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  • ISCHEMIA: new questions from a landmark trial
    Cardiovasc. Res. (IF 7.014) Pub Date : 2020-01-14
    Morrow A, Sidik N, Berry C.

    AnginaIschaemiaMicrovascularStentCABG

    更新日期:2020-01-15
  • Experimental animal models of coronary microvascular dysfunction
    Cardiovasc. Res. (IF 7.014) Pub Date : 2020-01-11
    Sorop O, van de Wouw J, Chandler S, et al.

    Coronary microvascular dysfunction (CMD) is commonly present in patients with metabolic derangements and is increasingly recognized as an important contributor to myocardial ischemia, both in the presence and absence of epicardial coronary atherosclerosis. The latter condition is termed ‘ischemia with non-obstructive coronary arteries’ (INOCA). Notwithstanding the high prevalence of INOCA, effective treatment remains elusive. Although to date there is no animal model for INOCA, animal models of CMD, one of the hallmarks of INOCA, offer excellent test models for enhancing our understanding of the pathophysiology of CMD and for investigating novel therapies. This article presents an overview of currently available experimental models of CMD – with an emphasis on metabolic derangements as risk factors – in dogs, swine, rabbits, rats and mice. In all the available animal models, metabolic derangements are most often induced by a high fat diet and/or diabetes mellitus via injection of alloxan or streptozotocin, but there is also a wide variety of spontaneous as well as transgenic animal models which develop metabolic derangements. Depending on number, severity and duration of exposure to risk factors — all these animal models show perturbations in coronary microvascular (endothelial) function and structure, similar to what has been observed in patients with INOCA and co-morbid conditions. The use of these animal models will be instrumental in identifying novel therapeutic targets and for the subsequent development and testing of novel therapeutic interventions to combat ischemic heart disease, the number one cause of death worldwide.

    更新日期:2020-01-13
  • Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis.
    Cardiovasc. Res. (IF 7.014) Pub Date : null
    Nicholas S Kirkby,Joan Raouf,Blerina Ahmetaj-Shala,Bin Liu,Sarah I Mazi,Matthew L Edin,Mark Geoffrey Chambers,Marina Korotkova,Xiaomeng Wang,Walter Wahli,Darryl C Zeldin,Rolf Nüsing,Yingbi Zhou,Per-Johan Jakobsson,Jane A Mitchell

    AIMS Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of eNOS, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2. Here we have used pharmacological tools and genetically modified mice to delineate mPGES-1 and COX-2 in the regulation of ADMA. METHODS AND RESULTS Inhibition of COX-2 but not mPGES-1 deletion resulted in increased plasma ADMA levels. mPGES-1 deletion but not COX-2 inhibition resulted in increased plasma prostacyclin levels. These differences were explained by distinct compartmentalisation of COX-2 and mPGES-1 in the kidney. Data from prostanoid synthase/receptor knockout mice showed that the COX-2/ADMA axis is controlled by prostacyclin receptors (IP and PPARβ/δ) and the inhibitory PGE2 receptor EP4, but not other PGE2 receptors. CONCLUSIONS These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA.

    更新日期:2020-01-13
  • Decreased Jagged1 Expression in Vascular Smooth Muscle Cells Delays Endothelial Regeneration in Arteriovenous Graft
    Cardiovasc. Res. (IF 7.014) Pub Date : 2020-01-08
    Guo Q, Huang F, Qing Y, et al.

    AimsIt is well-established that endothelial dysfunction promotes activation of vascular smooth muscle cell (VSMC). Whether decreased accumulation of VSMCs affects endothelial regeneration and functions in arteriovenous graft (AVG) remodeling has not been studied. We sought to identify mechanisms by which the Notch ligand, Jagged1, in VSMCs regulates endothelial cell (EC) functions in AVGs. Methods and ResultsAVGs were created in transgenic mice bearing VSMC-specific knockout (KO) or overexpression of Jagged1. VSMC migration, EC regeneration and its barrier functions as well as AVG remodeling were evaluated. Jagged1 expression was induced in VSMCs of neointima in the AVGs. Jagged1 KO in VSMCs inhibited the accumulation of extracellular matrix as well as VSMC migration. Fewer α-SMA-positive VSMCs were found in AVGs created in VSMC-specific Jagged1 KO mice (VSMCJagged1 KO mice) vs. in WT mice. Decreased VSMCs in AVGs were associated with deterioration of EC functions. In AVGs created in transgenic mice bearing Jagged1 KO in VSMCs exhibited delayed EC regeneration and impaired EC barrier function. Barrier dysfunction of ECs increased inflammatory cell infiltration and dysregulation of AVG remodeling and arterialization. The increased expression of IL-1β in macrophages was associated with expression of adhesion markers in ECs in AVGs created in VSMCJagged1 KO mice. In contrast, AVGs created in mice with overexpression of Jagged1 in VSMCs exhibited improved EC regeneration plus decreased macrophage infiltration. This led to AVG remodeling and arterialization. In co-cultures of ECs and VSMCs, Jagged1 deficiency in VSMCs suppressed N-cadherin and integrin β3 expression in ECs. Inhibition of integrin β3 activation delayed EC spreading and migration. Notably, Jagged1 overexpression in VSMCs or treatment with recombinant Jagged1 stimulated the expression of N-cadherin and integrin β3 in ECs. Jagged1-induced responses were blocked by inhibition of Notch signaling. ConclusionsJagged1 expression in VSMCs maintains EC barrier functions and blocks infiltration of macrophages. These responses promote remodeling and arterialization of AVGs. Translational perspectiveThe vein is subjected to arterial environment immediately after AVG or arteriovenous fistula surgery. ECs in the vein of the AVGs and arteriovenous fistulae are denuded and regenerated later. Deficiency of Jagged1 expression in VSMCs inhibits VSMC migration, proliferation, and interferes with arterialization of vein of the AVGs. These responses also delay EC regeneration and EC barrier function with increased inflammation leading to failed vascular remodeling of AVGs. Thus, a strategy to regulate Jagged1 expression will improve AVG arterialization and function.

    更新日期:2020-01-08
  • Diagnosis of coronary microvascular dysfunction in the clinic
    Cardiovasc. Res. (IF 7.014) Pub Date : 2020-01-06
    Ong P, Safdar B, Seitz A, et al.

    The coronary microcirculation plays a pivotal role in the regulation of coronary blood flow and cardiac metabolism. It can adapt to acute and chronic pathologic conditions such as coronary thrombosis or long-standing hypertension. Due to the fact that the coronary microcirculation cannot be visualized in human beings, in vivo its assessment remains challenging. Thus, the clinical importance of the coronary microcirculation is still often underestimated or even neglected. Depending on the clinical condition of the respective patient, several non-invasive (e.g. transthoracic Doppler-echocardiography assessing coronary flow velocity reserve, cardiac magnetic resonance imaging, positron emission tomography) and invasive methods (e.g. assessment of coronary flow reserve and microvascular resistance using adenosine, microvascular coronary spasm with acetylcholine) have been established for the assessment of coronary microvascular function. Individual patient characteristics, but certainly also local availability, methodical expertise and costs will influence which methods are being used for the diagnostic work-up (non-invasive and/or invasive assessment) in a patient with recurrent symptoms and suspected coronary microvascular dysfunction. Recently, the combined invasive assessment of coronary vasoconstrictor as well as vasodilator abnormalities has been titled interventional diagnostic procedure (IDP). It involves intracoronary acetylcholine testing for the detection of coronary spasm as well as coronary flow reserve and microvascular resistance assessment in response to adenosine using a dedicated wire. Currently, the IDP represents the most comprehensive coronary vasomotor assessment. Studies using the IDP to better characterize the endotypes observed will hopefully facilitate development of tailored and effective treatments.

    更新日期:2020-01-06
  • Leaders in Cardiovascular Research: Eric Olson
    Cardiovasc. Res. (IF 7.014) Pub Date : 2020-01-03
    Guzik T, Olson E.

    Gene editingHeart and muscle development and diseaseGene regulation

    更新日期:2020-01-04
  • Hitchhiker’s guide to microbiome studies
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-12-26
    Bartolomaeus T, Forslund S.

    MicrobiomeMethodsNext-generation sequencing

    更新日期:2019-12-27
  • Lansoprazole alleviates pressure overload-induced cardiac hypertrophy and heart failure in mice by blocking the activation of β-catenin
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-01-24
    Lin H, Li Y, Zhu H, et al.

