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Background Insulin and insulin-like growth factor 1 (IGF-1) signaling regulate cellular growth and glucose metabolism in the myocardium. However, their physiological role in cardiac conduction cells has never been explored. Therefore, we sought to determine the spatiotemporal function of insulin/IGF-1 receptors in the sinoatrial node (SAN). Methods We generated cardiac conduction cell-specific inducible IGF-1 receptor (IGF-1R) knockout (KO) (CSIGF1RKO), insulin receptor (IR) KO (CSIRKO), and IR/IGF-1R double KO (CSDIRKO) mice and evaluated their phenotypes. Results Telemetry measured electrocardiography found regular sinus rhythm in CSIGF1RKO mice, indicating that IGF-1R is dispensable for normal pacemaking. In contrast, CSIRKO and CSDIRKO mice exhibited profound sinus bradycardia. CSDIRKO mice showed a typical sinus node dysfunction characterized by junctional rhythm and sinus pauses on electrocardiography. Interestingly, the lack of an insulin receptor in the SAN cells of CSIRKO and CSDIRKO mice caused sinus nodal fibrosis. Mechanistically, hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) protein expression significantly decreased in the CSIRKO and CSDIRKO mice relative to the controls. A patch-clamp study of the SAN cells of CSIRKO mice marked a significant decrease in the funny current, which is responsible for spontaneous diastolic depolarization in the SAN. This result suggested that insulin receptor loss reduces the heart rate via downregulation of the HCN4 channel. Additionally, HCN1 expression was decreased in CSDIRKO mice explaining sinus node dysfunction. Conclusion Our results reveal a previously unrecognized insulin/IGF-1 signaling role in the sinus node structural maintenance and pacemaker function.

The insulin-like growth factor 1 receptor (IGF-1R) signaling in cardiomyocytes is implicated in physiological hypertrophy and myocardial aging. Although fibroblasts account for a small amount of the heart, they are activated when the heart is damaged to promote cardiac remodeling. However, the role of IGF-1R signaling in cardiac fibroblasts is still unknown. In this study, we investigated the roles of IGF-1 signaling during agonist-induced cardiac fibrosis and evaluated the molecular mechanisms in cultured cardiac fibroblasts. Using an experimental model of cardiac fibrosis with angiotensin II/phenylephrine (AngII/PE) infusion, we found severe interstitial fibrosis in the AngII/PE infused myofibroblast-specific IGF-1R knockout mice compared to the wild-type mice. In contrast, low-dose IGF-1 infusion markedly attenuated AngII-induced cardiac fibrosis by inhibiting fibroblast proliferation and differentiation. Mechanistically, we demonstrated that IGF-1-attenuated AngII-induced cardiac fibrosis through the Akt pathway and through suppression of rho-associated coiled-coil containing kinases (ROCK)2-mediated α-smooth muscle actin (αSMA) expression. Our study highlights a novel function of the IGF-1/IGF-1R signaling in agonist-induced cardiac fibrosis. We propose that low-dose IGF-1 may be an efficacious therapeutic avenue against cardiac fibrosis.

Tyrosine kinase inhibitors (TKIs) have shown clear survival benefits as effective targeted therapies in various hematological and solid malignancies. Important evidence, however, has shown that TKIs may lead to adverse effects such as cardiovascular toxicities, via off-target as well as on-target mechanisms. This review presents an overview of TKI-induced cardiotoxicity mechanisms, clinical manifestations, diagnosis, monitoring, and management options. Furthermore, we discuss current preclinical efforts and future investigations into alternative therapeutics for minimizing the cardiotoxicities associated with tyrosine kinase-targeted therapies. Accompanying with the significant improvements toward targeted anticancer treatment, cardiotoxicity-related adverse effects are increasingly reported and have become an important public health issue. The TKI-induced cardiovascular toxicities include myocardial ischemia, heart failure, QT prolongation, and hypertension. Thus, the early awareness of cardiotoxicities, initiation of appropriate management, and close follow-up, may enhance the benefits of TKI therapy.

Salicylates, one of the oldest medicinal compounds known to humans, have been reported to show anti-inflammatory effects via cyclooxygenase (COX) inhibition. However, the pathophysiological role of COX-2 in the heart is conflicting, and the role of sodium salicylate in the regulation of cardiac inflammation has not yet been elucidated. We aimed to investigate the effect of salicylate on COX-2 expression and its associated prostaglandin production using cultured neonatal rat cardiomyocytes. The cells were incubated in the presence or absence of sodium salicylate (8 mM). Treatment with sodium salicylate significantly increased COX-2 expression at both mRNA and protein levels, induced prostaglandin D2 release, and increased TNF-α mRNA expression in cardiomyocytes. In addition, salicylate treatment induced cardiomyocyte hypertrophy. Taken together, we demonstrated that salicylate induced COX-2 expression, which in turn resulted in the regulation of expression of several inflammatory mediators in cardiomyocytes.

In this paper, we propose a novel method for three-dimensional (3D) blood vessel modeling. Given the incomplete nature of medical images, a 3D blood vessel model that includes the intima and adventitia cannot be reconstructed with a single medical image. Intravascular ultrasound (IVUS) images are used to obtain detailed intimal and adventitial information. Then, X-ray angiogram images are used to calculate the position and orientation of IVUS images. Combining these medical images can generate a 3D blood vessel model. To visualize a blood vessel via IVUS, a catheter that is attached to a miniaturized ultrasound device is inserted into the blood vessel. The insertion of the catheter deforms the blood vessel. This deformation is reflected in the 3D blood vessel model that is developed from combining IVUS and X-ray angiogram images. To address this problem, we propose a novel method for 3D blood vessel modeling using undeformed intimal and adventitial information from IVUS images. Our proposed method has potential applications in hemodynamic analysis.

To understand the hemodynamic characteristics of arterial disease, the flow characteristics of abnormal blood vessels containing lesions and normal blood vessels before lesions form should be considered. In this study, abnormal arterial models were created using medical images from six patients with coronary artery disease using computational fluid dynamics (CFD) methods. In addition, normal models were created (6 cases) from the abnormal arterial models, allowing for comparison of flow characteristics. In curved areas and at bifurcations of the normal arterial models, blood flow tended to be stagnant or reverse. This low flow resulted in low wall shear stress and a high oscillatory shear index, which coincided with the locations of plaques in actual patients. In the abnormal models, on the other hand, high shear stress occurred in stenosis due to the presence of plaque. Additionally, low AWSS and high OSI were detected downstream of stenotic segments.