Determinants of cardiac output

Inotropy describes the stroke volume with a given preload and afterload.

Three indicies are used to approximate the inotropy.

1. The maximal rate of pressure increase, \(\frac{dP}{dT}\) in the LV, which occurs during isovolaemic contraction (although this is still partly preload dependant!)
2. The ejection fraction is a nasty, dirty approximation (because it is preload and afterload dependant!)
3. The left ventricular end systolic pressure volume linear relationship. This is the line of end-systolic (pressure,volume) points produced by sequential pressure-volume loops with different preloads (the \(\frac{d\text{LVESV}}{d\text{LVESP}}\) if you will)

\(\uparrow[Ca^{2+}]_{intracellular} \to \ \uparrow \text{Toponin-}Ca^{2+} \text{ binding} \to \ \uparrow \text{Active myosin units} \)

(This is how in-vivo way inotropy is modulated and how all intotropes except levosimendan work).

Intracellular calcium is modulated by extracellular calcium concerntration, and calcium conductance during phase 2 of the myocardial action potential.

\(\beta_1\) agonism increases adenylate cyclase \(\to\) increases cAMP \(\to\) increases PKA. PKA then phosphorylates two important targets: the L-type calcium channel of the sarcolemma and the SERCA transporter of the sarcoplasmic reticulum. The first increases calcium conductance into the cell during phase 2, and the second increases calcium export rate during phases 3 and 4.

Things that increase inotropy

1. The Anrep effect - \(\uparrow\)afterload increases intropy (on top of the Frank-Starling response) probably due to aldosterone \(\stackrel{probably}{\to\}) increased expression of L-type calcium channels
2. The Bowditch effect - \(\uparrow\)heart rate increases intotropy because there's not enough time for calcium efflux to finish
3. Catecholamines (endogenous or exogenous) directly stimulate \(\beta_1\) receptors. Ephedrine displaces catecholamines from sympathetic vesicles, which then stimulate \(\beta_1\) receptors.
4. PDE3 inhibitors (milrinone) prevent the breakdown of cAMP.
5. Exogenous calcium increases extracellular calcium concentration.
6. Thyroid hormone increases \(\beta_1\) receptor expression.
7. Digoxin competes with extracellular potassium for Na/K ATPase \(\to\) increased intracellular Na \(\to\) increased Na/Ca antiport via Na/Ca exchanger \(\to\) increased intracellular calcium
8. Insulin by increasing intracellular calcium by an unclear mechanism
9. Levosimendan by stabilizing troponin C in the open state (the only calcium-independant inotrope)

Things that decrease intotropy

1. Nonfunctional (e.g. Infarcted) myocardium, or the disorganized myocardium associated with cardiomyopathies, infiltration of myocardium by sarcoidosis, amyloidosis (typically transthyretin amyloid)
2. Hypoxia (hypoxaemic, anaemic, ischaemic, histotoxic): decreased ATP availability
3. Myocardial stunning (a transient decrease in inotropy following ischaemia that does not result in myocardial death)
4. Hypothermia - the myosin ATPase is temperature dependant
5. Acidosis - hydrogen competes with calcium for binding on troponin and the ryanodine receptor

Preload is the sarcomere length at end-diastole, which is approximated by left ventricular end diastolic volume.

From the definition of compliance, we have immediately

$$LVEDV = C_{\text{LV wall}} \cdot LVEDP$$

Determinants of LVEDP

1. Intrathoracic pressure (decreases RV preload, increases RV afterload, decreases LV preload, decreases LV afterload)
2. Atrial contribution (about 20% of LVEDV). Lost in AF, relatively higher in tachycardia or diastolic dysfunction.
3. Passive filling by the gradient between MSFP and CVP (increased by increased venous tone, increased blood volume, and diastolic time)
4. Afterload (an increased end-SYSTOLIC volume will result in an increased end-DIASTOLIC volume on the next stroke)

Determinants of LV compliance

1. Pericardial compliance (decreased by tamponade and constrictive pericarditis; increased by pericardotomy)
2. Wall thickness
3. Wall fibrosis
4. Lusitropy (active relaxation, inhalenced by catecholamines)

Frank-starling mechanism

The Frank-starling mechanism causes increased stroke volume as sarcomeres length increases. This is probably because

1. Stretch decreases the diameter of the myocyte (which has constant volume)
2. Titin acts as a mechanoceptor
3. These two things bring actin and myosin closer together
4. This increases the sensitivity of myofibrils for calcium
5. This also increases the number of myofilament cross-bridges that can interact

The relationship is concave-down (it plateaus out). With reduced contractility, the curve can begin to decrease beyond a maximum stroke volume.

This matches the LV output to the RV output and adapts to sudden changes in preload.

The afterload of the heart is the hydraulic input impedance of the aortic valve and vascular tree. If we think of this in Pouseillean terms:

$$Q = \frac{\Delta P}{I}$$

$$I = \frac{\Delta P}{Q}$$

$$I = \frac{LVSP}{Q}$$

$$I = \frac{\text{Aortic Systolic Pressure} + \text{Mean LVOT gradient}}{\text{Stroke volume}}$$

And like everything else in cardiology, we should normalize it to body surface area...

$$\text{Valvuloarterial Impedance} = \frac{\text{Aortic Systolic Pressure} + \text{Mean LVOT gradient}}{\text{Stroke volume index}}$$

Basically, if the afterload is high, we need a higher LV systolic pressure to force out the same amount of fluid.

Alternatively, we can think of afterload as the wall tension in the ventricle: the radial force exerted by a unit volume of myocardial tissue given by the Young-Laplace equation for a spherical shell:

$$\rho = \frac{P \cdot r}{2w}$$

$$\rho = \frac{\text{LVSP} \cdot \text{LV radius}}{2 \cdot {\text{LV wall thickness}}}$$

Therefore the things that increase afterload are:

1. Increased total peripheral resistance to flow (principally vessel radius and blood viscosity)
2. Decreased aortic and peripheral compliance (which results in increased hydraulic reactance)
3. Aortic stenosis and LVOT outlet obstruction
4. Increased chamber size

Afterload is decreased by:

1. Increasing wall thickness

The Venous return is the flow of blood from the venous to the heart. It equals cardiac output.

$$VR = CO$$

$$VR = \frac{MSFP - CVP}{\text{Systemic Venous Resistance}}$$

The mean systemic filling pressure (the pressure in the capillaries, or equivalently the pressure throughout the circulation during cardiac arrest). This is determined by:

1. The venous compliance (\(\downarrow\) by venoconstriction e.g. catecholamines \(\to \ \alpha_1\) agonism)
2. The total blood volume

The Guyton model involves two functions. The independent variable is the CVP. Then we consider the cardiac output and venous return as functions of the CVP.

The cardiac output CO(CVP): This has the usual Frank-Starling shape.

The venous return: this is constant (and maximal) below a CVP of 0cmH2O due to venous collapse, then falls with increasing CVP, because \(VR = \frac{MSFP - CVP}{\text{Systemic Venous Resistance}}\)

Of course, \(CO = \text{Venous return}\) - so the point where these two curves cross is the steady state operating point.

Three things can therefore affect the cardiac output in this model.

1. \(\uparrow\text{Stressed volume}\to\uparrow\text{MSFP}\to\ \ \uparrow\text{CO and }\uparrow\text{CVP}\)
2. \(\uparrow\text{Inotropy}\to\ \ \uparrow\text{CO and }\downarrow\text{CVP}\)
3. \(\uparrow\text{TPR}\to\uparrow\text{Arterial:Venous blood volumes}\to\ \ \downarrow\text{CO and }\downarrow\text{CVP}\)