    AimsProton pump inhibitors (PPIs) are widely used in patients receiving percutaneous coronary intervention to prevent gastric bleeding, but whether PPIs are beneficial for the heart is controversial. Here, we investigated the effects of lansoprazole on cardiac hypertrophy and heart failure, as well as the underlying mechanisms. Methods and resultsAdult male C57 mice were subjected to transverse aortic constriction (TAC) or sham surgery and then were treated with lansoprazole or vehicle for 5 weeks. In addition, cultured neonatal rat ventricular cardiomyocytes and fibroblasts were exposed to angiotensin II in the presence or absence of lansoprazole. At 5 weeks after TAC, the heart weight/body weight ratio was lower in lansoprazole-treated mice than in untreated mice, as was the lung weight/body weight ratio, while left ventricular (LV) fractional shortening and the maximum and minimum rates of change of the LV pressure were higher in lansoprazole-treated mice, along with less cardiac fibrosis. In cultured cardiomyocytes, lansoprazole inhibited angiotensin II-induced protein synthesis and hypertrophy, as well as inhibiting proliferation of fibroblasts. Lansoprazole decreased myocardial levels of phosphorylated Akt, phosphorylated glycogen synthase kinase 3β, and active β-catenin in TAC mice and in angiotensin II-stimulated cardiomyocytes. After overexpression of active β-catenin or knockdown of H+/K+-ATPase α-subunit, lansoprazole still significantly attenuated myocyte hypertrophy. ConclusionLansoprazole inhibits cardiac remodelling by suppressing activation of the Akt/GSK3β/β-catenin pathway independent of H+/K+-ATPase inhibition, and these findings may provide a novel insight into the pharmacological effects of PPIs with regard to alleviation of cardiac remodelling.

    更新日期:2019-12-19
  • Perinatal iron deficiency and a high salt diet cause long-term kidney mitochondrial dysfunction and oxidative stress
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-01-31
    Woodman A, Mah R, Keddie D, et al.

    AimsPerinatal iron deficiency (ID) alters developmental trajectories of offspring, predisposing them to cardiovascular dysfunction in later life. The mechanisms underlying this long-term programming of renal function have not been defined. We hypothesized perinatal ID causes hypertension and alters kidney metabolic function and morphology in a sex-dependent manner in adult offspring. Furthermore, we hypothesized these effects are exacerbated by chronic consumption of a high salt diet. Methods and resultsPregnant Sprague Dawley rats were fed either an iron-restricted or replete diet prior to and throughout pregnancy. Adult offspring were fed normal or high salt diets for 6 weeks prior to experimentation at 6 months of age. Blood pressure (BP) was assessed via indwelling catheters in anaesthetized offspring; kidney mitochondrial function was assessed via high-resolution respirometry; reactive oxygen species and nitric oxide were quantified via fluorescence microscopy. Adult males, but not females, exhibited increased systolic BP due to ID (P = 0.01) and high salt intake (P = 0.02). In males, but not in females, medullary mitochondrial content was increased by high salt (P = 0.003), while succinate-dependent respiration was reduced by ID (P < 0.05). The combination of perinatal ID and high salt reduced complex IV activity in the cortex of males (P = 0.01). Perinatal ID increased cytosolic superoxide generation (P < 0.001) concomitant with reduced nitric oxide bioavailability (P < 0.001) in male offspring, while high salt increased mitochondrial superoxide in the medulla (P = 0.04) and cytosolic superoxide within the cortex (P = 0.01). Male offspring exhibited glomerular basement membrane thickening (P < 0.05), increased collagen deposition (P < 0.05), and glomerular hypertrophy (interaction, P = 0.02) due to both perinatal ID and high salt. Female offspring exhibited no alterations in mitochondrial function or morphology due to either high salt or ID. ConclusionPerinatal ID causes long-term sex-dependent alterations in renal metabolic function and morphology, potentially contributing to hypertension and increased cardiovascular disease risk.

    更新日期:2019-12-19
  • Successful renal denervation decreases the platelet activation status in hypertensive patients
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-02-04
    Zaldivia M, Hering D, Marusic P, et al.

    AimsTo determine whether renal denervation (RDN) in hypertensive patients affects the platelet activation status. Methods and resultsWe investigated the effect of RDN on the platelet activation status in 41 hypertensive patients undergoing RDN. Ambulatory blood pressure (BP), plasma sympathetic neurotransmitter Neuropeptide Y, and platelet activation markers were measured at baseline, at 3 months, and 6 months after RDN. RDN significantly decreased BP at 3 months (150.6 ± 11.3/80.9 ± 11.4 mmHg to 144.7 ± 12.0/77.1 ± 11.1 mmHg; P < 0.01) and at 6 months (144.3 ± 13.8/78.3 ± 11.1 mmHg; P < 0.01). Plasma levels of the sympathetic neurotransmitter Neuropeptide Y, an indicator of sympathetic nerve activity, were significantly decreased at 3 months (0.29 ± 0.11 ng/mL to 0.23 ± 0.11 ng/mL; P < 0.0001) and at 6 months (0.22 ± 0.12 ng/mL; P < 0.001) after RDN. This was associated with a reduction in platelet membrane P-selectin expression (3 months, P < 0.05; 6 months, P < 0.05), soluble P-selectin (6 months, P < 0.05), circulating numbers of platelet-derived extracellular vesicles (EVs) (3 months, P < 0.001; 6 months, P < 0.01), and phosphatidylserine expressing EVs (3 months, P < 0.001; 6 months, P < 0.0001), indicative of a reduction in platelet activation status and procoagulant activity. Only patients who responded to RDN with a BP reduction showed inhibition of P-selectin expression at 3 months (P < 0.05) and 6 months (P < 0.05) as well as reduction of glycoprotein IIb/IIIa activation at 3 months (P < 0.05). Notably, 13 patients who took aspirin did not show significant reduction in platelet P-selectin expression following RDN. ConclusionOur results imply a connection between the sympathetic nervous system and the platelet activation status and provide a potential mechanistic explanation by which RDN can have favourable effects towards reducing cardiovascular complications.

    更新日期:2019-12-19
  • PBI-4050 reduces pulmonary hypertension, lung fibrosis, and right ventricular dysfunction in heart failure
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-02-07
    Nguyen Q, Nsaibia M, Sirois M, et al.

    AimsHeart failure with reduced ejection fraction (HFrEF) causes lung remodelling with myofibroblasts proliferation and fibrosis leading to a restrictive lung syndrome with pulmonary hypertension (PH) and right ventricular (RV) dysfunction. PBI-4050 is a first-in-class anti-fibrotic, anti-inflammatory, and anti-proliferative compound. The present study evaluated the therapeutic impact of PBI-4050 on PH in an HFrEF model. Methods and resultsHFrEF was induced after myocardial infarction (MI) in rats. Two weeks later, sham-operated and MI groups received PBI-4050 (200 mg/kg/day by gavage) or saline for 3 weeks. Animals were analysed according to infarct size as large (≥30% left ventricle) or medium MI (<30%). Large MI caused PH and RV hypertrophy (RVH) with a restrictive lung syndrome. PBI-4050 did not adversely affect left ventricular (LV) function but markedly reduced PH and RVH and improved RV dysfunction. PBI-4050 reduced lung remodelling and improved respiratory compliance with decreased lung fibrosis, alveolar wall cellular proliferation and α-smooth muscle actin expression. The increased expression of endothelin-1 (ET-1), transforming growth factor beta (TGF-β), interleukin-6 (IL-6) and of tissue inhibitor of metalloprotease-1 in the lungs from HFrEF were reduced with PBI-4050 therapy. Activation of isolated human lung fibroblasts (HLFs) to a myofibroblastic pro-fibrogenic phenotype was markedly reduced by PBI-4050. The fatty acid receptor GPR84 was increased in HFrEF lungs and in activated HLFs, and reduced by PBI-4050. GPR84 agonists activated fibrogenesis in HLFs and finally, PBI-4050 reduced ERK1/2 phosphorylation. ConclusionsPBI-4050 reduces PH and RVH in HFrEF by decreasing lung fibrosis and remodelling. This novel agent decreases the associated restrictive lung syndrome and recovers RV function. A contributing mechanism involves reducing the activation of lung fibroblasts by IL-6, TGF-β, and ET-1 by antagonism of GPR84 and reduced ERK1/2 phosphorylation. PBI-4050 is a novel promising therapy for targeting lung remodelling in group II PH.

    更新日期:2019-12-19
  • Stretching single titin molecules from failing human hearts reveals titin’s role in blunting cardiac kinetic reserve
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-02-18
    Chen M, Kiduko S, Saad N, et al.

    AimsHeart failure (HF) patients commonly experience symptoms primarily during elevated heart rates, as a result of physical activities or stress. A main determinant of diastolic passive tension, the elastic sarcomeric protein titin, has been shown to be associated with HF, with unresolved involvement regarding its role at different heart rates. To determine whether titin is playing a role in the heart rate (frequency-) dependent acceleration of relaxation (FDAR). W, we studied the FDAR responses in live human left ventricular cardiomyocytes and the corresponding titin-based passive tension (TPT) from failing and non-failing human hearts. Methods and resultsUsing atomic force, we developed a novel single-molecule force spectroscopy approach to detect TPT based on the frequency-modulated cardiac cycle. Mean TPT reduced upon an increased heart rate in non-failing human hearts, while this reduction was significantly blunted in failing human hearts. These mechanical changes in the titin distal Ig domain significantly correlated with the frequency-dependent relaxation kinetics of human cardiomyocytes obtained from the corresponding hearts. Furthermore, the data suggested that the higher the TPT, the faster the cardiomyocytes relaxed, but the lower the potential of myocytes to speed up relaxation at a higher heart rate. Such poorer FDAR response was also associated with a lesser reduction or a bigger increase in TPT upon elevated heart rate. ConclusionsOur study established a novel approach in detecting dynamic heart rate relevant tension changes physiologically on native titin domains. Using this approach, the data suggested that the regulation of kinetic reserve in cardiac relaxation and its pathological changes were associated with the intensity and dynamic changes of passive tension by titin.

