ABSTRACT
Background. Novel coronavirus-19 disease (COVID-19) is associated with significant cardiovascular morbidity and mortality. However, there have been very few reports on complete heart block (CHB) associated with COVID-19. This case series describes clinical characteristics, potential mechanisms, and short-term outcomes of critically ill COVID-19 patients complicated by CHB. Case Summary. We present three cases of new-onset CHB in critically ill COVID-19 patients. Patient 1 is a 41-year-old male with well-documented history of Familial Mediterranean Fever (FMF) who required mechanical ventilator support for acute hypoxic respiratory failure from severe COVID-19 pneumonia. He developed new-onset CHB without a hemodynamic derangement but subsequently had acute coronary syndrome complicated by cardiogenic shock. Patient 2 is a 77-year-old male with no past medical history who required intubation for severe COVID-19 pneumonia acute hypoxic respiratory failure. He developed CHB with sinus pause requiring temporary pacing but subsequently developed multiorgan failure. Patient 3 is 36-year-old lady 38 + 2 weeks pregnant, gravida 2 para 1 with no other medical history, who had an emergency Lower Section Caesarean Section (LSCS) as she required intubation for acute hypoxic respiratory failure. She exhibited new-onset CHB without hemodynamic compromise. The CHB resolved spontaneously after 24 hours. Discussion. COVID-19-associated CHB is a very rare clinical manifestation. The potential mechanisms for CHB in patients with COVID-19 include myocardial inflammation or direct viral infiltration as well as other causes such as metabolic derangements or use of sedatives. Patients diagnosed with COVID-19 should be monitored closely for the development of bradyarrhythmia and hemodynamic instability.
ABSTRACT
Articular cartilage is a dense extracellular matrix-rich tissue that degrades following chronic mechanical stress, resulting in osteoarthritis (OA). The tissue has low intrinsic repair especially in aged and osteoarthritic joints. Here, we describe three pro-regenerative factors; fibroblast growth factor 2 (FGF2), connective tissue growth factor, bound to transforming growth factor-beta (CTGF-TGFß), and hepatoma-derived growth factor (HDGF), that are rapidly released from the pericellular matrix (PCM) of articular cartilage upon mechanical injury. All three growth factors bound heparan sulfate, and were displaced by exogenous NaCl. We hypothesised that sodium, sequestered within the aggrecan-rich matrix, was freed by injurious compression, thereby enhancing the bioavailability of pericellular growth factors. Indeed, growth factor release was abrogated when cartilage aggrecan was depleted by IL-1 treatment, and in severely damaged human osteoarthritic cartilage. A flux in free matrix sodium upon mechanical compression of cartilage was visualised by 23Na -MRI just below the articular surface. This corresponded to a region of reduced tissue stiffness, measured by scanning acoustic microscopy and second harmonic generation microscopy, and where Smad2/3 was phosphorylated upon cyclic compression. Our results describe a novel intrinsic repair mechanism, controlled by matrix stiffness and mediated by the free sodium concentration, in which heparan sulfate-bound growth factors are released from cartilage upon injurious load. They identify aggrecan as a depot for sequestered sodium, explaining why osteoarthritic tissue loses its ability to repair. Treatments that restore matrix sodium to allow appropriate release of growth factors upon load are predicted to enable intrinsic cartilage repair in OA. SIGNIFICANCE STATEMENT: Osteoarthritis is the most prevalent musculoskeletal disease, affecting 250 million people worldwide.1 We identify a novel intrinsic repair response in cartilage, mediated by aggrecan-dependent sodium flux, and dependent upon matrix stiffness, which results in the release of a cocktail of pro-regenerative growth factors after injury. Loss of aggrecan in late-stage osteoarthritis prevents growth factor release and likely contributes to disease progression. Treatments that restore matrix sodium in osteoarthritis may recover the intrinsic repair response to improve disease outcome.
