Pivotal role of the sympathetic nerves of the human heart in mental stress responses and triggered cardiovascular catastrophes

Published:November 30, 2021DOI:https://doi.org/10.1016/j.autneu.2021.102925

      Abstract

      Mental stress can trigger cardiac catastrophes, explicitly evident during national disasters such as earthquakes. Activation of the cardiac sympathetic outflow and inhibition of the cardiac vagus are important mediating mechanisms. This manuscript describes efforts by the Human Neurotransmitters Research Laboratory of the Baker Institute in Melbourne to develop investigative methods to study the sympathetic nerves of the human heart, and to apply these in mental stress research. With laboratory mental stress, activation of the adrenal medulla was found to occur, accompanied by a regionalized sympathetic nervous response directed to the heart, but sparing the sympathetic outflow to the skeletal muscle vasculature. Patients with panic disorder are at increased cardiovascular risk. They exhibit high-level sympathetic activation during a panic attack, sometimes accompanied by coronary artery spasm. Patients with sudden ventricular arrhythmias causing collapse in the community were found to have as the predisposing substrate high baseline cardiac sympathetic activity, from previously unrecognized mild heart failure; it was surprising at the time that we did not find critical coronary artery stenosis as the substrate. In some the arrhythmia event had a behavioural trigger. In Takotsubo cardiomyopathy (“Broken Heart Syndrome”) the myocardial stunning appears to represent a catecholamine cardiomyopathy, from astronomically high plasma adrenaline concentrations, rather than be caused by activation of the cardiac sympathetic nerves. Some diseases (essential hypertension, heart failure, panic disorder) have forms of sympathetic neural enhancement which contribute to cardiovascular risk: reuptake of noradrenaline by sympathetic nerves after release is faulty and single sympathetic fibres fire in multiple salvos within a single cardiac cycle. Paradoxically, obesity-hypertension does not share in this sympathetic neural augmentation, which is present only in normal-weight hypertensive patients, providing the possible basis for an observed “Obesity Paradox” (longer survival in obesity-hypertension than in normal weight hypertension). Community-wide specific prevention of cardiovascular triggering is not currently possible, due to there being no available simple screening tests which could be applied to the community at-large for the commonest substrates, silent coronary artery disease and mild heart failure. Standard medical preventive measures for coronary atherosclerosis will of course be helpful. Targeted prevention of triggering can be done in those with a detected predisposing substrate, such as genetic Long QT Syndrome, and in survivors of a serious triggered event, who need detailed, appropriate testing.

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      References

        • Abdulla I.
        • Ward M.R.
        Tako-tsubo cardiomyopathy: how stress can mimic acute coronary occlusion.
        Med. J. Aust. 2007; 187: 357-360
        • Ackerman M.J.
        • Priori S.G.
        • Dubin A.M.
        • Triedman J.T.
        • Van Hare G.F.
        • Gold M.R.
        Beta-blocker therapy for long QT syndrome and catecholaminergic polymorphic ventricular tachycardia: are all beta-blockers equivalent?.
        Heart Rhythm. 2017; 14: E41-E44
        • Albert C.M.
        • Chae C.U.
        • Rexrode K.M.
        • Manson J.E.
        • Kawachi I.
        Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women.
        Circulation. 2005; 111: 480-487
        • Alvarenga M.E.
        • Richards J.C.
        • Lambert G.
        • Esler M.D.
        Psychophysiological mechanisms in panic disorder: a correlative analysis of noradrenaline spillover, neuronal noradrenaline reuptake, power spectral analysis of heart rate variability and psychological variables.
        Psychosom. Med. 2006; 68: 8-12
        • Ando S.
        • Imaizumi T.
        • Takeshita A.
        Effects of patterns of sympathetic nerve stimulation on vasoconstricting responses in the hindquarter of rabbits.
        J. Auton. Nerv. Syst. 1993; 45: 225-233
        • Barton D.A.
        • Dawood T.
        • Lambert E.A.
        • Esler M.D.
        • Haikerwal D.
        • Hotchkin E.
        • Brenchley C.
        • Socratous F.
        • Kaye D.M.
        • Schlaich M.P.
        • Hickie I.
        • Lambert G.W.
        Sympathetic activity in major depressive disorder: identifying those at increased cardiac risk?.
        J. Hypertens. 2007; 25: 2117-2124
        • Blombery P.A.
