Pathological Interplay and Clinical Complications between COVID-19 and Cardiovascular Diseases: An Overview in 2023.

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.

Underlying mechanism of atrial fibrillation-associated Nppa-I137T mutation and cardiac effect of potential drug therapy.

BACKGROUND: More than a hundred genetic loci have been associated with atrial fibrillation (AF). But the exact mechanism remains unclear and the treatment needs to be improved. OBJECTIVE: This study aimed to investigate the mechanism and potential treatment of NPPA mutation-associated AF. METHODS: Nppa knock-in (KI, p.I137T) rats were generated, and cardiac function was evaluated. Blood pressure was recorded using a tail-cuff system. The expression levels were measured using real-time polymerase chain reaction, enzyme-linked immunosorbent assay or Western blot analysis, and RNA-sequence analysis. Programmed electrical stimulation, patch clamp, and multielectrode array were used to record the electrophysical characteristics. RESULTS: Mutant rats displayed downregulated expression of atrial natriuretic peptide but elevated blood pressure and enlarged left atrial end-diastolic diameter. Further, gene topology analysis suggested that the majority of differently expressed genes in Nppa KI rats were related to inflammation, electrical remodeling, and structural remodeling. The expression levels of C-C chemokine ligand 5 and galectin-3 involved in remodeling were higher, while there were declined levels of Nav1.5, Cav1.2, and connexin 40. AF was more easily induced in KI rats. Electrical remodeling included abbreviated action potentials, effective refractory period, increased late sodium current, and reduced calcium current, giving rise to conduction abnormalities. These electrophysiological changes could be reversed by the late sodium current blocker ranolazine and the Nav1.8 blocker A-803467. CONCLUSION: Our findings suggest that structural remodeling related to inflammation and fibrosis and electrical remodeling involved in late sodium current underly the major effects of the Nppa (p.I137T) variant to induce AF, which can be attenuated by the late sodium current blocker and Nav1.8 blocker.

Engeletin mediates antiarrhythmic effects in mice with isoproterenol-induced cardiac remodeling.

OBJECTIVE: Engeletin is a potent natural compound with antioxidant and anti-inflammatory properties. However, its role in cardiac remodeling remains unclear. Herein, the aim of the present study was to explore the effects of engeletin on cardiac structural and electrical remodeling and its underlying mechanism. METHODS: and results: A cardiac remodeling mice model using isoproterenol (ISO)-induced myocardial fibrosis was constructed and divided into the following four groups: control group; engeletin group; ISO group; engeletin + ISO group. Our results demonstrated that engeletin alleviated ISO-induced myocardial fibrosis and dysfunction. Moreover, engeletin significantly prolonged the QT and corrected QT (QTc) intervals, effective refractory period (ERP), and action potential duration (APD), and enhanced connexin protein 43 (Cx43) and ion channel expressions, thereby decreasing ventricular fibrillation (VF) susceptibility. Additionally, dihydroethidium staining illustrated that engeletin decreased reactive oxygen species (ROS) production. Of note, engeletin also increased the levels of superoxide dismutase and glutathione and decreased the activity of malondialdehyde and L-Glutathione oxidized. Moreover, engeletin significantly increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Furthermore, in vitro administration of an Nrf2 inhibitor abolished the anti-oxidant properties of engeletin. CONCLUSION: Engeletin ameliorated cardiac structural and electrical remodeling, ion channel remodeling, and oxidative stress induced by ISO in mice, thereby reducing VF susceptibility. These effects may be attributed to the anti-oxidant properties of engeletin associated with the Nrf2/HO-1 pathway.

Downregulation of p300/CBP-associated factor inhibits cardiomyocyte apoptosis via suppression of NF-κB pathway in ischaemia/reperfusion injury rats.

