Cardiac Remodeling In Response Research Articles

T helper 17 cell responses induce cardiac hypertrophy and remodeling in essential hypertension.

An increasing body of evidence has shown that type 17 helper T (TH17) cell responses play an important role in the progression of cardiac remodeling stimulated by long‑term pressure overload. We aimed to investigate the relationship between TH17 responses and cardiac remodeling, and the prognostic value of TH17 responses in hypertensive patients. A total of 187 adults with hypertension and 70 healthy controls were enrolled in the present study. TH17 cell frequencies, matrix metallopeptidase 9, procollagen type I, and procollagen type III were studied at baseline. All adults underwent routine echocardiography to assess left ventricular diastolic function (LVDF) at baseline and after 24 months of follow‑up. The percentage of TH17 cells was increased in hypertensive patients, particularly in adults with left ventricular hypertrophy (LVH). Receiver operating characteristic (ROC) analysis revealed that the area under the curve (AUC) of TH17 cells for predicting of LVH was 0.943 (95% CI, 0.914-0.971; P <0.001) and the cutoff value was 2.3%. On logistic regression analysis, the percentage of TH17 cells was an independent predictor of LVH (odds ratio, 1.47; 95% CI, 2.23-2.28; P = 0.005). The percentage of TH17 cells significantly correlated with the levels of fibrotic parameters. According to the cutoff value of TH17 cells, patients with a lower level of TH17 cell differentiation had a better prognosis. The differentiation of TH17 cells reflected the cardiac hypertrophy and remodeling response to hypertension‑induced pressure overload, and it might be a potential inflammatory marker to predict the prognosis of hypertensive patients.

The Role of Tbx20 in Cardiovascular Development and Function

Tbx20 is a member of the Tbx1 subfamily of T-box-containing genes and is known to play a variety of fundamental roles in cardiovascular development and homeostasis as well as cardiac remodeling in response to pathophysiological stresses. Mutations in TBX20 are widely associated with the complex spectrum of congenital heart defects (CHDs) in humans, which includes defects in chamber septation, chamber growth, and valvulogenesis. In addition, genetic variants of TBX20 have been found to be associated with dilated cardiomyopathy and heart arrhythmia. This broad spectrum of cardiac morphogenetic and functional defects is likely due to its broad expression pattern in multiple cardiogenic cell lineages and its critical regulation of transcriptional networks during cardiac development. In this review, we summarize recent findings in our general understanding of the role of Tbx20 in regulating several important aspects of cardiac development and homeostasis and heart function.

Differential expression of exosomal circRNAs and regulatory framework genes in myocardial infarction patients with cardiac remodeling in response to Tongguan Capsules

Differential expression of exosomal circRNAs and regulatory framework genes in myocardial infarction patients with cardiac remodeling in response to Tongguan Capsules

Catecholamine-induced cardiomyopathy: an endocrinologist's perspective.

Although many endocrine diseases can be associated with acquired cardiomyopathy and heart failure, conditions except hypothyroidism, hyperthyroidism, phaeochromocytoma-paraganglioma (PPGL), and primary hyperaldosteronism are rare. PPGL is a rare catecholamine-secreting neuroendocrine tumour arising from the adrenal gland in 80-85% or extra-adrenal chromaffin cells of the autonomic neural ganglia in the remainder. The annual incidence of PPGL is 3-8 cases per million per year in the general population. Catecholamine-induced cardiomyopathy (CICMP) has got a prevalence of 8-11% among patients with PPGL. Hypertension, either sustained or episodic, is present in the vast majority (95%) of PPGL patients. However, among patients with CICMP, hypertension is present only in 65% of cases and the classical triad of paroxysmal headache, sweating, and palpitation is present only in 4%. Based on the cardiac remodelling in response to endogenous catecholamine excess, PPGL patients might present with one of the three CICMPs, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), or Takotsubo cardiomyopathy (TCM). Regardless of the subtypes, all CICMPs have many features in common - a dramatic clinical presentation, reversible cardiomyopathy, similar repolarisation electrocardiography changes, mild-moderate cardiac biomarker elevation, and normal coronary arteries on coronary angiography. CICMP should be suspected in patients with non-ischaemic, non-valvular forms of cardiomyopathy, even in those without definite features of catecholamine excess. PPGL associated TCM should be suspected in all acute coronary syndrome (ACS) patients exhibiting pronounced blood pressure variability with no culprit lesions on coronary angiography. This article will provide a review of the various CICMPs, their pathophysiology, clinical features, and the management options.

