The Frank-Starling mechanism

This chapter is relevant to Section G3(i)  of the 2017 CICM Primary Syllabus, which asks the exam candidate to "explain the Frank-Starling mechanism and its relationship to excitation-contraction coupling". Remarkably, the college examiners have never attempted to directly weaponise this section of the syllabus, though it does appear as shrapnel in the casing of other questions. This is mainly surprising because the subject matter is fundamental to cardiovascular physiology, and because there is a diagram which makes for easy question-writing (just ask them to draw and label it). 

In summary:

For the effects of pathophysiology on the Frank-Starling relationship, the best free offering is Jacob et al (1992), which is comprehensive and contains lovely diagrams. Mann's chapter from Data Interpretation in Anaesthesia is also excellent as it is presented in a question and answer format, like a viva station. In case one is unwilling to part with this subject after these twenty pages of text and references, one's weird needs will be satisfied by Keurs & Noble (1988), an entire 150-page book on the length-tension relationship. There is also a series of about ten articles titled "Studies on Starling's law of the heart", published in Circulation between 1960 and 1964, which contains even more permutations on this theme (i.e. every possible combination of cardiac variable and valve pathology you could think of). It would be pointless (also, probably harmful) to actually consume all of this literature in the course of exam preparation, and it is being left here for a purely decorative purpose, like a bowl of plastic fruit. 

The Frank-Starling Law

It is probably misnamed, as neither Ernest Frank nor Otto Frank discovered this thing. It was probably first noted either thirty or sixty years earlier. Apparently, in 1866 Elias Cyon first noticed it in the frog heart he was molesting, but he didn't write anything down and so it didn't happen. Similarly, Bowditch in the 1830s made recordings of the phenomenon, and though he noticed  certain Eigentümlichkeiten in the way the ventricle handled volume, he didn't think to mention it in his paper. 

Anyway. Starling's first descriptions of this phenomenon ran to the verbose. In 1920, he wrote:

The greater the length of the fibre and therefore the greater amount of the surface of its longitudinal contracule elements at the moment when it begins to contraxct, the greater will be the energy in the form of contractile stress set up in its contraction, and the more extensive wull be the chemical changes involved. This relation between the length of the heart fibre and the power of contraction I have called "the law of the heart". 

The editor of the Journal of Physiology clearly made Starling and Visscher (1926) cut it down to a more easily digestible form, which resembles the modern version:

 "the larger the diastolic volume of the heart ...the greater is the energy of its contraction." 

There are, unfortunately, as many modern versions as there are writers in the field of physiology; but at least they only vary the wording slightly.  "Diastolic volume" is occasionally substituted with another term like "preload", "pressure", "sarcomere stretch, "length",  etc,  and  "energy of contraction" is occasionally substituted with "force", "strength", "tension", or something more easily measured like cardiac output or stroke volume. No group of authors has given any evidence that any specific choice of language matters, which means that you can literally plot them in a grid and pick any combination of terms at random:

Random Definition Generator Matrix
for the Frank-Starling Relationship

	Preload	Sarcomere length	Stretch	Diastolic volume
Force
Strength
Tension
Cardiac output
Stroke volume
Energy

In any case, it all boils down to the relationship between cardiac filling and cardiac contraction. The Frank-Starling law is the observation that cardiac input and cardiac output are matched; it is a description of an intrinsic cardiac autoregulatory mechanism. It is a fundamental and ancient property of the myocardium; all vertebrate hearts and probably also insect hearts possess this ability, which probably makes it an essential engineering specification for building any circulatory system. 

Relationship of end-diastolic volume and stroke volume

In an exam scenario, the unprepared trainee who is confronted with a question like "define the Frank-Starling law" should immediately grab a piece of paper and scribble this diagram:

It is a stripped-down version of a graph published by Sarnoff & Berglund in 1954, where the contractility of the dog heart was controlled by means of ischaemia (they basically clamped the coronary arteries):

These are "ventricular function curves" and are discussed elsewhere. Here it will suffice to say that:

• Stroke volume increases with end-diastolic volume
• The relationship is not linear and plateaus at high end-diastolic volumes
• Increased contractility increases the stroke volume at any given end-diastolic volume
• With poor contractility, stroke volume may begin to decrease with increasing end-diastolic volume

