Cardiac Myocyte Death Research Articles

Early Cardiac Ischemia–Reperfusion Injury: Interactions of Autophagy with Galectin-3 and Oxidative Stress

Background: Cardiovascular diseases are the leading cause of death worldwide, including the United Arab Emirates. Ischemia–reperfusion (IR) injury results in the death of cardiac myocytes that were viable immediately before myocardial reperfusion. We aim to investigate the role of galectin-3 (Gal-3) in autophagy during ischemia–reperfusion injuries. Methods: Male C57B6/J and Gal-3 knockout (KO) mice were used for the murine model of IR injury. Heart samples and serum were collected 24 h post-IR and were processed for immunohistochemical and immunofluorescent labeling and an enzyme-linked immunosorbent assay. Results: There was a significant increase in left ventricle (LV) concentrations of Gal-3 in Gal-3 wild-type mice compared to sham mice. There were significantly higher concentrations of LV autophagy proteins and phospho-AMPK in IR Gal-3 KO mice than in IR Gal-3 wild-type mice, compared to lower concentrations of LV phospho-mTOR and p62 in IR Gal-3 KO than in IR wild-type mice. Antioxidant activities were higher in the LVs of IR Gal-3 wild-type mice, while oxidative stress was higher in the LVs of IR Gal-3 KO mice. Conclusions: Our study supports the interaction of Gal-3 with autophagy proteins, oxidative stress, and antioxidant proteins and demonstrates that the absence of Gal-3 can enhance autophagy in the heart after IR injury.

The effect of HIV seropositivity on inpatient outcomes in atrial tachyarrhythmias: a US population analysis

Abstract Background With the advent of antiretroviral therapy, the life expectancy of persons living with HIV(PLHIV) has been significantly prolonged and we are now seeing this group increasingly affected by chronic conditions. Atrial fibrillation is the most common sustained tachyarrhythmias in adults and commonly coexists with atrial flutter. HIV-1 especially has been shown to possess a specific cardiac tropism in which chronic immune activation and inflammation may lead to cytotoxicity and death of cardiac myocytes. It has also been associated with left atrial enlargement, which may increase arrhythmia generation and propagation. The effect of HIV on outcomes in atrial tachyarrhythmias have been poorly studied, so we therefore wanted to explore this influence on in-patient outcomes. Purpose To assess the effect of HIV seropositivity on inhospital outcomes of patients admitted with atrial fibrillation/flutter (AF) Method The study uses data from the HCUP-NIS database, which includes billing information from hospitals across the US. The study population included patients admitted with a principal diagnosis of atrial fibrillation or atrial flutter in 2020. Patients with HIV positivity were identified using ICD-10 codes. Multivariate regression was used to analyze outcomes while adjusting for confounders. They were classified into two groups: AF-only (AF-O) and AF with HIV (AF-H). Results A total of 400,715 patients were admitted with a primary diagnosis of atrial fibrillation/flutter in 2020, 1175 were PLHIV. Patients in the AF-H group were more likely to be younger, non-Caucasian, tobacco smokers, have lower median income, be uninsured, have HFrEF and CKD. They however had lower rates of HFpEF than persons in the AF-O group. After adjusting for hospital level confounders, the in-hospital mortality rate was similar between the two groups (aOR 0.46 95% CI 0.05-3.98, p=0.48). The rates of ischemic stroke/systemic embolization, major bleeding, in hospital respiratory failure, length of stay and total hospital charges were also not significantly different Conclusion The study suggests that AF patients with HIV have similar in-hospital mortality rates as patients without. There are significant differences in the economic and ethnic makeup of the two groups but these did not significantly influence the outcomes of interest. Larger cohorts will be needed to confirm these findings definitively, especially as more persons with HIV continue surviving past the sixth decade of life.

Abstract Tu048: Viscoelastic remodeling of the left ventricular myocardium in myocardial infarction

