A complete (preload) failure

Introduction

Some days ago, David Systrom offered an overview of his work on cardiopulmonary testing in ME/CFS during a virtual meeting hosted by the Massachusetts ME/CFS & FM Association and the Open Medicine Foundation. In this blog post, I present an introduction to the experimental setting used for Systrom’s work (paragraph 1), a brief presentation of his previous findings (paragraph 2), and an explanation of his more recent discoveries in his cohort of patients (paragraph 3). In paragraph 4 you’ll find a note on how to support his research.

1. Invasive Cardiopulmonary Exercise Testing

It is a test that allows for the determination of pulmonary, cardiac, and metabolic parameters in response to physical exertion of increasing workload. It is, mutatis mutandis, the human equivalent of an engine test stand. A stationary bike with a mechanical resistance that increases by 10 to 50 Watts for minute is usually employed for assessing the patient in a upright position, but a recumbent bike can also be used in some instances. Distinguishing between these two different settings might be of pivotal relevance in ME/CFS and POTS. I shall now briefly describe some of the measurements that can be collected during invasive cardiopulmonary exercise testing (iCPET) and their biological meaning. For a more accurate and in-depth account, please refer to (Maron BA et al. 2013), (Oldham WM et al. 2016). I have used these papers as the main reference for this paragraph, unless otherwise specified.

Gas exchange. A face mask collects the gasses exchanged by the patient during the experiment and allows for monitoring of both oxygen uptake per unit of time (named $VO_2$ ) and carbon dioxide output ( $VCO_2$ ), measured in mL/min. Gas exchange is particularly useful for the determination of the anaerobic threshold (AT), i.e. the point in time at which the diagram of $VCO_2$ in function of $VO_2$ displays an abrupt increase in its derivative: at this workload, the patient starts relying more on her anaerobic energy metabolism (glycolysis, for the most part) with a build-up of lactic acid in tissues and blood (see Figure 1).

**Figure 1.** Diagram of $VCO_2$ in function of $VO_2$ . The point in which there is a change in the derivative with respect to $VO_2$ is called “anaerobic threshold” (AT). AT is highlighted with a vertical line in this picture. This diagram is from an actual CPET of a patient.

**Figure 1.** Diagram of $VCO_2$ in function of $VO_2$ . The point in which there is a change in the derivative with respect to $VO_2$ is called “anaerobic threshold” (AT). AT is highlighted with a vertical line in this picture. This diagram is from an actual CPET of a patient.

Oxygen uptake for unit of time at AT (called $VO_2$ max) can be considered an integrated function of patient’s muscular, pulmonary, and cardiac efficiency during exercise. It is abnormal when its value is below 80% of what predicted according to patient’s age, sex, and height. Importantly, according to some studies there might be no difference in $VO_2$ max between ME/CFS patients and healthy controls, unless the exercise test is repeated a day after the first measure: in this case the value max $VO_2$ for patients is significantly lower than for controls (VanNess JM et al. 2007), (Snell CR and al. 2013).

Another measure derived from the assessing of gas exchange is minute ventilation (VE, measured in L/min) which represents the total volume of gas expired per minute. The link between VE and $VO_2$ is as follows:

$VO_2\;=\;VE\cdot(inspired\;VO_2\; -\; expired\;VO_2)$

Maximum voluntary ventilation (MVV) is the maximum volume of air that is voluntarily expired at rest. During incremental exercise, a healthy person should be able to maintain her VE at a value ∼0.7 MVV and it is assumed that if the ratio VE/MVV is above 0.7, then the patient has a pulmonary mechanical limit during exercise. If VE is normal, then an early AT suggests an inefficient transport of oxygen from the atmosphere to muscles, not due to pulmonary mechanics, thus linked to either pulmonary vascular abnormalities or muscular/mitochondrial abnormalities. It is suggested that an abnormally high derivative of the diagram of VE in function of $VCO_2$ and/or a high ratio VE/ $VCO_2$ at AT (these are measures of how efficiently the system gets rid of $CO_2$ ) are an indicator of poor pulmonary vascular function.

Respiratory exchange ratio (RER) is a measure of the effort that the patient puts into the exercise. It is measured as follows:

$RER=\frac{VCO_2}{VO_2}$

and an RER>1.05 indicates a sufficient level of effort. In this case the test can be considered valid.

