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Aim: Activation of both the Survivor Activating Factor Enhancement (SAFE) pathway (including Tumor Necrosis Factor-alpha (TNF-α) and Signal Transducer and Activator of Transcription-3 (STAT-3)) and the sphingolipid signalling pathway (including sphingosine kinase-1 (SK1) and sphingosine-1 phosphate (S1P)) play a key role in promoting cardioprotection against ischemia-reperfusion injury (IRI). We investigated whether the activation of the SAFE pathway by exogenous S1P is dependent on the activation of SK1 for cardioprotection., Materials and Methods: Isolated cardiomyocytes from TNF-α knockout (KO) mice, cardiomyocyte-specific STAT-3 KO mice and their wild-type (WT) littermates were exposed to simulated ischemia in the presence of a trigger of the SAFE pathway (S1P) and SK1 inhibitor (SK1-I). Similarly, isolated perfused hearts from adult TNF-α KO, STAT-3 KO and WT mice were subjected to IRI with S1P and/or SK1-I. Cell viability, infarct size (IS) and SK1 activity were assessed., Key Findings: In isolated cardiomyocytes and in isolated hearts subjected to simulated ischemia/IRI, S1P pretreatment decreased cell death in WT mice, an effect that was abrogated in the presence of SK1-I. S1P failed to reduce cell death after simulated ischemia/IRI in both cardiomyocytes or hearts isolated from TNF-α KO and STAT-3 KO mice. Interestingly, S1P pretreatment increased SK1 activity in WT and STAT-3 KO mice, with no changes in TNF-α KO mice., Significance: Our data strongly suggest SK1 as a key component to activate STAT-3 downstream of TNF-α in the SAFE pathway, paving the way for the development of novel cardioprotective strategies that may target SK1 to modulate the SAFE pathway and increase cell survival following IRI., 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 Inc.)

Purpose: Coronary artery bypass grafting (CABG) on cardiopulmonary bypass (CPB) is associated with myocardial ischemia-reperfusion injury (IRI), which may limit the benefit of the surgery. Both experimental and clinical studies suggest that Intralipid, a lipid emulsion commonly used for parenteral nutrition, can limit myocardial IRI. We therefore aimed to investigate whether Intralipid administered at reperfusion can reduce myocardial IRI in patients undergoing CABG on CPB., Methods: We conducted a randomized, double-blind, pilot trial in which 29 adult patients scheduled for CABG were randomly assigned (on a 1:1 basis) to receive either 1.5 ml/kg Intralipid 20% or Ringer's Lactate 3 min before aortic cross unclamping. The primary endpoint was the 72-h area under the curve (AUC) for troponin I., Results: Of the 29 patients randomized, 26 were included in the study (two withdrew consent and one was excluded before surgery). The 72-h AUC for troponin I did not significantly differ between the control and Intralipid group (546437 ± 205518 versus 487561 ± 115724 arbitrary units, respectively; P = 0.804). Other outcomes (including 72-h AUC for CK-MB, C-reactive protein, need for defibrillation, time to extubation, length of ICU and hospital stay, and serious adverse events) were similar between the two groups., Conclusion: In patients undergoing CABG on CPB, Intralipid did not limit myocardial IRI compared to placebo., Trial Registration: ClinicalTrials.gov Identifier: NCT02807727 (registration date: 16 June 2016)., (© 2024. The Author(s).)

Purpose: Patients hospitalized with COVID-19 may develop a hyperinflammatory, dysregulated cytokine "storm" that rapidly progresses to acute respiratory distress syndrome, multiple organ dysfunction, and even death. Remote ischaemic conditioning (RIC) has elicited anti-inflammatory and cytoprotective benefits by reducing cytokines following sepsis in animal studies. Therefore, we investigated whether RIC would mitigate the inflammatory cytokine cascade induced by COVID-19., Methods: We conducted a prospective, multicentre, randomized, sham-controlled, single-blind trial in Brazil and South Africa. Non-critically ill adult patients with COVID-19 pneumonia were randomly allocated (1:1) to receive either RIC (intermittent ischaemia/reperfusion applied through four 5-min cycles of inflation (20 mmHg above systolic blood pressure) and deflation of an automated blood-pressure cuff) or sham for approximately 15 days. Serum was collected following RIC/sham administration and analyzed for inflammatory cytokines using flow cytometry. The endpoint was the change in serum cytokine concentrations. Participants were followed for 30 days., Results: Eighty randomized participants (40 RIC and 40 sham) completed the trial. Baseline characteristics according to trial intervention were overall balanced. Despite downward trajectories of all cytokines across hospitalization, we observed no substantial changes in cytokine concentrations after successive days of RIC. Time to clinical improvement was similar in both groups (HR 1.66; 95% CI, 0.938-2.948, p 0.08). Overall RIC did not demonstrate a significant impact on the composite outcome of all-cause death or clinical deterioration (HR 1.19; 95% CI, 0.616-2.295, p = 0.61)., Conclusion: RIC did not reduce the hypercytokinaemia induced by COVID-19 or prevent clinical deterioration to critical care., Trial Registration: ClinicalTrials.gov Identifier: NCT04699227., (© 2022. The Author(s).)

Objective: This study aimed to study the relationship between auto-antibodies against apolipoprotein A1 (anti-apoA1 IgG), human immunodeficiency virus (HIV) infection, anti-retroviral therapy (ART), and the tryptophan pathways in HIV-related cardiovascular disease., Design: This case-control study conducted in South Africa consisted of control volunteers ( n  = 50), people living with HIV (PLWH) on ART ( n  = 50), and untreated PLWH ( n  = 44). Cardiovascular risk scores were determined, vascular measures were performed, and an extensive biochemical characterisation (routine, metabolomic, and inflammatory systemic profiles) was performed., Methods: Anti-apoA1 IgG levels were assessed by an in-house ELISA. Inflammatory biomarkers were measured with the Meso Scale Discovery® platform, and kynurenine pathway metabolites were assessed using targeted metabolomic profiling conducted by liquid chromatography-multiple reaction monitoring/mass spectrometry (LC-MRM/MS)., Results: Cardiovascular risk scores and vascular measures exhibited similarities across the three groups, while important differences were observed in systemic inflammatory and tryptophan pathways. Anti-apoA1 IgG seropositivity rates were 15%, 40%, and 70% in control volunteers, PLWH ART-treated, and PLWH ART-naïve, respectively. Circulating anti-apoA1 IgG levels were significantly negatively associated with CD4+ cell counts and positively associated with viremia and pro-inflammatory biomarkers (IFNγ, TNFα, MIPα, ICAM-1, VCAM-1). While circulating anti-apoA1 IgG levels were associated with increased levels of kynurenine in both control volunteers and PLWH, the kynurenine/tryptophan ratio was significantly increased in PLWH ART-treated., Conclusion: HIV infection increases the humoral response against apoA1, which is associated with established HIV severity criteria and kynurenine pathway activation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Frias, Pagano, Bararpour, Sidibé, Kamau, Fétaud-Lapierre, Hudson, Thomas, Lecour, Strijdom and Vuilleumier.)