Introduction. Myocardial infarction (MI) leads to cardiac myocyte death and the formation of a fibrotic scar in the left ventricular myocardium (LV). LV free wall (LVFW) remodeling in MI is known to significantly alter the biomechanical response of the LV and, in turn, LV function. While changes in the elastic behavior of the LVFW in MI have been reported, changes in the viscoelastic behavior of the LVFW remain understudied. Our objective in this study was to determine the changes in the stress relaxation behavior of the LVFW in MI. Methods. MI was induced in rats via the ligation of the LAD artery, and hearts were harvested for three groups: sham, 2-week (2wk), and 4wk post-MI (n=3 for each group). Prior to sacrifice, echocardiography was performed to estimate ejection fraction (EF). LVFW specimens were harvested and subjected to viscoelastic stress relaxation tests. The specimens were stretched to 15% along the circumferential and longitudinal directions and allowed to relax. The stress was normalized against the peak (initial) stress for each specimen for proper comparison across the groups. Results. The EF at 2wk and 4wk specimens was reduced compared to the sham specimens (Fig. 1A). The 4wk post-MI specimens showed slower stress relaxation compared to that in the sham and 2wk specimens in both directions (Figs. 1B, C). Considering a 2-minute stress relaxation span, the normalized stress in the 4wk specimens was significantly higher than the sham specimens in both directions (Fig. 1D). Conclusions. Our results suggest that the viscoelastic relaxation rate of the LVFW diminishes at late MI timepoints. A larger and more mature scar in the LVFW is expected to contribute to slower relaxation at late MI. Future studies can determine the effect of LVFW viscoelastic remodeling on LV diastolic dysfunction and impaired relaxation in MI.

Angiotensin II Is Involved in MLKL Activation During the Development of Heart Failure Following Myocardial Infarction in Rats.

Several reports assume that myocardial necroptotic cell death is induced during the development of chronic heart failure. Although it is well accepted that angiotensin II induces apoptotic cell death of cardiac myocytes, the involvement of angiotensin II in the induction of myocardial necroptosis during the development of heart failure is still unknown. Therefore, we examined the role of angiotensin II in myocardial necroptosis using rat failing hearts following myocardial infarction and cultured cardiomyocytes. We found that administration of azilsartan, an angiotensin II AT1 receptor blocker, or trandolapril, an angiotensin-converting enzyme inhibitor, to rats from the 2nd to the 8th week after myocardial infarction resulted in preservation of cardiac function and attenuation of mixed lineage kinase domain-like (MLKL) activation. Furthermore, the ratio of necroptotic cell death was increased in neonatal rat ventricular cardiomyocytes cultured with conditioned medium from rat cardiac fibroblasts in the presence of angiotensin II. This increase in necroptotic cells was attenuated by pretreatment with azilsartan. Furthermore, activated MLKL was increased in cardiomyocytes cultured in conditioned medium. Pretreatment with azilsartan also prevented the conditioned medium-induced increase in activated MLKL. These results suggest that angiotensin II contributes to the induction of myocardial necroptosis during the development of heart failure.

Diabetic Cardiomyopathy and Cell Death: Focus on Metal-Mediated Cell Death.

Cardiac myocyte death is an essential initiator of the pathogenesis and progression of various etiological cardiomyopathies, including diabetic cardiomyopathy (DCM), a disease that has been reported since 1972. Cardiac cell death has been detected in the hearts of patients with diabetes and in animal models, and the role of cell death in the pathogenesis of DCM has been extensively investigated. The first review by the authors, specifically focusing on "Cell death and diabetic cardiomyopathy," was published in the journal, Cardiovascular Toxicology in 2003. Over the past two decades, studies investigating the role of cardiac cell death in the pathogenesis of DCM have gained significant attention, resulting in the discovery of several new kinds of cell death involving different mechanisms, including apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and cuproptosis. After the 20th anniversary of the review published in 2003, we now provide an update with a focus on the potential role of metal-mediated cell death, ferroptosis, and cuproptosis in the development of DCM in compliance with this special issue. The intent of our review is to further stimulate work in the field to advance the body of knowledge and continue to drive efforts to develop more advanced therapeutic approaches to prevent cell death, particularly metal-dependent cell death, and, ultimately, to reduce or prevent the development of DCM.

Role of protease-activated receptor 4 in mouse models of acute and chronic kidney injury.