Repurposing From Oncology to Cardiology: Low-Dose 5-Azacytidine Attenuates Pathological Cardiac Remodeling in Response to Pressure Overload Injury

Recent evidence suggests that transcriptional reprogramming is involved in the pathogenesis of cardiac remodeling (cardiomyocyte hypertrophy and fibrosis) and the development of heart failure. 5-Azacytidine (5aza), an inhibitor of DNA methylation approved for hematological malignancies, has previously demonstrated beneficial effects on cardiac remodeling in hypertension. The aim of our work was to investigate whether pressure overload is associated with alterations in DNA methylation and if intervention with low-dose 5aza can attenuate the associated pathological changes. C57Bl6/J mice underwent surgical constriction of the aortic arch for 8 weeks. Mice began treatment 4 weeks post-surgery with either vehicle or 5aza (5 mg/kg). Cardiac structure and function was examined in vivo using echocardiography followed by post mortem histological assessment of hypertrophy and fibrosis. Global DNA methylation was examined by immunostaining for 5-methylcytosine (5MeC) and assessment of DNA methyltransferase expression. The results highlighted that pressure overload-induced pathological cardiac remodeling is associated with increased DNA methylation (elevated cardiac 5MeC positivity and Dnmt1 expression). Administration of 5aza attenuated pathological remodeling and diastolic dysfunction. These beneficial changes were mirrored by a treatment-related reduction in global 5MeC levels and expression of Dnmt1 and Dnmt3B in the heart. DNA methylation plays an important role in the pathogenesis of pressure overload-induced cardiac remodeling. Therapeutic intervention with 5aza, at a dose 5 times lower than clinically given for oncology treatment, attenuated myocardial hypertrophy and fibrosis. Our work supports the rationale for its potential use in cardiac pathologies associated with aberrant cardiac wound healing.

Abstract 354: The Role of the Liver Heart Axis During Cardiac Remodeling

Background: Hepatokine selenoprotein P (SeP) contributes to insulin resistance and hyperglycemia in patients with type 2 diabetes. Although clinical studies suggest the insulin resistance is an independent risk factor of heart failure and inhibition of SeP protects the heart from ischemia reperfusion injury, the role of SeP in pathogenesis of chronic heart failure is not well understood. Objective: We examined the role of SeP in the regulation of cardiac remodeling in response to pressure overload. Methods and Results: We measured serum SeP levels in 22 patients for heart failure with reduced ejection fraction (HFrEF; LVEF&lt;50%) and 22 normal subjects. Serum levels of SeP were significantly elevated in patients with HFrEF compared to in normal subjects (3.55 ± 0.43 vs 2.98 ± 0.43, p&lt;0.01). To examine the role of SeP in cardiac remodeling, SeP knockout (KO) and wild-type (WT) mice were subjected to pressure overload (transverse aortic constriction (TAC)) for 2 weeks. The mortality rate following TAC was significantly decreased in SeP KO mice compared to WT mice (22.5 % in KO mice (n=40) vs 52.3 % in WT mice (n=39) p&lt;0.01). LV weight/tibial length (TL) was significantly smaller in SeP KO mice than in WT mice (6.75 ± 0.24 vs 8.33 ± 0.32, p&lt;0.01). Lung weight/TL was significantly smaller in SeP KO than in WT mice (10.46 ± 0.44 vs 16.38 ± 1.12, p&lt;0.05). Interestingly, hepatic expression of SeP in WT was significantly increased by TAC. To determine whether hepatic overexpression of SeP affects TAC-induced cardiac hypertrophy, a hydrodynamic injection method was used to generate mice that overexpress SeP mRNA in the liver. Hepatic overexpression of SeP in SeP KO mice lead to a significant increase in LV weight/TL and Lung weight/TL after TAC compared to that in other SeP KO mice. Conclusions: These results suggest that serum levels of SeP were elevated in patients with heart failure with reduced ejection fraction and cardiac pressure overload induced hepatic expression of SeP in mice model. Gene deletion of SeP attenuated cardiac hypertrophy and dysfunction in response to pressure overload in mice. SeP possibly plays a pivotal role in promoting cardiac remodeling through the liver-heart axis.

Abstract 525: Adult Inducible Deletion of Endothelial Hypoxia-inducible Factor-2α Exaggerates Myocardial Infarction Induced Heart Failure and Cardiac Microvascular Barrier Dysfunction

