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This study investigates the effects of inositol (INO) supplementation on cardiac changes caused by Li in mice. The study involved 4 groups of C57BL6 mice (n=10 each): (i) mice orally administered with Li 2 CO 3 for 8 weeks, then 4 additional weeks without (Li_group) or (ii) with INO supplementation (Li_INOdelayed_group) (total of 12 weeks); (iii) mice given Li 2 CO 3 and INO supplementation concurrently for 12 weeks (Li+INO_group); (iv) one group left untreated (C-group). The INO was administered as a mixture of myo-inositol and d-chiro-inositol (80:1) in drinking water. The mice were characterised for heart morphology, function, electrical activity, arrhythmogenic susceptibility, and multiorgan histopathology (heart, liver and kidney). Cardiomyocyte size, protein expression of key signalling pathways related to hypertrophy, and transcription levels of ion channel subunits and hypertrophy markers were evaluated in the ventricle tissue. The study found that INO supplementation reduced the Li-induced cardiac adverse effects, including systolic impairment and increased susceptibility to arrhythmias. The positive effect on arrhythmias might be attributed to the restored expression levels of the potassium channel subunit Kv 1.5. Additionally, INO improved cardiomyocyte hypertrophy, possibly by inhibiting the Li-induced activation of the ERK1/2 signalling pathway and by restoring the normal expression level of BNP, and alleviated injury in the liver and kidney. The effect was preventive if INO supplementation was taken concurrently with Li and therapeutic if INO was administered after Li-induced cardiac impairments were established. These results provide new insights into the cardioprotective effect of INO and suggest a potential treatment approach for Li-induced cardiac disease., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Claudia Kusmic reports equipment, drugs, or supplies was provided by LoLi Pharma Srl. Elisa Lepore reports a relationship with LoLi Pharma Srl that includes: employment. Giampiero Forte reports a relationship with LoLi Pharma Srl that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Since the introduction of direct oral anticoagulants (DOACs) and their comparison with vitamin K antagonists (VKAs), conflicting results have been reported regarding the optimal treatment for left ventricular thrombosis (LVT)., Objectives: In this meta-analysis, we intend to comprehensively evaluate the safety and efficacy of these treatments., Methods: All clinical trials and cohorts that compared the efficacy or safety of VKAs with DOACs in the treatment of LVTs were systematically searched until April 15, 2023., Results: The results of 32 studies with a pooled sample size of 4213 patients were extracted for meta-analysis. DOACs, especially rivaroxaban and apixaban, cause faster resolution, lower mortality, and fewer complications (SSE and bleeding events) than VKAs in the management of LVTs., Conclusion: Compared with VKAs, DOACs result in significantly faster (only rivaroxaban) and safer resolution of left ventricular thrombosis., Competing Interests: Declaration of competing interest The authors have no competing interests to declare that are relevant to the content of this article. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors confirm that this review has not been published elsewhere, nor is it currently under consideration for publication elsewhere., (Copyright © 2024. Published by Elsevier Inc.)

Introduction and Objective: Mitral stenosis (MS) is one of the most frequently observed valvular heart lesions in developing countries and is due to different etiologies. The effects of anticoagulation in different types of left atrial appendage (LAA) are unknown. The current study aimed to determine the resolution of LAA thrombus on transesophageal echocardiography (TEE) after three months of optimal anticoagulation in patients with different types of LAA at baseline cardiac computed tomography of patients with severe MS., Methods: This prospective cohort study observed the frequency of LAA thrombus resolution after three months of anticoagulation therapy in patients with severe MS. The response rate in different morphologies of LAA and locations was also assessed. Thrombus resolution after three months of warfarin therapy was assessed on repeat TEE., Results: A total of 88 patients were included, mean age 37.95±11.87 years. Repeat TEE showed thrombus resolution in only 27.3% of patients. The rate of thrombus resolution was 8/12 (66.7%), 4/28 (14.3%), 8/36 (22.2%), and 4/12 (33.3%) for patients with cactus, cauliflower, chicken wing, and windsock LAA type, respectively. The resolution rate was 0/12 (0%), 4/44 (9.1%), and 20/32 (62.5%) for patients with thrombus in the base, body, and tip of the LAA, respectively., Conclusion: The cactus type of LAA morphology and thrombus at the LAA tip responded well to three months of anticoagulation, however, patients with thrombus in the LAA base and body and cauliflower and chicken wing morphology were non-responders and could benefit from early referral for surgical management., (Copyright © 2024 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Beta-blockers are commonly used drugs during pregnancy, especially in women with heart disease, and are regarded as relatively safe although evidence is sparse. Differences between beta-blockers are not well-studied., Methods: In the Registry of Pregnancy And Cardiac disease (ROPAC, n = 5739), a prospective global registry of pregnancies in women with structural heart disease, perinatal outcomes (small for gestational age (SGA), birth weight, neonatal congenital heart disease (nCHD) and perinatal mortality) were compared between women with and without beta-blocker exposure, and between different beta-blockers. Multivariable regression analysis was used for the effect of beta-blockers on birth weight, SGA and nCHD (after adjustment for maternal and perinatal confounders)., Results: Beta-blockers were used in 875 (15.2%) ROPAC pregnancies, with metoprolol (n = 323, 37%) and bisoprolol (n = 261, 30%) being the most frequent. Women with beta-blocker exposure had more SGA infants (15.3% vs 9.3%, p < 0.001) and nCHD (4.7% vs 2.7%, p = 0.001). Perinatal mortality rates were not different (1.4% vs 1.9%, p = 0.272). The adjusted mean difference in birth weight was -177 g (-5.8%), the adjusted OR for SGA was 1.7 (95% CI 1.3-2.1) and for nCHD 2.3 (1.6-3.5). With metoprolol as reference, labetalol (0.2, 0.1-0.4) was the least likely to cause SGA, and atenolol (2.3, 1.1-4.9) the most., Conclusions: In women with heart disease an association was found between maternal beta-blocker use and perinatal outcomes. Labetalol seems to be associated with the lowest risk of developing SGA, while atenolol should be avoided., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Aims: Direct oral anticoagulants (DOACs) are increasingly used off-label to treat patients with left ventricular thrombus (LVT). We analysed available meta-data comparing DOACs and vitamin K antagonists (VKAs) for efficacy and safety., Methods: We conducted a systematic search and meta-analysis of observational and randomized data comparing DOACs vs. VKAs in patients with LVT. Endpoints of interest were stroke or systemic embolism, thrombus resolution, all-cause death, and a composite bleeding endpoint. Estimates were pooled using a random-effects model meta-analysis, and their robustness was investigated using sensitivity and influential analyses., Results: We identified 22 articles (18 observational studies, 4 small randomized clinical trials) reporting on a total of 3587 patients (2489 VKA vs. 1098 DOAC therapy). The pooled estimates for stroke or systemic embolism [odds ratio (OR): 0.81; 95% confidence interval (CI): 0.57, 1.15] and thrombus resolution (OR: 1.12; 95% CI: 0.86, 1.46) were comparable, and there was low heterogeneity overall across the included studies. The use of DOACs was associated with lower odds of all-cause death (OR: 0.65; 95% CI: 0.46, 0.92) and a composite bleeding endpoint (OR: 0.67; 95% CI: 0.47, 0.97). A risk of bias was evident particularly for observational reports, with some publication bias suggested in funnel plots., Conclusion: In this comprehensive analysis of mainly observational data, the use of DOACs was not associated with a significant difference in stroke or systemic embolism, or thrombus resolution, compared with VKA therapy. The use of DOACs was associated with a lower rate of all-cause death and fewer bleeding events. Adequately sized randomized clinical trials are needed to confirm these findings, which could allow a wider adoption of DOACs in patients with LVT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Cyclophosphamide (CYP) is widely used to treat various types of cancer. In addition to the therapeutic properties of this drug, unfortunately, its side effects are still not fully understood. This study investigated the protective effect of curcumin (CURC) and berberine (BER) on CYP-induced cardiac damage. Thirty-six male rats were equally divided into the control, dimethyl sulfoxide (DMSO), CYP, CYP + CURC, CYP + BER and CYP + BER + CURC groups. Troponin-I, Creatine kinase-myocardial band (CK-MB), total cholesterol, triglyceride levels in serum samples, and reactive oxygen species (ROS), poly(ADP-ribose) polymerase-1 (PARP-1), and transient receptor potential melastatin 2 (TRPM2) channel levels in heart tissue were measured using an enzyme-linked immunoassay (ELISA) kit. In addition, histopathological examination and immunohistochemical investigation of the TRPM2 channel, fibroblast specific protein-1 (FSP1), transforming growth factor-beta- 1 (TGF-β1) and α-smooth muscle actin (α-SMA) expressions were determined in heart tissue. The CYP group's troponin-I, total cholesterol, triglyceride, CK-MB, ROS, PARP-1 and TRPM2 channel levels were higher than in the other groups in the ELISA measurements (p < 0.05). In contrast, these parameters in the group treated with CURC and BER together with CYP were lower than in the CYP group (p < 0.05). Additionally, CUR and BER reduced CYP-induced pathological damage, TRPM2, FSP1, TGF-β1 and α-SMA expressions. The data showed that CYP administration can cause cardiac damage by increasing the TRPM2 channel, TGF-β1, FSP1 and α-SMA expression levels. Therefore, we concluded that CURC and BER administration following CYP application may be used as therapeutic agents to prevent CYP-induced cardiac damage., (© 2024 Wiley Periodicals LLC.)