Arterial catheters. A sensor is placed just outside the right ventricle (pulmonary artery, Figure 2) and another one is placed in the radial artery: they allow for measures of intracardiac hemodynamics and arterial blood gas data, respectively. By using this setting, it is possible to indirectly estimate cardiac output (Qt) by using Fick equation:

$Qt=\frac{VO_2}{arterial\;O_2 - venous\;O_2}$

where the $arterial\;O_2$ is measured by the radial artery catheter and the venous one is measured by the one in the pulmonary artery (ml/L). An estimation for an individual’s predicted maximum Qt (L/min) can be obtained by dividing her predicted $VO_2$ max by the normal maximum value of $arterial\;O_2 - venous\;O_2$ during exercise, which is 149 mL/L:

$predicted\; Qt\;max=\frac{predicted\; VO_{2}max}{149 \frac{mL}{L}}$

If during iCPET the measured Qt max is below 80% of the predicted maximum cardiac output (as measured above), associated with reduced $VO_2$ max, then a cardiac abnormality might be suspected. Stroke volume (SV), defined as the volume of blood ejected by the left ventricle per beat, can be obtained from the Qt according to the following equation:

$Qt=SV\cdot HR\;\xrightarrow\;SV\;=\;\frac{Qt}{HR}\;=\;\frac{\frac{VO_2}{arterial\; O_2 - venous\; O_2}}{HR}$

where HR stands for heart rate. One obvious measure from the pulmonary catheter is the mean pulmonary artery pressure (mPAP). The right atrial pressure (RAP) is the blood pressure at the level of the right atrium. Pulmonary capillary wedge pressure (PCWP) is an estimation for the left atrial pressure. It is obtained by the pulmonary catheter. The mean arterial pressure (MAP) is the pressure measured by the radial artery catheter and it is a proxy for the pressure in the left atrium. RAP, mPAP, and PCWP are measured by the pulmonary catheter (the line in red) which from the right atrium goes through the tricuspid valve, enters the right ventricle, and then goes along the initial part of the pulmonary artery (figure 2).

**Figure 2.** Right atrial pressure (RAP) is the pressure of the right atrium, mean pulmonary arterial pressure (mPAP) is the pressure of the right ventricle, pulmonary capillary wedge pressure (PCWP) is an estimation of the pressure of the left atrium. Mean arterial pressure gives a measure of the pressure of the left ventricle. RAP, mPAP, and PCWP are measured by the pulmonary catheter (the line in red) which from the right atrium goes through the tricuspid valve, enters the right ventricle, and then goes across the initial part of the pulmonary artery (R).

Derived parameters. As seen, Qt (cardiac output) is derived from actual direct measures collected by this experimental setting, by using a simple mathematical model (Fick equation). Another derived parameter is pulmonary vascular resistance (PVR) which is obtained using the particular solution of the Navier-Stokes equations (the dynamic equation for Newtonian fluids) that fits the geometry of a pipe with a circular section. This solution is called the Poiseuille flow, and it states that the difference in pressure between the extremities of a pipe with a circular cross-section A and a length L is given by

$\Delta\;P\;=\;\frac{8\pi\mu L}{A^2}Q$

where $\mu$ is a mechanical property of the fluid (called dynamic viscosity) and Q is the blood flow (Maccallini P. 2007). As the reader can recognize, this formula has a close resemblance with Ohm’s law, with P analogous to the electric potential, Q analogous to the current, and $\frac{8\pi\mu L}{A^2}$ analogous to the resistance. In the case of PVR, Q is given by Qt while $\Delta\;P\;=\;mPAP\;-\;PCWP$ . Then we have:

$PVR\;=\;80\frac{\;mPAP\;-\;PCWP}{Qt}$

where the numeric coefficient is due to the fact that PVR is usually measured in $\frac{dyne\cdot s}{cm^5}$ and 1 dyne is $10^5$ Newton while 1 mmHg is 1333 N/m².

2. Preload failure

A subset of patients with exercise intolerance presents with preload-dependent limitations to cardiac output. This phenotype is called preload failure (PLF) and is defined as follows: RAP max < 8 mmHg, Qt and $VO_2$ max <80% predicted, with normal mPAP (<25 mmHg) and normal PVR (<120 $\frac{dyne\cdot s}{cm^5}$ ) (Maron BA et al. 2013). This condition seems prevalent in ME/CFS and POTS. Some of these patients have a positive cutaneous biopsy for small-fiber polyneuropathy (SFPN), even though there seems to be no correlation between hemodynamic parameters and the severity of SFPN. Intolerance to exercise in PLF seems to improve after pyridostigmine administration, mainly through potentiation of oxygen extraction in the periphery. A possible explanation for PLF in non-SFPN patients might be a more proximal lesion in the autonomic nervous system (Urbina MF et al. 2018), (Joseph P. et al. 2019). In particular, 72% of PLF patients fits the IOM criteria for ME/CFS and 27% meets the criteria for POTS. Among ME/CFS patients, 44% has a positive skin biopsy for SFPN. One possible cause for damage to the nervous system (both in the periphery and centrally) might be TNF-related apoptosis-inducing ligand (TRAIL) which has been linked to fatigue after radiation therapy; TRAIL increases during iCPET among ME/CFS patients (see video below).