Background: Myocardial ischemia occurs during myocardial infarction results in the stabilization of Hypoxia-inducible factors (HIFs). Hif2α expresses profoundly in vascular endothelial cells (EC), and its embryonic deletion increases vessel permeability. It has been shown that HIF2a is protective from renal and pulmonary injury. However, the direct role of ecHIF2α in ischemia heart disease is unknown. We hypothesized that ecHIF2a expression in response to myocardial infarction (MI) protects cardiac barrier dysfunction and against heart failure. Methods and Results: We generated the Inducible endothelial-specific knockout mice (ecHIF2a -/- ) by crossing Hif2a flox/flox mice with Cre ERT2 mice under the VE-cadherin promoter. Followed with MI, ecHIF2a -/- mice displayed worsened cardiac function determined by echocardiography, and they had increased mortality as compared to the controls. In vitro, we used primary mouse cardiac microvascular endothelial cells (mCMVEC) from ecHIF2a -/- mouse hearts. We found that under hypoxia condition or 1mM Dimethyloxalylglycine treatment, the deficiency of HIF2a in the mCMVEC increased endothelial permeability determined by trans-endothelial electrical resistance. The knocking down of HIF2a in HUVECs induced by a HIF2a siRNA led to impaired tube formation accessed by the significant reduction in total node counts, junctions, meshes, and full tube length compared to control-siRNA treated cells. HIF2α deletion and hypoxia both reduced endothelial cell migration, and interestingly, the retarded HIF2α-/- ECs migration seems to be independent of hypoxia. Moreover, apoptosis assay showed that ecHIF2a -/- ECs increased cell early apoptotic stage compared to WT in hypoxic conditions, but not in normoxia indicating the critical role of HIF2α in ECs survival during cardiac ischemia. Finally, several increased markers of inflammation, such as ICAM-1 and VCAM-1, are associated with HIF2a deletion. Conclusion: These data revealed an essential role of HIF2α in protecting cardiac remodeling in response to MI, which might through promoting endothelial cell migration, barrier function, as well as vascularization. Thus, HIF2α is a potential therapeutic target in the treatment of ischemic heart disease.

Cardiac Remodeling In Child And Adolescent Athletes In Association With Sport Discipline And Sex.

Continuous high training loads are associated with structural cardiac adaptations and development of an athletic heart in adult athletes, especially in sport disciplines with high dynamic training components. In child and adolescent athletes these effects are increasingly reported. However, study populations are still very small. PURPOSE: To determine cardiac dimensions indicating cardiac remodeling in child and adolescent athletes. METHODS: M Mode echocardiographs of 1021 athletes (m 575, f 446; 8-18 yrs; body surface area (BSA) 0.88-2.0 m2) from 19 sport disciplines were analyzed retrospectively. Sport disciplines were clustered into 9 groups according to Mitchell, categorizing sports by components of dynamic and static training loads. Groups were analyzed separately. Previous organized sporting experience (at least 3-13 yrs) was a requirement for inclusion. Left ventricular diameter (LVEDD), interventricular septal (IVS) and posterior wall (PW) thickness at end-diastole were analyzed and compared to cardiac z Scores (zS) for central European children. Deviations from normal mean (zS = 0) were defined as difference. Data was analyzed descriptively (median ± SD), Bland-Altman analysis was performed. RESULTS: For all analyzed parameters, athletic children and adolescents showed higher median zS though large deviations from the normal mean (zS>1.88) were only seen in single cases. Differences in sport discipline and sex were discovered. Throughout all disciplines, boys showed higher zS compared to girls (LVEDD 0.48±0.96 vs 0.22±0.92; IVS 0.47±0.99 vs 0.29±1.05; PW 0.53±0.76 vs 0.08±0.76), especially in disciplines with high dynamic training loads (Mitchel C I-III). Additionally, high zS were observed in the group of athletes with the highest static and low dynamic training load (Mitchell A III). CONCLUSIONS: Cardiac remodeling in response to athletic training starts at a young age, especially in boys exposed to high dynamic as well as static training loads. The development of zS for young athletes is essential to determine whether zS above the mean in this group are physiological adaptations or the beginning of pathologies. Differences between boys and girls and the high zS in boys with high static training loads indicate an association between fat free mass and cardiac dimensions stronger than BSA.

Sildenafil Recovers Burn-Induced Cardiomyopathy.

Background: Severe burn injury initiates a feedback cycle of inflammation, fibrosis, oxidative stress and cardiac mitochondrial damage via the PDE5A-cGMP-PKG pathway. Aim: To test if the PDE5A-cGMP-PKG pathway may contribute to burn-induced heart dysfunction. Methods: Sprague–Dawley rats were divided four groups: sham; sham/sildenafil; 24 h post burn (60% total body surface area scald burn, harvested at 24 h post burn); and 24 h post burn/sildenafil. We monitored heart function and oxidative adducts, as well as cardiac inflammatory, cardiac fibrosis and cardiac remodeling responses in vivo. Results: Sildenafil inhibited the burn-induced PDE5A mRNA level and increased the cGMP level and PKG activity, leading to the normalization of PKG down-regulated genes (IRAG, PLB, RGS2, RhoA and MYTP), a decreased ROS level (H2O2), decreased oxidatively modified adducts (malonyldialdehyde [MDA], carbonyls), attenuated fibrogenesis as well as fibrosis gene expression (ANP, BNP, COL1A2, COL3A2, αSMA and αsk-Actin), and reduced inflammation and related gene expression (RELA, IL-18 and TGF-β) after the burn. Additionally, sildenafil treatment preserved left ventricular heart function (CO, EF, SV, LVvol at systolic, LVPW at diastolic and FS) and recovered the oxidant/antioxidant balance (total antioxidant, total SOD activity and Cu,ZnSOD activity). Conclusions: The PDE5A-cGMP-PKG pathway mediates burn-induced heart dysfunction. Sildenafil treatment recovers burn-induced cardiac dysfunction.

Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling

The hexosamine biosynthetic pathway (HBP) plays critical roles in nutrient sensing, stress response, and cell growth. However, its contribution to cardiac hypertrophic growth and heart failure remains incompletely understood. Here, we show that the HBP is induced in cardiomyocytes during hypertrophic growth. Overexpression of Gfat1 (glutamine:fructose-6-phosphate amidotransferase 1), the rate-limiting enzyme of HBP, promotes cardiomyocyte growth. On the other hand, Gfat1 inhibition significantly blunts phenylephrine-induced hypertrophic growth in cultured cardiomyocytes. Moreover, cardiac-specific overexpression of Gfat1 exacerbates pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Conversely, deletion of Gfat1 in cardiomyocytes attenuates pathological cardiac remodeling in response to pressure overload. Mechanistically, persistent upregulation of the HBP triggers decompensated hypertrophy through activation of mTOR while Gfat1 deficiency shows cardioprotection and a concomitant decrease in mTOR activity. Taken together, our results reveal that chronic upregulation of the HBP under hemodynamic stress induces pathological cardiac hypertrophy and heart failure through persistent activation of mTOR.

Cardiomyocyte‐generated Monocyte Chemoattractant Protein 1 Contributes to Cardiac Inflammation During Adverse Remodeling in Pressure Overload

Attempts to normalize cardiac function in response to stress often lead to cardiovascular diseases associated with adverse remodeling. Cardiac inflammation is a hallmark feature of adverse remodeling. Although it is established that ischemic injury induces cardiac inflammation through release of substances from dying cells, mechanisms for inflammation in the context of nonischemic injury have been elusive. Our lab has previously shown that the cardiomyocyte is the initial site of transcription of pro‐inflammatory cytokines and chemokines such as MCP‐1, IL‐6, Il‐1β and Il‐18, in response to pressure overload and that this occurs in the absence of cell death. In addition, the NLRP3 inflammasome is activated in cardiomyocytes resulting in activation of caspase‐1 and generation of active forms of Il‐1β and IL‐18. Pharmacological blockade of NFκ‐β, MCP‐1 signaling, or NLRP3 inflammasome activation resulted in decreases in cardiac macrophage accumulation, fibrosis, and dysfunction. These results suggest that cardiomyocyte‐generated inflammatory mediators play a key role in adverse cardiac remodeling in response to pressure overload. However, the extent to which cardiomyocytes contribute to immune cell recruitment and remodeling through MCP‐1 and inflammasome generated Il‐1β and IL‐18 remains elusive.To address this question, we made cardiomyocyte‐specific MCP‐1 knockout (MCP1) mice and are currently breeding cardiac specific NLRP‐3 knockout mice. MCP1 and wildtype control (Ctl) mice were subjected to transaortic constriction (TAC) or sham surgery. Blood was collected from the mice at various timepoints and analyzed for serum amylyloid A (SAA) as a marker of systemic inflammation. At the conclusion of 3 or14 days post‐surgery, whole hearts were collected for analysis of gene expression and NLRP3 priming using qPCR. Caspase‐1 activity was used to measure NLRP3 inflammasome activation.Pro‐inflammatory cytokines were upregulated in TAC mice versus sham controls. Inflammasome priming and activation, as measured by IL‐1β and IL‐18 gene expression and caspase‐1 activity respectively, were unaffected by cardiomyocyte‐specific MCP‐1 deletion at 3 days post‐surgery. However, both IL‐1β and IL‐18 gene expression were reduced at 14 days post‐surgery in MCP1 TAC mice compared to Ctl TAC. This coincided with a reduction of CD68+ macrophage accumulation in the myocardium suggesting that infiltrating macrophages, recruited through cardiomyocyte‐generated MCP‐1, contribute to inflammatory gene expression at this time. We are currently assessing inflammasome activation in cardiomyocytes and macrophages following TAC in Ctl and MCP1 mice. Parallel experiments using cardiomyocyte NLRP‐3 KO mice will reveal the importance of inflammasome products made in the myocyte compartment. In other studies, we are assessing the contribution of cardiomyocyte‐generated cytokines and chemokines to systemic inflammation by measuring serum amyloid A. MCP1 TAC animals displayed a reduction in SAA compared to Ctl TAC animals at 14 days post‐surgery suggesting that cardiomyocyte‐derived MCP‐1 can contribute to persistent inflammation in pressure overloaded murine hearts.Support or Funding InformationR01HL145459‐01 (JHB, SM)T32HL007444‐37 (RSR, JC)

The effect of iron deficiency on cardiac resynchronization therapy: results from the RIDE-CRT Study.

