Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired [CPET] in [PASC], 2023, Singh et al.

[SNT Gatchaman]

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome
Inderjit Singh; Brooks P. Leitner; Yiwei Wang; Hanming Zhang; Phillip Joseph; Denyse D. Lutchmansingh; Mridu Gulati; Jennifer D. Possick; William Damsky; John Hwa; Paul M. Heerdt; Hyung J. Chun

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear.

We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET.

PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2–41.2) vs. 32.1 (26.8–38.0) mL/kg/min; p = 0.01].

The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated.

In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response.

PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.

Link | PDF (Pulmonary Circulation)

 

[SNT Gatchaman]

Follow-on from Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing (2021)

Using invasive cardiopulmonary exercise testing (iCPET), our group previously identified a subgroup of PASC patients with persistent exertional intolerance nearly a year after recovery from mild acute illness that was associated with impaired peak systemic oxygen extraction (EO2).

Recent proteomic evidence points to the possible contributions of persistent immune system dysregulation in PASC. [...] Accordingly, we sought to integrate our iCPET infrastructure with proteomic profiling to evaluate for aberrations in protein expression amongst PASC patients with persistent exertional intolerance.

We enrolled 21 consecutive PASC patients referred to the Yale New Haven Hospital Pulmonary Vascular Disease Clinic for iCPET evaluation of unexplained exertional intolerance between March 2020 and February 2021.

PASC patients were dichotomized into mildly reduced (EO2peak‐mild) and severely reduced (EO2peak‐severe) EO2 groups according to the median peak EO2 value.

Results from the current study need to be interpreted in the context of several limitations. First, data for this study were drawn from a small number of patients who had recovered from acute COVID‐19 illness. [...] Second, the current study is devoid of a healthy control group which would ideally consist of individuals with known prior SARS‐CoV‐2 exposure but without exertional intolerance.

 

[SNT Gatchaman]

EO2 is oxygen extraction. DO2 is oxygen delivery.

PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal DO2 (37 ± 9 vs. 42 ± 15 mL/kg/ min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). However, when dichotomized, PASC patients with EO2peak‐mild exhibited greater DO2 [42.9 (34.2–41.2) vs. 32.1 (26.8–38.0)mL/kg/min; p=0.01] (Figure 1a) and greater cardiac index [9.04 (7.65–11.92) vs. 7.56 (6.62–8.35) L/ min/m2] compared EO2peak‐severe. EO2peak‐mild group exhibited reduced EO2 compared to controls [0.52 (0.47–0.55) vs. 0.80 (0.76–0.81); p < 0.0001].

The top gene‐set enrichment pathway elevated in EO2peak‐severe group was the interleukin (IL)‐2/signal transducer and activator of transcription 5 signaling, while the top gene‐set enrichment pathway in the EO2peak‐mild group was oxidative phosphorylation.

In the EO2peak‐mild group, several proteins associated with oxidative phosphorylation and glycogen metabolism were elevated, including valosin containing protein lysine methyltransferase (VCPKMT), glycogen synthase 1 (GYS1), acyl‐CoA dehydrogenase medium chain (ACADM), and apoptosis inducing factor mitochondria associated‐1 (AIFM1).

 

[SNT Gatchaman]

PASC patients with EO2peak‐severe appear to exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction.

Consistent with our prior report, we demonstrate that PASC patients with exertional intolerance, but no long‐term cardio‐pulmonary disease sequalae, exhibit reduced peak VO2 as a function of impaired EO2 relative to controls.

PASC patients with EO2peak‐severe demonstrated elevated protein markers that are associated with persistent inflammation and endotheliopathy. Among these include ANGPT2 and IL‐12, both of which are multifaceted factors with pro‐inflammatory and microvascular regulatory properties. Elevated ANGPT2 has been associated with microvascular regression and systemic capillary rarefaction has been described in PASC.

It is therefore plausible that elevated ANGPT2 and IL‐12 associated microcirculatory rarefaction in EO2peak‐severe group resulted in impaired EO2 from a mismatch between microcirculatory perfusion and mitochondrial oxidative metabolism.

 

[SNT Gatchaman]

In the EO2peak‐mild group, several proteins associated with oxidative phosphorylation and glycogen metabolism were elevated, including [...] and apoptosis inducing factor mitochondria associated‐1 (AIFM1).

Apoptosis inducing factor mitochondria associated‐1 aka Apoptosis-inducing factor 1, mitochondrial aka AIFM1. Wikipedia entry.

Refs —
AIFM1 beyond cell death: An overview of this OXPHOS-inducing factor in mitochondrial diseases (2022, Lancet eBioMedicine)
Molecular characterization of a complex of apoptosis-inducing factor 1 with cytochrome c oxidase of the mitochondrial respiratory chain (2021, PNAS)
Apoptosis inducing factor and mitochondrial NADH dehydrogenases: redox-controlled gear boxes to switch between mitochondrial biogenesis and cell death (2021, Biological Chemistry)
Apoptosis-Inducing Factor (AIF) in Physiology and Disease: The Tale of a Repented Natural Born Killer (2018, Lancet eBioMedicine)

 

[John Mac]

Study Uncovers Reduced Exercise Tolerance and Other Changes in Long COVID

A recent study published in Pulmonary Circulation assesses changes in oxygen extraction following post-acute sequelae of SARS-Cov-2 infection (PASC) syndrome, or “long COVID.” PASC may affect half of patients who recover from COVID-19. One debilitating hallmark is a persistent decrease in exercise tolerance.

This study, led by Inderjit Singh, MBChB, BMedSci, FRCP, assistant professor (pulmonary, critical care, and sleep medicine) and Hyung J. Chun, MD, associate professor adjunct (cardiovascular medicine), assessed a cohort of patients using invasive cardio-pulmonary exercise testing, which was conducted in parallel for each patient with multiplex proteomics profiling evaluating thousands of circulating proteins. While prior studies have shown dysregulated alterations in the immune system following COVID-19 infection, no study to date had associated such findings with the impaired oxygen extraction that may be a critical driver of persistent exertional intolerance in long COVID patients.

“We previously demonstrated on invasive cardiopulmonary exercise testing (iCPET) that the pathophysiologic abnormality in patients with PASC was a primary peripheral limit to exercise characterized by impaired or systemic oxygen extraction,” states Singh. “This current study combined our iCPET capability with an unbiased proteomic analysis to better understand why PASC patients experience this impaired oxygen extraction phenomenon.”

https://medicine.yale.edu/news-arti...amics-and-proteomic-phenotypes-in-long-covid/

 

[Sean]

limit to exercise characterized by impaired or systemic oxygen extraction

Interesting. Does that mean the oxygen is getting to where it should be, but is not being used (appropriately)?