lecturer, and M. J. L. is a Wellcome SeniorResearch Fellow. This study was supported by a grant from the British HeartFoundation.

Correspondence should be addressed to J. W. D., Postgraduate Office,National Heart and Lung Institute, Dovehouse Street, London SW3 6LY.

REFERENCES

1. Francis GS. Development of arrhythmias in the patient with congestive heart failure:pathophysiology, prevalence and prognosis Am J Cardiol 1986; 57: 3B-7B.

2. Meinertz I’, Hofmann T, Kasper W, et al. Significance of ventricular arrhythmias inidiopathic dilated cardiomyopathy Am J Cardiol 1984; 53: 902-07

3. Schultze RA, Rouleau J, Rigo P, Bowers S, Strauss W, Pitt B. Ventricular arrhythmiasm the late hospital phase of acute myocardial infarction—related to left ventricularfunction detected by gated cardiac blood pool scanning. Circulation 1975, 52:1006-11.

4. Califf R, Burks J, Behar V, Margolis J, Wagner G. Relationship among ventriculararrhythmias, coronary artery disease and angiographic and electrocardiographicindicators of myocardial fibrosis. Circulation 1987; 57: 725-32.

5. Holmes J, Kubo SH, Cody JR, Kligfield P. Arrhythmias in ischaemic andnon-ischaemic dilated cardiomyopathy: prediction of mortality by ambulatoryelectrocardiography Am J Cardiol 1985; 55: 146-51.

6. Unverferth DV, Magorien RD, Moeschberger ML, Baker PB, Fetters JK, Leier CV.Factors influencing the one-year mortality of dilated cardiomyopathy Am JCordiol 1984, 54: 147-52.

7. Wilson JR, Schwartz JS, Sutton MS-J, et al. Prognosis in severe heart failure: relationto hemodynamic measurements and ventricular ectopic activity. J Am Coll Cardiol1983; 2: 403-10.

8. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide toprognosis in patients with chronic congestive heart failure. N Engl J Med 1984; 311:819-23.

9. Lab MJ. Contraction-excitation feedback m myocardium: physiological basis andclinical relevance. Circ Res 1982; 50: 757-66.

10. Dudel J, Trautwein W. Das aktionspotential und mechanogram des herzmuskelsunter dem einflus der dehnung. Cardiologie 1954; 25: 344-62.

11. Penefsky ZJ, Hofmann BF. Effects of stretch on mechanical and electrical properties ofcardiac muscle Am J Physiol 1963; 204: 433-38.

12. Deck KA. Anderungen des ruhepotentials und der Kabeleigenschaflen von Purkinje-Baden bei der dehnung. Pflugers Arch 1964; 280: 131-40.

13. Kaufmann R, Theophile U. Automatie fordernde dehnungseffects am Purkinje fadenpappilarmuskein und vorhoftrabekein von Rhesusaffen. Pflugers Arch 1967; 291:174-89.

14. Lab MJ. The effect on the left ventricular action potential of clamping the aorta.J Physiol (Lond) 1969; 202: 73-74P.

15. Lab MJ. Mechano-electric interaction in cardiac muscle [PhD thesis] London:

University of London: 1974.16. Lab MJ. Mechanically dependent changes in action potentials recorded from the intact

frog ventricle. Circ Res 1978; 42: 519-2817. Lab MJ. Depolarization produced by mechanical changes in normal and abnormal

myocardium. J Physiol (Lond) 1978; 284: 143-44P.18. Covell JW, Lab MJ, Pavalec R. Mechanical induction of paired action potentials in

intact heart in situ. J Physiol (Lond) 1981; 320: 34P.19. Jones CM, Lab MJ. Increased afterload reduces monophasic action potential duration

in porcine left ventricle in situ. J Physiol (Lond) 1985; 365: 62P.20. Lab MJ. Stress strain related depolarization in myocardium and arrhythmogenesis in

early ischaemia. In: Parrat J, ed. Early arrhythmias resulting from myocardialischaemia: mechanisms and prevention by drugs. London. MacMillan, 1982:81-91.

21 Franz MR, Burkhoff D, Yue DT, Sagawa K. Mechanically induced action potentialchanges and arrhythmia in isolated and in situ canine hearts. Cardiovasc Res 1989;23: 213-23.

22. Dean JW, Dilly S, Lab MJ. Reduced afterload increases monophasic action potentialduration in the in-situ left ventricle of anaesthetised pigs. J Physiol ( Lond) 1986;382: 112P.

23. Dean JW, Lab MJ. The effect of changes in afterload on the absolute refractory periodof the pig heart. PACE 1987; 10 (suppl ii): 987.

24. Lab MJ, Noble MIM. Do extrinsic reflexes mediate the right ventricular arrhythmiaproduced by pulmonary artery occlusion in anaesthetised dogs? Pflugers Arch 1988;411 (suppl 1). 52.