3. Latest updates from David Systrom

During the Massachusetts ME/CFS & FM Association and Open Medicine Foundation Fall 2020 Event on Zoom, David Systrom reported on the results of iCPET in a set of ME/CFS patients. The $VO_2$ max is lower in patients vs controls (figure 3, up). As mentioned before, $VO_2$ max is an index that includes contributions from cardiac performances, pulmonary efficiency, and oxygen extraction rate in the periphery. In other words, a low $VO_2$ max gives us no explanation on why it is low. This finding seems to be due to different reasons in different patients even though the common denominator among all ME/CFS patients of this cohort is a low pressure in the right atrium during upright exercise (low RAP, figure 3, left). But then, if we look at the slope of Qt in function of $VO_2$ (figure 3, right) we find three different phenotypes. Those with a high slope are defined “high flow” (in red in figure 3). Then we have a group with a normal flow (green) and a group with a low flow (blue). If we look then at the ability to extract oxygen by muscles (figure 3, below) expressed by the ratio

$\frac{arterial\;O_2 - venous\;O_2}{HB}$

we can see that the high flow patients reach the lowest score. In summary, all ME/CFS patients of this cohort present with poor $VO_2$ max and preload failure. A subgroup, the high flow phenotype, has poor oxygen extraction capacity at the level of skeletal muscles.

**Figure 3.** The results presented by David Systrom are here displayed around a schematic representation of the circulatory system. $VO_2$ is a global measure of the efficiency of the circulatory system. CO, which stands for cardiac output (indicated Qt in this blog post) is related to the output of the left half of the heart. RAP is the pressure of the right atrium. *By Paolo Maccallini.*

**Figure 3.** The results presented by David Systrom are here displayed around a schematic representation of the circulatory system. $VO_2$ is a global measure of the efficiency of the circulatory system. CO, which stands for cardiac output (indicated Qt in this blog post) is related to the output of the left half of the heart. RAP is the pressure of the right atrium. *By Paolo Maccallini.*

Now the problem is: what is the reason for the preload failure? And in the high flow phenotype, why the muscles can’t properly extract oxygen from blood? As mentioned, about 44% of ME/CFS patients in this cohort has SFPN but there is no correlation between the density of small-fibers in the skin biopsies and the hemodynamic parameters. Eleven patients with poor oxygen extraction (high flow) had their muscle biopsy tested for mitochondrial function (figure 4) and all but one presented a reduction in the activity of citrate synthase (fourth column): this is the enzyme that catalyzes the last/first step of Krebs cycle and it is considered a global biomarker for mitochondrial function. Some patients also have defects in one or more steps of the electron transport chain (fifth column) associated with genetic alterations (sixth column). Another problem in high flow patients might be a dysfunctional vasculature at the interface between the vascular system and skeletal muscles (but this might be true for the brain too), rather than poor mitochondrial function.

**Figure 4.** Eleven patients with high flow (poor oxygen extraction) underwent a muscle biopsy. Mitochondrial function has been assessed in these samples and all the patients but one presented a reduced activity for the enzyme citrate synthase (4th column). Defects in the oxygen transport chain and in the mitochondrial chromosome have also been documented in 4 of them (column 5th and column 6th).

The use of an acetylcholinesterase inhibitor (pyridostigmine) improved the ability to extract oxygen in the high flow group, without improving cardiac output, as measured with a CPET, after one year of continuous use of the drug. This might be due to better regulation of blood flow in the periphery. This paragraph is an overview of the following video:

4. Funding

The trial on the use of pyridostigmine in ME/CFS at the Brigham & Women’s Hospital by Dr. David Systrom is funded by the Open Medicine Foundation (R). This work is extremely important, as you have seen, both for developing diagnostic tools and for finding treatments for specific subgroups of patients. Please, consider a donation to the Open Medicine Foundation to speed up this research. See how to donate.

The equations of this blog post were written using $\LaTeX$ (see this article).

2 thoughts on “A complete (preload) failure”

Ken (@KenSmithNC) says:

December 3, 2020 at 5:47 pm

What are the chances that this leads to a biomarker for MECFS?

LikeLike

1. Paolo Maccallini says:
  
  December 3, 2020 at 6:04 pm
  
  This line of research might have the potential to lead to the mechanism behind one of the phenotypes (or subgroups, or diseases) that we collectively call ME/CFS. So, not only to a biomarker but to some sort of explanation for the symptoms and hopefully to a treatment. But it is very hard to do predictions, I think, because in science, almost by definition, you don’t know what you are going to discover. The phenotype with preload failure and poor oxygen extraction (‘high flow’ group) seems particularly interesting and one might speculate that it is the subgroup that more than the others has the potential to be conquered in the next future.
  
  LikeLike