Improve Heart Function Research Articles

Effectiveness of sacubitril/valsartan for patients with cancer therapy‑related cardiac dysfunction: A systematic review of descriptive studies.

The present review assessed the effectiveness of sacubitril/valsartan in patients with cancer therapy-related cardiac dysfunction (CTRCD). Studies that included patients with CTRCD treated with sacubitril/valsartan were retrieved from the Medline, Embase, Cochrane Library and ClinicalTrials databases. Only descriptive studies on sacubitril/valsartan for patients with CTRCD were included in this review; therefore, all variables were qualitatively analyzed. A total of five studies comprising 109 patients were included. The duration from anticancer therapy to heart failure (HF) or from HF to the use of sacubitril/valsartan exhibited interindividual variations. In patients with CTRCD who were treated with sacubitril/valsartan, the left ventricular ejection fraction improved, N-terminal pro-B-type natriuretic peptide levels decreased and exercise tolerance improved, as indicated by the change in the New York Heart Association functional class. These clinical, echocardiographic and biochemical improvements were found for different dosages or treatment durations of sacubitril/valsartan. No difference was found between the baseline and follow-up serum creatinine and potassium levels. These findings, which are limited to descriptive studies, support the effectiveness of sacubitril/valsartan in improving heart function following CTRCD.

Thymus transplantation regulates blood pressure and alleviates hypertension-associated heart and kidney damage via transcription factors FoxN1 pathway

Previous studies have found that thymus is involved in the process of hypertension. However, whether thymus transplantation alleviates target organ damage in hypertensive mice remains unknown. The aim of this study was to evaluate the effects of thymus transplantation on blood pressure and target organ changes in mice with hypertension. Mice were randomly divided into normal control group (Con), hypertensive group (HTN) and thymus transplantation group (HTN + Trans). Thymus of neonatal mice was transplanted into the renal capsule of the transplantation group. After transplantation, the mouse tail noninvasive pressure was measured and heart function was evaluated weekly. Then mice were euthanized and organs or tissues were harvested at 4 weeks post-transplantation. The blood pressure of HTN + Trans group was lower than that in the HTN group. The expression of FoxN1, Aire, ATRAP, thymosin β4 and the content of sjTREC in thymus of HTN group was decreased and the number of naïve T cells in HTN group was lower compared with other two groups. The ratio of cTEC/mTEC in HTN group was higher than that in Con group and lower than that in HTN + Trans group. Cardiac pathology showed cardiac hypertrophy and fibrosis in HTN group whereas thymus transplantation improved heart function and structure. Altogether, our findings demonstrated thymus transplantation could improve thymus function of hypertensive mice, which increased the expression of thymus transcription factor FoxN1, affected the proportion of T cell subsets, and increased thymosin β4 thereby reducing blood pressure and reversing the progression of target organ damage.

Syringin exerts anti‐inflammatory and antioxidant effects by regulating SIRT1 signaling in rat and cell models of acute myocardial infarction

This study aimed to investigate the role of syringin in improving heart function during myocardial ischemia/reperfusion (I/R) and to determine whether the sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (SIRT1/PGC-1α) pathway contributes to this cardioprotective effect in vivo and in vitro. H9c2 cells were incubated with H2 O2 for 12 h. The effect of syringin was assessed by measuring cell viability; the apoptotic rate; Keap1/NRF2/HO-1 activation; and the levels of proinflammatory cytokines, oxidative products, and antioxidative enzymes. In addition, SIRT1 was silenced via short hairpin RNA (shRNA)-SIRT1 transfection to evaluate its involvement in syringin-mediated protection. Syringin rescued cells from H2 O2 -induced reductions in viability, antioxidative enzyme levels, and NRF2/HO-1 activation; likewise, syringin inhibited apoptosis, inflammation, and oxidative stress. We also created a rat model of I/R by ligating the left anterior descending coronary artery for 30 min, followed by reperfusion for 12 min. Syringin was then intraperitoneally injected, and the effect on infarct size and cardiac function was examined after 7 days. NRF2/HO-1 activity and the levels of myocardial proinflammatory cytokines, oxidative products, and antioxidative enzymes were measured. In comparison to the untreated I/R group, the syringin treatment group exhibited improved cardiac function and reduced cardiac lesion and infarct size. Syringin administration also markedly reduced the levels of proinflammatory cytokines and reactive oxygen species and promoted antioxidative enzyme expression and NRF2/HO-1 pathway activation. Syringin may serve a protective role in animal and cell models of I/R by improving cardiac function, inhibiting the inflammatory response, and activating the antioxidative response.