Human induced pluripotent stem cell (hiPSC)-derived cardiac organoids (COs) have shown great potential in modelling human heart development and cardiovascular diseases, a leading cause of global death. However, several limitations such as low reproducibility, limited vascularization and difficulty in formation of cardiac chamber were yet to be overcome. We established a new method for robust generation of COs, via combination of methodologies of hiPSC-derived vascular spheres and directly differentiated cardiomyocytes from hiPSCs, and investigated the potential application of human COs in cardiac injury modelling and drug evaluation. The human COs we built displayed a vascularized and chamber-like structure, and hence were named vaschamcardioids (vcCOs). These vcCOs exhibited approximately 90% spontaneous beating ratio. Single-cell transcriptomics identified a total of six cell types in the vcCOs, including cardiomyocytes, cardiac precursor cells, endothelial cells, fibroblasts, etc. We successfully recaptured the processes of cardiac injury and fibrosis in vivo on vcCOs, and showed that the FDA-approved medication captopril significantly attenuated cardiac injury-induced fibrosis and functional disorders. In addition, the human vcCOs exhibited an obvious drug toxicity reaction to doxorubicin in a dose-dependent manner. We developed a three-step method for robust generation of chamber-like and vascularized complex vcCOs, and our data suggested that vcCOs might become a useful model for understanding pathophysiological mechanisms of cardiovascular diseases, developing intervention strategies and screening drugs., (© 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Calcium regulation is essential in virtually any cell due to its critical role as a second messenger in multiple signaling pathways [...].

Objective: To explore the therapeutic effect of levosimendan in patients with prolonged ventilator weaning and cardiac dysfunction., Method: Patients with prolonged ventilator weaning and cardiac dysfunction were randomly allocated to receive conventional treatment (control group) or intravenous infusion of levosimendan for 24 h based on conventional treatment (levosimendan group). Weaning success rates were then compared between the two groups. The study was retrospectively registered with Research Registry (ID No. researchregistry10304)., Results: A total of 40 patients were included (20 per group). Within 3 days after initiation of treatment, significantly more cases were successfully weaned in the levosimendan group versus control group (eight versus four cases, respectively). Among the eight patients who underwent pulse indicator continuous cardiac output monitoring in the levosimendan group, the global ejection fraction increased 24 h after treatment, and the cardiac function index and cardiac index increased 72 h after treatment., Conclusion: For patients requiring prolonged mechanical ventilation who have concomitant cardiac dysfunction, levosimendan may be considered to increase the probability of weaning success., Competing Interests: Declaration of conflicting interestThe authors declare that there are no conflicts of interest.

