Bidirectional longitudinal associations between balance performance and depressive symptoms in older adults: A cross-lagged panel model.

BACKGROUND: Evidence on the temporal sequences between balance and depressive symptoms is limited, and no studies have compared the strength of each direction. This study aimed to assess the association between balance performance and depressive symptoms among community-dwelling older adults, and further to explore the driving factors in the dynamic association. METHODS: Data were obtained from the English Longitudinal Study of Aging (ELSA). Overall, 3971 community-residing adults aged 50 years or older were assessed at 2004/05, 2008/09, and 2012/13. Balance was measured using three progressively more difficult tasks (side-by-side, semi-tandem, and full-tandem). Depressive symptoms were determined with a dichotomous eight-item version of the Center for Epidemiologic Studies Depression Scale (CES-D). Cross-lagged panel models were used to test the reciprocal relationships between balance and depressive symptoms. RESULTS: Our analyses revealed that earlier poorer balance predicted later worse depressive symptoms consistently across waves (ßW2-W4 = -0.058, P < .05, ßW4-W6 = -0.067, P < .001). Conversely, the higher scores of depressive symptoms at wave 4 predicted lower level of balance at wave 6 (ßW4-W6 = -0.038, P = .018). The cross-lagged effects of balance on depressive symptoms were over all stronger than the reverse effects. CONCLUSIONS: These findings add novel insights into the temporal directionality of balance and depressive symptoms among community-dwelling older adults, and suggest that a predominance of balance disorder effects. Interventional strategy should aim to increase balance ability from earlier stages to promote successful aging.

Study on the Formation Mechanism of Acetaldehyde during the Low-Temperature Oxidation of Coal.

The threshold dilution ratio of acetaldehyde is much larger than those of other odor compounds generated during the spontaneous combustion process and so it is the most important odorant. Studying the mechanism by which acetaldehyde is generated can provide the necessary theoretical support for acetaldehyde-based odor analysis. In the present work, the release of acetaldehyde was monitored while heating lignite, long-flame coal, and coking coal specimens under either air or nitrogen. The data show that acetaldehyde was primarily produced by the oxidation of active sites in the coal rather than by the pyrolysis of oxygen-containing functional groups. Based on quantum chemistry and coal-oxygen reaction theory, the transition state approach was used to further study the formation of acetaldehyde during the low-temperature oxidation of coal. Using density functional theory, three different coal molecule structures were modeled and optimized structures for acetaldehyde formation and the energies, bond lengths, and virtual frequencies of each reaction stagnation point were obtained at the B3LYP-D3/6-311G** and M062X-D3/Def2-TZVP levels. The results indicate that the low-temperature oxidation of coal to generate acetaldehyde involves the capture of H atoms from aliphatic side chains to generate peroxy radicals. These radicals then attack unsaturated C atoms through complex inversions to generate peroxides. In the third step of this process, the O-O single bonds in the peroxides break in response to thermal energy to form carbonyl groups. Finally, specific C-C or C-O bonds on the aliphatic side chains are thermally cleaved to generate acetaldehyde.

TAK1 Activation by NLRP3 Deficiency Confers Cardioprotection Against Pressure Overload-Induced Cardiomyocyte Pyroptosis and Hypertrophy.

A comprehensive view of the role of NLRP3/caspase-1/GSDMD-mediated pyroptosis in pressure overload cardiac hypertrophy is presented in this study. Furthermore, mitigation of NLRP3 deficiency-induced pyroptosis confers cardioprotection against pressure overload through activation of TAK1, whereas this salutary effect is abolished by inhibition of TAK1 activity, highlighting a previously unrecognized reciprocally regulatory role of NLRP3-TAK1 governing inflammation-induced cell death and hypertrophic growth. Translationally, this study advocates strategies based on inflammation-induced cell death might be exploited therapeutically in other inflammatory and mechanical overload disorders, such as myocardial infarction and mitral regurgitation.

Surgically Induced Cardiac Volume Overload by Aortic Regurgitation in Mouse.

Aortic regurgitation (AR) is a common valvular heart disease that exerts volume overload on the heart and represents a global public health problem. Although mice are widely applied to shed light on the mechanisms of cardiovascular disease, mouse models of AR, especially those induced by surgery, are still paucity. Here, a mouse model of AR was described in detail which is surgically induced by disruption of the aortic valves under high-resolution echocardiography. In accordance with regurgitated blood flow, AR mouse hearts present a distinctive and clinically relevant volume overload phenotype, which is characterized by eccentric hypertrophy and cardiac dysfunction, as evidenced by echocardiographic and invasive hemodynamic evaluation. Our proposal, in a reliable and reproducible manner, provides a practical guide on the establishment and assessment of a mouse model of AR for future studies on molecular mechanisms and therapeutic targets of volume overload cardiomyopathy.