Protease-activated receptor 4 (PAR4) is a G protein-coupled receptor activated by thrombin. In the platelet, response to thrombin PAR4 contributes to the predominant procoagulant microparticle formation, increased fibrin deposition, and initiation of platelet-stimulated inflammation. In addition, PAR4 is expressed in other cell types, including endothelial cells. Under inflammatory conditions, PAR4 is overexpressed via epigenetic demethylation of the PAR4 gene, F2RL3. PAR4 knockout (KO) studies have determined a role for PAR4 in ischemia-reperfusion injury in the brain, and PAR4 KO mice display normal cardiac function but present less myocyte death and cardiac dysfunction in response to acute myocardial infarction. Although PAR4 has been reported to be expressed within the kidney, the contribution of PAR4 to acute kidney injury (AKI) and chronic kidney disease (CKD) is not well understood. Here we report that PAR4 KO mice are protected against kidney injury in two mouse models. First, PAR4 KO mice are protected against induction of markers of both fibrosis and inflammation in two different models of kidney injury: 1) 7 days following unilateral ureter obstruction (UUO) and 2) an AKI-CKD model of ischemia-reperfusion followed by 8 days of contralateral nephrectomy. We further show that PAR4 expression in the kidney is low in the control mouse kidney but induced over time following UUO. PAR4 KO mice are protected against blood urea nitrogen (BUN) and glomerular filtration rate (GFR) kidney function pathologies in the AKI-CKD model. Following the AKI-CKD model, PAR4 is expressed in the collecting duct colocalizing with Dolichos biflorus agglutinin (DBA), but not in the proximal tubule with Lotus tetragonolobus lectin (LTL). Collectively, the results reported in this study implicate PAR4 as contributing to the pathology in mouse models of acute and chronic kidney injury.NEW & NOTEWORTHY The contribution of the thrombin receptor protease-activated receptor 4 (PAR4) to acute kidney injury (AKI) and chronic kidney disease (CKD) is not well understood. Here we report that PAR4 expression is upregulated after kidney injury and PAR4 knockout (KO) mice are protected against fibrosis following kidney injury in two mouse models. First, PAR4 KO mice are protected against unilateral ureter obstruction. Second, PAR4 KO mice are protected against an AKI-CKD model of ischemia-reperfusion followed by contralateral nephrectomy.

TCH-165 attenuates cardiac ischaemia/reperfusion injury by balancing mitochondrial dynamics via increasing proteasome activity

The proteasome is the main complex responsible for maintaining intracellular protein homeostasis, impairment of which is associated with cardiac ischaemia/reperfusion (I/R) injury. The small molecule TCH-165 has been found to activate the 20S proteasome to remove disordered proteins in multiple myeloma and glioblastoma. However, the preventive effect of TCH-165 against I/R-mediated cardiac impairment in mice remains largely unknown. Here, a cardiac I/R model was established in mice. Heart function was assessed with echocardiography. Cardiac infarction, myocyte death, and superoxide level were evaluated by 2,3,5-triphenyltetrazolium chloride (TTC)-Evans blue staining, terminal deoxynucleotidyl transferase-mediated dUTP nick and labelling (TUNEL) assay and immunostaining, respectively. Our results showed that TCH-165 treatment markedly ameliorated I/R-mediated cardiac dysfunction and decreased the infarct size, apoptosis, and superoxide levels. Mechanistically, TCH-165 increased immunoproteasome subunit expression/activity, increasing pro-fission protein dynamin-1-like protein (DNM1L, also known as DRP1) degradation and the expression of the pro-fusion proteins mitofusin 1/2 (Mfn1/2) and thereby leading to mitochondrial fission/fusion balance. In vitro experiments confirmed that inhibition of proteasome activity by epoxomicin abolished the protective effect of TCH-165 against hypoxia/reoxygenation (H/R)-induced increases in cardiomyocyte apoptosis, superoxide production and mitochondrial fission. In summary, TCH-165 is a newly discovered inducer of immunoproteasome activity that exerts a preventive effect against cardiac I/R damage by targeting Drp1 degradation, indicating that it may be as a potential therapeutic candidate for ischaemic heart disease.

Effects of Δ9-Tetrahydrocannabinol and the Aminoalkylindole K2/Spice Constituent JWH-073 on Cardiac Tissue and Mesenteric Vascular Reactivity.

