BACKGROUND:The coronavirus disease 2019 (COVID-19) involves all organs of the body, of which the interaction with cardiovascular diseases is the most important. SUMMARY:Numerous studies have reported that COVID-19 patients complicated with cardiovascular comorbidities (hypertension, coronary heart disease, chronic heart failure (HF), cerebrovascular disease) are more likely to develop into critical illness and have higher mortality. Conversely, COVID-19 may also cause myocardial injury in patients through various pathological mechanisms such as direct virus attack on cardiomyocytes, overactivation of immune response, microthrombus formation, which may lead to fatal acute ST-segment elevation myocardial infarction, arrhythmia, acute worsening of chronic HF, etc. In addition, the symptoms of the so-called long-COVID may remain in some patients who survived the acute viral infection. Positional tachycardia has been widely reported, and cardiovascular autonomic disorders are thought to play a pathogenic role. KEY MESSAGE:The review summarizes the interaction between COVID-19 and cardiovascular disease in terms of pathological mechanism, clinical features, and sequelae. Therapeutic and rehabilitation programs after COVID-19 infection are compiled and need to be further standardized in the future.

There has been increasing evidence that chronic immune activation plays critical roles in the pathogenesis of DCM. CD4(+) LAP(+) Tregs are a newly identified T cell subset with suppressive function on the immune response. This study was designed to investigate whether the circulating frequency and function of CD4(+)LAP(+) Tregs would be impaired in patients with DCM. The results demonstrated that DCM patients had a significantly lower frequency of circulating CD4(+)LAP(+) Tregs compared with control donors. CD4(+)LAP(+) Tregs from DCM patients showed compromised function to suppress proliferation of CD4(+) LAP(-)CD25(int/low) T cells and proliferation and IgG production of B cells. Moreover, B cell proliferation and IgG subset production could be directly suppressed by CD4(+) LAP(+) Tregs. TGF-β and contact-dependent mechanisms were involved in CD4(+)LAP(+) Treg-mediated suppression. Correlation analysis suggested that CD4(+)LAP(+) Treg frequency was positively correlated with LVEF and negatively correlated with serum IgG3 and NT-proBNP concentration in patients with DCM. Our results are the first to demonstrate that the frequencies of CD4(+)LAP(+) Tregs in patients with DCM are reduced and that their suppressive function is compromised. Defective CD4(+) LAP(+) Tregs may be an underlying mechanism of immune activation in DCM patients.

AIMS Recently, interleukin (IL)-9 was found to be involved in the pathogenesis of many inflammatory diseases. Here, we tested whether IL-9 was related to atherosclerosis and investigated the underlying mechanisms. METHODS AND RESULTS IL-9R was expressed in mouse aortic endothelial cells (MAECs) and aortic tissues, and IL-9 levels were elevated in plasma and aortic arches in Apolipoprotein E-deficient (ApoE-/-) mice. ApoE-/- mice fed a western diet for 10 weeks were administered recombinant mouse IL-9 (rIL-9) or anti-IL-9 neutralizing monoclonal antibody (mAb). Mice treated with rIL-9 developed markedly larger plaques in both the aorta and aortic root. Immunohistochemical studies demonstrated increases in both vascular endothelial adhesion molecule-1 (VCAM-1) expression and the infiltration of inflammatory cells, including T cells and macrophages, in plaques. However, treatment with the anti-IL-9 mAb caused the opposite effect. The administration of rIL-9 did not affect the splenic T cell or peripheral monocyte subsets. Meanwhile, IL-9 induced VCAM-1 expression in MAECs mainly via a STAT3-dependent pathway, consequently increasing monocyte-endothelial adhesion. Moreover, treatment with anti-VCAM-1 mAb partially abrogated the IL-9-induced increase in plaque area. In addition, CD4(+)IL-9(+) T cells and IL-9 were increased in patients with acute coronary syndrome, and the levels of IL-9 in culture supernatants and soluble VCAM-1 (sVCAM-1) in plasma were significantly positively correlated in the enrolled patients. CONCLUSION Our results demonstrated that IL-9 exerted pro-atherosclerotic effects in ApoE-/- mice at least partially by inducing VCAM-1 expression, which mediated inflammatory cell infiltration into atherosclerotic lesions.