Background: Sepsis-induced cardiac dysfunction (SICD) is a serious complication of sepsis that is associated with increased mortality. Ferroptosis has been reported in the SICD. TaoHe ChengQi decoction (THCQD), a classical traditional Chinese medicinal formula, has multiple beneficial pharmacological effects. The potential effects of THCQD on the SICD remain unknown., Purpose: To investigate the effect of THCQD on SICD and explore whether this effect is related to the regulation of myocardial ferroptosis through nuclear factor erythroid 2-related factor 2 (Nrf2) activation., Methods: We induced sepsis in a mouse model using cecal ligation and puncture (CLP) and administered THCQD (2 and 4 g/kg) and dexamethasone (40 mg/kg). Mice mortality was recorded and survival curves were plotted. Echocardiography, hematoxylin and eosin staining, and analysis of serum myocardial injury markers and inflammatory factors were used to evaluate cardiac pathology. Myocardial ferroptosis was detected by quantifying specific biomarker content and protein levels. Through HPLC-Q-Exactive-MS analysis, we identified the components of the THCQD. Network pharmacology analysis and Cellular Thermal Shift Assay (CETSA) were utilized to predict the targets of THCQD for treating SICD. We detected the expression of Nrf2 using Western blotting or immunofluorescence. An RSL3-induced ferroptosis model was established using neonatal rat cardiomyocytes (NRCMs) to further explore the pharmacological mechanism of THCQD. In addition to measuring cell viability, we observed changes in NRCM mitochondria using electron microscopy and JC-1 staining. NRF2 inhibitor ML385 and Nrf2 knockout mice were used to validate whether THCQD exerted protective effects against SICD through Nrf2-mediated ferroptosis signaling., Results: THCQD reduced mortality in septic mice, protected against CLP-induced myocardial injury, decreased systemic inflammatory response, and prevented myocardial ferroptosis. Network pharmacology analysis and CETSA experiments predicted that THCQD may protect against SICD by activating the Nrf2 signaling pathway. Western blotting and immunofluorescence showed that THCQD activated Nrf2 in cardiac tissue. THCQDs consistently mitigated RSL3-induced ferroptosis in NRCM, which is related to Nrf2. Furthermore, the pharmacological inhibition of Nrf2 and genetic Nrf2 knockout partially reversed the protective effects of THCQD on SICD and ferroptosis., Conclusion: The effect of THCQD on SICD was achieved by activating Nrf2 and its downstream pathways., Competing Interests: Declaration of competing interest All the authors have declared that no conflicts of interest., (Copyright © 2024. Published by Elsevier GmbH.)

Chronic kidney disease (CKD) induces cardiac inflammation and fibrosis and reduces survival. We previously demonstrated that G protein-coupled receptor 68 (GPR68) promotes cardiac inflammation and fibrosis in mice with 5/6 nephrectomy (5/6Nx) and patients with CKD. However, no method of GPR68 inhibition has been found that has potential for therapeutic application. Here, we report that Cephalotaxus harringtonia var. nana extract and homoharringtonine ameliorate cardiac inflammation and fibrosis under CKD by suppressing GPR68 function. Reagents that inhibit the function of GPR68 were explored by high-throughput screening using a medicinal plant extract library (8,008 species), and we identified an extract from Cephalotaxus harringtonia var. nana as a GPR68 inhibitor that suppresses inflammatory cytokine production in a GPR68 expression-dependent manner. Consumption of the extract inhibited inflammatory cytokine expression and cardiac fibrosis and improved the decreased survival attributable to 5/6Nx. Additionally, homoharringtonine, a cephalotaxane compound characteristic of C. harringtonia, inhibited inflammatory cytokine production. Homoharringtonine administration in drinking water alleviated cardiac fibrosis and improved heart failure and survival in 5/6Nx mice. A previously unknown effect of C. harringtonia extract and homoharringtonine was revealed in which GPR68-dependent inflammation and cardiac dysfunction were suppressed. Utilizing these compounds could represent a new strategy for treating GPR68-associated diseases, including CKD., Competing Interests: Declaration of competing interest All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All the authors have read and approved the submission for publication., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chronic heart disease (CHD) is still a major global cause of morbidity and mortality, necessitating effective therapeutic interventions to mitigate its progression. Omega-3 fatty acids (FAs) have garnered attention for their potential anti-inflammatory and endothelial-protective properties in CHD management. The present study aims to assess the efficacy of Omega-3 FA supplementation on markers of inflammation and endothelial function in patients with CHD. To achieve this, we used the relevant keywords to search international databases (Web of Science, PubMed, Embase, and Scopus) and extract publications evaluating the effectiveness of omega-3 FA supplementation on inflammation markers and endothelial function in patients with CHD. STATA (version 15) and the random and fixed-effects models were used to evaluate the collected data. Thirteen clinical trial studies met inclusion criteria, with a total sample size of 853 individuals (406 cases and 447 controls). The cases had a mean age of 58 ± 10.3 years. The pooled results indicated that omega-3 Omega-3 FA supplementation significantly reduced the level of circulating IL-6 (SMD = -0.47, 95% CI -1.29 to 0.35, %, p < 0.001), hs-CRP (SMD = -0.21, 95% CI -0.70 to 0.28, p = 0.01), and TNF-α (SMD = -0.56, 95% CI -1.14 to 0.01, p < 0.001) in patients with CHD. Also, findings revealed that a daily supplement of omega-3 significantly increased FMD by 0.34% (95% CI: 0.14-0.54%, p < 0.001) as compared with placebo by a fixed-effect model in patients with CHD. These findings underscore the potential therapeutic utility of omega-3 fatty acid supplementation in modulating inflammation and endothelial dysfunction in patients with CHD.

Background: Vitamin K antagonists (VKAs) are the recommended first-line treatment for left ventricular thrombus (LVT); however, direct oral anticoagulants (DOACs) have been considered an alternative therapy., Objectives: To evaluate the efficacy and safety of DOACs compared with VKAs therapy in patients with LVT., Methods: PubMed, Embase, and Cochrane were systematically searched for randomized clinical trials or cohort studies that compared DOACs versus VKAs for LVT. Risk ratios (RRs) were computed for binary endpoints, with 95% confidence intervals (95% CIs). Statistical significance was defined as p value < 0.05., Results: A total of 4 randomized clinical trials and 29 cohort studies were included, with 4,450 patients assigned to either DOACs or VKAs. There was no significant difference between groups for stroke or systemic embolic (SSE) events (RR 0.84; 95% CI 0.65 to 1.07; p = 0.157), stroke (RR 0.73; 95% CI 0.48 to 1.11; p = 0.140), systemic embolic (SE) events (RR 0.69; 95% CI 0.40 to 1.17; p = 0.166), thrombus resolution (RR 1.05; 95% CI 0.99 to 1.11; p = 0.077), any bleeding (RR 0.78; 95% CI 0.60 to 1.00; p = 0.054), clinically relevant bleeding (RR 0.69; 95% CI 0.46 to 1.03; p = 0.066), minor bleeding (RR 0.73; 95% CI 0.43 to 1.23; p = 0.234), major bleeding (RR 0.87; 95% CI 0.42 to 1.80; p = 0.705), and all-cause mortality (RR 1.05; 95% CI 0.79 to 1.39; p = 0.752). Compared with VKAs, rivaroxaban significantly reduced SSE events (RR 0.35; 95% CI 0.16 to 0.91; p = 0.029) and SE events (RR 0.39; 95% CI 0.16 to 0.95; p = 0.037)., Conclusions: DOACs had a similar rate of thromboembolic and hemorrhagic events, as well as thrombus resolution, compared to VKAs in the treatment of LVTs. Rivaroxaban therapy had a significant reduction in thromboembolic events, compared to VKAs.