Doxorubicin (DOX) is an anthracycline antibiotic widely used as a chemotherapeutic agent to treat solid tumours and hematologic malignancies. Although useful in the treatment of cancers, the benefit of DOX is limited due to its cardiotoxic effect that is observed in a large number of patients. In the literature, there is evidence that the presence of various factors may increase the risk of developing DOX-induced cardiotoxicity. A better understanding of the role of these different factors in DOX-induced cardiotoxicity may facilitate the choice of the therapeutic approach in cancer patients suffering from various cardiovascular risk factors. In this review, we therefore discuss the latest findings in both preclinical and clinical research suggesting a link between DOX-induced cardiotoxicity and various risk factors including sex, age, ethnicity, diabetes, dyslipidaemia, obesity, hypertension, cardiovascular disease and co-medications., Competing Interests: 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., (© 2023 The Authors.)

Ischaemic heart disease (IHD) is a leading cause of death worldwide. Understanding prosurvival signalling pathways that protect against ischaemia-reperfusion injury (IRI) may assist in the development of novel cardioprotective strategies against IHD. In this regard, the transcription factor, nuclear factor kappa-B (NFκB) is activated by tumour necrosis factor (TNF), but its role in TNF-induced cytoprotection is unknown. Therefore, to investigate the role of NFκB in TNF-induced cytoprotection, C2C12 cells were pretreated with TNF (0.5 ng/ml) in the presence and absence of an NFκB inhibitor, pyrrolidine derivative of dithiocarbamate (PDTC; 100 µM). Cells were subjected to simulated IRI and treated with PDTC, either during TNF exposure or at reperfusion. Phosphorylation of IkB was measured after the TNF stimulus. Cytoprotection by TNF in cells subjected to IRI (cell viability: 43.7 ± 8.1% in control vs 70.6 ± 6.1% with TNF, p < 0.001) was abrogated by co-administration of PDTC (40.6 ± 1.9%, p < 0.001 vs TNF) but not by exposure to PDTC at reperfusion (70.7 ± 1.7%). Cytosolic IkB phosphorylation [1.5 ± 0.2 arbitrary units (AU) for TNF vs 1.0 ± 0.0 for untreated, p < 0.01]) was increased after TNF exposure and this increase was abolished by co-administration with PDTC (0.8 ± 0.3 AU, p < 0 01 vs TNF). Our data suggest that NFκB acts as a key component in TNF-induced cytoprotection. These findings may pave the way for the development of novel therapeutic drugs that target TNF/NFκB signalling to protect against IHD.

Preconditioning, postconditioning, and remote conditioning of the myocardium enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and the potential to provide novel therapeutic paradigms for cardioprotection. While many signaling pathways leading to endogenous cardioprotection have been elucidated in experimental studies over the past 30 years, no cardioprotective drug is on the market yet for that indication. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic preclinical evaluation of promising cardioprotective therapies prior to their clinical evaluation, since ischemic heart disease in humans is a complex disorder caused by or associated with cardiovascular risk factors and comorbidities. These risk factors and comorbidities induce fundamental alterations in cellular signaling cascades that affect the development of ischemia/reperfusion injury and responses to cardioprotective interventions. Moreover, some of the medications used to treat these comorbidities may impact on cardioprotection by again modifying cellular signaling pathways. The aim of this article is to review the recent evidence that cardiovascular risk factors as well as comorbidities and their medications may modify the response to cardioprotective interventions. We emphasize the critical need for taking into account the presence of cardiovascular risk factors as well as comorbidities and their concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. This will hopefully maximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patients with multiple comorbidities. SIGNIFICANCE STATEMENT: Ischemic heart disease is a major cause of mortality; however, there are still no cardioprotective drugs on the market. Most studies on cardioprotection have been undertaken in animal models of ischemia/reperfusion in the absence of comorbidities; however, ischemic heart disease develops with other systemic disorders (e.g., hypertension, hyperlipidemia, diabetes, atherosclerosis). Here we focus on the preclinical and clinical evidence showing how these comorbidities and their routine medications affect ischemia/reperfusion injury and interfere with cardioprotective strategies., (Copyright © 2023 by The Author(s).)

Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies, all of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task, in particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models do not represent a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on an organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and state-of-the-art animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction, and refinement (3R) as a guiding concept., Competing Interests: Conflict of interest: L.B. is supported by unrestricted grants form Astra Zeneca. A.D. is co-founder of InVitroSys GmbH, a start-up developing equipment for biomimetic tissue culture. T.E. is co-founder of EHT Technologies GmbH, a university spin-off providing equipment for the generation of EHT. P.F. is the founder and CEO of Pharmahungary Group, a group of R&D companies. L.F. has received institutional research grants and non-financial support from European Union, British Heart Foundation, Medical Research Council (UK), DFG and several biomedical companies. L.F. is listed as inventor of two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571 and Markers for Atrial Fibrillation WO 2016012783). L.F. has served on the Roche Advisory Board on the topic New Biomarkers in Atrial Fibrillation. S.H. is independent consultant or receives research grant from to Astra Zeneca, Bayer, Merck, and Pfizer. The APHP, which employs J.-S.H., has received research grants from Bioserenity, Sanofi, Servier and Novo Nordisk. J.-S.H. has received speaker, advisory board or consultancy fees from Amgen, Astra Zeneca, Bayer, Bristol-Myers Squibb, Novartis, Novo Nordisk, and WeHealth. The UMCU, which employs L.W.v.L. has received speaker, advisory board or consultancy fees and/or research grants from Abbott, Vifor, Novartis, Medtronic, Roche, and Sopachem. J.L. has received research grants from Medtronic. P.v.d.M. received consultancy and/or research grants from Vifor Pharma, AstraZeneca, Servier, Novartis, Pfizer, Ionis. R.P. is co-founder of Pluriomics (Ncardia) and River BioMedics. R.S. received speaker fees from Amgen, Recordati and Sanofi and research grants from Sanofi. T.T. filed and licensed patents in the filled of non-coding RNAs. T.T. is founder and shareholder of Cardior Pharmaceuticals, a clinical-stage biotech company. T.T. received support and/or holds advisory seats at Boehringer Ingelheim, Novo Nordisk, Sanofi-Genzyme, Takeda, Amicus Therapeutics. All other authors have declared no conflict of interest., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: Conflict of interest: None declared.

