Isn’t the heart in command? Yet science says otherwise

“The heart is not commanded”, goes a well-known adage. Well, the reality documented in a new, interesting work that has just been published provides further evidence that exactly the opposite is true. As has long been known, the heart rate at rest (i.e. away from relevant physical exercise) exhibits a precise daily rhythm: faster during the waking period and slower during the rest period. Not surprisingly, following this circadian cycle, pathological cardiac events have very different distributions between day and night. According to the explanation that has been around for nearly a century, the circadian rhythm of the resting heart rate has been attributed to the parasympathetic nervous system, specifically the vagus nerve in humans, traditionally associated with “resting and digesting” functions. This hypothesis had already proved to be poorly supported; now, a new study has shown that the heart’s circadian rhythm at rest is actually dictated by the sympathetic system, usually associated with fight-or-flight responses.

In this type of short-term response, the sympathetic system releases catecholamines such as adrenaline which act on the sinus node, our natural pacemaker, altering the heart rate within seconds by stimulating the β-adrenergic receptors which induce in turn changes in the conductance of cardiac ion channels, changing the electrical activity of the heart. This type of induction of rapid responses, however, is unable to account for the long time-scale rhythm change observed in day-night alternation. The described mechanism is exactly the same also in mice: also in their heart, the β-adrenergic receptors are mainly responsible for the response to the signals of the sympathetic nervous system, and also the rodents show a circadian cycle of cardiac rhythm and electrical activity exactly similar to the human one. In the new study, the researchers therefore first tried to prevent the action of the sympathetic system on the heart in mice with a classic drug that acts on β-adrenergic receptors, i.e. a β-blocker: propranolol, which anyone affected by arrhythmia problems or know others with such problems. Under these conditions, long-term pharmacological β-adrenergic blockade could be observed to alter the day-night rhythm of the heart rate. However – and here came the important point – the alteration selectively concerned the sinus node, i.e. our biological pacemaker: in particular, it was seen that a series of important regulatory genes, which in untreated mice exhibited a change of day-night activity, they lost this daily synchronization in mice treated with the β-blocker for a long time. In contrast, many genes that exhibit similar day-night cycles in the rest of the heart remained in sync. This means that the sympathetic nervous system, through its activity, controls not only the immediate electrical activity of the sinus node, in the immediate responses mentioned above, but also slower and more persistent rhythm changes, which instead correspond to the of local activity of specific genes of that important structure.

Therefore, it is our sympathetic nervous system that commands a sort of remodeling of the electrical sensitivity over a 24-hour period, with a completely independent mechanism from the one used when it is necessary to induce peaks of cardiac activity in response to sudden stress, a commonly accepted mechanism and hitherto considered exclusive. Now, this result leads to some important considerations concerning the life of a large number of Italians. In fact, β-blockers such as propranolol are commonly indicated to treat a wide variety of conditions, some of which are very common: arterial hypertension, angina pectoris, arrhythmias, essential tremor, tachycardias related to anxiety-producing states, and then post- heart attack and migraine, not to mention other rarer indications. The mechanism of action of β-blockers on the sympathetic nervous system, and through that on the regulation of the sleep-wake rhythm of the heart at rest, has been elucidated thanks to the work just described: this new knowledge obviously has the potential for the development of new targeted chronotherapies, which can best integrate the therapeutic administration with the natural circadian heart rhythm. In the end, therefore, it is our neurons that send our heart to sleep: it is increasingly clear that the heart really rules.