Factors influencing caspase-6 levels in patients with dyspnea associated with long COVID

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Abstract

BACKGROUND: Apoptosis is a genetically programmed form of cell death. It is essential for maintaining homeostasis in the body. A key feature of apoptosis is the maintenance of normal cell population, with caspases playing a central role and potentially contributing to the pathogenesis of specific long COVID phenotypes. Identifying the role of caspases and their association with clinical markers may provide additional evidence for the causes of this syndrome.

AIM: To determine the role of caspase-6 in patients with dyspnea or its equivalents in long COVID.

METHODS: A single-center, cross-sectional observational study was conducted over a 3-year period, when 878 patients sought medical care for dyspnea or its equivalents at an outpatient clinic, with 186 patients included in the study.

RESULTS: All patients in the study had caspase-6 levels within the reference range. Caspase-6 concentration in the long COVID group (group 1, n = 86) was significantly lower than that in the control group (group 2, n = 100) with no history of COVID-19. To identify risk factors for decreased apoptotic activity and increased pro-inflammatory responses, 86 patients with long COVID and dyspnea were stratified into two subgroups based on caspase-6 levels: 33 patients (38.4%) with caspase-6 > 26.5 pg/ml and 53 patients (61.6%) with caspase-6 ≤ 26.5 pg/ml. Severe COVID-19 pneumonia was associated with a nearly 7-fold increase in the relative risk (RR) of reduced apoptotic activity and an increase in pro-inflammatory responses in the post-COVID period: RR 6.85; 95% confidence interval (CI) 1.02–143.74. It also increased the risk of elevated N-terminal pro-B-type natriuretic peptide level > 120 pg/ml by more than 2-fold (RR 2.41; 95% CI 1.27–5.14), carotid-femoral pulse wave velocity > 10.6 m/s by 4-fold (RR 4.10; 95% CI 1.45–11.77), aortic pulse wave velocity > 8.3 m/s by 3-fold (RR 3.22; 95% CI 1.31–9.62), increased ferritin level > 152.5 ng/ml. It reduced transferrin saturation < 19.8% by 2.5-fold (RR 2.49; 95% CI 1.23–5.75), and increased tissue inhibitor of metalloproteinases-1 level > 376.1 ng/ml by 69% (RR 1.69; 95% CI 1.10–2.72).

CONCLUSION: Long COVID-related dyspnea is associated with reduced caspase-6 levels, which correlate with impaired apoptotic activity and heightened inflammatory responses. Proposed pathophysiological mechanisms underlying caspase-6 deficiency include activation of myocardial stress pathways, increased collagen deposition, hyperferritinemia, and arterial stiffness.

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About the authors

Olga V. Masalkina

Academician Wagner Perm State Medical University

Author for correspondence.
Email: omasalkina@mail.ru
ORCID iD: 0009-0006-3364-0591
SPIN-code: 4394-5330

MD, Cand. Sci. (Medicine), Associate Professor
Russian Federation, Perm

Anna I. Chernyavina

Academician Wagner Perm State Medical University

Email: anna_chernyavina@list.ru
ORCID iD: 0000-0002-0051-6694
SPIN-code: 2387-6781

MD, Dr. Sci. (Medicine), Associate Professor

Russian Federation, Perm

Natalya A. Koziolova

Academician Wagner Perm State Medical University

Email: nakoziolova@mail.ru
ORCID iD: 0000-0001-7003-5186
SPIN-code: 1044-0503

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Perm

Elena A. Polyanskaya

Academician Wagner Perm State Medical University

Email: eapolyanskaya@gmail.com
ORCID iD: 0000-0002-3694-3647
SPIN-code: 6413-8930

MD, Dr. Sci. (Medicine), Associate Professor

Russian Federation, Perm

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Supplementary files

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2. Fig. 1. ROC curve for caspase-6 level (pg/mL) in patients with shortness of breath, depending on a history of novel coronavirus infection and the presence of long-term post-COVID syndrome.

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3. Fig. 2. ROC curve for the N-terminal fragment of brain natriuretic peptide (pg/mL) in patients with dyspnea in long-term post-COVID syndrome as a risk factor for decreased apoptosis activity and increased risk of proinflammatory responses.

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4. Fig. 3. ROC curve for the carotid-femoral pulse wave velocity (m/s) in patients with dyspnea in long-term post-COVID syndrome as a risk factor for decreased apoptosis activity and an increased risk of proinflammatory reactions.

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5. Fig. 4. ROC curve for aortic pulse wave velocity (m/s) in patients with dyspnea in long-term post-COVID syndrome as a risk factor for decreased apoptosis activity and an increased risk of proinflammatory reactions.

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6. Fig. 5. ROC curve for ferritin (ng/mL) in patients with dyspnea in long-term post-COVID syndrome as a risk factor for decreased apoptosis activity and an increased risk of proinflammatory reactions.

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7. Fig. 6. Concentration of the tissue inhibitor of metalloproteinase 1 by groups.

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8. Fig. 7. ROC curve for the tissue inhibitor of metalloproteinase 1 in patients with dyspnea in long-term post-COVID syndrome as a risk factor for decreased apoptosis activity and an increased risk of proinflammatory reactions.

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