Significance: Risk factors in the environment such as air pollution and traffic noise contribute to the development of chronic noncommunicable diseases. Recent Advances: Epidemiological data suggest that air pollution and traffic noise are associated with a higher risk for cardiovascular, metabolic, and mental disease, including hypertension, heart failure, myocardial infarction, diabetes, arrhythmia, stroke, neurodegeneration, depression, and anxiety disorders, mainly by activation of stress hormone signaling, inflammation, and oxidative stress. Critical Issues: We here provide an in-depth review on the impact of the environmental risk factors air pollution and traffic noise exposure (components of the external exposome) on cardiovascular health, with special emphasis on the role of environmentally triggered oxidative stress and dysregulation of the circadian clock. Also, a general introduction on the contribution of circadian rhythms to cardiovascular health and disease as well as a detailed mechanistic discussion of redox regulatory pathways of the circadian clock system is provided. Future Directions: Finally, we discuss the potential of preventive strategies or "chrono" therapy for cardioprotection. Antioxid. Redox Signal . 37, 679-703.

Purpose: Coronavirus disease 19 (COVID-19) has, to date, been diagnosed in over 130 million persons worldwide and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several variants of concern have emerged including those in the United Kingdom, South Africa, and Brazil. SARS-CoV-2 can cause a dysregulated inflammatory response known as a cytokine storm, which can progress rapidly to acute respiratory distress syndrome (ARDS), multi-organ failure, and death. Suppressing these cytokine elevations may be key to improving outcomes. Remote ischemic conditioning (RIC) is a simple, non-invasive procedure whereby a blood pressure cuff is inflated and deflated on the upper arm for several cycles. "RIC in COVID-19" is a pilot, multi-center, randomized clinical trial, designed to ascertain whether RIC suppresses inflammatory cytokine production., Methods: A minimum of 55 adult patients with diagnosed COVID-19, but not of critical status, will be enrolled from centers in the United Kingdom, Brazil, and South Africa. RIC will be administered daily for up to 15 days. The primary outcome is the level of inflammatory cytokines that are involved in the cytokine storm that can occur following SARS-CoV-2 infection. The secondary endpoint is the time between admission and until intensive care admission or death. The in vitro cytotoxicity of patient blood will also be assessed using primary human cardiac endothelial cells., Conclusions: The results of this pilot study will provide initial evidence on the ability of RIC to suppress the production of inflammatory cytokines in the setting of COVID-19., Trial Registration: NCT04699227, registered January 7th, 2021., (© 2021. The Author(s).)

Circadian rhythms are internal regulatory processes controlled by molecular clocks present in essentially every mammalian organ that temporally regulate major physiological functions. In the cardiovascular system, the circadian clock governs heart rate, blood pressure, cardiac metabolism, contractility, and coagulation. Recent experimental and clinical studies highlight the possible importance of circadian rhythms in the pathophysiology, outcome, or treatment success of cardiovascular disease, including ischaemic heart disease. Disturbances in circadian rhythms are associated with increased cardiovascular risk and worsen outcome. Therefore, it is important to consider circadian rhythms as a key research parameter to better understand cardiac physiology/pathology, and to improve the chances of translation and efficacy of cardiac therapies, including those for ischaemic heart disease. The aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to highlight key aspects of circadian rhythms to consider for improvement of preclinical and translational studies related to ischaemic heart disease and cardioprotection. Applying these considerations to future studies may increase the potential for better translation of new treatments into successful clinical outcomes., Competing Interests: Conflict of interest: P.F. is the founder and CEO of Pharmahungary Group, a group of R&D companies. L.W.V.L. Outside the current work: consultancy fees to UMCU from Abbott, Medtronic, Vifor, and Novartis., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Doxorubicin (DOX) is an anthracycline antibiotic frequently used against a wide range of cancers, including breast cancer. Although the drug is effective as a treatment against cancer, many patients develop heart failure (HF) months to years following their last treatment with DOX. The challenge in preventing DOX-induced cardiotoxicity is that symptoms present after damage has already occurred in the myocardium. Therefore, early biomarkers to assess DOX-induced cardiotoxicity are urgently needed. A better understanding of the mechanisms involved in the toxicity is important as this may facilitate the development of novel early biomarkers or therapeutic approaches. In this review, we discuss the role of high-density lipoprotein (HDL) particles and its components as possible key players in the early development of DOX-induced cardiotoxicity. HDL particles exist in different subclasses which vary in composition and biological functionality. Multiple cardiovascular risk factors are associated with a change in HDL subclasses, resulting in modifications of their composition and physiological functions. There is growing evidence in the literature suggesting that cancer affects HDL subclasses and that healthy HDL particles enriched with sphingosine-1-phosphate (S1P) and apolipoprotein A1 (ApoA1) protect against DOX-induced cardiotoxicity. Here, we therefore discuss associations and relationships between HDL, DOX and cancer and discuss whether assessing HDL subclass/composition/function may be considered as a possible early biomarker to detect DOX-induced cardiotoxicity., (© 2022. The Author(s).)

The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2-ERIC-PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings., (© 2022. The Author(s).)

Competing Interests: Conflict of interest statement The authors report no conflict of interest.

Acute myocardial infarction (AMI) and the heart failure (HF) which may follow are among the leading causes of death and disability worldwide. As such, new therapeutic interventions are still needed to protect the heart against acute ischemia/reperfusion injury to reduce myocardial infarct size and prevent the onset of HF in patients presenting with AMI. However, the clinical translation of cardioprotective interventions that have proven to be beneficial in preclinical animal studies, has been challenging. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic in vivo preclinical assessment of the efficacy of promising cardioprotective interventions prior to their clinical evaluation. To address this, we propose an in vivo set of step-by-step criteria for IMproving Preclinical Assessment of Cardioprotective Therapies ('IMPACT'), for investigators to consider adopting before embarking on clinical studies, the aim of which is to improve the likelihood of translating novel cardioprotective interventions into the clinical setting for patient benefit., (© 2021. The Author(s).)