Cardiovascular diseases (CVDs), particularly heart failure, are major contributors to early mortality globally. Heart failure poses a significant public health problem, with persistently poor long-term outcomes and an overall unsatisfactory prognosis for patients. Conventionally, treatments for heart failure have focused on lowering blood pressure; however, the development of more potent therapies targeting hemodynamic parameters presents challenges, including tolerability and safety risks, which could potentially restrict their clinical effectiveness. Adenosine has emerged as a key mediator in CVDs, acting as a retaliatory metabolite produced during cellular stress via ATP metabolism, and works as a signaling molecule regulating various physiological processes. Adenosine functions by interacting with different adenosine receptor (AR) subtypes expressed in cardiac cells, including A 1 AR, A 2A AR, A 2B AR, and A 3 AR. In addition to A 1 AR, A 3 AR has a multifaceted role in the cardiovascular system, since its activation contributes to reducing the damage to the heart in various pathological states, particularly ischemic heart disease, heart failure, and hypertension, although its role is not as well documented compared to other AR subtypes. Research on A 3 AR signaling has focused on identifying the intricate molecular mechanisms involved in CVDs through various pathways, including G i or G q protein-dependent signaling, ATP-sensitive potassium channels, MAPKs, and G protein-independent signaling. Several A 3 AR-specific agonists, such as piclidenoson and namodenoson, exert cardioprotective impacts during ischemia in the diverse animal models of heart disease. Thus, modulating A 3 ARs serves as a potential therapeutic approach, fueling considerable interest in developing compounds that target A 3 ARs as potential treatments for heart diseases.

Introduction: Cardiac dysfunction after sepsis the most common and severe sepsis-related organ failure. The severity of cardiac damage in sepsis patients was positively associated to mortality. It is important to look for drugs targeting sepsis-induced cardiac damage. Our previous studies found that 4-phenylbutyric acid (PBA) was beneficial to septic shock by improving cardiovascular function and survival, while the specific mechanism is unclear., Objectives: We aimed to explore the specific mechanism and PBA for protecting cardiac function in sepsis., Methods: The cecal ligation and puncture-induced septic shock models were used to observe the therapeutic effects of PBA on myocardial contractility and the serum levels of cardiac troponin-T. The mechanisms of PBA against sepsis were explored by metabolomics and network pharmacology., Results: The results showed that PBA alleviated the sepsis-induced cardiac damage. The metabolomics results showed that there were 28 metabolites involving in the therapeutic effects of PBA against sepsis. According to network pharmacology, 11 hub genes were found that were involved in lipid metabolism and amino acid transport following PBA treatment. The further integrated analysis focused on 7 key targets, including Comt, Slc6a4, Maoa, Ppara, Pparg, Ptgs2 and Trpv1, as well as their core metabolites and pathways. In an in vitro assay, PBA effectively inhibited sepsis-induced reductions in Comt, Ptgs2 and Ppara after sepsis., Conclusions: PBA protects sepsis-induced cardiac injury by targeting Comt/Ptgs2/Ppara, which regulates amino acid metabolism and lipid metabolism. The study reveals the complicated mechanisms of PBA against sepsis., (© 2024. The Author(s).)

Despite advances in the management of type 2 diabetes mellitus (T2DM), one-third of patients with diabetes do not achieve the desired glycemic goal. Considering this inadequacy, many agents that activate glucokinase have been investigated over the last two decades but were withdrawn before submission for marketing permission. Dorzagliatin is the first glucokinase activator that has been granted approval for T2DM, only in China. As overstimulation of glucokinase is linked with pathophysiological disturbances such as fatty liver and cardiovascular issues and a loss of therapeutic efficacy with time. This review aims to highlight the benefits of glucokinase activators vis-à-vis the risks associated with chronic enzymatic activation. We discuss the multisystem disturbances expected with chronic activation of the enzyme, the lessons learned with glucokinase activators of the past, the major efficacy and safety findings with dorzagliatin and its pharmacological properties, and the status of other glucokinase activators in the pipeline. The approval of dorzagliatin in China was based on the SEED and the DAWN trials, the major pivotal phase III trials that enrolled patients with T2DM with a mean glycosylated hemoglobin of 8.3-8.4%, and a mean age of 53-54.5 years from multiple sites in China. Patients with uncontrolled diabetes, cardiac diseases, organ dysfunction, and a history of severe hypoglycemia were excluded. Both trials had a randomized double-blind placebo-controlled phase of 24 weeks followed by an open-label phase of 28 weeks with dorzagliatin. Drug-naïve patients with T2DM with a disease duration of 11.7 months were enrolled in the SEED trial while the DAWN trial involved patients with T2DM with a mean duration of 71.5 months and receiving background metformin therapy. Compared with placebo, the decline in glycosylated hemoglobin at 24 weeks was more with dorzagliatin with an estimated treatment difference of - 0.57% in the SEED trial and - 0.66% in the DAWN trial. The desired glycosylated hemoglobin (< 7%) was also attained at more than two times higher rates with dorzagliatin. The glycemic improvement was sustained in the SEED trial but decreased over 52 weeks in the DAWN trial. Hyperlipidemia was observed in 12-14% of patients taking dorzagliatin versus 9-11% of patients receiving a placebo. Additional adverse effects noticed over 52 weeks with dorzagliatin included an elevation in liver enzymes, hyperuricemia, hyperlacticacidemia, renal dysfunction, and cardiovascular disturbances. Considering the statistically significant improvement in glycosylated hemoglobin with dorzagliatin in patients with T2DM, the drug may be given a chance in treatment-naïve patients with a shorter disease history. However, with the waning therapeutic efficacy witnessed in patients with long-standing diabetes, which was also one of the potential concerns with previously tested molecules, extended studies involving patients with chronic and uncontrolled diabetes are needed to comment upon the long-term therapeutic performance of dorzagliatin. Likewise, evidence needs to be generated from other countries, patients with organ dysfunction, a history of severe hypoglycemia, cardiac diseases, and elderly patients before extending the use of dorzagliatin. Apart from monitoring lipid profiles, long-term safety studies of dorzagliatin should involve the assessment of serum uric acid, lactate, renal function, liver function, and cardiovascular parameters., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In the primary care setting providers have more tools available than ever before to impact positively obesity, diabetes, and their complications, such as renal and cardiac diseases. It is important to recognise what is available for treatment taking into account diabetes heterogeneity. For those who develop type 2 diabetes (T2DM), effective treatments are available that for the first time have shown a benefit in reducing mortality and macrovascular complications, in addition to the well-established benefits of glucose control in reducing microvascular complications. Some of the newer medications for treating hyperglycaemia have also a positive impact in reducing heart failure (HF). Technological advances have also contributed to improving the quality of care in patients with diabetes. The use of technology, such as continuous glucose monitoring systems (CGM), has improved significantly glucose and glycated haemoglobin A1c (HbA1c) values, while limiting the frequency of hypoglycaemia. Other technological support derives from the use of predictive algorithms that need to be refined to help predict those subjects who are at great risk of developing the disease and/or its complications, or who may require care by other specialists. In this review we also provide recommendations for the optimal use of the new medications; sodium-glucose co-transporter-2 inhibitors (SGLT2i) and Glucagon-like peptide-receptor agonists 1 (GLP1RA) in the primary care setting considering the relevance of these drugs for the management of T2DM also in its early stage., (© 2023 John Wiley & Sons Ltd.)