Background: Although use of Cannabis sativa is not associated with serious adverse effects, recreational use of aminoalkylindole (AAI) cannabinoid receptor agonists found in K2/Spice herbal blends has been reported to cause adverse cardiovascular events, including angina, arrhythmia, changes in blood pressure, ischemic stroke, and myocardial infarction. Δ9-Tetrahydrocannabinol (Δ9-THC) is the primary CB1 agonist found in cannabis and JWH-073 is one of the AAI CB1 agonists found in K2/Spice brands sold to the public. Methods: This study used in vitro, in vivo, and ex vivo approaches to investigate potential differences on cardiac tissue and vascular effects betweenJWH-073 and Δ9-THC. Male C57BL/6 mice were treated with JWH-073 or Δ9-THC and cardiac injury was assessed by histology. Effects of JWH-073 and Δ9-THC on H9C2 cell viability and ex vivo mesenteric vascular reactivity were also determined. Results: JWH-073 or Δ9-THC induced typical cannabinoid effects of antinociception and hypothermia but did not promote death of cardiac myocytes. No differences in cell viability were observed in cultured H9C2 cardiac myocytes after 24 h of treatment. In isolated mesenteric arteries from drug-naive animals, JWH-073 produced significantly greater maximal relaxation (96%±2% vs. 73%±5%, p<0.05) and significantly greater inhibition of phenylephrine-mediated maximal contraction (Control 174%±11%KMAX) compared with Δ9-THC (50%±17% vs. 119%±16%KMAX, p<0.05). Discussion: These findings suggest that neither cannabinoid at the concentrations/dose studied caused cardiac cell death, but JWH-073 has the potential for greater vascular adverse events than Δ9-THC through an increased vasodilatory effect.

A Micro-anatomical Model of the Infarcted Left Ventricle Border Zone to Study the Influence of Collagen Undulation.

Myocardial infarction (MI) results in cardiac myocyte death and often initiates the formation of a fibrotic scar in the myocardium surrounded by a border zone. Myocyte loss and collagen-rich scar tissue heavily influence the biomechanical behavior of the myocardium which could lead to various cardiac diseases such as systolic heart failure and arrhythmias. Knowledge of how myocyte and collagen micro-architecture changes affect the passive mechanical behavior of the border zone remains limited. Computational modeling provides us with an invaluable tool to identify and study the mechanisms driving the biomechanical remodeling of the myocardium post-MI. We utilized a rodent model of MI and an image-based approach to characterize the three-dimensional (3-D) myocyte and collagen micro-architecture at various timepoints post-MI. Left ventricular free wall (LVFW) samples were obtained from infarcted hearts at 1-week and 4-week post-MI (n = 1 each). Samples were labeled using immunoassays to identify the extracellular matrix (ECM) and myocytes. 3-D reconstructions of the infarct border zone were developed from confocal imaging and meshed to develop high-fidelity micro-anatomically accurate finite element models. We performed a parametric study using these models to investigate the influence of collagen undulation on the passive micromechanical behavior of the myocardium under a diastolic load. Our results suggest that although parametric increases in collagen undulation elevate the strain amount experienced by the ECM in both early- and late-stage MI, the sensitivity of myocytes to such increases is reduced from early to late-stage MI. Our 3-D micro-anatomical modeling holds promise in identifying mechanisms of border zone maladaptation post-MI.

Contractile Adaptation of the Left Ventricle Post-myocardial Infarction: Predictions by Rodent-Specific Computational Modeling.

Myocardial infarction (MI) results in cardiac myocyte death and the formation of a fibrotic scar in the left ventricular free wall (LVFW). Following an acute MI, LVFW remodeling takes place consisting of several alterations in the structure and properties of cellular and extracellular components with a heterogeneous pattern across the LVFW. The normal function of the heart is strongly influenced by the passive and active biomechanical behavior of the LVFW, and progressive myocardial structural remodeling can have a detrimental effect on both diastolic and systolic functions of the LV leading to heart failure. Despite important advances in understanding LVFW passive remodeling in the setting of MI, heterogeneous remodeling in the LVFW active properties and its relationship to organ-level LV function remain understudied. To address these gaps, we developed high-fidelity finite-element (FE) rodent computational cardiac models (RCCMs) of MI using extensive datasets from MI rat hearts representing the heart remodeling from one-week (1-wk) to four-week (4-wk) post-MI timepoints. The rat-specific models (n = 2 for each timepoint) integrate detailed imaging data of the heart geometry, myocardial fiber architecture, and infarct zone determined using late gadolinium enhancement prior to terminal measurements. The computational models predicted a significantly higher level of active tension in remote myocardium in early post-MI hearts (1-wk post-MI) followed by a return to near the control level in late-stage MI (3- and 4-wk post-MI). The late-stage MI rats showed smaller myofiber ranges in the remote region and in-silico experiments using RCCMs suggested that the smaller fiber helicity is consistent with lower contractile forces needed to meet the measured ejection fractions in late-stage MI. In contrast, in-silico experiments predicted that collagen fiber transmural orientation in the infarct region has little influence on organ-level function. In addition, our MI RCCMs indicated that reduced and potentially positive circumferential strains in the infarct region at end-systole can be used to infer information about the time-varying properties of the infarct region. The detailed description of regional passive and active remodeling patterns can complement and enhance the traditional measures of LV anatomy and function that often lead to a gross and limited assessment of cardiac performance. The translation and implementation of our model in patient-specific organ-level simulations offer to advance the investigation of individualized prognosis and intervention for MI.

