Sinoatrial node
A small patch of self-firing cells at the junction of the superior vena cava and right atrium that depolarises on its own and, under normal conditions, faster than the tissue below it — so it sets the rate for every beat.
What it normally does
The node sits at the junction of the superior vena cava and the right atrium, at the top of the crista terminalis. Depolarisation spreads from there inferiorly and leftwards across the atria, which is why a sinus P wave is upright in leads II, III and aVF and precedes each QRS at a fixed interval.
When the P wave is absent, inverted in the inferior leads, or unrelated to the QRS, the node is not the one driving the heart — that is how a junctional or ectopic atrial escape rhythm is separated from true sinus bradycardia at the bedside.
Nodal cells have no stable resting potential to sit at. From a maximum diastolic potential of roughly -60 mV a slow inward current (the funny current, I_f, flowing through HCN channels and carried by mixed sodium and potassium movement, net sodium in) drifts them up to threshold, and L-type calcium current then carries the upstroke — so the heart beats with no instruction from the brain. Neither current is exclusive to the node: L-type calcium channels also run the AV node, the working myocardium and vascular smooth muscle, and HCN channels are found in the AV node, conducting tissue, neurons and the retina. Rhythmic calcium release from the sarcoplasmic reticulum contributes to the drift as well.
Change either current and the rate changes — which is how ivabradine (HCN), verapamil and diltiazem (L-type calcium) and beta blockers (removing the sympathetic drive that steepens both) all produce bradycardia, and why none of them acts on the node alone.
Under normal conditions the node fires faster than the tissue below it, so it captures the heart and everything downstream follows. Below it sits a hierarchy of slower back-ups: the AV junction around 40 to 60 a minute, the ventricle around 20 to 40. Being driven from above holds those back-ups quiet (overdrive suppression), so they take several seconds to wake once the drive stops. The hierarchy is only a default — a faster ectopic focus or a re-entrant circuit can and does take over.
When the node stops or a fast atrial rhythm suddenly terminates, there is a pause before the suppressed escape pacemaker wakes — the pause, not the slow rate itself, is what drops cerebral perfusion and causes the dizziness or syncope of sinus node dysfunction and tachy-brady syndrome.
Rate is set by a tug-of-war between vagal and sympathetic input acting on those same two currents, and at rest the vagus wins: the intrinsic rate of the denervated node is about 100 a minute in a young adult and falls with age, while the resting rate is nearer 70. Vagal acetylcholine acting on M2 receptors lowers cAMP and opens I_KACh; sympathetic noradrenaline acting on beta-1 receptors raises cAMP, which binds HCN directly and steepens the drift.
Blocking the vagus (atropine) raises the rate and blocking sympathetic drive (a beta blocker) lowers it — and it explains why atropine does nothing when there is no vagal brake left to remove, as in a fibrosed node or block below the node.
The sinoatrial nodal artery arises from the right coronary artery in roughly 60% of people and from the left circumflex in most of the rest. The right coronary artery also supplies the inferior wall of the left ventricle in a right-dominant circulation.
An inferior infarct and a slow sinus rate turn up together — partly from ischaemia of the node itself, partly from vagal afferents fired by the ischaemic inferior wall (the Bezold–Jarisch reflex).
What goes wrong
- Sinus tachycardia← from “Rate is set by a tug-of-war between vagal and …”
Sympathetic drive rises or vagal tone falls, so cAMP rises in nodal cells, the funny current and L-type calcium current steepen, and threshold arrives sooner — a rate above 100 a minute. The node is working perfectly; it is answering something: fever, pain, blood loss, dehydration, anxiety, thyrotoxicosis, sepsis, pulmonary embolism, salbutamol.
Sinus tachycardia is a sign, not a diagnosis — find and treat what the node is answering; rate-slowing a compensatory tachycardia removes the patient's compensation.
You would find: Regular, narrow QRS, an upright inferior P wave before every QRS, and a rate that moves with the patient — it settles when the pain is treated or the fluid goes up. In a young Aboriginal or Torres Strait Islander patient with fever and joint pain, a tachycardia out of proportion to the fever raises carditis from acute rheumatic fever, which remains common in remote communities of northern and central Australia.
- Sinus bradycardia← from “Rate is set by a tug-of-war between vagal and …”
Vagal tone dominates, sympathetic drive is blunted, or the intrinsic pacemaker itself slows — either way the diastolic drift to threshold flattens and firing falls below 60 a minute. Causes track back to those two things, autonomic tone and intrinsic rate: athletic training, sleep, vomiting or straining, raised intracranial pressure, hypothyroidism (thyroid hormone normally upregulates HCN expression), hypothermia, and above all drugs.
Treat the patient, not the number — symptoms and perfusion decide, and the medication chart is checked before the node is blamed.
You would find: Regular slow rate with a normal upright inferior P wave before every QRS. Whether it matters is decided by the patient, not the number: an asymptomatic athlete at 45 needs nothing; the same rate with dizziness, breathlessness, chest pain or hypotension needs action.
