Myocardial Response Research Articles

Abstract P367: ‘Youthful’ Phenotype Of C-kit+ Cardiac Fibroblasts

Introduction: Fibroblasts are critical contributors to myocardial development, tissue homeostasis and remodeling. Cardiac fibroblast population heterogeneity and plasticity present a challenge for categorization of biological and functional properties. Distinct molecular markers and associated signaling pathways provide valuable insight for cardiac fibroblast biology and interventional strategies to influence injury response and remodeling. Receptor tyrosine kinase c-Kit mediates cell survival, proliferation, migration, and is activated by pathological injury. However, the biological significance of c-Kit within cardiac fibroblast population has not been addressed. Approach: An inducible c-Kit reporter mouse detects promoter activation with Green Fluorescent Protein (GFP) expression in cardiac interstitial cells (CICs). Coincidence of GFP and c-Kit with the DDR2 fibroblast marker was confirmed at protein level using flow cytometry and immunohistochemistry. Subsequently, cardiac fibroblasts expressing DDR2 with or without c-Kit were isolated and characterized in vitro . Results: A subset of DDR2 + cardiac fibroblasts also express c-Kit with coincidence in ~8% of total CICs. Pathological injury induces coincidence as well as expression of c-Kit and DDR2. Cultured cardiac DDR2+ fibroblasts that are c-Kit+ exhibit youthful morphological and functional phenotypes compared to c-Kit- cells including 1) significantly smaller size, 2) higher cellular motility, 3) enhanced proliferation, 4) less multinucleation, 5) decreased senescence-associated β-galactosidase staining, and 6) down-regulation of p53 senescence marker. Mechanistically, c-Kit expression correlates with signaling implicated in proliferation and cell migration including phospho-ERK and pro-Caspase 3. Conclusion: The phenotype of c-kit+ on DDR2+ cardiac fibroblasts correlates with multiple characteristics of ‘youthful’ cells. To our knowledge, this represents the first evaluation of c-Kit biology within DDR2+ cardiac fibroblast population and provides a fundamental basis for future studies to influence myocardial biology, cardiac remodeling, and response to pathological injury.

New insights into the roles of glucocorticoid signaling dysregulation in pathological cardiac hypertrophy

Pathological cardiac hypertrophy is a process of abnormal remodeling of the myocardium in response to stress overload or ischemia that results in myocardial injury, which is an independent risk factor for the increased morbidity and mortality of heart failure. Elevated circulating glucocorticoids (GCs) levels are associated with an increased risk of pathological cardiac hypertrophy, but the exact role remains unclear. In the heart, GCs exerts physiological and pharmacological effects by binding the glucocorticoid receptor (GR, NR3C1). However, under the state of tissue damage or oxidative stress, GCs can also bind the closely related mineralocorticoid receptor (MR, NR3C2) to exert a detrimental effect on cardiac function. In addition, the bioavailability of GCs at the cellular level is mainly regulated by tissue-specific metabolic enzymes 11β-hydroxysteroid dehydrogenases (11β-HSDs), including 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and type 2 (11β-HSD2), which catalyze the interconversion of active GCs. In this paper, we provide an overview of GC signaling and its physiological roles in the heart and highlight the dynamic and diverse roles of GC signaling dysregulation, mediated by excessive ligand GCs levels, GR/MR deficiency or overexpression, and local GCs metabolic disorder by 11β-HSDs, in the pathology of cardiac hypertrophy. Our findings will provide new ideas and insights for the search for appropriate intervention targets for pathological cardiac hypertrophy.