Interpreting High-Sensitive Troponins in Patients with Hypertension.

As the high-sensitivity cardiac troponin (hs-cTn) becomes more broadly used, physicians must understand the strengths and limitations of using the hs-cTn in the hypertensive population. The most common cause of hs-cTn elevation is cardiac myocyte injury and death; alternate mechanisms for hs-cTn elevation in the absence of cardiac myocyte death are not clearly understood. Hs-cTn elevation has been found in significant proportions of patients with asymptomatic hypertension, in patients with acute hypertensive crisis, and has even been used to predict patients who will go on to develop hypertension. While the mechanisms remain undefined, there is evidence that elevations in hs-cTn are associated with both short- and long-term morbidity and mortality. While ongoing research further defines the relationship between hypertension and hs-cTn, the emergency medicine physician must make clinical decisions today regarding the utility of this increasingly used biomarker. Given the current evidence, clinical context must be utilized including a complete clinical picture, EKGs findings, and importantly serial hs-cTn when needed to establish whether myocardial injury or myocardial infarction is occurring.

Identification of Infarct Border Zone Using Late Gadolinium Enhanced MRI in Rats

BackgroundFollowing acute myocardial infarction (MI), cardiac myocyte death and the formation of a fibrotic scar in the left ventricular free wall (LVFW) alters the biomechanical behavior of the myocardium resulting in changes to organ‐level function. Despite significant advances in understanding LVFW remodeling in the setting of MI, the extent of tissue remodeling in the regions where infarct tissue transitions to healthy tissue, commonly called the border zone (BZ), is not well understood. Additionally, the effect of alterations in biomechanical behavior of the BZ on LV pump function remains understudied. We hypothesize that image‐based cardiac modeling can effectively address this gap. To this end, our objective was to develop an automated method to identify the infarct and BZ regions in rats using ex‐vivo late gadolinium‐enhanced magnetic resonance images (LGE‐MRI) and make use of these delineations to study regional structural remodeling in MI.MethodsAnterobasal MI was induced in Wistar‐Kyoto rats (n=2) by ligating the left anterior descending artery. Prior to sacrifice, subjects in the infarct group were given gadolinium contrast agent for MRI enhancement. Animals were sacrificed at 4 weeks post‐infarct and cardiac MRI scans were performed at an isotropic 100 µm resolution. The mean value of the voxel signal‐intensity (SI) of the posterobasal region of the heart was calculated and is hereafter referred to as the baseline SI (BSI). The image voxels were then segmented in to three regions by using the following SIs as threshold value cutoffs: i) SI of greater than 125% of BSI was considered infarcted myocardium, ii) SI between 115% and 125% of BSI was considered BZ, iii) SI of less than 115% BSI was considered remote myocardium. The geometry and dimensions of the infarct region were confirmed with measurements from the excised heart of the animal.ResultsIncreased SI was noted in the anterobasal region of the infarcted hearts (Fig 1), indicating myocyte necrosis and scar formation. Mean SI of the infarct region defined via this method was 1.6‐fold larger compared to that of the remote region. The infarct region resulting from the automated identification method closely matched the gemometry and dimensions of the infarct scar region of the excised hearts.ConclusionsThe extent of myocardial remodeling in LVFW during the post‐infarct healing process determines the contractile behavior in the LVFW and influences long‐term outcomes. Automated identification of infarct, BZ, and remote myocardium regions using LGE‐MRI is a step towards image‐based characterization of the heterogenous remodeling in the LVFW. Additionally, our algorithm enables the simple definition of a BZ of varied size and could allow us to better understand the influence of distinct regional remodeling events on organ‐level function as MI proceeds from early‐stage scarring to late‐stage remodeling.

TRAF2, an Innate Immune Sensor, Reciprocally Regulates Mitophagy and Inflammation to Maintain Cardiac Myocyte Homeostasis

Mitochondria are essential for cardiac myocyte function, but damaged mitochondria trigger cardiac myocyte death. Although mitophagy, a lysosomal degradative pathway to remove damaged mitochondria, is robustly active in cardiac myocytes in the unstressed heart, its mechanisms and physiological role remain poorly defined. We discovered a critical role for TRAF2, an innate immunity effector protein with E3 ubiquitin ligase activity, in facilitating physiological cardiac myocyte mitophagy in the adult heart, to prevent inflammation and cell death, and maintain myocardial homeostasis.