        • Heinzow B.G.J.
        Cardiac and pulmonary norepinephrine release and removal in the dog.
        Circ. Res. 1983; 53: 688-694
        • Bratton B.
        • Davies P.
        • Janig W.
        • McAllen R.
        Ganglionic transmission in a vasomotor pathway studied in vivo.
        J. Physiol. 2010; 588: 1647-1659
        • Cannon W.B.
        Bodily Changes in Pain, Hunger, Fear and Rage. D Appleton and Co, Baltimore: New York1929: 5-8
        • DiBona G.F.
        • Esler M.
        Translational medicine: the antihypertensive effect of renal denervation.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010; 298: R245-R253
        • Eisenhofer G.
        • Friberg P.
        • Rundqvist B.
        • Quyyumi A.A.
        • Lambert G.
        • Kaye D.M.
        • Kopin I.J.
        • Goldstein D.S.
        • Esler M.D.
        Cardiac sympathetic nerve function in congestive heart failure.
        Circulation. 1996; 93: 1667-1676
        • Esler M.
        Mental stress and human cardiovascular disease.
        Neurosci. Biobehav. Rev. 2016; 74: 269-276
        • Esler M.
        b. Sympathetic activation in essential hypertension: understanding the toxic trifecta.
        Heart Lung Circ. 2018; 27: 271-273
        • Esler M.
        • Meredith I.
        Responses of the human sympathetic nervous system to stressors.
        in: Sheppard K.E. Boublik J.H. Funder J.W. Stress and Reproduction, Ares Symposium Publications. Volume 86. Raven Press, New York1992: 19-30
        • Esler M.
        • Jackman G.
        • Bobik A.
        • Kelleher D.
        • Jennings G.
        • Leonard P.
        • Skews H.
        • Korner P.
        Determination of norepinephrine apparent release rate and clearance in humans.
        Life Sci. 1979; 25: 1461-1470
        • Esler M.
        • Blombery P.
        • Leonard P.
        • Jennings G.
        • Korner P.
        Radiotracer methodology for the simultaneous estimation of total, and renal, sympathetic nervous system activity in humans.
        Clin. Sci. 1982; 63: 285S-287S
        • Esler M.
        • Jennings G.
        • Korner P.
        • Blombery P.
        • Sacharias N.
        • Leonard P.
        Measurement of total and organ-specific norepinephrine kinetics in humans.
        Am. J. Physiol. 1984; 247 (Endocrinol Metab 10)E21-E28
        • Esler M.
        • Jennings G.
        • Korner P.
        • Willett I.
        • Dudley F.
        • Hasking G.
        • Anderson W.
        • Lambert G.
        The assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover.
        Hypertension. 1988; 11: 3-20
        • Esler M.
        • Jennings G.
        • Lambert G.
        Measurement of overall and cardiac norepinephrine release into plasma during cognitive challenge.
        Psychoneuroendocrinology. 1989; 14: 477-481
        • Esler M.
        • Wallin G.
        • Dorward P.
        • Eisenhofer G.
        • Westerman R.
        • Meredith I.
        • Lambert G.
        • Cox H.
        • Jennings G.
        Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in man.
        Am. J. Phys. 1991; 260: R817-R823
        • Esler M.
        • Lambert G.
        • Schlaich M.
        • Dixon J.
        • Sari E.
        • Lambert E.
        a. Obesity paradox in hypertension. Is this because sympathetic activation in obesity-hypertension takes a benign form?.
        Hypertension. 2018; 71: 22-33
        • Esler M.
        • Jennings G.
        • Schlaich M.
        • Lambert G.
        • Thompson J.
        • Lambert E.
        • Guo L.
        • Alvarenga M.
        • Esler D.
        • Eikelis N.
        • Kaye D.
        The adrenal medulla in cardiovascular medicine: an untold story.
        J. Hypertens. 2021; 39: 819-829
        • Guidicessi J.R.
        • Wilde A.A.
        • Ackerman M.J.
        The genetic architecture of long QT syndrome: a critical appraisal.
        Trends Cardiovasc. Res. 2018; 28: 453-464
        • Harikrishnan K.N.
        • Khan A.W.
        • Corcoran S.J.
        • Esler M.D.
        • El-Osta A.
        Targeting refractory NET chromatin by EZH2 inhibition in postural tachycardia syndrome.