Hepatic cell mobilization for protection against ischemic myocardial injury

The heart is capable of activating protective mechanisms in response to ischemic injury to support myocardial survival and performance. These mechanisms have been recognized primarily in the ischemic heart, involving paracrine signaling processes. Here, we report a distant cardioprotective mechanism involving hepatic cell mobilization to the ischemic myocardium in response to experimental myocardial ischemia–reperfusion (MI-R) injury. A parabiotic mouse model was generated by surgical skin-union of two mice and used to induce bilateral MI-R injury with unilateral hepatectomy, establishing concurrent gain- and loss-of-hepatic cell mobilization conditions. Hepatic cells, identified based on the cell-specific expression of enhanced YFP, were found in the ischemic myocardium of parabiotic mice with intact liver (0.2 ± 0.1%, 1.1 ± 0.3%, 2.7 ± 0.6, and 0.7 ± 0.4% at 1, 3, 5, and 10 days, respectively, in reference to the total cell nuclei), but not significantly in the ischemic myocardium of parabiotic mice with hepatectomy (0 ± 0%, 0.1 ± 0.1%, 0.3 ± 0.2%, and 0.08 ± 0.08% at the same time points). The mobilized hepatic cells were able to express and release trefoil factor 3 (TFF3), a protein mitigating MI-R injury as demonstrated in TFF3−/− mice (myocardium infarcts 17.6 ± 2.3%, 20.7 ± 2.6%, and 15.3 ± 3.8% at 1, 5, and 10 days, respectively) in reference to wildtype mice (11.7 ± 1.9%, 13.8 ± 2.3%, and 11.0 ± 1.8% at the same time points). These observations suggest that MI-R injury can induce hepatic cell mobilization to support myocardial survival by releasing TFF3.

Dynamics of Left Ventricular Myocardial Work in Patients Hospitalized for Acute Heart Failure

BackgroundThe left ventricular ejection fraction (LVEF) is the most commonly used measure describing pumping efficiency, but it is heavily dependent on loading conditions and therefore not well-suited to study pathophysiologic changes. The novel concept of echocardiography-derived myocardial work (MyW) overcomes this disadvantage as it is based on LV pressure–strain loops. We tracked the in-hospital changes of indices of MyW in patients admitted for acute heart failure (AHF) in relation to their recompensation status and explored the prognostic utility of MyW indices Methods and ResultsWe studied 126 patients admitted for AHF (mean 73 ± 12 years, 37% female, 40% with a reduced LVEF [<40%]), providing pairs of echocardiograms obtained both on hospital admission and prior to discharge. The following MyW indices were derived: global constructive and wasted work (GCW, GWW), global work index (GWI), and global work efficiency. In patients with HF with reduced ejection fraction with decreasing N-terminal prohormone B-natriuretic peptide levels during hospitalization, the GCW and GWI improved significantly, whereas the GWW remained unchanged. In patients with HF with preserved ejection fraction, the GCW and GWI were unchanged; however, in patients with no decrease or eventual increase in N-terminal prohormone B-natriuretic peptide, we observed an increase in GWW. In all patients with AHF, higher values of GWW were associated with a higher risk of death or rehospitalization within 6 months after discharge (per 10-point increment hazard ratio 1.035, 95% confidence interval 1.005–1.065). ConclusionsOur results suggest differential myocardial responses to decompensation and recompensation, depending on the HF phenotype in patients presenting with AHF. The GWW predicted the 6-month prognosis in these patients, regardless of LVEF. Future studies in larger cohorts need to confirm our results and identify determinants of short-term and longer term changes in MyW.

Inhibition of TNFAIP1 ameliorates the oxidative stress and inflammatory injury in myocardial ischemia/reperfusion injury through modulation of Akt/GSK-3β/Nrf2 pathway

Tumor necrosis factor α-induced protein 1 (TNFAIP1) has been documented as a vital regulator of apoptosis and oxidative stress under various pathological conditions. However, whether TNFAIP1 plays a role in myocardial ischemia/reperfusion (I/R) injury has not been well investigated. This work aimed to evaluate the possible role of TNFAIP1 in mediating myocardial I/R injury. Firstly, we demonstrated that TNFAIP1 expression was dramatically increased in rat cardiomyocytes following hypoxia/reoxygenation (H/R) in vitro, and in rat myocardial tissues following I/R treatment in vivo. Silencing of TNFAIP1 alleviated H/R-induced apoptosis, oxidative stress and inflammatory response in rat cardiomyocytes in vitro. Moreover, knockdown of TNFAIP1 ameliorated I/R-induced myocardial injury, infarction size, cardiac apoptosis, oxidative stress and inflammatory response in vivo. Further investigation elucidated that knockdown of TNFAIP1 enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling associated with modulation of the Akt/glycogen synthase kinase-3β (GSK-3β) pathway in vitro and in vivo. Inhibition of Akt markedly abrogated TNFAIP1-knockdown-mediated Nrf2 activation in cardiomyocytes following H/R injury. In addition, suppression of Nrf2 significantly diminished TNFAIP1-knockdown-induced cardioprotective effects in H/R-exposed cardiomyocytes. In summary, this work elucidates that inhibition of TNFAIP1 ameliorates myocardial I/R injury by potentiating Nrf2 signaling via the modulation of the Akt/GSK-3β pathway. Our study highlights a vital role of the TNFAIP1/Akt/GSK-3β/Nrf2 pathway in mediating myocardial I/R injury and suggests TNFAIP1 as an attractive target for treatment of this disease.