Long-term prognostic value of dynamic function assessment of intermediate coronary lesion with computational physiology.

This study sought to investigate the dynamic functional changes of coronary intermediate lesions using quantitative flow ratio (QFR) and its implication on long-term clinical outcomes. Physiology-guided percutaneous coronary intervention in patients with angiographic intermediate lesions has been associated with favorable outcomes. This study consecutively enrolled 1130 patients with deferred intermediate lesions at baseline angiography and subsequently received second-time angiography between 9 months and 2 years later from two centers in China. The functional changes of intermediate lesions at angiographic follow-up (ΔQFR) were defined as (baseline QFR-follow-up QFR)/years. The primary outcome was vessel-oriented composite endpoint (VOCE), defined as the composite of vessel-related cardiac death, vessel-related myocardial infarction (MI), and ischemia-driven target vessel revascularization (ID-TVR) at angiographic follow-up for up to 5 years. Retrospective QFR assessment was available in 820 patients (996 intermediate lesions). QFR ≤ 0.80 at second-time angiography was associated with significantly higher 5-year VOCE (41.9% vs. 13.4%, p < 0.0001). In 777 intermediate lesions with baseline QFR > 0.80, mean ΔQFR was 0.03 ± 0.07 (median: 0.006; Q1: 0; and Q3: 0.04). The optimal cutoff of ΔQFR for predicting the primary outcome was 0.03 (area under the curve [AUC]: 0.68). The cumulative event rate of VOCE in patients with ΔQFR ≥ 0.03 was significantly higher than in those with ΔQFR < 0.03 (33.8% vs. 12.2%, p < 0.0001), driven by higher vessel-related MI and ID-TVR. The ΔQFR was a useful tool for evaluating the dynamic functional change of deferred intermediate lesions, as it demonstrates good prognostic value for long-term target vessel-related adverse events.

Involvement of Endoplasmic Reticulum Stress-Mediated Activation of C/EBP Homologous Protein in Aortic Regurgitation-Induced Cardiac Remodeling in Mice.

Aortic regurgitation (AR) is a volume overload disease causing eccentric left ventricular (LV) hypertrophy and eventually heart failure. There is currently no approved drug to treat patients with AR. Endoplasmic reticulum (ER) stress and ER stress-mediated apoptosis is involved in many cardiovascular diseases, but whether they also participate in AR-induced heart failure is still elusive. In this study, we found ER stress activation in myocardial samples from patients with AR. With a unique murine model of AR which induced eccentric cardiac hypertrophy and heart failure, we also found aggravation of cardiac ER stress and apoptosis, as evidenced by a reduction of Bcl-2/Bax ratio and an increase of caspase-3 cleavage. We then examined the signaling effectors involved in ER-initiated apoptosis and found volume overload specifically activated C/EBP homologous protein (CHOP), but not caspase-12 or Jun N-terminal kinase (JNK). Interestingly, tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, improved cardiac function, and suppressed ER stress, apoptosis, and CHOP. Furthermore, genetic knockdown of CHOP inhibited cardiac Bcl-2/Bax ratio reduction and caspase-3 activation and rescued cardiac dysfunction. In summary, our findings suggest that ER stress-CHOP signaling is involved in the development of volume overload cardiac hypertrophy induced by AR through promoting cardiomyocytes apoptosis and provide a previously unrecognized target in heart failure induced by volume overload.

Troponin T Elevation After Percutaneous Left Atrial Appendage Occlusion.

