Clinical Science and Molecular Medicine (1975) 48, 29 1s-293s.
Electrical and dynamic responses of the human hyperkinetic heart to sympathetic stimuli
C . B A R T O R E L L I , A . POLESE, C. F I O R E N T I N I , F. M A G R I N I , M . T . O L I V A R I AND M. GUAZZI Centro Ricerche Cardiouascolari del Consiglio Nazionale delle Ricerche, Istituto di Clinicn Medira I I , nntl Istituto Ricerche Cardiouascolari, Uniiiersity of Milan, Milan, Italy
Summary
as the pathophysiological basis of the primary hyperkinetic heart syndrome described by Gorlin (1 962). Subjects presenting with this syndrome appear ideal for studying the electrical and dynamic responses of the heart to sympathetic activation, such as induced by stressful stimuli, in a human experimental model in which the cardiac reactivity to adrenergic influences is emphasized.
1. The elevated beta-receptor responsiveness to adrenergic stimuli makes subjects with the primary hyperkinetic cardiac syndrome ideal for studying the electrical and dynamic responses of the heart to sympat hetic activation. 2. In twelve men presenting with the syndrome, the effects of mental arithmetic and painful (cold) stress on the cardiac inotropic state were tested and correlated with the concomitant electrocardiographic changes. 3. Arithmetic and cold evoked responses opposite and divergent from the base-line state: the former induced vasodilatation, enhancement of cardiac rate, output, contractility and deep T wave inversion; the latter caused vasoconstriction, cardiac depression and full restoration of repolarization. 4. The sympathetic outflow elicited by stress is not generalized, but selectively directed to different circulatory levels in relation to the stimulus at work; cardiac sympathetic stimulation or inhibition has opposite effects on the repolarization phase.
Materials and methods
Key words : baroreceptors, cardiac inotropic state.
Introduction The human electrocardiogram may be altered by sympathetic nervous influences to an extent sufficient to simulate organic heart disorders. An increased beta-receptor reactivity to adrenergic stimuli has been documented (Frohlich, Tarazi & Dustan, 1969) Correspondence: Dr Maurizio Guazzi, lstituto Ricerche Cardiovascolari, Via Francesco Sforza, 35, 20122 Milano, Italy.
Twelve men, whose ages were between 14 and 30 years, were diagnosed as having the syndrome. Palpitations, chest discomfort, rapid heart action, systolic murmur, increased voltage of the QRS and with flat, ‘tucked’ or inverted T waves, and haemodynamic signs of enhanced left ventricular inotropism in the base-line state, were the major features in these subjects. Two types of stressful stimuli were tested on them: mental (the patient was asked to count backwards from 200 as rapidly as possible) and painful (standard cold pressor test with the left hand immersed to the wrist level in water at 3°C for 5 min). Changes in the inotropic state of the heart, which were considered as reflecting sympathetic influences, were correlated with the concomitant changes in the electrocardiogram. The following functions were recorded in the base-line state, and within the first 3 min of stress: heart rate, arterial, right atrial, pulmonary arterial and pulmonary wedge pressures, cardiac output, phonocardiogram and carotid sphygmogram. The following variables were also calculated : cardiac index, stroke index, total peripheral resistance, left ventricular ejection mean rate index, mean rate of
291s
C. Bartorelli et al.
292s
TABLE I . Cardiouascdar reactiiiity to stressful stimuli Results are expressed as mean values+ SD. Measurement Systolic pressure Diastolic pressure Mean pressure Heart rate Cardiac index Total peripheral resistance Mean systolic ejection rate Mean rate of isovolumic pressure development
APIAt
Basal state
Arithmetic"'
Cold"'
154.2k8.8 75,3* 5 101.8f6 91.5+ 18.7 5494+ 1044 799+ 187
1 8 4 2 10.3 96+ 6 125.3f 8.2 111+12 7550+ 990 7 2 3 t 136
189+ 12.7 1 0 8 t 8.3 135+ 10.5 85+ 9.8 4680k 730 1201+ I78
227.8+ 24
285.2+ 23
l 8 3 + I3
26.8f 12.5 1.74+0,55
4.5 f 2.6 I .2 f0.09
7.4+ 5.3 1.32+0.3
' I ) All resultsin this column were significantly different ( P < 0.01) from the corresponding value for the basal state.
isovolumic pressure development electromechanical A f / A t .