249 Prognostic role of diagnostic criteria of acute myocardial infarction

Abstract Aims The term acute myocardial infarction (AMI) reflects cell death of cardiac myocytes caused by ischaemia. The Fourth Universal Definition of Myocardial Infarction (UDMI) defined AMI by a typical rise and fall in the level of biochemical markers of myocardial necrosis together with criteria of myocardial ischaemia. However, the prognostic role of each single diagnostic criteria has never been explored. To evaluate the prognostic role of the different diagnostic criteria of AMI according to the Fourth UDMI. Methods and results We enrolled all consecutive patients with AMI admitted from 2016 to 2019. We used a combination of criteria, according to the current ESC guidelines, to meet the diagnosis, namely the detection of an increase and/or decrease of high-sensitivity cardiac troponin I, with at least one value above the 99th percentile of the upper reference limit and at least one of the following: symptoms of ischaemia; ECG changes (new ST-T changes or new left bundle branch block); development of pathological Q waves in the ECG; imaging evidence of new loss of viable myocardium or new regional wall motion abnormality, in our study evaluated by transthoracic echocardiogram. All-cause mortality and a composite endpoint of all-cause mortality, re-hospitalization for heart failure, and myocardial re-infarction were collected. The predictive value of diagnostic criteria alone and its association were evaluated using Kaplan–Meier survival curves and subsequent Cox-regression analysis to find independent predictors of adverse events. 2386 patients were evaluated. The median follow-up time was 23.3 ± 14.5 months. The total number of events was 703 (29.5%). Kaplan–Meier curves showed that major adverse cardiac events (MACEs) were statistically different depending on the diagnostic criteria of AMI at admission. Particularly, clinical criteria alone showed a better predictive value (P &amp;lt; 0.001) than other diagnostic AMI criteria. Multivariable Cox-regression model demonstrated that clinical criteria were the independent predictor of good prognosis in patients with AMI (HR = 0.43; 95% CI: 0.28–0.67; P &amp;lt; 0.001). Conversely, the other diagnostic criteria (electrocardiographic and echocardiographic) and the combination of all diagnostic criteria were not independent prognostic factors of MACEs (HR = 1.1; 95% CI: 0.6–2.4, P = 0.6; HR = 1.1; 95% CI: 0.7–1.9, P = 0.6; HR = 0.9; 95% CI: 0.7–1.0, P = 0.2, respectively). Conclusions Our data suggest that the prognosis is considerably better among patients with a diagnosis of AMI if clinical criteria alone are present at admission. We also demonstrated that clinical criteria are a strong prognostic predictor of good outcomes in patients with AMI. We hypothesize that the absence of electrocardiographic and echocardiographic alterations could indirectly indicate a smaller infarct sizes that contribute to patients’ outcome.

Evaluation of the effect of diastolic function on prognosis of patient with septic shock

Abstract Background Septic shock remains the leading cause of death in the intensive care unit (ICU), with an increasing incidence and a current mortality rate of approximately 30 %. Sepsis was defined by the presence of at least two criteria of systemic inflammatory response syndrome associated with a clinically or microbiologically documented, or a highly suspected infection. Severe sepsis was defined as a sepsis associated with at least one organ failure different from that responsible for the infection. Septic shock was defined as a severe sepsis associated with low blood pressure despite adequate vascular filling which required a vasopressor support. Cardiac dysfunction in sepsis is driven primarily by release of cytokines, mitochondrial dysfunction, and tissue hypoxia that leads to cardiac myocyte injury and death. Aim of the Work The aim of this study was to evaluate the effect of diastolic function on prognosis of septic shock in patients admitted to an intensive care unit (ICU). Patient and Methods This study was conducted on (50) patients with septic shock admitted to an intensive care unit (ICU) from November 2017 to November 2018. Results These patients was divided according to cardiac echocardiography findings into two groups:-Group 1:- 25 patients with preserved diastolic function and diastolic dysfunction grade I; 12 Male and 13 Female were included in the study, the average age was 43.44±13.69.Group 2:- Another 25 patients with diastolic dysfunction grade II and grade III; 11 Males and 14 Females were included in the study, the average age was 47.28±15.7. Conclusion We recommend assessment of patients admitted to the ICU with septic shock via echocardiography to determine the grade of diastolic dysfunction and using diastolic dysfunction as a predictive risk factor in various score assessment of ICU patients. Our study was limited by decreased sample size and we recommend further studies with increased sample size..

