Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus

Abstract

Emerging as a new epidemic, long COVID or post-acute sequelae of coronavirus disease 2019 (COVID-19), a condition characterized by the persistence of COVID-19 symptoms beyond 3 months, is anticipated to substantially alter the lives of millions of people globally. Cardiopulmonary symptoms including chest pain, shortness of breath, fatigue, and autonomic manifestations such as postural orthostatic tachycardia are common and associated with significant disability, heightened anxiety, and public awareness. A range of cardiovascular (CV) abnormalities has been reported among patients beyond the acute phase and include myocardial inflammation, myocardial infarction, right ventricular dysfunction, and arrhythmias. Pathophysiological mechanisms for delayed complications are still poorly understood, with a dissociation seen between ongoing symptoms and objective measures of cardiopulmonary health. COVID-19 is anticipated to alter the long-term trajectory of many chronic cardiac diseases which are abundant in those at risk of severe disease. In this review, we discuss the definition of long COVID and its epidemiology, with an emphasis on cardiopulmonary symptoms. We further review the pathophysiological mechanisms underlying acute and chronic CV injury, the range of post-acute CV sequelae, and impact of COVID-19 on multiorgan health. We propose a possible model for referral of post-COVID-19 patients to cardiac services and discuss future directions including research priorities and clinical trials that are currently underway to evaluate the efficacy of treatment strategies for long COVID and associated CV sequelae.

Keywords: COVID-19; Cardiovascular disease; Coronavirus; Long COVID; Long term; Post-acute sequelae of COVID-19.

Graphical Abstract

Central illustration depicting (A) Pathophysiological mechanisms underlying acute and chronic severe acute respiratory syndrome coronavirus 2-induced myocardial injury (including effects of vaccine) and its relation with timing of infection and onset of long COVID symptoms, (B) post-COVID-19 cardiovascular sequelae, (C) anticipated long-term cardiovascular complications and outcomes, and (D) the unpredictable trajectory of long COVID and its impact on mental health, ability to work, exercise tolerance, and potential to exacerbate the obesity epidemic. ACE2, angiotensin-converting enzyme 2; CCL, chemokine ligand; COVID, coronavirus disease; IL, interleukin; IFN, interferon; Ig, immunoglobulin; PCR, polymerase chain reaction; POTS, postural orthostatic tachycardia syndrome; RNA, ribonucleic acid; TNF, tumour necrosis factor.

Figure 1

Long COVID is characterized by a diverse range of symptoms and signs spanning multiple organ systems including the respiratory system, neurological system, cardiovascular system, gastrointestinal system, dermatological system, endocrine/genitourinary systems, and skeletal muscle/joints as illustrated here. PTSD, post-traumatic stress disorder.

Figure 2

Factors that contribute to variability in prevalence estimates of long COVID. Prevalence estimates of long COVID are highly variable across studies due to a number of factors that introduce bias. These include differences in cohort characteristics, age, and sex of subjects enrolled, timing of assessment, sociodemographic factors, vaccines and variants, pre-existing health problems, sample size, study design, and variability in questionnaires or tools used. HCW, healthcare workers; m, months; PCR, polymerase chain reaction; wks, weeks.

Figure 3

Suggested possible algorithm for follow-up care and management of post-acute cardiovascular sequelae of COVID-19. Given the pressures imposed by a backlog of referrals to cardiology services during the COVID-19 pandemic, appropriate referral of patients post-acute COVID-19 is of utmost importance. This figure provides a suggested framework for referral of long COVID patients to cardiology services and the potential role of additional investigations in specific cases where appropriate. BNP, B-type natriuretic peptide; CCTA, coronary computed tomography angiography; CMR, cardiac magnetic resonance; CRP, C-reactive protein; CTPA, computed tomography pulmonary angiography; ECG, electrocardiogram; HbA1c, glycated haemoglobin; NS, nervous system; POTS, postural orthostatic tachycardia syndrome; Trop, troponin.