and
mean
Results Table 1 reports the average haemodynamic values in the steady state and the cardiovascular response to stressful stimuli. It is of interest to consider not only the different mechanism of the pressor reactions, but also and primarily the different influences of the stimuli on the inotropic state of the heart. Arithmetic and cold evoked a similar degreeof pressureelevation, which in the former was induced exclusively through an increase in output, and in the latter through an increase in resistance, resistance and output showing a n opposite pattern in the two conditions and a divergent direction from the steady state. Cardiac contractility, evaluated through the left ventricular mean systolic ejection rate, mean rate of isovolumic pressure development, and mean AP/At (Diamond, Forrester, Chatterjee, Wegner & Swan, 1972), was like cardiac output markedly enhanced during the arithmetic stimulus and significantly depressed during cold stress. Heart rate basically followed the same direction as output and contractility. In the electrocardiogram deep T wave inversion in each patient, and ST-segment depression in a few cases, were unequivocally and strictly time-related to mental stimulation. The response of the repolarization phase to the painful sensation of cold moved in an opposite direction: the T wave became definitely positive, showing throughout the test a voltage higher than before and after. During cold, also, the time-relation between stimulus, electro-
cardiogram and haemodynamic events was clear and immediate. lsoproterenol duplicated the alteration in the electrocardiogram induced through the mental test. These alterations could not be elicited by any means after beta-blockade. Discussion Evidence is unequivocal that the greatest repolarization changes became manifest during mental stress concomitant with enhancement in myocardial contractility. This suggests that they were concomitant with and consequent upon adrenergicstimulation of the heart. The changes in the electrocardiogram induced by isoproterenol and their disappearance after beta-blockade support this view. The critical time-relation between stimulus and electrocardiographic and circulatory events is in favour of a neural, rather than a humoral effect. Such interpretation is also supported by the finding of prompt cardiac depression and restoration of the repolarization phase by cold, hardly compatible with humoral inhibition. Whether an asynchronous repolarization process (Biberman, Sarma & Surawicz, 1971), or a n enhancement of the positive after-potential, indicated by Cannon & Sjostrand (1953) as responsible for the electrocardiogram alterations in circumstances of autonomic imbalance, cause the changes in question is impossible to say from the available data. It is reasonable to conceive cardiac stimulation and peripheral vasoconstriction, probably both of adrenergic origin, respectively as the primary mechanisms of the circulatory responses to mental and painful stimuli; the associated vasodilatation in
Stress and cardiac hyperkinesis
the former, and cardiac inhibition in the latter, appear as consequent or concomitant phenomena. In the second hypothesis a double (cardiac excitatory and vasodepressor) and reciprocal central action of the two different stimuli have to be admitted (Randall, 1965). In the first hypothesis, the most likely mechanism would appear that of baroreceptor stimulation as a consequence of the arterial pressure elevation. That the cardiac inhibition occurring during cold is primarily mediated through a decrease of adrenergic tone is supported by two observations: disappearance of the inhibition after beta-blockade and persistence of the same after atropinization. According to the baroreceptor interpretation, during mental stimulation the sympathetic drive to the heart is of such strength as to be capable of inducing hypertension, and of overcoming the baroreceptor inhibitory action: cardiac inhibition is a classical response to baroreceptor activation (Heymans & Neil, 1958). Whether the mechanism of this unrestrained sympathetic discharge is a central or a peripheral one is impossible to say. The conclusion, however, seems feasible that the primary nervous outflow elicited by stressful stimuli
293s
is, at least in subjects with this disorder, not unspecific and generalized, but selectively directed to different levels of the circulatory system in relation to the kind of stimulus at work. In particular, the heart seems to be the target organ of the mental stimuli.
References BIBERMAN, L., SARMA, R.N. & SURAWICZ, B. (1971) T wave abnormalities during hyperventilation and isoproterenol infusion. American Heart Journal, 81, 166-174. CANNON,P. & S J ~ S T R A NT. D ,(1953) The occurrence of a positive after-potential in the ECG in different physiological and pathological conditions. Acta Medica Scandinavica, 146, 191-208. DIAMOND, G., FORRESTER, J.S., CHATTERJEE, K., WEGNER, S. & SWAN,H.J.C. (1972) Mean electromechanical AP/At. An indirect index of the peak rate of rise of left ventricular pressure. American Journal of Cardiology, 30, 338-342. FROHLICH, E.D., TARAZI,R.C. & DUSTAN,H.P. (1969) Hyperdynamic beta-adrenergic circulatory state. Increased beta-receptor responsiveness. Archices of Internal Medicine, 123, 1-7. GORLIN, R. (1962) The hyperkinetic heart syndrome. Journal of the American Medical Association. 182, 823-829. HEYMANS, C. & NEIL,E. (1958) ReBexogenic Areas of the Cardiovnscular System. Churchill, London. RANDALL,W.C. (1965) Nervous Control of the Heart. Williams & Wilkins, Baltimore.