    更新日期:2019-12-19
  • Focal TLR4 activation mediates disturbed flow-induced endothelial inflammation
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-02-20
    Qu D, Wang L, Huo M, et al.

    AimsDisturbed blood flow at arterial branches and curvatures modulates endothelial function and predisposes the region to endothelial inflammation and subsequent development of atherosclerotic lesions. Activation of the endothelial Toll-like receptors (TLRs), in particular TLR4, contributes to vascular inflammation. Therefore, we investigate whether TLR4 can sense disturbed flow (DF) to mediate the subsequent endothelial inflammation. Methods and resultsEn face staining of endothelium revealed that TLR4 expression, activation, and its downstream inflammatory markers were elevated in mouse aortic arch compared with thoracic aorta, which were absent in Tlr4mut mice. Similar results were observed in the partial carotid ligation model where TLR4 signalling was activated in response to ligation-induced flow disturbance in mouse carotid arteries, and such effect was attenuated in Tlr4mut mice. DF in vitro increased TLR4 expression and activation in human endothelial cells (ECs) and promoted monocyte-EC adhesion, which were inhibited in TLR4-knockdown ECs. Among endogenous TLR4 ligands examined as candidate mediators of DF-induced TLR4 activation, fibronectin containing the extra domain A (FN-EDA) expressed by ECs was increased by DF and was revealed to directly interact with and activate TLR4. ConclusionOur findings demonstrate the indispensable role of TLR4 in DF-induced endothelial inflammation and pinpoint FN-EDA as the endogenous TLR4 activator in this scenario. This novel mechanism of vascular inflammation under DF condition may serve as a critical initiating step in atherogenesis.

    更新日期:2019-12-19
  • Epidermal growth factor-like repeats of SCUBE1 derived from platelets are critical for thrombus formation
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-03-01
    Liao W, Wu M, Peng C, et al.

    AimsSCUBE1 [signal peptide-CUB-epidermal growth factor (EGF) domain-containing protein 1], expressed in endothelial cells (ECs) and platelets, exists in soluble or membrane forms. We previously showed that soluble SCUBE1 is a biomarker for platelet activation and also an active participant of thrombosis. However, whether the adhesive module of its EGF-like repeats is essential and the specific contribution of SCUBE1 synthesized in ECs or platelets to thrombosis in vivo remain unclear. Methods and resultsWe generated new mutant (Δ2) mice lacking the entire EGF-like repeats to evaluate the module’s functional importance during thrombogenesis in vivo. The Δ2 platelet-rich plasma showed markedly impaired platelet aggregation induced by agonists including adenosine diphosphate, collagen, the thrombin agonist PAR-4 peptide and the thromboxane A2 analogue U46619. Consistently, genetic ablation of the EGF-like repeats diminished arterial thrombosis and protected Δ2 mice against lethal thromboembolism. On flow chamber assay, whole blood isolated from Δ2 or wild-type (WT) mice pre-treated with blocking antibodies against the EGF-like repeats showed a significant decrease in platelet deposition and thrombus formation on collagen-coated surfaces under arterial shear rates. Moreover, we created animals expressing SCUBE1 only in ECs (S1-EC) or platelets (S1-PLT) by reciprocal bone-marrow transplantation between WT and Δ2 mice. The time of carotid arterial thrombosis induced by ferric chloride was normal in S1-PLT chimeric mice but much prolonged in S1-EC animals. ConclusionsWe demonstrate that platelet-derived SCUBE1 plays a critical role in arterial thrombosis via its adhesive EGF-like repeats in vivo and suggest targeting these adhesive motifs of SCUBE1 for potential anti-thrombotic strategy.

    更新日期:2019-12-19
  • Macrophage-derived MMP-8 determines smooth muscle cell differentiation from adventitia stem/progenitor cells and promotes neointima hyperplasia
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-03-07
    Yang F, Chen Q, Yang M, et al.

    AimsEmerging evidence has suggested that adventitia stem/progenitor cells (AdSPCs) migrate into the intima of arteries in response to injury, where they differentiate towards smooth muscle cells (SMCs) and participate in neointimal hyperplasia. We have previously identified matrix metalloproteinase-8 (MMP8) as a key player in atherogenesis. In this study, we aimed to investigate the functional roles of macrophage-derived MMP8 in AdSPC differentiation and injury-induced arterial remodelling. Methods and resultsWe first observed an important role for MMP8 in SMC differentiation from embryonic stem cells, but this effect was not seen in AdSPCs. Instead, through macrophages/AdSPCs co-culture and macrophage conditional culture medium studies, we have demonstrated that the MMP8 protein secreted from macrophages promotes SMC differentiation from AdSPCs. Mechanistically, we showed that macrophage-derived MMP8 promotes SMC differentiation from AdSPCs through modulating transforming growth factor-β activity and a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10)/Notch1 signalling. We further demonstrated that the binding site for CBF1, Suppressor of Hairless, and Lag-1 (CSL) within SMC gene promoters is responsible for Notch1 mediated SMC differentiation. Finally, we demonstrated that macrophage-derived MMP8 increased injury-induced neointimal SMC hyperplasia by activating ADAM10/Notch1 signalling. ConclusionsWe have identified macrophage-derived MMP8 as a regulator in SMC differentiation from AdSPCs and neointimal SMC hyperplasia in response to injury. Our data provide new insights into the roles of MMP8 in AdSPC differentiation and the pathogenesis of neointima formation in the context of angiographic restenosis, and therefore may aid in the development of novel therapeutic agents for the prevention of this disease.

    更新日期:2019-12-19
  • Sialyltransferase7A promotes angiotensin II-induced cardiomyocyte hypertrophy via HIF-1α-TAK1 signalling pathway
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-03-11
    Yan X, Zhao R, Feng X, et al.

    AimsSialylation is up-regulated during the development of cardiac hypertrophy. Sialyltransferase7A (Siat7A) mRNA is consistently over-expressed in the hypertrophic left ventricle of hypertensive rats independently of genetic background. The aims of this study were: (i) to detect the Siat7A protein levels and its roles in the pathological cardiomyocyte hypertrophy; (ii) to elucidate the effect of sialylation mediated by Siat7A on the transforming-growth-factor-β-activated kinase (TAK1) expression and activity in cardiomyocyte hypertrophy; and (iii) to clarify hypoxia-inducible factor 1 (HIF-1) expression was regulated by Siat7A and transactivated TAK1 expression in cardiomyocyte hypertrophy. Methods and resultsSiat7A protein level was increased in hypertrophic cardiomyocytes of human and rats subjected to chronic infusion of angiotensin II (ANG II). Delivery of adeno-associated viral (AAV9) bearing shRNA against rat Siat7A into the left ventricular wall inhibited ventricular hypertrophy. Cardiac-specific Siat7A overexpression via intravenous injection of an AAV9 vector encoding Siat7A under the cardiac troponin T (cTNT) promoter aggravated cardiac hypertrophy in ANG II-treated rats. In vitro, Siat7A knockdown inhibited the induction of Sialyl-Tn (sTn) antigen and cardiomyocyte hypertrophy stimulated by ANG II. Mechanistically, ANG II induced the activation of TAK1-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling in parallel to up-regulation of Siat7A in hypertrophic cardiomyocytes. Siat7A knockdown inhibited activation of TAK1-NF-κB pathway. Interestingly, HIF-1α expression was increased in cardiomyocytes stimulated by ANG II but decreased after Siat7A knockdown. HIF-1α knockdown efficiently decreased TAK1 expression. ChIP and luciferase assays showed that HIF-1α transactivated the TAK1 promoter region (nt −1285 to −1274 bp) in the cardiomyocytes following ANG II stimulus. ConclusionSiat7A was up-regulated in hypertrophic myocardium and promoted cardiomyocyte hypertrophy via activation of the HIF-1α-TAK1-NF-κB pathway.

    更新日期:2019-12-19
  • Carbon monoxide improves haemodynamics during extracorporeal resuscitation in pigs
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-03-14
    Wollborn J, Steiger C, Ruetten E, et al.

