Reduced Exercise Capacity, Chronotropic Incompetence, and Early Systemic Inflammation in Cardiopulmonary Phenotype Long Coronavirus Disease 2019.

BACKGROUND: Mechanisms underlying persistent cardiopulmonary symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (postacute sequelae of coronavirus disease 2019 [COVID-19; PASC] or "long COVID") remain unclear. This study sought to elucidate mechanisms of cardiopulmonary symptoms and reduced exercise capacity. METHODS: We conducted cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults >1 year after SARS-CoV-2 infection, compared those with and those without symptoms, and correlated findings with previously measured biomarkers. RESULTS: Sixty participants (median age, 53 years; 42% female; 87% nonhospitalized; median 17.6 months after infection) were studied. At CPET, 18/37 (49%) with symptoms had reduced exercise capacity (<85% predicted), compared with 3/19 (16%) without symptoms (P = .02). The adjusted peak oxygen consumption (VO2) was 5.2 mL/kg/min lower (95% confidence interval, 2.1-8.3; P = .001) or 16.9% lower percent predicted (4.3%-29.6%; P = .02) among those with symptoms. Chronotropic incompetence was common. Inflammatory markers and antibody levels early in PASC were negatively correlated with peak VO2. Late-gadolinium enhancement on CMR and arrhythmias were absent. CONCLUSIONS: Cardiopulmonary symptoms >1 year after COVID-19 were associated with reduced exercise capacity, which was associated with earlier inflammatory markers. Chronotropic incompetence may explain exercise intolerance among some with "long COVID."

The Association Between Mobile App Use and Change in Functional Capacity Among Cardiac Rehabilitation Participants: Cohort Study.

BACKGROUND: Cardiac rehabilitation (CR) is underused in the United States and globally, with participation disparities across gender, socioeconomic status, race, and ethnicities. The pandemic led to greater adoption of telehealth CR and mobile app use. OBJECTIVE: Our primary objective was to estimate the association between CR mobile app use and change in functional capacity from enrollment to completion in patients participating in a CR program that offered in-person, hybrid, and telehealth CR. Our secondary objectives were to study the association between mobile app use and changes in blood pressure (BP) or program completion. METHODS: We conducted a retrospective cohort study of participants enrolled in CR at an urban CR program in the United States. Participants were English speaking, at least 18 years of age, participated in the program between May 22, 2020, and May 21, 2022, and downloaded the CR mobile app. Mobile app use was quantified by number of exercise logs, vitals logs, and education material views. The primary outcome was change in functional capacity, measured by change in 6-minute walk distance (6MWD) from enrollment to completion. The secondary outcome was change in BP from enrollment to completion. We estimated associations using multivariable linear or logistic regression models adjusted for age, sex, race, ethnicity, socioeconomic status by ZIP code, insurance, and primary diagnosis for CR referral. RESULTS: A total of 107 participants (mean age 62.9, SD 13.02 years; 90/107, 84.1% male; and 57/105, 53.3% self-declared as White Caucasian) used the mobile app and completed the CR program. Participants had a mean 64.0 (SD 54.1) meter increase in 6MWD between enrollment and completion (P<.001). From enrollment to completion, participants with an elevated BP at baseline (≥130/80 mmHg) experienced a significant decrease in BP (systolic BP -11.5 mmHg; P=.002 and diastolic BP -7.7 mmHg; P=.003). We found no significant association between total app interactions and change in 6MWD (coefficient -0.03, 95% CI -0.1 to 0.07; P=.59) or change in BP (systolic coefficient 0.002, 95% CI -0.03 to 0.03; P=.87 and diastolic coefficient -0.005, 95% CI -0.03 to 0.02; P=.65). There was no significant association between total exercise logs and change in 6MWD (coefficient 0.1, 95% CI -0.3 to 0.4; P=.57) or total BP logs and change in BP (systolic coefficient -0.02, 95% CI -0.1 to 0.06; P=.63 and diastolic coefficient -0.02, 95% CI -0.09 to 0.04; P=.50). There was no significant association between total app interactions and completion of CR (adjusted odds ratio 1.00, 95% CI 0.99-1.01; P=.44). CONCLUSIONS: CR mobile app use as part of an in-person, hybrid, or telehealth CR program was not associated with greater improvement in functional capacity or BP or with program completion.

Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID.

BACKGROUND: Mechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 "PASC" or "Long COVID") remain unclear. This study sought to elucidate mechanisms of cardiopulmonary symptoms and reduced exercise capacity using advanced cardiac testing. METHODS: We performed cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults > 1 year after confirmed SARS-CoV-2 infection in Long-Term Impact of Infection with Novel Coronavirus cohort (LIINC; substudy of NCT04362150 ). Adults who completed a research echocardiogram (at a median 6 months after SARS-CoV-2 infection) without evidence of heart failure or pulmonary hypertension were asked to complete additional cardiopulmonary testing approximately 1 year later. Although participants were recruited as a prospective cohort, to account for selection bias, the primary analyses were as a case-control study comparing those with and without persistent cardiopulmonary symptoms. We also correlated findings with previously measured biomarkers. We used logistic regression and linear regression models to adjust for potential confounders including age, sex, body mass index, time since SARS-CoV-2 infection, and hospitalization for acute SARS-CoV-2 infection, with sensitivity analyses adjusting for medical history. RESULTS: Sixty participants (unselected for symptoms, median age 53, 42% female, 87% non- hospitalized) were studied at median 17.6 months following SARS-CoV-2 infection. On maximal CPET, 18/37 (49%) with symptoms had reduced exercise capacity (peak VO 2 <85% predicted) compared to 3/19 (16%) without symptoms (p=0.02). The adjusted peak VO 2 was 5.2 ml/kg/min (95%CI 2.1-8.3; p=0.001) or 16.9% lower actual compared to predicted (95%CI 4.3- 29.6; p=0.02) among those with symptoms compared to those without symptoms. Chronotropic incompetence was present among 12/21 (57%) with reduced VO 2 including 11/37 (30%) with symptoms and 1/19 (5%) without (p=0.04). Inflammatory markers (hsCRP, IL-6, TNF-α) and SARS-CoV-2 antibody levels measured early in PASC were negatively correlated with peak VO 2 more than 1 year later. Late-gadolinium enhancement on CMR and arrhythmias on ambulatory monitoring were not present. CONCLUSIONS: We found evidence of objectively reduced exercise capacity among those with cardiopulmonary symptoms more than 1 year following COVID-19, which was associated with elevated inflammatory markers early in PASC. Chronotropic incompetence may explain exercise intolerance among some with cardiopulmonary phenotype Long COVID. Key Points: Long COVID symptoms were associated with reduced exercise capacity on cardiopulmonary exercise testing more than 1 year after SARS-CoV-2 infection. The most common abnormal finding was chronotropic incompetence. Reduced exercise capacity was associated with early elevations in inflammatory markers.

Clinical Outcomes and Qualitative Perceptions of In-person, Hybrid, and Virtual Cardiac Rehabilitation.

PURPOSE: Cardiac rehabilitation (CR) is evolving to include both in-person and virtual delivery. Our objective was to compare, in CR patients, the association of in-person, hybrid, and virtual CR with change in performance on the 6-min walk test (6MWT) between enrollment and completion. METHODS: Patients enrolled in CR between October 22, 2019, and May 10, 2021, were categorized into in-person, hybrid, or virtual groups by number of in-person and virtual visits. All patients received individualized exercise training and health behavior counseling. Cardiac rehabilitation was delivered to patients in the hybrid and virtual cohorts using synchronous video exercise and/or asynchronous telephone visits. Measurements at CR enrollment and completion included the 6MWT, blood pressure (BP), depression, anxiety, waist-to-hip ratio, and cardiac self-efficacy. RESULTS: Of 187 CR patients, 37/97 (38.1%) were in-person patients and 58/90 (64.4%) were hybrid/virtual patients ( P = .001). Compared to in-person (51.5 ± 59.4 m) improvement in the 6MWT was similar in hybrid (63.4 ± 55.6; P = .46) and virtual (63.2 ± 59.6; P = .55) compared with in-person (51.5 ± 59.4). Hybrid and virtual patients experienced similar improvements in BP control and anxiety. Virtual patients experienced less improvement in depression symptoms. There were no statistically significant changes in waist-to-hip ratio or cardiac self-efficacy. Qualitative themes included the adaptability of virtual CR, importance of relationships between patients and CR staff, and need for training and organizational adjustments to adopt virtual CR. CONCLUSIONS: Hybrid and virtual CR were associated with similar improvements in functional capacity to in-person. Virtual and hybrid CR have the potential to expand availability without compromising outcomes.