Electrical and dynamic responses of the human hyperkinetic heart to sympathetic stimuli
C . B A R T O R E L L I , A . POLESE, C. F I O R E N T I N I , F. M A G R I N I , M . T . O L I V A R I AND M. GUAZZI Centro Ricerche Cardiouascolari del Consiglio Nazionale delle Ricerche, Istituto di Clinicn Medira I I , nntl Istituto Ricerche Cardiouascolari, Uniiiersity of Milan, Milan, Italy
Summary
as the pathophysiological basis of the primary hyperkinetic heart syndrome described by Gorlin (1 962). Subjects presenting with this syndrome appear ideal for studying the electrical and dynamic responses of the heart to sympathetic activation, such as induced by stressful stimuli, in a human experimental model in which the cardiac reactivity to adrenergic influences is emphasized.
1. The elevated beta-receptor responsiveness to adrenergic stimuli makes subjects with the primary hyperkinetic cardiac syndrome ideal for studying the electrical and dynamic responses of the heart to sympat hetic activation. 2. In twelve men presenting with the syndrome, the effects of mental arithmetic and painful (cold) stress on the cardiac inotropic state were tested and correlated with the concomitant electrocardiographic changes. 3. Arithmetic and cold evoked responses opposite and divergent from the base-line state: the former induced vasodilatation, enhancement of cardiac rate, output, contractility and deep T wave inversion; the latter caused vasoconstriction, cardiac depression and full restoration of repolarization. 4. The sympathetic outflow elicited by stress is not generalized, but selectively directed to different circulatory levels in relation to the stimulus at work; cardiac sympathetic stimulation or inhibition has opposite effects on the repolarization phase.
Materials and methods
Key words : baroreceptors, cardiac inotropic state.
Introduction The human electrocardiogram may be altered by sympathetic nervous influences to an extent sufficient to simulate organic heart disorders. An increased beta-receptor reactivity to adrenergic stimuli has been documented (Frohlich, Tarazi & Dustan, 1969) Correspondence: Dr Maurizio Guazzi, lstituto Ricerche Cardiovascolari, Via Francesco Sforza, 35, 20122 Milano, Italy.
Twelve men, whose ages were between 14 and 30 years, were diagnosed as having the syndrome. Palpitations, chest discomfort, rapid heart action, systolic murmur, increased voltage of the QRS and with flat, ‘tucked’ or inverted T waves, and haemodynamic signs of enhanced left ventricular inotropism in the base-line state, were the major features in these subjects. Two types of stressful stimuli were tested on them: mental (the patient was asked to count backwards from 200 as rapidly as possible) and painful (standard cold pressor test with the left hand immersed to the wrist level in water at 3°C for 5 min). Changes in the inotropic state of the heart, which were considered as reflecting sympathetic influences, were correlated with the concomitant changes in the electrocardiogram. The following functions were recorded in the base-line state, and within the first 3 min of stress: heart rate, arterial, right atrial, pulmonary arterial and pulmonary wedge pressures, cardiac output, phonocardiogram and carotid sphygmogram. The following variables were also calculated : cardiac index, stroke index, total peripheral resistance, left ventricular ejection mean rate index, mean rate of
291s
C. Bartorelli et al.
292s
TABLE I . Cardiouascdar reactiiiity to stressful stimuli Results are expressed as mean values+ SD. Measurement Systolic pressure Diastolic pressure Mean pressure Heart rate Cardiac index Total peripheral resistance Mean systolic ejection rate Mean rate of isovolumic pressure development
APIAt
Basal state
Arithmetic"'
Cold"'
154.2k8.8 75,3* 5 101.8f6 91.5+ 18.7 5494+ 1044 799+ 187
1 8 4 2 10.3 96+ 6 125.3f 8.2 111+12 7550+ 990 7 2 3 t 136
189+ 12.7 1 0 8 t 8.3 135+ 10.5 85+ 9.8 4680k 730 1201+ I78
227.8+ 24
285.2+ 23
l 8 3 + I3
26.8f 12.5 1.74+0,55
4.5 f 2.6 I .2 f0.09
7.4+ 5.3 1.32+0.3
' I ) All resultsin this column were significantly different ( P < 0.01) from the corresponding value for the basal state.
isovolumic pressure development electromechanical A f / A t .
