Long-term cardiovascular health and physical functioning of non-hospitalised ex-COVID-19 patients: a case-control study

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation (Nederlandse Hartstichting) Background/Introduction SARS-CoV-2 and the associated coronavirus disease 2019 (COVID-19) has substantial acute effects on cardiovascular health and physical functioning, but the long-term effects are less clear, especially in individuals that recover from COVID-19 at home, representing ~95% of all cases. Purpose We compared cardiovascular health and physical functioning of non-hospitalised ex-COVID-19 patients versus age- and sex-matched healthy peers. Methods We recruited non-hospitalised adults with PCR-proven COVID-19 and age- and sex-matched controls for this case-control study. Duration of COVID-19 illness and presence of residual complaints were inquired. Cardiovascular health status and physical functioning were assessed through a series of measurements: blood pressure, blood biomarkers (NT-proBNP, high-sensitive cardiac troponin I, C-reactive protein), carotid-femoral pulse wave velocity (ARTSENS), handgrip strength, 4-metre gait speed, habitual physical activity (days per week with at least 30 minutes of moderate physical activity) and quality of life based on the 12-item short form. Results We included 101 ex-COVID-19 patients (median age 59.0 [54.5-65.5], 59 (58.4%) male) at a median of 5.0 [4.0-7.0] months post-infection and 101 age- and sex-matched controls (median age 58.0 [54.0-64.5], 58 (57.4%) male). Median duration of COVID-19 illness was 8.0 days [6.0-14.0] and 32.3% of the cases reported residual complaints at the time of inclusion. We found no differences between ex-COVID-19 patients and controls in blood pressure (134-81 vs. 133-81 mmHg, p=0.40 and p=0.30 for systolic and diastolic pressures respectively), concentrations of NT-proBNP (8.50 vs. 7.00 pmol/L, p=0.22), high-sensitive cardiac troponin I (4.11 vs. 3.38 ng/L, p=0.06), C-reactive protein (4.00 vs. 4.00 mg/L, p=0.93) and carotid-femoral pulse wave velocity (6.63 vs. 7.01 m/s, p=0.30). Ex-COVID-19 patients showed higher handgrip strength compared to controls (43 kg vs. 38 kg, p=0.004), but 4-metre gait speed (2.62 vs. 2.56 s, p=0.33), habitual physical activity levels (6.0 vs. 6.0 days, p=0.16) and reported quality of life (86.4% vs. 88.6%, p=0.10) were not different between groups. Conclusion(s) Cardiovascular health and physical functioning parameters were not different between non-hospitalised ex-COVID-19 patients and age- and sex-matched controls at five months post-infection. This suggests that individuals who recovered from COVID-19 at home do not have an increased cardiovascular risk or impaired physical functioning in the long-term.

COVID-19 survivors are physically inactive with high levels of sedentary time, regardless of patient characteristics, disease severity or cardiac dysfunction

