and its relation to the result of exercise electrocardiology. Eur. Heart J 2000; 21: 466â74. ... 20 (Abstr Suppl): 371. European Heart Journal (2000) 21, 424â426.
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procedure should be based on coronary anatomy and on the functional severity of a lesion, without forgetting continuous medical therapy. But why don’t I, as well as the surgeons, use these principles more often? R. SEABRA-GOMES Hospital Santa Cruz, Lisbon, Portugal
References [1] Piek JJ, Boersma E, di Mario C et al. on behalf of the DEBATE Study Group. Angiographic and Doppler flowderived parameters for assessment of coronary lesion severity and its relation to the result of exercise electrocardiology. Eur Heart J 2000; 21: 466–74. [2] Kern MJ, de Bruyne B, Pijls NHJ From research to clinical practice: current role of intracoronary physiologically based decision making in the cardiac catheterization laboratory. J Am Coll Cardiol 1997; 30: 613–20. [3] Serruys PW, di Mario C, Piek J et al. for the DEBATE Study Group. Prognostic value of intracoronary flow velocity and diameter stenosis in assessing the short- and long-term
[4] [5]
[6]
[7]
[8]
outcomes of coronary balloon angioplasty. The DEBATE Study (Doppler Endpoints Balloon Angioplasty Trial Europe). Circulation 1997; 96: 3369–77. Serruys PW, de Bruyne B, Sousa E et al. DEBATE II: Final results of the 6-month follow-up. Eur Heart J 1999; 20 (Abstr Suppl): 371. Lafont AM. The FROST Study Group. The French Optimal Stenting Trial (FROST): A multicenter, prospective randomized study comparing systematic stenting to angiography/ coronary flow reserve guided stenting: 6 month clinical and angiographic follow-up. J Am Coll Cardiol 1999; 33 (Suppl A): 89A. Di Mario C. The DESTINI-CFR (Doppler Endpoints Stent International Investigation) Study group. Doppler and QCA guided aggressive PTCA has the same target lesion revascularization of stent implantation: 6-month-results of the DESTINI study. J Am Coll Cardiol 1999; 33 (Suppl A): 47A. Di Francesco L, Di Mario C, De Gregorio J et al. on behalf of the DESTINI-CFR Investigators. Clinical, angiographic and physiologic predictors of major adverse cardiac events (MACE) after stent implantation. J Am Coll Cardiol 1999; 33 (Suppl A): 12A. Bech GJW, Pijls NHJ, de Bruyne B et al. on behalf of the DEFER Investigators. Deferral versus performance of PTCA based on coronary pressure derived fractional flow reserve: the DEFER study. Eur Heart J 1999; 20 (Abstr Suppl): 371.
European Heart Journal (2000) 21, 424–426 doi: 10.1053/euhj.1999.1966, available online at http://www.idealibrary.com on
Neural-natriuretic hormone interactions See page 498 for the article to which this Editorial refers Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are both produced by the heart and secreted into the blood stream. They are of considerable interest to cardiologists. The levels of ANP are raised in cardiac failure[1–5] as are those of BNP[6–8] which is of possible diagnostic use, but their importance in the pathophysiology of cardiac failure remains to be completely clarified. ANP is also raised in patients with cardiac transplantation[9–13] in which situation the heart is denervated, raising a number of questions about the relationships between natriuretic peptide secretion and function and that of the cardiac nerves.