    AimsHeart disease of different aetiology remains the leading cause of cardiac arrest (CA). Despite efforts to improve the quality of cardiopulmonary resuscitation (CPR), subsequent myocardial and systemic damage after CA still present a major long-term burden. Low-dose carbon monoxide (CO) is known to exert protective effects in cardiovascular pathophysiology but clinical applications are challenged by unfavourable delivery modes. We tested the hypothesis that extracorporeal resuscitation (E-CPR) in combination with controlled fast onset CO delivery results in improved cardiac physiology and haemodynamics. Damage-associated molecular pattern (DAMP) signalling may be part of the molecular mechanism. Methods and resultsIn an established porcine model, E-CPR was performed. While E-CPR leads to similar results as compared to a conventional CPR strategy, CO delivery in combination with E-CPR demonstrated significant cardioprotection. Cardiac performance analysis using echocardiography and thermodilution techniques showed a CO-dependent improved cardiac function compared to severe myocardial dysfunction in CPR and E-CPR (left ventricular ejection fraction: Sham 49 ± 5; CPR 26 ± 2; E-CPR 25 ± 2; CO-E-CPR 31 ± 4; P < 0.05). While sublingual microcirculation was significantly compromised in CPR and E-CPR, CO delivery demonstrated a significant improvement in microvascular function (microvascular flow index: Sham 2.9 ± 0.1; CPR 2.2 ± 0.1; E-CPR 1.8 ± 0.1; CO-E-CPR 2.7 ± 0.1; P < 0.01). Histological and serological myocardial damage markers were significantly reduced (hsTroponin-T Sham 0.01 ± 0.001; CPR 1.9 ± 0.2; E-CPR 3.5 ± 1.2; CO-E-CPR 0.5 ± 0.2 ng/mL; P < 0.05). DAMP signalling was decreased ipse facto leading to influence of cardioprotective heat shock and cyclooxygenase response. ConclusionsCO treatment restores myocardial function and improves systemic macro- and microhaemodynamics in E-CPR through a reduction in DAMPs.

    更新日期:2019-12-19
  • Adipolin/CTRP12 protects against pathological vascular remodelling through suppression of smooth muscle cell growth and macrophage inflammatory response
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-03-15
    Ogawa H, Ohashi K, Ito M, et al.

    AimsSecreted factors produced by adipose tissue are involved in the pathogenesis of cardiovascular disease. We previously identified adipolin, also known as C1q/TNF-related protein 12, as an insulin-sensitizing adipokine. However, the role of adipolin in vascular disease remains unknown. Here, we investigated whether adipolin modulates pathological vascular remodelling. Methods and resultsAdipolin-knockout (APL-KO) and wild-type (WT) mice were subjected to wire-induced injury of the femoral artery. APL-KO mice showed increased neointimal thickening after vascular injury compared with WT mice, which was accompanied by an enhanced inflammatory response and vascular cell proliferation in injured arteries. Adipolin deficiency also led to a reduction in transforming growth factor-β (TGF-β) 1 protein levels in injured arteries. Treatment of cultured macrophages with adipolin protein led to a reduction in lipopolysaccharide-stimulated expression of inflammatory mediators, including tumour necrosis factor (TNF)-α, interleukin (IL) 6, and monocyte chemotactic protein (MCP)-1. These effects were reversed by inhibition of TGF-β receptor II (TGF-βRII)/Smad2 signalling. Adipolin also reduced platelet-derived growth factor (PDGF)-BB-stimulated proliferation of vascular smooth muscle cells (VSMCs) through a TGF-βRII/Smad2-dependent pathway. Furthermore, adipolin treatment significantly increased TGF-β1 concentration in media from cultured VSMCs and macrophages. ConclusionThese data indicate that adipolin protects against the development of pathological vascular remodelling by attenuating macrophage inflammatory responses and VSMC proliferation.

    更新日期:2019-12-19
  • Coupling of the Na+/K+-ATPase to Ankyrin B controls Na+/Ca2+ exchanger activity in cardiomyocytes
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-04-05
    Skogestad J, Aronsen J, Tovsrud N, et al.

    AimsAnkyrin B (AnkB) is an adaptor protein that assembles Na+/K+-ATPase (NKA) and Na+/Ca2+ exchanger (NCX) in the AnkB macromolecular complex. Loss-of-function mutations in AnkB cause the AnkB syndrome in humans, characterized by ventricular arrhythmias and sudden cardiac death. It is unclear to what extent NKA binding to AnkB allows regulation of local Na+ and Ca2+ domains and hence NCX activity. Methods and resultsTo investigate the role of NKA binding to AnkB in cardiomyocytes, we synthesized a disruptor peptide (MAB peptide) and its AnkB binding ability was verified by pulldown experiments. As opposed to control, the correlation between NKA and NCX currents was abolished in adult rat ventricular myocytes dialyzed with MAB peptide, as well as in cardiomyocytes from AnkB+/− mice. Disruption of NKA from AnkB (with MAB peptide) increased NCX-sensed cytosolic Na+ concentration, reduced Ca2+ extrusion through NCX, and increased frequency of Ca2+ sparks and Ca2+ waves without concomitant increase in Ca2+ transient amplitude or SR Ca2+ load, suggesting an effect in local Ca2+ domains. Selective inhibition of the NKAα2 isoform abolished both the correlation between NKA and NCX currents and the increased rate of Ca2+ sparks and waves following NKA/AnkB disruption, suggesting that an AnkB/NKAα2/NCX domain controls Ca2+ fluxes in cardiomyocytes. ConclusionNKA binding to AnkB allows ion regulation in a local domain, and acute disruption of the NKA/AnkB interaction using disruptor peptides lead to increased rate of Ca2+ sparks and waves. The functional effects were mediated through the NKAα2 isoform. Disruption of the AnkB/NKA/NCX domain could be an important pathophysiological mechanism in the AnkB syndrome.

    更新日期:2019-12-19
  • Genome-wide association study identifies locus at chromosome 2q32.1 associated with syncope and collapse
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-05-03
    Hadji-Turdeghal K, Andreasen L, Hagen C, et al.

    AimsSyncope is a common condition associated with frequent hospitalization or visits to the emergency department. Family aggregation and twin studies have shown that syncope has a heritable component. We investigated whether common genetic variants predispose to syncope and collapse. Methods and resultsWe used genome-wide association data on syncope on 408 961 individuals with European ancestry from the UK Biobank study. In a replication study, we used the Integrative Psychiatric Research Consortium (iPSYCH) cohort (n = 86 189), to investigate the risk of incident syncope stratified by genotype carrier status. We report on a genome-wide significant locus located on chromosome 2q32.1 [odds ratio = 1.13, 95% confidence interval (CI) 1.10–1.17, P = 5.8 × 10−15], with lead single nucleotide polymorphism rs12465214 in proximity to the gene zinc finger protein 804a (ZNF804A). This association was also shown in the iPSYCH cohort, where homozygous carriers of the C allele conferred an increased hazard ratio (1.30, 95% CI 1.15–1.46, P = 1.68 × 10−5) of incident syncope. Quantitative polymerase chain reaction analysis showed ZNF804A to be expressed most abundantly in brain tissue. ConclusionWe identified a genome-wide significant locus (rs12465214) associated with syncope and collapse. The association was replicated in an independent cohort. This is the first genome-wide association study to associate a locus with syncope and collapse.

    更新日期:2019-12-19
  • High-sensitivity C-reactive protein in chronic heart failure: patient characteristics, phenotypes, and mode of death
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-07-26
    Pellicori P, Zhang J, Cuthbert J, et al.

    AimsPlasma concentrations of high-sensitivity C-reactive protein (hsCRP) are often raised in chronic heart failure (CHF) and might indicate inflammatory processes that could be a therapeutic target. We aimed to study the associations between hsCRP, mode and cause of death in patients with CHF. Methods and resultsWe enrolled 4423 patients referred to a heart failure clinic serving a local population. CHF was defined as relevant symptoms or signs with either a reduced left ventricular ejection fraction <40% or raised plasma concentrations of amino-terminal pro-B type natriuretic peptide (NT-proBNP >125 pg/mL). The median [interquartile range (IQR)] plasma hsCRP for patients diagnosed with CHF (n = 3756) was 3.9 (1.6–8.5) mg/L and 2.7 (1.3–5.1) mg/L for those who were not (n = 667; P < 0.001). Patients with hsCRP ≥10 mg/L (N = 809; 22%) were older and more congested than those with hsCRP <2 mg/L (N = 1117, 30%). During a median follow-up of 53 (IQR 28–93) months, 1784 (48%) patients with CHF died. Higher plasma hsCRP was associated with greater mortality, independent of age, symptom severity, creatinine, and NT-proBNP. Comparing a hsCRP ≥10 mg/L to <2 mg/L, the hazard ratio for all-cause mortality was 2.49 (95% confidence interval 2.19–2.84; P < 0.001), for cardiovascular (CV) mortality was 2.26 (1.91–2.68; P < 0.001), and for non-CV mortality was 2.96 (2.40–3.65; P < 0.001). ConclusionIn patients with CHF, a raised plasma hsCRP is associated with more congestion and a worse prognosis. The proportion of deaths that are non-CV also increases with higher hsCRP.

    更新日期:2019-12-19
  • Statistics on mortality following acute myocardial infarction in 842 897 Europeans
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-07-26
    Alabas O, Jernberg T, Pujades-Rodriguez M, et al.