- Sick sinus syndrome (sinus node dysfunction)← from “Under normal conditions the node fires faster …”
Age-related fibrosis and ion-channel remodelling replace or degrade nodal tissue, so firing becomes unreliable. The node drops beats or stops altogether (sinus pause or arrest) and, because the escape pacemakers below have been overdrive-suppressed, they are slow to wake — cerebral perfusion falls for those few seconds, and that is the dizziness or the faint.
Symptomatic, drug-independent sinus node dysfunction is a pacemaker problem, not a drug problem — no oral agent reliably speeds a fibrosed node.
You would find: An older patient with dizziness, fatigue or blackouts. The resting ECG in clinic is often normal, so the diagnosis is made by catching symptoms and rhythm together on a Holter or event monitor.
- Tachy-brady syndrome← from “Under normal conditions the node fires faster …”
The same diseased atrium that makes the node unreliable also generates fast atrial rhythms. A run of atrial fibrillation or flutter overdrive-suppresses the node hard; when it terminates, the sick node is too slow to restart and a long conversion pause follows — fast, then dangerously slow.
Pause on conversion is the signature — pacemaker first, then the rate-controlling drug the patient also needs (and anticoagulation is decided on stroke risk, separately from rhythm).
You would find: Palpitations and blackouts in the same patient, often with a documented pause at the moment a fast atrial rhythm stops. The trap: the drug that controls the fast phase worsens the slow phase, which is why many of these patients need a pacemaker before rate control can be given safely.
- Drug-induced bradycardia← from “Nodal cells have no stable resting potential t…”
Drugs that remove sympathetic input (beta blockers), block the L-type calcium current (verapamil, diltiazem) or raise vagal tone (digoxin) do exactly what they are designed to do at the node, and their effects add up. Reduced renal clearance (digoxin, atenolol, sotalol) or a new interacting drug can convert a previously tolerated regimen into symptomatic bradycardia.
Reversible bradycardia wearing the costume of sick sinus syndrome — read the medication chart and check renal function before referring for a pacemaker.
You would find: A patient on a beta blocker plus verapamil or diltiazem, or one whose renal function has dropped so a renally cleared drug has accumulated. Stop or reduce the drug and reassess before labelling the node as diseased.
- Bradycardia complicating inferior myocardial infarction← from “The sinoatrial nodal artery arises from the ri…”
Occlusion of the right coronary artery removes the blood supply to the sinoatrial node in the majority of people, and the ischaemic inferior wall simultaneously fires vagal afferents that brake the node further. Sinus bradycardia, sinus arrest and AV block therefore cluster with inferior infarction.
Inferior STEMI plus bradycardia is anatomy plus reflex, not coincidence — and it is one of the settings where atropine actually works.
You would find: Bradycardia with ST elevation in II, III and aVF. Often vagally mediated and atropine-responsive in the first hours, and frequently transient after reperfusion.
What we give, and how it works
Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.
- Binds
- muscarinic M2 receptors (competitive antagonist), and M1–M3 receptors everywhere else in the body
- Which does
- prevents acetylcholine-driven inhibition of adenylyl cyclase and opening of I_KACh, so cAMP and the funny current recover and the diastolic drift steepens
- So you see
- heart rate rises within a minute or two, provided the underlying vagal tone was the thing holding it down
- And the same mechanism causes
- the same receptor blockade elsewhere produces dry mouth, blurred vision and loss of accommodation, urinary retention, constipation and — because it crosses into the brain — confusion or delirium, which is a real risk in the older patients most likely to be bradycardic
Catches people out: It lifts a brake; it does not press an accelerator. If the node is fibrosed (sinus node dysfunction) or the block is below the AV node (Mobitz II, complete heart block with a wide escape), there is no vagal brake to remove and atropine does little or nothing — the answer is pacing, with a chronotropic infusion as a bridge.
- Binds
- beta-1 adrenoceptors (competitive antagonists; carvedilol also blocks alpha-1, nebivolol adds nitric-oxide-mediated vasodilation)
- Which does
- lowers cAMP in nodal cells, so the funny current and L-type calcium current are less steep and phase 4 depolarisation flattens; the same fall in cAMP slows AV nodal conduction and reduces contractility
- So you see
- slower resting and, more importantly, slower exercise heart rate; less angina, better rate control in atrial fibrillation, improved survival in heart failure with reduced ejection fraction
- And the same mechanism causes
- the intended blockade taken further gives bradycardia, AV block and hypotension, a blunted heart rate response to exercise and to hypoglycaemia (so warning symptoms are masked in insulin-treated diabetes), fatigue, and — as beta-1 selectivity is only relative — bronchospasm in susceptible airways
- Handling
- atenolol and sotalol are renally cleared and accumulate as renal function falls, which is a common route into symptomatic bradycardia in older patients; metoprolol, carvedilol and bisoprolol are less dependent on renal clearance
Catches people out: Among the commonest reasons a patient is bradycardic on arrival. Before diagnosing sinus node dysfunction, read the medication chart — beta blockers, verapamil, diltiazem and digoxin all slow the node and their effects stack. Do not start or up-titrate in decompensated heart failure; taper rather than stop abruptly after chronic use.