Atrial natriuresis Our interest in this subject goes back to the 1950s, when it was realized that then unknown circulating substances existed which influenced urine production. Blood volume expansion, caused natriuresis[14], and left atrial distension caused increased sodium
excretion and free water diuresis[15]. Although it was already known that these effects were abolished by section of the vagus nerves[16], there was continued interest in a humoral efferent mechanism. The effects are accompanied by falls in plasma arginine vasopressin[17] and plasma renin activity[18]. The discovery that atrial myocardial extract produced a natriuresis when injected intravenously[19] led to an explosion of interest and publications concerning the mediator, ANP. At this time, the enthusiasm was such that everyone seemed to assume that ANP was the mediator of atrial natriuresis, making it necessary to re-test the hypothesis that the mediator was a neuronal reflex[16]. For this it was necessary to avoid vagal section which denervates many organs and to denervate the heart only. This experiment proved that atrial natriuresis in response to left atrial distension is mediated by the cardiac nerves[20] even though the release of ANP was not impaired[21]. It was subsequently also shown (again with normal ANP responses) that dogs with denervated hearts had an impaired natriuretic response to intravenous saline infusion[22,23]. The residual response in this case appears to be related to higher arginine vasopressin and plasma renin activity levels in the denervated 2000 The European Society of Cardiology
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dogs, which drop during the saline load[23]. Subsequently, this blunted response to saline loading has been confirmed in humans with heart transplants[11,24], with normal ANP release following central blood volume increase by exercise[10]. Thus, this type of atrial diuresis occurs because of stimulation of afferent nerve receptors in the atrium while the associated rise of ANP does not participate in the mechanism. Interestingly, it has been confirmed that, as the workers in the 1950s postulated, the efferent mechanism is humoral[25,26], but not due to ANP. The natriuretic response could be caused by a decrease in the levels of arginine vasopressin and plasma renin activity or by an increase of a humoral Na + K + pump inhibitor[27].
Tachycardia induced diuresis The well known diuresis that accompanies tachyarrhythmias[28] has also been extensively studied with atrial pacing[29], which causes release of ANP, as the model. The diuresis caused is, however, mainly a water diuresis associated with suppression of arginine vasopressin release[30]; the high ANP concentrations are not associated with any significant changes in sodium clearance[31]. As with the natriuresis of blood volume expansion, this effect involves a reflex with cardiac afferent nerves[29,32], with the efferent effect possibly caused by arginine vasopressin inhibition.
The effect of heart denervation on ANP levels The dog with a chronically denervated heart is a relatively pure model of denervation compared with human heart transplantation because there is no ischaemic or perfusion damage, no rejection process and no immunosuppressive drugs are administered. Basal ANP levels in the dog model are not significantly different from those in control dogs[23,32]. One heart transplantation report found that ANP levels (high pre-operatively) returned to normal after the operation[33], but most studies have found that the ANP levels remain elevated above those of controls[9–13]. BNP (mainly secreted from the ventricle) is also raised[34]. The raised ANP levels in heart transplant patients led, curiously, to the concept that ANP release was under tonic control (suppression) by the cardiac nerves[35]; release of this suppression was postulated as the cause of increased ANP levels in heart transplant recipients. It is a curious hypothesis because this
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is clearly not the case in chronically denervated dogs, and it would be unlikely that man differed from dog in this respect. However, the loss of a circadian rhythm of ANP following heart transplantation[36] was thought to be compatible with the neural control of ANP hypothesis. That evidence can no longer be accepted in the light of the study by McDowell et al.[37] published in this issue. This paper describes the persistence of diurnal oscillations of ANP concentration in patients with heart transplants. We are strongly of the opinion that the neural control hypothesis is not correct.