Background: Cardiac troponin T (cTNT) has been widely used in detecting cardiac damage. Elevated cTNT level has been reported to be associated with increased mortality in multiple cardiac conditions. It is not uncommon to observe an increased level of cTNT in patients after left atrial appendage occlusion (LAAO). The objective of the study is to study the incidence, significance, and factors associated with cTNT elevation after LAAO. Methods: We prospectively included patients who underwent LAAO from January 2019 to July 2020 in Fudan Zhongshan Hospital. Patients were divided into those with elevated cTNT after procedure and those with normal postprocedure cTNT. All individuals were followed up for 1 year. The primary outcome is major adverse cardiovascular events, which include myocardial infarction, heart failure, cardiac death, and stroke. The second outcome is periprocedure complication, including chest pain, tachycardia, cardiac tamponade, change of electrocardiograph, and atrial thrombus. Results: A total of 190 patients were enrolled. Of the patients, 85.3% had elevated cTNT after LAAO, while 14.7% of them did not. Exposure time, dosage of contrast, types of devices, shapes, and sizes of LAA could contribute to elevated postprocedure cTNT. We found that patients with a Watchman device were more likely to have elevated postprocedure cTNT than those with a Lambre device (89.2 vs. 76.7%, p = 0.029). LAAO shapes were associated with cTNT levels in patients with a Watchman device, while the diameter of the outer disc and LAA depth mattered for the Lambre device. There was no significant difference in the primary and second outcome between the two groups (p-value: 0.619, 0.674). Conclusion: LAAO was found to be commonly accompanied with cTNT elevation, which might not to be related to the complications and adverse cardiac outcomes within 1 year of follow-up. Moreover, eGFR at baseline, exposure time, dosage of contrast, types of LAAO device, and LAA morphology could contribute to cTNT elevation.

Hypertrophic Preconditioning Attenuates Myocardial Ischaemia-Reperfusion Injury by Modulating SIRT3-SOD2-mROS-Dependent Autophagy.

BACKGROUND: Ischaemic preconditioning elicited by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischaemic insult. Here, we test the hypothesis that short-term non-ischaemic stimulation of hypertrophy renders the heart resistant to subsequent ischaemic injury. METHODS AND RESULTS: Transient transverse aortic constriction (TAC) was performed for 3 days in mice and then withdrawn for 4 days by aortic debanding, followed by subsequent exposure to myocardial ischaemia-reperfusion (I/R) injury. Following I/R injury, myocardial infarct size and apoptosis were significantly decreased, and cardiac dysfunction was markedly improved in the TAC preconditioning group compared with the control group. Mechanistically, TAC preconditioning markedly suppressed I/R-induced autophagy and preserved autophagic flux by deacetylating SOD2 via a SIRT3-dependent mechanism. Moreover, treatment with an adenovirus encoding SIRT3 partially mimicked the effects of hypertrophic preconditioning, whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning. Furthermore, in vivo lentiviral-mediated knockdown of Beclin 1 in the myocardium ameliorated the I/R-induced impairment of autophagic flux and was associated with a reduction in cell death, whereas treatment with a lentivirus encoding Beclin 1 abolished the cardioprotective effect of TAC preconditioning. CONCLUSIONS: The present study identifies TAC preconditioning as a novel strategy for induction of an endogenous self-defensive and cardioprotective mechanism against cardiac injury. Specifically, TAC preconditioning reduced myocardial autophagic cell death in a SIRT3/SOD2 pathway-dependent manner.

Predictors and long-term prognosis of left ventricular aneurysm in patients with acute anterior myocardial infarction treated with primary percutaneous coronary intervention in the contemporary era.

BACKGROUND: Primary percutaneous coronary intervention (PCI) has been the standard reperfusion strategy for patients with acute myocardial infarction (AMI) in the contemporary era. Meanwhile, the incidence and prognosis of left ventricular aneurysm (LVA) in AMI patients remain ambiguous. The aim of the current study is to identify the predictor and long-term prognosis of LVA in patients with acute anterior myocardial infarction. METHODS: We prospectively enrolled 942 consecutive patients with acute anterior myocardial infarction who were treated by primary PCI. The baseline characteristics, procedural features, and one-year clinical outcomes were compared between the patients with and without LVA. The primary endpoint of major adverse cardiovascular and cerebrovascular events (MACCEs) was defined as a composite of cardiac death, target vessel revascularization, and ischemic stroke. Multiple logistic regression was applied to predict LVA formation and the receiver operating characteristic (ROC) curves were plotted to evaluate the accuracy of the multivariate analysis model. RESULTS: The general incidence of LVA was 15.92%. At one-year clinical follow-up, patients in the LVA group had significantly higher incidence of MACCEs (15.33% vs. 6.44%, P<0.01), mainly driven by an increased incidence of cardiac death (8.00% vs. 2.78%, P<0.01), target vessel revascularization (5.33% vs. 2.27%, P=0.03), and ischemic stroke (4.00% vs. 1.39%, P=0.03). Multivariate analysis found that longer symptom-to-balloon time (S2B) [odds ratio (OR): 1.16, 95% confidence interval (CI): 1.11-1.21, P<0.01], higher initial and residual SYNTAX score (iSS, OR: 1.19, 95% CI: 1.14-1.24, P<0.01; rSS, OR: 1.33, 95% CI: 1.22-1.45, P<0.01), lower left ventricular ejection fraction (LVEF) (OR: 1.15, 95% CI: 1.11-1.18, P<0.01), and persistent ST segment elevation (OR: 1.89, 95% CI: 1.06-3.38, P=0.03) were independent predictors of LVA formation. CONCLUSIONS: LVA is still common in patients with acute anterior myocardial infarction in the contemporary PCI era, and the prognosis of these patients was significantly worse during the one-year clinical follow-up. Strategies of prompt reperfusion and complete revascularization may be helpful in preventing LVA formation and improving clinical outcomes.