Inflammatory responses play an important role in the pathogenesis of adverse ventricular remodeling after myocardial infarction (MI). We previously demonstrated that interleukin (IL)-17A plays a pathogenic role in myocardial ischemia/reperfusion injury and viral myocarditis. However, the role of IL-17A in post-MI remodeling and the related mechanisms have not been fully elucidated. Acute MI was induced by permanent ligation of the left anterior descending coronary artery in C57BL/6 mice. Repletion of IL-17A significantly aggravated both early- and late-phase ventricular remodeling, as demonstrated by increased infarct size, deteriorated cardiac function, increased myocardial fibrosis, and cardiomyocyte apoptosis. By contrast, genetic IL-17A deficiency had the opposite effect. Additional studies in vitro indicated that IL-17A induces neonatal cardiomyocyte (from C57BL/6 mice) apoptosis through the activation of p38, p53 phosphorylation, and Bax redistribution. These data demonstrate that IL-17A induces cardiomyocyte apoptosis through the p38 mitogen-activated protein kinase (MAPK)-p53-Bax signaling pathway and promotes both early- and late-phase post-MI ventricular remodeling. IL-17A might be an important target in preventing heart failure after MI.

Persistent inflammatory responses participate in the pathogenesis of adverse ventricular remodeling after myocardial infarction (MI). We hypothesized that regulatory T (Treg) cells modulate inflammatory responses, attenuate ventricular remodeling and subsequently improve cardiac function after MI. Acute MI was induced by ligation of the left anterior descending coronary artery in rats. Infiltration of Foxp3+ Treg cells was detected in the infarcted heart. Expansion of Treg cells in vivo by means of adoptive transfer as well as a CD28 superagonistic antibody (JJ316) resulted in an increased number of Foxp3+ Treg cells in the infarcted heart. Subsequently, rats with MI showed improved cardiac function following Treg cells transfer or JJ316 injection. Interstitial fibrosis, myocardial matrix metalloproteinase-2 activity and cardiac apoptosis were attenuated in the rats that received Treg cells transfer. Infiltration of neutrophils, macrophages and lymphocytes as well as expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β were also significantly decreased, and the CD8+ cardiac-specific cytotoxic T lymphocyte response was inhibited. Expression of interleukin (IL)-10 in the heart, however, was increased. Additional studies in vitro indicated that Treg cells directly protect neonatal rat cardiomyocytes against LPS-induced apoptosis, and this protection depends on the cell–cell contact and IL-10 expression. Furthermore, Treg cells inhibited proinflammatory cytokines production by cardiomyocytes. These data demonstrate that Treg cells serve to protect against adverse ventricular remodeling and contribute to improve cardiac function after myocardial infarction via inhibition of inflammation and direct protection of cardiomyocytes.

The representative FACS plots shown in Fig. 5A were incorrect. The same data were used to generate the control and the native LDL plots in the original figure. We have now replaced these representative plots with new data from the same donor. This correction does not change the interpretation of the results or the conclusions. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 288, NO. 52, p. 37365, December 27, 2013 © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.