Cardiomyocyte apoptosis is the main reason of cardiac injury after myocardial ischaemia-reperfusion (I/R) injury (MIRI), but the role of p300/CBP-associated factor (PCAF) on myocardial apoptosis in MIRI is unknown. The aim of this study was to investigate the main mechanism of PCAF modulating cardiomyocyte apoptosis in MIRI. The MIRI model was constructed by ligation of the rat left anterior descending coronary vessel for 30 min and reperfusion for 24 h in vivo. H9c2 cells were harvested after induced by hypoxia for 6 h and then reoxygenation for 24 h (H/R) in vitro. The RNA interference PCAF expression adenovirus was transfected into rat myocardium and H9c2 cells. The area of myocardial infarction, cardiac function, myocardial injury marker levels, apoptosis, inflammation and oxidative stress were detected respectively. Both I/R and H/R remarkably upregulated the expression of PCAF, and downregulation of PCAF significantly attenuated myocardial apoptosis, inflammation and oxidative stress caused by I/R and H/R. In addition, downregulation of PCAF inhibited the activation of NF-κB signalling pathway in cardiomyocytes undergoing H/R. Pretreatment of lipopolysaccharide, a NF-κB pathway activator, could blunt these protective effects of PCAF downregulation on myocardial apoptosis in MIRI. These results highlight that downregulation of PCAF could reduce cardiomyocyte apoptosis by inhibiting the NF-κB pathway, thereby providing protection for MIRI. Therefore, PCAF might be a promising target for protecting against cardiac dysfunction induced by MIRI.

miR-145 attenuates cardiac fibrosis through the AKT/GSK-3ß/ß-catenin signaling pathway by directly targeting SOX9 in fibroblasts.

Myocardial infarction (MI) will inevitably result in cardiac fibrosis. In this study, we investigated the effect of microRNA-145 (miR-145) and transcription factor sex-determining region Y box 9 (SOX9) in the production of cardiac fibrosis induced by MI. MI rat models were established by left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD, the cardiac fibrosis level was assessed by Masson's trichrome staining. Cardiac fibroblasts (CFs) exposed to hypoxia were used to simulate MI-induced fibrosis. Flow cytometry, cell counting kit-8, and transwell assays were used to examine changes in CF apoptosis, proliferation, and migration, respectively. miR-145 expression was measured by quantitative real-time polymerase chain reaction. Immunofluorescence and Western blot analysis were performed to determine the relative expression of proteins. In comparison to the sham-operated group, the expression of miR-145 was significantly downregulated in the infarction peripheral area, whereas, SOX9 was upregulated. In the infarcted heart, the overexpression of miR-145 significantly ameliorated cardiac fibrosis and cardiac function, and there was a negative correlation between miR-145 and SOX9 expressions in hypoxic CFs in vitro. In addition, SOX9 was verified to be a functional target of miR-145. Overexpression of miR-145 or inhibition of SOX9 decreased CF proliferation, migration, and fibrosis, but augmented their apoptotic rate. Moreover, the upregulation of miR-145 or suppression of SOX9 inhibited AKT and ß-catenin signaling in hypoxic CFs. Taken together, this study highlights a potential treatment for cardiac fibrosis through the targeted regulation of SOX9 by miR-145, and our findings indicate that miR-145 exerts anti-fibrotic effects in MI via the negative regulation of SOX9 and its downstream AKT/GSK-3ß/ß-catenin pathways.

Over-expression of Kv4.3 gene reverses cardiac remodeling and transient-outward K+ current (Ito) reduction via CaMKII inhibition in myocardial infarction.