Difference in inflammation, atherosclerosis, and platelet activation between coronary artery aneurysm and coronary artery ectasia.

BACKGROUND: Coronary artery aneurysm (CAA) and coronary artery ectasia (CAE) may be two different types of coronary artery dilatation with unknown etiology. This study aimed to compare the differences between CAA and CAE and to investigate their pathogenesis and the necessity of antiplatelet therapy. METHODS: One hundred patients each with confirmed CAA, CAE, and normal coronary artery (NCA) from September 2017 to July 2019 were included. All patients completed examinations of the ankle-brachial index (ABI), pulse wave rate, and carotid ultrasonography; and were tested for routine blood, lipid, and immune parameters. Blood samples were collected 1 week after the withdrawal of antiplatelet drugs, and vascular inflammatory indexes, platelet activation indexes, thromboelastography, and the platelet aggregation rate were measured. Analysis of variance and the chi-square or Fisher exact test were used for statistical analysis. RESULTS: The perinuclear anti-neutrophil cytoplasmic antibody (ANCA), endothelial-1, matrix metalloproteinase-9, and tumor necrosis factor-α were significantly higher in CAE than in NCA, while cytoplasmic ANCA was appreciably higher in CAE than in CAA (P<0.05). Myeloperoxidase and growth/differentiation factor-15 were significantly higher in CAE than in CAA and NCA (P<0.05). ABI was significantly lower in CAA and CAE than in NCA (P<0.05), low-density lipoprotein/high-density lipoprotein was significantly higher in CAA than in NCA (P<0.05), and the detection rate of carotid artery thickening was significantly higher in CAA than in CAE and NCA (P<0.05). The Gensini and SYNTAX scores were significantly higher in CAA than in CAE (P<0.05). The percentages of CD62P and PAC-1 were higher in CAA and CAE than in NCA (P<0.05). The arachidonic acid aggregation rate in CAA and adenosine 5'-diphosphate aggregation rate in CAE were significantly higher than in NCA (P<0.05). The values of thrombin formation time and reaction time were significantly lower in CAE than in NCA (P<0.05), and the α angle was significantly higher in CAE than in NCA. CONCLUSIONS: CAE was closely related to inflammation, whereas CAA was closely related to atherosclerosis. Platelet activation was present in both diseases; therefore, antiplatelet therapy is recommended.

Platelet function testing guided antiplatelet therapy reduces cardiovascular events in Chinese patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention: The PATROL study.

BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor has become the standard of care to reduce thrombotic events in patients with acute coronary syndrome or after percutaneous coronary intervention (PCI). The role of routine platelet function testing (PFT) in patients treated with DAPT after PCI remains controversial and evidence of PFT-guided antiplatelet therapy for patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI is limited. METHODS: We analyzed 1,353 consecutive STEMI patients undergoing primary PCI. PFT was performed 72 hr postprocedure using a vasodilator-stimulated phosphoprotein assay. The primary endpoint of major adverse cardio-cerebral events (MACCEs) was defined as a composite of all-cause death, cardiac death, nonfatal myocardial infarction, target vessel revascularization, and ischemic stroke. Patients with high platelet reactivity (HPR) were randomized to receive an intensified antiplatelet strategy by switching from clopidogrel to ticagrelor (HPR switch group) or to continue on clopidogrel (HPR nonswitch group). One-year clinical outcomes were compared among the groups. RESULTS: The baseline clinical characteristics were comparable across all groups (all p > .05). At the 1-year clinical follow-up, the primary endpoint of MACCE was significantly higher in the HPR nonswitch group than in the non-HPR and HPR switch groups (19.49% vs. 10.20% or 8.57%, p < .05), which was mainly caused by higher mortality (14.87% vs. 4.51% or 5.71%, p < .05). Major bleeding events were comparable across the groups. CONCLUSIONS: In STEMI patients with HPR, identified by vasodilator stimulated phosphoprotein (VASP)-determined PFT, switching clopidogrel to ticagrelor could significantly improve 1-year clinical outcomes without increasing the risk of bleeding.