Towards automated assessment of drug efficacy on cardiomyopathic human heart function.

Structural and functional abnormalities of ventricular myocardium related to Hypertrophic and Dilated Cardiomyopathies (HCM and DCM) are commonly caused by inherited mutations in sarcomeric proteins. Automating predictions of mutation and drug effects on human cardiac muscle function could enhance early diagnosis and evaluation of response to treatments for cardiomyopathies. However, the development of automation tools that integrate results from multiple experiments, conducted under various experimental conditions at different time and spatial scales from multiple species, is a significant challenge. Such automation tools usually require large sets of training data, which are extremely limited or even nonexistent from humans, thus any information generated could be significantly inaccurate or even misleading. Recent advances in multiscale computational tools, coupled with multiple experiments, for the translation of data concerning sarcomere level molecular interactions, including the effect of drugs, to the level of cardiac muscle fibers and tissues, might provide the most relevant approach for generating databases for automation algorithms. Using the MUSICO platform for precise modeling of protein-protein interactions and Ca2+ regulation in cardiac muscle cells, coupled with the finite element (FE) solver Mexie via Mijailovich-Prodanovic surrogate model, we can simulate experimental data from various sources. These tools collectively enable quantitative assessment of the changes in human cardiac muscle contractile responses caused by HCM and DCM extending from the molecular level to whole organ function, as well as prediction of improvements of cardiac muscle function by drugs. Our simulations successfully predicted pressure and volume changes due to troponin-C mutations and the effect of drugs, disopyramide and digoxin, in improving heart function in HCM and DCM, respectively, during multiple heartbeats in human heart. These simulations can potentially provide sufficient information for physicians to evaluate the progress of disease and the efficacy of administrated therapeutics.

Investigating the sarcolemma-sarcomere connection and force transmission in the heart.

External mechanical signals are communicated through cardiac muscle cells by converting them to internal biochemical signals during mechanotransduction. In the heart, altered transmission of these signals can affect myocardial structure and function. This study examines the impact of sarcospan deletion, a sarcolemma protein, on cardiac muscle mechanics. Sarcospan is an integral member of the dystrophin-glycoprotein complex (DGC) and we are interested in investigating how it influences sarcomere contractile function. Measurements of cardiac contractile parameters were conducted using permeabilized left ventricular papillary muscle bundles obtained from wild-type and SSPN-deficient (SSPN-/-) mouse hearts. Myofilament Ca2+-sensitivity and cooperativity of thin filament activation was similar between WT and SSPN-/- cardiac muscle preparations. However, SSPN-/- muscle bundles exhibited a significantly faster rate of tension redevelopment (kTR) at submaximal activation conditions (pCa 5.8) but no significant changes in maximal kTR (recorded at maximal Ca2+ activation, pCa 4.5). Maximal steady-state isometric force and sinusoidal stiffness were proportionally increased in SSPN-/- cardiac muscle preparations during Ca2+ activation. These intriguing observations suggest that SSPN may play an inherent role in balancing pathways involved in force transmission and its deletion may cause compensatory remodeling of sarcomeric proteins (e.g. isoform switching or protein modification) changing mechanical properties of cardiac muscle. Mouse hearts lacking SSPN-/- exhibit increased sarcolemmal expression of integrin-linked kinase (ILK) and vinculin. ILK is an important biomechanical sensor shown to regulate cardiac contractility and ventricular hypertrophy whereas increasing vinculin expression has been shown to improve heart function and impact myofilament organization. Further examination of the WT and SSPN-/- myofibrils will allow us to assess sarcomere protein alterations that contribute to increased force at submax and max levels of Ca2+ activation. Therefore, the concentric enlargement observed in SSPN-/- mouse hearts could be explained by remodeling of the sarcomere itself.

Plain Language Summary of Publication of the safety and efficacy of ARRY-371797 in people with dilated cardiomyopathy and a faulty LMNA gene.

