Cardiopulmonary exercise testing with invasive hemodynamic monitoring (iCPET) has been used at both Massachusetts General Hospital (MGH) and Brigham and Women’s Hospital (BWH) at Harvard Medical School to evaluate heart or lung-derived reasons for otherwise unexplained shortness of breath (dyspnea) or fatigue.
The figure to the right shows the deoxygenated systemic venous and pulmonary arterial (blue) and oxygenated pulmonary venous and systemic arterial (red) circulations of the left and right sides of the heart. In a significant portion of iCPET studies, the heart and lungs were not the origins of the fatigue or dyspnea. Many of patients had been referred for iCPET testing because they had a diagnosis of ME/CFS as well as dyspnea and fatigue. In this significant cohort of patients, the iCPET studies showed a characteristic pattern of “preload failure” (PLF) that was also associated with postural orthostatic tachycardia syndrome (POTS) and/or post-exertion malaise (PEM).
This preload failure (PLF) was demonstrated by two distinct forms: low and high flow. The PLF (low flow) phenotype could be caused by multiple possibilities but in our hypothesis, there is a failure to decrease venous capacitance in response to exercise. The normal exercise response leads to a decrease in venous capacitance. Sympathetic activation of veins decreases venous compliance, increases venous tone, increases central venous pressure, and promotes venous return. This response augments cardiac output through the Frank-Starling mechanism. This is the normal exercise response that tends to shift a portion of the blood volume from the venous to the arterial side of the circulation and increases cardiac output. Normally, 60 - 75% of the total blood volume resides on the venous side of the circulation. By shifting a portion of the blood to the arterial side, venous return to the heart increases, end diastolic volume and pressure in the left ventricle increase, and stroke volume increases. The figure below shows the large veins of the thorax (blue) returning deoxygenated blood to the right atrium as venous return. If this venous return does not enhance with exercise, a low flow PLF phenotype could be observed. This failure to reduce venous capacitance could result from an imbalance between the sympathetic and parasympathetic nervous systems, which control venous smooth muscle tone and capacitance.
There is another but less likely possibility for this low flow phenotype, which is a pre-existing reduced overall blood volume. This second possibility seems less plausible because even when one liter of saline is given to these ME/CFS patients just prior to the iCPET study to increase their blood volume, the PLF persists.
On the other hand, the PLF (high flow) phenotype could be caused by two general possibilities: peripheral arterial-venous shunt effects or deficient oxygen delivery or utilization. This first possibility could occur when peripheral vessels shunt blood through the microcirculation without effective perfusion of the peripheral capillary system. A shunt effect occurs when blood flow is inappropriately high in one of the communications between the arterial (red) vessels and venous (blue) vessels bypassing the peripheral tissues and therefore, failing to release oxygen into the tissues.
The second general possibility is that blood travels through the peripheral capillary system normally but cellular oxygen uptake and/or utilization by the mitochondria is deficient. To date, these mechanisms have not been sufficiently evaluated in ME/CFS patients to determine whether they are active in many, if not all, ME/CFS patients. The figure below shows the mitochondria (blue) with a highlighted internal elastic membrane (green), which is where a large electrical potential difference, an electron transport chain, and hydrogen pumps are present to contribute to the synthesis of adenosine triphosphate (ATP), the energy currency of the body. This second general possibility could either be the result of poor oxygen uptake from the microcirculation by the peripheral cells or a mitochondrial failure to efficiently utilize oxygen to synthesize ATP. We propose to evaluate these distinct potential mechanisms that could result in PLF. If these potential mechanisms are seen at least in some patients, drugs and devices can be tested to address these mechanisms and therefore these new drugs would become focused treatments of either POTS or PEM in ME/CFS patients who demonstrate PLF.
Preload Failure (low flow). The low flow phenotype suggests an inadequate blood volume return to the heart. The reason for the low blood flow return to the heart remains unclear; however, patients with POTS have demonstrated this exercise phenotype by iCPET suggesting that neurohumoral control of the vascular system might be impaired. This latter observation serves as a starting point for the consideration of additional diagnostic testing (i.e., screening for adrenal insufficiency, tilt-table testing, nerve conduction studies) and therapeutic intervention (i.e., hydration, increased sodium intake, Fludrocortisone, Pyridostigmine (Mestinon), Midodrine, monitored graded exercise training), although there are no longitudinal, interventional studies to support any specific recommendation.
