Cardiology: Form and function
Cardiac cycle
The cardiac cycle is the sequence of events that occurs during a heartbeat. The amount of blood ejected by the ventricle in this process is the stroke volume (SV), ∼70 mL, and cardiac output is the volume ejected per minute (SV × heart rate).
Towards the end of diastole (G) all chambers of the heart are relaxed. The valves between the atria and ventricles are open (AV valves: right, tricuspid; left, mitral), because atrial pressure remains slightly greater than ventricular pressure until the ventricles are fully distended. The pulmonary and aortic (semilunar) outflow valves are closed, as pulmonary artery and aortic pressure are greater than the respective ventricular pressures. The cycle begins when the sinoatrial node initiates the heartbeat.
Atrial systole (A)
Contraction of the atria completes ventricular filling. At rest, the atria contribute less than 20% of ventricular volume, but this proportion increases with heart rate, as diastole shortens and there is less time for ventricular filling. There are no valves between the veins and atria, so some blood regurgitates into the veins. The a wave of atrial and venous pressure traces reflects atrial systole.
Ventricular volume after filling is known as end‐diastolic volume (EDV) and is ∼120–140 mL. The equivalent pressure (end‐diastolic pressure, EDP) is <10 mmHg and is higher in the left ventricle than in the right due to the more muscular and therefore stiffer left ventricular wall. EDV is an important determinant of the strength of the subsequent contraction (Starling’s law). Atrial depolarization causes the P wave of the ECG.
Ventricular systole
Ventricular contraction causes a sharp rise in ventricular pressure, and the atrioventricular (AV) valves close once this exceeds atrial pressure. Closure of the AV valves causes the first heart sound (S1). Ventricular depolarization is associated with the QRS complex of the ECG. During the initial phase of ventricular contraction pressure is less than that in the pulmonary artery and aorta, so the outflow valves remain closed. This is isovolumetric contraction (B), as ventricular volume does not change. The increasing pressure causes the AV valves to bulge into the atria, resulting in the small atrial pressure wave (c wave), followed by a fall (x descent). Note the jugular venous pulse reflects the right atrial pressure and has corresponding a, c and v waves, and x and y descents.
Ejection
The outflow valves open when pressure in the ventricle exceeds that in its respective artery. Note that mean pulmonary artery pressure (∼15 mmHg) is considerably less than that in the aorta (∼80 mmHg).
Flow into the arteries is initially very rapid (rapid ejection phase, C), but as contraction wanes ejection is reduced (reduced ejection phase, D). Rapid ejection can sometimes be heard as a murmur.
Active contraction ceases during the second half of ejection, and the muscle repolarizes. This is associated with the T wave of the ECG.
Ventricular pressure towards the end of the reduced ejection phase is slightly less than that in the artery, but blood continues to flow out of the ventricle because of momentum. Eventually the flow briefly reverses, causing closure of the outflow valve and a small increase in aortic pressure, the dicrotic notch. Closure of the semilunar valves is associated with the second heart sound (S2).
The ventricle ejects ∼70 mL of blood (SV), so if EDV is 120 mL, 50 mL is left in the ventricle at the end of systole (end‐systolic volume). The proportion of EDV that is ejected (stroke volume/EDV) is the ejection fraction. During the last two‐thirds of systole atrial pressure rises as a result of filling from the veins (v wave).
Diastole – relaxation and refilling
Following closure of the outflow valves the ventricles are rapidly relaxing. Ventricular pressure is still greater than atrial pressure, however, and the AV valves remain closed. This is isovolumetric relaxation (E). When ventricular pressure falls below atrial pressure, the AV valves open, and atrial pressure falls (y descent) as the ventricles refill (rapid ventricular refilling, F). This is assisted by elastic recoil of the ventricular walls, essentially sucking in the blood. A third heart sound (S3) may be heard. As the ventricles relax completely refilling slows (reduced refilling, G). This continues during the last two‐thirds of diastole due to venous flow. At rest, diastole is twice the length of systole, but decreases proportionately during exercise and as heart rate increases.
The pressure–volume loop
Ventricular pressure plotted against volume generates a loop. The shape of the loop is affected by contractility and compliance (‘stretchiness’) of the ventricle and factors that alter refilling or ejection (e.g. central venous pressure, afterload). The bottom dotted line shows the passive elastic properties of the ventricle (compliance). If compliance was decreased as a result of fibrotic damage following an infarct, the curve would be steeper. The area of the loop (Δ pressure × Δ volume) is a measure of work done during a beat and is an indicator of cardiac function. A clinical estimate of stroke work is calculated from mean arterial pressure × stroke volume.
