i editorial - Europe PMC

5 downloads 0 Views 647KB Size Report
45, 1975. 20. Cox WV, LEWISTON ME, ROBERTSON HF: The effect of stellate ganglionectomy on the cardiac function of intact dogs. Am Heart J 12: 285, 1936.
I EDITORIAL

Implications of neural regulation of the heart in health and disease J.A. ARMOUR,* MD, PH D

Over the last decade interest in nervous control of the heart has become rekindled.1 Early investigators demonstrated the importance of the parasympathetic2 and sympathetic3 nervous systems in cardiovascular regulation, and by the beginning of this century neural regulation was considered to be the dominant influence in cardiac physiology and a primary causative factor in coronary artery spasm and angina pectoris.4 However, cardiovascular concepts were altered following the demonstration by Frank5 that the diastolic volume of the heart significantly affects systolic contraction. Frank observed that if the diastolic filling volume is increased the subsequent contraction ejects a greater volume owing to more vigorous contraction. Because this mechanism depends upon changing lengths or volumes of the heart muscle in diastole it has been called "heterometric autoregulation". This concept was applied to the mammalian heart early in the 1 900s by several laboratories,6'7 but was later labelled the Starling mechanism. Impetus to full acceptance of heterometric autoregulation was given by the elegantly conceived series of experiments by Lundin8 with in vitro techniques. Since that time experiments correlating microscopic structure with function9 have greatly helped to emphasize the importance of this hypothesis. This article reviews some of the implications derived from the mounting evidence that the autonomic nervous system exerts a significant physiologic influence on the heart in health and disease. Scientific evidence It has recently been demonstrated that ventricular contraction varies from one region to another throughout systole; thus, it is difficult to accept that a single factor determines contractile behaviour throughout a chamber in systole. Microscopic investigation has shown *Associate professor, department of physiology and biophysics, Daihousie University, Halifax Reprint requests to: Dr. JA. Armour, Department of physiology and biophysics, Daihousie University, Sir Charles Tupper Medical Building, University Avenue, Halifax, NS B3H 4H7

that myofibrils may be contracting in one region while those in an adjacent region may be unchanged or even lengthening.'0 Contractile patterns can differ widely within one chamber, but the two ventricles can also contract relatively independently." The right ventricular sinus (inflow region) can, for example, display increased contractility while the conus (outflow tract) has decreased contractility, or vice versa.'2" Papillary muscles can exhibit localized decreased contraction while other areas show augmentation.14 Similar observations have been made in humans with noninvasive techniques.'5 The ability of the heart to enlarge within its relatively tight pericardial sac during diastole may also limit heterometric autoregulation. Thus, the observation that end-diastolic volumes during exercise are significantly smaller'6 has puzzled investigators'7 because the data were explained with the thesis of heterometric autoregulation. The importance of neural regulation of the heart superimposed on heterometric autoregulation is currently gaining greater recognition,' whereas a decade ago it was thought to play only a minor role.' That neural regulation can affect the development of arrhythmias'0 or change ventricular fibrillation thresholds'0 is now well established. The antiarrhythmic effects of thoracic sympathectomy have been elucidated.20-22 The autonomic nervous system profoundly affects cardiac contractility,"'1" and blood flow in the coronary arteries is regulated by both syn.pathetic23'24 and parasympathetic23 nerves. Gregg and Bedynek25 have demonstrated that relatively rapid occlusion of a main coronary vessel in a conscious animal produces only minor functional changes, thus challenging present concepts that a physical obstruction is the lethal component of angina pectoris. Recent experimentation in our laboratory has demonstrated that the total coronary vasculature is more complex than had been realized. There is, for instance, enormous collateralization between medium-sized coronary arteries. There is also substantial neural regulation of the coronary venous system,26 which may exert an important control over the blood supply to the heart. Thus, efferent autonomic nerves significantly modify not only the heart's chronoCMA JOURNAL/JULY 19, 198o/,YOL. 123

