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Most stimulants of EDRF production fall intothree main categories: (a) neurotransmitters andhormones (with species differences); (b) agentsreleased during thrombosis; and (c) the physicalstimulus of flow. Substance P and vasoactive intestinal

polypeptide are among the most potent stimulators ofEDRF release and it is possible that locally releasedneurotransmitters can cause EDRF-mediatedvasodilatation in small vessels where diffusion

distances from adventitial nerve endings are short.Since vasopressin stimulates EDRF release incerebral but not other arteries,24 EDRF may play arole in maintaining cerebral perfusion in shock.Several agents released during platelet activation andthrombosis-ATP, ADP, 5-HT and thrombin-allstimulate EDRF release in vitro, suggesting thatEDRF may have an anti-haemostatic function

locally.25 What may turn out to be its most importantphysiological role, however, is that of mediatingvasodilatation in response to increased flow, throughthe signal of shear stress on the endothelium.26,27 Bythis means EDRF provides a flow-related dilatorfeedback to opposi the constrictor feedback ofthe myogenic response to increased intraluminal

pressure. EDRF will thus coordinate vasomotor

changes in different parts of the same vascular bed: adecrease in small vessel resistance, for example, willlead to flow-related endothelium-mediated dilatationin proximal vessels. Nevertheless, the evidence

suggests that EDRF has a greater influence inresistance arteries, where shear stress is higher, than inconduit arteries.28 This finding complicates the

interpretation of mechanisms underlying auto-

regulation, metabolic vasodilatation, and pharma-cological actions. In coordinating flow throughout thevascular bed, EDRF will also limit the extra work ofincreased flow.28 The implications of such a

fundamental role are far reaching.What of the pathophysiological role of EDRF?

Whether local loss of EDRF activity plays a part in the. pathogenesis of "coronary vasospasm" is not known,

but endothelial damage can induce a susceptibility tolocal spasm in experimental animals,13,29 there is lossof endothelium-dependent relaxation in hyper-lipidaemic rabbits,3° and acetylcholine-induced

dilatation is lost in human epicardial coronary arteriesat sites of atheroma.31 The spasm of coronary arterieswhich occurs in workers in explosives factories onnitrovasodilator "withdrawal" suggests reboundreduction of a tonic cyclic-GMP-mediated vaso-dilator influence. The cerebral vasoconstriction that

complicates subarachnoid haemorrhage could be dueto inhibition of EDRF action by haemoglobin, actingas a chemical sink for EDRF in cerebrospinal fluid. Inexperimental models of hypertension there is loss ofendothelium-dependent relaxation.1o,32 Ageing itselfimpairs endothelium-dependent vasodilatation.33 Anobvious question is whether disorders of endothelialfunction might contribute to atherogenesis.Nitrovasodilators, and therefore presumably EDRF,influence mass transport through the wall of largearteries.34 Could a decline in EDRF activity favourlipid deposition and participate in a slow vicious circleof events which leads to atheroma? Atheroma tends tooccur at sites of low shear stress and thus presumablyof low EDRF activity.34 Does the observation thatexperimental atheroma can be prevented bypharmacological calcium antagonists35,36 have anyclinical counterpart in which EDRF could play therole of an endogenous "calcium antagonist"? EDRFhas opened up a new chapter of vascular physiology.

Thrombolytic Therapy for AcuteMyocardial Infarction

"Would you give intravenous streptokinase to a44-year-old man with a clinical diagnosis of

myocardial infarction seen 2 hours after the onset ofhis pain?" was the question asked by D. Julian at ameeting on thrombolytic therapy for coronary heartattacks at the Royal Society of Medicine last month.All the cardiologists present agreed they would,confirming that there is now a consensus on

thrombolytic therapy for acute myocardial infarction.The evidence for this stand was reviewed by D.Chamberlain and Julian and is based largely on theremarkable GISSI study from Italyl (from whichfurther follow-up data are expected soon), preliminary

24. Katusic ZS, Shepherd JT, Vanhoutte PM. Vasopressin causes endothelium-dependent relaxations of the canine basilar artery. Circ Res 1986; 55: 575-79.