Molecular pathways in sepsis-induced cardiomyocyte pyroptosis: Novel finding on long non-coding RNA ZFAS1/miR-138–5p/SESN2 axis

ObjectiveZNFX1 antisense RNA1 (ZFAS1) has been emerged as a tumor oncogene or suppressor. However, understanding the biological role and underlying molecular mechanism of ZFAS1 in sepsis induced myocardial injury (SIMI) requires more evidence. This study was assigned to probe the effect of lncRNA ZFAS1 on sepsis-induced pyroptosis in cardiomyocytes and its underlying mechanism. MethodsSerums of 22 patients with sepsis-induced myocardial injury (SIMI) and 24 healthy controls were collected to determine the expression levels of ZFAS1 and miR-138–5p. Cardiomyocytes (H9C2) or rats were treated by lipopolysaccharide (LPS) to establish in vivo and in vitro sepsis models. H&E staining was applied to observe myocardial injury of rats. The interactions between ZFAS1 and miR-138–5p as well as miR-138–5p and SESN2 were determined by dual-luciferase reporter gene assay and RNA pull-down assay. TUNEL staining was applied to inspect apoptosis level and CCK-8 to measure cell viability. The mRNA levels of ZFAS1, miR-138–5p and SESN2 were measured by qRT-PCR, while the protein expressions of SESN2 and pyroptosis-related proteins (Caspase-1, ASC and NLRP3) were assessed by Western blotting. Levels of inflammatory factors (TNF-α, IL-1β, IL-6 and IL-18) were evaluated by ELISA. ResultsPatients with SIMI had suppressed ZFAS1 and increased miR-138–5p expression when compared with those in healthy controls. LPS treatment in rats triggered myocardial injury accompanied by interstitial edema and moderate inflammatory cell infiltration. Besides, LPS caused elevated cell apoptosis rate and enhanced cell pyroptosis and inflammation in sepsis cell models. However, ZFAS1 overexpression or SESN2 overexpression in LPS induced rats and in H9C2 cells had meliorated myocardial injury and inflammatory response, indicating that ZFAS1 and SESN2 can inhibit sepsis-induced pyroptosis of cardiomyocytes. MiR-138–5p is a target gene of ZFAS1, while miR-138–5p can negatively mediate SESN2. ZFAS1 alleviated sepsis induced cardiomyocyte pyroptosis by exerting competing endogenous RNA (ceRNA) function to indirectly regulate SESN2, which evidenced by loss and gain functions of ZFAS1 and SESN2. ConclusionLncRNA ZFAS1 serves as a ceRNA of miR-138–5p to up-regulate the expression of SESN2, thereby ameliorating sepsis-induced cardiomyocyte pyroptosis.

Predictors for the prolonged R wave peak time among patients with arterial hypertension.

Hypertension (HT) is prevalent in the general population and is associated with significant cardiovascular adverse events. Major structural and electrical remodeling occurs in the ventricular myocardium in response to the pressure overload. Increased left ventricular mass (LVM) and myocardial fibrosis contribute to the prolongation of the R wave peak time (RWPT), which may indicate electrical remodeling in patients with HT. We evaluated predictors for prolonged RWPT among patients with a previous diagnosis of HT. Consecutive patients who had a previous diagnosis of arterial HT and presented to the cardiology clinic for routine visit were included in the study. The standard 12-lead surface electrocardiography (ECG) and transthoracic echocardiography (TTE) was performed on all the patients included in the study for evaluating RWPT and the epicardial fat tissue (EFT). The upper limit for the RWPT was accepted as 40 milliseconds (ms). Between February 2019 and February 2020, 453 patients were screened; and of these, 237 were included in the study. The mean age was 62.1±11.2 years, and 41.8% of the included patients were men. The mean RWPT of the study population was 41.9±10.8. The RWPT was prolonged in 55 patients, and the remaining 172 patients had normal RWPT. In the univariate analysis, EFT (Odds ratio [OR] 1.222; 95% confidence interval [CI] 1.077-1386; p=0.002), the left ventricular mass index (LVMI) (OR 1.011; 95% CI 1.001-1.021; p=0.026), and fragmented QRS (fQRS) (OR 2.679; 95% CI 1.433-5.004; p=0.002) were associated with a prolonged RWPT. Multivariate analysis revealed that only EFT (OR 1.211; 95% CI 1.061-1.383; p=0.005) and fQRS (OR 2.796; 95% CI 1.459-5.359; p=0.002) predicted prolonged RWPT. Among the patients with HT, EFT and fQRS predicted prolonged RWPT. These findings may suggest that compared with increased LVM, myocardial fibrosis had a more significant impact on ventricular activation time.