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance.

Importance: The association of value-based medication benefits with diabetes health outcomes is uncertain., Objective: To assess the association of a preventive drug list (PDL) value-based medication benefit with acute, preventable diabetes complications., Design, Setting, and Participants: This cohort study used a controlled interrupted time series design and analyzed data from a large, national, commercial health plan from January 1, 2004, through June 30, 2017, for patients with diabetes aged 12 to 64 years enrolled through employers that adopted PDLs (intervention group) and matched and weighted members with diabetes whose employers did not adopt PDLs (control group). All participants were continuously enrolled and analyzed for 1 year before and after the index date. Subgroup analysis assessed patients with diabetes living in lower-income and higher-income neighborhoods. Data analysis was performed between August 19, 2020, and December 1, 2023., Exposure: At the index date, intervention group members experienced employer-mandated enrollment in a PDL benefit that was added to their follow-up year health plan. This benefit reduced out-of-pocket costs for common cardiometabolic drugs, including noninsulin antidiabetic agents and insulin. Matched control group members continued to have cardiometabolic medications subject to deductibles or co-payments at follow-up., Main Outcomes and Measures: The primary outcome was acute, preventable diabetes complications (eg, bacterial infections, neurovascular events, acute coronary disease, and diabetic ketoacidosis) measured as complication days per 1000 members per year. Intermediate measures included the proportion of days covered by and higher use (mean of 1 or more 30-day fills per month) of antidiabetic agents., Results: The study 10 588 patients in the intervention group (55.2% male; mean [SD] age, 51.1 [10.1] years) and 690 075 patients in the control group (55.2% male; mean [SD] age, 51.1 [10.1] years) after matching and weighting. From baseline to follow-up, the proportion of days covered by noninsulin antidiabetic agents increased by 4.7% (95% CI, 3.2%-6.2%) in the PDL group and by 7.3% (95% CI, 5.1%-9.5%) among PDL members from lower-income areas compared with controls. Higher use of noninsulin antidiabetic agents increased by 11.3% (95% CI, 8.2%-14.5%) in the PDL group and by 15.2% (95% CI, 10.6%-19.8%) among members of the PDL group from lower-income areas compared with controls. The PDL group experienced an 8.4% relative reduction in complication days (95% CI, -13.9% to -2.8%; absolute reduction, -20.2 [95% CI, -34.3 to -6.2] per 1000 members per year) compared with controls from baseline to follow-up, while PDL members residing in lower-income areas had a 10.2% relative reduction (95% CI, -17.4% to -3.0%; absolute, -26.1 [95% CI, -45.8 to -6.5] per 1000 members per year)., Conclusions and Relevance: In this cohort study, acute, preventable diabetes complication days decreased by 8.4% in the overall PDL group and by 10.2% among PDL members from lower-income areas compared with the control group. The results may support a strategy of incentivizing adoption of targeted cost-sharing reductions among commercially insured patients with diabetes and lower income to enhance health outcomes.

Studies involving the immune response in Chagas disease suggest an imbalance in the immune response of symptomatic patients, with an inflammatory profile dominating in Chagas heart disease, mainly by tumour necrosis factor (TNF). TNF is considered a key cytokine in immunopathology in chronic carriers in several processes during the immune response. Our work aimed to evaluate regulatory (interleukin [IL]-4 and IL-10) and inflammatory (TNF, interferon-gamma [IFN-γ], IL-2 and IL-6) cytokines in peripheral blood mononuclear cells culture supernatants. of affected patients with undetermined clinical forms-IND (n = 13) mild heart form-CARD1 (n = 13) and severe cardiac form-CARD2 (n = 16), treated in vitro with two TNF blockers, Adalimumab (ADA) and Etanercept (ETA) alone or in association with Benznidazole (BZ). The results indicate that ADA was more competent in blocking TNF (compared to ETA) in all groups but with much lower levels in the CARD2 group. ETA statistically decreased TNF levels only in the CARD2 group. IFN-γ increased in the CARD2 group after treatment with ETA relative to ADA. IL-4 had its levels decreased when treated by both drugs. IL-2 was detected in cells from CARD2 carriers compared to the NEG group after treatment with both drugs. The association with BZ decreased levels of IL-2/TNF and increased IL-4. These data reinforce the participation of TNF in severe Chagas heart disease and bring perspectives on using these blockers in the immunological treatment of Chagas disease since the use of BZ is extremely limited in these patients., (© 2024 John Wiley & Sons Ltd.)

Backgrounds: Omega-3 supplements are endorsed for heart failure (HF) patients to reduce hospitalizations and mortality, offering anti-inflammatory and cardioprotective benefits., Methods: A comprehensive search was conducted in various databases until November 2022. Eligible studies included clinical trials on patients with HF. Data extraction covered study details, omega-3 specifics, outcomes, and limitations. The JADAD scale was used to assess the risk of bias in randomized controlled trials., Results: The review process involved 572 records from database searches, resulting in 19 studies after eliminating duplicates and screening. These studies assessed the impact of omega-3 on various clinical outcomes, such as mortality, hospitalization, cardiac function, and quality of life. Studied duration varied from weeks to years. Omega-3 supplementation demonstrated potential benefits such as improved heart function, reduced inflammation, and decreased risk of cardiovascular events., Conclusion: Omega-3 supplementation could benefit heart disease treatment, potentially reducing therapy duration and improving outcomes. Starting omega-3 supplementation for HF patients seems favorable., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Mitochondria dysfunctions are typical hallmarks of cardiac disorders (CDs). The multiple tasks of this energy-producing organelle are well documented, but its pathophysiologic involvement in several manifestations of heart diseases, such as altered electromechanical coupling, excitability, and arrhythmias, is still under investigation. The human 18 kDa translocator protein (TSPO) is a protein located on the outer mitochondrial membrane whose expression is altered in different pathological conditions, including CDs, making it an attractive therapeutic and diagnostic target. Currently, only a few TSPO ligands are employed in CDs and cardiac imaging. In this Perspective, we report an overview of the emerging role of TSPO at the heart level, focusing on the recent literature concerning the development of TSPO ligands used for fighting and imaging heart-related disease conditions. Accordingly, targeting TSPO might represent a successful strategy to achieve novel therapeutic and diagnostic strategies to unravel the fundamental mechanisms and to provide solutions to still unanswered questions in CDs.