Predictors and prognosis of left ventricular thrombus in post-myocardial infarction patients with left ventricular dysfunction after percutaneous coronary intervention.

BACKGROUND: We aimed to investigate the predictors and prognosis of left ventricular thrombus (LVT) in patients admitted for post-myocardial infarction (MI) and left ventricular dysfunction after contemporary percutaneous coronary intervention (PCI). METHODS: We prospectively enrolled 267 consecutive post-MI patients with left ventricular ejection fraction (LVEF) <0.45 based on the Shanghai East Hospital PCI database since 2012. Altogether 25 (9.36%) patients were selected as the LVT group. Baseline, angiographic, procedural characteristics and 1-year clinical outcomes were compared by Chi-square test, t-test or Kaplan-Meier survival analysis as appropriate. Receiver operating characteristic (ROC) curves were plotted for the accuracy of the multivariate analysis model. A multiple logistic regression was applied to predict LVT formation. RESULTS: The independent risk factors of LVT were left ventricular aneurysm [odds ratio (OR): 1.29, 95% confidence interval (CI): 1.09-1.52, P<0.01], incomplete revascularization (OR: 0.05, 95% CI: 0.01-0.35, P<0.01), SYNTAX score (OR: 1.28, 95% CI: 1.14-1.43, P<0.01) and D-dimer (OR: 1.90, 95% CI: 1.19-3.04, P<0.01). The SYNTAX score and D-dimer effectively indicated the development of LVT with optimal cutoff values of 29.50 and 1.53 mg/L, respectively. Patients with LVT had significantly worse outcomes at 1-year clinical follow-up, especially higher incidence of ischemic or hemorrhagic stroke. CONCLUSIONS: This study indicated that the presence of left ventricular aneurysm, incomplete revascularization, higher SYNTAX score and D-dimer level were the independent predictors of LVT formation in post-MI and LV dysfunction patients, which related to worse clinical outcomes. Future studies for early intervention and complete revascularization in high-risk subgroup patients are expected.

Mechanical stresses induce paracrine ß-2 microglobulin from cardiomyocytes to activate cardiac fibroblasts through epidermal growth factor receptor.

By employing a proteomic analysis on supernatant of mechanically stretched cardiomyocytes, we found that stretch induced a significantly high level of ß-2 microglobulin (ß2M), a non-glycosylated protein, which is related to inflammatory diseases but rarely known in cardiovascular diseases. The present data showed that serum ß2M level was increased in patients with hypertension and further increased in patients with chronic heart failure (HF) as compared with control group, and the high level of serum ß2M level correlated to cardiac dysfunction in these patients. In pressure overload mice model by transverse aortic constriction (TAC), ß2M levels in serum and heart tissue increased progressively in a time-dependent manner. Exogenous ß2M showed pro-fibrotic effects in cultured cardiac fibroblasts but few effects in cardiomyocytes. Adeno-associated virus 9 (AAV9)-mediated knockdown of ß2M significantly reduced cardiac ß2M level and inhibited myocardial fibrosis and cardiac dysfunction but not cardiac hypertrophy at 4 weeks after TAC. In vitro, mechanical stretch induced the rapid secretion of ß2M mainly from cardiomyocytes by activation of extracellular-regulated protein kinase (ERK). Conditional medium (CM) from mechanically stretched cardiomyocytes activated cultured cardiac fibroblasts, and the effect was partly abolished by CM from ß2M-knockdown cardiomyocytes. In vivo, knockdown of ß2M inhibited the increase in phosphorylation of epidermal growth factor receptor (EGFR) induced by TAC. In cultured cardiac fibroblasts, inhibition of EGFR significantly attenuated the ß2M-induced the activation of EGFR and pro-fibrotic responses. The present study suggests that ß2M is a paracrine pro-fibrotic mediator and associated with cardiac dysfunction in response to pressure overload.

