Output is not set by the heart alone,
it is where two curves cross.

The determinants of stroke volume

The Frank–Starling mechanism

Starling’s law of the heart: the force of contraction of ventricular muscle is proportional to its initial resting fibre length. Three mechanisms underlie it, and the second is the one that distinguishes a good answer:

• Actin–myosin overlap. Stretch toward the optimal sarcomere length of about 2.2 µm increases the number of available cross-bridges.
• Length-dependent calcium sensitivity. Stretch increases the affinity of troponin C for calcium, so the same calcium transient generates more force. This is the dominant mechanism in cardiac muscle, and it is why the cardiac length–tension curve is so much steeper than the skeletal one.
• Reduced myofilament lattice spacing and titin-mediated restoring force contribute.

Functionally it does two things without any nervous input: it matches output to filling beat by beat, and it keeps the outputs of the two ventricles equal. A transient mismatch loads the lagging ventricle, which then ejects more.

Venous return and the coupled operating point

• VR — venous return, L min⁻¹
• MSFP — mean systemic filling pressure, mmHg: the pressure everywhere in the systemic circulation if the heart were stopped and flow allowed to equalise. About 7 mmHg. It is set by blood volume and by venous tone — that is, by the relation between the volume in the system and its capacitance.
• RAP — right atrial pressure, mmHg, the downstream pressure
• RVR — resistance to venous return, mmHg min L⁻¹

What promotes venous return

• Blood volume and venous tone — both raise mean systemic filling pressure. Sympathetic venoconstriction recruits blood from the unstressed volume of the splanchnic and cutaneous beds into the stressed compartment, and can mobilise several hundred millilitres within seconds.
• The skeletal muscle pump with competent venous valves — intermittent compression raises deep venous pressure, and the valves impose one-way flow.
• The respiratory (thoracic) pump — inspiration lowers intrathoracic and therefore right atrial pressure while raising intra-abdominal pressure, widening the gradient.
• The cardiac pump — descent of the atrioventricular ring during ejection enlarges the atrium and lowers its pressure (the x descent), and rapid ventricular relaxation contributes diastolic suction.
• Gravity below the level of the heart, and posture generally.

Right ventricular output

The determinants are the same — heart rate and stroke volume, with stroke volume set by preload, afterload and contractility — but the values differ. Right ventricular afterload is set by pulmonary vascular resistance, pulmonary artery pressure and pulmonary valve function, and pulmonary vascular resistance is uniquely U-shaped with lung volume: minimal at functional residual capacity, higher at both extremes as alveolar vessels are compressed above and extra-alveolar vessels collapse below. Hypoxia, hypercarbia and acidosis all raise it.

Three further determinants are specific to the right ventricle and are the ones most often omitted: heart rhythm, synchrony of contraction and ventricular interdependence — the two ventricles share a septum and a pericardium, so distension of one impairs the filling of the other.

Measuring cardiac output

• V̇O₂ — oxygen consumption, mL min⁻¹ (about 250 at rest)
• CaO₂ — arterial oxygen content, mL dL⁻¹ (about 20)
• CvO₂ — mixed venous oxygen content, mL dL⁻¹ (about 15)

Worked: CO = 250 ÷ (200 − 150) mL L⁻¹ = 250 ÷ 50 = 5 L min⁻¹. Note the unit conversion — contents are usually quoted per decilitre and must be per litre for the arithmetic to work. This is the Fick principle (conservation of mass), not Fick’s law of diffusion, and confusing the two is a standard trap.

Compliance: the reservoir function

• C — compliance, mL mmHg⁻¹
• E — elastance, mmHg mL⁻¹
• ΔV — change in volume; ΔP — change in transmural pressure

The veins are about twenty times more compliant than the arteries, and hold roughly 65–70% of the total blood volume at a mean pressure of only a few mmHg. Two ideas follow. The venous system is the body’s volume reservoir, and venoconstriction is a way of giving a transfusion from the patient’s own splanchnic bed. And the arterial system is a pressure reservoir: the aorta accepts about half the stroke volume during systole and discharges it during diastole, converting intermittent ejection into near-continuous capillary flow. That is the Windkessel effect, and its loss with ageing is precisely why pulse pressure widens.