An organ-on-a-chip model for pre-clinical drug evaluation in progressive non-genetic cardiomyopathy

Angiotensin II (Ang II) presents a critical mediator in various pathological conditions such as non-genetic cardiomyopathy. Osmotic pump infusion in rodents is a commonly used approach to model cardiomyopathy associated with Ang II. However, profound differences in electrophysiology and pharmacokinetics between rodent and human cardiomyocytes may limit predictability of animal-based experiments. This study investigates the application of an Organ-on-a-chip (OOC) system in modeling Ang II-induced progressive cardiomyopathy. The disease model is constructed to recapitulate myocardial response to Ang II in a temporal manner. The long-term tissue cultivation and non-invasive functional readouts enable monitoring of both acute and chronic cardiac responses to Ang II stimulation. Along with mapping of cytokine secretion and proteomic profiles, this model presents an opportunity to quantitatively measure the dynamic pathological changes that could not be otherwise identified in animals. Further, we present this model as a testbed to evaluate compounds that target Ang II-induced cardiac remodeling. Through assessing the effects of losartan, relaxin, and saracatinib, the drug screening data implicated multifaceted cardioprotective effects of relaxin in restoring contractile function and reducing fibrotic remodeling. Overall, this study provides a controllable platform where cardiac activities can be explicitly observed and tested over the pathological process. The facile and high-content screening can facilitate the evaluation of potential drug candidates in the pre-clinical stage.

English

BACKGROUND India is leading the world in incidence, prevalence, complications and mortality due to coronary artery disease (CAD). Various risk factors for acute coronary syndrome (ACS) are diabetes, hypertension, dyslipidaemia, smoking and obesity. It has been proposed that high serum ferritin levels are associated with enhancement in myocardial ischaemic response along with decreased ischaemic threshold in the setting up of acute ischaemic conditions. In this study, we wanted to measure and compare serum ferritin levels in patients of acute coronary syndrome and healthy controls to know the association between serum ferritin levels and risk of acute coronary syndrome. METHODS 60 patients of acute coronary syndrome admitted at Sri Guru Ram Das Hospital, Vallah Sri Amritsar were taken as cases and 60 age and sex matched healthy controls were taken. Serum ferritin levels were measured in both the cases and controls and were compared. RESULTS Most of the patients of ACS were in the age group of 51 - 60 years. Hypertension was the most common risk factor observed followed by diabetes mellitus (DM). Mean serum cholesterol levels were higher in cases. The most common vessel involved in ACS was left anterior descending artery (LAD). The difference in mean serum ferritin levels of cases and controls was statistically significant with higher levels in cases as compared to controls. These patients also had higher risk of developing heart failure and had a longer hospital stay. CONCLUSIONS The difference between serum ferritin levels in cases of ACS and controls was statistically significant. People with raised serum ferritin levels are at a greater risk of developing ACS as compared to those with normal serum ferritin levels. KEYWORDS Acute Coronary Syndrome, Serum Ferritin, Systolic Function, Diastolic Function, Mortality, Hospital Stay

Effects of Sodium-Glucose Linked Transporter 2 Inhibition With Ertugliflozin on Mitochondrial Function, Energetics, and Metabolic Gene Expression in the Presence and Absence of Diabetes Mellitus in Mice.

