A novel methodology for the synchronous collection and multimodal visualisation of continuous neurocardiovascular and neuromuscular physiological data in adults with long COVID

Reports suggest that adults with post-COVID-19 syndrome or long COVID may be affected by orthostatic intolerance syndromes, with autonomic nervous system dysfunction as a possible causal factor of neurocardiovascular instability (NCVI). Long COVID can also manifest as prolonged fatigue, which may be linked to neuromuscular function impairment (NMFI). The current clinical assessment for NCVI monitors neurocardiovascular performance upon the application of orthostatic stressors such as an active (i.e. self-induced) stand or a passive (tilt table) standing test. Lower limb muscle contractions may be important in orthostatic recovery via the skeletal muscle pump. In this study, adults with long COVID were assessed with a protocol that, in addition to the standard NCVI tests, incorporated simultaneous lower limb muscle monitoring for NMFI assessment. To accomplish such an investigation, a wide range of continuous non-invasive biomedical technologies were employed, including digital artery photoplethysmography for the extraction of cardiovascular signals, near-infrared spectroscopy for the extraction of regional tissue oxygenation in brain and muscle, and electromyography for assessment of timed muscle contractions in the lower limbs. With the novel technique described and exemplified in this paper, we were able to integrate signals from all instruments used in the assessment in a precisely synchronized fashion. We demonstrate that it is possible to visualize the interactions between all different physiological signals during the combined NCVI/NMFI assessment. Multiple counts of evidence were collected, which can capture the dynamics between skeletal muscle contractions and neurocardiovascular responses. The proposed multimodal data visualization can offer an overview of the functioning of the muscle pump during both supine rest and orthostatic recovery and can conduct comparison studies with signals from multiple participants at any given time in the assessment. This could help researchers and clinicians generate and test hypotheses based on the multimodal inspection of raw data, in long COVID and other clinical cohorts.

Reduced calf muscle pump function is a risk factor for venous thromboembolism: A population-based cohort study

The calf muscle pump is a major determinate of venous return in the legs but has not been studied as a risk factor for venous thromboembolism (VTE). A population-based cohort study of Olmsted County, Minnesota residents was performed using calf pump function (CPF) measurements from venous plethysmography studies from 1998-2015. Patients with a history of VTE were excluded. Nursing validated VTE outcomes from the Rochester Epidemiology Project were identified after the index study date and patients with reduced CPF (rCPF) were compared to patients with normal CPF. 1532 patients with recorded CPF (28% air and 72% strain gauge plethysmography) were included: 591 (38.5%) had normal CPF, 353 (23.0%) had unilateral rCPF, and 588 (38.3%) had bilateral rCPF. Any VTE occurred in 87 patients (5.7%) after a median follow-up of 11.7 years (range 0-22.0 years; Table 2). Comparing patients with bilateral reduced to bilateral normal CPF, the unadjusted HR for incident VTE was 2.0 (95% CI 1.2-3.4) and after adjusting for age, BMI, and CCI, the HR was 1.68 (95% CI 0.98-2.89). The adjusted HR for ipsilateral DVT was evaluated in 3,064 legs comparing legs with reduced to normal CPF and was 1.71 (95% CI 1.03-2.84). Mortality was significantly higher in both the bilateral (p<0.001) and unilateral (p<0.001) rCPF groups compared to normal CPF. Our results demonstrate that CPF is a risk factor for VTE in an otherwise low-risk ambulatory population and might be a useful component in risk stratification models.

Reduced Calf Muscle Pump Function Is a Risk Factor for Venous Thromboembolism and Mortality