The pandemic of coronavirus disease (COVID)-19 is a global threat, causing high mortality, especially in the elderly. The main symptoms and the primary cause of death are related to interstitial pneumonia. Viral entry also into myocardial cells mainly via the angiotensin converting enzyme type 2 (ACE2) receptor and excessive production of pro-inflammatory cytokines, however, also make the heart susceptible to injury. In addition to the immediate damage caused by the acute inflammatory response, the heart may also suffer from long-term consequences of COVID-19, potentially causing a post-pandemic increase in cardiac complications. Although the main cause of cardiac damage in COVID-19 remains coagulopathy with micro- (and to a lesser extent macro-) vascular occlusion, open questions remain about other possible modalities of cardiac dysfunction, such as direct infection of myocardial cells, effects of cytokines storm, and mechanisms related to enhanced coagulopathy. In this opinion paper, we focus on these lesser appreciated possibilities and propose experimental approaches that could provide a more comprehensive understanding of the cellular and molecular bases of cardiac injury in COVID-19 patients. We first discuss approaches to characterize cardiac damage caused by possible direct viral infection of cardiac cells, followed by formulating hypotheses on how to reproduce and investigate the hyperinflammatory and pro-thrombotic conditions observed in the heart of COVID-19 patients using experimental in vitro systems. Finally, we elaborate on strategies to discover novel pathology biomarkers using omics platforms., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Objectives: In pulmonary arterial hypertension (PAH), right ventricular (RV) dysfunction develops via mechanisms involving oxidative stress. Moderate and chronic red wine (RW) consumption reduces oxidative stress and confers cardioprotection but its effect on PAH is unknown. We evaluated whether moderate and chronic consumption of reduced-alcohol RW (RARW) confers cardioprotection in a monocrotaline (MCT)-induced PAH rat model., Results: Rats were randomly grouped: control; MCT; RARW; MCT + RARW. Wine was diluted to mimic moderate intake for humans, and consumed from 7 days before, until 28 days after MCT-injection. Echocardiography measured pulmonary artery acceleration time (PAAT) and RV thickness. Conjugated dienes (CD), and thiobarbituric acid reactive substances (TBARS) concentrations were assessed. MCT induced RV thickness and decreased PAAT compared to controls [1.22 ± 0.09 mm vs 0.46 ± 0.02 mm and 14 ± 1 vs 23 ± 2 m/s, respectively (p < 0.001)]. Chronic RARW consumption limited MCT-induced RV hypertrophy and increased PAAT. CD and TBARS increased in MCT-treated animals compared to controls (672 ± 43 nmol/L vs 453 ± 35 nmol/L; p < 0.01 and 13 ± 2 µmol/L vs 4 ± 0.3 µmol/L; p < 0.01). RARW reduced MCT-induced CD (472 ± 27 nmol/L vs 672 ± 43 nmol/L; p < 0.01)., Conclusion: Chronic and moderate intake of RARW ameliorates MCT-induced PAH in rats, which may be partly attributable to reduction of lipid peroxidation., (© 2021. The Author(s).)

Objectives: Major trauma in adults induces immune dysfunction, with diminished expression of human leukocyte antigen-DR on circulating monocytes. No pediatric data are available. This study described the kinetics of human leukocyte antigen-DR on circulating monocytes following major pediatric trauma and relationships between human leukocyte antigen-DR on circulating monocytes and outcomes., Design: Prospective observational study., Setting: PICU and trauma unit at a tertiary-care university hospital in South Africa., Patients: Children between 1 month and 13 years hospitalized for severe brain trauma or trauma with an Injury Severity Score greater than or equal to 16, from November 2016 to March 2017., Interventions: None., Measurements and Main Results: We included 36 children. Median (interquartile range) age and Injury Severity Score were 7 years (4.9-10.5 yr) and 25 years (22.7-30 yr), respectively. Blood samples (n = 83) for standardized human leukocyte antigen-DR on circulating monocytes measurement were collected at days 1-2, 3-4, and 8-9 after injury (D1, D3, and D8, respectively). On D1, median (interquartile range) human leukocyte antigen-DR on circulating monocytes was markedly reduced relative to normal values (7,031 [5,204-11,201] antibodies per cell). There was a significant increase in human leukocyte antigen-DR on circulating monocytes from D1 to D8. Although all patients with secondary infections (n = 8; 22%) had human leukocyte antigen-DR on circulating monocytes less than 15,000 antibodies per cell at D3, human leukocyte antigen-DR on circulating monocytes levels were not associated with the occurrence of secondary infections (p = 0.22). At D3, human leukocyte antigen-DR on circulating monocytes was significantly higher in patients discharged home (n = 21) by Day 30 after trauma compared with those who died or were still hospitalized (n = 14) (p = 0.02)., Conclusions: Pediatric severe trauma induced an early and dramatic decrease in human leukocyte antigen-DR on circulating monocytes expression. This alteration of innate immunity was not associated with the occurrence of secondary infection, possibly due to a lack of statistical power. However, human leukocyte antigen-DR on circulating monocytes at Day 3 is a potential indicator of those at high risk of secondary infection and worse outcomes., Competing Interests: Dr. Morrow’s institution received funding from National Research Foundation, and she received funding from University of Cape Town and Imperial College Press (royalties). Dr. Argent received funding from N. Kelly Attorneys and from various conferences as an invited speaker. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Ischaemic heart disease (IHD) is a complex disorder and a leading cause of death and morbidity in both men and women. Sex, however, affects several aspects of IHD, including pathophysiology, incidence, clinical presentation, diagnosis as well as treatment and outcome. Several diseases or risk factors frequently associated with IHD can modify cellular signalling cascades, thus affecting ischaemia/reperfusion injury as well as responses to cardioprotective interventions. Importantly, the prevalence and impact of risk factors and several comorbidities differ between males and females, and their effects on IHD development and prognosis might differ according to sex. The cellular and molecular mechanisms underlying these differences are still poorly understood, and their identification might have important translational implications in the prediction or prevention of risk of IHD in men and women. Despite this, most experimental studies on IHD are still undertaken in animal models in the absence of risk factors and comorbidities, and assessment of potential sex-specific differences are largely missing. This ESC WG Position Paper will discuss: (i) the importance of sex as a biological variable in cardiovascular research, (ii) major biological mechanisms underlying sex-related differences relevant to IHD risk factors and comorbidities, (iii) prospects and pitfalls of preclinical models to investigate these associations, and finally (iv) will provide recommendations to guide future research. Although gender differences also affect IHD risk in the clinical setting, they will not be discussed in detail here., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Due to the abundance of lipoproteins in blood, it is challenging to characterize the biological functions and components of blood-derived extracellular vesicles. The aim of this study was to develop a multiple-step purification protocol to separate serum exosomes from serum proteins and lipoproteins and assess their regenerative potential. Exosomes were isolated by concentrating them in human serum using ultracentrifugation (UC), followed sequentially by density gradient (DG) UC and size exclusion chromatography (SEC). Purity and characterization were assessed by western blots, Lipoprint®, enzyme-linked immunosorbent assay, electron microscopy, mass spectrometry, and nanoparticle tracking analysis. Functionality was assessed by cell proliferation analysis and with an in vivo subcutaneous angiogenesis model. SEC alone isolated nano-sized vesicles possessing vesicle markers TSG101 and CD9, but there was a substantial presence of apolipoprotein B, predominantly derived from very-low- and intermediate-density lipoprotein particles. This was reduced to an undetectable level using the combined UC DG SEC approach. Mass spectrometry identified 224 proteins in UC DG SEC isolates relative to the 135 from SEC, with considerable increases in exosome-related proteins and reductions in lipoproteins. A consistent but limited increase in human dermal fibroblast proliferation and evidence of neovascularization enhancement were observed after exposure to UC DG SEC exosomes. An UC DG SEC purification protocol considerably improved the removal of lipoproteins during isolation of serum exosomes. The purified exosomes stimulated cell proliferation and potentially increased an in vivo angiogenic response. This multistep purification allows for more accurate identification of serum exosome functional activity and composition., (© 2020 John Wiley & Sons Ltd.)