91

tropism (rate) and inotropism (contraction) but also the coronary circulation. The concomitant increase in knowledge of afferent neural mechanisms in cardiovascular regulation has been reviewed by Thor6n.'7 Atrial"'8"9 and ventricular1'27-'0 mechanoreceptors (receptors that respond to mechanical pressures or distortions) have been investigated and tentative functions ascribed to some of them; for instance, functional differences between right and left atrial receptors have been proposed.29 As well, specific and nonspecific afferent nerve fibres have been shown to be activated by decreased blood flow in the coronary arteries.28'31'31 Although it may be premature to be certain about the many reflex functions of these fibres, it has been demonstrated that they can alter the dynamics of the heart. Efferent parasympathetic and sympathetic cardiac nerves are known to innervate highly specific regions of the heart."'2-'4 It is not surprising that recent evidence suggests that discrete afferent fibres'7-31'33 can reflexly effect specific cardiovascular responses.8'31'33'34 It appears that highly specific regions of the heart can,, through reflex mechanisms, effect changes in the same or other regions of the heart within one cardiac cycle.34 It may well be that the carotid artery and pulmonary mechanoreceptors predominantly control parasympathetic cardiac efferent activity while the heart and great vessel mechanoreceptors predominantly control sympathetic efferent activity. Thus, through feedback mechanisms (both positive and negative) neural regulation can alter heterometric autoregulation throughout each cardiac cycle. Also, neuronal feedback mechanisms are important to blood flow distribution within the heart. Ligation of coronary arteries can activate receptors,31 such as the constantly firing afferent receptors, which may be chemoreceptors,'8 as well as alter cardiac mechanoreceptors.3' Such receptor mechanisms are thought to reflexly alter the dynamics of the heart via efferent cardiac nerves and the circulatory catecholamines (such as epinephrine), so that the ensuing complex responses may be characterized by either hypotension or hypertension."33 It may be that ischemia in one region of the ventricle activates primarily the parasympathetic nervous system (as when infarction is accompanied by bradycardia and hypotension) while in another region it activates primarily the sympathetic cardiac nerves (as when infarction is accompanied by tachycardia with or without hypertension), or a combination of effects may occur. These negative and positive feedback mechanisms31'34 are important factors when therapy is considered. For instance, ischemia may activate receptors that in turn would reflexly augment myocardial contraction; this would increase the ischemic changes and, in turn, contractility would be further augmented. Thus, a positive feedback mechanism would compound the difficulty. It may be that reflexes from the hearf" and aorta36 account in part for the observation 45 years ago that pain arising from the heart or aorta was frequently abolished when nerves were cut.37 Dysfunction of these normal regulatory mechanisms could have profound effects during pathophysiologic processes. In this con92 CMA JOURNAL/JULY 19, 1980/VOL. 123

text we should also note that neural mechanisms have been imputed to initiate atheromatous changes in blood vessels.38 These physiologic concepts help to explain the effects of angina pectoris on the mind,39.40 effects clearly described by Osler.4 They may also contribute to our understanding of angina at rest.35 When treating angina pectoris, with or without evidence of myocardial damage (e.g., enzyme changes), one is struck by the importance of the emotional component of this disease as an isolated or additive factor; physical effort as the predominant factor may be much less common than has been thought. Owing to the significance of the great and often forgotten emotional aspects of angina41 would it not be valid to re-emphasize the psychologic components42'43 in an attempt to control altered feedback mechanisms? Conclusions Braunwald considered coronary spasm to be only an "attractive alternative"44 and atheromatous stenosis to be the basic cause of all angina.45 Although fixed stenosis is obviously important to coronary circulation, surely the demonstration of vasospasm during coronary artery catheterization is convincing evidence of its occurrence and possible significance in angina pectoris." The role of the extensive collateral circulation is ignored by those who emphasize mechanical stenosis. Baroldi and colleagues47 found that 62% of patients who died within 25 days of presenting with clinical and pathologic evidence of myocardial infarction had no acute occlusive coronary artery lesion. The functional capabilities of collateral vessels have been underestimated; physiologic evidence has demonstrated how cardiac nerves significantly affect not only cardiac rate and contraction but also coronary vascular function.23'32 In this light can we really limit ourselves to the mechanistic (stenotic) approach to angina? Is it not valid to question the mass application of surgical intervention in this disease,48 and is it not timely that a scientific evaluation of this treatment of coronary atherosclerosis has begun?494' Caution should also be applied to the surgical removal of cardiac nerves or ganglia52 until more is known about the anatomy of the thoracic autonomic nervous system.53 Coronary artery bypass surgery has become so enthroned in the past decade that physicians have forgotten that coronary artery blood flow is physiologically modifiable - and significantly so. Might not some of the enormous expenditures incurred by the surgical approach to coronary vascular disease be redirected to the prevention of a disease that in many instances may be completely amenable to medical therapy? A broad understanding of modern physiologic concepts is of considerable importance for the treatment of cardiovascular diseases. As the many facets of autonomic neural regulation of the heart unfold, this aspect of cardiac therapy will likewise gain importance. References 1. RANDALL WC (ed): Neural Regulation of the Heart, Oxford U Pr, New York, 1977