Cardiopulmonary exercise testing to evaluate post-acute sequelae of COVID-19 ("Long COVID"): a systematic review and meta-analysis.

Importance: Reduced exercise capacity is commonly reported among individuals with Long COVID (LC). Cardiopulmonary exercise testing (CPET) is the gold-standard to measure exercise capacity to identify causes of exertional intolerance. Objectives: To estimate the effect of SARS-CoV-2 infection on exercise capacity including those with and without LC symptoms and to characterize physiologic patterns of limitations to elucidate possible mechanisms of LC. Data Sources: We searched PubMed, EMBASE, and Web of Science, preprint severs, conference abstracts, and cited references in December 2021 and again in May 2022. Study Selection: We included studies of adults with SARS-CoV-2 infection at least three months prior that included CPET measured peak VO 2 . 3,523 studies were screened independently by two blinded reviewers; 72 (2.2%) were selected for full-text review and 36 (1.2%) met the inclusion criteria; we identified 3 additional studies from preprint servers. Data Extraction and Synthesis: Data extraction was done by two independent reviewers according to PRISMA guidelines. Data were pooled with random-effects models. Main Outcomes and Measures: A priori primary outcomes were differences in peak VO 2 (in ml/kg/min) among those with and without SARS-CoV-2 infection and LC. Results: We identified 39 studies that performed CPET on 2,209 individuals 3-18 months after SARS-CoV-2 infection, including 944 individuals with LC symptoms and 246 SARS-CoV-2 uninfected controls. Most were case-series of individuals with LC or post-hospitalization cohorts. By meta-analysis of 9 studies including 404 infected individuals, peak VO 2 was 7.4 ml/kg/min (95%CI 3.7 to 11.0) lower among infected versus uninfected individuals. A high degree of heterogeneity was attributable to patient and control selection, and these studies mostly included previously hospitalized, persistently symptomatic individuals. Based on meta-analysis of 9 studies with 464 individuals with LC, peak VO 2 was 4.9 ml/kg/min (95%CI 3.4 to 6.4) lower compared to those without symptoms. Deconditioning was common, but dysfunctional breathing, chronotropic incompetence, and abnormal oxygen extraction were also described. Conclusions and Relevance: These studies suggest that exercise capacity is reduced after SARS-CoV-2 infection especially among those hospitalized for acute COVID-19 and individuals with LC. Mechanisms for exertional intolerance besides deconditioning may be multifactorial or related to underlying autonomic dysfunction.

Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults: A Systematic Review and Meta-analysis.