BackgroundInhibitors of the sodium‐glucose linked transporter 2 improve cardiovascular outcomes in patients with or without type 2 diabetes mellitus, but the effects on cardiac energetics and mitochondrial function are unknown. We assessed the effects of sodium‐glucose linked transporter 2 inhibition on mitochondrial function, high‐energy phosphates, and genes encoding mitochondrial proteins in hearts of mice with and without diet‐induced diabetic cardiomyopathy.Methods and ResultsMice fed a control diet or a high‐fat, high‐sucrose diet received ertugliflozin mixed with the diet (0.5 mg/g of diet) for 4 months. Isolated mitochondria were assessed for functional capacity. High‐energy phosphates were assessed by 31P nuclear magnetic resonance spectroscopy concurrently with contractile performance in isolated beating hearts. The high‐fat, high‐sucrose diet caused myocardial hypertrophy, diastolic dysfunction, mitochondrial dysfunction, and impaired energetic response, all of which were prevented by ertugliflozin. With both diets, ertugliflozin caused supernormalization of contractile reserve, as measured by rate×pressure product at high work demand. Likewise, the myocardial gene sets most enriched by ertugliflozin were for oxidative phosphorylation and fatty acid metabolism, both of which were enriched independent of diet.ConclusionsErtugliflozin not only prevented high‐fat, high‐sucrose–induced pathological cardiac remodeling, but improved contractile reserve and induced the expression of oxidative phosphorylation and fatty acid metabolism gene sets independent of diabetic status. These effects of sodium‐glucose linked transporter 2 inhibition on cardiac energetics and metabolism may contribute to improved structure and function in cardiac diseases associated with mitochondrial dysfunction, such as heart failure.

Protective effects of ginsenoside Rc against acute cold exposure-induced myocardial injury in rats.

Ginsenoside Rc is one of the cardinal bioactive components of Panax ginseng. The present study aimed to investigate whether ginsenoside Rc exerted protective effects against acute cold exposure-induced myocardial injury in rats. Forty rats were randomly assigned into four groups: Control, model, ginsenoside Rc 10 mg/kg, and 20 mg/kg groups. Rats were intragastrically administrated with ginsenoside Rc (10, 20 mg/kg) or vehicle daily for 7 days. On the seventh day, all rats except the control group were exposed to low temperature. Cardiac function, myocardial enzyme activities, hemorheology, and inflammatory response were detected. Histopathological examination and apoptosis of cardiac tissues were performed. The expressions of silent information regulator 1 (SIRT1), B-cell lymphoma (Bcl-2), Bcl-2-associated X (Bax), procaspase-3, and the mRNA (messenger RNA) level of SIRT1 were measured by western blot and real-time quantitative polymerase chain reaction (PCR) analysis. Ginsenoside Rc significantly improved cardiac function, diminished the activities of lactate dehydrogenase (LDH), aspartate aminotransferase, and creatine kinase isoenzyme (CK-MB), and regulated abnormal hemorheology in acute cold-exposed rats (p < 0.05 or p < 0.01). Furthermore, ginsenoside Rc could attenuate myocardial histological changes and structural abnormalities, decrease apoptotic cells and reduce the mRNA levels and activity of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 (p < 0.01). In addition, ginsenoside Rc upregulated the expressions of SIRT1, Bcl-2, and procaspase-3 and downregulated that of Bax (p < 0.01). The changes in both the mRNA and protein expression levels of SIRT1 were similar. The results of the current study suggested that ginsenoside Rc could alleviate acute cold exposure-induced myocardial injury in rats by inhibiting cardiomyocyte apoptosis via regulating SIRT1 expression and attenuating the inflammatory responses. PRACTICAL APPLICATION: The current study indicated that ginsenoside Rc could alleviate acute cold exposure-induced myocardial injury in rats. Ginsenoside Rc could be potentially used as a bioactive ingredient in processed functional food products or food supplements to prevent from acute cold exposure-induced myocardial injury.

Features of autophagy in the cytoplasm of endotheliocytes of blood capillaries in severe burn septicotoxemia

Burn injury and its consequences are an important medical and social problem, given the high mortality and disability rates. The leading cause of death in patients with extensive and deep burns is burn septicotoxemia.Material and methods. The material was the heart muscle of the anterior, posterior and lateral walls of the left ventricle of those who died from burn disease during septicotoxemia. The control group included cases of male mortality as a result of “acute coronary death”. The study of the ultrastructure of endotheliocytes of blood capillaries of the myocardium has been carried out.Results and discussion. Ultrastructural analysis of endotheliocytes of blood capillaries of the myocardium showed that in burn septicotoxemia, intracellular degradation processes are observed in the form of swelling of the cytoplasm and organelles, a decrease in the concentration of vesicular structures, as well as activation of autophagy due to the appearance of autophagosomes and autolysosomes in the cytoplasm. Activation of autophagy should be considered as a naturally developing compensatory reaction aimed at preserving the cellular pool of endotheliocytes of the blood capillaries of the myocardium in response to the alterative effect caused by burn septicotoxemia.Conclusion. The obtained data can serve as a justification for the manifestation of left ventricular contractile insufficiency, which is a consequence of endothelial dysfunction and microcirculatory disorders in the myocardium in burn septicotoxemia.