    AimsTo compare ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) mortality between Sweden and the UK, adjusting for background population rates of expected death, case mix, and treatments. Methods and resultsNational data were collected from hospitals in Sweden [n = 73 hospitals, 180 368 patients, Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART)] and the UK [n = 247, 662 529 patients, Myocardial Ischaemia National Audit Project (MINAP)] between 2003 and 2013. There were lower rates of revascularization [STEMI (43.8% vs. 74.9%); NSTEMI (27.5% vs. 43.6%)] and pharmacotherapies at time of hospital discharge including [aspirin (82.9% vs. 90.2%) and (79.9% vs. 88.0%), β-blockers (73.4% vs. 86.4%) and (65.3% vs. 85.1%)] in the UK compared with Sweden, respectively. Standardized net probability of death (NPD) between admission and 1 month was higher in the UK for STEMI [8.0 (95% confidence interval 7.4–8.5) vs. 6.7 (6.5–6.9)] and NSTEMI [6.8 (6.4–7.2) vs. 4.9 (4.7–5.0)]. Between 6 months and 1 year and more than 1 year, NPD remained higher in the UK for NSTEMI [2.9 (2.5–3.3) vs. 2.3 (2.2–2.5)] and [21.4 (20.0–22.8) vs. 18.3 (17.6–19.0)], but was similar for STEMI [0.7 (0.4–1.0) vs. 0.9 (0.7–1.0)] and [8.4 (6.7–10.1) vs. 8.3 (7.5–9.1)]. ConclusionShort-term mortality following STEMI and NSTEMI was higher in the UK compared with Sweden. Mid- and longer-term mortality remained higher in the UK for NSTEMI but was similar for STEMI. Differences in mortality may be due to differential use of guideline-indicated treatments.

    更新日期:2019-12-19
  • Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides, and oxidation of protein kinase G1α redox signalling
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-08-01
    Feelisch M, Akaike T, Griffiths K, et al.

    AimsUnder hypoxic conditions, nitrite (NO2−) can be reduced to nitric oxide (NO) eliciting vasorelaxation. However, nitrite also exerts vasorelaxant effects of potential therapeutic relevance under normal physiological conditions via undetermined mechanisms. We, therefore, sought to investigate the mechanism(s) by which nitrite regulates the vascular system in normoxia and, specifically, whether the biological effects are a result of NO generation (as in hypoxia) or mediated via alternative mechanisms involving classical downstream targets of NO [e.g. effects on protein kinase G1α (PKG1α)]. Methods and resultsEx vivo myography revealed that, unlike in thoracic aorta (conduit vessels), the vasorelaxant effects of nitrite in mesenteric resistance vessels from wild-type (WT) mice were NO-independent. Oxidants such as H2O2 promote disulfide formation of PKG1α, resulting in NO- cyclic guanosine monophosphate (cGMP) independent kinase activation. To explore whether the microvascular effects of nitrite were associated with PKG1α oxidation, we used a Cys42Ser PKG1α knock-in (C42S PKG1α KI; ‘redox-dead’) mouse that cannot transduce oxidant signals. Resistance vessels from these C42S PKG1α KI mice were markedly less responsive to nitrite-induced vasodilation. Intraperitoneal (i.p.) bolus application of nitrite in conscious WT mice induced a rapid yet transient increase in plasma nitrite and cGMP concentrations followed by prolonged hypotensive effects, as assessed using in vivo telemetry. In the C42S PKG1α KI mice, the blood pressure lowering effects of nitrite were lower compared to WT. Increased H2O2 concentrations were detected in WT resistance vessel tissue challenged with nitrite. Consistent with this, increased cysteine and glutathione persulfide levels were detected in these vessels by mass spectrometry, matching the temporal profile of nitrite’s effects on H2O2 and blood pressure. ConclusionUnder physiological conditions, nitrite induces a delayed and long-lasting blood pressure lowering effect, which is NO-independent and occurs via a new redox mechanism involving H2O2, persulfides, and PKG1α oxidation/activation. Targeting this novel pathway may provide new prospects for anti-hypertensive therapy.

    更新日期:2019-12-19
  • A plasma proteogenomic signature for fibromuscular dysplasia
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-08-19
    Olin J, Di Narzo A, d’Escamard V, et al.

    AimsFibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test. Methods and resultsFemales with ‘multifocal’ FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%. ConclusionFMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.

    更新日期:2019-12-19
  • Palliative care for people living with heart failure: European Association for Palliative Care Task Force expert position statement
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-08-29
    Sobanski P, Alt-Epping B, Currow D, et al.

    Contrary to common perception, modern palliative care (PC) is applicable to all people with an incurable disease, not only cancer. PC is appropriate at every stage of disease progression, when PC needs emerge. These needs can be of physical, emotional, social, or spiritual nature. This document encourages the use of validated assessment tools to recognize such needs and ascertain efficacy of management. PC interventions should be provided alongside cardiologic management. Treating breathlessness is more effective, when cardiologic management is supported by PC interventions. Treating other symptoms like pain or depression requires predominantly PC interventions. Advance Care Planning aims to ensure that the future treatment and care the person receives is concordant with their personal values and goals, even after losing decision-making capacity. It should include also disease specific aspects, such as modification of implantable device activity at the end of life. The Whole Person Care concept describes the inseparability of the physical, emotional, and spiritual dimensions of the human being. Addressing psychological and spiritual needs, together with medical treatment, maintains personal integrity and promotes emotional healing. Most PC concerns can be addressed by the usual care team, supported by a PC specialist if needed. During dying, the persons’ needs may change dynamically and intensive PC is often required. Following the death of a person, bereavement services benefit loved ones. The authors conclude that the inclusion of PC within the regular clinical framework for people with heart failure results in a substantial improvement in quality of life as well as comfort and dignity whilst dying.

    更新日期:2019-12-19
  • Periodontitis is associated with hypertension: a systematic review and meta-analysis
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-09-24
    Muñoz Aguilera E, Suvan J, Buti J, et al.

    Recent evidence suggests a link between periodontitis (PD) and hypertension, but the nature of this association remains unclear. The overall aim of this review was to critically appraise the evidence linking these two common disorders. Systematic search was conducted for studies published up to December 2018. Prevalence of hypertension in patients with PD (moderate/severe groups) vs. those without PD (non-PD) was the primary outcome. Additional outcomes included adjusted mean difference in systolic (SBP) and diastolic (DBP) blood pressure (BP) levels in PD vs. non-PD, assessment of biomarkers in PD and hypertension, and BP changes after periodontal therapy. From 81 studies selected, 40 were included in quantitative meta-analyses. Diagnoses of moderate-severe PD [odds ratio (OR) = 1.22; 95% confidence interval (CI): 1.10–1.35] and severe PD (OR = 1.49; 95% CI: 1.09–2.05) were associated with hypertension. Prospective studies confirmed PD diagnosis increased likelihood of hypertension occurrence (OR = 1.68; 95% CI: 0.85–3.35). Patients with PD exhibited higher mean SBP [weighted mean difference (WMD) of 4.49 mmHg; 95% CI: 2.88–6.11] and DBP (2.03 mmHg; 95% CI: 1.25–2.81) when compared with non-PD. Lastly, only 5 out of 12 interventional studies confirmed a reduction in BP following periodontal therapy, ranging from 3 to 12.5 mmHg of SBP and from 0 to 10 mmHg of DBP. PD is associated with increased odds of hypertension (SORT C) and higher SBP/DBP levels. The evidence suggesting that PD therapy could reduce BP is inconclusive. Although additional research is warranted on this association, these results suggest that oral health assessment and management of PD could not only improve oral/overall health and quality of life but also be of relevance in the management of patients with hypertension.

    更新日期:2019-12-19
  • New insight sheds light as to how nitrite might reduce blood pressure height: is this alright?
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-10-09
    Van Beusecum J, Harrison D.

    This editorial refers to ‘Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides, and oxidation of protein kinase G1α redox signalling’, by M. Feelisch et al., pp. 51–62.

    更新日期:2019-12-19
  • The enigma of anti-inflammatory therapy for the management of heart failure
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-10-30
    Sack M.

    This editorial refers to ‘High sensitivity C-reactive protein in chronic heart failure: patient characteristics, phenotypes and mode of death’, by P. Pellicori et al., pp. 91–100.

    更新日期:2019-12-19
  • Cardiovascular risk of electronic cigarettes: a review of preclinical and clinical studies
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-11-07
    Buchanan N, Grimmer J, Tanwar V, et al.

    Cigarette smoking is the most preventable risk factor related to cardiovascular morbidity and mortality. Tobacco usage has declined in recent years; however, the use of alternative nicotine delivery methods, particularly e-cigarettes, has increased exponentially despite limited data on their short- and long-term safety and efficacy. Due to their unique properties, the impact of e-cigarettes on cardiovascular physiology is not fully known. Here, we summarize both preclinical and clinical data extracted from short- and long-term studies on the cardiovascular effects of e-cigarette use. Current findings support that e-cigarettes are not a harm-free alternative to tobacco smoke. However, the data are primarily derived from acute studies. The impact of chronic e-cigarette exposure is essentially unstudied. To explore the uniqueness of e-cigarettes, we contemplate the cardiovascular effects of individual e-cigarette constituents. Overall, data suggest that exposure to e-cigarettes could be a potential cardiovascular health concern. Further preclinical research and randomized trials are needed to expand basic and clinical investigations before considering e-cigarettes safe alternatives to conventional cigarettes.

    更新日期:2019-12-19
  • Multi-omics applied to fibromuscular dysplasia: first steps on a new research avenue
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-11-11
    Bruno R, Mischak H, Persu A.

    This editorial refers to ‘A plasma proteogenomic signature for fibromuscular dysplasia’, by J.W. Olin et al., pp. 63–77.