AimsCardiac resynchronization therapy (CRT) improves functional status, induces reverse left ventricular remodelling, and reduces hospitalization and mortality in patients with symptomatic heart failure, left ventricular systolic dysfunction, and QRS prolongation. However, the impact of iron deficiency on CRT response remains largely unclear. The purpose of the study was to assess the effect of functional and absolute iron deficiency on reverse cardiac remodelling, clinical response, and outcome after CRT implantation.Methods and resultsThe relation of iron deficiency and cardiac resynchronization therapy response (RIDE‐CRT) study is a prospective observational study. We enrolled 77 consecutive CRT recipients (mean age 71.3 ± 10.2 years) with short‐term follow‐up of 3.3 ± 1.9 months and long‐term follow‐up of 13.0 ± 3.2 months. Primary endpoints were reverse cardiac remodelling on echocardiography and clinical CRT response, assessed by change in New York Heart Association classification. Echocardiographic CRT response was defined as relative improvement of left ventricular ejection fraction ≥ 20% or left ventricular global longitudinal strain ≥ 20%. Secondary endpoints were hospitalization for heart failure and all‐cause mortality (mean follow‐up of 29.0 ± 8.4 months). At multivariate analysis, iron deficiency was identified as independent predictor of echocardiographic (hazard ratio 4.97; 95% confidence interval 1.15–21.51; P = 0.03) and clinical non‐response to CRT (hazard ratio 4.79; 95% confidence interval 1.30–17.72, P = 0.02). We found a significant linear‐by‐linear association between CRT response and type of iron deficiency (P = 0.004 for left ventricular ejection fraction improvement, P = 0.02 for left ventricular global longitudinal strain improvement, and P = 0.003 for New York Heart Association response). Iron deficiency was also significantly associated with an increase in all‐cause mortality (P = 0.045) but not with heart failure hospitalization.ConclusionsIron deficiency is a negative predictor of effective CRT therapy as assessed by reverse cardiac remodelling and clinical response. Assessment of iron substitution might be a relevant treatment target to increase CRT response and outcome in chronic heart failure patients.

Hyperlipidemia inhibits the protective effect of lisinopril after myocardial infarction via activation of dendritic cells.

To investigate the prevention of cardiac remodelling and inflammatory immune response after myocardial infarction (MI) via ACEI regulating dendritic cells (DCs), we explored whether the protective effect of ACEI was repressed under hyperlipidemic environment. In vivo, the survival rate and left ventricular function of the mice were recorded on day 7 after MI. Tissue samples of the myocardium, spleen, bone marrow and peripheral blood were assessed for Ang II concentration, inflammatory cytokines and DCs expression. In vitro, DCs were treated with ox‐LDL + Ang II, simulating the internal environment of MI in ApoE−/− mice to explore the mechanism involved in the DCs maturation and inflammation. Under hyperlipidemic circumstances, we found that the cardioprotective effect of ACEI was attenuated through regulating DCs maturation and inflammation after MI, affecting survival rate and left ventricular function. Effects of lisinopril on the release of spleen‐derived DCs and myocardial infiltration were also reduced under hyperlipidemic conditions. In vitro, immune maturation and inflammation of DCs were further induced by ox‐LDL on the basis of Ang II treatment, as indicated by the upregulation of CD83, CD86, and the expressions of cytokines and chemokines. Furthermore, ox‐LDL could activate TLR4‐MyD88 signalling pathway, promoting IRAK‐4 and NF‐κB. The present study demonstrated that ACEI reduced the recruitment of DCs to the infarct site, leading to a higher survival rate and improved function. However, this effect was inhibited under hyperlipidemic environment. TLR4‐MyD88 signalling pathway may be responsible for the molecular mechanism involved in the immune maturation and inflammation of DCs induced by ox‐LDL.

NADPH oxidase-4 promotes eccentric cardiac hypertrophy in response to volume overload.

AimsChronic pressure or volume overload induce concentric vs. eccentric left ventricular (LV) remodelling, respectively. Previous studies suggest that distinct signalling pathways are involved in these responses. NADPH oxidase-4 (Nox4) is a reactive oxygen species-generating enzyme that can limit detrimental cardiac remodelling in response to pressure overload. This study aimed to assess its role in volume overload-induced remodelling.Methods and resultsWe compared the responses to creation of an aortocaval fistula (Shunt) to induce volume overload in Nox4-null mice (Nox4−/−) vs. wild-type (WT) littermates. Induction of Shunt resulted in a significant increase in cardiac Nox4 mRNA and protein levels in WT mice as compared to Sham controls. Nox4−/− mice developed less eccentric LV remodelling than WT mice (echocardiographic relative wall thickness: 0.30 vs. 0.27, P < 0.05), with less LV hypertrophy at organ level (increase in LV weight/tibia length ratio of 25% vs. 43%, P < 0.01) and cellular level (cardiomyocyte cross-sectional area: 323 µm2 vs. 379 μm2, P < 0.01). LV ejection fraction, foetal gene expression, interstitial fibrosis, myocardial capillary density, and levels of myocyte apoptosis after Shunt were similar in the two genotypes. Myocardial phospho-Akt levels were increased after induction of Shunt in WT mice, whereas levels decreased in Nox4−/− mice (+29% vs. −21%, P < 0.05), associated with a higher level of phosphorylation of the S6 ribosomal protein (S6) and the eIF4E-binding protein 1 (4E-BP1) in WT compared to Nox4−/− mice. We identified that Akt activation in cardiac cells is augmented by Nox4 via a Src kinase-dependent inactivation of protein phosphatase 2A.ConclusionEndogenous Nox4 is required for the full development of eccentric cardiac hypertrophy and remodelling during chronic volume overload. Nox4-dependent activation of Akt and its downstream targets S6 and 4E-BP1 may be involved in this effect.