The arterial waveform

Pulse pressure (systolic minus diastolic) is determined by stroke volume and arterial compliance. It is therefore widened by a large stroke volume, by aortic regurgitation and by the stiff arteries of age, and narrowed by hypovolaemia, tamponade and aortic stenosis — which is why a narrowing pulse pressure is an earlier sign of blood loss than a falling systolic pressure.

The microcirculation and Starling forces

• J_v — net fluid flux across the capillary wall, mL min⁻¹
• K_f — filtration coefficient: the product of the hydraulic conductivity of the wall and the surface area available
• P_c — capillary hydrostatic pressure, about 32 mmHg at the arteriolar end falling to about 15 mmHg at the venular end
• P_i — interstitial hydrostatic pressure, about −3 mmHg
• σ — reflection coefficient (sigma), between 0 and 1: how effectively the wall excludes protein. Near 1 in the brain, near 0 in the hepatic sinusoids
• π_c — capillary oncotic pressure, about 25 mmHg, mostly from albumin
• π_i — interstitial oncotic pressure, about 8 mmHg

Capillary hydrostatic pressure is far more sensitive to changes in arteriolar than in venular tone in one direction, but a rise in venous pressure is transmitted almost fully to the capillary — which is why venous obstruction and right heart failure produce oedema so readily.

The classical picture of filtration at the arteriolar end and reabsorption at the venular end has been revised: the revised Starling principle holds that the relevant oncotic gradient is across the endothelial glycocalyx into the subglycocalyx space, not across the whole wall, so most capillary beds filter along their whole length and the filtrate returns as lymph. Damage to the glycocalyx — by sepsis, ischaemia–reperfusion, surgery or hypervolaemia — increases K_f and reduces σ, which is a large part of why the critically ill leak.

Anatomy, briefly but completely

Both coronary arteries arise from the aortic sinuses immediately above the aortic valve; eddies in the sinuses of Valsalva keep the ostia patent during systole. The left main divides into the left anterior descending (interventricular septum, anterior wall and apex, by septal and diagonal branches) and the circumflex (lateral and posterior left ventricle; supplies the sinoatrial node in about 40% of people). The right coronary artery supplies the right atrium and ventricle, the sinoatrial node in about 60%, and — in the 85–90% who are right-dominant — gives the posterior descending artery, which supplies the atrioventricular node and the inferior septum.

Venous drainage has three routes, and omitting them is a recorded error when the question asks about the coronary circulation: the coronary sinus (about 85%, into the right atrium), the anterior cardiac veins (directly into the right atrium), and the Thebesian veins (draining directly into all four chambers, including the left).

Phasic flow

• CPP — coronary perfusion pressure for the left ventricle, mmHg
• AoDP — aortic diastolic pressure, mmHg
• LVEDP — left ventricular end-diastolic pressure, mmHg — the tissue pressure the vessel must overcome

More generally, coronary perfusion pressure is aortic root pressure minus the higher of the intraventricular pressure and the venous pressure. That is why the right coronary artery, facing a chamber at about 25 mmHg in systole, is perfused throughout the cycle at a perfusion pressure of roughly 80–95 mmHg, while the left, facing a chamber at 120 mmHg, sees a perfusion pressure that ranges from about 80 mmHg in diastole to effectively zero in systole.

Unique features of the coronary circulation

The oxygen balance

The baroreceptor reflex

Sensors. Stretch receptors in the adventitia of the carotid sinus and the aortic arch. They are mechanoreceptors, so they respond to the rate of change of pressure as well as its absolute value, and they are most sensitive around 80–150 mmHg. Firing increases as pressure rises.

Afferents. The carotid sinus by the glossopharyngeal nerve (IX), by the nerve of Hering; the aortic arch by the vagus (X). Both terminate in the nucleus tractus solitarius in the medulla.

