Exercise intolerance in HFpEF: diagnosing and ranking its causes using personalized O2 pathway analysis, 2018, Houstis et al.

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Link
Citation: Houstis, Nicholas E., et al. "Exercise intolerance in heart failure with preserved ejection fraction: diagnosing and ranking its causes using personalized O2 pathway analysis." Circulation 137.2 (2018): 148-161.
Authors: Nicholas E. Houstis, Aaron S. Eisman, Paul P. Pappagianopoulos, Luke Wooster, Cole S. Bailey, Peter D. Wagner, and Gregory D. Lewis
Abstract:
Background:
Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with a pressing shortage of therapies. Exercise intolerance is a cardinal symptom of HFpEF, yet its pathophysiology remains uncertain.
Methods:
We investigated the mechanism of exercise intolerance in 134 patients referred for cardiopulmonary exercise testing: 79 with HFpEF and 55 controls. We performed cardiopulmonary exercise testing with invasive monitoring to measure hemodynamics, blood gases, and gas exchange during exercise. We used these measurements to quantify 6 steps of oxygen transport and utilization (the O2 pathway) in each patient with HFpEF, identifying the defective steps that impair each one’s exercise capacity (peak Vo2). We then quantified the functional significance of each O2 pathway defect by calculating the improvement in exercise capacity a patient could expect from correcting the defect.
Results
peak Vo2 was reduced by 34±2% (mean±SEM, P<0.001) in HFpEF compared with controls of similar age, sex, and body mass index. The vast majority (97%) of patients with HFpEF harbored defects at multiple steps of the O2 pathway, the identity and magnitude of which varied widely. Two of these steps, cardiac output and skeletal muscle O2 diffusion, were impaired relative to controls by an average of 27±3% and 36±2%, respectively (P<0.001 for both). Due to interactions between a given patient’s defects, the predicted benefit of correcting any single one was often minor; on average, correcting a patient’s cardiac output led to a 7±0.5% predicted improvement in exercise intolerance, whereas correcting a patient’s muscle diffusion capacity led to a 27±1% improvement. At the individual level, the impact of any given O2 pathway defect on a patient’s exercise capacity was strongly influenced by comorbid defects.
Conclusions:
Systematic analysis of the O2 pathway in HFpEF showed that exercise capacity was undermined by multiple defects, including reductions in cardiac output and skeletal muscle diffusion capacity. An important source of disease heterogeneity stemmed from variation in each patient’s personal profile of defects. Personalized O2 pathway analysis could identify patients most likely to benefit from treating a specific defect; however, the system properties of O2 transport favor treating multiple defects at once, as with exercise training.

 

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This was referenced by "Long COVID and chronic fatigue syndrome/myalgic encephalitis share similar pathophysiologic mechanisms of exercise limitation" (Swathi et al.) which was recently discussed here. While the Swathi et al. paper applies O2 pathway analysis to ME/CFS, the Houstis et al. paper applies it to HFpEF and explains it in more detail. I read the Houstis et al. paper mainly because I was interested in more deeply understanding O2 pathway analysis.

Here is my summary of the basics of O2 pathway analysis.

1. The patient undertakes an invasive cardiopulmonary exercise test (iCPET). This involves pedaling at a gradual increasing work level while catheters and a metabolic cart are used to simultaneously measure various pressures and gas concentrations.
2. At peak exercise, certain key parameters are recorded. These are:
   1. Rate of oxygen consumption (VO2)
   2. Rate of carbon dioxide production
   3. Arterial partial pressure of carbon dioxide
   4. Arterial partial pressure of oxygen
   5. Mixed venous partial pressure of oxygen
   6. Hemoglobin concentration
3. These key parameters are substituted into a system of differential and algebraic equations describing aspects of human physiology. This system is solved to compute the following un-measured physiological parameters.
   1. Cardiac output
   2. Lung diffusion capacity
   3. Skeletal muscle diffusion capacity
   4. Alveolar ventilation
   5. Mitochondrial oxidative phosphorylation capacity
   6. Alveolar partial pressure of oxygen
   7. Intramitochondrial partial pressure of oxygen
   8. O2 concentration profile over the pulmonary capillaries
   9. O2 concentration profile over the muscle capillaries

The authors use O2 pathway analysis in two main ways:

• First, to compare the computed physiological parameters between patients and controls.
• Second, to predict the effect correcting deficits in these physiological parameters on VO2Max.

A key finding from this analysis is that many HFpEF patients have multiple interacting physiologic deficits, and therefore correcting a single deficit might only have a modest effect.

 

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Some Thoughts​

An immediate question that comes to mind is how much trust can we place in the system of algebraic and differential equations that are used to derive the un-measured physiologic parameters. The authors claim “Each of the biophysical principles described by these equations was discovered many years ago and has been extensively validated” , but they do admit several potential sources of error.


One particularly interesting potential source of error is the following: the authors compute “skeletal muscle diffusion capacity” as one of their output parameters. However, they admit that a low computed skeletal muscle diffusion capacity could reflect either: a) truly impaired skeletal muscle O2 extraction or b) A shunting effect, whereby there is a failure of the neurovascular system to divert sufficient blood to exercising muscle. The authors say that empirically distinguishing between these two cases would require the use of a femoral catheter during the iCPET. They do present some indirect evidence favoring a) in HFpEF.


This potential source of error interests me because the Swathi et al. paper reported a major deficit in skeletal muscle diffusion capacity in ME/CFS patients as calculated by O2 pathway analysis. Presumably the Swathi et al. paper is susceptible to the same kind of potential confounding discussed here. I wonder what would happen if Swathi et al’s ME/CFS exercise tests were to be repeated with femoral catheter measurements. Would we see evidence of true impaired muscular O2 diffusion, or would we instead see neurovascular failure?