The Art of Intercellular Wireless Communications: Exosomes in Heart Disease and Therapy

Exosomes are nanoscale membrane-bound extracellular vesicles secreted by most eukaryotic cells in the body that facilitates intercellular communication. Exosomes carry several signaling biomolecules, including miRNA, proteins, enzymes, cell surface receptors, growth factors, cytokines and lipids that can modulate target cell biology and function. Due to these capabilities, exosomes have emerged as novel intercellular signaling mediators in both homeostasis and pathophysiological conditions. Recent studies document that exosomes (both circulating or released from heart tissue) have been actively involved in cardiac remodeling in response to stressors. Also, exosomes released from progenitor/stem cells have protective effects in heart diseases and shown to have regenerative potential in the heart. In this review we discuss- the critical role played by circulating exosomes released from various tissues and from cells within the heart in cardiac health; the gap in knowledge that needs to be addressed to promote future research; and exploitation of recent advances in exosome engineering to develop novel therapy.

Collaborative Regulation of LRG1 by TGF-β1 and PPAR-β/δ Modulates Chronic Pressure Overload-Induced Cardiac Fibrosis.

Despite its established significance in fibrotic cardiac remodeling, clinical benefits of global inhibition of TGF (transforming growth factor)-β1 signaling remain controversial. LRG1 (leucine-rich-α2 glycoprotein 1) is known to regulate endothelial TGFβ signaling. This study evaluated the role of LRG1 in cardiac fibrosis and its transcriptional regulatory network in cardiac fibroblasts. Pressure overload-induced heart failure was established by transverse aortic constriction. Western blot, quantitative reverse transcription polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to evaluate the expression level and pattern of interested targets or pathology during fibrotic cardiac remodeling. Cardiac function was assessed by pressure-volume loop analysis. LRG1 expression was significantly suppressed in left ventricle of mice with transverse aortic constriction-induced fibrotic cardiac remodeling (mean difference, -0.00085 [95% CI, -0.0013 to -0.00043]; P=0.005) and of patients with end-stage ischemic-dilated cardiomyopathy (mean difference, 0.13 [95% CI, 0.012-0.25]; P=0.032). More profound cardiac fibrosis (mean difference, -0.014% [95% CI, -0.029% to -0.00012%]; P=0.048 for interstitial fibrosis; mean difference, -1.3 [95% CI, -2.5 to -0.2]; P=0.016 for perivascular fibrosis), worse cardiac dysfunction (mean difference, -2.5 ms [95% CI, -4.5 to -0.4 ms]; P=0.016 for Tau-g; mean difference, 13% [95% CI, 2%-24%]; P=0.016 for ejection fraction), and hyperactive TGFβ signaling in transverse aortic constriction-operated Lrg1-deficient mice (mean difference, -0.27 [95% CI, -0.47 to -0.07]; P<0.001), which could be reversed by cardiac-specific Lrg1 delivery mediated by adeno-associated virus 9. Mechanistically, LRG1 inhibits cardiac fibroblast activation by competing with TGFβ1 for receptor binding, while PPAR (peroxisome proliferator-activated receptor)-β/δ and TGFβ1 collaboratively regulate LRG1 expression via SMRT (silencing mediator for retinoid and thyroid hormone receptor). We further demonstrated functional interactions between LRG1 and PPARβ/δ in cardiac fibroblast activation. Our results established a highly complex molecular network involving LRG1, TGFβ1, PPARβ/δ, and SMRT in regulating cardiac fibroblast activation and cardiac fibrosis. Targeting LRG1 or PPARβ/δ represents a promising strategy to control pathological cardiac remodeling in response to chronic pressure overload.