25. De Mey JG, Claeys M, Vanhoutte PM. Endothelium-dependent inhibitory effects ofacetylcholine, adenosine triphosphate, thrombin and arachidonic acid in the caninefemoral artery. J Pharmacol Exp Ther 1982; 222: 166-73.

26. Holtz J, Forstermann U, Pohl U, Giesler M, Bassenge E. Flow-dependent,endothelium-mediated dilation of epicardial coronary arteries in conscious dogs:effects of cyclooxygenase inhibition. J Cardiovasc Pharmacol 1984; 6: 1161-69.

27. Rubanyi GM, Romero JC, Vanhoutte PM. Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 1986; 250: H1145-49.

28. Griffith TM, Edwards DH, Davies RL, Harrison TJ, Evans KT. EDRF coordinatesthe behaviour of resistance vessels. Nature (in press).

29. Brum JM, Sufan Q, Lane G, Bove A. Increased vasoconstrictor activity of proximalcoronary arteries with endothelial damage in intact dogs. Circulation 1984; 70:1066-73.

30. Verbeuren TJ, Jordaens F, Zonnekeyn L, Van Hove CE, Coene M-C, Herman AG.Endothelium-dependent and endothelium-independent contractions andrelaxations in isolated arteries of control and hypercholesterolaemic rabbits. CircRes 1986; 58: 552-64.

31. Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasoconstriction induced byacetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986; 315:1046-51.

32. Van de Voorde J, Leusen I. Endothelium-dependent and independent relaxation ofaortic rings from hypertensive rats. Am J Physiol 1986; 250: H711-17.

33. Shirasaki Y, Su C, Lee TJ-F, Kolm P, Cline WH, Nickols GA. Endothelialmodulation of vascular relaxation to nitrovasodilators in ageing and hypertensionJ Pharmacol Exp Ther 1986; 239: 861-66.

34. Caro CG, Lever MJ. The mass transport of the arterial wall: effect of mechanicalstresses and vasoactive agents, including nitrates. Z Kardiol 1983; 72 (suppl 3):178-81.

35. Henry PD, Bentley KI. Suppression of atherogenesis in cholesterol-fed rabbit treatedwith nifedipine. J Clin Invest 1981; 68: 1366-69.

36. Fleckenstein A. Model experiments on anticalcinotic and antiarteriosclerotic arterialprotection with calcium antagonists. J Mol Cell Cardiol 1987; 19 (suppl II): 109-21

1. Gruppo Italiano per lo Studio della Streptochinast nell’Infarto Miocardico (GISSI)Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction.Lancet 1986; i: 397-401.

139

results from the ISIS-2 study, and pooled data fromother smaller intravenous and intracoronary studies.3,4All these reports have confirmed a reduction in

mortality by about 15-20% in the treated group; theoutcome is even better for patients who were giventreatment early. Angiographic studies have shownthat an occluding thrombus is present in

approximately 80-90 % of patients with acute

infarction studied within 4 h of the onset of

symptoms.5 Intracoronary streptokinase will open theinfarct-related artery in about 70-90% of patientswithin 30 min,6,7 and intravenous therapy with

streptokinase or one of the newer agents (tissueplasminogen activator [tPA] and acylatedstreptokinase-plasminogen complex [APSAC]) inabout 45-75%. Although immediate perfusionrates are higher with tPA and its greater specificitymakes it theoretically more attractive,lo,11 thereocclusion rates are also higher.8 Intravenous

streptokinase is therefore the most widely usedtreatment, but APSAC looks promising. S. Hillisfrom Glasgow suggested that reperfusion can often beinferred from a reduction of chest pain and STsegment elevation, onset of arrhythmias, smaller thanexpected Q wave, and an earlier peak of creatine kinaselevels.There are two major difficulties with routine use of

intravenous streptokinase. Since early treatment-within 1-5 h-is likely to be more successful, it is

imperative to reduce delay. Secondly, what should bedone about any residual stenosis in the artery? Swifthospital admission is uncommon in the UK:

J. Birkhead found that the time from onset of pain toadmission in Northampton varied from 13 to 505 min,with a median time of 80 min, and on average 70 minwere spent moving the patient from the accident andemergency department to the coronary care unit. Thefigures are inevitably better in Brighton, wherepatients have been educated to call an ambulance

directly after the onset of pain; on average anambulance is summoned after 42 min, a further 43

2. ISIS Steering Committee. Intravenous streptokmase given within 0-4 hours of onsetof myocardial infarction reduced mortality in ISIS-2. Lancet 1987; i: 502.

3. Yusuf S, Collins R, Peto R, et al. Intravenous and intracoronary fibrinolytic therapy inacute myocardial infarction: overview of results on mortality, reinfarction and sideeffects from 33 randomised controlled trials. Eur Heart J 1985; 6: 556-85.

4. Patel B, Kloner RA. Analysis of reported randomized trials of streptokinase therapy foracute myocardial infarction m the 1980s. Am J Cardiol 1987; 59: 501-04.

5. DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion duringthe early hours of transmural myocardial infarction: N Engl J Med 1980; 303:897-902.

6. Rentrop KP. Thrombolytic therapy in patients with acute myocardial infarction.Circulation 1985; 71: 627-31

7. Kennedy JW, Ritchie JL, Davis KB, Fritz JK. Western Washington randomized trialof intracoronary streptokinase in acute myocardial infarction. N Engl J Med 1983;309: 1477-82.

8. Sherry S. Recombinant tissue plasminogen activator (rt-PA): is it the thrombolyticagent of choice for an evolving myocardial infarction? Am J Cardiol 1987; 59:984-89.

9. Taylor GJ, Mikell FL, Moses HW, et al. Intravenous streptokinase therapy for acutemyocardial infarction in community hospitals. Am J Cardiol 1984; 54: 256-60.

10. Verstraete M, Bernard R, Bory M, et al. Randomised trial of intravenous recombinanttissue-type plasminogen activator versus intravenous streptokinase in acute

myocardial infarction. Lancet 1985; i: 842-47.11. TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) trial. N Engl

J Med 1985, 312: 932-36.12. Been M, De Bono DP, Muir AL, et al. Coronary thrombolysis with intravenous

anisoylated plasminogen in streptokinase complex BRL 26921. Br Heart J 1985;53: 253-59.

min is taken to move the patient to hospital, and then25 min elapse before the patient receives intravenousthrombolytic therapy. However, with a delay of thisorder it is possible that most patients will receivethrombolytic therapy within 1-5 h, which is likely toproduce the best results. Although asking patients tocall the emergency services directly rather than theirgeneral practitioner has reduced the delay in Brightonfrom 6 h to less than 2 h, many GPs at the meeting feltuncomfortable about adopting this system generallyand it may be more suitable for urban areas. -In ruralareas a combined policy of on-the-spot GP treatmentand well-equipped coronary ambulances may be abetter option.What about the difficulty of diagnosing the early

stages of myocardial infarction? The history is still themost important factor; electrocardiograms can bemisleading. It is therefore worrying that some patientswith a dissectng aneurysm, oesophageal ulcer, orperforated peptic ulcer will be given thrombolytictherapy in error. The benefit of thrombolytic therapyhas to be substantial to allow for these occasionalmistakes. J. P. Boissel from Lyons reported on theEuropean Myocardial Infarction Project which beganin 1984 and which is designed to start treatment asearly as possible by giving thrombolytic therapy athome before the patient is transferred to hospital.ECGs are obtained before therapy is given. Thefalse-positive rate of history plus ECG was