Heart sounds and murmurs
Heart sounds are caused by vibrations in the blood. S1 and S2 are each formed of two components (one for each valve). Normally, these may not be distinguishable, but they can ‘split’, so two distinct sounds are heard. S1 is comprised of M1 and T1, due to closure of the mitral and tricuspid valves, respectively. Splitting of S1 is always pathological, and commonly due to conduction defects. S2 is comprised of A2, and P2, closure of aortic and pulmonary valves. A2 slightly precedes P2, and a split is often heard in healthy young people, especially during inspiration and exercise. A large split may relate to conduction defects or high outflow pressures. S3 is due to rapid ventricular filling and is often heard in
young healthy people or when EDP is high (e.g. heart failure). S4 (not shown) is associated with atrial systole, and rarely heard unless EDP is high.
Murmurs are caused by turbulence. Valve stenosis (narrowing) increases blood velocity and thus turbulence.
Stenosis of the AV valves causes a soft diastolic murmur during ventricular filling. Semilunar valve stenosis causes a loud systolic murmur during ejection. Valve leakage (regurgitation, incompetence) also causes murmurs. AV valve regurgitation causes a pansystolic murmur (throughout systole) as blood leaks back into the atria, whereas semilunar valve regurgitation causes early diastolic murmurs as arterial blood leaks back into the ventricle.
Control of cardiac output
Cardiac output (CO) is stroke volume (SV) × heart rate (HR), and at rest ∼5 L/min; during strenuous exercise this can rise to >25 L/min. SV is influenced by the filling pressure (preload), cardiac muscle force, and pressure against which the heart has to pump (afterload), which are all modulated by the autonomic nervous system (ANS). The heart and vasculature form a closed system, so except for transient perturbations venous return must equal CO.
Filling pressure and Starling’s law of the heart
Right ventricular (RV) end‐diastolic pressure (EDP) is dependent on right atrial and therefore central venous pressure (CVP); left ventricular (LV) EDP is dependent on pulmonary venous pressure. EDP and the compliance of the ventricle (how easy it is to inflate) determine ventricular end‐diastolic volume (EDV). As EDP (and so EDV) increases, the force of the following contraction, and thus SV, increases. This is known as the Frank–Starling relationship, and the graph relating SV to EDP is called a ventricular function curve. The force of contraction is dependent on muscle stretch, and Starling’s law of the heart states ‘The energy released during contraction depends on the initial fibre length.’
As muscle is stretched more myosin crossbridges can form, increasing force. Cardiac muscle has a steeper relationship between stretch and force than skeletal muscle, because in the heart stretch also increases Ca2+ sensitivity of troponin C. The function curve is therefore steep, so small changes in EDP can lead to large increases in SV.
Importance of Starling’s law
The most important consequence of Starling’s law is that SV is matched between right and left ventricles. If, for example, RV SV increases, the amount of blood in the lungs and thus pulmonary vascular pressure will also increase. As the latter determines LV EDP, LV SV increases due to Starling’s law, until it again matches that of the RV when input to and output from the lungs equalize and the pressure stops rising. This represents a rightward shift along the function curve. Starling’s law thus explains how CVP, although only perceived by the RV, also influences LV function and CO, and why postural hypotension and haemorrhage reduce CO. It also allows the heart to sustain output against an increased afterload (e.g. hypertension, valve stenosis), as this leads to accumulation of venous blood and a raised EDP/EDV. Ventricular force therefore increases according to Starling’s law, until CO is restored at the expense of an increased EDP. The same occurs when contractility is reduced, which is why EDP is high in heart failure. As an increase in LV EDP represents an increase in RV afterload, for the same reasons CVP may also rise. A consequence of the above is that the ejection fraction (SV/EDV) will be reduced; this and an enlarged heart (high EDV) are characteristic of systolic heart failure.
The autonomic nervous system
The ANS strongly influences CO and is central to control of blood pressure. Sympathetic stimulation increases heart rate whereas parasympathetic stimulation decreases it. Sympathetic stimulation also increases cardiac muscle force (without any change in EDV), termed an increase in contractility; the function curve therefore shifts upwards. Agents that affect contractility are called inotropes. Parasympathetic stimulation does not affect ventricular contractility.
Sympathetic stimulation also causes arterial and venous vasoconstriction. An often overlooked point is that these
differ in effect. Arterial vasoconstriction increases total peripheral resistance (TPR) and thus reduces flow, so downstream pressure and venous return fall. However, unlike arteries veins are highly compliant (stretch easily) and contain ∼70% of blood volume.