However, the first interventional trial with Pyridostigmine to treat PLF with iCPET as an outcome measure has been proposed. A summary for “The Exercise Response to Pharmacologic Cholinergic Stimulation in Preload Failure”. This is a Phase 3 clinical trial (Principal Investigator: Dr. David Systrom, BWH) posted September 17, 2018 (NCT03674541) as an interventional trial with Pyridostigmine (Mestinon®) to improve the response to exercise for patients with ME/CFS. This is a study, which is intended for 25 patients, is not yet enrolling.
Pyridostigmine, which is an acetylcholinesterase inhibitor in the cholinergic family of medications, works by blocking acetylcholinesterase action and therefore increasing the levels of acetylcholine. Often pyridostigmine has been used off-label in ME/CFS patients to enhance cholinergic stimulation of norepinephrine release at the post-ganglionic synapse. In the figure to the left, the drug effect would be to increase the acetylcholine and norepinephrine contents in the gap between the nerve and its ganglionic receptor. This is thought to improve venoconstriction at the site of exercising muscle, leading to improved return of blood to the heart and increased filling of the heart to more appropriate levels during peak exercise. Retrospective studies have shown that noninvasive measurements of exercise capacity, including oxygen uptake, end-tidal carbon dioxide, and ventilatory efficiency improve after treatment with Pyridostigmine. A published iCPET study from the BWH is the first to assess invasive hemodynamics after Pyridostigmine administration.
Preload Failure (high flow). The patients with high flow form of the PLF show an unexpectedly high mixed venous oxygen content in the pulmonary artery blood sampling. This is seen when, as described above, either an arterio-venous shunt or a reduced oxygen delivery or utilization is present. Interestingly in other studies, PLF patients often have 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, reduced cellular oxygen uptake, or intrinsic mitochondrial dysfunction. Regardless of the etiology, this finding is suggestive of generalized circulatory dysregulation as a component of the pathogenesis of exercise intolerance in impaired patients. These later possibilities suggest that therapeutic interventions for patients with high flow PLF to increase their intravascular volume (e.g., oral hydration, fludrocortisone, salt tabs) may be less effective than therapies directed at vascular tone (e.g., Midodrine, Pyridostigmine). Midodrine is a prodrug, which forms an active metabolite, desglymidodrine, which is an α1-receptor agonist and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure.
We propose to evaluate ME/CFS patients who have been identified as being impaired with PLF either by a single iCPET or by sequential iCPET. Our hypothesis is that at least a very significant portion of ME/CFS patients demonstrate PLF, which is a failure to increase ventricular filling pressures and venous return in response to exercise or they demonstrate PLF by either arterial venous shunting effects or defective oxygen uptake or mitochondrial oxygen utilization. We will evaluate large vessel vascular capacitance and blood volume. Additional diagnostic testing (i.e., screening for adrenal insufficiency, tilt-table testing, nerve conduction studies) and therapeutic intervention (i.e., hydration, increased sodium intake, β-adrenergic receptor antagonists, fludrocortisone, pyridostigmine, and/or midodrine), compression stockings, and monitored exercise training) will be employed based upon individual patient findings. Similarly, we will evaluate the presence of peripheral shunting and oxygen delivery or utilization.
In addition, longer term outcome evaluations will be conducted at 6 - 24 months follow up CPET/iCPET evaluations in those patients who consent. In those longer term outcome studies, improvements in ventricular filling pressures in response to exercise will be evaluated relative to any changes in the symptoms of dyspnea and fatigue with appropriate interventions. In the appropriate mechanistic circumstances, therapies will be tested and one of the outcomes will be the improvements in the iCPET findings.
Participation in the Studies
For the near term, the iCPET studies are conducted according to normal clinical indications. A biorepository for blood samples has been ongoing at the BWH for many years. There are plans to dig more deeply into the mechanisms that underlie both the low and high flow forms of the Preload Failure. For the moment, the best opportunity to participate in these activities are based upon the referral from clinicians for a clinical evaluation of a patient’s unexplained dyspnea and fatigue. Future studies are on the drawing board and will be updated as they become available.
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