β-blockers in heart failure

contraction). No adverse reactions were noted. The 5 control wounds (5 patients) had no clinical improvement (0% contraction). Whereas other growth factor clinical trials have focused on directly applying exogenous growth factor molecules,45 our approach was to manipulate endogenous growth factors already present in the wound area. Although it is evident that mechanisms of wound healing are multifactorial, the accelerated wound healing that we observed is consistent with a mechanism in which sucralfate binds and protects local bFGF from degradation, thereby increasing the local concentration of this angiogenic molecule. Our findings suggest that patients with non-healing venous stasis ulcers may benefit from the angiogenic activity of topical sucralfate. Dimitris

Tsakayannis,

William W Li,

Syed Razvi, Nicholas Spirito

Department of Surgery, St Elizabeth’s Medical Center, Boston, MA 02135, USA; and Division of Medical Services, Massachusetts General Hospital, Boston

those in heart failure-are more at risk from catecholamine-induced arrhythmias than from falling cardiac output. We have been sufficiently concerned that &bgr;1-blockade might be the wrong treatment for patients with ischaemic heart disease to mount a randomised prospective outcome comparison of &bgr;1-selective and non-selective &bgr;-blockers in high-risk patients, to which over 1100 patients have so far been recruited. Wagstein’s study was not large enough to include mortality as a sole endpoint. The fact that 50% more patients on &bgr;-blockade died suddenly than in the placebo group serves only as a warning that future trials should be large enough to consider whether the treatment spares the heart-until it kills the patient.

arguably,

Morris J Brown Clinical Pharmacology Unit, University of Cambridge, PO Box 110, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK

1

1 Folkman J. The angiogenic activity of FGF and its possible clinical applications. In: Sara VR, ed. Growth factors: from genes to clinical application. New York: Raven Press, 1990: 201-16. 2 Folkman J, Ingber DE. Angiogenesis: regulatory role of heparin and related molecules. In: Lane DA, Lindahl E, eds. Heparin. London: Edward Arnold, 1989: 317-33. 3 Folkman J, Szabo S, Stovroff M, McNeil P, Li W, Shing Y. Duodenal ulcer: discovery of a new mechanism and development of angiogenic therapy that accelerates healing. Ann Surg 1991; 214(4): 414-27. 4 Knighton D, Ciresi K, Fiegel V, Schumerth S, Butler E, Gerra F. Stimulation of repair in chronic, nonhealing cutaneous ulcers using platelet-derived wound healing formula. Surg Gynecol Obstet 1990; 170: 56-60. 5 Robson M, Phillips L, Lawrence T, et al. The safety and effect of topically applied recombinant basic fibroblast growth factor on the healing of chronic pressure sores. Ann Surg 1992; 216(4): 401-08.

&bgr;-blockers in heart failure SIR-Wagstein and colleagues (Dec 11, p 1441) follow up their earlier observations that &bgr;-blockade can be beneficial in heart failure with a formal prospective comparison. There is an alternate explanation for this apparent benefit (other than upregulation of &bgr;-receptor number), which both accounts for increased P-receptor responsiveness despite the continued presence of &bgr;-blockade and emphasises the need for caution in extrapolating from the observed reduction in morbidity to any possible change in mortality from heart failure. The upregulation by &bgr;-blockade of &bgr;-receptor number previously recorded in non-failing heartsl is probably too modest to cause any striking change on contractility, even if these &bgr;-receptors could somehow be occupied despite the &bgr;-blocker. However, treatment with selective &bgr;1-blockers casuses up to a 10-fold increase in the responsiveness of cardiac &bgr;2-adrenoceptors, an occurrence originally recorded in isolated strips of human atrium and subsequently confirmed with salbutamol dose-response curves both in a comparison of atenolol and untreated patients undergoing coronary artery catheterisation and prospectively in a placebo-controlled crossover study in healthy volunteers. 2.3 The mechanism of this receptor crosstalk could be either increased availability, during &bgr;1-blockade, of the stimulatory G-protein to couple with &bgr;2-receptors, or to reduced phosphorylation of the receptor by cyclic AMP dependent kinase.4 The dose-response curve for adrenaline is shifted so far to the left that circulating concentrations of adrenaline in heart failure would cause 10-50% of maximum contractility. The clinical consequences of this mechanism are intriguing, but might include the paradoxical benefit from &bgr;-blockade in heart failure, especially since there seems in heart failure to be relative preservation of &bgr;2-receptor number and function.On the other hand, most patients receiving &bgr;-blockers-including,

2

3

4 5

Michel MC, Pingsmann A, Beckering JJ, Zerkowski H, Doetsch N, Brodde OE. Selective regulation of &bgr;1- and &bgr;2-adrenoceptors in the human heart by chronic &bgr;-adrenoceptor antagonist treatment. Br J Pharmacol 1988; 94: 685-92. Motomura S, Deighton NM, Zerkowski H, Doetsch N, Michel MC, Brodde OE. Chronic &bgr;1-adrenoceptor antagonist treatment sensitises &bgr;2-adrenoceptors, but desensitises M2-muscarinic receptors in the human right atrium. Br J Pharmacol 1990; 101: 363-69. Hall JA, Ferro A, Dickerson JEC, Brown MJ. &bgr;-adrenoreceptor subtype cross-regulation in the human heart. Br Heart J 1993; 69: 332-37. Brown MJ. What do beta-blockers really do? A view from both sides of the receptor. J R Coll Physicians Lond 1993; 27: 420-27. Kaumann AJ, Sanders L, Hall JA, Murray KJ, Brown MJ. Stimulation of &bgr;1- and &bgr;2-adrenoceptors in human ventricular myocardium from failing hearts hastens the onset of relaxation. Br J Pharmacol 1992; 105: 283P.

Heart block in fluoxetine

a

patient on propranolol and

SIR-There are several reports of bradycardia and syncopel-4 in association with fluoxetine and an interaction between fluoxetine and lipophilic &bgr;-blockers has been postulated.5 We report here a case of complete heart block in a man taking fluoxetine and propranolol. A 53-year-old male was admitted to hospital having lost consciousness for several minutes, after which he felt dizzy and unwell. There was no previous cardiac history and he had no chest pain, breathlessness, or palpitations. For several years he had been taking lorazepam 1 mg four times daily and propranolol 40 mg twice daily for anxiety. 2 weeks before admission he had been started on fluoxetine 20 mg once daily for depression. On arrival in hospital he had a regular pulse of 30/minute, but was warm and well perfused with a blood pressure of 115/70 mm Hg. An electrocardiogram showed complete heart block with an escape rhythm of 30/minute. Both propranolol and fluoxetine were stopped and a temporary pacing wire was inserted. Initially, he remained pacemaker dependent in complete heart block, but 2 days later he reverted to sinus rhythm with a rate of 60/minute. His electrocardiogram at that time showed complete left bundle branch block with left axis deviation. Subsequently, a permanent pacemaker was inserted without complication and propranolol was reintroduced with no adverse effects on conduction. Although there were no old electrocardiograms for comparison, the persistence of complete left bundle branch block several days after the withdrawal of all drugs suggests pre-existing conduction disease. It seems unlikely that propranolol alone was responsible for the development of complete heart block, since he had been taking this drug for several years. By contrast, the reversal to sinus rhythm 2 days 425