Myocardial Vascular Function Assessed by Dynamic Oxygenation-sensitive Cardiac Magnetic Resonance Imaging Long-term Following Cardiac Transplantation.

Coronary vascular function is related to adverse outcomes following cardiac transplantation (CTx) in patients with or without cardiac allograft vasculopathy (CAV). The noninvasive assessment of the myocardial vascular response using oxygenation-sensitive cardiac magnetic resonance (OS-CMR has not been investigated in stable long-term CTx recipients). CTx patients were prospectively recruited to complete a CMR study with a breathing maneuver of hyperventilation followed by a voluntary apnea. Changes in OS-sensitive signal intensity reflecting the myocardial oxygenation response were monitored and expressed as % change in response to these breathing maneuvers. Myocardial injury was further investigated with T2-weighted imaging, native and postcontrast T1 measurements, extracellular volume measurements, and late gadolinium enhancement. Forty-six CTx patients with (n = 23) and without (n = 23) CAV, along with 25 healthy controls (HC), were enrolled. The OS response was significantly attenuated in CTx compared with HC at the 30-second time-point into the breath-hold (2.63% ± 4.16% versus 6.40% ± 5.96%; P = 0.010). Compared with HC, OS response was lower in CTx without CAV (2.62% ± 4.60%; P < 0.05), while this response was further attenuated in patients with severe CAV (grades 2-3, -2.24% ± 3.65%). An inverse correlation was observed between OS-CMR, ventricular volumes, and diffuse fibrosis measured by extracellular volume mapping. In heart transplant patients, myocardial oxygenation is impaired even in the absence of CAV suggesting microvascular dysfunction. These abnormalities can be identified by oxygenation-sensitive CMR using simple breathing maneuvers.

Everyday Discrimination and Mental Stress-Induced Myocardial Ischemia.

Mental stress-induced myocardial ischemia (MSIMI), a transient myocardial ischemic response to mental stress, is associated with poorer outcomes among patients with coronary heart disease and is more likely to occur among women. However, predictors of MSIMI are not well explored. The current study investigated the association between experiences of everyday discrimination and MSIMI among patients with recent myocardial ischemia and contrasted the results with conventional stress-induced myocardial ischemia (CSIMI). We examined sex differences in associations. We studied 295 post-MI patients (145 women, 150 men). Provocation of myocardial ischemia with mental stress (speech task) and conventional stress (exercise or pharmacologic) was assessed by myocardial perfusion imaging. Frequency of exposure to everyday discrimination was assessed via questionnaire using the Everyday Discrimination Scale (EDS). The mean age was 51 years in both women and men, and the EDS score ranged from 10 to 38 (mean [standard deviation] = 17 [6] years). After multivariable analysis, each standard deviation increase in the EDS score (more frequent exposure) was associated with an increased odds of MSIMI (odds ratio [OR] = 1.57 [1.10-2.23]). The EDS score was not associated with CSIMI (OR = 0.86 [0.64-1.17]). Women demonstrated a twofold increase (OR = 1.96 [1.13-3.38], p = .02) in the adjusted odds of MSIMI, with each standard deviation increase in the EDS score compared with a 1.4-fold increase (OR = 1.40 [0.80-2.44], p = .24) among men; however, interaction was not statistically significant. Among post-MI patients, everyday discrimination was positively associated with occurrence of MSIMI, but not with CSIMI; associations were more pronounced among women.

Continuous-Flow Left Ventricular Assist Device Explantation After More Than 5 Years of Circulatory Support and Ventricular Reconditioning

Continuous-flow left ventricular assist devices have proved to be effective, durable, life-saving tools in patients with end-stage heart failure. However, because of the risks associated with mechanical circulatory support (including stroke, infection, gastrointestinal bleeding, and device malfunction), the optimal goal of device therapy is myocardial recovery and device removal. Ventricular reconditioning and pump explantation after continuous-flow support have been reported; however, little is known about variables that govern the pace and degree of myocardial response in patients who experience such recovery. We describe our long-term pump-weaning strategy for a 25-year-old man who had a continuous-flow device implanted and then needed more than 5 years of support from it before developing cardiac reserve sufficient to enable pump explantation. To our knowledge, this is the longest period of uninterrupted continuous-flow device support to end in successful pump deactivation and a return to medical therapy. This case highlights the importance of actively and persistently pursuing a device-weaning strategy in all patients who need left ventricular assist device therapy.