2. HOFF HE: Vagal stimulation before the Webers. Ann Med Hist 8: 138, 1936 3. FRENCH R: The origins of the sympathetic nervous system from Vesalius to Riolan. Med Hist 15: 45, 1971 4. OSLER W: The Lumleian lectures on angina pectoris. Lancet 1: 839, 1910 5. FRANK 0: On the dynamics of cardiac muscle. Am Heart J 58: 200, 1959 6. PATTERSON SW, PIPER H, STARLING EH: The regulation of the heart beat. J Physiol (Lond) 48: 465, 1914 7. WIGGERS C: Some factors controlling the shape of the pressure curve in the right ventricle. Am J Pllysiol 33: 382, 1914 8. LUNDIN G: Mechanical properties of cardiac muscles. Acta Physiol Scand 7 (suppl 20): 4, 1944 9. SARNOFF SJ, MITCHELL JH: The regulation of the per-

formance of the heart. Am I Med 30: 747, 1961 10. JOHNSON EA, SOMMER JR: A strand of cardiac muscle. Its ultrastructure and the electrophysiological implications of its geometry. I Cell Bid 33: 103, 1967 11. ARMOUR JA, LIPPINCOTT DB, RANDALL WC: Functional anatomy of the interventricular septum. Cardiology 58: 65, 1973

12. ARMOUR JA, PACE JB, RANDALL WC: Interrelationship of architecture and function of the right ventricle. Am

I Phy-

siol 218: 174, 1970 13. ARMOUR JA, LIPPINCOTT DB, RANDALL WC: Regional dynamic behavior of the total right ventricle. Proc Soc

Exp Biol Med 142: 703, 1973 14. ARMOUR JA, RANDALL WC: Physiologic behavior of the in situ papillary muscle. Proc Soc Exp Biol Med 143:

736, 1973 15. BORER JS, BACHARACH SL, GREEN MV, et al: Real-time radionuclide cineangiography in the noninvasive evaluation of global and regional left ventricular function at rest and during exercise in patients with coronary-artery disease. N Engl I Med 296: 839, 1977 16. RUSHMER RF, SMITH 0, FRANKLIN D: Mechanisms of cardiac control on exercise. Circ Res 7: 602, 1959 17. HARRISON DC, GOLDBLATT A, BRAUNWALD E: Studies on cardiac dimensions in intact, unanesthetized man. Part 1. Description of techniques and their validation. Circ Res

13: 448, 1963 18. ARMOUR JA, HAGEMAN GR, RANDALL WC: Arrhythmias induced by local cardiac nerve stimulation. Am I Physiol

223: 1068, 1972 19. KLIKS BR, BURGESS MJ, ABILDSHOv JA: Influence of sympathetic tone on ventricular fibrillation threshold during experimental coronary occlusion. Anl I Cardiol 36:

45, 1975 20. Cox WV, LEWISTON ME, ROBERTSON HF: The effect of stellate ganglionectomy on the cardiac function of intact

dogs. Am Heart J 12: 285, 1936 21. HARRIS AS, ESTANDIA A, TILLOTSON RF: Ventricular ectopic rhythms and ventricular fibrillation following cardiac sympathectomy and coronary occlusion. Am J Physiol 165: 505, 1951 22. SCHAAL SF, WALLACE AG, SEALY WC: Protective influence of cardiac denervation against arrhythmias of myocardial infarction. Cardiovasc Res 3: 241, 1969 23. BERNE RM, DEGEEST H, LEVY MN: Influence of the cardiac nerves on coronary resistance. A in I Physiol 208: 763, 1965 24. UCHIDA Y, UEDA H: Non-uniform blood flow through the ischemic myocardium induced by stellate ganglion stimula-

tion. Ipa Circ J 36: 673, 1972 25. GREGG DE, BEDYNEK JL: Compensatory changes in the heart during progressive coronary artery stenosis, in Pri-

mary and Secondary Angina Pectori., MASER! A, KLASSEN GA, LESCH M (eds), Grune, New York, 1978, p 3 26. ARMOUR JA, KLASSEN GA, HODGSON E, et al: The control of coronary venous flow. Fed Proc 39: 532, 1980 27. THOR.N P: Role of cardiac vagal C-fibers in cardiovas-