This plain language summary describes the results of a study looking at the effects of a medicine called ARRY-371797 (also known as PF-07265803) in people with dilated cardiomyopathy (DCM for short) caused by a faulty LMNA gene. This condition is called LMNA-related DCM. DCM happens when the heart becomes bigger and weaker than normal, impacting functional capacity and leading to symptoms of heart failure. This means the heart is not able to pump blood around the body as easily, and people are unable to do as much in their daily lives (like getting dressed and going shopping). People may inherit a faulty LMNA gene from one of their parents, or a faulty LMNA gene may develop when mistakes happen during cell growth and replication. ARRY-371797 targets a specific mechanism in the body that can lead to heart problems in people with a faulty LMNA gene. As ARRY-371797 is not currently approved for use outside of clinical trials, it doesn't currently have an easily recognizable trade name. 12 American people (average age 50years) with LMNA-related DCM took part in the study and received 400mg or 100mg of ARRY-371797 twice daily for 48weeks. People knew which dose of ARRY-371797 they were taking. People were checked after 4, 12, 24, 36 and 48weeks of taking ARRY-371797 to see how far they could walk in the 6-minute walk test (6MWT for short). The level of NT-proBNP in their blood was also measured. NT-proBNP is a biomarker used to measure the severity of heart failure. A biomarker is something found in the body that can be measured to indicate the extent of a disease. -After taking ARRY-371797 for 12weeks, people were able to walk further in the 6MWT and had lower levels of NT-proBNP in their blood. This suggests improvement in functional capacity (exercise tolerance) and heart function. Researchers also asked people about their quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ for short), and looked for any side effects. -Researchers saw some improvement in KCCQ scores. -Researchers saw no major side effects that they considered to be related to ARRY-371797 treatment. A side effect is something that people feel was caused by a medicine or treatment. Overall, this study showed that people with LMNA-related DCM who took ARRY-371797 had improved functional capacity (exercise tolerance), improved heart function, and improved quality of life. Phase 2 study (NCT02057341) Phase 2 long-term extension study (NCT02351856) Phase 3 REALM-DCM study (NCT03439514).

Sexual activity in terms of cardiac rehabilitation after cardiovascular incidents

Cardiovascular diseases (CVD) are still the leading cause of death. Environmental factors such as smoking, low physical activity and poor diet have the greatest impact on the incidence of the disease. For patients after a cardiovascular incident, cardiac rehabilitation is the key to recovery. One possible path of rehabilitation is sexual activity (SA). Sexual activities are similar to mild/moderate physical activity during a short period. Most patients are recommended to involve in sexual activity after prior comprehensive evaluation of physical condition. Before involving in sexual activity the general condition of the patient needs to be checked. A useful method for this is a stress testing. The patients with stable cardiac symptoms and good functional capacity are at a low risk of recurrent cardiovascular events, and others require treatment or improvement of heart function. The most efficient way to provide SA is a sexual counseling. Evidence suggests that relatively few cardiac patients receive sexual counseling, which can result in negative outcomes ranging from psychological, physical, and quality of life. Sexual problems and concerns are prevalent, including patient and partner fear of causing another heart attack. It is because people still believe that sexual activity is too risky and they cease all of it. Sexual counseling is needed across health care settings to ensure that patients receive information to safely resume SA.

Hypoxia-Elicited Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Alleviate Myocardial Infarction by Promoting Angiogenesis through the miR-214/Sufu Pathway.

Myocardial infarction is a leading cause of mortality worldwide. Angiogenesis in the infarct border zone is vital for heart function restoration after myocardial infarction. Hypoxia-induced MSC modification is a safe and effective approach for angiogenesis in clinical therapy; however, the mechanism still requires further investigation. In our study, we preconditioned human umbilical cord mesenchymal stem cells (huMSCs) with hypoxia and isolated the small extracellular vesicles (sEVs) to promote cardiac repair. We also investigated the potential mechanisms. huMSCs were preconditioned with hypoxia (1% O2 and 5% CO2 at 37°C for 48 hours), and their sEVs were isolated using the Total Exosome Isolation reagent kit. To explore the role of miR-214 in MSC-derived sEVs, sEVs with low miR-214 expression were prepared by transfecting miR-214 inhibitor into huMSCs before hypoxia pretreatment. Scratch assays and tube formation assays were performed in sEVs cocultured with HUVECs to assess the proangiogenic capability of MSC-sEVs and MSChyp-sEVs. Rat myocardial infarction models were used to investigate the ability of miR-214-differentially expressed sEVs in cardiac repair. Echocardiography, Masson's staining, and immunohistochemical staining for CD31 were performed to assess cardiac function, the ratio of myocardial fibrosis, and the capillary density after sEV implantation. The potential mechanism by which MSChyp-sEVs enhance angiogenesis was explored in vitro by RT-qPCR and western blotting. Tube formation and scratch assays demonstrated that the proangiogenic capability of huMSC-derived sEVs was enhanced by hypoxia pretreatment. Echocardiography and Masson's staining showed greater improvements in heart function and less ventricular remodeling after MSChyp-sEV transplantation. The angiogenic capability was reduced following miR-214 knockdown in MSChyp-sEVs. Furthermore, Sufu, a target of miR-214, was decreased, and hedgehog signaling was activated in HUVECs. We found that hypoxia induced miR-214 expression both in huMSCs and their sEVs. Transplantation of MSChyp-sEVs into a myocardial infarction model improved cardiac repair by increasing angiogenesis. Mechanistically, MSChyp-sEVs promote HUVEC tube formation and migration by transferring miR-214 into recipient cells, inhibiting Sufu expression, and activating the hedgehog pathway. Hypoxia-induced vesicle modification is a feasible way to restore heart function after myocardial infarction.