Why is ANP raised after heart transplantation? Of the two techniques of heart transplantation, the earlier, biatrial technique left a residuum of the recipient’s old atrium, which is innervated. However the high ANP levels cannot be attributed to neural control of these remnants because they still occur with the newer bicaval technique[34,37]. Although ANP levels are not significantly different[34,37] between the two techniques, BNP appears to be significantly higher with the biatrial technique[34]. Moreover, the raised BNP levels in the biatrial transplant patients correlated with indices of left ventricular dysfunction. These authors attributed the lower BNP levels in patients subjected to the bicaval operation to the better left and right ventricular diastolic performance. This leads us to suggest, with some temerity, that the raised ANP levels in heart transplant patients have the same significance that they have in innervated patients with heart disease, i.e. an index, probably not as good as BNP[6–8] of cardiac damage. Our cardiac surgical friends should not be upset about this as there are obvious reasons why donor hearts may be damaged pre-operatively to a varying degree—illness of the donor, ischaemia, perfusion with unphysiological solutions at low temperatures, reperfusion injury, etc. An important recent paper[38] describes a good correlation between BNP levels and other indices of cardiac dysfunction following heart transplantation; this is compatible with our proposal. If we are correct in this assumption, it leaves us with the same questions that we have in heart failure patients— these natriuretic peptides may be useful diagnostically, but what on earth are they doing? A. J. DRAKE-HOLLAND M. I. M. NOBLE Imperial College of Science Technology and Medicine, London, U.K. Eur Heart J, Vol. 21, issue 6, March 2000
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References [1] Moe GW, Angus C, Howard RJ, Armstrong PW. Pathophysiological role of changing atrial size and pressure in modulation of atrial natriuretic factor during evolving experimental heart failure. Cardiovasc Res 1990; 24: 570–7. [2] Moe GW, Grima EA, Angus C et al. Response of atrial natriuretic factor to acute and chronic increase of atrial pressures in experimental heart failure in dogs. Circulation 1991; 83: 1780–7. [3] Moe GW, Grima EA, Wong NLM, Howard RJ, Armstrong PW. Dual natriuretic peptide system in experimental heart failure. J Am Coll Cardiol 1993; 22: 891–8. [4] Lerman A, Gibbons RJ, Rodeheffer RJ et al. Circulating N-terminal atrial natriuretic peptide as a marker for symptomless left-ventricular dysfunction. Lancet 1993; 341: 1105–9. [5] Ray SG, Morton JJ, Dargie HJ. Relationship of renin, angiotensin II and atrial natriuretic factor to clinical status in the early post-infarct period in patients with left ventricular dysfunction. Eur Heart J 1994; 15: 793–800. [6] Morita E, Yasue H, Yoshimura M et al. Increased plasma levels of brain natriuretic peptide in patients with acute myocardial infarction. Circulation 1993; 88: 92–5. [7] Motwani JG, McAlpine H, Kennedy N, Struthers AD. Plasma brain natriuretic peptide as an indicator for angiotensin-converting enzyme inhibition after myocardial infarction. Lancet 1993; 341: 1009–13. [8] Richards AM, Crozier IG, Yandle TG, Espiner EA, Ikram H, Nicholls MG. Brain natriuretic factor: regional plasma concentrations and correlations with haemodynamic state in cardiac disease. Br Heart J 1993; 69: 414–7. [9] Szekkeres T, Artnerdworzak E, Puschendorf B et al. Correlation of atrial natriuretic peptide and cyclic guanosine monophosphate plasma concentrations in patients with heart disorders during rest and exercise. Eur J Clin Chem Clin Biochem 1993; 31: 69–74. [10] Perrault H, Melin B, Jimenez C et al. Fluid regulating and sympathoadrenal hormonal responses to peak exercise following cardiac transplantation. J Appl Physiol 1994; 76: 230–5. [11] Braith RW, Mills RM, Wilcox CS, Davis GL, Wood CE. Breakdown of blood pressure and body fluid homeostasis in heart transplant recipients. J Am Coll Cardiol 1996; 27: 375–83. [12] Braith RW, Mills RM, Wilcox CS, Convertino VA, Davis GL, Limacher MC. Fluid homeostasis after heart transplantation: the role of cardiac denervation. J Heart Lung Transplant. 1996; 15: 872–80. [13] Geny B, Piquard F, Follenius M et al. Endothelin participated in increased circulating atrial natriuretic peptide early after human heart transplantation. J Heart Lung Transplant 1998; 17: 167–75. [14] De Wardener HE, Mills IH, Clapham WF, Hayter CJ. Studies on the efferent mechanism of the sodium diuresis which follows the administration of intravenous saline in the dog. Clin Sci 1961; 21: 249–58. [15] Henry JP, Pearce JW. The possible role of cardiac atrial stretch receptors in the induction of changes in urine flow. J Physiol 1956; 131: 572–85. [16] Henry JP, Gauer OH, Reeves JL. Evidence on the atrial location of receptors influencing urine flow. Circ Res 1956; 4: 85–90. [17] Ledsome JR, Wilson N. The relationship between plasma vasopressin concentration and urinary excretion during left atrial distension. Pfluegers Arch 1984; 400: 381–7. [18] Zehr JE, Hasbargen JA, Kurz KD. Reflex suppression of renin during distension of cardiopulmonary receptors in dogs. Circ Res 1976; 38: 232–9.
