GSDMD-mediated pyroptosis promotes cardiac remodeling in pressure overload.

BACKGROUND: Gasdermin D (GSDMD) forms membrane pores to execute pyroptosis. But the mechanism of how cardiomyocyte pyroptosis induces cardiac remodeling in pressure overload remains unclear. We investigated the role of GSDMD-mediated pyroptosis in the pathogenesis of cardiac remodeling in pressure overload. METHODS: Wild-type (WT) and cardiomyocyte-specific GSDMD-deficient (GSDMD-CKO) mice were subjected to transverse aortic constriction (TAC) to induce pressure overload. Four weeks after surgery, left ventricular structure and function were evaluated by echocardiographic, invasive hemodynamic and histological analysis. Pertinent signaling pathways related to pyroptosis, hypertrophy and fibrosis were investigated by histochemistry, RT-PCR and western blotting. The serum levels of GSDMD and IL-18 collected from healthy volunteers or hypertensive patients were measured by ELISA. RESULTS: We found TAC induced cardiomyocyte pyroptosis and release of pro-inflammatory cytokines IL-18. The serum GSDMD level was significantly higher in hypertensive patients than in healthy volunteers, and induced more dramatic release of mature IL-18. GSDMD deletion remarkably mitigated TAC-induced cardiomyocyte pyroptosis. Furthermore, GSDMD deficiency in cardiomyocytes significantly reduced myocardial hypertrophy and fibrosis. The deterioration of cardiac remodeling by GSDMD-mediated pyroptosis was associated with activating JNK and p38 signaling pathways, but not ERK or Akt signaling pathway. CONCLUSION: In conclusion, our results demonstrate that GSDMD serves as a key executioner of pyroptosis in cardiac remodeling induced by pressure overload. GSDMD-mediated pyroptosis activates JNK and p38 signaling pathways, and this may provide a new therapeutic target for cardiac remodeling induced by pressure overload.

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.

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.

HSF1 deficiency accelerates the transition from pressure overload-induced cardiac hypertrophy to heart failure through endothelial miR-195a-3p-mediated impairment of cardiac angiogenesis.

Heat shock transcription factor 1 (HSF1) deficiency aggravates cardiac remodeling under pressure overload. However, the mechanism is still unknown. Here we employed microRNA array analysis of the heart tissue of HSF1-knockout (KO) mice to investigate the potential roles of microRNAs in pressure overload-induced cardiac remodeling under HSF-1 deficiency, and the profiles of 478 microRNAs expressed in the heart tissues of adult HSF1-KO mice were determined. We found that the expression of 5 microRNAs was over 2-fold higher expressed in heart tissues of HSF1-KO mice than in those of wild-type (WT) control mice. Of the overexpressed microRNAs, miR-195a-3p had the highest expression level in HSF1-null endothelial cells (ECs). Induction with miR-195a-3p in ECs significantly suppressed CD31 and VEGF, promoted AngII-induced EC apoptosis, and impaired capillary-like tube formation. In vivo, the upregulation of miR-195a-3p accentuated cardiac hypertrophy, increased the expression of ß-MHC and ANP, and compromised systolic function in mice under pressure overload induced by transverse aortic constriction (TAC). By contrast, antagonism of miR-195a-3p had the opposite effect on HSF1-KO mice. Further experiments confirmed that AMPKα2 was the direct target of miR-195a-3p. AMPKα2 overexpression rescued the reduction of eNOS and VEGF, and the impairment of angiogenesis that was induced by miR-195a-3p. In addition, upregulation of AMPKα2 in the myocardium of HSF1-null mice by adenovirus-mediated gene delivery enhanced CD31, eNOS and VEGF, reduced ß-MHC and ANP, alleviated pressure overload-mediated cardiac hypertrophy and restored cardiac function. Our findings revealed that the upregulation of miR-195a-3p due to HSF1 deficiency impaired cardiac angiogenesis by regulating AMPKα2/VEGF signaling, which disrupted the coordination between the myocardial blood supply and the adaptive hypertrophic response and accelerated the transition from cardiac hypertrophy to heart failure in response to pressure overload.

Differential cardiac hypertrophy and signaling pathways in pressure versus volume overload.