Cardiovascular diseases (CVDs) are characterized by abnormalities in the heart, blood vessels, and blood flow. CVDs comprise a diverse set of health issues. There are several types of CVDs like stroke, endothelial dysfunction, thrombosis, atherosclerosis, plaque instability and heart failure. Identification of a new drug for heart disease takes longer duration and its safety efficacy test takes even longer duration of research and approval. This chapter explores drug repurposing, nano-therapy, and plant-based treatments for managing CVDs from existing drugs which saves time and safety issues with testing new drugs. Existing drugs like statins, ACE inhibitor, warfarin, beta blockers, aspirin and metformin have been found to be useful in treating cardiac disease. For better drug delivery, nano therapy is opening new avenues for cardiac research by targeting interleukin (IL), TNF and other proteins by proteome interactome analysis. Nanoparticles enable precise delivery to atherosclerotic plaques, inflammation areas, and damaged cardiac tissues. Advancements in nano therapeutic agents, such as drug-eluting stents and drug-loaded nanoparticles are transforming CVDs management. Plant-based treatments, containing phytochemicals from Botanical sources, have potential cardiovascular benefits. These phytochemicals can mitigate risk factors associated with CVDs. The integration of these strategies opens new avenues for personalized, effective, and minimally invasive cardiovascular care. Altogether, traditional drugs, phytochemicals along with nanoparticles can revolutionize the future cardiac health care by identifying their signaling pathway, mechanism and interactome analysis., (Copyright © 2024. Published by Elsevier Inc.)

Background: Allium sativum L. (Garlic) is a well-recognized plant of great nutraceutical value with pharmacological evidences. It is full of dietary as well as pharmaceutical properties and has been used in traditional medications for a long time. It is known for good antioxidant, antifungal, antibacterial, anti-diabetic, anti-inflammatory, anticancer, and antiviral effects, along with other therapeutic roles in cardiovascular diseases, anti-atherosclerotic, antihypertensive, anti-thrombotic, blood pressure, bone and skin related problems etc. Objective: Considering the potential of garlic in the treatment of cardiovascular/heart-related diseases, the main objective of this study was to prepare a subject-centric mini-review focusing on its chemistry and pharmacology in heart-related issues., Methods: In order to prepare this mini-review article, an extensive online literature search was performed to find out the most recent studies related to this topic. These studies were briefly reviewed, assessed, and discussed to explore the possible capability of garlic for the cure of cardiovascular problems., Result: Several experiments on mice models, rat models as well as on humans show the effective role of various forms of garlic in cardiovascular or heart-related ailments. After reviewing the available publications on garlic in heart-related issues, authors found that garlic and its sulfur (S)-based organic constituents may have advantageous applications in the treatment of cardiovascular diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cardiomyopathy is a common complication and significantly increases the risk of death in septic patients. Our previous study demonstrated that post-treatment with dexmedetomidine (DEX) aggravates septic cardiomyopathy. However, the mechanisms for the side effect of DEX post-treatment on septic cardiomyopathy are not well-defined. Here we employed a cecal ligation and puncture (CLP) model and α 2A -adrenoceptor deficient (Adra2a -/- ) mice to observe the effects of DEX post-treatment on myocardial metabolic disturbances in sepsis. CLP mice displayed significant cardiac dysfunction, altered mitochondrial dynamics, reduced cardiac lipid and glucose uptake, impaired fatty acid and glucose oxidation, enhanced glycolysis and decreased ATP production in the myocardium, almost all of which were dramatically enhanced by DEX post-treatment in septic mice. In Adra2a -/- mice, DEX post-treatment did not affect cardiac dysfunction and metabolic disruptions in CLP-induced sepsis. Additionally, Adra2a -/- mice exhibited impaired cardiac function, damaged myocardial mitochondrial structures, and disturbed fatty acid metabolism and glucose oxidation. In sum, DEX post-treatment exacerbates metabolic disturbances in septic cardiomyopathy in a α 2A -adrenoceptor dependent manner., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: There is still no effective treatment for heart failure with preserved left ventricular ejection fraction (HFpEF), and therapies to improve prognosis are urgently needed. Clinical studies in patients with HFpEF have shown that statins and HMG-CoA reductase inhibitors may reduce their mortality rate. However, the mechanisms underlying the effects of statins on HFpEF remain unknown. In the present study, we examined whether simvastatin administration inhibits the development of cardiac fibrosis in HFpEF model mice. We further examined the contribution of the Smad and mitogen-activated protein (MAP) kinase pathways to the transforming growth factor-β (TGF-β) signaling pathway in the development of HFpEF., Methods: HFpEF animals were prepared by feeding C57BL/6 N mice a high-fat diet and providing water containing N[w]-nitro-l-arginine methyl ester hydrochloride (l-NAME) for 15 weeks. Simvastatin (30 mg/kg/day) or vehicle was administered orally daily during the experimental period. Cardiac function was measured by echocardiography, and cardiac fibrosis was evaluated by Masson's trichrome staining. Changes in the TGF-β signaling proteins in myocardial tissue were examined by Western blotting., Results: A high-fat diet and l-NAME solution load induced cardiac diastolic dysfunction with cardiac fibrosis. Simvastatin treatment markedly attenuated cardiac fibrosis and reduced cardiac diastolic dysfunction. In addition, simvastatin prevented the increase in phosphorylation levels of Smad (Smad2 and Smad3) and MAPK (c-Raf, Erk1/2) pathway proteins downstream of the TGF-β receptor in cardiac tissue., Conclusions: Our present study demonstrated that simvastatin attenuated diastolic dysfunction by reducing cardiac fibrosis in HFpEF hearts. Furthermore, our findings suggest that the mechanisms by which simvastatin attenuates HFpEF development involve, at least in part, inhibition of the TGF-β signaling pathway, which is activated in the HFpEF heart., (© 2023 S. Karger AG, Basel.)