Alpha lipoic acid–loaded electrospun fibrous patch films protect heart in acute myocardial infarction mice by inhibiting oxidative stress

Oxidative stress, characterized by excessive accumulation of reactive oxygen species (ROS), is involved in acute myocardial infarction (AMI)-related pathological processes and vascular reperfusion therapy injury. Alpha lipoic acid (LA) exhibits excellent antioxidant properties, however, its application is limited by inherent characteristics, including rapid clearance and extensive volume distribution. In this study, we hypothesized that scavenging cardiac ROS using adequately delivered LA could promote heart repair. Here, we report a new strategy for dynamic-release LA to treat AMI disease. In particular, this involves using poly(lactic-co-glycolic) (PLGA) copolymers as carriers to form a thin film (LA@PLGA) via electrospinning technology to achieve controlled release of LA, which essentially blocking local ROS production in damaged hearts. The drug-loading capacity and capsulation efficiency of this compound film could be regulated by determining the dose proportions of LA and PLGA. The incubation of LA@PLGA showed strong anti-oxidative activity and anti-apoptosis effect in hydrogen peroxide–administered primary cardiomyocytes. Patching LA@PLGA on the infarcted cardiac surfaces of AMI mice dramatically improved heart functions and reduced cardiac fibrosis throughout ventricular remodeling process. Importantly, the attenuation of detrimental pathologies was observed, including oxidative stress, senescence, DNA damage, cytokine-related processes, apoptosis, and ferroptosis. These results suggest that PLGA-carried LA can reduce ROS damage and restore heart function after myocardial damage, demonstrating a great potential for LA drugs in treating AMI disease.

INOS aggravates pressure overload-induced cardiac dysfunction via activation of the cytosolic-mtDNA-mediated cGAS-STING pathway.

Background: Sterile inflammation contributes to the pathogenesis of cardiac dysfunction caused by various conditions including pressure overload in hypertension. Mitochondrial DNA (mtDNA) released from damaged mitochondria has been implicated in cardiac inflammation. However, the upstream mechanisms governing mtDNA release and how mtDNA activates sterile inflammation in pressure-overloaded hearts remain largely unknown. Here, we investigated the role of inducible NO synthase (iNOS) on pressure overload-induced cytosolic accumulation of mtDNA and whether mtDNA activated inflammation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Methods: To investigate whether the cGAS-STING cascade was involved in sterile inflammation and cardiac dysfunction upon pressure overload, cardiomyocyte-specific STING depletion mice and mice injected with adeno-associated virus-9 (AAV-9) to suppress the cGAS-STING cascade in the heart were subjected to transverse aortic constriction (TAC). iNOS null mice were used to determine the role of iNOS in cGAS-STING pathway activation in pressure-stressed hearts. Results: iNOS knockout abrogated mtDNA release and alleviated cardiac sterile inflammation resulting in improved cardiac function. Conversely, activating the cGAS-STING pathway blunted the protective effects of iNOS knockout. Moreover, iNOS activated the cGAS-STING pathway in isolated myocytes and this was prevented by depleting cytosolic mtDNA. In addition, disruption of the cGAS-STING pathway suppressed inflammatory cytokine transcription and modulated M1/M2 macrophage polarization, and thus mitigated cardiac remodeling and improved heart function. Finally, increased iNOS expression along with cytosolic mtDNA accumulation and cGAS-STING activation were also seen in human hypertensive hearts. Conclusion: Our findings demonstrate that mtDNA is released into the cytosol and triggers sterile inflammation through the cGAS-STING pathway leading to cardiac dysfunction after pressure overload. iNOS controls mtDNA release and subsequent cGAS activation in pressure-stressed hearts.

Therapeutic silencing of lncRNA RMST alleviates cardiac fibrosis and improves heart function after myocardial infarction in mice and swine.

