Unexplained exertional dyspnea caused by low ventricular filling pressures: results from clinical invasive cardiopulmonary exercise testing (Oldham et al., 2016)
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC4860548/
This paper might now be considered a classic in that it clearly showed that
you can have exercise intolerance without any heart or lung problems. (which many people had doubted)
The patients with this form of exercise intolerance have an abnormally low blood pressure in the veins that return blood from the extremities to the heart. This phenomenon results in "inadequate venous return" and "inadequate Right Atrial Pressure (RAP)", which is a form of "preload failure". (Clearly, there are lots of different jargon to describe the same fundamental phenomenon.)
Because of this,
the flow of blood from the extremities to the heart is simply too slow to keep up with any exertion, regardless of how hard the heart and lungs try to work.
The following are some critical points from the article's discussion about patients who have this type of exercise intolerance without any heart or lung problems:
These results cannot be explained by either submaximal effort or deconditioning.
[...]
Presuming adequate intravascular volume and similarly functioning respiratory and muscle pumps, the etiology of inadequate venous return may be a consequence of impaired venoconstriction of capacitance vessels in the impaired population.
(emphasis added)
So how does "impaired venoconstriction of capacitance vessels" lead to exercise intolerance?
- The veins that return blood from the muscle tissues to the heart, known as "capacitance vessels", fail to constrict as they normally would during exercise, leading to a low blood pressure inside these veins.
- This means that blood is not being efficiently pulled out of the "capillary beds" that provide blood to the muscle tissues.
- Some of the blood may end up being pulled through an "arterio-venous shunt" that bypasses the "capillary beds" and muscle tissues altogether.
- The end result of this situation is that insufficient blood is being provided to the "capillary beds" that provide blood and oxygen to the muscle and other tissues.
- Because the muscle tissues are not receiving enough oxygen to support aerobic metabolism, they pass the "anaerobic threshold" and switch to using anaerobic metabolism, which doesn't require oxygen and generates lactic acid.
- Although it was not discussed in this paper, if the tissues fail to receive a consistent supply of oxygen over time, the small nerve fibers in those tissues may die, since nerve fibers (specifically, axons) must receive a consistent supply of oxygen and nutrients to survive. When the small nerve fibers die, it is called "Small Fiber Neuropathy" or SFN.
So,
why would the veins that return blood from the muscle tissues to the heart fail to constrict as they normally would during exercise? Normally, the autonomic nervous system would constrict these veins as soon as vigorous exercise commences. The failure of the autonomic nerves to constrict these veins is therefore a form of
dysautonomia.
The authors talk specifically about patients with postural orthostatic tachycardia syndrome (POTS), another form of
dysautonomia. (It is common to find multiple types of dysautonomia together.) They considered whether low blood volume might be the issue, so they gave patients a saline infusion before exercise to increase their blood volume:
We further show that POTS patients had persistently low [venous return of blood to the heart] despite receiving an average of 1 L of normal saline before the test, suggesting that venous capacitance is the issue rather than total [blood] volume.
(emphasis added)
But the authors noted that the failure of veins to constrict might not be the only contributor to the observed exercise intolerance. The authors also considered the possibility that
arterio-venous shunting, perhaps also due to
dysautonomia, might deprive the muscle tissues of blood flow. Furthermore, the authors also considered the possibility that impaired muscle metabolism, such as problems with the
mitochondrial energy cycle, might also contribute to the exercise intolerance:
Interestingly, impaired patients had decreased systemic oxygen extraction normalized to [Hb], as compared to normal ones (0.81 ± 0.12 vs. 0.87 ± 0.09, P = 0.04), which is consistent with abnormal blood flow distribution to metabolically inactive vascular beds (e.g., impaired splanchnic vasoconstriction with exercise), shunting past oxidative muscle fiber capillary beds, or intrinsic mitochondrial dysfunction.
(emphasis added)
Lastly, the authors noted that infection or inflammation might cause or contribute to this special type of exercise intolerance:
Anecdotally, several of these patients report a severe illness before symptom onset, in many cases occurring 1 year or more before their evaluation, suggesting that an infectious or inflammatory etiology may contribute.
(emphasis added)
P.S. Finally, it is important to remember that exercise intolerance is not the same as exertion intolerance:
Exercise Intolerance vs. PEM/Exertion Intolerance
https://forums.phoenixrising.me/threads/exercise-intolerance-vs-pem-exertion-intolerance.86876/
EDIT: updates, corrections