Heat-shock transcription factor 1 is critically involved in the ischaemia-induced cardiac hypertrophy via JAK2/STAT3 pathway.

Cardiac hypertrophy after myocardial infarction (MI) is an independent risk factor for heart failure. Regression of cardiac hypertrophy has emerged as a promising strategy in the treatment of MI patients. Here, we have been suggested that heat-shock transcription factor 1 (HSF1) is a novel repressor of ischaemia-induced cardiac hypertrophy. Ligation of left anterior descending coronary was used to produce MI in HSF1-deficient heterozygote (KO), HSF1 transgenic (TG) mice and their wild-type (WT) littermates, respectively. Neonatal rat cardiomyocytes (NRCMs) were treated by hypoxia to mimic MI in vitro. The HSF1 phosphorylation was significantly reduced in the infarct border zone of mouse left ventricles (LVs) 1 week after MI and in the hypoxia-treated NRCMs. HSF1 KO mice showed more significant maladaptive cardiac hypertrophy and deteriorated cardiac dysfunction 1 week after MI compared to WT MI mice. Deficiency of HSF1 by siRNA transfection notably increased the hypoxia-induced myocardial hypertrophy in NRCMs. Mechanistically, Janus kinase 2 (JAK2) and its effector, signal transducer and activator of transcription 3 (STAT3) were found to be significantly increased in the LV infarct border zone of WT mice after MI as well as the NRCMs treated by hypoxia. These alterations were more significant in HSF1 KO mice and NRCMs transfected with HSF1 SiRNA. Inversely, HSF1 TG mice showed significantly ameliorated cardiac hypertrophy and heart failure 1 week after LAD ligation compared to their WT littermates. Our data collectively demonstrated that HSF1 is critically involved in the pathological cardiac hypertrophy after MI via modulating JAK2/STAT3 signalling and may constitute a potential therapeutic target for MI patients.

Ryanodine Receptor Type 2 Plays a Role in the Development of Cardiac Fibrosis under Mechanical Stretch Through TGFß-1.

Ryanodine receptor type 2 (RyR-2), the main Ca2+ release channel from sarcoplasmic reticulum in cardiomyocytes, plays a vital role in the regulation ofmyocardial contractile function and cardiac hypertrophy. However, the role of RyR-2 in cardiac fibrosis during the development of cardiac hypertrophy remains unclear.In this study, we examined whether RyR-2 regulates TGFß1, which is secreted from cardiomyocytes and exerts on cardiac fibrosis using cultured cardiomyocytes and cardiac fibroblasts of neonatal rats. The expression of RyR-2 was found only in cardiomyocytesbut not in cardiac fibroblasts. Mechanical stretch induced upregulation of TGFß1 in cardiomyocytes and RyR-2 knockdown significantly suppressed the upregulation of TGFß1 expression. The transcript levels of collagen genes were also decreased in fibroblasts compare with wild type, although the expression of both two kinds was higher than those in stationary cardiomyocytes (non-stretch). With the inhibition of the TGFß1-neutralizing antibody, the expression of collagen genes has no significant difference between the mechanically stretched cardiomyocytes and non-stretchedones. These results indicate that RyR-2 regulated TGFß1 expression in mechanically stretched cardiomyocytes and TGFß1 promoted collagen formation of cardiac fibroblasts by a paracrine mechanism.RyR-2 in mechanical stretch could promote the development of cardiac fibrosis involving TGFß1-dependent paracrine mechanism. Our findings provided more insight into comprehensively understanding the molecular role of RyR-2 in regulating cardiac fibrosis.

Ultrasound biomicroscopy validation of a murine model of cardiac hypertrophic preconditioning: comparison with a hemodynamic assessment.