Rationale: Cardiac fibrosis is an adverse consequence of aberrant fibroblast activation and extracellular matrix (ECM) deposition following myocardial infarction (MI). Recently, long noncoding RNAs (lncRNAs) have been reported to participate in multiple cardiac diseases. However, the biological functions of lncRNA rhabdomyosarcoma 2-associated transcript (RMST) in cardiac fibrosis remain largely unknown. Methods: The role of RMST in regulating cardiac fibroblast (CF) proliferation, fibroblast-to-myofibroblast transition (FMT), and ECM production, which were induced by transforming growth factor-β1, was evaluated through immunofluorescence staining, cell contraction assay, cell migration assay, qRT-PCR, and western blot. The therapeutic effect of RMST silencing was assessed in murine and porcine MI models. Results: The present study showed that RMST expression was upregulated and associated with cardiac fibrosis in murine and porcine MI models. Further loss-of-function studies demonstrated that RMST silencing in vitro significantly inhibited CF proliferation, FMT, and ECM production. Accordingly, RMST knockdown in vivo alleviated cardiac fibrosis and improved cardiac contractile function in MI mice. Moreover, RMST acted as a competitive endogenous RNA of miR-24-3p. miR-24-3p inhibition abolished, while miR-24-3p agomir reproduced, the RMST knockdown-mediated effects on CF fibrosis by regulating the lysyl oxidase signaling pathway. Finally, the therapeutic potential of RMST knockdown was evaluated in a porcine MI model, and local RMST knockdown significantly inhibited cardiac fibrosis and improved myocardial contractile function in pigs after MI. Conclusion: Our findings identified RMST as a crucial regulator of cardiac fibrosis, and targeting RMST may develop a novel and efficient therapeutic strategy for treating fibrosis-related cardiac diseases.

Cardioprotection of Water Spinach (Ipomoea aquatica), Wood Apple (Limonia acidissima) and Linseed (Linum usitatissimum L.) on Doxorubicin-Induced Cardiotoxicity and Oxidative Stress in Rat Model.

The aim of this study was to investigate the pharmacological efficacy of 3 functional foods (Water spinach, Wood apple, and Linseed) against doxorubicin-induced cardiotoxicity and oxidative stress in rat models. Twenty-five Wistar Albino rats (male and female) were equally classified into 5 groups. Except for the normal control (NC) group, the animals received 2.5 mg/kg doxorubicin (DOX) intra-peritoneal injection at 48 hours intervals to create a dose of 15 mg/kg overall for 14 days. Simply a standard diet was given to the NC and DOX groups. In the 3 treatment groups such as water spinach (DOX + WS), wood apple (DOX + WA), and linseed (DOX + LS), rats were given 14 gm/day/rat fried water spinach, mashed wood apple, roasted linseed, respectively mixed with regular rat diet at 1:1 ratio. Blood and heart samples were collected by sacrificing all the rats on the last of the experiment day (the 15th day). LDH (lactate dehydrogenase), CK-MB (creatine kinase myocardial band), MDA (malondialdehyde), and SOD (superoxide dismutase) were analyzed. Additionally, histopathological analysis was conducted for final observation. The functional foods were indicated to lower the serum cardiac biomarkers (LDH and CK-MB) as well as stress marker (MDA) significantly (P < .05) and improved heart function and oxidative stress. However, the change in serum SOD level was noted as statistically insignificant (P > .05). The biochemical outcomes of the food intervention groups were supported by the histological findings found in those groups. Consuming the investigated foods containing antioxidant phytochemicals may combat cardiac toxicity and oxidative stress. Nonetheless, thorough investigations and clinical monitoring are required to understand these functional foods' mechanism of action and dose-response effects in treating cardiotoxicity and oxidative stress.

6-Gingerol Alleviates Ferroptosis and Inflammation of Diabetic Cardiomyopathy via the Nrf2/HO-1 Pathway.