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[19] DeBold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 1981; 28: 89–94. [20] Kaczmarczyk G, Drake A, Eisele R et al. The role of the cardiac nerves in the regulation of sodium excretion in conscious dogs. Pfluegers Arch 1981; 390: 125–30. [21] Goertz KL, Wang BC, Geer PG, Leadley RJJ, Reinhardt HW. Atrial stretch increases sodium excretion independently of release of atrial peptides. Am J Physiol 1986; 250: R946–R950. [22] Pichet R, Gutkowska J, Cantin M, Lavallee M. Hemodynamic and renal response to volume expansion in dogs with cardiac denervation. Am J Physiol 1988; 254: F780–F786. [23] Williams TDL, Travill CM, Noble MIM et al. Mechanisms of impaired excretion of fluid load after cardiac denervation in dogs. Am J Physiol 1990; 259: R70–R75. [24] Mertes PM, Detalance N, Carteaux JP et al. Endocrine response to plasma volume expansion during the early postoperative period in heart transplant recipients. J Heart Lung Transplant 1993; 12: 1001–8. [25] Rabelink TJ, van Tilborg KA, Hene´ RJ, Koomans HA. Natriuretic response to head-out immersion in humans with recent kidney transplants. Clin Sci 1993; 85: 471–7. [26] Drake-Holland AJ, Song G, Belcher PR, Noble MIM. Natriuresis caused by blood volume expansion in dogs is not mediated by the renal nerves. Exptl Physiol 1996; 81: 285–95. [27] Pamani MB, Burris JF, Jemione JF, Huot SJ, Koomans HA. Humoral Na+K+ pump inhibitory activity in essential hypertension and in normotensive subjects after acute volume expansion. Am J Hypertens 1989; 2: 524–31. [28] Wood P. Polyuria in paroxysmal tachycardia and paroxysmal atrial flutter and fibrillation. Br Heart J 1963; 25: 273–82. [29] Goetz KL, Bond GC. Reflex diuresis during tachycardia in the dog: evaluation of the role of atrial and sinoaortic receptors. Circ Res 1973; 32: 434–41. [30] Boykin J, Cadnapaphornchai P, McDonald KM, Schrier RW. Mechanism of diuretic response associated with atrial tachycardia. Am J Physiol 1975; 229: 1486–91. [31] Walsh KP, Williams TDM, Canepa-Anson R, Pitts E, Lightman SL, Sutton R. Effects of endogenous atrial natriuretic peptide released by rapid atrial pacing in dogs. Am J Physiol 1987; 253: R599–R604. [32] Williams TDM, Walsh KP, Canepa-Anson R et al. Atrial natriuretic peptide response to rapid atrial pacing in cardiacdenervated dogs. Am J Physiol 1989; 257: R162–R167. [33] Weston MW, Cintron GB, Giordano AT, Vesely DL. Normalization of circulating atrial natriuretic peptides in cardiac transplant recipients. Am Heart J 1994; 127: 129–42. [34] ElGamel A, Yonan NA, Keevil B et al. Significance of raised natriuretic peptides after bicaval and standard cardiac transplantation. Ann Thorac Surg 1997; 63: 1095–100. [35] Mertes PM, Detalance N, Pinelli G, Villemot JP, Burlet C, Boulange M. Changes in endocrine control of electrolyte homeostasis and blood pressure pressure following heart and lung transplantation — a comparative study. Chest 1992; 101: 1050–5. [36] Gugini P, Lucia P, Scibilia C et al. 24-hour pattern of atrial natriuretic peptide in heart transplantation-evidence for lack of circadian rhythm — temporal interrelationships with plasma renin activity, aldosterone and cortisol. Internat J Cardiol 1993; 42: 7–14. [37] McDowell G, Cave M, Bainbridge A et al. Is the secretion of atrial natriuretic peptide in man under neural control? Eur Heart J 2000; 21: 498–503. [38] Masters RG, Davies RA, Veinot JP, Hendry PJ, Smith SJ, de Bold AJ. Discoordinate modulation of natriuretic peptides during acute cardiac allograft rejection in humans. Circulation 1999; 100: 287–91.