    更新日期:2019-12-19
  • Cardiovascular research highlights from the UK Biobank: opportunities and challenges
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-11-28
    Raisi-Estabragh Z, Petersen S.

    UK BiobankBig dataEpidemiologyCardiovascular disease

    更新日期:2019-12-19
  • Minding the gaps in post-myocardial infarction mortality between Sweden and the UK
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-11-28
    Peterson B, Bhatt D.

    This editorial refers to ‘Statistics on mortality following acute myocardial infarction in 842897 Europeans’, by O.A. Alabas et al., pp. 149–157.

    更新日期:2019-12-19
  • Scientific highlights from the Great Wall International Congress of Cardiology 2019
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-12-16
    Du J, Zhang J.

    ChinaCongressConferenceCardiology

    更新日期:2019-12-19
  • Scientists on the Spot: The complex inheritance of cardiac disorders
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-12-18
    Patel J, Bezzina C.

    Inherited cardiac arrhythmia syndromesSudden cardiac deathGenome-wide association studyPolygenic risk score

    更新日期:2019-12-19
  • ‘Veni, Vidi, Vici’: how to arm your troops in the battlefield of cardiac repair
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-12-18
    Bollini S.

    ExosomesCardiac repairFibrosisCAR-T cellActivate myofibroblast

    更新日期:2019-12-19
  • Highlights of AHA Scientific Sessions 2019: novel approaches in cardiovascular risk reduction
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-12-18
    Akoumianakis I.

    American Heart AssociationCardiologyClinical trialsCardiovascular medicineCardiovascular research

    更新日期:2019-12-19
  • Is the glass half full or half empty after PARAGON-HF?
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-12-18
    Cohen-Solal A, Logeart D.

    HFpEFSacubitril/valsartanPARAGONHeart failure

    更新日期:2019-12-19
  • The DAPA-HF trial marks the beginning of a new era in the treatment of heart failure with reduced ejection fraction
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-12-18
    Verma S.

    SGLT2 inhibitorHeart failureReduced ejection fraction

    更新日期:2019-12-19
  • The polarity protein Scrib limits atherosclerosis development in mice
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-04-05
    Schürmann C, Dienst F, Pálfi K, et al.

    AimsThe protein Scrib (Scribble 1) is known to control apico-basal polarity in epithelial cells. The role of polarity proteins in the vascular system remains poorly characterized; however, we previously reported that Scrib maintains the endothelial phenotype and directed migration. On this basis, we hypothesized that Scrib has anti-atherosclerotic functions. Methods and resultsTamoxifen-induced Scrib-knockout mice were crossed with ApoE−/− knockout mice and spontaneous atherosclerosis under high-fat diet (HFD), as well as accelerated atherosclerosis in response to partial carotid artery ligation and HFD, was induced. Deletion of Scrib resulted in increased atherosclerosis development in both models. Mechanistically, flow- as well as acetylcholine-induced endothelium-dependent relaxation and AKT phosphorylation was reduced by deletion of Scrib, whereas vascular permeability and leucocyte extravasation were increased after Scrib knockout. Scrib immune pull down in primary carotid endothelial cells and mass spectrometry identified Arhgef7 (Rho Guanine Nucleotide Exchange Factor 7, βPix) as interaction partner. Scrib or Arhgef7 down-regulation by siRNA reduced the endothelial barrier function in human umbilical vein endothelial cells. Gene expression analysis from murine samples and from human biobank material of carotid endarterectomies indicated that loss of Scrib resulted in endothelial dedifferentiation with a decreased expression of endothelial signature genes. ConclusionsBy maintaining a quiescent endothelial phenotype, the polarity protein Scrib elicits anti-atherosclerotic functions.

    更新日期:2019-11-22
  • Altered C10 domain in cardiac myosin binding protein-C results in hypertrophic cardiomyopathy
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-05-03
    Kuster D, Lynch T, IV, Barefield D, et al.

    AimsA 25-base pair deletion in the cardiac myosin binding protein-C (cMyBP-C) gene (MYBPC3), proposed to skip exon 33, modifies the C10 domain (cMyBP-CΔC10mut) and is associated with hypertrophic cardiomyopathy (HCM) and heart failure, affecting approximately 100 million South Asians. However, the molecular mechanisms underlying the pathogenicity of cMyBP-CΔC10mutin vivo are unknown. We hypothesized that expression of cMyBP-CΔC10mut exerts a poison polypeptide effect leading to improper assembly of cardiac sarcomeres and the development of HCM. Methods and resultsTo determine whether expression of cMyBP-CΔC10mut is sufficient to cause HCM and contractile dysfunction in vivo, we generated transgenic (TG) mice having cardiac-specific protein expression of cMyBP-CΔC10mut at approximately half the level of endogenous cMyBP-C. At 12 weeks of age, significant hypertrophy was observed in TG mice expressing cMyBP-CΔC10mut (heart weight/body weight ratio: 4.43 ± 0.11 mg/g non-transgenic (NTG) vs. 5.34 ± 0.25 mg/g cMyBP-CΔC10mut, P<0.05). Furthermore, haematoxylin and eosin, Masson’s trichrome staining, as well as second-harmonic generation imaging revealed the presence of significant fibrosis and a greater relative nuclear area in cMyBP-CΔC10mut hearts compared with NTG controls. M-mode echocardiography analysis revealed hypercontractile hearts (EF: 53.4%±2.9% NTG vs. 66.4% ± 4.7% cMyBP-CΔC10mut; P<0.05) and early diastolic dysfunction (E/E′: 28.7 ± 3.7 NTG vs. 46.3 ± 8.4 cMyBP-CΔC10mut; P<0.05), indicating the presence of an HCM phenotype. To assess whether these changes manifested at the myofilament level, contractile function of single skinned cardiomyocytes was measured. Preserved maximum force generation and increased Ca2+-sensitivity of force generation were observed in cardiomyocytes from cMyBP-CΔC10mut mice compared with NTG controls (EC50: 3.6 ± 0.02 µM NTG vs. 2.90 ± 0.01 µM cMyBP-CΔC10mut; P<0.0001). ConclusionExpression of cMyBP-C protein with a modified C10 domain is sufficient to cause contractile dysfunction and HCM in vivo.

    更新日期:2019-11-22
  • Targeting the highly abundant circular RNA circSlc8a1 in cardiomyocytes attenuates pressure overload induced hypertrophy
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-05-22
    Lim T, Aliwarga E, Luu T, et al.

    AimsWe and others have previously described the expression landscape of circular RNA (circRNA) in mouse and human hearts. However, the functional relevance of many of these abundantly expressed cardiomyocyte circRNA remains to be fully explored. Among the most abundant circRNA, one stems from the sodium-calcium exchanger gene, Slc8a1, exon 2 locus. Because of its very high abundance in cardiomyocytes we investigated the possible role of circSlc8a1 in the heart. Methods and resultsWe performed a miRNA screen using an array of 752 miRNAs with RNA recovered from a pull-down of endogenous cardiomyocyte circSlc8a1. MicroRNA-133a (miR-133a), with a prior well-recognized role in cardiac hypertrophy, was highly enriched in the fraction of circSlc8a1 pull-down (adjusted P-value < 0.001). We, therefore, followed-up validation of the functional interaction between circSlc8a1 and miR-133 using luciferase assays and reciprocal pull-down assays. In vivo, AAV9-mediated RNAi knockdown of circSlc8a1 attenuates cardiac hypertrophy from pressure-overload, whereas forced cardiomyocyte specific overexpression of circSlc8a1 resulted in heart failure. Molecular analyses showed targets of miR-133a including serum response factor (Srf), connective tissue growth factor (Ctgf), adrenoceptor beta 1 (Adrb1), and adenylate cyclase 6 (Adcy6) to be regulated by circSlc8a1-directed intervention of knockdown and overexpression. ConclusionIn summary, circSlc8a1 can function as an endogenous sponge for miR-133a in cardiomyocytes. We propose that circSlc8a1 may serve as a novel therapeutic target for cardiac hypertrophy.

    更新日期:2019-11-22
  • FoxO1 inhibits autophagosome-lysosome fusion leading to endothelial autophagic-apoptosis in diabetes
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-01-23
    Zhang H, Ge S, He K, et al.