25. Lerman BB, Burkhoff D, Yue DT, Sagawa K. Mechanoelectric feedback:

independent role of preload and contractility in modulation of canine ventricularexcitability. J Clin Invest 1985; 76: 1843-50

26. Ford EL, Campbell NP. Effect of myocardial shortening velocity on duration ofelectrical and mechanical systole. Br Heart J 1980; 44: 179-83.

27. Taggart P, Sutton PMI, Treasure T, et al. Monophasic action potentials at

discontinuation of cardiopulmonary bypass: evidence for contraction-excitationfeedback in man. Circulation 1988; 77: 1266-75.

28. Levine JH, Guarnieri T, Kadish AH, White RI, Calkins H, Kan JS. Changes inmyocardial repolarization changes in patients undergoing balloon valvuloplasty forcongenital pulmonary stenosis: evidence for contraction excitation feedback inhumans. Circulation 1988; 77: 70-77.

29. Noble D, Cohen I. The interpretation of the T-wave of the electrocardiogram.Cardiovasc Res 1978; 12: 13-27.

30. Rosen MR The links between basic and clinical cardiac electrophysiology Circulation1988; 77: 251-63

31 Lab MJ, Yardley J. Regional differences in electrical restitution of the pig left ventricle.J Physiol (Lond) 1984; 353: 70P.

32. Khatib SY, Lab MJ. Differences in electrical activity in the apex and base of leftventricle produced by changes in mechanical conditions of contraction. J Physiol(Lond) 1982; 324: 25-26P.

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33. Reiter MJ, Synhorst DP, Mann DE Electrophysiological effects of acute ventriculardilatation in the isolated rabbit heart. Circ Res 1988; 62: 554-62.

34. Kaufmann R, Lab MJ, Hennekes R, Krause H. Feedback interaction of mechanicaland electrical events in the isolated ventricular myocardium (cat papillary muscle)Pflugers Arch 1971; 332: 96-116

35. Lab MJ, Allen D, Orchard C. The effects of shortening on myoplasmic calciumconcentration and on the action potential m mammalian ventricular muscle. CircRes 1984; 55: 825-29.

36. Mullins LJ. The generation of electric currents in cardiac fibers by Na/Ca exchange.Am J Physiol 1979; 263: C103-10

37. Colquhoun D, Neher E, Reuter H, Stevens H. Inward current channels activated byintracellular Ca2 + in cultured cardiac cells. Nature 1981, 294: 752-54.

38. Bigger JT. Prevalence and possible mechanisms of ventricular arrhythmias incongestive heart failure. In Wood C, ed New perspectives in cardiovascularmedicine, no 4. Arrhythmias in heart failure: new frontiers. Oxford Royal Societyof Medicine services, 1988. 11-27.

39 Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality inchronic congestive heart failure. Results of a Veterans Administration cooperativestudy. N Engl J Med 1986; 314: 1547-52.

40 Meissner MD, Kay HR, Spielman SRI, Greenspan AM, Cutalek SP, Horowitz LN.Acute antiarrhythmic drug efficacy is independently related to left ventricularfunction. J Am Coll Cardiol 1986, 7: 130.

41. The cardiac arrhythmia pilot study (CAPS) investigators. The effect of encainide,flecamide, imipramine, and moricizine on ventricular arrhythmias occurring 6-60days after myocardial infarction: results of a randomized, double blind multicentertrial. Am J Cardiol 1988; 61: 501-09.

42. Cleland JGF, Dargie HJ, Findlay IN, Wilson JT. Clinical haemodynamic andantiarrhythmic effects of long term treatment with amiodarone of patients in heartfailure Br Heart J 1987; 57: 436-45.

43. Nicklas JM, Mickleson JK, Das SK, Morady F, Schork MA, Pitt B. Prospective,randomized, double-blind, placebo-controlled trial of low dose amiodarone in

patients with severe heart failure and frequent ventricular ectopy, Circulation 1988,178 (suppl II): abstr 0105.

44. Cote P, Bourassa MG, Delaye J, Janin A, Froment R, David P. Effects of amiodaroneon cardiac and coronary hemodynamics and on myocardial metabolism in patientswith coronary artery disease. Circulation 1979, 59: 1165-72.

45. Singh BN, Jewitt DE, Downey JM, Kirk ES, Sonnenblick EH. Effects of amiodaroneand L8040, novel antianginal and antiarrhythmic drugs, on cardiac and coronaryhemodynamics and on cardiac intracellular potentials. Clin Exp Pharmacol Physiol1976; 3: 427-42.

46 Cleland JG, Dargie HJ, Hodsman GP, et al. Captopril in heart failure: a double blindcontrolled trial. Br Heart J 1984; 52: 530-35

47. Cleland JG, Dargie JH, Ball SG, et al. Effects of enalapril in heart failure: a doubleblind study of effects on exercise performance, renal function, hormones andmetabolic state. Br Heart J 1985; 54: 305-12.