P2590A liver-derived secretory protein, selenoprotein P causes pressure overload-induced cardiac hypertrophys

Abstract Background Hepatokine selenoprotein P (SeP) contributes to insulin resistance and hyperglycemia in patients with type 2 diabetes. Inhibition of SeP protects the heart from ischemia reperfusion injury and serum levels of SeP are elevated in patients with heart failure with reduced ejection fraction. Objective We investigated the role of SeP in the regulation of cardiac remodeling in response to pressure overload. Methods and results To examine the role of SeP in cardiac remodeling, transverse aortic constriction (TAC) was subjected to SeP knockout (KO) and wild-type (WT) mice for 2 weeks. Hepatic expression of SeP in WT was significantly increased by TAC. LV weight/tibial length (TL) was significantly smaller in SeP KO mice than in WT mice (6.75±0.24 vs 8.33±0.32, p&lt;0.01). Lung weight/TL was significantly smaller in SeP KO than in WT mice (10.46±0.44 vs 16.38±1.12, p&lt;0.05). TAC-induced cardiac upregulation of the fetal type genes, including atrial and brain natriuretic factors, was significantly attenuated in SeP KO compared to WT. Furthermore, azan staining revealed that there was significantly less interstitial fibrosis in hearts after TAC in SeP KO than in WT mice. To determine whether hepatic overexpression of SeP affects TAC-induced cardiac hypertrophy, a hydrodynamic injection method was used to generate mice that overexpress SeP mRNA in the liver. Hepatic overexpression of SeP in SeP KO mice lead to a significant increase in LV weight/TL and Lung weight/TL after TAC compared to that in other SeP KO mice. Conclusions These results suggest that cardiac pressure overload induced hepatic expression of SeP and the absence of endogenous SeP attenuated cardiac hypertrophy, dysfunction and fibrosis in response to pressure overload in mice. SeP possibly plays a maladaptive role against progression of heart failure through the liver-heart axis.

P4996The adult heart requires baseline expression of the transcription factor Hand2 to withstand right ventricular pressure overload

Abstract Introduction Heart and neural crest derivatives expressed-2 (Hand2) has been identified as an important embryonic basic helix-loop-helix-transcription factor, with different functions in the development of the first and second heart field, from which the left and right ventricle originate, respectively. Our previous work revealed that Hand2, under conditions of left ventricular (LV) pressure overload, is re-expressed in the adult heart and activates a “fetal gene” program contributing to pathological cardiac remodeling. Ablation of cardiac expression of Hand2 resulted in protection to cardiac stress and attenuated maladaptive remodeling. Purpose In this study, we aimed at unraveling the role of Hand2 during cardiac remodeling in response to right ventricular (RV) pressure overload induced by pulmonary artery banding (PAB). Methods Hand2F/F and MCM− Hand2F/F mice were treated with tamoxifen (control and knockout, respectively) and subjected to six weeks of RV pressure overload induced by PAB. Echocardiographic and MRI derived hemodynamic parameters, and molecular remodelling were assessed for experimental groups and compared to sham-operated controls (Fig. 1a). RNA sequencing and gene ontology enrichment analysis were performed to compare the dysregulated genes between the pressure overloaded RV of the control and Hand2 knockout mice. Results After six weeks of increased pressure load (Fig. 1b), levels of Hand2 increased in the control banded animals but, as expected, remained absent in the knockout hearts (Fig. 1c). In contrast to the what was previously observed for the pressure overloaded LV, in the pressure loaded RV, Hand2 depletion resulted in more severe remodelling and dysfunction as reflected by increased hypertrophic growth, increased RV end-diastolic and end-systolic volumes as well as decreased RV ejection fraction (Fig. 1d–g). In addition, RNA sequencing revealed a distinct set of genes that are dysregulated in the pressure-overloaded RV, compared to the previously described pressure-overloaded LV. These include components of the extracellular matrix structure, collagen assembly and organization and several types of collagens. Genes associated with inflammation response, adhesion and muscle organization were also affected in the RV of the Hand2 KO mice (Fig. 1h). Figure 1 Conclusion Cardiac-specific depletion of Hand2 is associated with severe cardiac dysfunction in conditions of RV pressure overload. While inhibiting Hand2 expression can prevent cardiac dysfunction in conditions of LV pressure overload, the same does not hold true for conditions of RV pressure overload. This study highlights the need to better understand the molecular mechanisms driving pathological remodelling of the RV, in contrast to the LV, in order to better diagnose and treat patients with RV or LV failure.