Venoconstriction reduces venous compliance and hence capacity (amount of blood they contain), and therefore has the same effect as increasing blood volume, that is, CVP increases. Venoconstriction does not significantly impede flow because venous resistance is very low compared to TPR. Sympathetic stimulation can thus increase CO by increasing heart rate, contractility and CVP.
Venous return and vascular function curves
Blood flow is driven by the arterial–venous pressure difference, so venous return will be impeded by a rise in CVP. This is at first glance inconsistent with Starling’s law if CO must equal venous return. However, factors that affect CVP (blood volume, venoconstriction) also affect the relationship between CVP and venous return (vascular function curves). If the heart stops, pressure will equalize between the arterial and venous circulations (mean circulatory pressure, PMC), which depends on the volume and compliance of the vasculature, primarily the veins. By definition CVP equals PMC when venous return (i.e. CO) is zero. The curve levels off at negative CVP due to venous collapse. Increasing blood volume or venoconstriction increases PMC and so shifts the curve to the right, whereas blood loss does the reverse. Arterial vasoconstriction and an increase in TPR on the other hand reduces blood flow and venous return, but as resistance arteries contain little of the blood volume, and the decrease in diameter required to increase their resistance is small, there is an insignificant change in vascular volume or PMC. Thus, the net effect is to reduce the slope of the curve. A reduction in TPR does the opposite.
Guyton’s analysis helps us to understand the function of the cardiovascular system by combining vascular and cardiac function curves into one graph. The cardiac function curve is now shown as CO plotted against CVP (i.e. RV EDP). The only point at which CO and venous return are equal, and so the only point where the system is in equilibrium, is where the two function curves cross (A), the equilibrium (or operating) point. Thus, increasing blood volume or venoconstriction shifts the equilibrium point (B) and CO and CVP are both increased. Blood loss or venous dilatation do the opposite (C), which is why nitrovasodilators, which primarily dilate veins, reduce cardiac work.
Positive inotropes (e.g. digoxin) increase cardiac contractility and shift the cardiac function curve upwards. At equilibrium (D) CO is thus increased but CVP reduced, explaining why digoxin reduces symptoms in heart failure. Analysis of heart failure is illuminating. The initial fall in CO is limited by an elevated CVP. Central mechanisms mediated via the ANS then provide further compensation to maintain blood pressure, by increasing TPR, venoconstriction and renal retention of salt and water. Combined, these raise and flatten the vascular function curve (see above), so at equilibrium CO may be largely restored, but at the expense of a greatly increased CVP (F).
Haemodynamics
Relationships between pressure, resistance and flow
Haemodynamics is the study of the relationships between pressure, resistance and the flow of blood in the cardiovascular system.
Although the properties of this flow are enormously complex, they can largely be derived from simpler physical laws governing the flow of liquids through single tubes.
When a fluid is pumped through a closed system, its flow (Q) is determined by the pressure head developed by the pump (P1–P2 or ΔP), and by the resistance (R) to that flow, according to Darcy’s law (analogous to Ohm’s law):
or for the systemic circulation as a whole:
where CO is cardiac output, MABP is mean arterial blood pressure, TPR is total peripheral resistance (also referred to as the systemic vascular resistance, SVR) and CVP is central venous pressure.
Because CVP is ordinarily close to zero, this equation is typically simplified to MABP ≈ CO × TPR.
MABP is the arterial blood pressure averaged over the cardiac cycle, and since diastole lasts roughly twice as long as systole, it can be approximated as MABP ≈ (DBP + (SBP – DBP)/3) where SBP and DBP refer to the systolic and diastolic arterial blood pressures, respectively.
TPR cannot be measured and is calculated as:
TPR can be expressed in peripheral resistance units (PRU, also termed Wood units) as pressure in mmHg divided by cardiac output in mL/min (i.e. mmHg × min × L−1). However, pressure and flow can also be expressed as dynes/cm2 and cm3/sec, respectively, such that resistance in cgs units is dynes × sec × cm−5. Taking into account that 1 mmHg = 1330 dynes/cm2, the value of TPR in cgs units can be calculated from that in PRU by multiplying by 80. Thus, for example, if MABP is 95 mm/Hg and CO is 5200 mL/min, the TPR in PRU is ~18 and in cgp units is ~1460.
Resistance to flow is caused by frictional forces within a fluid and depends on the viscosity of the fluid and the dimensions of the tube, as described by Poiseuille’s law:
so that:
Here, V is the viscosity of the fluid, L is the tube length and r is the inner radius (= ½ the diameter) of the tube. Because flow depends on the fourth power of the tube radius in this equation, small changes in radius have a powerful effect on flow. For example, a 20% decrease in radius reduces flow by about 60%.
