Regulation of cardiac responses to increased load:role of endothelin-1, angiotensin II and collagen XV

Abstract Chronic overload of the heart is the major cause of left ventricular hypertrophy (LVH) and eventually heart failure. It is generally accepted that autocrine/paracrine factors, such as angiotensin II (Ang II) and endothelin-1 (ET-1) contribute to the development of LVH. Cardiac hypertrophy and failure are characterized by attenuated responsiveness to β- adrenergic stimulation and accumulation of collagenous material to the left ventricular wall. The present study aimed to characterize the roles of ET-1 and Ang II in the regulation of cardiac function. The role of the plasmamembrane Ca2+-ATPase (PMCA) in ET-1 induced cardiac responses and the role of type XV collagen in cardiac function were also studied. Both ET-1 infusion and mechanical loading were able to induce positive inotropic effect and induction of early response genes in isolated perfused hearts. ET-1 also induced strong vasoconstriction. Cardiomyocyte-specific PMCA overexpression inhibited the ET-1 induced hypertrophic response, while inotropic response remained unaltered. ET-1 was found to induce release of adrenomedullin (AM), a potent vasorelaxing and inotropic peptide. Infusion of AM antagonized the vasoconstrictive effect of ET-1 independently of nitric oxide. In hypertrophied rat hearts ET-1 was found to contribute significantly to the Frank-Starling response, a fundamental mechanism regulating contractile performance of the heart. In mice hearts, ET-1 was found to play a dual role in load induced elevation of contractile strength: ETA receptors mediated an increase, while ETB receptors mediated an inhibitory effect on contrcatile force. Ang II was not contributing to the contractile response to load in either rat or mice hearts. Blunted response to β-adrenergic stimulus and increased vulnerability as a result of exercise was observed in mice lacking collagen XV. In conclusion, the present results underscore the importance of the local factors, especially ET-1, in regulation of cardiac function, not only in terms of hypertrophic but also in terms of contractile response to load. The results also suggest a role for PMCA in regulation of cardiac function. Lack of type XV collagen was found to result in cardiac dysfunction with many features similar to those of early heart failure

Connective Tissue Growth Factor Inhibition Enhances Cardiac Repair and Limits Fibrosis After Myocardial Infarction

Peer reviewe

Dasatinib targets c-Src kinase in cardiotoxicity

Abstract Dasatinib is a multitargeted kinase inhibitor used for treatment of chronic myeloid leukemia and acute lymphoblastic leukemia. Unfortunately, treatment of cancer patients with some kinase inhibitors has been associated with cardiotoxicity. Cancer treatment with dasatinib has been reported to be associated with cardiotoxic side effects such as left ventricular dysfunction, heart failure, pericardial effusion and pulmonary hypertension. Here we aimed to investigate the molecular mechanisms underlying the cardiotoxicity of dasatinib. We found that among the resident cardiac cell types, cardiomyocytes were most sensitive to dasatinib-induced cell death. Exposure of cardiomyocytes to dasatinib attenuated the activity of extracellular signal-regulated kinase (ERK), which is a downstream target of dasatinib target kinase c-Src. Similar to dasatinib, c-Src depletion in cardiomyocytes compromised cardiomyocyte viability. Overexpression of dasatinib-resistant mutant of c-Src rescued the toxicity of dasatinib on cardiomyocytes, whereas forced expression of wild type c-Src did not have protective effect. Collectively, our results show that c-Src is a key target of dasatinib mediating the toxicity of dasatinib to cardiomyocytes. These findings may influence future drug design and suggest closer monitoring of patients treated with agents targeting c-Src for possible adverse cardiac effects

Remote ischemic preconditioning and hypoxia-induced biomarkers in acute myocardial infarction:study on a porcine model

