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  Conference on Retroviruses
and Opportunistic Infections
February 12-16, 2022
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Post-Acute Long COVID: Lower Heart Rates During Exercise Point to Autonomic Dysfunction Causing Symptoms
  2022 CROI, February 12-16 and 22-24, 2022
Mark Mascolini
Researchers working with the US LIINC Cohort tied persistent inflammation—-gauged by high-sensitivity C-reactive protein (hsCRP) and IL-6—to pericardial effusion and lowered exercise capacity more than 1 year after acute infection [1]. Lower heart rates during exercise suggested autonomic dysfunction caused symptoms. LIINC, Long-term Impact of Infection With Novel Coronavirus (COVID-19), is a study of people who have recovered from acute infection with SAR-CoV-2 [2].The authors published an article on this study after CROI [3].
A growing volume of research addresses so-called postacute sequelae of COVID-19 (PASC or Long COVID). In the United States researchers organized the COVID Recovery Cohort to study these conditions [2]. A team from the University of California, San Francisco, and other centers analyzed members of this cohort to examine heart/lung components of Long COVID.
These investigators noted that several cardiac findings that arise in acute COVID-19 are linked to death: elevated cardiac markers, impaired cardiac function, arrhythmias (especially atrial fibrillation), and, rarely, acute myocarditis, heart attack, and stroke. They added that in Long COVID (or PASC) cardiopulmonary symptoms last for at least 12 months, although cardiac function typically returns to normal in 3 to 6 months after acute COVID. Cardiac inflammation is a possible component of PASC. Precise mechanisms of cardiopulmonary PASC remain unknown, the investigators said, but many suspect cardiac inflammation plays a role.
In creating the group for this study, the researchers aimed to overselect people with cardiovascular symptoms in an attempt to understand why people with COVID have these symptoms. Cohort members were mostly outpatients recruited from the community. The study cohort included adults with PCR-identified SARS-CoV-2 infection and excluded pregnant women and people with major cardiovascular disease before they got COVID. The primary outcome of this analysis was cardiopulmonary PASC, defined as chest pain, shortness of breath, or heart palpitations in the 2 weeks before the study visit but not present before COVID.
All participants had cardiopulmonary exercise testing (CPET) on a stationary bike to measure oxygen consumption, carbon dioxide production, exercise capacity (peak VO2), and other variables. Research links peak VO2 to mortality and surgical results in people with heart failure, lung disease, cancer, and other diseases. The researchers estimated associations between symptoms and exercise outcomes with linear and logistic regression adjusted for age, sex, body mass index, and time since SARS-CoV-2 infection.
Of the 120 study participants, 56 (47%) had cardiopulmonary symptoms after acute COVID. Median age was younger in the group with symptoms (51 vs 55). Twenty-seven of 45 women (60%), compared with 29 of 75 men (39%) had heart/lung symptoms. The proportion of people who went to the hospital with acute COVID was substantially higher in people with than without cardiopulmonary symptoms (38% vs 13%).
Most people with cardiopulmonary PASC, 86%, had 2 or more symptoms. But testing showed that resting cardiac and pulmonary function are not associated with cardiopulmonary PASC: Comparing people with versus without cardiopulmonary PASC, the researchers found normal cardiac biomarkers in both groups, normal cardiac function on echocardiography, normal spirometry (a pulmonary function test), and no arrhythmias during ambulatory rhythm monitoring.
In a subset of 33 people who had cardiac MRI, 27% had pericardial effusion, which was associated with systemic inflammation (odds ratio [OR] 7.1 (95% confidence interval [CI] 0.8 to 66, P = 0.08) per doubling of IL-6 and OR 4.4 (95% CI 1.0 to 20, P = 0.05) per doubling of hsCRP). But effusions were not tied to myocardial inflammation.
CPET documented reduced exercise capacity in 30 people 18 months after SARS-CoV-2 infection: In analyses adjusted for age, sex, time since SARS-CoV-2 infection, body mass index, and hospital admission for COVID, peak VO2 was 7.0 mL/kg/min lower in people with cardiopulmonary symptoms (95% CI 0.3 to 13.6, P = 0.04). Cardiopulmonary PASC was nonsignificantly linked to lower exercise capacity (OR 1.71 per 1 MET decrease, 95% CI 0.91 to 3.21, P = 0.10). And having two or more symptoms was nearly significantly linked to lower exercise capacity (OR 3.09 per 1 MET decrease, 95% CI 0.97 to 9.87, P = 0.06).
Next the researchers asked why exercise capacity is lowered in people with cardiopulmonary PASC. They found that obesity, COVID hospital admission, and inflammation (measured by IL-6 and hsCRP) are all associated with lower exercise capacity. For example, higher hsCRP, signaling greater inflammation, meant lower peak VO2 (beta -2.9, 95% CI -5.1 to -0.7, P = 0.01). The investigators noted that chronotropic incompetence (inability of raise heart rate to meet the body’s metabolic demands) is the prime driver of reduced exercise capacity, exerting a greater impact than cardiac dysfunction, obesity, or deconditioning. Comparison of people with and without cardiopulmonary symptoms tied chronotropic incompetence to cardiopulmonary PASC, although the association could be described only as a trend (OR 4.4, 95% CI 0.5 to 35.3, P = 0.17).
CPET and ambulatory rhythm monitoring suggested autonomic dysfunction causes chronotropic incompetence in people with PASC. Specifically, chronotropic incompetence on CPET corresponded to three ambulatory monitoring findings: lower heart rate variability, lower maximum and minimum heart rate, and higher average heart rate. Finally, the researchers showed that higher hsCRP (indicating more inflammation) is associated with cardiopulmonary symptoms (OR 1.32 per hsCRP doubling, 95% CI 1.01 to 1.73, P = 0.02), reduced exercise capacity (OR 2.92 per hsCRP doubling, 95% CI 0.81 to 10.4, P = 0.10), and chronotropic incompetence (OR 1.95 per hsCRP doubling, 95% CI 1.04 to 3.63, P = 0.04).
COVID Recovery Cohort investigators summarized their findings in four key takeaways:
• People recovering from COVID have reduced exercise capacity, which is linked to cardiopulmonary PASC.
• Chronotropic incompetence accounted for most of the lower exercise capacity.
• Autonomic dysfunction drives chronotropic incompetence and probably cardiopulmonary PASC.
• Systemic inflammation is linked to cardiopulmonary symptoms, reduced exercise capacity, chronotropic incompetence, and other markers of autonomic dysfunction.
These findings give researchers another reason to find remedies for systemic inflammation. And the study adds chronotropic incompetence to the list of conditions needing further focused study.
1. Durstenfeld MS, Peluso MJ, Kaveti P, et al. Inflammation, exercise capacity, chronotropy, and symptoms in post-acute COVID-19. 2022 CROI, February 12-16 and 22-24, 2022. Abstract 99.
2. ClinicalTrials.gov. Long-term impact of infection with novel coronavirus (COVID-19) (LIINC). ClinicalTrials.gov identifier NCT04362150. https://clinicaltrials.gov/ct2/show/NCT04362150
3. Durstenfeld MS, Peluso MJ, Kelly JD, et al. Role of antibodies, inflammatory markers, and echocardiographic findings in post-acute cardiopulmonary symptoms after SARS-CoV-2 infection. JCI Insight. Published April 7, 2022. https://insight.jci.org/articles/view/157053