Diabetes mellitus (DM) can induce cardiomyocyte injury and lead to diabetic cardiomyopathy (DCM) which presently has no specific treatments and consequently increase risk of mortality. To characterize the therapeutic effect of 6-gingerol (6-G) on DCM and identify its potential mechanism. In vivo streptozotocin- (STZ-) induced DM model was established by using a high-fat diet and STZ, followed by low-dose (25 mg/kg) and high-dose (75 mg/kg) 6-G intervention. For an in vitro DCM model, H9c2 rat cardiomyoblast cells were stimulated with high glucose (glucose = 33 mM) and palmitic acid (100 μM) and then treated with 6-G (100 μM). Histological and echocardiographic analyses were used to assess the effect of 6-G on cardiac structure and function in DCM. Western blotting, ELISA, and real-time qPCR were used to assess the expression of ferroptosis, inflammation, and the Nrf2/HO-1 pathway-related proteins and RNAs. Protein expression of collagen I and collagen III was assessed by immunohistochemistry, and kits were used to assay SOD, MDA, and iron levels. The results showed that 6-G decreased cardiac injury in both mouse and cell models of DCM. The cardiomyocyte hypertrophy and interstitial fibrosis were attenuated by 6-G treatment in vivo and resulted in an improved heart function. 6-G inhibited the expression of ferroptosis-related protein FACL4 and the content of iron and enhanced the expression of anti-ferroptosis-related protein GPX4. In addition, 6-G also diminished the secretion of inflammatory cytokines, including IL-1β, IL-6, and TNF-α. 6-G treatment activated the Nrf2/HO-1 pathway, enhanced antioxidative stress capacity proved by increased activity of SOD, and decreased MDA production. Compared with in vivo, 6-G treatment of H9c2 cells treated with high glucose and palmitic acid could produce a similar effect. These findings suggest that 6-G could protect against DCM by the mechanism of ferroptosis inhibition and inflammation reduction via enhancing the Nrf2/HO-1 pathway.

Luhong Formula and Hydroxysafflor yellow A protect cardiomyocytes by inhibiting autophagy

BackgroundHeart failure (HF) is the terminal stage of all heart diseases that is characterized by irreversible cardiomyocyte injury. Equilibrium of autophagy is essential for cardiac cell survival. The Luhong formula (LHF) has been clinically applied for decades, and has exhibited significant efficacy in improving heart function and alleviating the symptoms of angina pectoris. PurposeTo clarify the mechanism of action of LHF and one of its main constituents, hydroxysafflor yellow A (HYSA), in protecting ischemic cardiomyocytes by inhibiting autophagy. MethodsCell viability was detected by CCK-8 assay with LHF or HYSA pretreatment followed by hypoxic damage. Immunofluorescence of GFP-LC3-H9C2 and GFP-LC3-HeLa cells was used to observe autophagic flux. Beclin 1 and HIF1α protein expression were assessed using western blotting. LHF was orally administered to Wistar rats following myocardial infarcion. Echocardiography was performed before the rats were sacrificed; immunohistochemistry and western blotting were used to evaluate Beclin 1 and HIF1α expression in the myocardial tissue. Hematoxylin and eosin staining as well as Masson's trichrome staining were used to measure cardiac structure and myocardial fibrosis. ResultsLHF and HYSA reversed the hypoxia-induced decrease in cell viability in vitro. LHF and HYSA induced the aggregation of GFP-LC3 puncta and reduced the expression of Beclin 1 protein in H9C2, suggesting that LHF and HYSA may inhibit autophagy activity. Pretreatment with reactive oxygen species (ROS) inducers and inhibitors revealed that LHF and HYSA inhibited autophagy by suppressing cellular ROS. Further studies demonstrated that LHF and HYSA reduced the ROS levels by inhibiting HIF1α. LHF delayed fibrosis and protected heart function in vivo in a rat model of HF following myocardial infarction. Western blotting and immunohistochemistry revealed that LHF effectively reduced the expression of Beclin 1 and HIF1α in the infarcted area of the rat heart. ConclusionThese results demonstrate that hydroxysafflor yellow A is the representative bioactive compounent of Luhong Formula on regulating autophagy to protectect cardiomyocytes from hypoxia injury. LHF and HYSA inhibit cardiac autophagy by suppressing HIF1α-mediated ROS production. This study helps to further clarify the underlying mechanism of LHF and provide a scientific basis for its development as a novel cardiovascular therapeutic agent.

Resveratrol Attenuates Sepsis-Induced Cardiomyopathy in Rats through Anti-Ferroptosis via the Sirt1/Nrf2 Pathway