Hyperlipidaemia is a well-established risk factor for cardiovascular diseases and therefore, many animal model have been developed to mimic the human abnormal elevation of blood lipid levels. In parallel, extensive research for the alleviation of ischaemia/reperfusion injury has revealed that hyperlipidaemia is a major co-morbidity that attenuates the cardioprotective effect of conditioning strategies (preconditioning, postconditioning and remote conditioning) and that of pharmacological interventions by interfering with cardioprotective signalling pathways. In the present review article, we summarize the existing data on animal models of hypercholesterolaemia (total, low density and HDL abnormalities) and hypertriglyceridaemia used in ischaemia/reperfusion injury and protection from it. We also provide recommendations on preclinical animal models to be used for translations of the cardioprotective strategies into clinical practice. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc., (© 2019 The British Pharmacological Society.)

Risk factors in the environment such as air pollution and mental stress contribute to the development of chronic non-communicable disease. Air pollution was identified as the leading health risk factor in the physical environment, followed by water pollution, soil pollution/heavy metals/chemicals and occupational exposures, however neglecting the non-chemical environmental health risk factors (e.g. mental stress and noise). Epidemiological data suggest that environmental risk factors are associated with higher risk for cardiovascular, metabolic and mental diseases, including hypertension, heart failure, myocardial infarction, diabetes, arrhythmia, stroke, depression and anxiety disorders. We provide an overview on the impact of the external exposome comprising risk factors/exposures on cardiovascular health with a focus on dysregulation of stress hormones, mitochondrial function, redox balance and inflammation with special emphasis on the circadian clock. Finally, we assess the impact of circadian clock dysregulation on cardiovascular health and the potential of environment-specific preventive strategies or "chrono" therapy for cardioprotection. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc., (© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The introduction of antiretroviral therapy (ART) has improved the life expectancy of patients infected with human immunodeficiency virus (HIV). However, this population is at an increased risk for noncommunicable diseases, including atherosclerotic cardiovascular disease (CVD). Both ART and viral infection may be potential contributors to the pathophysiology of HIV-related CVD. The mechanisms behind this remain unclear, but it is critical to delineate early biomarkers of cardiovascular risk in the HIV population. In this review, we postulate that potential biomarkers could include alterations to high-density lipoprotein (HDL). Indeed, recent data suggest that HIV and ART may induce structural changes of HDL, thus resulting in shifts in HDL subclass distribution and HDL functionality.

Cardiovascular diseases (CVDs) are the leading causes of death worldwide. CVD pathophysiology is often characterized by increased stiffening of the heart muscle due to fibrosis, thus resulting in diminished cardiac function. Fibrosis can be caused by increased oxidative stress and inflammation, which is strongly linked to lifestyle and environmental factors such as diet, smoking, hyperglycemia, and hypertension. These factors can affect gene expression through epigenetic modifications. Lysyl oxidase like 2 (LOXL2) is responsible for collagen and elastin cross-linking in the heart, and its dysregulation has been pathologically associated with increased fibrosis. Additionally, studies have shown that, LOXL2 expression can be regulated by DNA methylation and histone modification. However, there is a paucity of data on LOXL2 regulation and its role in CVD. As such, this review aims to gain insight into the mechanisms by which LOXL2 is regulated in physiological conditions, as well as determine the downstream effectors responsible for CVD development.

Type 2 diabetes (T2D) is characterized by metabolic derangements that cause a shift in substrate preference, inducing cardiac interstitial fibrosis. Interstitial fibrosis plays a key role in aggravating left ventricular diastolic dysfunction (LVDD), which has previously been associated with the asymptomatic onset of heart failure. The latter is responsible for 80% of deaths among diabetic patients and has been termed diabetic cardiomyopathy (DCM). Through in silico prediction and subsequent detection in a leptin receptor-deficient db/db mice model (db/db), we confirmed the presence of previously identified potential biomarkers to detect the early onset of DCM. Differential expression of Lysyl Oxidase Like 2 (LOXL2) and Electron Transfer Flavoprotein Beta Subunit (ETFβ), in both serum and heart tissue of 6-16-week-old db/db mice, correlated with a reduced left-ventricular diastolic dysfunction as assessed by high-resolution Doppler echocardiography. Principal component analysis of the combined biomarkers, LOXL2 and ETFβ, further displayed a significant difference between wild type and db/db mice from as early as 9 weeks of age. Knockdown in H9c2 cells, utilising siRNA of either LOXL2 or ETFβ, revealed a decrease in the expression of Collagen Type I Alpha1 (COL1A1), a marker known to contribute to enhanced myocardial fibrosis. Additionally, receiver-operating curve (ROC) analysis of the proposed diagnostic profile showed that the combination of LOXL2 and ETFβ resulted in an area under the curve (AUC) of 0.813, with a cut-off point of 0.824, thus suggesting the favorable positive predictive power of the model and further supporting the use of LOXL2 and ETFβ as possible early predictive DCM biomarkers.