OBJECTIVE: Previous study has shown that Kv4.3, a main coding subunit generating cardiac transient-outward K+ current (Ito), can inhibit Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. Based on these observations, we speculate that over-expression of Kv4.3 gene could reverse not only Ito reduction but also cardiac remodeling in the rat myocardial infarction (MI) model. METHODS AND RESULTS: Healthy male Sprague-Dawley (SD) rats were used to establish MI model by ligation of left anterior descending coronary artery, and adenovirus integrated with Kv4.3 gene (AD-Kv4.3) was delivered in infarct border zone by intramyocardial injection. The hearts were harvested for histological analysis (HE or Masson trichrome staining), western blot or patch clamp 4 weeks after MI. Our data showed that the application of AD-Kv4.3 could reduce myocardial infarct size and fibrosis, and its cardioprotective effects were similar with medicine therapy (combination of metoprolol and captopril). Moreover, Kv4.3 over-expression significantly improved MI-induced cardiac dysfunction and enhanced Ito density while decreasing corrected QT (QTc) intervals and cardiac electrophysiological instability. Western blot showed that Kv4.3 transfection reduced CaMKII, PLB-17 and ryanodine receptor2 (RyR2 Ser2814) phosphorylation level, at same time increased SERCA2 expression dramatically. CONCLUSION: Over-expression of Kv4.3 can not only attenuate cardiac electrophysiological instability and cardiac performance, but also reduce myocardial infarct area and cardiac fibrosis. Like traditional anti-remodeling therapy-angiotensin converting enzyme inhibitor (ACEI) combined with ß-adrenergic receptor blocker, over-expression of Kv4.3 seems to be an effective and safe therapy for both structural and electrical remodeling induced by MI via CaMKII inhibition.

Over-expression of microRNA-145 drives alterations in ß-adrenergic signaling and attenuates cardiac remodeling in heart failure post myocardial infarction.

BACKGROUND: Numerous studies have highlighted the crucial role of microRNA-145 (miR-145) in coronary atherosclerosis and myocardial ischemia reperfusion injury. However, effects of miR-145 on ß-adrenergic signaling and cardiac remodeling in heart failure (HF) remains unclarified. METHODS AND RESULTS: We established HF model in rats with left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD ligation, rats showed substantial aggravation of cardiac dilation and electrophysiological instability. Up-regulation of miR-145 ameliorated HF-induced myocardial fibrosis and prolonged action potential duration. Echocardiography revealed increased basal contractility and decreased left ventricular inner-diameter in miR-145 over-expressed heart, while cardiac response to ß-adrenergic receptor (ßAR) stimulation was reduced. Furthermore, miR-145 increased L-type calcium current (ICa) density while decreased ICa response to ß-adrenergic stimulation with isoproterenol. The alterations in ßAR signaling might be predominant due to miR-145-mediated activation of Akt/CREB cascades. At high frequency pacing, Ca2+ transient, cell shortening and frequency of Ca2+ waves were significantly improved in AD-miR-145 group. Western blotting revealed that increased expression of Cav1.2, Ca2+-ATPase, ß2AR, GNAI3 and decreased level of CaMKII might be attributed to the cardioprotective effects of miR-145. CONCLUSION: miR-145 effectively alleviates HF-related cardiac remodeling by improving cardiac dilation, fibrosis, intracellular Ca2+ mishandling and electrophysiological instability.

MicroRNA-145 Protects against Myocardial Ischemia Reperfusion Injury via CaMKII-Mediated Antiapoptotic and Anti-Inflammatory Pathways.

MicroRNA-145 (miR-145) has been shown to play an important role in cardiovascular system disorders; however, the underlying mechanism is not completely understood. The purpose of this study was aimed at elucidating the cardioprotective effects of miR-145 against myocardial ischemia/reperfusion (I/R) injury. We established a rat myocardial I/R model with 45 min left anterior descending coronary artery (LAD) occlusion and 2 h reperfusion. The levels of myocardial enzymes, apoptotic, inflammatory, and oxidative indices were determined. The arrhythmia score was assessed by programmed electrical stimulation (PES). Quantitative real-time PCR and western blot were applied to evaluate the expression levels of miR-145 and related target proteins, respectively. I/R injury decreased the expression of miR-145; however, upregulated miR-145 markedly reduced the elevation of ST segment, decreased corrected QT (QTc) intervals, and attenuated I/R-induced electrophysiological instability. Furthermore, miR-145 suppressed myocardium apoptotic, inflammatory, and oxidative response as well as the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII), ryanodine receptor2 (RyR2 Ser2814), apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinases (JNK), and nuclear translocation of nuclear factor kappa-B (NF-κB) p65. In summary, overexpression of miR-145 alleviates I/R-induced myocardial electrophysiological instability and apoptotic and inflammatory response via inhibition of the CaMKII-mediated ASK1 antiapoptotic pathway and NF-κB p65 anti-inflammatory pathways.