Cardiovascular abnormalities of long-COVID syndrome: Pathogenic basis and potential strategy for treatment and rehabilitation

Abstract

Cardiac injury and sustained cardiovascular abnormalities in long-COVID syndrome, i.e. post-acute sequelae of coronavirus disease 2019 (COVID-19) have emerged as a debilitating health burden that has posed challenges for management of pre-existing cardiovascular conditions and other associated chronic comorbidities in the most vulnerable group of patients recovered from acute COVID-19. A clear and evidence-based guideline for treating cardiac issues of long-COVID syndrome is still lacking. In this review, we have summarized the common cardiac symptoms reported in the months after acute COVID-19 illness and further evaluated the possible pathogenic factors underlying the pathophysiology process of long-COVID. The mechanistic understanding of how Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) damages the heart and vasculatures is critical in developing targeted therapy and preventive measures for limiting the viral attacks. Despite the currently available therapeutic interventions, a considerable portion of patients recovered from severe COVID-19 have reported a reduced functional reserve due to deconditioning. Therefore, a rigorous and comprehensive cardiac rehabilitation program with individualized exercise protocols would be instrumental for the patients with long-COVID to regain the physical fitness levels comparable to their pre-illness baseline.

Keywords: Cardiac rehabilitation; Exercise intolerance; Hypoxia inducible factor 1; Inflammation; Long-COVID syndrome; SARS-CoV-2 tropism.

Fig. 1

Schematic summary of potential mechanisms involving direct viral toxicity and hypoxic injury underlying the cardiovascular sequelae of long-COVID syndrome Abbreviations: ACE2, angiotensin converting enzyme 2; TMPRSS2, transmembrane serine protease 2; ADAM17, a disintegrin and metalloprotease 17; Ang I, angiotensin 1; Ang II, angiotensin 2; ARVC, arrhythmogenic right ventricular cardiomyopathy; ATR2, angiotensin 2 receptor; HIF-1α, hypoxia-inducible factor 1α; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; ROS, reactive oxygen species; NF-kB, nuclear factor kappa B; NO, nitric oxide; vWF, von Willebrand factor; IL1, interleukin 1; IL6, interleukin 6; IL8, interleukin 8; TNFα, tumor necrosis factor α; long-COVID, post-acute sequelae of coronavirus disease 2019; SARS-CoV-2, ​severe acute respiratory syndrome coronavirus 2.

Fig. 2

Schematic summary of potential mechanisms involving metabolic, thromboembolic, and immunoinflammatory dysregulation underlying the cardiovascular sequelae of long-COVID syndrome Abbreviations: C5b, Complement 5-b; C6, Complement 6; C7, Complement 7; C8, Complement 8; C9, Complement 9; MAC, membrane attack complex; NO, nitric oxide; iNOS, inducible nitric oxide synthase; vWF, von Willebrand factor; IL1, interleukin-1; IL8, interleukin-8; TCR, T cell receptor; MHC, major histocompatibility complex; long-COVID, post-acute sequelae of coronavirus disease 2019; CVA, cerebral vascular accident; PE, pulmonary embolism; CAD, coronary artery disease.

Fig. 3

Schematic summary of clinical management and exploratory approach to cardiac injury in long-COVID syndrome Abbreviations: GDMT, guideline-directed medical therapy; BB, Beta blocker; Cas9, CRISPR associated protein 9; CCB, calcium channel blocker; CMR, cardiovascular magnetic resonance; CPET, cardiopulmonary exerciser testing; ECG, electrocardiogram; HIF-1α, hypoxia inducible factor 1α; IL1, interleukin 1; IL6, interleukin 6; SARS-CoV-2 RNA, Severe acute respiratory syndrome coronavirus 2 ribonucleic acid; sgRNA, single guided ribonucleic acid; siRNA, small interfering ribonucleic acid; TNFα, tumor necrosis factor α; long-COVID, post-acute sequelae of coronavirus disease 2019.