Mozambique has low levels of detection, treatment, and control of hypertension. However, data on target organ damage and clinical outcomes are lacking. The authors aimed at characterizing the clinical profile, pattern of target organ damage, and short-term outcomes of patients referred to a first referral urban hospital in a low-income setting in Africa. We conducted a prospective descriptive cohort study from February 2016 to May 2017 in Maputo, Mozambique. Adult patients with systolic and diastolic blood pressure ≥180 mm Hg and/or ≥110 mm Hg, respectively, or any systolic blood pressure above 140 mm Hg and/or diastolic blood pressure above 90 mm Hg in the presence of target organ damage (with or without antihypertensive treatment) were submitted to detailed physical examination, funduscopy, laboratory profile, electrocardiography, and echocardiography. Six months after the occurrence of complications (stroke, heart failure, and renal failure), hospital admission and death were assessed. Overall, 116 hypertensive patients were recruited (mean age 57.5 ± 12.8 years old; 111[95.7%] black; 81[70%] female) of which 79 had severe hypertension. The baseline mean values recorded for systolic and diastolic blood pressure were 192.3 ± 23.6 and 104.2 ± 15.2 mm Hg, respectively. Most patients (93; 80.2%) were on antihypertensive treatment. Patients' risk profile revealed dyslipidemia, obesity, and diabetes in 59(54.1%), 48(42.5%), and 23(19.8%), respectively. Target organ damage was found in 111 patients. The commonest being left atrial enlargement 91(84.5%), left ventricular hypertrophy 57(50.4%), hypertensive retinopathy 30(26.3%), and chronic kidney disease 27(23.3%). Major events during 6-month follow-up were hospitalizations in 10.3% and death in 8.6% of the patients. Worsening of target organ damage occurred in 10 patients: four stroke, two heart failure, and four renal damage. Patients with severe hypertension and target organ damage were young with high-risk profile, low hypertension control, and high occurrence of complications during short-term follow-up. Efforts to improve high blood pressure control are needed to reduce premature mortality in this highly endemic poor setting., (© 2019 Wiley Periodicals, Inc.)

Purpose: High density lipoprotein (HDL) protects against myocardial infarction via mechanisms that remain unclear. STAT3 (signal transducer and activator of transcription 3) plays a key role in HDL-induced cardioprotection. In the heart, microRNAs (miRNAs) are involved in ischemia reperfusion injury. We therefore investigated whether the cardioprotective effect of HDL modulates miRNAs as a downstream target of STAT3 activation., Methods: STAT3 cardiomyocyte deficient mice (STAT3-KO) and wildtype littermates (STAT3-WT) were submitted to left coronary ligature and reperfused (IR) with or without injection of HDL. Infarct size (IS) was determined and cardiac miRNA expression was evaluated after reperfusion in sham, IR and IR+HDL hearts by microarray analysis. In vitro, neonatal rat ventricular cardiomyocytes were submitted to hypoxia with or without HDL incubation. Cell viability and miRNA expression were analysed., Results: In vivo, HDL reduced IS from 40.5±4.3% to 24.4±2.1% (p<0.05) in STAT3-WT mice. HDL failed to protect in STAT3-KO mice. In STAT3-WT mice, both miR-34b and miR-337 were increased in IR compared to sham and IR+HDL groups (p<0.05). These miRNAs were not modulated in STAT3-KO mice. In vitro, incubation with HDL improved cell viability against hypoxia (p<0.05). The expression of miR-34b and miR-337 was increased by hypoxia and reduced by HDL treatment (p<0.05). In cardiomyocytes transfected with miRNA mimics, HDL failed to improve cell viability against hypoxia., Conclusions: Our study, performed both in vivo and in vitro, delineates a novel cardioprotective signalling pathway activated by HDL, involving STAT3-mediated decrease of miR-34b and miR-337 expression., Competing Interests: The authors have declared that no competing interests exist.

Although rollout of combined antiretroviral treatment (cART) has blunted human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) onset, there is increased development of cardiovascular diseases (CVDs) in HIV-infected individuals. While most HIV-infected individuals on cART achieve viral suppression, this may not necessarily result in complete immunological recovery. This study therefore evaluated T-cell-mediated changes and coagulation markers in HIV-positive individuals to ascertain their potential to increase CVD risk. Eighty participants were recruited (Worcester, South Africa), and fasted blood was collected to evaluate: 1 ) immune activation (CD38 expression on CD4 + and CD8 + T cells) and thrombus formation [tissue factor (CD142)] on CD4 + and CD8 + T cells; 2 ) monocyte subpopulations (nonclassical, intermediate, and classical); and 3 ) classical regulatory T (Treg) cells with activation markers [glycoprotein A repetitions predominant (GARP) and special AT-rich sequence-binding protein 1 (SATB-1)]. High- and low-density lipoprotein subclasses (Lipoprint) were also determined. This study revealed four key findings for HIV-positive patients: 1 ) coexpression of the CD142 coagulation marker together with immune activation on both CD4 + and CD8 + T cells during chronic infection stages; 2 ) Treg cell activation and upregulated GARP and SATB-1 contributing to Treg dysfunction in chronic HIV; 3 ) proatherogenic monocyte subset expansion with significant correlation between T-cell activation and macrophage activation (marker: CD163); and 4 ) significant correlation between immune activation and lipid subclasses, revealing crucial changes that can be missed by traditional lipid marker assessments (LDL and HDL). These data also implicate lipopolysaccharide-binding protein as a crucial link between immune activation, lipid alterations, and increased CVD risk. NEW & NOTEWORTHY With combined antiretroviral treatment rollout, HIV-AIDS patients are increasingly associated with cardiovascular diseases onset. This study demonstrated the significant interplay between adaptive immune cell activation and monocyte/macrophage markers in especially HIV-positive individuals with virological failure and on second line treatment. Our data also show a unique link between immune activation and lipid subclass alterations, revealing important changes that can be missed by traditional lipid marker assessments (e.g., LDL and HDL).

Aims: Although there is evidence linking sugar-sweetened beverage (SSB) intake with the development of cardio-metabolic diseases, the underlying mechanisms remain unclear. The current study therefore evaluated the effects of SSB consumption by establishing a unique in-house in vivo experimental model., Main Methods: Male Wistar rats were divided into two groups: a) one consuming a popular local SSB (SSB- Jive), and b) a control group (Control-water) for a period of three and six months (n = 6 per group), respectively. Rats were gavaged on a daily basis with an experimental dosage amounting to half a glass per day (in human terms) (SSB vs. water). Cardiac function was assessed at baseline (echocardiography) and following ex vivo ischemia-reperfusion of the isolated perfused working rat heart. Oral glucose tolerance tests and mitochondrial respiratory analyses were also performed. In addition, the role of non-oxidative glucose pathways (NOGPs), i.e. the polyol pathway, hexosamine biosynthetic pathway (HBP) and PKC were assessed., Key Findings: These data show that SSB intake: a) resulted in increased weight gain, but did not elicit major effects in terms of insulin resistance and cardiac function after three and six months, respectively; b) triggered myocardial NOGP activation after three months with a reversion after six months; and c) resulted in some impairment in mitochondrial respiratory capacity in response to fatty acid substrate supply after six months., Significance: SSB intake did not result in cardiac dysfunction or insulin resistance. However, early changes at the molecular level may increase risk in the longer term.