Background: Sepsis-induced cardiomyopathy (SIC) is a severe myocardial dysfunction secondary to septicemia. It is a major concern owing to the high mortality and morbidity, which are greatly influenced by ferroptosis. Resveratrol (RSV) is a naturally existing agonist of the silent information regulator 1 (Sirt1). It has cardioprotective effects against sepsis-induced myocardial injury, However, the detailed mechanism is unknown. Methods: In this study, cecal ligation and puncture (CLP)-induced septic rats were employed to assess the changes in ferroptosis with RSV administration. According to the different treatments the rats were divided into the following groups: (1) the Sham, (2) CLP, (3) CLP + RSV at various doses (10, 30, and 50 mg/kg), and (4) CLP + Fer-1(a ferroptotic inhibitor) groups. After 24 h, the structure and function of the cardiac system in rats were evaluated, and mitochondrial morphology, ferroptosis-related biomarkers, and the levels of Sirt1/Nrf2 were assessed. Results: The rats that underwent CLP had suffered cardiac dysfunction, accompanied with myocardial damage, impaired mitochondria, elevated lipid peroxidation, and reduced Sirt1/Nrf2 expression in the myocardium. High-dose RSV successfully improved heart function, reversing the abnormalities in a dose-dependent manner. We then used EX527, a selective Sirt1 inhibitor, to further identify the intermediate signaling targets of RSV that regulate ferroptosis. EX527 diminished the curative effects of high-doses RSV. Conclusions: Summarily, our findings suggest a novel mechanism of RSV in reducing SIC: ferroptosis inhibition via upregulation of Sirt1/Nrf2 signaling pathways. This may be an effective therapeutic approach against organ failure in sepsis, particularly SIC.

Cardioprotective Effects of Aconite in Isoproterenol-Induced Myocardial Infarction in Rats.

Myocardial infarction (MI) is a severe clinical condition caused by decreased or complete cessation of blood flow to a portion of the myocardium. Aconite, the lateral roots of Aconitum carmichaelii Debx., is a well-known Chinese medicine for treatment of heart failure and related cardiac diseases. The present study is aimed at investigating the cardioprotective effect of aconite on isoproterenol- (ISO)- induced MI. The qualitative analysis of aqueous extracts from brained aconite (AEBA) was conducted by HPLC. A rat model of MI induced by ISO was established to examine the effects of AEBA. The cardiac function was assessed by echocardiography. The serum levels of SOD, CK-MB, cTnT, and cTnI were detected to estimate myocardial injury. The pathological changes of heart tissue were evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, and Masson's trichrome staining. The expressions of abnormal vascular remodeling and hypoxia-related components and the levels of inflammation-associated genes and proteins were detected by RT-qPCR, western blotting, and immunofluorescence. The contents of benzoylaconine, benzoylmesaconine, benzoylhypacoitine, and hypaconitine in AEBA were 1.35 μg/g, 37.35 μg/g, 57.10 μg/g, and 2.46 μg/g, respectively. AEBA obviously improved heart function through promoting echocardiographic parameters, radial strain, and circumferential strain. The data of TTC staining, HE staining, and Masson's trichrome staining disclosed that AEBA could significantly reduce infarct size, inhibit inflammatory cell infiltration, and decrease the myocardial fibrosis. Moreover, AEBA distinctly suppressed the serum levels of SOD, MDA, CK-MB, cTnT, and cTnI in ISO-induced rats. The results of RT-qPCR indicated that AEBA inhibited the expressions of hypoxia- and inflammation-related genes, including VEGF, PKM2, GLUT-1, LDHA, TNF-α, IL-1β, IL-6, and COX2. In addition, the western blotting and immunofluorescence analyses further confirmed the results of RT-qPCR. In summary, our results indicate that the AEBA could improve ISO-induced myocardial infarction by promoting cardiac function, alleviating myocardial hypoxia, and inhibiting inflammatory response and fibrosis in heart tissue.

Five critically ill pregnant women/parturients treated with extracorporeal membrane oxygenation

BackgroundMaternal mortality has always been a major medical concern. Recently, the successful application of extracorporeal membrane oxygenation (ECMO) technology in the rescue of near-death patients has been reported.Case presentationThis study retrospectively analyzed 5 cases of critically ill pregnant women/parturients treated with ECMO for respiratory and circulatory failure in the Wuxi People’s Hospital from 2018 to 2020. The mean age of the 5 cases was 30.2 years. Among them, Cases 1 and 5 were treated with Venoarterial (VA) ECMO. Case 1 was diagnosed with congenital heart disease, atrial septal defect, and severe pulmonary hypertension. VA ECMO was applied before cesarean section and was successfully removed after double lung transplantation, but the patient died 10 months after delivery from lung infection. While Case 5 was diagnosed with systemic lupus erythematosus, lupus nephritis, thrombotic vascular disease, HELLP syndrome, and cerebral hemorrhage. VA ECMO was applied 39 days after cesarean section, and the patient died 40 days after delivery due to multiple organ failure. Cases 3 and 4 were treated with Venovenous (VV) ECMO. Case 3 was diagnosed with refractory postpartum hemorrhage, and Case 4 was diagnosed with postpartum hypoglycemic coma, aspiration pneumonia, and shock. They were treated with VV ECMO after delivery, and all survived after successful evacuation. Another Case (Case 2) was diagnosed with postpartum pelvic infection, sepsis and septic shock, and was treated with VA ECMO at 15 days after delivery. The patient changed to VV ECMO at 30 days after delivery due to significant improvement in heart function and poor lung function, but eventually died of multiple organ failure. For the 5 cases, the mean duration of ECMO was 8.7 days, the mean duration of intensive care was 22.0 days, and the mean length of hospital stay was 57.6 days. As a result, 3 patients gradually returned to normal with significant improvement in ventilation and oxygenation after ECMO treatment.ConclusionsECMO technology can be used to treat some of the critical obstetric patients with respiratory and circulatory failure that is ineffective to conventional treatment, but it has no therapeutic effect on the primary disease.