Naringin attenuates rat myocardial ischemia/reperfusion injury via PI3K/Akt pathway-mediated inhibition of apoptosis, oxidative stress and autophagy.

Naringin (NRG) has been reported to exert cardioprotective effects against multiple cardiovascular diseases, including lipopolysaccharide-induced and hyperglycemia-induced myocardial injury. However, the role of NRG in myocardial ischemia/reperfusion (I/R) injury remains unclear. In the present study, the PI3K/Akt pathway was investigated to evaluate the possible mechanisms underlying the roles of NRG in myocardial ischemia/reperfusion (I/R) injury. The levels of cardiac enzymes were measured by ELISA to evaluate the optimal dosage of NRG that could protect against myocardial I/R injury. Rats were administered 100 mg/kg of NRG and activities of myocardial enzymes, the level of cardiac apoptosis and inflammation, oxidant response, autophagy indicators and echocardiography were evaluated. The level of corresponding proteins was measured using western blotting. The results indicated that NRG elicited the best cardioprotective effects at a dose of 100 mg/kg by significantly reducing the levels of myocardial enzymes, apoptosis, inflammation, oxidative response and infarct size. Furthermore, NRG alleviated contractile dysfunction by increasing the left ventricular ejection fraction and fractional shortening. In addition, NRG markedly promoted the phosphorylation of Akt, while decreasing the level of autophagy indicator beclin-1 and the microtubule-associated protein 1B-light chain 3 (LC3B) II/ LC3BI ratio. However, PI3K/Akt inhibitor (LY294002) partially reduced the NRG induced phosphorylation of Akt and the reduction in beclin-1, along with the LC3BII/LC3BI ratio. The results of the present study demonstrated that NRG could attenuate myocardial I/R injury.

Moderate Aortic Stenosis: What is it and When Should We Intervene?

Current guidelines recommend aortic valve replacement in patients with severe aortic stenosis in the presence of symptoms or a left ventricular ejection fraction <50%. However, patients with less than severe aortic stenosis may also experience symptoms and recent literature suggests that the prognosis is not as benign as previously reported. There are no recommendations for patients with moderate aortic stenosis and left ventricular dysfunction, despite the high associated morbidity and mortality. There is also some evidence that these patients may benefit from early aortic valve intervention. It is recognised that aortic stenosis not only affects the valve but also has a complex myocardial response. This review discusses the natural history of moderate aortic stenosis along with the role of multimodality imaging in risk stratification in these patients.

Piceatannol protects against sepsis-induced myocardial dysfunction via direct inhibition of JAK2

Sepsis-induced myocardial dysfunction (SIMD) represents one of the serious complications secondary to sepsis, which is a leading cause of the high mortality rate among septic cases. Subsequent cardiomyocyte apoptosis, together with the uncontrolled inflammatory response, has been suggested to be closely related to SIMD. Piceatannol (PIC) is verified with potent anti-apoptotic and anti‐inflammatory effects, but its function and molecular mechanism in SIMD remain unknown so far. This study aimed to explore the potential role and mechanism of action of PIC in resisting SIMD. The interaction of PIC with JAK2 proteins was evaluated by molecular docking, molecular dynamics (MD) simulation and surface plasmon resonance imaging (SPRi). The cecal ligation and puncture-induced septicemia mice and the LPS-stimulated H9C2 cardiomyocytes were prepared as the models in vivo and in vitro, separately. Molecular docking showed that JAK2-PIC complex had the −8.279 kcal/mol binding energy. MD simulations showed that JAK2-PIC binding was stable. SPRi analysis also showed that PIC has a strong binding affinity to JAK2. PIC treatment significantly ameliorated the cardiac function, attenuated the sepsis-induced myocardial loss, and suppressed the myocardial inflammatory responses both in vivo and in vitro. Further detection revealed that PIC inhibited the activation of the JAK2/STAT3 signaling, which was tightly associated with apoptosis and inflammation. Importantly, pre-incubation with a JAK2 inhibitor (AG490) partially blocked the cardioprotective effects of PIC. Collectively, the findings demonstrated that PIC restored the impaired cardiac function by attenuating the sepsis‐induced apoptosis and inflammation via suppressing the JAK2/STAT3 pathway both in septic mice and H9C2 cardiomyocytes.