Importance: Reduced exercise capacity is commonly reported among individuals with COVID-19 symptoms more than 3 months after SARS-CoV-2 infection (long COVID-19 [LC]). Cardiopulmonary exercise testing (CPET) is the criterion standard to measure exercise capacity and identify patterns of exertional intolerance. Objectives: To estimate the difference in exercise capacity among individuals with and without LC symptoms and characterize physiological patterns of limitations to elucidate possible mechanisms of LC. Data Sources: A search of PubMed, EMBASE, Web of Science, preprint servers, conference abstracts, and cited references was performed on December 20, 2021, and again on May 24, 2022. A preprint search of medrxiv.org, biorxiv.org, and researchsquare.com was performed on June 9, 2022. Study Selection: Studies of adults with SARS-CoV-2 infection more than 3 months earlier that included CPET-measured peak oxygen consumption (V̇o2) were screened independently by 2 blinded reviewers; 72 (2%) were selected for full-text review, and 35 (1%) met the inclusion criteria. An additional 3 studies were identified from preprint servers. Data Extraction and Synthesis: Data extraction was performed by 2 independent reviewers according to the PRISMA reporting guideline. Data were pooled using random-effects models. Main Outcomes and Measures: Difference in peak V̇o2 (in mL/kg/min) among individuals with and without persistent COVID-19 symptoms more than 3 months after SARS-CoV-2 infection. Results: A total of 38 studies were identified that performed CPET on 2160 individuals 3 to 18 months after SARS-CoV-2 infection, including 1228 with symptoms consistent with LC. Most studies were case series of individuals with LC or cross-sectional assessments within posthospitalization cohorts. Based on a meta-analysis of 9 studies including 464 individuals with LC symptoms and 359 without symptoms, the mean peak V̇o2 was -4.9 (95% CI, -6.4 to -3.4) mL/kg/min among those with symptoms with a low degree of certainty. Deconditioning and peripheral limitations (abnormal oxygen extraction) were common, but dysfunctional breathing and chronotropic incompetence were also described. The existing literature was limited by small sample sizes, selection bias, confounding, and varying symptom definitions and CPET interpretations, resulting in high risk of bias and heterogeneity. Conclusions and Relevance: The findings of this systematic review and meta-analysis study suggest that exercise capacity was reduced more than 3 months after SARS-CoV-2 infection among individuals with symptoms consistent with LC compared with individuals without LC symptoms, with low confidence. Potential mechanisms for exertional intolerance other than deconditioning include altered autonomic function (eg, chronotropic incompetence, dysfunctional breathing), endothelial dysfunction, and muscular or mitochondrial pathology.

Bergeyella cardium: Clinical Characteristics and Draft Genome of an Emerging Pathogen in Native and Prosthetic Valve Endocarditis.

Bergeyella cardium is a new species in the family Flavobacteriaceae that was recently described in 3 cases of native valve infective endocarditis. We report the first case of B. cardium prosthetic valve endocarditis, provide the first draft genome of this species, and review the microbiologic characteristics of this emerging pathogen.

Wilson's Disease and Cardiac Myopathy.

Wilson's disease is a well-characterized disorder known to cause liver and brain disease due to abnormal copper deposition. Data regarding copper infiltration of the heart is conflicting, and the risk of heart disease has not been well described. We aimed to determine whether Wilson's disease is associated with cardiac myopathy, clinically evident in the atria as atrial fibrillation (AF) and in the ventricles as heart failure (HF). We longitudinally assessed 14.3 million patients in the California Healthcare Cost and Utilization Project database from 2005 through 2009 for diagnoses of Wilson's disease, AF, HF, and covariates using International Classification of Diseases-9th Edition codes. Cirrhosis and appendicitis diagnoses were assessed for positive and negative validation, respectively. We identified 463 patients with Wilson's disease. As expected in validation analyses, patients with Wilson's disease had a threefold greater risk of cirrhosis (hazard ratio [HR] 2.85, 95% confidence interval [CI] 2.81 to 2.90, p <0.0001) and no increased risk of appendicitis (HR 0.24, 95% CI 0.04 to 1.71, p = 0.16). Patients with Wilson's disease exhibited a 29% higher risk of AF after adjusting for age, gender, race, income, hypertension, diabetes, renal disease, hyperlipidemia, obesity, coronary disease, and obstructive sleep apnea (HR 1.29, 95% CI 1.15 to 1.45, p <0.0001). After adjusting for the same covariates, patients with Wilson's disease had a 55% higher risk of incident HF (HR 1.55, 95% CI 1.41 to 1.71, p <0.0001). Patients with Wilson's disease have an increased risk of AF and HF, supporting the need for careful surveillance for heart disease. These findings also suggest that the role of copper metabolism in heart disease should be more broadly investigated.