In mice, myocardial hypertrophic preconditioning (HP), which is produced by the removal of short-term transverse aortic constriction (TAC), was recently reported to render the heart resistant to hypertrophic responses induced by subsequent reconstriction (Re-TAC). However, there is no efficient noninvasive method for ensuring that the repeated aortic manipulations were successfully performed. We previously demonstrated that ultrasound biomicroscopy (UBM) is a noninvasive and effective approach for predicting TAC success. Here, we investigated the value of UBM for serial predictions of load conditions in establishing a murine HP model. C57BL/6J mice were subjected to a sham operation, TAC, or Re-TAC, and the peak flow velocity at the aortic banding site (PVb) was measured by UBM. Left ventricular end-systolic pressure (LVESP) was examined by micromanometric catheterization. The PVb was positively associated with LVESP (R2 = 0.8204, P < 0.001, for TAC at 3 days and R2 = 0.7746, P < 0.001, for Re-TAC at 4 wk). PVb and LVESP values were markedly elevated after aortic banding, became attenuated to the sham-operated level after debanding, and increased after aortic rebanding. The cardiac hypertrophic responses were examined by UBM, histology, RT-PCR, and Western blot analysis. Four weeks after the last operation, with PVb ≥ 3.5 m/s as an indicator of successful aortic constriction, Re-TAC mice showed less cardiac hypertrophy, fetal gene expression, and ERK1/2 activation than TAC mice. Therefore, we successfully established a UBM protocol for the serial assessment of aortic flow and the prediction of LVESP during repeated aortic manipulations in mice, which might be useful for noninvasive evaluations of the murine HP model.NEW & NOTEWORTHY We successfully developed an ultrasound biomicroscopy protocol for the serial assessment of aortic bandings and the relevant left ventricular pressure in a murine model of cardiac hypertrophic preconditioning. The protocol may be of great importance in the successful establishment of the hypertrophic preconditioning model for further mechanistic and pharmacological studies.

Heat shock transcription factor 1 protects against pressure overload-induced cardiac fibrosis via Smad3.

Fibrotic cardiac muscle exhibits high stiffness and low compliance which are major risk factors of heart failure. Although heat shock transcription factor 1 (HSF1) was identified as an intrinsic cardioprotective factor, the role that HSF1 plays in cardiac fibrosis remains unclear. Our study aims to investigate the role of HSF1 in pressure overload-induced cardiac fibrosis and the underlying mechanism. HSF1 phosphorylation was significantly downregulated in transverse aortic constriction (TAC)-treated mouse hearts and mechanically stretched cardiac fibroblasts (cFBs). HSF1 transgenic (TG) mice, HSF1 deficient heterozygote (KO) mice, and their wild-type littermates were subjected to sham or TAC surgery for 4 weeks. HSF1 overexpression significantly attenuated pressure overload-induced cardiac fibrosis and dysfunction. Conversely, HSF1 KO mice showed deteriorated fibrotic response and cardiac dysfunction upon TAC. Moreover, we uncovered that overexpression of HSF1 protected against fibrotic response of cFBs to pressure overload. Mechanistically, we observed that the phosphorylation and the nuclear distribution of the Smad family member 3 (Smad3) were significantly decreased in HSF1-overexpressing mouse hearts, while being greatly increased in HSF1 KO mouse hearts upon TAC, compared to the control hearts, respectively. Similar alteration of Smad3 phosphorylation and nuclear distribution were found in isolated mouse cardiac fibroblasts and mechanically stretched cFBs. Constitutively active Smad3 blocked the anti-fibrotic effect of HSF1 in cFBs. Furthermore, we found a direct binding of phosphorylated HSF1 and Smad3, which can be suppressed by mechanical stress. In conclusion, the present study demonstrated for the first time that HSF1 acts as a novel negative regulator of cardiac fibrosis by blocking Smad3 activation. KEY MESSAGES: HSF1 activity is decreased in fibrotic hearts. HSF1 overexpression attenuates pressure overload-induced cardiac fibrosis and dysfunction. Deficiency of HSF1 deteriorates fibrotic response and cardiac dysfunction upon TAC. HSF1 inhibits phosphorylation and nuclear distribution of Smad3 via direct binding to Smad3. Active Smad3 blocks the anti-fibrotic effect of HSF1.

The effects of different angiotensin II type 1 receptor blockers on the regulation of the ACE-AngII-AT1 and ACE2-Ang(1-7)-Mas axes in pressure overload-induced cardiac remodeling in male mice.