P6306Hyperlipidemia inhibits the protective effect of lisinopril after myocardial infarction via activation of dendritic cells

Abstract Background In clinical situation, patients with myocardial infarction (MI) usually suffered from hyperlipidemia, hypertension, renal dysfunction or diabetes as well and the interaction of those risk factors may affect the effectiveness of ACEI. Dendritic cell (DC) is a potent central immunoregulator that orchestrates various types of inflammatory cells in innate and adoptive immunity. The role of DCs in the inflammation of cardiovascular disease is a hotspot of international research. Purpose To investigate the improvement of cardiac remodeling and inflammatory immune response after MI via ACEI regulating DCs and explore that whether the protective effect of ACEI is under the circumstance of hyperlipidemia. Methods In vivo, MI mice models were created via coronary artery ligation. We detected the survival and left ventricular function on day 7 after MI. Tissue samples of the myocardium, spleen, bone marrow and peripheral blood were obtained and assessed for Ang2 concentration, inflammatory cytokines and DCs expression via immunohistochemistry, ELISA, flow cytometry and western blot. In vitro, we treated DCs with ox-LDL+AngIIfor 48 hours simulating the internal environment of MI in ApoE−/− mice to explore the mechanism involved in the DCs maturation and inflammation. Results Under the circumstance of hyperlipidemia, the cardioprotective effect of ACEI is attenuated through regulating DCs maturation and inflammation after MI, including survival rate (Figure 1) and left ventricular function. The number of DCs in cardiac tissue were increased in MI mice with hyperlipidemia (Figure 2), when compared with the WT group. The expression of the maturity phenotype related molecules, such as CD83, on the DCs in spleen were also increased in the ApoE−/− mice. Then, the expressions of inflammatory cytokines, such as IL-6 and TNF-α. In vitro, it was found that the immune maturation and inflammation of DCs could be further induced by ox-LDL on the basis of AngIItreatment, as indicated by the upregulation of CD83 and CD86, the expressions of cytokines and chemokines. Furthermore, ox-LDL could activate the toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88) signaling pathway, promoting the phosphorylation of interleukin-1 receptor associated kinase (IRAK)-4 and the nuclear transferring of nuclear factor-kappaB (NF-κB). Conclusion We proved ACEI reduces the recruitment of DCs to the infarct, leading to a higher survival rate and improved function and remodeling through decreased inflammation resulting from immune response after MI. However, this effect was inhibited under the circumstance of hyperlipidemia. TLR4-MyD88 signaling pathway might be the possible molecular mechanism involved in the immune maturation and inflammation of DCs induced by ox-LDL on the basis of AngII. Acknowledgement/Funding the Youth fund of the National Natural Science Foundation of China, Grant 81600280

P629Voluntary exercise associated with myokine production ameliorates cardiac remodeling and inflammation in a myocardial infarction mouse model

Abstract Background Left ventricular (LV) remodeling, through excessive inflammation, leads to heart failure. Exercise (Ex) training is associated with a risk reduction in heart failure through direct and indirect mechanisms by which Ex contributes an anti-inflammatory effect. During Ex, contracting muscle fibers release myokines, including interleukins (ILs), tumor necrosis factor α (TNF-α), follistatin-like protein 1 (FSTL-1), and fibroblast growth factor 21 (FGF-21), into the bloodstream. These myokines may have beneficial effects on other damaged organs, such as an infarcted myocardium, through anti-inflammatory effects. However, the exact mechanisms of the anti-inflammatory effects of voluntary Ex in myocardial infarction (MI) are poorly understood. Therefore, we investigated the effect of voluntary Ex on cardiac remodeling and inflammation, the relationship between cardiac remodeling and skeletal muscle (SKM) response, and circulating myokine levels in a mouse model of MI. Methods Twelve-week-old male C57BL/6J mice were used and divided into the following 4 groups: sham operation (Sham), MI, Sham+Ex, and MI+Ex. MI was induced by ligation of the left anterior descending coronary artery. Ex groups began voluntary wheel running for 4 weeks after the operation. An echocardiography was performed at baseline and 4 weeks after the operation. The mRNA levels in the LV infarcted area and SKM were measured with RT-PCR and western blot analysis. Plasma levels of myokines were also measured with immunoassays. Results Four weeks after MI induction, echocardiographic evaluation showed that the MI mice had a larger LV end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD) than the Sham mice. The MI mice also showed higher mRNA levels of TNF-α, IL-1β, IL-6, and IL-10 in the LV tissue when compared to the Sham mice. These changes were significantly ameliorated in the MI+Ex mice. Interestingly, in the MI+Ex mice, mRNA levels of IL-6, IL-1β, FSTL-1, and FGF-21 in the SKM were significantly higher than in the MI mice, while there were no significant differences in TNF-α and IL-10 levels in all groups. Similarly, protein expression levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, sirtuin-1, and mitochondrial transcriptional factor A of mitochondrial function markers in SKM were also significantly higher in the MI+Ex mice than in the MI mice. Furthermore, there were significant correlations between plasma levels of IL-1β, but not other myokines, and LVEDD, and LVESD. In addition, there was also a significant correlation between the SKM IL-1β level and LVESD in the Sham+Ex mice (all, P&lt;0.05). Conclusions Amelioration of cardiac remodeling and inflammation by voluntary Ex is associated with increased myokines, especially IL-1β, in a MI mouse model. These results suggest that increased myokine levels, through voluntary exercise, may play an important role in the prevention of cardiac remodeling after MI.