Morbidity and mortality from ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and are increasing worldwide. Patients with IHD or HF might benefit from novel therapeutic strategies, such as cell-based therapies. We recently discussed the therapeutic potential of cell-based therapies and provided recommendations on how to improve the therapeutic translation of these novel strategies for effective cardiac regeneration and repair. Despite major advances in optimizing these strategies with respect to cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. Major obstacles are the low engraftment and survival rate of transplanted cells in the harmful microenvironment of the host tissue, and the paucity or even lack of endogenous cells with repair capacity. Therefore, new ways of delivering cells and their derivatives are required in order to empower cell-based cardiac repair and regeneration in patients with IHD or HF. Strategies using tissue engineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplanted area, and have recently received much attention for this purpose. Here, we summarize knowledge on novel approaches emerging from the TE scenario. In particular, we will discuss how combinations of cell/bio-materials (e.g. hydrogels, cell sheets, prefabricated matrices, microspheres, and injectable matrices) combinations might enhance cell retention or cell delivery in the transplantation areas, thereby increase the success rate of cell therapies for IHD and HF. We will not focus on the use of classical engineering approaches, employing fully synthetic materials, because of their unsatisfactory material properties which render them not clinically applicable. The overall aim of this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to proceed in research with these novel TE strategies combined with cell-based therapies to boost cardiac repair in the clinical settings of IHD and HF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Although cross-sectional studies have shown that obesity is associated with lower concentrations of large high-density lipoprotein (HDL) subclasses, it is unknown if changes in HDL subclasses are related to changes in body fat and its distribution over time. We therefore assessed changes in HDL subclass distribution over a 5.5-year free-living follow-up period in 24 black South African women. At baseline and follow-up, body composition and body fat distribution were measured using anthropometry, dual X-ray absorptiometry, and computerized tomography. HDL subclass distribution was quantified using Lipoprint®. Over the 5.5-year follow-up period, body fat (+17.3 ± 4.5 kg, p < 0.05) and trunk fat mass (+7.4 ± 1.9%, % fat mass, FM, p < 0.05) increased, while leg fat mass (-2.53 ± 0.56%, % FM, p < 0.001) and the distribution of large (-6.43 ± 2.12%, p < 0.05) HDL subclasses decreased. A percentage decrease in large HDL subclasses was associated with a percentage increase in central fat mass (visceral adipose tissue (VAT) area, p < 0.05) and a percentage decrease in peripheral fat mass (leg fat mass). These preliminary findings suggest that a relative redistribution of body fat from the periphery to the abdominal region were associated with a decrease HDL subclass size in black South African women and provide a novel link between body fat distribution and lipidology in this population.

Background: Obesity is associated with a change in high-density lipoprotein (HDL) function and subclass. Exercise training reduces cardiovascular risk in obese patients. We aimed to explore the effect of an exercise training stimulus on HDL functionality and subclass in obese women., Methods: Thirty-two obese black South African women were randomly assigned to exercise (combined aerobic and resistance exercise) or control (no exercise) conditions for 12-weeks. Pre- and post-testing included venous blood sampling for analysis of lipid profile and HDL functionality, by measuring cellular cholesterol efflux capacity, reduction in endothelial vascular cell adhesion molecule (VCAM) expression (anti-inflammatory function), paraoxonase (PON) (antioxidative function) and platelet activating factor acetylhydrolase (PAF-AH) activities (anti-thrombotic function). PON-1 and PAF-AH expression were determined in serum and in isolated HDL using Western blotting. Levels of large, intermediate and small HDL subclasses were measured using the Lipoprint® system., Results: Exercise training resulted in a decrease in body mass index (- 1.0 ± 0.5% vs + 1.2 ± 0.6%, p = 0.010), PON activity (- 8.7 ± 2.4% vs + 1.1 ± 3.0%, p = 0.021), PAF-AH serum expression (- 22.1 ± 8.0% vs + 16.9 ± 9.8, p = 0.002), and the distribution of small HDL subclasses (- 10.1 ± 5.4% vs + 15.7 ± 6.6%, p = 0.004) compared to controls. Exercise did not alter HDL cellular cholesterol efflux capacity and anti-inflammatory function., Conclusions: These results demonstrate the potential for exercise training to modify HDL subclass distribution and HDL function in obese women., Trial Registration: Clinical trials number: PACTR201711002789113 .

The master mammalian circadian clock (i.e. central clock), located in the suprachiasmatic nucleus of the hypothalamus, orchestrates the synchronization of the daily behavioural and physiological rhythms to better adapt the organism to the external environment in an anticipatory manner. This central clock is entrained by a variety of signals, the best established being light and food. However, circadian cycles are not simply the consequences of these two cues but are generated by endogenous circadian clocks. Indeed, clock machinery is found in mainly all tissues and cell types, including cells of the vascular system such as endothelial cells, fibroblasts, smooth muscle cells and stem cells. This machinery physiologically contributes to modulate the daily vascular function, and its disturbance therefore plays a major role in the pathophysiology of vascular dysfunction. Therapies targeting the circadian rhythm may therefore be of benefit against vascular disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The role of the diet as well as the impact of the dietary habits on human health and disease is well established. Apart from its sleep regulatory effect, the indoleamine melatonin is a well-established antioxidant molecule with multiple health benefits. Convincing evidence supports the presence of melatonin in plants and foods with the intake of such foods affecting circulating melatonin levels in humans. While numerous actions of both endogenous melatonin and melatonin supplementation are well described, little is known about the influence of the dietary melatonin intake on human health. In the present review, evidence for the cardiovascular health benefits of melatonin supplementation and dietary melatonin is discussed. Current knowledge on the biological significance as well as the underlying physiological mechanism of action of the dietary melatonin is also summarized. Whether dietary melatonin constitutes an alternative preventive treatment for cardiovascular disease is addressed.