Background: Venous return from the lower extremities is pumped upwards to the right side of the heart in a process that is facilitated by one-way valves and the venous muscle pump, of which the calf muscle pump is a major contributor1-3. Venous plethysmography can quantitatively assess calf pump function (CPF). The association between the CPF and venous thromboembolism (VTE) has not been investigated. Methods: Venous plethysmography (VP) data (strain gauge or air plethysmography) from the Mayo Clinic Vascular Lab database (1998-2015) of CPF (bilaterally reduced, unilaterally reduced, and bilateral normal) were examined in Olmsted County Residents. The Rochester Epidemiology Project (REP) captures the population of Olmsted County and contains demographic information, medical diagnoses, hospital admissions, and surgical procedures as well as validated VTE events and death. Patients with signs of obstructed outflow in either extremity on the venous plethysmography (a possible sign of acute or chronic deep vein thrombosis) study were excluded. Patients with a history of VTE diagnosed before the physiologic study were also excluded. If more than one measurement of calf muscle pump function was performed, only the first measurement was used. The primary outcome was a composite of any VTE, including proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE). Results: 1703 Olmsted County residents had venous plethysmography studies performed. MN research authorization was denied in 64 patients and 107 were excluded for any documented VTE preceding index VP study. 1532 patients with recorded CPF (28% air and 72% strain gauge plethysmography) were studied: 591 (38.5%) had normal CPF, 353 (23.0%) had unilateral reduced CPF (rCPF), and 588 (38.3%) had bilateral rCPF. The mean age was 64.4 (SD 18.4), 68.9% were female, and the mean BMI was 29.5 (SD 6.4). Any VTE occurred in 87 patients (5.7%) after a mean follow up of 10.9 years (range 0-22.0 years). Isolated lower extremity DVT (excluding concurrent PE) occurred in 49 patients and PE+/-DVT occurred in 38 patients. Death occurred in 352 patients (23%). Bilateral rCPF compared to bilateral normal CPF was associated with VTE (p=0.007), DVT only (p=0.02) and death (p<0.001) but not PE+/-DVT (p=0.13). Unilateral rCPF compared to bilateral normal CPF was not associated with VTE, but was associated with death (p<0.001). Kaplan-Meier curves for VTE and death are shown in Figure 1. The hazard ratio for bilateral rCPF compared to bilateral normal CPF for VTE was 2.0 (95% CI 1.2-3.4) and for DVT only was 2.2 (95% CI 1.1-4.2). A sensitivity analysis for the main outcome of VTE did not show significant interaction based on the type of plethysmography (strain vs. air), by age stratified at 65 years, sex, or BMI stratified at 30 (p>0.1 for each comparison). Conclusion: In this population-based study of Olmsted County residents with no prior VTE, rCPF function as measured by venous plethysmography is associated with increased risk for VTE, particularly lower extremity proximal DVT. More research is required to understand what additional measures of venous physiology influence these findings and whether CPF could be used in VTE risk stratification. Disclosures No relevant conflicts of interest to declare.

Calf muscle pump function as a predictor of all-cause mortality

Calf muscle pump (CMP) promotes venous return from the lower extremity and contributes to preload and cardiac output. Impaired CMP function may reflect a measure of frailty or cumulative disease burden or may impede cardiac function. The study objective was to test the hypothesis that impaired CMP negatively impacts survival. Consecutive adult patients who underwent venous strain gauge plethysmography at the Mayo Clinic Gonda Vascular Laboratory (January 1, 1998 – December 31, 2011) were assessed for overall survival. Patients with venous incompetence, venous obstruction or unilateral calf pump dysfunction were excluded. Risk of mortality was assessed with Cox proportional hazard ratios and after adjusting for Charlson Comorbidity Index variables. Over the study period, 2728 patients were included in the analysis. Compared to patients with normal CMP, those with impaired CMP were older ( p < 0.001), predominantly female ( p = 0.01) and had higher mean Charlson scores ( p < 0.001). Patients with impaired CMP had a higher mortality rate at 5 (8.9% vs 2.4%), 10 (17.5% vs 5.9%), and 15 years (22.8% vs 8.3%) compared to those with normal CMP ( p < 0.001 for each comparison). Of patients with heart failure, those with impaired CMP had worse survival at each 5-year increment compared to those with normal CMP ( p < 0.05 at each increment). In conclusion, impaired CMP appears to be an independent predictor of poor outcomes after adjusting for variables within the Charlson Comorbidity Index. The association between impaired CMP, heart failure, and mortality may represent a negative impact on circulatory function or a surrogate measure of frailty.