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation Background More than 250 million cases of the coronavirus disease-2019 (COVID-19) infection were confirmed across the globe since 2020, leading to a substantial number of COVID-19 related hospital admissions. Many COVID-19 survivors experience long-term health consequences, but data on physical activity patterns and the impact on recovery post-infection are scarce. Purpose This study aimed to objectively assess physical (in)activity patterns among COVID-19 survivors and to explore the association with patient characteristics, disease severity and cardiac dysfunction. We hypothesized that COVID-19 survivors will demonstrate low volumes of physical activity and a high sedentary time, especially those with a more severe disease course (e.g. longer hospital duration;admission to intensive care), cardiac dysfunction, and persistent symptoms at 3-6 months post-discharge. Methods In this cross-sectional cohort study, we objectively assessed physical activity, sedentary behaviour and sleep duration for 24 hrs/day during 8 subsequent days in COVID-19 survivors at 3-6 months post-hospitalisation. Activity patterns were compared across pre-defined subgroups based on patient- and disease characteristics, cardiac biomarker release during hospitalisation, abnormal transthoracic echocardiogram regarding left- and right ventricular function and volumes at 3-6 months of follow-up, and persistence of symptoms post-discharge. Results Physical activity patterns were assessed in 37 patients (60±10 years old;78% male) at 125 [116;132] days after discharge. Patients spent 4.2 [3.2;5.3] hrs/day in light-intensity physical activity and 1.0 [0.8;1.4] hrs/day in moderate-to-vigorous intensity physical activity. Median sleep duration was 8.6 [8.2;9.1] hrs/day. Time spent sitting was 9.8 [8.7;11.2] hrs/day, which was accumulated in 6.0 [4.7;6.9] prolonged sitting bouts (≥30 min) and 41.4 [31.5;48.1] short sitting bouts (<30 min, Central Figure). No differences in activity patterns were found across subgroups, but sleep duration was slightly higher in women versus men (9.2 vs 8.5 hrs/day, p=0.03) and patients with versus without persistent symptoms (9.1 vs 8.3 hrs/day, p=0.02). Conclusions COVID-19 survivors are physically inactive for most of their time at 3-6 months post-hospitalisation. Physical (in)activity patterns are not impacted by patient- nor disease characteristics, underlining the need for a uniform approach for re-activation of COVID-19 survivors. Central Figure. A: objectively measured light-intensity physical activity (LIPA), moderate-to-vigorous intensity physical activity (MVPA), sleep duration and sedentary time in COVID-19 patients at 3-6 months post-hospitalisation (median and interquartile range). B: sitting bout frequency (mean + standard deviation). Central Figure

Sustained endothelial, coagulation and inflammatory cytokine activation without macrovascular dysfunction at 3 months after COVID-19: A reflection on SARS-CoV-2 induced thrombo-inflammation

Background: Endothelial damage caused by COVID-19 may imperil the cardiovascular health of millions. More than a year since WHO declared the COVID-19 pandemic, information on the lasting effects of this infection on the cardiovascular system beyond the acute phase is still lacking. Purpose: To study macrovascular endothelial dysfunction and activation, coagulation and inflammation, 3 months after resolution of acute COVID- 19 symptoms. Methods: A cross-sectional observational cohort study was conducted including 203 patients with PCR confirmed COVID-19 disease, 6-20 weeks after acute COVID-19. The primary endpoint was macrovascular endothelial function, assessed by the carotid artery reactivity (CAR) test. The CAR measures the carotid artery diameter in response to hand in icewater immersion. A historic cohort of 313 subjects served as controls. Propensity score matching was used to correct for baseline differences. Plasma endothelin-1 (ET-1), interleukin (IL)-1ra, IL-6, IL-18 were measured by ELISA. ET-1 levels were also measured in a partially overlapping COVID-19 cohort of which plasma samples were available during the acute phase. Coagulation enzyme:inhibitor complexes for thrombin:antithrombin (TAT), factor (F) IXa:AT, FVIIa:AT, FXIa:AT, FXIa:alpha 1 antitrypsin (a1AT), FXIa:C1 esterase inhibitor (C1inh), kallikrein(PKa):C1inh and von Willebrand Factor:antigen (vWF:Ag), were assessed by in house developed ELISA. Results: After propensity score matching, the prevalence of macrovascular dysfunction did not differ between the COVID-19 (22.5%) versus the historical control cohort (18.6%, RD -3.92%, 95%-CI -15 to 7.19, p=0.49). Plasma concentrations of markers for endothelial activation were elevated (>1 SD above normal);ET-1 (64.9%), and vWF:Ag (80.8%). In controls, ET- 1 levels were significantly lower as compared to COVID-19 patients during the acute phase and after 3 months. ET-1 levels were significantly higher 3 months after COVID-19 as compared to the acute phase. Cytokines were high in a majority of patients: IL-18 (73.9%), IL-6 (51.2%), and IL- 1ra (48.9%). TAT and FIXa:AT, reflecting a prothrombotic state, were high in 48.3% and 29.6% of the patients, respectively. FVIIa:AT, as marker of the extrinsic pathway, was elevated (35%). Markers of contact activation were also increased: PKa:C1inh (16.3%), FXIa:AT (16.3%), FXIa:a1AT (20.7%), and FXIa:C1inh (17.7%) (picture 1). Conclusions: At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction as compared to matched historic controls;there was evidence, however, of sustained thrombo-inflammation, indicated by high circulating concentrations of ET-1, vWF:Ag, proinflammatory cytokines, and markers of coagulation (picture 2). Elevated IL-18 levels could potentially induce arterial inflammation and subsequent atherogenesis. Our data highlight the importance of further studies on SARS-CoV-2 related thrombo-inflammation, as well as longer follow-ups in recovered patients. (Figure Presented).

Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19.

INTRODUCTION: Endothelial damage and thrombosis caused by COVID-19 may imperil cardiovascular health. More than a year since the WHO declared COVID-19 pandemic, information on its effects beyond the acute phase is lacking. We investigate endothelial dysfunction, coagulation and inflammation, 3 months post-COVID-19. MATERIALS AND METHODS: A cohort study was conducted including 203 patients with prior COVID-19. Macrovascular dysfunction was assessed by measuring the carotid artery diameter in response to hand immersion in ice-water. A historic cohort of 312 subjects served as controls. Propensity score matching corrected for baseline differences. Plasma concentrations of endothelin-1 were measured in patients post-COVID-19, during the acute phase, and in matched controls. Coagulation enzyme:inhibitor complexes and inflammatory cytokines were studied. RESULTS AND CONCLUSIONS: The prevalence of macrovascular dysfunction did not differ between the COVID-19 (18.6%) and the historic cohort (22.5%, RD -4%, 95%CI: -15-7, p = 0.49). Endothelin-1 levels were significantly higher in acute COVID-19 (1.67 ± 0.64 pg/mL) as compared to controls (1.24 ± 0.37, p < 0.001), and further elevated 3 months post-COVID-19 (2.74 ± 1.81, p < 0.001). Thrombin:antithrombin(AT) was high in 48.3%. Markers of contact activation were increased in 16-30%. FVIIa:AT (35%) and Von Willebrand Factor:antigen (80.8%) were elevated. Inflammatory cytokine levels were high in a majority: interleukin(IL)-18 (73.9%), IL-6 (47.7%), and IL-1ra (48.9%). At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction; there was evidence, however, of sustained endothelial cell involvement, coagulation activity and inflammation. Our data highlight the importance of further studies on SARS-CoV-2 related vascular inflammation and thrombosis, as well as longer follow-up in recovered patients.

Impact of COVID-19 lockdown on physical activity and sedentary behaviour in Dutch cardiovascular disease patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) lockdown restrictions may impact lifestyle and therefore also physical (in)activity patterns in patients with cardiovascular disease (CVD). This study aimed to evaluate the effect of lockdown on physical activity and sedentary behaviour. METHODS: A total of 1565 Dutch CVD patients participated in this prospective cohort study, in which we compared physical activity and sedentary behaviour before and during the COVID-19 lockdown period. Baseline measures were assessed in 2018 and data on follow-up measures were collected between 17 and 24 April 2020 (5 weeks after the introduction of COVID-19 lockdown restrictions). Validated questionnaires were used to assess physical activity and sedentary behaviour. RESULTS: Moderate-to-vigorous physical activities increased from 1.6 (0.9, 2.8) to 2.0 (1.0, 3.5) h/day [median (interquartile range)] (p < 0.001) during the COVID-19 lockdown, mainly due to an increase in time spent walking and doing odd jobs. In contrast, time spent exercising significantly declined [1.0 (0.0, 2.3) to 0.0 (0.0, 0.6) h/week], whereas sedentary time increased from 7.8 (6.1, 10.4) to 8.9 (6.8, 11.4) h/day (p < 0.001). The absolute increase in physical activity was 13 (-36, 81) min/day, whereas sedentary behaviour increased by 55 (-72, 186) min/day. CONCLUSION: Despite a small increase in physical activities, the larger increase in sedentary time induced a net reduction in habitual physical activity levels in Dutch CVD patients during the first-wave COVID-19 lockdown. Since a more inactive lifestyle is strongly associated with disease progression and mortality, we encourage CVD patients and their caregivers to explore novel solutions to increase physical activity levels and reduce sedentary time during (and beyond) the COVID-19 pandemic.