OBJECTIVES:This study tested whether interleukin (IL)-17A is involved in the pathogenesis of mouse myocardial ischemia/reperfusion (I/R) injury and investigated the mechanisms. BACKGROUND:Inflammatory processes play a major role in myocardial I/R injury. We recently identified IL-17A as an important cytokine in inflammatory cardiovascular diseases such as atherosclerosis and viral myocarditis. However, its role in myocardial I/R injury remains unknown. METHODS:The involvement of IL-17A was assessed in functional assays in mouse myocardial I/R injury by neutralization/repletion or genetic deficiency of IL-17A, and its mechanism on cardiomyocyte apoptosis and neutrophil infiltration were further studied in vivo and in vitro. RESULTS:Interleukin-17A was elevated after murine left coronary artery ligation and reperfusion. Intracellular cytokine staining revealed that γδT lymphocytes but not CD4(+) helper T cells were a major source of IL-17A. Anti-IL-17A monoclonal antibody treatment or IL-17A knockout markedly ameliorated I/R injury, as demonstrated by reduced infarct size, reduced cardiac troponin T levels, and improved cardiac function. This improvement was associated with a reduction in cardiomyocyte apoptosis and neutrophil infiltration. In contrast, repletion of exogenous IL-17A induced the opposite effect. In vitro study showed that IL-17A mediated cardiomyocyte apoptosis through regulating the Bax/Bcl-2 ratio, induced CXC chemokine-mediated neutrophil migration and promoted neutrophil-endothelial cell adherence through induction of endothelial cell E-selectin and inter-cellular adhesion molecule-1 expression. CONCLUSIONS:IL-17A mainly produced by γδT cells plays a pathogenic role in myocardial I/R injury by inducing cardiomyocyte apoptosis and neutrophil infiltration.

Animal studies suggest that regulatory T (T(reg)) cells play a beneficial role in ventricular remodeling and our previous data have demonstrated defects of T(reg) cells in patients with chronic heart failure (CHF). However, the mechanisms behind T(reg-)cell defects remained unknown. We here sought to elucidate the mechanism of T(reg-)cell defects in CHF patients.We performed flow cytometry analysis and demonstrated reduced numbers of peripheral blood CD4(+)CD25(+)FOXP3(+)CD45RO(-)CD45RA(+) naïve T(reg) (nT(reg)) cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+)CD45RA(-) memory T(reg) (mT(reg)) cells in CHF patients as compared with non-CHF controls. Moreover, the nT(reg)/mT(reg) ratio (p<0.01), CD4(+)CD25(+)FOXP3(+)CD45RO(-) CD45RA(+)CD31(+) recent thymic emigrant T(reg) cell (RTE-T(reg)) frequency (p<0.01), and T-cell receptor excision circle levels in T(reg) cells (p<0.01) were lower in CHF patients than in non-CHF controls. Combined annexin-V and 7-AAD staining showed that peripheral T(reg) cells from CHF patients exhibited increased spontaneous apoptosis and were more prone to interleukin (IL)-2 deprivation- and CD95 ligand-mediated apoptosis than those from non-CHF individuals. Furthermore, analyses by both flow cytometry and real-time polymerase chain reaction showed that T(reg)-cell frequency in the mediastinal lymph nodes or Foxp3 expression in hearts of CHF patients was no higher than that of the non-CHF controls.Our data suggested that the T(reg)-cell defects of CHF patients were likely caused by decreased thymic output of nascent T(reg) cells and increased susceptibility to apoptosis in the periphery.

Objective:To investigate the effect of interleukin-17(IL-17) in myocardial ischemia reperfusion injury (IRI) in rat.Method:The myocardial ischemia reperfusion injury model was performed by temporary occlusion of left anterior descending in rats. The expression of IL-17 in myocardial tissue was detected by Real time-PCR and western blot at different times after reperfusion. The source of IL -17 was confirmed by flow cytometry. Rats were treated with anti-IL-17 antibody in vivo for determining if IL -17 was involved in myocardial IRI. Result:The expression of IL-17 was detected as early as 1 hour after reperfusion,lasted for 24 hours,and showed no peak in this period. The results of flow cytometry revealed that CD4+T lymphocyte was a major source of IL-17 in myocardial tissue after reperfusion. Administration of anti-IL-17 resulted in a significant decrease in serum troponin T and myocardial infarct size. Conclusion:IL-17 is involved in the pathogenesis of myocardial IRI.