Considering the cardiovascular system as a whole, the different types or sizes of blood vessels (e.g. arteries, arterioles, capillaries) are arranged sequentially, or in series. In this case, the resistance of the entire system is equal to the sum of all the resistances offered by each type of vessel:
Calculations taking into account the estimated lengths, radii and numbers of the various sizes of blood vessels show that the arterioles, and to a lesser extent the capillaries and venules, are primarily responsible for the resistance of the cardiovascular system to the flow of blood. In other words, Rarteriole makes the largest contribution to Rtotal. Because according to Darcy’s law the pressure drop in any section of the system is proportional to the resistance of that section,
the steepest fall in pressure is in the arterioles.
Although the various sizes of blood vessel are arranged in series, each organ or region of the body is supplied by its own major arteries which emerge from the aorta. The vascular beds for the various organs are therefore arranged in parallel with each other. Similarly, the vascular beds within each organ are mainly arranged into parallel subdivisions (e.g. the arteriolar resistances Rarteriole are in parallel with each other). For ‘n’ vascular beds arranged in parallel:
An important consequence of this relationship is that the blood flow to a particular organ can be altered (by adjustments of the resistances of the arterioles in that organ) without greatly affecting pressures and flows in the rest of the system. This can be accomplished, as a consequence of Poiseuille’s law, by relatively small dilatations or constrictions of the arterioles within an organ or vascular bed.
Because there are so many small blood vessels (e.g. millions of arterioles, billions of venules, trillions of capillaries), the overall cross‐sectional area of the vasculature reaches its peak in the microcirculation. As the velocity of the blood at any level in the system is equal to the total flow (the cardiac output) divided by the cross‐sectional area at that level, the blood flow is slowest in the capillaries, favouring O2–CO2 exchange and tissue absorption of nutrients. The capillary transit time at rest is 0.5–2 s.
Blood viscosity
Very viscous fluids like motor oil flow more slowly than less viscous fluids like water. Viscosity is caused by frictional forces within a fluid that resist flow. Although the viscosity of plasma is similar to that of water, the viscosity of blood is normally three to four times that of water, because of the presence of blood cells, mainly erythrocytes. In anaemia, where the cell concentration (haematocrit) is low, viscosity and therefore vascular resistance decrease and CO rises. Conversely, in the high‐haematocrit condition polycythaemia, vascular resistance and blood pressure are increased.
Laminar flow
As liquid flows steadily through a long tube, frictional forces are exerted by the tube wall. These, in addition to viscous forces within the liquid, set up a velocity gradient across the tube in which the fluid adjacent to the wall is motionless, and the flow velocity is greatest at the centre of the tube. This is termed laminar flow and occurs in the microcirculation, except in the smallest capillaries. One consequence of laminar flow is that erythrocytes tend to move away from the vessel wall and align themselves edgewise in the flow stream. This reduces the effective viscosity of the blood in the microcirculation (the Fåhraeus–Lindqvist effect), helping to minimize resistance.
Wall tension
In addition to the pressure gradient along the length of blood vessels, there exists a pressure difference across the wall of a blood vessel. This transmural pressure is equal to the pressure inside the vessel minus the interstitial pressure. The transmural pressure exerts a circumferential tension on the wall of the blood vessel that tends to distend it, much as high pressure within a balloon stretches it. According to the Laplace/Frank law:
where Pt is the transmural pressure, r is the vessel radius and μ is the wall thickness. In the aorta, where Pt and r are high, atherosclerosis may cause thinning of the arterial wall and the development of a bulge or aneurysm. This increases r and decreases μ, setting up a vicious cycle of increasing wall tension which, if not treated, may result in vessel rupture.
Blood pressure and flow in the arteries and arterioles
Factors controlling arterial blood pressure
The mean arterial blood pressure is equal to the product of the cardiac output (about 5 L/min at rest) and the total peripheral resistance (TPR). Because the total drop of mean pressure across the systemic circulation is about 100 mmHg, TPR is calculated to be 100 mmHg/5000 mL/min, or 0.02 mmHg/mL/min. The unit mmHg/mL/min is referred to as a peripheral resistance unit (PRU), so that TPR is normally about 0.02 PRU.
Systolic pressure is mainly influenced by the stroke volume, the left ventricular ejection velocity and aortic/arterial stiffness and rises when any of these increase. Conversely, diastolic pressure rises with an increase in TPR. Arterial pressure falls progressively during diastole, so that a shortening of the diastolic interval associated with a rise in the heart rate also increases diastolic pressure.