Angiotensin II (AngII) type 1 receptor blockers (ARBs) have been effectively used in hypertension and cardiac remodeling. However, the differences among them are still unclear. We designed this study to examine and compare the effects of several ARBs widely used in clinics, including Olmesartan, Candesartan, Telmisartan, Losartan, Valsartan and Irbesartan, on the ACE-AngII-AT1 axis and the ACE2-Ang(1-7)-Mas axis during the development of cardiac remodeling after pressure overload. Although all of the six ARBs, attenuated the development of cardiac hypertrophy and heart failure induced by transverse aortic constriction (TAC) for 2 or 4weeks in the wild-type mice evaluated by echocardiography and hemodynamic measurements, the degree of attenuation by Olmesartan, Candesartan and Losartan tended to be larger than that of the other three drugs tested. Additionally, the degree of downregulation of the ACE-AngII-AT1 axis and upregulation of the ACE2-Ang(1-7)-Mas axis was higher in response to Olmesartan, Candesartan and Losartan administration in vivo and in vitro. Moreover, in angiotensinogen-knockdown mice, TAC-induced cardiac hypertrophy and heart failure were inhibited by Olmesartan, Candesartan and Losartan but not by Telmisartan, Valsartan and Irbesartan administration. Furthermore, only Olmesartan and Candesartan could downregulate the ACE-AngII-AT1 axis and upregulate the ACE2-Ang(1-7)-Mas axis in vitro. Our data suggest that Olmesartan, Candesartan and Losartan could effectively inhibit pressure overload-induced cardiac remodeling even when with knockdown of Ang II, possibly through upregulation of the expression of the ACE2-Ang(1-7)-Mas axis and downregulation of the expression of the ACE-AngII-AT1 axis. In contrast, Telmisartan, Valsartan and Irbesartan only played a role in the presence of AngII, and Losartan had no effect in the presence of AngII in vitro.

Mechanical Stress Regulates Endothelial Progenitor Cell Angiogenesis Through VEGF Receptor Endocytosis.

The clinical goal of cell-based treatment for chronic heart failure is to coordinately reconstitute the cardiomyocytes and associated circulation environment including coronary resistance arteries, arterioles, and capillary profiles.(1)) This goal can be possibly achieved by implementing multipotent adult stem cells. However, it remains a challenge to modify the capillary network in the decompensated heart. A mechanical stress model was used in this study to mimic the hemodynamic and hormonal states of the decompensated heart in vitro. The angiogenesis role of endothelial progenitor cells (EPCs) under stress has been well-recognized in vascular repair. We investigated the molecular mechanisms of EPCs in this model. We found that expression of vascular endothelial growth factor (VEGF) in EPCs was significantly decreased by mechanical stress, and this effect was accompanied by a decrease in angiogenesis in vitro. Interestingly, the defective angiogenesis can be reversed by upregulating the membrane VEGF receptor (VEGFR) endocytosis. An atypical protein kinase C (aPKC) inhibitor can promote the VEGFR internalization in EPCs and enhance the formation of vascular networks. Thus, the upregulation of VEGFR endocytosis in EPCs could be a potential therapy for the cell-based treatment of chronic heart failure by enhancing the cardiomyocytes.

Exenatide Reduces Tumor Necrosis Factor-α-induced Apoptosis in Cardiomyocytes by Alleviating Mitochondrial Dysfunction.

BACKGROUND: Tumor necrosis factor-α (TNF-α) plays an important role in progressive contractile dysfunction in several cardiac diseases. The cytotoxic effects of TNF-α are suggested to be partly mediated by reactive oxygen species (ROS)- and mitochondria-dependent apoptosis. Glucagon-like peptide-1 (GLP-1) or its analogue exhibits protective effects on the cardiovascular system. The objective of the study was to assess the effects of exenatide, a GLP-1 analogue, on oxidative stress, and apoptosis in TNF-α-treated cardiomyocytes in vitro. METHODS: Isolated neonatal rat cardiomyocytes were divided into three groups: Control group, with cells cultured in normal conditions without intervention; TNF-α group, with cells incubated with TNF-α (40 ng/ml) for 6, 12, or 24 h without pretreatment with exenatide; and exenatide group, with cells pretreated with exenatide (100 nmol/L) 30 mins before TNF-α (40 ng/ml) stimulation. We evaluated apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry, measured ROS production and mitochondrial membrane potential (MMP) by specific the fluorescent probes, and assessed the levels of proteins by Western blotting for all the groups. RESULTS: Exenatide pretreatment significantly reduced cardiomyocyte apoptosis as measured by flow cytometry and TUNEL assay at 12 h and 24 h. Also, exenatide inhibited excessive ROS production and maintained MMP. Furthermore, declined cytochrome-c release and cleaved caspase-3 expression and increased bcl-2 expression with concomitantly decreased Bax activation were observed in exenatide-pretreated cultures. CONCLUSION: These results suggested that exenatide exerts a protective effect on cardiomyocytes, preventing TNF-α-induced apoptosis; the anti-apoptotic effects may be associated with protection of mitochondrial function.