Background: The pathogenesis of type 2 diabetes (T2D) in black African women is complex and differs from that in their white counterparts. However, earlier studies have been cross-sectional and provide little insight into the causal pathways. Exercise training is consistently used as a model to examine the mechanisms underlying insulin resistance and risk for T2D., Objective: The objective of the study was to examine the mechanisms underlying the changes in insulin sensitivity and secretion in response to a 12-week exercise intervention in obese black South African (SA) women., Methods: A total of 45 obese (body mass index, BMI: 30-40 kg/m 2 ) black SA women were randomized into a control (n=22) or experimental (exercise; n=23) group. The exercise group completed 12 weeks of supervised combined aerobic and resistance training (40-60 min, 4 days/week), while the control group maintained their typical physical activity patterns, and both groups were requested not to change their dietary patterns. Before and following the 12-week intervention period, insulin sensitivity and secretion (frequently sampled intravenous glucose tolerance test) and its primary and secondary determinants were measured. Dietary intake, sleep quality and quantity, physical activity, and sedentary behaviors were measured every 4 weeks., Results: The final sample included 20 exercise and 15 control participants. Baseline sociodemographics, cardiorespiratory fitness, anthropometry, cardiometabolic risk factors, physical activity, and diet did not differ between the groups (P>.05)., Conclusions: The study describes a research protocol for an exercise intervention to understand the mechanisms underlying insulin sensitivity and secretion in obese black SA women and aims to identify causal pathways underlying the high prevalence of insulin resistance and risk for T2D in black SA women, targeting specific areas for therapeutic intervention., Trial Registration: Pan African Clinical Trial Registry PACTR201711002789113; http://www.pactr.org/ATMWeb/ appmanager/atm/atmregistry?&#95;nfpb=true&&#95;pageLabel=portals&#95;app&#95;atmregistry&#95;portal&#95;page&#95;13 (Archived by WebCite at http://www.webcitation.org/6xLEFqKr0)., (©Julia H Goedecke, Amy E Mendham, Louise Clamp, Pamela A Nono Nankam, Melony C Fortuin-de Smidt, Lindokuhle Phiri, Lisa K Micklesfield, Dheshnie Keswell, Nicholas J Woudberg, Sandrine Lecour, Ali Alhamud, Mamadou Kaba, Faith M Lutomia, Paul J van Jaarsveld, Anniza de Villiers, Steven E Kahn, Elin Chorell, Jon Hauksson, Tommy Olsson. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 18.04.2018.)

Aims: Acute heart failure (AHF) is a burden disease, with high mortality and re-hospitalisations. Using an ex-vivo model of AHF, we have previously reported that sphingosine-1-phosphate (S1P) confers cardioprotection. However, the mechanisms remain to be elucidated. In the present study, we aimed to examine the role of the cardioprotective signal transducer and activator of transcription 3 (STAT3) in S1P mediated improved functional recovery in AHF., Material and Methods: Isolated hearts from male Long-Evans rats were subjected to hypotensive AHF for 35 min followed by a recovery phase of 30 min (n ≥ 4/group). S1P (10 nM) was given during either the hypotensive or the recovery phase with/without an inhibitor of STAT3, AG490. Functional parameters were recorded throughout the experiment., Key Findings: Following an AHF insult, S1P, given during the recovery phase, improved the heart rate (HR) compared to the control (175.2 ± 30.7 vs. 71.6 ± 27.4 beats per minute (BPM); p < 0.05), with no changes in the left ventricular developed pressure. This effect was associated with an increase in phosphorylated STAT3 levels in the nucleus. Addition of AG490 with S1P abolished the cardioprotective effect of S1P (42.3 ± 17.1 vs. 148.8 ± 26.4 BPM for S1P; p < 0.05)., Significance: Our data suggest that S1P protects in an ex-vivo rat heart model of AHF by activation of STAT3 and provide further evidence for the usage of S1P as a potential therapy in patients suffering from AHF., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The cholesterol concentrations of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) have traditionally served as risk factors for cardiovascular disease. As such, novel therapeutic interventions aiming to raise HDL cholesterol have been tested in the clinical setting. However, most trials led to a significant increase in HDL cholesterol with no improvement in cardiovascular events. The complexity of the HDL particle, which exerts multiple physiological functions and is comprised of a number of subclasses, has raised the question as to whether there should be more focus on HDL subclass and function rather than cholesterol quantity. We review current data regarding HDL subclasses and subclass-specific functionality and highlight how current lipid modifying drugs such as statins, cholesteryl ester transfer protein inhibitors, fibrates and niacin often increase cholesterol concentrations of specific HDL subclasses. In addition this review sets out arguments suggesting that the HDL3 subclass may provide better protective effects than HDL2.

The survivor activating factor enhancement (SAFE) pathway was discovered as an alternative intrinsic pro-survival signaling pathway to the reperfusion injury salvage kinase pathway for cardioprotection against ischemia-reperfusion injury. The delineation of this pathway, made of key components such as cytokines of the immune system and transcription factors, has brought major advancements in our understanding on how the heart is able to protect itself against ischemia-reperfusion injury. In this viewpoint, we describe the major steps leading to the discovery of the SAFE pathway in small animal models to date and we discuss its translation to large animals and humans.

Extracellular vesicles (EVs)-particularly exosomes and microvesicles (MVs)-are attracting considerable interest in the cardiovascular field as the wide range of their functions is recognized. These capabilities include transporting regulatory molecules including different RNA species, lipids, and proteins through the extracellular space including blood and delivering these cargos to recipient cells to modify cellular activity. EVs powerfully stimulate angiogenesis, and can protect the heart against myocardial infarction. They also appear to mediate some of the paracrine effects of cells, and have therefore been proposed as a potential alternative to cell-based regenerative therapies. Moreover, EVs of different sources may be useful biomarkers of cardiovascular disease identities. However, the methods used for the detection and isolation of EVs have several limitations and vary widely between studies, leading to uncertainties regarding the exact population of EVs studied and how to interpret the data. The number of publications in the exosome and MV field has been increasing exponentially in recent years and, therefore, in this ESC Working Group Position Paper, the overall objective is to provide a set of recommendations for the analysis and translational application of EVs focussing on the diagnosis and therapy of the ischaemic heart. This should help to ensure that the data from emerging studies are robust and repeatable, and optimize the pathway towards the diagnostic and therapeutic use of EVs in clinical studies for patient benefit., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: ST2 receptor, which is a member of the Toll-like/interleukin-1 (IL-1) receptor family, has been found to be increased in the serum of patients 1 day after myocardial infarction. Several other studies have shown that soluble ST2 levels correlate with severity of heart failure (HF), left ventricular ejection fraction, creatinine clearance, B-type natriuretic peptide and C-reactive protein, and are predictors of mortality in HF. Most of these studies were not only limited to ischemic heart disease but also concentrated on left-sided HF. We therefore decided to study the relationship between soluble ST2 and some markers of right ventricular (RV) function in a cohort of hypertensive HF subjects., Patients and Methods: This is a prospective cohort study of hypertensive HF patients presenting to the University of Abuja Teaching Hospital, Abuja, over a 12-month period. ST2 was measured in plasma sample by the enzyme-linked immunosorbent assay (ELISA) method. Right ventricular diameters in diastole (RVDD) and right atrial area (RAA) were obtained on echocardiography, while right ventricular systolic pressure (RVSP) was estimated from echocardiography by the addition of the pressure gradient between the right ventricle and right atrium (RA) to the pressure in the RA., Results: There was a significant correlation between RVSP and soluble ST2 ( t =0.75, p <0.0001), RVDD ( t =0.28, p =0.004) and RAA ( t =0.46, p =0.002)., Conclusion: In a cohort of hypertensive HF subjects, soluble ST2 correlates significantly with RVSP, RVDD and RAA., Competing Interests: Disclosure The authors report no conflicts of interest in this work.