In order to obtain efficient NO donor drugs to treat hypoxic cardiac disease, a series of hypoxia-targeted NO donor compounds were prepared and screened. Among them, a representative compound H3 was found to selectively release NO under hypoxia with a higher ratio than isosorbide dinitrate (ISDN). In vitro study indicated that H3 had a strong capability of alleviating vascular dilation and reducing myocardial hypoxic injury due to its effective regulation of vascular dilatation and myocardial injury-related proteins in H9c2 cells even at low concentrations. By intraperitoneal injection or intragastric administration, in vivo animal tests revealed that H3 possessed a potent antimyocardial hypoxic injury effect superior to ISDN. These findings suggest that H3 has a better effect on alleviating hypoxic cardiac disease than the conventional drug, owing to its hypoxia-targeted release of NO.

Objectives: To assess the occurrence of thrombosis and major bleeding in children with congenital or acquired heart disease (CAHD) treated with VKA and to identify risk factors for these serious adverse events (SAE)., Study Design: All children enrolled in our VKA dedicated educational program between 2008 and 2022 were prospectively included. The time in therapeutic range (TTR) was calculated to evaluate the stability of anticoagulation. Statistical analysis included Cox proportional hazard models., Results: We included 405 patients. Median follow-up was 18.7 (9.3-49.4) months. The median TTR was 83.1 % (74.4 %-95.3 %). No deaths occurred because of bleeding or thrombotic events. The incidences of thrombotic and major bleeding events were 0.9 % (CI95 % [0.1-1.8]) and 2.3 % (CI95 % [0.9-3.8]) per patient year, respectively. At 1 and 5 years, 98.3 % (CI95 % [96.2 %-99.2 %]) and 88.7 % (CI95 % [81.9 % 93.1 %]) of patients were free of any SAE, respectively. Although the mechanical mitral valve (MMV) was associated to major bleeding events (HR = 3.1 CI95 % [1.2-8.2], p = 0.02) in univariate analysis, only recurrent minor bleeding events (HR = 4.3 CI95 % [1.6-11.7], p < 0.01) and global TTR under 70 % (HR = 4.7 CI95 % [1.5-15.1], p < 0.01) were independent risk factors in multivariable analysis. In multivariable analysis, giant coronary aneurysms after Kawasaki disease (HR = 7.8 [1.9-32.0], p = 0.005) was the only risk factor for thrombotic events., Conclusion: Overall, VKA therapy appears to be safe in children with CAHD. Suboptimal TTR, regardless of the indication for VKA initiation, was associated with bleeding events., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Cardiotoxicity is a common side-effect of many cancer therapeutics; however, to-date there has been very little push to understand the mechanisms underlying this group of pathologies. This has led to the emergence of cardio-oncology, a field of medicine focused on understanding the effects of cancer and its treatment on the human heart. Here, we describe how mechanistic modeling approaches have been applied to study open questions in the cardiovascular system and how these approaches are being increasingly applied to advance knowledge of the underlying effects of cancer treatments on the human heart. A variety of mechanistic, mathematical modeling techniques have been applied to explore the link between common cancer treatments, such as chemotherapy, radiation, targeted therapy, and immunotherapy, and cardiotoxicity, nevertheless there is limited coverage in the different types of cardiac dysfunction that may be associated with these treatments. Moreover, cardiac modeling has a rich heritage of mathematical modeling and is well suited for the further development of novel approaches for understanding the cardiotoxicities associated with cancer therapeutics. There are many opportunities to combine mechanistic, bottom-up approaches with data-driven, top-down approaches to improve personalized, precision oncology to better understand, and ultimately mitigate, cardiac dysfunction in cancer patients., Competing Interests: Declaration of Competing Interest A conflicting interest exists when professional judgement concerning a primary interest (such as patient’s welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). It may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Despite widespread use, dosing regimens for antenatal corticosteroid (ACS) therapy are poorly unoptimized. ACS therapy exerts a programming effect on fetal development, which may be associated with an increased risk of cardiovascular disease. Having demonstrated that low-dose steroid therapy is an efficacious means of maturing the preterm lung, we hypothesized that a low-dose steroid exposure would exert fewer adverse functional and transcriptional changes on the fetal heart. We tested this hypothesis using low-dose steroid therapy (10 mg delivered to the ewe over 36 h via constant infusion) and compared cardiac effects with those of a higher dose treatment (30 mg delivered to the ewe over 24 h by intramuscular injection; simulating currently employed clinical ACS regimens). Fetal cardiac function was assessed by ultrasound on the day of ACS treatment initiation. Transcriptomic analyses were performed on fetal myocardial tissue. Relative to saline control, fetuses in the higher-dose clinical treatment group had significantly lower ratios between early diastolic ventricular filling and ventricular filling during atrial systole, and showed the differential expression of myocardial hypertrophy-associated transcripts including βMHC, GADD45γ, and PPARγ. The long-term implications of these changes remain unstudied. Irrespective, optimizing ACS dosing regimens to maximize respiratory benefit while minimizing adverse effects on key organ systems, such as the heart, offers a means of improving the acute and long-term outcomes associated with this important obstetric therapy., (© 2023. The Author(s).)