Efferents. Increased afferent traffic inhibits the sympathetic outflow and excites the vagal outflow from the nucleus ambiguus; reduced traffic does the reverse. The response acts on all four terms at once — heart rate, contractility, arteriolar tone and venous capacitance — and, since MAP = CO × SVR + RAP, all four defend the pressure.

The reflex resets over one to two days to a new prevailing pressure, which is why it defends against acute change but does not prevent established hypertension. It is depressed by volatile agents, propofol and opioids — the single most important reason induction causes hypotension in a patient whose pressure was being maintained by sympathetic tone.

The other reflexes

• Cardiopulmonary (low-pressure) receptors. Stretch receptors in the atria, ventricles and great veins sensing filling rather than pressure. Atrial distension causes the Bainbridge reflex (a rise in heart rate), reduces sympathetic tone to the kidney, inhibits antidiuretic hormone and releases atrial natriuretic peptide — so the response to a volume load is natriuresis and diuresis.
• Peripheral chemoreceptors. Carotid and aortic bodies respond to a fall in PaO₂ below about 60 mmHg, a rise in PaCO₂, acidaemia and severe hypotension. The primary cardiovascular effect is sympathetic vasoconstriction with bradycardia; the accompanying hyperventilation causes a secondary tachycardia through pulmonary stretch receptors, so the net effect in a breathing patient is a rise in rate.
• Central chemoreceptor and CNS ischaemic response. At a cerebral perfusion pressure below about 40 mmHg, medullary ischaemia produces a massive sympathetic discharge — the last-ditch defence of cerebral perfusion. With raised intracranial pressure this appears as Cushing’s triad: hypertension, bradycardia and irregular respiration.
• Bezold–Jarisch reflex. Stimulation of ventricular mechano- and chemoreceptors in an underfilled, vigorously contracting ventricle produces bradycardia, vasodilatation and hypotension — one explanation for the sudden bradycardic collapse occasionally seen during high spinal anaesthesia.
• Oculocardiac and other vagal reflexes. Traction on the extraocular muscles, on the peritoneum or on the cervix produces bradycardia by a trigeminal or vagal afferent with a vagal efferent.

Humoral control

• Renin–angiotensin–aldosterone. Renin is released from the juxtaglomerular apparatus in response to reduced renal perfusion, reduced sodium delivery to the macula densa, and β₁ stimulation. Angiotensin II is a potent arteriolar vasoconstrictor, releases aldosterone and antidiuretic hormone, and stimulates thirst. Timescale: minutes to hours, then days.
• Antidiuretic hormone (vasopressin). Released from the posterior pituitary in response to a rise in plasma osmolality of as little as 1%, or to a fall in volume of 10% or more. At the higher concentrations reached in haemorrhage it is a V₁-mediated vasoconstrictor as well as an antidiuretic.
• Natriuretic peptides. ANP from the atria and BNP from the ventricles in response to stretch. They vasodilate, increase glomerular filtration, inhibit renin and aldosterone, and antagonise the whole sodium-retaining axis.
• Adrenal catecholamines. Adrenaline predominates from the medulla and acts on β receptors at low concentration and α at high.
• Endothelial mediators. Nitric oxide (continuous tonic vasodilatation, released by shear stress) and prostacyclin against endothelin-1, the most potent endogenous vasoconstrictor known.

Local control and autoregulation

Autoregulation is the maintenance of near-constant organ blood flow across a range of perfusion pressures, independent of nerves and hormones. Two mechanisms: the myogenic response, in which vascular smooth muscle contracts when stretched (the Bayliss effect), and metabolic control, in which accumulating adenosine, K⁺, H⁺, CO₂ and a falling PO₂ vasodilate.

Two related phenomena are worth naming. Reactive hyperaemia is the overshoot in flow after a period of occlusion, from accumulated metabolites. Functional (active) hyperaemia is the increase in flow that accompanies increased tissue activity — the mechanism by which exercising muscle recruits its enormous flow reserve.