The Great Heart Failure Mystery

This post is best viewed from the blog website: http://siriasis.blogspot.com/


Motivation: One of the "bread and butter" diagnoses in inpatient medicine is systolic heart failure exacerbation - we all see it, we all treat it, but do we understand it?  I first wondered about this question last year during my basic medicine clerkship.  The etiology of systolic heart failure  is usually answered with some notion of overstretching the heart.  For me, the difficulty was that it is easy to see how overstretching a single muscle fiber can lead to weakness, but do we really overstretch an entire organ - especially an already dilated organ (like the enlarged heart in dilated cardiomyopathy)?

The traditional teaching and general consensus for decompensated systolic heart failure is that with volume overload, pre-load exceeds the capacity of the Frank-Starling compensation and then an inverse relation holds with increased filling resulting in decreased cardiac output.  The presumed basis is that there may be lack of productive overlap of muscle fibers with increased filling.  But, is there solid empirical data for this explanation?

The answer is shockingly no.  I have even asked cardiologists to confirm this assessment.  Of course, lack of data does not imply that the traditional teaching is false.  So, are there physiological studies about the response of the dilated heart to filling?

Paper: Evidence of the Frank-Starling Mechanism in the Failing Human Heart.  Holubarsch, C., et. al. Circulation (1996); 94: 683-689. http://circ.ahajournals.org/cgi/content/full/94/4/683

Method: Five human hearts with end-stage dilated cardiomyopathy were excised from patients receiving heart transplants.  The average ejection fraction of these hearts was 17%.  These hearts were kept alive artificially (really cool!)  using oxygenated blood.  Pressure and volume relationships were directly measured.  The hearts were paced using epicardial leads.  For controls, two healthy hearts were used which were originally destined for transplantation but could not be transplanted due to technical reasons.

Results:
For this experiment, I think that pictures tell more than any description.  So, I will paste some of the key graphs and point out the pertinent results:

In the graph on the left, the x-axis describes the volume of the left ventricle.  In Figure A, as the volume increases, the pressure inside the ventricle increases.




In B, we see that as the volume increases the diastolic pressure increases and the generated systolic pressure increases as well (the Frank Starling mechanism).  For perspective, the hearts here are really being filled up - the average diastolic volume is about 120 mL.





C.  Observe in this figure that as the LV is being filled up, the net generated pressure (which is simply systolic pressure minus diastolic pressure) decreases despite an intact Frank-Starling mechanism (the diastolic pressure increases at a faster rate than the systolic pressure at high volumes).

In the figure on the right, to investigate the state of Frank-Starling effect on muscle strips rather than whole organ, individual muscle strips were isolated from healthy hearts (top curve) and from failing hearts (bottom curve).  The total tension generated was measured in response to different muscle lengths.  As seen, the healthy heart was able to generate a lot more force in response to increased stretch.  But, while the response of the failing heart was more moderate, there is no evidence of "falling-off" the Starling curve.






Conclusion: This paper does not conclusively answer the physiologic basis of dilated cardiomyopathy but sheds some light on couple of areas.  (1) Even in failing hearts with weak contractility, the Frank-Starling effect is likely preserved even when stretched out by volume overload.  (2) Besides preload, cardiac contractility is controlled by two other factors: heart rate (increased contractility at increased heart rates) and neurohumoral responses (such as to catecholamines).  It may be possible that increased volume somehow upsets the responses to the latter two mechanisms rather than disrupting the Frank-Startling mechanism.  Anyway, there is a story yet to be told ....