cular control. Rev Physiol Biochem Pharmacol 86: 1, 1979

28. ARMOUR JA: Physiological behavior of thoracic cardiovascular receptors. Ani J Pliysiol 225: 177, 1973 29. PAINTAL AS: Vagal sensory receptors and their reflex effects. Physiol Rei' 53: 159, 1973 30. HEss GL, ZUPERKLJ EJ, COON RL, et al: Sympathetic afferent nerve activity of left ventricular origin. Am J Physiol 227: 543, 1974 31. BROWN AM: Excitation of afferent cardiac sympathetic nerve fibres during myocardial ischaemia. J Physiol (Lond) 190: 35, 1967 32. MALLIANI A: Nervous reflex mechanisms during acute myocardial ischemia, in Primary and Secondary A ngina Pectoris, op cit, p 329 33. HAGEMAN GR, URTHALER F, JAMES TN: Neural pathways

of a cardiogenic hypertensive reflex. Am I Phyxiol 235: H345, 1978 34. ARMOUR JA: Instant to instant reflex cardiac regulation. Cardiology 61: 309, 1976 35. MASERI A, SEvERI 5, CHIERCHIA 5, et al: Characteristics, incidence and pathogenetic mechanisms of "primary" an-

gina at rest, in Primary and Secondary A ngina Pectoris, op cit, p 265 36. Liov F, MALLIANI A, PAGAN M, et al: Reflex hemodynamic responses initiated from the thoracic aorta. Circ Rex 34: 78, 1974 37. WHITE JC: The neurological mechanism of cardio-aortic pain. Proc Assoc Rex Neri' Med Dix 15: 181, 1935 38. GUTSTEIN WI-I, HARRISON I, PARL F, et al: Neural factors

contribute to athenogenesis. Science 199: 449, 1978 39. RAAB W: Emotional and sensory stress factors in myOcardial pathology. Neurogenic and hormonal mechanisms in pathogenesis, therapy, and prevention. Ani Heart 1 72:

538, 1966 40. REISER MF: Emotional aspects of cardiac disease. Am J Pxychiar 107: 781, 1951 41. GLASS DC: Stress, behavior patterns, and coronary disease. Am Sci 65: 177, 1977 42. MILLER NE: Learning of visceral and glandular responses.

Scie,lce 163: 434, 1969 43. MILLER NE, DWORKIN BR: Effects of learning on visceral

functions - biofeedback. N Emigi I Med 296: 1274, 1977 44. BRAUNWALD E: Coronary spasm and acLlte myocardial infarction - new possibility for treatment and prevention (E). N Engi I Med 299: 1301, 1978 45. HILLIS LD, BRAUNWALD E: Coronary-artery spasm. Ibid. p 695 46. SEWELL WH: Coronary spasm as a primary cause of myocardial infarction. A preliminary report. A,Igiology 17:

1, 1966 47. BAROLD[ C, RADICE F, ScHMID C, et al: Morphology of acLlte myocardial infarction in relation to coronary thrombosis. Am Heart 1 87: 65, 1974

48. RUSSEK HI: Prognosis in severe angina pectoris: medical versus sLlrgical therapy. Am Heart 1 83: 762, 1972 49. KoucI-IouKos NT, OBERMAN A, RUSSELL RO, et al: Surgical versus medical treatment of OccitIsive disease confined to the left anterior descending coronary artery. Amii I Cardiol 35: 836, 1975 50. MURPHY ML, HULTGREN HN, DETRE K, et al: Treatment of chronic stable angina. A preliminary report of survival

data of the randomized Veterans Administration Cooperative Study. N Engi I Med 297: 621, 1977 51. TAKARO T, HULTGREN RN, LIPTON l-IJ, et al: The VA

cooperative randomized study of surgery for coronary arterial occlusive disease. 11. Subgroup with significant left main lesions. Circulatioll 54 (suppl 3): 107, 1976 52. TARAZI RG, ESTAFANOUS EG, FOUAD FM: Unilateral stel-

late block as the treatment of hypertension after coronary bypass surgery - implications of a new therapeutic approach. Am I Cardiol 42: 1013, 1978 53. HOPKINS DA, ARMOUR JA, NEWMAN D: Cells of origin

of sympathetic postganglionic and sensory fibres in physiologically identified canine cardiac nerves. Fed Proc 39: 839, 1980

CMA JOURNAL/JULY 19, 1980/VOL. 123

93