    AimsInadequate autophagy contributed to endothelial dysfunction in diabetic patients. We aimed to investigate the relationship between inadequate autophagy and endothelial cells (ECs) apoptosis in diabetes and its underlying mechanism. Methods and resultsAortic intima and ECs were isolated from diabetic patients. Cultured human aortic endothelial cells (HAECs) were stimulated with advanced glycation end products (AGEs). The expression of autophagy and apoptosis-related proteins were determined by western blotting. Autophagosomes were observed by electron microscopy. The fusion of autophagosome and lysosomes was detected by immunofluorescence. Compared with non-diabetic subjects, the levels of LC3-II, p62, FoxO1, and Ac-FoxO1 were increased in ECs from diabetic patients, accompanied by the decreased expressions of Atg14, STX17, and co-localization of LC3-II/LAMP2 and Atg14/STX17. Long-term stimulation with AGEs up-regulated LC3-II and p62 expression and the number of autophagosomes with decreased level of Atg14, STX17, Ras-related protein 7 (Rab7), and co-localization of LC3-II/LAMP2 and Atg14/STX17 in HAECs. The apoptosis rates were increased with elevated cleaved-caspase-3 and declined Bcl-2 expression. Inhibition of autophagy with 3-methyladenine could reduce long-term AGEs-induced apoptosis. Higher levels of FoxO1, Ac-FoxO1, and Ac-FoxO1 binding to Atg7 were detected in AGEs-treated HAECs. AGEs-induced FoxO1 enhanced Akt activity, decreased SIRT1-deacetylase activity by phosphorylation and elevated Ac-FoxO1. Knockout of FoxO1 reduced AGEs-induced autophagy and promoted the expression of Atg14 and the co-localization of LC3-II/LAMP 2 and Atg14/STX17. ConclusionInadequate autophagy with impaired autophagosome-lysosomal fusion exists in aortic intima and ECs from diabetic patients. FoxO1 mediates AGEs-induced ECs autophagic apoptosis through impairing autophagosome-lysosomes fusion by inhibiting Atg14 expression.

    更新日期:2019-11-22
  • An N-/L-type calcium channel blocker, cilnidipine, suppresses autonomic, electrical, and structural remodelling associated with atrial fibrillation
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-05-22
    Tajiri K, Guichard J, Qi X, et al.

    AimsAutonomic dysfunction can promote atrial fibrillation (AF) and results from AF-related remodelling. N-type Ca2+-channels (NTCCs) at sympathetic nerve terminals mediate Ca2+-entry that triggers neurotransmitter release. AF-associated remodelling plays an important role in AF pathophysiology but the effects of NTCC inhibition on such remodelling is unknown. Here, we investigated the ability of a clinically available Ca2+-channel blocker (CCB) with NTCC-blocking activity to suppress the arrhythmogenic effects of AF-promoting remodelling in dogs. Methods and resultsMongrel dogs were kept in AF by right atrial tachypacing at 600 bpm. Four groups were studied under short-term AF (7 days): (i) Shams, instrumented but without tachypacing (n = 5); (ii) a placebo group, tachypaced while receiving placebo (n = 6); (iii) a control tachypacing group receiving nifedipine (10 mg orally twice-daily; n = 5), an L-type CCB; and (iv) a cilnidipine group, subjected to tachypacing and treatment with cilnidipine (10 mg orally twice-daily; n = 7), an N-/L-type CCB. With cilnidipine therapy, dogs with 1-week AF showed significantly reduced autonomic changes reflected by heart rate variability (decreases in RMSSD and pNN50) and plasma norepinephrine concentrations. In addition, cilnidipine-treated dogs had decreased extracellular matrix gene expression vs. nifedipine-dogs. As in previous work, atrial fibrosis had not yet developed after 1-week AF, so three additional groups were studied under longer-term AF (21 days): (i) Shams, instrumented without tachypacing or drug therapy (n = 8); (ii) a placebo group, tachypaced while receiving placebo (n = 8); (iii) a cilnidipine group, subjected to tachypacing during treatment with cilnidipine (10 mg twice-daily; n = 8). Cilnidipine attenuated 3-week AF effects on AF duration and atrial conduction, and suppressed AF-induced increases in fibrous-tissue content, decreases in connexin-43 expression and reductions in sodium-channel expression. ConclusionsCilnidipine, a commercially available NTCC-blocking drug, prevents AF-induced autonomic, electrical and structural remodelling, along with associated AF promotion.

    更新日期:2019-11-22
  • CircSlc8a1, breaking a vicious circle in cardiac hypertrophy
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-05-30
    Jahn C, Bär C, Thum T.

    This editorial refers to ‘Targeting the highly abundant circular RNA 1 circSlc8a1 in cardiomyocytes attenuates pressure overload induced hypertrophy’, by T.B. Lim et al., pp. 1998–2007.

    更新日期:2019-11-22
  • Frontiers in positron emission tomography imaging of the vulnerable atherosclerotic plaque
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-06-24
    MacAskill M, Newby D, Tavares A.

    Rupture of vulnerable atherosclerotic plaques leading to an atherothrombotic event is the primary driver of myocardial infarction and stroke. The ability to detect non-invasively the presence and evolution of vulnerable plaques could have a huge impact on the future identification and management of atherosclerotic cardiovascular disease. Positron emission tomography (PET) imaging with an appropriate radiotracer has the potential to achieve this goal. This review will discuss the biological hallmarks of plaque vulnerability before going on to evaluate and to present PET imaging approaches which target these processes. The focus of this review will be on techniques beyond [18F]FDG imaging, some of which are clinically advanced, and others which are on the horizon. As inflammation is the primary driving force behind atherosclerotic plaque development, we will predominantly focus on approaches which either directly, or indirectly, target this process.

    更新日期:2019-11-22
  • Myosin binding protein-C and hypertrophic cardiomyopathy: role of altered C10 domain
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-07-02
    Hossain M, Elbeck Z, Siga H, et al.

    This editorial refers to ‘Altered C10 domain in cardiac myosin binding protein-C results in hypertrophic cardiomyopathy’, by D.W.D. Kuster et al., pp. 1986–1997.

    更新日期:2019-11-22
  • SCRIBbling the role of endothelial polarity in atherosclerosis
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-07-04
    Donners M, Biessen E.

    This editorial refers to ‘The polarity protein Scrib limits atherosclerosis development in mice’, by C. Schürmann et al., pp. 1963–1974.

    更新日期:2019-11-22
  • Scientists on the Spot: non-coding RNAs and heart failure
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-10-09
    Antoniades C, Condorelli G.

    Watch the interview here: https://www.youtube.com/watch?v=JaXpCskCP5o.

    更新日期:2019-11-22
  • Why did remote ischaemic conditioning not improve clinical outcomes in acute myocardial infarction in the CONDI-2/ERIC-PPCI trial?
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-10-17
    Hausenloy D, Bøtker H.

    New treatments are needed to reduce myocardial infarct (MI) size and preserve left ventricular (LV) function, in order to improve clinical outcomes in patients presenting with acute ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PPCI).1 Remote ischaemic conditioning (RIC), in which brief cycles of ischaemia and reperfusion are applied to an organ or tissue (including a limb) away from the heart, has been shown to reduce MI size in animal models of acute myocardial ischaemia/reperfusion injury (IRI).2 The ability to deliver the cardioprotective RIC stimulus by simply inflating and deflating a pneumatic cuff placed on the upper arm or thigh, to induce brief cycles of ischaemia and reperfusion3 has facilitated the translation of RIC into the clinical setting.

    更新日期:2019-11-22
  • David Garcia-Dorado: a true pioneer in cardiac ischaemia/reperfusion injury
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-10-24
    Hausenloy D, Davidson S.

    Researchers in the field of cardiac ischaemia and reperfusion (IR) injury over the past 30 years will be very familiar with the name David Garcia-Dorado. Not only because of his tireless efforts as co-Editor-in-Chief (with Hans Michael Piper) of this journal but also due to his outstanding contributions to research and the cardiovascular research community. Together with Michael Piper, David spent 10 years at the helm of Cardiovascular Research, during a period of rapid change in the publication process. Meanwhile, he managed to continue a highly active research programme, publishing in total over 400 research articles, reviews, and letters throughout his career. Here, we would like to highlight some of David’s key research contributions to the field of cardiac IR injury, while of course also recognizing an excellent team of fellow researchers (not least, those of the Cardiology Department of which he was head, at Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, Spain) and collaborators who have contributed to the research we describe below.

    更新日期:2019-11-22
  • Biotin interference in high-sensitivity cardiac troponin T testing: a real-world evaluation in acute cardiac care
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-10-30
    Vroemen W, van Doorn W, Kimenai D, et al.

    The United States Food and Drug Administration recently issued a safety communication to warn for biotin interference in cardiac troponin assays.1 Cardiac troponins are the gold standard biomarkers for diagnosing acute myocardial infarction (AMI). Cardiac troponin concentrations can be falsely low in patients using dietary supplements containing high levels of biotin.1 Since the prevalence of dietary supplement intake is ≥30% in the USA and Europe, substantial clinical concern has risen that AMI might be missed.1,2 Analytical interference of biotin especially applies to cardiac troponin immunoassays exploiting the biotin–streptavidin interaction in the assay configuration.3 Therefore, we evaluated the real-world prevalence of biotin interference in high-sensitivity cardiac troponin T (hs-cTnT, Roche Diagnostics, Basel, Switzerland) testing in acute cardiac care.

    更新日期:2019-11-22
  • Emulating Leonardo da Vinci (1452–1519): the convergence of science and art in biomedical research and practice
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-10-31
    Pasipoularides A.

    Aristotelian cause-and-effectRenaissance medicineLeonardo, curious-polymathLeonardo's 4-chambered-heartVortices in valve-closureEmulating Leonardo

    更新日期:2019-11-22
  • Beyond beta-blockers: targeting the sympathetic nervous system for the prevention and treatment of atrial fibrillation
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-11-05
    Pfenniger A, Arora R.

    This editorial refers to ‘An N-/L-type calcium channel blocker, cilnidipine, suppresses autonomic, electrical, and structural remodelling associated with atrial fibrillation’, by K. Tajiri et al., pp. 1975–1985.