- Binds
- L-type (Ca_v1.2) calcium channels; verapamil is the more cardioselective of the two, diltiazem intermediate
- Which does
- reduces calcium entry, so the nodal upstroke is smaller and slower, AV nodal conduction is delayed and refractoriness lengthened, and myocyte excitation–contraction coupling is weakened
- So you see
- slower ventricular rate in atrial fibrillation, less angina, and a measurable fall in contractility
- And the same mechanism causes
- bradycardia and AV block from the nodal effect, decompensation of heart failure from the negative inotropy, ankle oedema and flushing from arteriolar dilatation, and constipation from L-type channel blockade in gut smooth muscle (verapamil especially)
- Handling
- both inhibit CYP3A4 and P-glycoprotein, so they raise digoxin and statin concentrations — a relevant trap in the same patient being rate-controlled
Catches people out: Combining one of these with a beta blocker, particularly intravenously, can suppress the sinoatrial and AV nodes together and cause profound bradycardia, complete heart block or asystole. Because they are negative inotropes they are avoided in heart failure with reduced ejection fraction. Amlodipine is a dihydropyridine, acts mainly on vascular smooth muscle and lacks this nodal effect.
- Binds
- HCN channels in the sinoatrial node, blocked from inside the pore and preferentially when the channel is open (use-dependent), so the faster the node fires the more it is slowed
- Which does
- reduces the inward funny current, flattening the phase 4 drift so threshold is reached later; nothing else about the action potential or about calcium handling is changed
- So you see
- pure heart rate reduction — no fall in blood pressure, no negative inotropy, no effect on AV conduction
- And the same mechanism causes
- bradycardia, and luminous visual phenomena (phosphenes — transient enhanced brightness) from block of the closely related HCN current in retinal photoreceptors; an increased incidence of atrial fibrillation is also seen
- Handling
- metabolised by CYP3A4, so strong inhibitors such as clarithromycin, ketoconazole and diltiazem raise concentrations and exaggerate the bradycardia
Catches people out: It only works if the sinoatrial node is setting the rate. In atrial fibrillation the node is not in charge and ivabradine does not control the ventricular rate. It is not a substitute for a beta blocker where a beta blocker is tolerated, since it has no effect on the AV node, contractility or blood pressure.
- Binds
- beta-1 adrenoceptors (isoprenaline is a non-selective beta-1/beta-2 agonist; adrenaline is a non-selective alpha and beta agonist)
- Which does
- Gs-coupled rise in cAMP steepens the funny current and increases L-type calcium current, so the node fires sooner and the myocardium contracts harder
- So you see
- heart rate and cardiac output rise within seconds of titration and fall again as soon as the infusion is reduced
- And the same mechanism causes
- the same adrenergic drive causes ventricular ectopy and tachyarrhythmias, and raises myocardial oxygen demand while shortening diastole, so it can worsen ischaemia — and isoprenaline's beta-2 vasodilation can drop the diastolic pressure it was given to protect
Catches people out: This is a holding measure, not a treatment. If the node is structurally failing, the rate falls again the moment the infusion stops, so pacing should be organised in parallel rather than afterwards.
- Binds
- Na+/K+-ATPase (direct), plus vagal afferent and central effects that raise parasympathetic outflow to the nodes
- Which does
- raises intracellular sodium and hence calcium via the sodium-calcium exchanger, increasing contractility; the vagal effect lowers cAMP and opens I_KACh in nodal tissue, slowing conduction and lengthening AV nodal refractoriness
- So you see
- slower resting ventricular rate in atrial fibrillation with a small increase in contractility, and no fall in blood pressure
- And the same mechanism causes
- toxicity follows directly from the mechanism: excess vagal effect and pump inhibition give bradycardia, sinus arrest and AV block at the same time as calcium-loaded cells become automatic, producing the characteristic combination of a slow ventricular response with ectopy, plus nausea, anorexia and yellow-green visual disturbance
- Handling
- renally cleared with a narrow therapeutic index — falling renal function, hypokalaemia (which increases binding to the pump), hypomagnesaemia and interacting drugs such as verapamil, diltiazem and amiodarone all push it toward toxicity
Catches people out: Vagally mediated rate control is overridden by sympathetic drive, so it controls the rate poorly during exertion, sepsis or pain. It appears in this topic mainly as a cause of bradycardia and as a drug that accumulates when renal function falls.
Bradycardia during an inferior myocardial infarction is not a coincidence: the right coronary artery supplies the inferior wall and, in about 60% of people, the sinoatrial node as well — and the ischaemic inferior wall fires vagal afferents that brake the node further, which is why this bradycardia often does respond to atropine while the bradycardia of a fibrosed node does not. And sinus tachycardia is a sign, not a diagnosis — slowing it before finding what the node is answering removes the patient's compensation.
Now test whether it stuck
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