        Circ. Res. 2020; https://doi.org/10.1161/CIRCRESAHA.119.315654
        • Hass M.
        Neuropeptide Y. A cardiac sympathetic cotransmitter?.
        in: Goldstein D.S. McCarthy Catecholamines – Bridging Basic Science With Clinical Medicine. Academic Press, 1998: 338-348
        • Kahan T.P.
        • Hjemdahl P.
        • Dahlof C.
        Relationship between the overflow of endogenous and radiolabelled noradrenaline from canine blood perfused gracilis muscle.
        Acta Physiol. Scand. 1984; 122: 571-582
        • Kahn A.W.
        • Ziemann M.
        • Corcoran S.
        • Harikrishnan K.N.
        • Okabe J.
        • Rafehi H.
        • Maxwell S.S.
        • Esler M.D.
        • El-Osta A.
        NET silencing by let-7i in postural tachycardia syndrome.
        JCI Insight. 2017; https://doi.org/10.1172/jci.insight.90183
        • Kawachi I.
        • Colditz G.A.
        • Ascherio A.
        • Rimm E.B.
        • Giovannucci E.
        • Stampfer M.J.
        • Willet W.C.
        Prospective study of phobic anxiety and risk of coronary heart disease in men.
        Circulation. 1994; 89: 992-1997
        • Kaye D.M.
        • Lefkovits J.
        • Jennings G.L.
        • Bergin P.
        • Broughton A.
        • Esler M.D.
        Adverse consequences of high sympathetic nervous activity in the failing human heart.
        J. Am. Coll. Cardiol. 1995; 26: 1257-1263
        • Lambert E.
        • Straznicky N.
        • Schlaich M.P.
        • Dawood T.
        • Hotchkin E.
        • Esler M.D.
        • Lambert G.W.
        Differing patterns of sympathoexcitation in normal weight and obesity-related hypertension.
        Hypertension. 2007; 50: 862-868
        • Lambert E.
        • Eikelis N.
        • Esler M.
        • Dawood T.
        • Schlaich M.
        • Bayles R.
        • Socratous F.
        • Agrotis A.
        • Jennings G.
        • Lambert G.
        • Vaddadi G.
        a. Altered sympathetic nervous reactivity and norepinephrine transporter expression in patients with postural tachycardia syndrome.
        Circ. Arrhythm. Electrophysiol. 2008; 1: 103-109
        • Lambert E.
        • Dawood T.
        • Schlaich M.
        • Straznicky N.
        • Esler M.
        • Lambert G.
        Single-unit sympathetic discharge pattern in pathological conditions associated with elevated cardiovascular risk.
        Clin. Exp. Pharm. Physiol. 2008; 35: 503-507
        • Lambert E.A.
        • Schlaich M.P.
        • Dawood T.
        • Sari C.
        • Chopra R.
        • Barton D.A.
        • Kaye D.M.
        • Elam M.
        • Esler M.D.
        • Lambert G.W.
        Single-unit muscle sympathetic nervous activity and it relation to cardiac noradrenaline spillover.
        J. Physiol. 2011; 589: 2597-2605
        • Leor J.
        • Poole W.K.
        • Kloner R.A.
        Sudden cardiac death triggered by an earthquake.
        N. Engl. J. Med. 1996; 334: 413-419
        • Lundberg J.M.
        • Rudehill A.
        • Sollevi A.
        • Theodorsson-Norheim E.
        • Hamberger B.
        Frequency- and reserpine-dependent chemical coding of sympathetic transmission: differential release of noradrenaline and neuropeptide Y from pig spleen.
        Neurosci. Lett. 1986; 63: 96-100
        • Macefield V.
        • Wallin B.G.
        • Vallbo A.B.
        The discharge behaviour of single vasoconstrictor motoneurones in human muscle nerves.
        J. Physiol. Lond. 1994; 481: 799-809
        • Macefield V.G.
        • Rundqvist B.
        • Sverrisdottir Y.B.
        • Wallin B.G.
        • Elam M.
        Firing properties of single muscle vasoconstrictor neurons in the sympathoexcitation associated with congestive heart failure.
        Circulation. 1999; 100: 1708-1713
        • Manger W.M.
        • Gifford R.W.
        Clinical and Experimental Pheochromocytoma. Blackwell Science, Cambridge, Massachusetts1996: 421-423
        • Mansour V.M.