    更新日期:2019-11-22
  • A look back: diagnosing myocardial infarction in the era of high-sensitivity troponin after the High-STEACS trial
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-11-07
    Anand A, Mills N.

    High-sensitivity cardiac troponinMyocardial infarctionUniversal definition

    更新日期:2019-11-22
  • Forecasting the development of acute kidney injury using a recurrent neural network
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-11-07
    Kallenberger S, Schmidt C.

    Artificial intelligenceDeep learningRecurrent neural networkAcute kidney failureDisease prevention

    更新日期:2019-11-22
  • High impact Cardiovascular Research: beyond the heart and vessels
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-11-07
    Small H, Guzik T.

    Hot topicsImpact factorDiabetesNon-coding RNA

    更新日期:2019-11-22
  • A current understanding of drug-induced QT prolongation and its implications for anticancer therapy
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-01-23
    Roden D.

    The QT interval, a global index of ventricular repolarization, varies among individuals and is influenced by diverse physiologic and pathophysiologic stimuli such as gender, age, heart rate, electrolyte concentrations, concomitant cardiac disease, and other diseases such as diabetes. Many drugs produce a small but reproducible effect on QT interval but in rare instances this is exaggerated and marked QT prolongation can provoke the polymorphic ventricular tachycardia “torsades de pointes”, which can cause syncope or sudden cardiac death. The generally accepted common mechanism whereby drugs prolong QT is block of a key repolarizing potassium current in heart, IKr, generated by expression of KCNH2, also known as HERG. Thus, evaluation of the potential that a new drug entity may cause torsades de pointes has relied on exposure of normal volunteers or patients to drug at usual and high concentrations, and on assessment of IKr block in vitro. More recent work, focusing on anticancer drugs with QT prolonging liability, is defining new pathways whereby drugs can prolong QT. Notably, the in vitro effects of some tyrosine kinase inhibitors to prolong cardiac action potentials (the cellular correlate of QT) can be rescued by intracellular phosphatidylinositol 3,4,5-trisphosphate, the downstream effector of phosphoinositide 3-kinase. This finding supports a role for inhibition of this enzyme, either directly or by inhibition of upstream kinases, to prolong QT through mechanisms that are being worked out, but include enhanced inward “late” sodium current during the plateau of the action potential. The definition of non-IKr-dependent pathways to QT prolongation will be important for assessing risk, not only with anticancer therapies but also with other QT prolonging drugs and for generating a refined understanding how variable activity of intracellular signaling systems can modulate QT and associated arrhythmia risk.

    更新日期:2019-11-18
  • Circulating blood cells and extracellular vesicles in acute cardioprotection
    Cardiovasc. Res. (IF 7.014) Pub Date : 2019-12-24
    Davidson S, Andreadou I, Barile L, et al.

    During an ST-elevation myocardial infarction (STEMI), the myocardium undergoes a prolonged period of ischaemia. Reperfusion therapy is essential to minimize cardiac injury but can paradoxically cause further damage. Experimental procedures to limit ischaemia and reperfusion (IR) injury have tended to focus on the cardiomyocytes since they are crucial for cardiac function. However, there is increasing evidence that non-cardiomyocyte resident cells in the heart (as discussed in a separate review in this Spotlight series) as well as circulating cells and factors play important roles in this pathology. For example, erythrocytes, in addition to their main oxygen-ferrying role, can protect the heart from IR injury via the export of nitric oxide bioactivity. Platelets are well-known to be involved in haemostasis and thrombosis, but beyond these roles, they secrete numerous factors including sphingosine-1 phosphate (S1P), platelet activating factor, and cytokines that can all strongly influence the development of IR injury. This is particularly relevant given that most STEMI patients receive at least one type of platelet inhibitor. Moreover, there are large numbers of circulating vesicles in the blood, including microvesicles and exosomes, which can exert both beneficial and detrimental effects on IR injury. Some of these effects are mediated by the transfer of microRNA (miRNA) to the heart. Synthetic miRNA molecules may offer an alternative approach to limiting the response to IR injury. We discuss these and other circulating factors, focussing on potential therapeutic targets relevant to IR injury. Given the prevalence of comorbidities such as diabetes in the target patient population, their influence will also be discussed. This article is part of a Cardiovascular Research Spotlight Issue entitled ‘Cardioprotection Beyond the Cardiomyocyte’, and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

    更新日期:2019-11-18
  • GHSR Deficiency Exacerbates Cardiac Fibrosis: Role in Macrophage Inflammasome Activation and Myofibroblast Differentiation.
    Cardiovasc. Res. (IF 7.014) Pub Date : null
    Mo Wang,Lei Qian,Jing Li,Hao Ming,Li Fang,Yingjia Li,Man Zhang,Yaohua Xu,Yiqian Ban,Weizhen Zhang,Youyi Zhang,Yahan Liu,Nanping Wang

    AIMS Sustained activation of β-adrenergic signaling induces cardiac fibrosis, which marks progression to heart failure. GHSR (growth hormone secretagogue receptor) is the receptor for ghrelin, which is an orexigenic gastric hormone with newly defined cardiovascular effects. The present study determined the effects of GHSR deficiency in a mouse model of isoproterenol (ISO)-induced cardiac fibrosis and examined the underlying mechanism. METHODS AND RESULTS Histochemical studies showed that GHSR deficiency exacerbated cardiac fibrosis. Quantitative RT-PCR, western blotting and immunofluorescence staining demonstrated that cardiac fibroblasts isolated from GHSR-/- mice exhibited increased expression of marker genes for myofibroblast trans-differentiation (α-SMA, SM22, and calponin) upon Transforming growth factor-β (TGF-β) treatment compared to wild-type mice. RNA-Sequencing of heart transcriptomes revealed that differentially expressed genes in GHSR-/- hearts were enriched in such biological processes as extracellular matrix (ECM) organization, inflammatory response, lipid metabolism, cell cycle, migration and adhesion. Particularly, GHSR deficiency increased Wnt/β-catenin pathway activation in ISO-induced myocardial fibrosis. In addition, loss of GHSR in macrophages instigated inflammasome activation with increased cleavage and release of IL-18. CONCLUSIONS These results for the first time demonstrated that GHSR deficiency aggravated ISO-induced cardiac fibrosis, suggesting that GHSR was a potential target for the intervention of cardiac fibrosis. TRANSLATIONAL PERSPECTIVE We revealed a cardiac protective role of GHSR, a receptor for gastric hormone ghrelin. Our study provided a novel therapeutic strategy against cardiac fibrosis.

    更新日期:2019-11-01
  • Lipidomics links oxidized phosphatidylcholines and coronary arteritis in Kawasaki disease.
    Cardiovasc. Res. (IF 7.014) Pub Date : null
    Yasutaka Nakashima,Yasunari Sakai,Yumi Mizuno,Kenji Furuno,Keiichi Hirono,Shinichi Takatsuki,Hiroyuki Suzuki,Yoshihiro Onouchi,Tohru Kobayashi,Kazuhiro Tanabe,Kenji Hamase,Tomofumi Miyamoto,Ryohei Aoyagi,Makoto Arita,Kenichiro Yamamura,Tamami Tanaka,Hisanori Nishio,Hidetoshi Takada,Shouichi Ohga,Toshiro Hara

    AIMS Coronary arteritis is a life-threatening complication that may arise in the acute stage of Kawasaki disease (KD), the leading cause of systemic vasculitis in childhood. Various microorganisms and molecular pathogens have been reported to cause KD. However, little is known about the key molecules that contribute to the development of coronary arteritis in KD. METHODS AND RESULTS To identify causative molecules for coronary arteritis in KD, we prospectively recruited 105 patients with KD and 65 disease controls in 4 different parts of Japan from 2015 to 2018. During this period, we conducted lipidomics analyses of their sera using liquid chromatography (LC)-mass spectrometry (MS). The comprehensive LC-MS system detected a total of 27,776 molecules harboring the unique retention time and m/z values. In the first cohort of 57 KD patients, we found that a fraction of these molecules showed enrichment patterns that varied with the sampling region and season. Among them, 28 molecules were recurrently identified in KD patients, but not in controls. The second and third cohorts of 48 more patients with KD revealed that these molecules were correlated with inflammatory markers (leukocyte counts and C-reactive proteins) in the acute stage. Notably, two of these molecules (m/z values: 822.55 and 834.59) were significantly associated with the development of coronary arteritis in the acute stage of KD. Their fragmentation patterns in the tandem MS/MS analysis were consistent with those of oxidized phosphatidylcholines. Further LC-MS/MS analysis supported the concept that reactive oxygen species caused the non-selective oxidization of phosphatidylcholines in KD patients. In addition, the concentrations of LOX-1 ligand containing apolipoprotein B in the plasma of KD patients were significantly higher than in controls. CONCLUSION These data suggest that inflammatory signals activated by oxidized phospholipids are involved in the pathogenesis of coronary arteritis in KD. Because the present study recruited only Japanese patients, further examinations are required to determine whether oxidized phosphatidylcholines might be useful biomarkers for the development of coronary arteritis in broad populations of KD.

    更新日期:2019-11-01
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