approximately 15%, and surprisingly the percentagedid not change greatly over the next few hours.However, these results mean that about 15 % of

patients who do not have an infarction will receivethrombolytic therapy, although the policy does notappear to have caused any major problems so far.S. Holmberg reported that the Thrombolysis Early inAcute Heart Attack Trial (TEAHAT) in Sweden, inwhich tPA is given intravenously, also aims to treatpatients at home before their transfer to hospital. Thediagnosis is made on the history of pain alone withoutan ECG. As a result, time to treatment has beenreduced by 46 min. Mortality results of both thesestudies are awaited with interest; it will be importantto ascertain both harmful and beneficial effects of

thrombolytic therapy if treatment is to be given veryearly-ie, when the diagnosis of impending infarctionis made without an ECG.

Management of residual stenosis in the affectedartery is another contentious issue. E. Sowton pointedout that many studies have documented residualstenosis in about 80-90% of patients after

thrombolysis.13 He felt therefore that angioplastyshould follow thrombolysis, but this approach is

impractical except in a few well-equipped centres.Nevertheless, the ulcerated thrombogenic plaqueremains after thrombolysis, and reocclusion occurs in

13. Serruys PW, Wijns W, Van Den Brand M, et al. Is transluminal coronary angioplastymandatory after successful thrombolysis? Quantitative coronary angiographicstudy. Br Heart J 1983; 50: 257-65.

140

about 15-20% and is related to the degreeof residual stenosis. 14 Anticoagulant therapymay help to prevent reocc1usion.15 Paradoxically,streptokinase and APSAC, which cause a more

profound and generalised haemostatic defect, may beassociated with less risk of reocclusion than tPA. Theprospect is daunting if all patients were to needangiography after successful thrombolysis, but thereis some reassurance from other studies that suchmeasures may not be necessary. R. Norris from NewZealand found that the percentage of patients with apositive exercise test after thrombolysis was similar tothat in the control group and also the reinfarction rateswere equal, suggesting that residual stenosis may notbe such a problem. This view was reinforced by datapresented by P. Sleight from the GISSI study, whichsuggest that angina rates are similar iri both treatedand control groups and that there does not appear tobe a pronounced increase in the necessity for coronaryartery bypass grafting in the treated group. Perhapsthe stenosis remodels over the ensuing days andmonths and becomes less severe.16 However, it wasgenerally agreed at the meeting that patients whosecondition remained unstable should be referred for

angiography. Moreover, all patients who have hadthrombolytic therapy should have ’exercise tests tó

determine whether early ischaemia occurs, and thosewith strongly positive tests should be referred forangiography with a view to angioplasty or coronaryartery bypass grafting. Symptoms and the results- ofexercise testing, are probably more important than theangiographic appearance of the residual stenosis.

In the UK a major stumbling block to this evensimpler approach is the fact that out of 206 healthauthorities, 57 have no cardiovascular physician andno facilities at all for exercise testing and these districtsallegedly "care for" 9-2 million people. 17 Andthrombosis causes about 350 000 infarctions per yearand about 299 000 deaths in men aged 45 to 65.Facilities will have to be improved nationwide if, asnow seems likely, thrombolysis is considered as

routine and efficacious therapy. However, it has takena long time and a circuitous route to move fromHerrick’s suggestion in 1912 that thrombosis is thecause of myocardial infarction to effective

thrombolytic treatment—yet the means were

available to do this nearly 50 years ago when

streptokinase was first isolated. 18 Will the next 50years be more fruitful for patients with myocardialinfarction? _

.

14. Harrison DG, Ferguson DW, Collins SM, et al. Rethrombosis after reperfusion withstreptokinase: importance of geometry of residual lesions. Circulation 1984; 69:991-99.