Mechanical overload can be classified into pressure overload and volume overload, causing concentric and eccentric cardiac hypertrophy, respectively. Here, we aimed to differentiate the load-mediated signaling pathways involved in pressure versus volume overload cardiac hypertrophy. Pressure or volume overload was imposed on C57BL/6J mice by transverse aortic constriction (TAC) or aortic regurgitation (AR), respectively. After surgery (2 wk), left ventricular structure and function were evaluated by echocardiographic, hemodynamic, and histological analyses. Signaling pathways related to hypertrophy, fibrosis, angiogenesis, and apoptosis were studied by histological analysis, RT-PCR, and Western blot analysis. Although mean wall stress was similar in both TAC and AR mice, systolic wall stress was significantly increased in TAC and diastolic wall stress was mainly elevated in AR. TAC or AR induced concentric or eccentric compensated hypertrophy, respectively. TAC was associated with more significant fibrosis and apoptosis, whereas AR was associated with more significant angiogenesis. MAPK kinase family, ß-arrestin-2, Akt, and Ca2+-related signaling pathways were markedly activated in TAC but mildly upregulated or unchanged in AR. Pressure overload and volume overload induce different phenotypic and molecular adaptations in cardiac hypertrophy. Most load-related signaling pathways assessed in this study predominate in pressure but not volume overload. The stimulus-specific heterogeneity in the signaling pathways requires distinct manipulations for further mechanistic and pharmacological studies. NEW & NOTEWORTHY Using the transverse aortic constriction mouse model and the newly developed aortic regurgitation mouse model, we delineated the prominent differences between concentric and eccentric cardiac hypertrophy on morphological, functional, and molecular levels. Our findings are important for the precise diagnosis and treatment of these two types of cardiac hypertrophy. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/chinese-english-language-podcast-on-differential-cardiac-remodeling-in-tac-vs-ar/ .

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.

Characterization of coronary flow reserve and left ventricular remodeling in a mouse model of chronic aortic regurgitation with carvedilol intervention.

OBJECTIVES: We hypothesized that left ventricular (LV) remodeling might be exaggerated by an impaired coronary flow reserve in mice with chronic severe aortic regurgitation, and carvedilol, a ß-adrenoceptor blocker, could regress the course. METHODS: Severe aortic regurgitation was induced by retrograde puncture of the aortic valve leaflets under sonographic guidance in 12-week-old male C57BL/6J mice. Four weeks after regurgitation, the mice were treated with carvedilol (30 mg/kg/d) or not treated (control). Before and 4 weeks after carvedilol treatment, the coronary flow reserve and LV structure and function were evaluated by echocardiography. Cardiomyocytes and fibrosis were validated by histologic analysis. RESULTS: Four-week aortic regurgitation caused a decreased LV ejection fraction and an increased LV end-systolic volume index. Regurgitation also impaired the coronary flow reserve due to an increase in the basal coronary peak diastolic velocity and velocity-time integral combined with the absence of substantial changes in the hyperemic coronary peak diastolic velocity and velocity-time integral. Four more weeks of regurgitation further deteriorated LV remodeling and coronary perfusion in the control group. In contrast, the carvedilol-treated group showed attenuated LV remodeling and a higher coronary flow reserve by decreasing the basal peak diastolic velocity and velocity-time integral without substantial changes in the hyperemic peak diastolic velocity and velocity-time integral. The coronary flow reserve and its pretreatment versus posttreatment difference were positively correlated with the pretreatment versus posttreatment LV ejection fraction and end-systolic volume index differences. In the carvedilol-treated group, subendocardial fibrosis was significantly reduced (P < .05), and the cardiomyocyte cross-sectional area tended to be smaller. CONCLUSIONS: In mice with chronic severe aortic regurgitation, carvedilol therapy significantly improves the impaired coronary flow reserve and sufficiently attenuates adverse LV remodeling. Sustained coronary flow reserve impairment indicates progressive LV remodeling.

The interplay between autophagy and apoptosis in the diabetic heart.

Diabetic cardiomyopathy is characterized by ventricular dysfunction that occurs in diabetic patients independent of coronary artery disease, hypertension, and any other cardiovascular diseases. Diabetic cardiomyopathy has become a major cause of diabetes-related mortality. Thus, an urgent need exists to clarify the mechanism of pathogenesis. Emerging evidence demonstrates that diabetes induces cardiomyocyte apoptosis and suppresses cardiac autophagy, indicating that the interplay between the autophagy and apoptotic cell death pathways is important in the pathogenesis of diabetic cardiomyopathy. This review highlights recent advances in the crosstalk between autophagy and apoptosis and its importance in the development of diabetic cardiomyopathy. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy".

Insights into the activation and inhibition of angiotensin II type 1 receptor in the mechanically loaded heart.

