The sympathetic regulation of the heart

Dr Murray Esler discusses the role of the sympathetic innervation to the heart with relevance to Takotsubo cardiomyopathy The spinal cells of origin for the sympathetic nerves of the heart lie in the intermediolateral cell column of the upper 3–4 thoracic segments of the spinal cord. These cardiac pre-ganglionic neurons relay primarily through the stellate (cervicothoracic) and thoracic sympathetic ganglia. The output of post-ganglionic fibres from these ganglia are grouped in the superior, middle and inferior cardiac nerves, to be distributed to the cardiac plexus of nerves on the surface of the heart, then to the individual anatomical components receiving sympathetic innervation. Intrinsic cardiac ganglia are enmeshed in the cardiac neural plexus, and participate in autonomic regulatory influences on the heart. Central reflex and behavioural sympathetic control of the heart resides in four hierarchical levels of the neuroaxis: cortex (insular cortex, anterior cingulate cortex); subcortical forebrain (hypothalamus, amygdala); brainstem (including rostral ventrolateral medulla, caudal ventrolateral medulla, nucleus tractus solitarius, periaqueductal gray, raphe nuclei); spinal level (pre-ganglionic sympathetic neurons of intermediolateral column). From some of these brain regions there are direct, monosynaptic relays to the spinal pre-ganglionic neurons. With behavioural stimuli, CNS inputs to sympathetic outflow from the insular cortex, hypothalamus, and amygdala are prominent. In many and diverse circumstances the sympathetic nerves are pivotal in increasing heart rate, left ventricular contractility (and consequently cardiac output), and cardiac myocyte depolarization rates. This is evident in the responses to exercise, gravity (with standing), blood pressure reduction and blood loss, acute mental stress and environmental exposure to cold. 1–3 The cardiac sympathetic nerves, however, are not engaged with some stimuli which lead to sympathetic stimulation elsewhere, such as dietary sodium restriction, which causes preferential renal sympathetic stimulation. 4 Adrenal medullary secretion of adrenaline commonly but not invariably occurs in parallel with the stimulation of the cardiac sympathetic outflow, contributing to the cardiac responses. Cardiac vagal responses typically occur in parallel, usually being reciprocal (inverse). The principal sympathetic transmitter in the heart, and elsewhere, is noradrenaline. The influence of sympathetic neural signals on cardiac effector tissues is primarily terminated by neuronal reuptake of the transmitter, mediated by the specific noradrenaline transporter (NET), a 64 kDa membrane-bound protein. Disposition of noradrenaline after its release in the heart is much more dependent on neuronal reuptake, approximately 95%, 5 than in all other organs; accordingly, cardiac excitation is particularly susceptible to pharmacological or disease-related reuptake block. A subsidiary sympathetic transmitter is neuropeptide Y (NPY), which is released at high rates of sympathetic nerve firing. NPY can cause vasoconstriction, and perhaps surprisingly, release of vagal acetylcholine. Cardiac sympathetic neural activity at rest, and with evoked responses, can be quantified measuring the outwards flux of noradrenaline from the heart to plasma (cardiac ‘noradrenaline spillover’). This can be done using isotope dilution, with intravenous infusion of tritiated noradrenaline, and sampling from the coronary sinus. The isotope dilution method is needed because noradrenaline flux from the heart to plasma is bidirectional, so that measurements of the net overflow of noradrenaline into the coronary sinus is not sufficiently sensitive. The methodology is rather complex, but does provide a valid measure of cardiac sympathetic activity, unlike attempted shortcuts, using measurements of heart rate variability and low frequency heart rate spectral power. Using the cardiac noradrenaline spillover method, it is possible to document large increases in cardiac sympathetic activity during experimental mental stress in the laboratory, with doubling or trebling of cardiac noradrenaline spillover rates. 1–3 One stressor used involves the challenge of asking the experimental participant to perform difficult mental arithmetic, maintained against a background of applied distractions, and impatience shown by the experimenter. 3 Documentation of high-level cardiac sympathetic activation during ‘real life’ mental stress events has also been possible, in patients with panic disorder experiencing panic attacks in the research laboratory. 6 The largest increase in cardiac sympathetic activity is seen with aerobic exercise, where 10- to 20-fold increase in cardiac noradrenaline spillover is observed. The activation of the cardiac sympathetic outflow in heart failure is not much less than this. In the context of Takotsubo cardiomyopathy, the influences of gender and aging on the sympathetic nervous system, and in particular on the cardiac sympathetic nerves and their regulation of the heart are important, given the gender and age demography of this disorder. With clinical microneurography, which measures sympathetic nerve firing in the outflow to skeletal muscle vasculature, resting sympathetic nervous activity increase with aging. This effect is evident in men, but even more pronounced in women. 7 In the sympathetic nerves of the human heart there are a constellation of biological influences of aging and gender. Cardiac noradrenaline spillover, indicative of resting sympathetic activity, is higher in older human subjects. 8 Further, the increase in cardiac sympathetic activity and noradrenaline spillover with laboratory mental stress is greater in older than in younger people. 2 Neuronal reuptake of noradrenaline is impaired in older people, which will augment sympathetic neural signals, especially in the heart, causing greater cardiac stimulation. 8 And there is another peculiarity in older people: adrenaline is co-released from the sympathetic nerves of the heart. Approximately 10% of the catecholamine released from sympathetic nerves of the aging heart is adrenaline. 9 This is not seen in health in youth or middle age. Whether these changes in the neurobiology of sympathetic nerves with age and gender pre-dispose to Takotsubo cardiomyopathy is not known. They probably do. All augment the neural response to mental stress in the heart. Further, the affinity of adrenaline for cardiac β 2 -adrenoceptors exceeds that of noradrenaline But there is another relevant consideration. The distribution of the sympathetic nerves in the left ventricle is such that there is a very distinct concentration gradient, from the base of the left ventricle to the apex, with nerve density approximately ten-fold higher in the left ventricular base. 10 This is the converse of the distribution of left ventricular dysfunction in Takotsubo cardiomyopathy, least in the base of the ventricle, worst in the cardiac apex, with apical ballooning. It is pertinent to ask whether this is compatible with the sympathetic nerves of the heart participating as a prime mover in the pathogenesis of the disorder. Conflict of interest: Salary support as an NHMRC Senior Principal Research Fellow. References are available as supplementary material at European Heart Journal online.