48. Webster MWI, Fitzpatrick MA, Nicholls MG, Ikram H, Wells JE. Effect of enalaprilon ventricular arrhythmias in congestive heart failure. Am J Cardiol 1985; 56:566-69.

49. The CONSENSUS trial study group. Effects of enalapril on mortality in severecongestive heart failure. Results of the Cooperative North Scandinavian EnalaprilSurvival Study (CONSENSUS). N Engl J Med 1987; 316: 1429-35.

50 Schaper J, Schaper W. Ultrastructural correlates of reduced cardiac function in humanheart disease. Eur Heart J 1983; 4 (suppl A) 137-42.

51 Stewart DE, Ikram H, Espiner EA, Nicholls MG. Arrhythmogenic potential ofdiuretic induced hypokalaemia in patients with mild hypertension and ischaemicheart disease. Br Heart J 1985; 54: 290-97.

52. Holland OB, Nixon JV, Kuhnert L. Diuretic-induced ventricular ectopic activity AmJ Med 1981; 70: 762-68.

53. Francis GS. Neurohumoral mechanisms involved in congestive heart failure Am JCordiol 1985, 55a: 15-21.

54. Doherty JD, Manley BS, Cobbe S. Electrophysiological changes in an animal model ofcongestive cardiac failure Clin Sci 1988; 74 (suppl 18): 30P.

Peptide Regulatory Factors

PEPTIDE REGULATORY FACTORS INEMBRYONIC DEVELOPMENT

J. M. W. SLACK

Imperial Cancer Research Fund, Developmental Biology Unit,Department of Zoology, Oxford University, South Parks Road,

Oxford OXI 3PS

DURING the embryonic stages of human life, rules areestablished for cellular growth and differentiation of thepostnatal and adult organism. So, to understand why thingsgo wrong in adults, we need to know how they are

constructed in the first place. In the past few years the roleof peptide regulatory factors (PRFs) in embryonicdevelopment has generated intense interest. In this contextit is important to remember that these factors are not onlymitogens but also may exhibit many other biologicalactivities.

THE EMBRYO AND THE ADULT

In adult organisms growth is confmed to particularsites-eg, basal layer of many epithelia, intestinal crypts, orbone marrow-and the conditions permitting such growthare strictly local. Thus, epidermal cells displaced inwards bya hypodermic needle do not usually grow in their newposition. One therefore expects to find locally acting growthfactors in such places. In an embryo, and to a lesser extent ina growing postnatal organism, growth is much more

widespread and involves not only renewal tissues but alsoprecursors of cells that do not divide in the adult (neurons,muscle cells) and those that divide only after tissue damage(many glandular and connective tissues). The different sortsof control necessary in the embryo, or during tissue

regeneration, are likely to be associated with additionalpatterns of PRF activity.

Embryonic life is not merely a time of rapid growth. In theearly embryo, populations of cells in different positionsbecome determined to follow different developmentalpathways as a result of inductive interactions.1 In some casesthe chemical signals leading to embryonic induction also actas growth factors. This discovery not only promises asolution to the longstanding mysteries of induction but alsosuggests that a common biochemical machinery controlsboth cell growth and developmental decision making.

I shall now review the properties of the fibroblast growthfactor (FGF), insulin-like growth factor (IGF), and

transforming growth factor beta (TFG-0) classes of growthfactor and consider the evidence for their involvement in the

growth control and inductive interactions of early and latedevelopment.

FIBROBLAST GROWTH FACTOR FAMILY

FGF, as its name suggests, was first defined as a singlefactor that was mitogenic for fibroblasts. It is now knownthat there are at least five structurally related proteins. BasicFGF (bFGF) is relatively abundant in pituitary, brain,adrenals, and ovary2 whereas acidic FGF (aFGF) isrestricted to brain and other neural tissues. Both forms are

mitogenic for fibroblasts but are even more mitogenic forcapillary endothelial cells and are thought to be among theangiogenesis factors secreted by tumours and other tissuesthat require a blood supply. Indeed, aFGF is often known asendothelial cell growth factor. Both bFGF and aFGF bindvery tightly to heparin and, perhaps more importantly, toheparan sulphate, which is widely distributed on cellsurfaces and in extracellular structures such as basementmembranes. Consequently, the FGFs are unlikely to bepresent in free solution in body fluids but will be foundsequestered in the vicinity of the cells that secrete them-asone would expect for a locally acting factor. Since aFGF andbFGF lack a signal sequence of the type normally possessedby secreted proteins, either they are exported by someunknown mechanism or they can be released only when cellsdie and disintegrate. An FGF receptor that binds bothaFGF and bFGF has been detected on various cell types.