In the heart, mechanical load is a crucial regulator of myocardial structure and function; however, mechanical overload is a pathogenesis or comorbidity existing in a variety of heart diseases, such as hypertension, aortic regurgitation and myocardial infarction. Mechanical overload can be generally differentiated into 2 types, pressure overload (PO) and volume overload (VO), causing concentric and eccentric cardiac hypertrophy, respectively. The angiotensin II (AngII) type 1 receptor (AT1-R) is a 7 transmembrane G protein-coupled receptor that plays a critical role in load-induced cardiac hypertrophy. Early studies revealed the involvement of autocrine/paracrine mechanisms through stretch-induced release of AngII. Recent conceptually inspiring studies unraveled that the AT1-R could be also directly activated by mechanical stress. The activated AT1-R initiates intricate intracellular signaling pathways through G protein-dependent and G protein-independent mechanisms. AT1-R blocker (ARB) antagonizes the activation of AT1-R to regress cardiac remodeling. Some ARBs show properties of inverse agonism and arrestin-biased agonism at the AT1-R, which are potential therapeutic targets for the treatment of load-induced cardiac hypertrophy. This review summarizes the progress in the understanding of ligand- and mechanical stress-dependent activation of AT1-R, highlights recent data that investigate the role of AT1-R in the differentiation of PO- and VO-induced cardiac hypertrophy, and discusses the clinical relevance of inverse agonism and biased agonism of AT1-R ligands.

Aliskiren ameliorates pressure overload-induced heart hypertrophy and fibrosis in mice.

AIM: Aliskiren (ALK) is a renin inhibitor that has been used in the treatment of hypertension. The aim of this study was to determine whether ALK could ameliorate pressure overload-induced heart hypertrophy and fibrosis, and to elucidate the mechanisms of action. METHODS: Transverse aortic constriction (TAC) was performed in mice to induce heart pressure overload. ALK (150 mg·kg(-1)·d(-1), po), the autophagy inhibitor 3-methyladenine (10 mg·kg(-1) per week, ip) or the PKCßI inhibitor LY333531 (1 mg·kg(-1)·d-(1), po) was administered to the mice for 4 weeks. Heart hypertrophy, fibrosis and function were evaluated based on echocardiography, histological and biochemical measurements. Mechanically stretched cardiomyocytes of rats were used for in vitro experiments. The levels of signaling proteins were measured using Western blotting, while the expression of the relevant genes was analyzed using real-time QRT-PCR. RESULTS: TAC induced marked heart hypertrophy and fibrosis, accompanied by high levels of Ang II in plasma and heart, and by PKCßI/α and ERK1/2 phosphorylation in heart. Meanwhile, TAC induced autophagic responses in heart, i.e. increases in autophagic structures, expression of Atg5 and Atg16 L1 mRNAs and LC3-II and Beclin-1 proteins. These pathological alterations in TAC-mice were significantly ameliorated or blocked by ALK administration. In TAC-mice, 3-methyladenine administration also ameliorated heart hypertrophy, fibrosis and dysfunction, while LY333531 administration inhibited ERK phosphorylation and autophagy in heart. In mechanically stretched cardiomyocytes, CGP53353 (a PKCßI inhibitor) prevented ERK phosphorylation and autophagic responses, while U0126 (an ERK inhibitor) blocked autophagic responses. CONCLUSION: ALK ameliorates heart hypertrophy, fibrosis and dysfunction in the mouse model in setting of chronic pressure overload, via suppressing Ang II-PKCßI-ERK1/2-regulated autophagy.

Olmesartan attenuates cardiac remodeling through DLL4/Notch1 pathway activation in pressure overload mice.

