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Aims: Cardiac miR-132 activation leads to adverse remodelling and pathological hypertrophy. CDR132L is a synthetic lead-optimized oligonucleotide inhibitor with proven preclinical efficacy and safety in heart failure (HF) early after myocardial infarction (MI), and recently completed clinical evaluation in a Phase 1b study (NCT04045405). The aim of the current study was to assess safety and efficacy of CDR132L in a clinically relevant large animal (pig) model of chronic heart failure following MI., Methods and Results: In a chronic model of post-MI HF, slow-growing pigs underwent 90 min left anterior descending artery occlusion followed by reperfusion. Animals were randomized and treatment started 1-month post-MI. Monthly intravenous (IV) treatments of CDR132L over 3 or 5 months (3× or 5×) were applied in a blinded randomized placebo-controlled fashion. Efficacy was evaluated based on serial magnetic resonance imaging, haemodynamic, and biomarker analyses. The treatment regime provided sufficient tissue exposure and CDR132L was well tolerated. Overall, CDR132L treatment significantly improved cardiac function and reversed cardiac remodelling. In addition to the systolic recovery, diastolic function was also ameliorated in this chronic model of HF., Conclusion: Monthly repeated dosing of CDR132L is safe and adequate to provide clinically relevant exposure and therapeutic efficacy in a model of chronic post-MI HF. CDR132L thus should be explored as treatment for the broad area of chronic heart failure., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Increasing knowledge of the processes leading to heart failure (HF) has allowed significant developments in therapies for HF over the past few decades. Despite the evolution of HF treatment, it still places a large burden on patients and health care systems across the world.We used clinicaltrials.gov to gather information about clinical trials as of August 2023 studying pharmacotherapy for HF. We included interventional trials that were "active, not recruiting", "recruiting", or looking for participants but "not yet recruiting". In total, 119 studies met our criteria of ongoing clinical trials studying novel as well as currently approved HF pharmacotherapies. The major interventions were novel medications/already approved medications for other diseases 29 % (34 trials), sodium-glucose co-transporter inhibitors 21 % (25 trials), angiotensin receptor blocker-neprilysin inhibitors 10 % (12 trials), diuretics 14 % (17 trials) and mineralocorticoid receptor antagonists 5 % (6 trials). Ongoing research will aid in reducing the impact of HF and we summarize clinical trials leading the way to better HF treatment in this review., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The immune system is intimately involved in the pathophysiology of heart failure. However, it is currently underused as a therapeutic target in the clinical setting. Moreover, the development of novel immunomodulatory therapies and their investigation for the treatment of patients with heart failure are hampered by the fact that currently used, evidence-based treatments for heart failure exert multiple immunomodulatory effects. In this Review, we discuss current knowledge on how evidence-based treatments for heart failure affect the immune system in addition to their primary mechanism of action, both to inform practising physicians about these pleiotropic actions and to create a framework for the development and application of future immunomodulatory therapies. We also delineate which subpopulations of patients with heart failure might benefit from immunomodulatory treatments. Furthermore, we summarize completed and ongoing clinical trials that assess immunomodulatory treatments in heart failure and present several therapeutic targets that could be investigated in the future. Lastly, we provide future directions to leverage the immunomodulatory potential of existing treatments and to foster the investigation of novel immunomodulatory therapeutics., (© 2023. Springer Nature Limited.)

Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non-coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long-term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling., (© 2022 European Society of Cardiology.)

Tachycardiomyopathy is characterised by reversible left ventricular dysfunction, provoked by rapid ventricular rate. While the knowledge of mitochondria advanced in most cardiomyopathies, mitochondrial functions await elucidation in tachycardiomyopathy. Pacemakers were implanted in 61 rabbits. Tachypacing was performed with 330 bpm for 10 days (n = 11, early left ventricular dysfunction) or with up to 380 bpm over 30 days (n = 24, tachycardiomyopathy, TCM). In n = 26, pacemakers remained inactive (SHAM). Left ventricular tissue was subjected to respirometry, metabolomics and acetylomics. Results were assessed for translational relevance using a human-based model: induced pluripotent stem cell derived cardiomyocytes underwent field stimulation for 7 days (TACH-iPSC-CM). TCM animals showed systolic dysfunction compared to SHAM (fractional shortening 37.8 ± 1.0% vs. 21.9 ± 1.2%, SHAM vs. TCM, p < 0.0001). Histology revealed cardiomyocyte hypertrophy (cross-sectional area 393.2 ± 14.5 µm 2 vs. 538.9 ± 23.8 µm 2 , p < 0.001) without fibrosis. Mitochondria were shifted to the intercalated discs and enlarged. Mitochondrial membrane potential remained stable in TCM. The metabolite profiles of ELVD and TCM were characterised by profound depletion of tricarboxylic acid cycle intermediates. Redox balance was shifted towards a more oxidised state (ratio of reduced to oxidised nicotinamide adenine dinucleotide 10.5 ± 2.1 vs. 4.0 ± 0.8, p < 0.01). The mitochondrial acetylome remained largely unchanged. Neither TCM nor TACH-iPSC-CM showed relevantly increased levels of reactive oxygen species. Oxidative phosphorylation capacity of TCM decreased modestly in skinned fibres (168.9 ± 11.2 vs. 124.6 ± 11.45 pmol·O 2 ·s -1 ·mg -1 tissue, p < 0.05), but it did not in isolated mitochondria. The pattern of mitochondrial dysfunctions detected in two models of tachycardiomyopathy diverges from previously published characteristic signs of other heart failure aetiologies., (© 2022. The Author(s).)