A Neonatal Mouse Model for Pressure Overload: Myocardial Response Corresponds to Severity.

The heart regeneration after apical resection and myocardial infarction in neonatal mice has been studied for years. However, the response of neonatal mouse heart under pressure overload is seldom explored. This study aimed to induce pressure overload in neonatal mice through a transverse aortic constriction (TAC) with different-gauge needles so as to investigate the effect of pressure overload on cardiomyocyte proliferation and hypertrophy in these mice. Myocardial hypertrophy was evaluated by echocardiographic, pathological, and molecular analyses. Cardiomyocyte proliferation was detected by immune-staining of phospho-histone H3, Ki67, and 5-bromo-2-deoxyuridine. Mild pressure overload induced with a 30-gauge needle stimulated cardiomyocyte proliferation, adaptive hypertrophy, and angiogenesis. The heart function was not hampered even 21 days after the surgery. Moderate pressure overload induced with a 32-gauge needle led to pathological myocardial hypertrophy, fibrosis, and heart failure 7 days after the surgery. The gene and protein expression levels of markers of hypertrophy and fibrosis increased in 32-gauge TAC group compared with that in sham and 30-gauge TAC groups. The mice barely survived after severe pressure overload induced with a 34-gauge needle. The findings of this study might provide new insights into cardiomyocyte proliferation and hypertrophy in neonatal mice under pressure overload.

Would the (too?) normal adaptation to exercise in sickle cell trait carrier be a reflection of preventive mechanisms against potential myocardial and muscle injury?

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Commission, Region Guadeloupe Background. Sickle cell trait (SCT) is an inherited red blood cell condition without medical consequence in most cases. However, its strong association with increased risk of exercise-induced sudden death (independent of pre-existing disease) or exertional collapse has been demonstrated in athletes, military recruits and firefighters. The mechanisms potentially leading to cardiac arrest during or after exercise in SCT have not been fully elucidated although contributing factors have been identified (the main one being rhabdomyolysis) or suspected. Warm environment (even without dehydration) can contribute to the occurrence of fatal events. Purpose. The aims of this study were to 1) compare the biomarkers of myocardial and muscle injury response (and their determinants) to exercise in SCT carriers and controls performing a hard bout of exercise 2) identify the potential deleterious role of warmth during exercise and recovery in SCT and non-SCT. Methods. Nine otherwise healthy 21 ± 3yo male students with SCT and 11 non-SCT (comparable in physical fitness, regular exercise participation and body mass index) were included. The volunteers performed in a randomized order 3 sessions: cycling exercise in a control (21°C) and warm (31°C) environment followed by recovery in a room at 21°C, and both exercise and recovery in a warm environment. The exercise was as follows: 18-min rectangular moderate intensity period + maximal incremental test + 3 30-s supramaximal sprints spaced with 20-s resting intervals. Recovery and hydration were planned between each exercise part. The ECG was monitored throughout exercise. Blood was sampled before and at the end of the exercise but also during the recovery including a meal up to 130-min after the end of exercise. Results. No evidence of severe cardiac injury (ECG and biomarkers), rhabdomyolysis or occlusive events (clinical signs and biomarkers), infection (complete blood count), inflammation (biomarkers) or electrolyte imbalance (ionogram) was observed in the SCT carriers of this study: indices were comparable between SCT and non-SCT carriers, with normal exercise-related evolutions and normal recovery. Interestingly, some indices however converge towards a profile with lower complication risk in SCT. The lactate concentrations tended to be lower in SCT than non-SCT during exercise (p = 0.062) and were significantly lower during the recovery in particular after exercising at 31°C but not at 21°C. The leukocytes count was lower in SCT than non-SCT (p = 0.043) and increased in a greater extent with exercise in the later (p = 0.041). The exercise-induced increase in cortisol and glucose concentrations observed in non-SCT did not occur in SCT carriers (interactions p and p = 0.040 and p = 0.033). Conclusions. Although these results do not evidence pathophysiological mechanisms, they feed the hypothesis of "storm" against which protective mechanisms could have developed and that may fail under particular conditions.