Abstract Objectives: Remote ischemic preconditioning (RIPC) mitigates acute myocardial infarction (AMI). We hypothesized that RIPC reduces the size and severity of AMI and explored molecular mechanisms behind this phenomenon. Design: In two series of experiments, piglets underwent 60 min of the circumflex coronary artery occlusion, resulting in AMI. Piglets were randomly assigned into the RIPC groups (n = 7 + 7) and the control groups (n = 7 + 7). The RIPC groups underwent four 5-min hind limb ischemia-reperfusion cycles before AMI. In series I, the protective efficacy of RIPC was investigated by using biomarkers and echocardiography with a follow-up of 24 h. In series II, the heart of each piglet was harvested for TTC-staining to measure infarct size. Muscle biopsies were collected from the hind limb to explore molecular mechanisms of RIPC using qPCR and Western blot analysis. Results: The levels of CK-MBm (p = 0.032) and TnI (p = 0.007) were lower in the RIPC group. Left ventricular ejection fraction in the RIPC group was greater at the end of the follow-up. The myocardial infarct size in the RIPC group was smaller (p = 0.033). Western blot indicated HIF1α stabilization in the skeletal muscle of the RIPC group. PCR analyses showed upregulation of the HIF target mRNAs for glucose transporter (GLUT1), glucose transporter 4 (GLUT4), phosphofructokinase 1 (PFK1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), enolase 1 (ENO1), lactate dehydrogenase (LDHA) and endothelial nitric oxidate synthase (eNOS). Conclusions. Biochemical, physiologic, and histologic evidence confirms that RIPC decreases the size of AMI. The HIF pathway is likely involved in the mechanism of the RIPC

Endothelin-1 is associated with mortality that can be attenuated with high intensity statin therapy in patients with stable coronary artery disease

Abstract Background: All coronary artery disease (CAD) patients do not benefit equally of secondary prevention. Individualized intensity of drug therapy is currently implemented in guidelines for CAD and diabetes. Novel biomarkers are needed to identify patient subgroups potentially benefitting from individual therapy. This study aimed to investigate endothelin-1 (ET-1) as a biomarker for increased risk of adverse events and to evaluate if medication could alleviate the risks in patients with high ET-1. Methods: A prospective observational cohort study ARTEMIS included 1946 patients with angiographically documented CAD. Blood samples and baseline data were collected at enrollment and the patients were followed for 11 years. Multivariable Cox regression was used to assess the association between circulating ET-1 level and all-cause mortality, cardiovascular (CV) death, non-CV death and sudden cardiac death (SCD). Results: Here we show an association of circulating ET-1 level with higher risk for all-cause mortality (HR: 2.06; 95% CI 1.5–2.83), CV death, non-CV death and SCD in patients with CAD. Importantly, high intensity statin therapy reduces the risk for all-cause mortality (adjusted HR: 0.05; 95% CI 0.01–0.38) and CV death (adjusted HR: 0.06; 95% CI 0.01–0.44) in patients with high ET-1, but not in patients with low ET-1. High intensity statin therapy does not associate with reduction of risk for non-CV death or SCD. Conclusions: Our data suggests a prognostic value for high circulating ET-1 in patients with stable CAD. High intensity statin therapy associates with reduction of risk for all-cause mortality and CV death in CAD patients with high ET-1

MANTA versus ProGlide vascular closure devices in transfemoral transcatheter aortic valve implantation

Abstract Background: The MANTA system is a novel vascular closure device (VCD) and its safety and efficacy were compared to the ProGlide VCD in patients undergoing transfemoral transcatheter aortic valve implantation (TAVI). Methods: This is a retrospective study including 222 patients who underwent transfemoral TAVI at three Finnish University Hospitals. The MANTA VCD was used in 107 patients and their outcome was compared with that of 115 patients in whom the arterial access was closed with the ProGlide VCD. Results: VARC-2 VCD failure occurred less frequently in the MANTA cohort (3.7% vs. 7.8%, p = 0.378), but the difference did not reach statistical significance. When adjusted for the introducer outer diameter, the MANTA cohort had similar rates of VARC-2 major vascular complications (9.3% vs. 12.2%, adjusted: p = 0.456), VARC-2 life-threatening/disabling bleeding (9.3% vs. 6.1%, adjusted: p = 0.296) and need of invasive treatment of bleeding (4.7% vs. 7.0%, adjusted: p = 0.416) compared to the ProGlide cohort. Additional VCDs were more frequently needed in the ProGlide cohort (58.3% vs. 1.9%, p < 0.0001). Conclusions: In patients undergoing transfemoral TAVI, the MANTA VCD showed a similar risk of VARC-2 vascular and bleeding complications compared to the ProGlide VCD, but it reduced significantly the need of additional VCDs for completion of hemostasis