Abstract MP265: The Role Of Phosphodiesterase 10a In Tumor Growth And Doxorubicin-induced Cardiotoxicity.

Cyclic nucleotide phosphodiesterases (PDEs), through the degradation of cyclic nucleotides, play critical roles in cardiovascular biology and disease. PDE10A is able to hydrolyze both cAMP and cGMP. Its high expression in medium spiny neurons of the human striatum has led to the development of several PDE10A inhibitors with the intent to treat various psychiatric/neurodegenerative disorders, such as schizophrenia and Huntington's disease. Our previous study has reported the upregulation of PDE10A expression in failing hearts and demonstrated the protective effects of PDE10A deficiency/inhibition against cardiac hypertrophy, fibrosis, and dysfunction in mouse models of heart failure. Doxorubicin (DOX) is an effective chemotherapeutic agent against a variety of cancers. While its therapeutic utility is limited by the development of dose-dependent cardiotoxicity. In the current study, we aim to determine the role of PDE10A in cancer and cardiotoxicity induced by DOX. We found that PDE10A inhibition or deficiency alleviated DOX-induced cardiotoxicity in vivo, as well as cardiac myocyte (CM) death and atrophy in vitro. In ovarian cancer cells, PDE10A inhibition induced cell death and reduced cell proliferation; as well as potentiated the effect of DOX on antagonizing cancer cells. Interestingly, in nude mice with ovarian cancer xenografts, PDE10A inhibition attenuated ovarian tumor growth while protected DOX-induced cardiotoxicity. RNAseq and bioinformatics analysis uncovered a number of PDE10A-regulated signaling pathways and cellular processes involved in DOX-induced cardiotoxicity. Mechanistic studies further revealed that PDE10A regulates CM death and atrophy via different mechanistic actions: regulating CM death via a cGMP-dependent while cAMP-independent mechanism; and regulating CM atrophy via a mechanism dependent on both cGMP and cAMP. Several PDE10A inhibitors have been tested in humans and successfully passed phase I clinical trials for safety. Thus, our findings suggest that PDE10A may be a safe "druggable" target for cancer therapy by simultaneously preventing DOX-induced cardiotoxicity and antagonizing tumor growth.

"Regulatory Roles for miR-126 in Inflammatory Response and Programmed Death of Cardiac Myocytes Driven by Acidosis During Simulated Ischemia"

Cardiac myocyte cell death by apoptosis accompanies heart disease of both ischemic and nonischemic origin...

Free fatty acid receptor 4 responds to endogenous fatty acids to protect the heart from pressure overload.

Free fatty acid receptor 4 (Ffar4) is a G-protein-coupled receptor for endogenous medium-/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress. In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodelling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-day post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signalling and oxylipin synthesis and the reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced the production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, the activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high-density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signalling-deficient Ffar4 R270H polymorphism correlated with eccentric remodelling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC. Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.