Molecular mechanisms underlying the beneficial effects of exercise and dietary interventions in the prevention of cardiometabolic diseases.

Cardiometabolic diseases still represent a major cause of mortality worldwide. In addition to pharmacological approaches, lifestyle interventions can also be adopted for the prevention of these morbid conditions. Lifestyle changes include exercise and dietary restriction protocols, such as calorie restriction and intermittent fasting, which were shown to delay cardiovascular ageing and elicit health-promoting effects in preclinical models of cardiometabolic diseases. Beneficial effects are mediated by the restoration of multiple molecular mechanisms in heart and vessels that are compromised by metabolic stress. Exercise and dietary restriction rescue mitochondrial dysfunction, oxidative stress and inflammation. They also improve autophagy. The result of these effects is a marked improvement of vascular and heart function. In this review, we provide a comprehensive overview of the molecular mechanisms involved in the beneficial effects of exercise and dietary restriction in models of diabetes and obesity. We also discuss clinical studies and gap in animal-to-human translation.

Chinese expert consensus on the management of cardiovascular comorbidities in patients with chronic obstructive pulmonary disease

Patients with chronic obstructive pulmonary disease(COPD) often have co-existent systemic diseases(comorbidities), among which cardiovascular diseases (CVD) are the most common. The interactions between COPD and CVD are manifested in shared risk factors, disease severity, common symptoms, risks for exacerbations and disease progression, as well as therapeutic interventions. However, there is a knowledge gap in the management of COPD comorbidities. This expert consensus aims to increase the awareness, and to promote early diagnosis and proper management of cardiovascular comorbidities of COPD in medical professionals in China. The experts recommend that differential diagnosis should be performed for exertional dyspnea, a common symptom of COPD and cardiovascular diseases especially heart failure. Screening for cardiovascular diseases is needed in patients with COPD, and should be managed accordingly. COPD and comorbid CVD should be treated according to usual guidelines. Patients with COPD tolerate well to most of the medications for CVD. Selective β1-blockers for cardiovascular diseases are not contraindicated in COPD, but should be initiated from lower doses, and symptoms of airflow limitation be monitored. Likewise, β2-agonists and antimuscarinic drugs for COPD are generally safe for patients with comorbid CVD. Optimization of COPD management can improve heart function and cardiovascular outcomes.

Metabolomic and transcriptomic studies of improvements in myocardial infarction due to Pycr1 deletion.

Myocardial infarction (MI) remains a major challenge to cardiovascular health worldwide, with poor healing leaving a direct impact on patients' quality of life and survival. Metabolic abnormalities after MI are receiving increasing attention. Our previous studies showed that enhancing proline catabolism ameliorates hypoxic damage to myocardial cells; therefore, we sought to determine whether reducing the synthesis of endogenous proline also affects MI. We analysed GEO datasets associated with MI and western blot of mouse heart tissue in an MI model to demonstrate pyrroline-5-carboxylate reductase 1 (Pycr1) expression level after MI. We constructed Pycr1 KO mice by CRISPR/Cas9 technology to explore the effect of Pycr1 gene KO after MI using transcriptomic and metabolomic techniques. In this study, we found reduced mRNA and protein expression levels of Pycr1 in the hearts of mice after MI. We observed that Pycr1 gene KO has a protective effect against MI, reducing the area of MI and improving heart function. Using transcriptomics approaches, we found 215 upregulated genes and 247 downregulated genes after KO of the Pycr1 gene, indicating that unsaturated fatty acid metabolism was affected at the transcriptional level. Metabolomics results revealed elevated content for 141 metabolites and decreased content for 90 metabolites, among which the levels of fatty acids, glycerol phospholipids, bile acids, and other metabolites increased significantly. The changes in these metabolites may be related to the protective effect of Pycr1 KO on the heart after MI. Pycr1 gene KO has a protective effect against MI and our research will lay a solid foundation for the development of future Pycr1-related drug targets.