Cellular mechanism of the Frank-Starling relationship

It would probably do wonders for the credibility of this resource if the author quoted more papers published north of the 1960s. Solaro (2007) gives a very brief editorial rundown, which is actually enough for the casual reader. Zhang (2016) has an entire doctoral dissertation on the subject, available to registered members of EThOS.  The middle ground in detail is held by Fuchs (2002) which is a satisfying compromise of depth and breadth, but you'd have to buy Molecular Control Mechanisms in Striated Muscle Contraction in order to read it. Some effort has been made to melt these excellent works down into short memorable point-form statements, as below:

• The main underlying mechanism is that with increasing sarcomere length, the sarcomeres become more sensitive to calcium somehow, and the force of their contraction increases as the result.
• There are multiple competing theories as to how this happens, and all of them have some sort of crippling problems
• One prevailing theory is:
  • The myocyte is cylindrical
  • By stretching (increasing its length) without changing its volume, you make it thinner
  • This means all the thick and thin filaments are now brought closer together
  • Thus, all the molecular reagents of the force-generating crossbridge reactions are in closer proximity
  • This should increase the likelihood of such reactions taking place, all without increasing the concentration of the reagents (i.e calcium)
• This reduction in space between filaments has been demonstrated experimentally, but nobody has actually ever been able to demonstrate that the filaments do what they were supposed to do with the calcium.
• Moreover, not everybody has been able to demonstrate that the reduction of interfilament space correlates with increased contractility.
• In spite of these major gaps in its credibility, this hypothesis is presented in all the major textbooks, and it would be relatively safe for exam candidates to hang their hats on it, as the examiners are unlikely to be aware of any controversy.

The Frank-Starling mechanism is closely allied to the generic concepts required to understand the length-tension relationship of striated muscle. Without revisiting a whole chapter of musculoskeletal physiology, the latter can be summarised as the observation that the amount of force a muscle is able to generate is dependent on the degree to which it is stretched, and that that there is an optimal length at which this force is maximal. The main difference between skeletal muscle and cardiac muscle here is that cardiac muscle has a much steeper length-tension response relationship, mainly because of the increase in calcium sensitivity that occurs with increased stretch.

The functional significance of the Frank-Starling mechanism

The main reason for this mechanism is the need to match the output of the heart to constant changes in the right and left cardiac output, and to adjust rapidly (within one beat) to sudden changes in preload conditions. To illustrate the point, let us consider a preposterous scenario where there is no Frank-Starling mechanism. If the stroke volume remained the same irrespective of loading conditions, the ventricle would dilate hideously with increasing preload. If the right heart were to increase its output but the left one did not, there would also be an accumulation of blood in the pulmonary circulation. Similarly, if the RV decreased its output, without adjusting to the change in pulmonary blood flow the left ventricle would rapidly empty the pulmonary circulation. 

Thus, in uncharacteristically laconic point form, the main functional significance of the Frank-Starling mechanism is:

• The Frank-Starling mechanism smoothes out perturbations in cardiac output because the stroke volume adjustment is more rapid than what could be accomplished by the autonomic nervous system or other regulatory mechanisms.
• The two main functions are the matching of RV and LV cardiac output, as well as the rapid adaptation to changes in preload.
• The adaptation of left ventricular stroke volume to right ventricular stroke volume (Jacob et al, 1992):
  • Preload for the right and left ventricle changes over the course of the normal breathing cycle 
  • Under some conditions, eg. increased respiratory effort or abrupt volume changes (Franklin et al, 1962) the output of the right heart may increase or decrease as compared to the left.
  • The Frank-Starling mechanism ensures that the left ventricle adjusts its output in the same way as the right, so that there is no increase or decrease in pulmonary blood volume.
• The adaptation of cardiac output to abrupt changes in preload (Chaui-Berlinck et al, 2017)
  • Changes in end-diastolic volume due to changes in heart rate, eg. in the delay following an extrasystole. 
  • Changes in venous return associated with body position
  • Changes in venous return with sudden vigorous exercise (Horwitz et al, 1972):
    • With exercise, venous return is increased:
    • Sympathetic nervous system produces vasoconstriction
    • The muscle pump increases venous vascular resistance.
    • Both effects increase mean systemic filling pressure.