Objective: To determine the efficacy of sacubitril/valsartan plus dapagliflozin in the treatment of patients with pulmonary arterial hypertension (PAH) due to left heart disease and to explore new treatment regimen for PAH due to left heart disease., Methods: This study is a randomized controlled trial (RCT) study of 120 patients with PAH due to left heart disease admitted to the cardiovascular department of our hospital from Dec. 2019 to Dec. 2021. The patients were randomized 1:1 to the study group and control group. All patients were given baseline treatments targeting left heart disease and symptoms of PAH. In addition to the baseline treatments, patients in the control group were given sacubitril/valsartan tablets, while patients in the study group were given sacubitril/valsartan tablets plus dapagliflozin tablets. After 6 months of treatment, parameters including left heart function and exercise tolerance, Hemodynamics (left ventricular end systolic diameter [LVSED], left ventricular end diastolic diameter [LVEDD], left ventricular ejection fraction [LVEF], 6 min walk distance (6MWD), mean pulmonary artery pressure (mPAP) and pulmonary artery systolic pressure (PASP)), vascular endothelial function (plasma endothelin (ET) -1 and nitric oxide [NO]), heart failure markers (plasma N-terminal pro-brain natriuretic peptide (NT-proBNP)], inflammatory factors (serum C reactive protein [CRP], interleukin (IL)-6, and tumor necrosis factor (TNF)-α], and adverse drug reactions (ADRs) were assessed in both groups., Results: Both groups had reduced LVESD and LVEDD, increased LVEF, and extended 6MWD after 6 months of treatment. The improvements in these parameters were significantly greater in the study group than in the control group (all P  < 0.05). In addition, both the mPAP and PASP showed a decrease, and the mPAP and PASP in the study group were lower than those in the control group ( p <0.05). Furthermore, both groups had decreased plasma ET-1 and NT-proBNP but increased plasma NO after 6 months of treatment. The improvements in these parameters were significantly greater in the study group than in the control group (all P  < 0.05). Serum CRP, IL-6 and TNF-α levels were decreased in both groups after 6 months of treatment, and were significantly lower in the study group than in the control group (all P  < 0.05). There was no significant difference in the overall incidence of ADRs between the two groups ( P  > 0.05)., Conclusion: Sacubitril/valsartan plus dapagliflozin in the treatment with PAH due to left heart disease can improve left heart function of patients by improving vascular endothelial functions and alleviating inflammation, which helps to reduce the PAH process. Therefore, this combination treatment is safe and effective in PAH due to left heart disease., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Accidental hypothermia, recognized by core temperature below 35 °C, is a lethal condition with a mortality rate up to 25%. Hypothermia-induced cardiac dysfunction causing increased total peripheral resistance and reduced cardiac output contributes to the high mortality rate in this patient group. Recent studies, in vivo and in vitro, have suggested levosimendan, milrinone and isoprenaline as inotropic treatment strategies in this patient group. However, these drugs may pose increased risk of ventricular arrhythmias during hypothermia. Our aim was therefore to describe the effects of levosimendan, milrinone and isoprenaline on the action potential in human cardiomyocytes during hypothermia., Methods: Using an experimental in vitro-design, levosimendan, milrinone and isoprenaline were incubated with iCell 2 hiPSC-derived cardiomyocytes and cellular action potential waveforms and contraction were recorded from monolayers of cultured cells. Experiments were conducted at temperatures from 37 °C down to 26 °C. One-way repeated measures ANOVA was performed to evaluate differences from baseline recordings and one-way ANOVA was performed to evaluate differences between drugs, untreated control and between drug concentrations at the specific temperatures., Results: Milrinone and isoprenaline both significantly increases action potential triangulation during hypothermia, and thereby the risk of ventricular arrhythmias. Levosimendan, however, does not increase triangulation and the contractile properties also remain preserved during hypothermia down to 26 °C., Conclusions: Levosimendan remains a promising candidate drug for inotropic treatment of hypothermic patients as it possesses ability to treat hypothermia-induced cardiac dysfunction and no increased risk of ventricular arrhythmias is detected. Milrinone and isoprenaline, on the other hand, appears more dangerous in the hypothermic setting., (© 2023. Norwegian Air Ambulance Foundation.)

Background: Direct oral anticoagulants (DOACs) represent a cornerstone of adult venous thromboembolism (VTE) treatment. Recently, randomized controlled trials (RCTs) investigating DOACs in pediatrics have been performed., Objectives: To evaluate the efficacy and safety of DOACs in the pediatric population., Methods: We systematically searched MEDLINE (PubMed), EMBASE, and ClinicalTrials.gov from initiation up to August 20, 2022, for RCTs comparing DOACs to standard of care (SOC) in patients aged <18 years according to PRISMA guidelines (PROSPERO registration CRD42022353870). The primary analysis was performed according to the anticoagulation intensity and clinical setting (ie, prophylaxis in cardiac disease or treatment in VTE). Efficacy outcomes were all-cause mortality and VTE. Safety outcomes were major bleeding (MB), clinically relevant non-MB, any bleeding, serious adverse events, and discontinuation due to adverse events (AEs)., Results: Seven RCTs were included in the systematic review and 6 in the meta-analysis (3 prophylaxis in cardiac disease and 3 treatment in VTE). DOACs showed a significant reduction of VTE recurrence for treatment (odds ratio [OR] = 0.42; 95% CI, 0.19-0.94) and a nonsignificant reduction in VTE occurrence in prophylaxis (OR = 0.22; 95% CI, 0.03-1.55). No differences were observed for any bleeding, serious AEs, and MB in prophylaxis. Nonsignificant trends were observed for clinically relevant non-MB, MB in treatment, and discontinuation due to AE in prophylaxis. We found a significant increase in discontinuation due to AE in treatment., Conclusions: DOAC treatment seems to reduce VTE compared with SOC without major safety issues in the pediatric population, whereas DOAC prophylaxis seems at least comparable to SOC., Competing Interests: Declarations of competing interests R.G. received support for congress participation from Mylan and acted as a consultant for Daiichi-Sankyo, outside this work. M.C. received support for congress participation from Abbvie. F.S. received fees as speaker or member of Advisory Boards from Bayer, MSD, Angelini, and Dompè. D.F. received fees in the last 2 years as speaker or member of Advisory Boards from the following companies: Alfasigma, Astellas, Bayer, Grünenthal, Lundbeck, Molteni, and SPA. All other authors declare no competing interests., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD., Methods: The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9 -/- mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice., Results: In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9 -/- mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9 -/- mice, confirming target specificity., Conclusion: Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Abstract: Cardiovascular diseases (CVDs) are the foremost cause of morbidity and mortality worldwide. Current clinical interventions include invasive approaches for progressed conditions and pharmacological assistance for initial stages, which has systemic side effects. Preventive, curative, diagnostic, and theranostic (therapeutic + diagnostic) approaches till date are not very useful in combating the ongoing CVD epidemic, which demands a promising efficient alternative approach. To combat the growing CVD outbreak globally, the ideal strategy is to make the therapeutic intervention least invasive and direct to the heart to reduce the bystander effects on other organs and increase the bioavailability of the therapeutics to the myocardium. The application of nanoscience and nanoparticle-mediated approaches have gained a lot of momentum because of their efficient passive and active myocardium targeting capability owing to their improved specificity and controlled release. This review provides extensive insight into the various types of nanoparticles available for CVDs, their mechanisms of targeting (eg, direct or indirect), and the utmost need for further development of bench-to-bedside cardiac tissue-based nanomedicines. Furthermore, the review aims to summarize the different ideas and methods of nanoparticle-mediated therapeutic approaches to the myocardium till date with present clinical trials and future perspectives. This review also reflects the potential of such nanoparticle-mediated tissue-targeted therapies to contribute to the sustainable development goals of good health and well-being., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)