and
mean
Results Table 1 reports the average haemodynamic values in the steady state and the cardiovascular response to stressful stimuli. It is of interest to consider not only the different mechanism of the pressor reactions, but also and primarily the different influences of the stimuli on the inotropic state of the heart. Arithmetic and cold evoked a similar degreeof pressureelevation, which in the former was induced exclusively through an increase in output, and in the latter through an increase in resistance, resistance and output showing a n opposite pattern in the two conditions and a divergent direction from the steady state. Cardiac contractility, evaluated through the left ventricular mean systolic ejection rate, mean rate of isovolumic pressure development, and mean AP/At (Diamond, Forrester, Chatterjee, Wegner & Swan, 1972), was like cardiac output markedly enhanced during the arithmetic stimulus and significantly depressed during cold stress. Heart rate basically followed the same direction as output and contractility. In the electrocardiogram deep T wave inversion in each patient, and ST-segment depression in a few cases, were unequivocally and strictly time-related to mental stimulation. The response of the repolarization phase to the painful sensation of cold moved in an opposite direction: the T wave became definitely positive, showing throughout the test a voltage higher than before and after. During cold, also, the time-relation between stimulus, electro-
cardiogram and haemodynamic events was clear and immediate. lsoproterenol duplicated the alteration in the electrocardiogram induced through the mental test. These alterations could not be elicited by any means after beta-blockade. Discussion Evidence is unequivocal that the greatest repolarization changes became manifest during mental stress concomitant with enhancement in myocardial contractility. This suggests that they were concomitant with and consequent upon adrenergicstimulation of the heart. The changes in the electrocardiogram induced by isoproterenol and their disappearance after beta-blockade support this view. The critical time-relation between stimulus and electrocardiographic and circulatory events is in favour of a neural, rather than a humoral effect. Such interpretation is also supported by the finding of prompt cardiac depression and restoration of the repolarization phase by cold, hardly compatible with humoral inhibition. Whether an asynchronous repolarization process (Biberman, Sarma & Surawicz, 1971), or a n enhancement of the positive after-potential, indicated by Cannon & Sjostrand (1953) as responsible for the electrocardiogram alterations in circumstances of autonomic imbalance, cause the changes in question is impossible to say from the available data. It is reasonable to conceive cardiac stimulation and peripheral vasoconstriction, probably both of adrenergic origin, respectively as the primary mechanisms of the circulatory responses to mental and painful stimuli; the associated vasodilatation in
Stress and cardiac hyperkinesis
the former, and cardiac inhibition in the latter, appear as consequent or concomitant phenomena. In the second hypothesis a double (cardiac excitatory and vasodepressor) and reciprocal central action of the two different stimuli have to be admitted (Randall, 1965). In the first hypothesis, the most likely mechanism would appear that of baroreceptor stimulation as a consequence of the arterial pressure elevation. That the cardiac inhibition occurring during cold is primarily mediated through a decrease of adrenergic tone is supported by two observations: disappearance of the inhibition after beta-blockade and persistence of the same after atropinization. According to the baroreceptor interpretation, during mental stimulation the sympathetic drive to the heart is of such strength as to be capable of inducing hypertension, and of overcoming the baroreceptor inhibitory action: cardiac inhibition is a classical response to baroreceptor activation (Heymans & Neil, 1958). Whether the mechanism of this unrestrained sympathetic discharge is a central or a peripheral one is impossible to say. The conclusion, however, seems feasible that the primary nervous outflow elicited by stressful stimuli
293s
is, at least in subjects with this disorder, not unspecific and generalized, but selectively directed to different levels of the circulatory system in relation to the kind of stimulus at work. In particular, the heart seems to be the target organ of the mental stimuli.
References BIBERMAN, L., SARMA, R.N. & SURAWICZ, B. (1971) T wave abnormalities during hyperventilation and isoproterenol infusion. American Heart Journal, 81, 166-174. CANNON,P. & S J ~ S T R A NT. D ,(1953) The occurrence of a positive after-potential in the ECG in different physiological and pathological conditions. Acta Medica Scandinavica, 146, 191-208. DIAMOND, G., FORRESTER, J.S., CHATTERJEE, K., WEGNER, S. & SWAN,H.J.C. (1972) Mean electromechanical AP/At. An indirect index of the peak rate of rise of left ventricular pressure. American Journal of Cardiology, 30, 338-342. FROHLICH, E.D., TARAZI,R.C. & DUSTAN,H.P. (1969) Hyperdynamic beta-adrenergic circulatory state. Increased beta-receptor responsiveness. Archices of Internal Medicine, 123, 1-7. GORLIN, R. (1962) The hyperkinetic heart syndrome. Journal of the American Medical Association. 182, 823-829. HEYMANS, C. & NEIL,E. (1958) ReBexogenic Areas of the Cardiovnscular System. Churchill, London. RANDALL,W.C. (1965) Nervous Control of the Heart. Williams & Wilkins, Baltimore.