        • Wilkinson D.J.C.
        • Jennings G.L.
        • Schwarz R.G.
        • Thompson J.M.
        • Esler M.D.
        Panic disorder: coronary spasm as a basis for cardiac risk?.
        Med. J. Aust. 1998; 168: 390-392
        • Marques F.
        • Eikelis N.
        • Bayles R.
        • Lambert E.
        • Straznicky N.
        • Hering D.
        • Esler M.
        • Head G.
        • Barton D.
        • Schlaich M.
        • Lambert G.A.
        Polymorphism in the norepinephrine transporter gene is associated with affective and cardiovascular disease through a microRNA mechanism.
        Mol. Psychiatry. 2016; https://doi.org/10.1038/mp.2016.40
        • Meredith I.T.
        • Broughton A.
        • Jennings G.L.
        • Esler M.D.
        Evidence for a selective increase in resting cardiac sympathetic activity in some patients suffering sustained out of hospital ventricular arrhythmias.
        N. Engl. J. Med. 1991; 325: 618-624
        • Morris M.J.
        • Cox H.S.
        • Lambert G.W.
        • Kaye D.M.
        • Jennings G.L.
        • Meredith I.T.
        • Esler M.D.
        Region-specific plasma NPY concentrations and overflows at rest and during sympathetic activation in man.
        Hypertension. 1997; 29: 137-143
        • Nilsson H.
        • Ljung B.
        • Sjoblom N.
        • Wallin B.G.
        The influence of the sympathetic impulse pattern on contractile responses of rat mesenteric arteries and veins.
        Acta Physiol. Scand. 1985; 123: 303-309
        • Pierpont G.L.
        • DeMaster E.G.
        • Reynolds S.
        • Pederson J.
        • Cohn J.N.
        Ventricular myocardial catecholamines in primates.
        J. Lab. Clin. Med. 1985; 106: 205-210
        • Rumantir M.S.
        • Vaz M.
        • Jennings G.L.
        • Collier G.
        • Kaye D.M.
        • Seals D.R.
        • Wiesner G.H.
        • Brunner-La Rocca H.P.
        • Esler M.D.
        Neural mechanisms in human obesity-related hypertension.
        J. Hypertens. 1999; 17: 1125-1133
        • Rumantir M.S.
        • Kaye D.M.
        • Jennings G.L.
        • Vaz M.
        • Hastings J.
        • Esler M.D.
        Phenotypic evidence of faulty norepinephrine reuptake in essential hypertension.
        Hypertension. 2000; 36: 824-829
        • Rundqvist B.
        • Elam M.
        • Bergmann-Sverrisdottir Y.
        • Eisenhofer G.
        • Friberg P.
        Increased cardiac adrenergic drive precedes generalized sympathetic activation in human heart failure.
        Circulation. 1997; 95: 169-175
        • Sato H.
        • Tateishi H.
        • Uchida T.
        • Dote K.
        • Ishihara M.
        Takotsubo-like left ventricular dysfunction due to multivessel coronary spasm.
        in: Komoda K. Haze K. Hori M. Clinical Aspects of Myocardial Injury: From Ischemia to Heart Failure. Kagaku Hyoron Sha Publishing Co, Tokyo1990: 56-64
        • Thompson J.M.
        • Jennings G.L.
        • Chin J.P.F.
        • Esler M.D.
        Measurement of human sympathetic nervous responses to stressors by microneurography.
        J. Auton. Nerv. Syst. 1994; 49: 277-281
        • Wilkinson D.J.C.
        • Thompson J.M.
        • Lambert G.W.
        • Jennings G.L.
        • Schwarz R.G.
        • Jefferys D.
        • Turner A.G.
        • Esler M.D.
        Sympathetic activity in patients with panic disorder at rest, under laboratory mental stress and during panic attacks.
        Arch. Gen. Psychiatry. 1998; 55: 511-520
        • Wittstein I.S.
        • Thiemann D.R.
        • Lima J.A.
        • Baughman K.L.
        • Schulman S.P.
        • Gerstinblith G.
        • Wu K.C.
        • Rade J.J.
        • Bivalacqua T.J.
        • Champion H.C.
        Neurohumoral features of myocardial stunning due to sudden emotional stress.
        N. Engl. J. Med. 2005; 352: 539-548