BACKGROUND: Notch1 signaling controls the cardiac adaptation to stress. We therefore aimed to validate whether olmesartan, a widely used angiotensin II type 1 receptor blocker, ameliorates cardiac remodeling and dysfunction via delta-like ligand 4 (DLL4)/Notch1 pathway in mice with chronic pressure overload. METHODS: Cardiac pressure overload was produced by transverse aortic constriction (TAC). A total of 35 wide-type C57BL/6J mice were randomly divided into sham group, TAC group, TAC + olmesartan group, and TAC + olmsartan + DAPT group (DAPT: γ-secretase inhibitor, Notch signaling inhibitor). Saline (10 mL·kg(-1)·d(-1)) or the same volume of olmesartan liquor (3 mg·kg(-1) d(-1)) was administered by gavage, and DAPT (10 µmole·kg(-1)·d(-1)) by peritoneal injection. After 28 days of treatment, cardiac hemodynamics, echocardiography, and histology were evaluated, followed by quantitative polymerase chain reaction of fetal gene (ANP and SAA) expression. Notch1-related proteins and ERK1/2 were examined by western blot, and the serum level of angiotensin II was determined by means of enzyme-linked immunosorbent assay kits. RESULTS: Persistent pressure overload-induced left ventricular hypertrophy, dysfunction, fibrosis, and microcirculation dysfunction, together with the upregulation of angiotensin II, ERK1/2, and fetal gene expression. By the activation of DLL4/Notch1, olmesartan decreased left ventricular hypertrophy and fibrosis, preserved cardiac function, and improved capillary density and coronary perfusion. All these curative effects were suppressed by pharmacological blockade of Notch signaling with DAPT. CONCLUSIONS: Our findings identify a heretofore unknown pharmacological mechanism that olmesartan improves cardiac remodeling and function via DLL4/Notch1 pathway activation in mice with chronic pressure overload, which may present a new therapeutic target for hypertension.

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.

Comparison between adenosine and isoflurane for assessing the coronary flow reserve in mouse models of left ventricular pressure and volume overload.

Adenosine and high-concentration isoflurane are commonly used to induce hyperemia for assessment of coronary flow reserve (CFR) in mice, but high-concentration isoflurane may exacerbate cardiac dysfunction, leading to impaired CFR. However, there is no study be found comparing the effects of adenosine and isoflurane on CFR and corresponding cardiac function. High-resolution echocardiography and invasive hemodynamic assessment were performed in 20 mice 2 wk after transverse aortic constriction (TAC), aortic regurgitation (AR), and corresponding sham operation. CFR was calculated as the ratio of hyperemic to basal peak diastolic velocity (CFRpdv) or diastolic velocity-time integral (CFRdvti). In the sham-operated mice, no differences were observed between the effects of adenosine and isoflurane on CFR, left ventricular systolic function (left ventricular ejection fraction and fractional shortening), left ventricular end-systolic pressure, maximal contraction and relaxation velocity (+dp/dt and -dp/dt), alteration of left ventricular pressure (ΔLVP), or ±dp/dt (Δdp/dt). But adenosine-derived results were significantly higher than isoflurane-derived ones in both the TAC and the AR groups. Moreover, CFRpdv or CFRdvti was positively correlated with both LVEF and LVFS. Compared with adenosine-derived CFR, isoflurane-derived CFR may be underestimated in the TAC and the AR mice, which is probably associated with suppressed cardiac function.

Noninvasive estimation of infarct size in a mouse model of myocardial infarction by echocardiographic coronary perfusion.

OBJECTIVES: Animal models of myocardial infarction (MI) are widely used not only in analyses of the mechanisms but also in testing the efficacy of therapeutic strategies for the disease. It is therefore critically important but almost impossible to exactly evaluate the validity of coronary artery ligation in a mouse model of MI except by anatomic and histologic analyses. We explored a noninvasive method to estimate MI through analyses of coronary perfusion by transthoracic echocardiography in mice before and 1 day after ligation of the left anterior descending coronary artery. METHODS: Transthoracic echocardiography-based cardiac function, geometry, and coronary perfusion, electrocardiographic findings, and serum troponin I levels were examined in C57BL6/J mice subjected to left anterior descending artery ligation. The histologic infarct size was confirmed by staining the heart with 2,3,5-triphenyltetrazolium chloride. RESULTS: Among all parameters, the postoperative hyperemic peak diastolic velocity and coronary flow reserve were most correlated with infarct size (R² = .8028 and .5825, respectively; both P < .0001). With an infarct size of 30% or greater indicating successful ligation and less than 30% indicating unsuccessful ligation, receiver operating characteristic curve analysis showed that the postoperative hyperemic peak diastolic velocity and coronary flow reserve most effectively indicated the infarct size level with optimal cutoff values of 480.16 mm/s and 1.89, respectively. Furthermore, impaired cardiac function, an eccentrically expanded left ventricle, typical pathologic electrocardiographic findings, and elevated troponin I levels were observed most often in the mice with an impaired hyperemic peak diastolic velocity and coronary flow reserve. CONCLUSIONS: The echocardiographic hyperemic peak diastolic velocity and coronary flow reserve can estimate the histologic infarct size in mice with coronary occlusion.

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.

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.

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.

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.