15. Kaplan K, Davison R, Parker M, et al. Role of heparin after intravenous thrombolytictherapy for acute myocardial infarction. Am J Cardiol 1987; 59: 241-44

16 Cribier A, Saoudi N, Berland J, Letac B. Regression of residual coronary stenosis afterrecanalization by fibrinolysis in myocardial infarction. Quantitative analysis ofcoronary angiography immediately after obstruction removal, at a 15 day and 3month follow up. Arch Mal Coeur 1985; 78: 353-60.

17. Chamberlain D, Bailey L, Julian D. Staffing and facilities in cardiology in the UnitedKingdom 1984. Third biennial survey. Br Heart J 1986; 55: 311-20.

18. Tillett WS, Garner RL. The fibrinolytic activity of haemolytic streptococci. J ExpMed 1933; 58: 485-502.

HOME MONITORING FOR INFANTILEAPNOEA

INFANTILE apnoea and home monitoring was the subjectof a National Institutes of Health consensus developmentconference last year. The consensus statement has now been

published1 (to be followed shortly be a lengthy report); itdoes not confine itself to prevention of sudden infant deathsyndrome (SIDS), but deploys separate categories forinfants with apnoea of prematurity, mature infants withapnoea, and infants who suffer apparent life-threateningevents (ALTE). ALTE is preferred to the perhapsmisleading term near-miss SIDS. The statement will

undoubtedly be of immense value to health workers (generalpractitioners and health visitors in particular) who

infrequently meet a family who wish to discuss homemonitoring.

For clinicians who regularly see infants in whom homemonitoring might be considered, the NIH statement

highlights certain inadequacies and incongruities in thepresent policy. Most babies - considered for home

monitoring will either have suffered an ALTE or be thesibling of a SIDS victim. There are no data to show thathome monitoring reduces the subsequent morbidity ormortality of these infants; babies have died despite beingmonitored and even when there has been immediate accessto full resuscitation facilities.2 Although heart rate andrespiration are the most commonly monitored variables,there is no evidence to suggest that apnoea or a defect incardiac function is the primary abnormality in SIDS, andfew infants presenting with an ALTE or siblings of SIDSvictims have shown such abnormalities despite intensiveinvestigation. Nevertheless, the small group of infants inwhom such changes have been demonstrated may benefitfrom cardiorespiratory monitoring and therefore theirconsideration as a separate group, as suggested in the NIHstatement, seems sensible.Both infants who suffer an ALTE and siblings of SIDS

victims without demonstrable cardiorespiratory anomaly ontesting are at increased risk for sudden death compared withcontrols.3 The anxiety generated by this knowledge leadsparents and doctors to consider home monitoring. Somegroups feel that such a step is counterproductive, sincemonitoring heightens anxiety and focuses the parents’attention on the monitor and not on the child. As a result, theparents may overlook important changes in the infant’swellbeing.4 Other workers do not share this view,s and manyare sympathetic to parents who, having been frightened bysome previous event, wish to know if their child stopsbreathing.The report states unequivocally that there is no case for

monitoring normal newboms but agrees that monitoring isindicated for certain specific groups,--eg, infants who havesuffered one or more severe ALTEs (requiring mouth-to-mouth resuscitation or vigorous stimulation); preterminfants with apnoea; siblings of two or more SIDS victims;

1 Consensus Statement. National Institutes of Health consensus developmentconference on infantile apnea and home monitoring, Sept 29-Oct 1, 1986.Pediatrics 1987; 79: 292-99.

2. Lewak N. Sudden infant death syndrome in a hospitalised infant on an apnea monitorPediatrics 1975; 56: 296-98.

3. Steinschneider A Infants characterized as high risk for SIDS: general researchimplications. In: Tildon JT, Roeder LM, Steinschneider A. eds Sudden infantdeath syndrome. New York: Academic Press, 1983: 693-704.

4. Emery JL, Waite AJ, Carpender RG, Limench SR, Blake D. Apnoea monitorscompared with weighing scales for siblings after cot death. Arch Dis Child 1985; 60:1055-60.

5. Swift PG. Apnoea monitoring and cot deaths. Arch Dis Child 1987; 62: 98-99.