CIGARETTES THAT BROKE HER HEART: COPD-INDUCED TAKOTSUBU CARDIOMYOPATHY

SESSION TITLE: Medical Student/Resident Obstructive Lung Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Takotsubo cardiomyopathy (TCM) is a form of sudden transient LV dysfunction often associated with severe emotional and physical stressors; that mimics ACS. Currently, there are limited studies showing the relationship between COPD and TCM. We present a case of Takotsubo cardiomyopathy in a post-menopausal female secondary to AECOPD. CASE PRESENTATION: A 70-year-old female with a history of COPD, HTN, and smoking presented with severe midsternal chest pain and SOB associated with increased cough and sputum production. On arrival, she was tachycardic, tachypneic, and hypoxic. She had decreased air entry in bilateral lung fields with expiratory wheeze, respiratory acidosis, and hyperinflated lungs on CXR. She received multiple Ipratropium-Albuterol nebulizations for AECOPD resulting in symptomatic improvement. Further workup revealed EKG findings of new hyperacute T waves in V3-V6, TWI in V1 and V2; and up-trending Troponin I which peaked at 7.13. She was managed as Type I NSTEMI with Aspirin, Clopidogrel & IV Heparin. Emergent LHC showed 60% occlusion of RCA. TTE revealed a hyperkinetic base with hypokinetic apical and mid anterior wall, new-onset reduced LVEF of 40 to 45%, consistent with TCM. Her noncritical coronary artery disease was not considered to be contributing to her symptom burden and did not correspond to her EKG and echocardiographic findings. Follow up TTE in 6 months revealed improvement in LVEF to 55 to 60% with a resolution of apical hypokinesis. Given the history of no further psychosocial stressors most likely etiology for her TCM was stress related to acute COPD. DISCUSSION: AECOPD related respiratory failure leading to hypoxemia and hypercapnia has been identified as a potential physical trigger of TCM. Catecholamine excess plays a central role in stress-related apical myocardial stunning and coronary vasospasm; reducing the viability of myocytes via cAMP-mediated calcium overload resulting in contraction band necrosis. Hypoxia with coexisting acidosis causes cardiomyocyte damage through activation of BCL-2 family of proapoptotic proteins leading to changes in mitochondrial permeability and DNA fragmentation. Potential mechanisms include sympathetic overstimulation due to the administration of beta-agonist in the setting of endogenous catecholamine excess from the stress of respiratory failure and concurrent administration of ipratropium resulting in inhibition of parasympathetic system, tachycardia, and rarely paradoxical bronchospasm. It is unclear whether respiratory failure from COPD leading to hypoxia and hypercapnia or repeated use of Albuterol-Ipratropium caused TCM in our patient. CONCLUSIONS: In our case, we highlight that by early recognition of COPD induced TCM; complications could be minimized by limiting the use of beta-agonists and treating ongoing cardiac dysfunction. Further studies are required to establish the exact mechanism of COPD induced TCM. Reference #1: Sharkey S, Windenburg D, et al. "Natural History and Expansive Clinical Profile of Stress (Tako-Tsubo) Cardiomyopathy.” J Am Coll Cardiol., 2010 Jan 26; 55(4):333-341. DOI: https://doi.org/10.1016/j.jacc.2009.08.057 Reference #2: Wittstein I, Thiemann D, et al. "Neurohumoral features of myocardial stunning due to sudden emotional stress.” N Engl J Med. 2005 Feb 10; 352:539-548 https://doi.org/10.1056/NEJMoa043046 Reference #3: Kubasiak, Lori A. and Hernandez, Olga M. and Bishopric, Nanette H. and Webster, Keith A., "Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3.” Proceedings of the National Academy of Science, 2002 Oct; 99(20): 12825-12830. DOI = 10.1073/pnas.202474099 DISCLOSURES: No relevant relationships by Tahreem Ahmad, source=Web Response No relevant relationships by Khubaib Ahmad, source=Web Response No relevant relationships by Waqas Ali, source=Web Response No relevant relationships by Pranali Santhoshini Pachika, source=Web Response

EIF4A3-Induced circ-BNIP3 Aggravated Hypoxia-Induced Injury of H9c2 Cells by Targeting miR-27a-3p/BNIP3

Acute myocardial infarction (AMI) results from long-term diminished blood supply diminishment (ischemia) to the heart, and the main reason for ischemia is hypoxia. BCL2 interaction protein 3 (BNIP3) can be upregulated by hypoxia and participates in the mediation of hypoxia-activated apoptosis in cardiac myocyte death. The purpose of this study was to interrogate the mechanism of BNIP3 in hypoxia-activated cardiac myocyte injury. Cell viability and apoptosis were evaluated by Cell counting kit 8 (CCK-8), 5-ethynyl-2’-deoxyuridine (EdU), TdT-mediated dUTP Nick-End Labeling (TUNEL), and caspase-3 activity assays. Molecular interactions were assessed by RNA immunoprecipitation (RIP) and pull-down assays. Gene levels were assessed via quantitative real-time PCR and western blot. BNIP3 expression was upregulated by hypoxia in H9c2 cells. We found that circ-BNIP3 (hsa_circ_0005972), whose annotated gene was BNIP3, was induced by hypoxia and positively regulated BNIP3 expression. Knockdown of BNIP3 or circ-BNIP3 reversed the effect of hypoxia in attenuating H9c2 cell viability and inducing apoptosis. circ-BNIP3 sponged miRNA-27a-3p (miR-27a-3p) to upregulate BNIP3 expression. Moreover, eukaryotic translation initiation factor 4A3 (EIF4A3) bound with the upstream region of the circ-BNIP3 mRNA transcript and induced circ-BNIP3 expression in H9c2 cells. EIF4A3-induced circ-BNIP3 aggravated hypoxia-caused injury of H9c2 cells through targeting miR-27a-3p/BNIP3 pathway, indicating circ-BNIP3 as a new target for relieving hypoxia-induced injury of cardiac myocytes.