Background: To evaluate the cerebral metabolism in patients with heart failure (HF)., Methods: One hundred and two HF patients were prospectively enrolled, who underwent gated 99m Tc-sestamibi single photon emission computed tomography (SPECT)/CT, cardiac and cerebral 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT. Fifteen healthy volunteers served as controls. Patients were stratified by extent of hibernating myocardium (HM) and left ventricular ejection fraction (LVEF) into 4 groups where Group1: HM < 10% (n = 33); Group2: HM ≥ 10%, LVEF < 25% (n = 34); Group3: HM ≥ 10%, 25% ≤ LVEF ≤ 40% (n = 16) and Group 4: LVEF > 40% (n = 19). The standardized uptake value (SUV) in the whole brain (SUV whole-brain ) and the SUV ratios (SUVR) in 24 cognition-related brain regions were determined. SUV whole-brain and SUVRs were compared between the 4 patient groups and the healthy controls., Results: SUV whole-brain (r = 0.245, P = 0.013) and SUVRs in frontal areas, hippocampus, and para-hippocampus (r: 0.213 to 0.308, all P < 0.05) were correlated with HM. SUV whole-brain differed between four patient groups and the healthy volunteers (P = 0.016) and SUV whole-brain in Group 1 was lower than that in healthy volunteers (P < 0.05). SUVRs of Group 3 in frontal areas were the highest among four patient subgroups (P < 0.05)., Conclusions: Cerebral metabolism in the whole brain was reduced but maintained in cognition-related frontal areas in HF patients with HM and moderately impaired global left ventricular function., (© 2020. American Society of Nuclear Cardiology.)

Cancer therapies with anthracyclines have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of B-cell lymphoma and to examine whether doxorubicin (DOX)-treated ACT-iPSC cardiomyocytes (CM) can recapitulate the clinical features exhibited by patients, and thus help uncover a DOX-dependent pathomechanism. ACT-iPSC CM generated from individuals with CD20 + B-cell lymphoma who had received high doses of DOX and suffered cardiac dysfunction were studied and compared to control-iPSC CM from cancer survivors without cardiac symptoms. In cellular studies, ACT-iPSC CM were persistently more susceptible to DOX toxicity including augmented disorganized myofilament structure, changed mitochondrial shape, and increased apoptotic events. Consistently, ACT-iPSC CM and cardiac fibroblasts isolated from fibrotic human ACT myocardium exhibited higher DOX-dependent reactive oxygen species. In functional studies, Ca 2+ transient amplitude of ACT-iPSC CM was reduced compared to control cells, and diastolic sarcoplasmic reticulum Ca 2+ leak was DOX-dependently increased. This could be explained by overactive CaMKIIδ in ACT CM. Together with DOX-dependent augmented proarrhythmic cellular triggers and prolonged action potentials in ACT CM, this suggests a cellular link to arrhythmogenic events and contractile dysfunction especially found in ACT engineered human myocardium. CamKIIδ inhibition prevented proarrhythmic triggers in ACT. In contrast, control CM upregulated SERCA2a expression in a DOX-dependent manner, possibly to avoid heart failure conditions. In conclusion, we developed the first human patient-specific stem cell model of DOX-induced cardiac dysfunction from patients with B-cell lymphoma. Our results suggest that DOX-induced stress resulted in arrhythmogenic events associated with contractile dysfunction and finally in heart failure after persistent stress activation in ACT patients., (© 2022. The Author(s).)

Approximately 7 million people are affected by acute myocardial infarction (MI) each year, and despite significant therapeutic and diagnostic advancements, MI remains a leading cause of mortality worldwide. Preclinical animal models have significantly advanced our understanding of MI and have enabled the development of therapeutic strategies to combat this debilitating disease. Notably, some drugs currently used to treat MI and heart failure (HF) in patients had initially been studied in preclinical animal models. Despite this, preclinical models are limited in their ability to fully reproduce the complexity of MI in humans. The preclinical model must be carefully selected to maximise the translational potential of experimental findings. This review describes current experimental models of MI and considers how they have been used to understand drug mechanisms of action and support translational medicine development. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

This is the first part of a scientific statement from the Heart Failure Association (HFA) of the European Society of Cardiology focused upon the pathophysiology of Takotsubo syndrome and is complimentary to the previous HFA position statement on Takotsubo syndrome which focused upon clinical management. In part 1 we provide an overview of the pathophysiology of Takotsubo syndrome and fundamental questions to consider. We then review and discuss the central role of catecholamines and the sympathetic nervous system in the pathophysiology, and the direct effects of high surges in catecholamines upon myocardial biology including β-adrenergic receptor signalling, G-protein coupled receptor kinases, cardiomyocyte calcium physiology, myofilament physiology, cardiomyocyte gene expression, myocardial electrophysiology and arrhythmogenicity, myocardial inflammation, metabolism and energetics. The integrated effects upon ventricular haemodynamics are discussed and integrated into the pathophysiological model., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Coronary heart disease is one of the leading causes of death in industrialized nations. Even though revascularization strategies improved the outcome of patients after acute myocardial infarction, about 30% of patients develop chronic heart failure. Ischemic heart disease and heart failure are characterized by an adverse remodeling of the heart, featuring cardiomyocyte hypertrophy, increased fibrosis, and capillary rarefaction. Therefore, novel therapeutic approaches for the treatment of heart failure, such as reducing ischemia/reperfusion injury, fibrosis, or hypertrophy, are needed. Here microRNAs (miRNAs) come into play. For heart failure, cardiac stress and several cardiovascular diseases, individual miRNAs, and whole miRNA clusters have been implicated as disease relevant and dysregulated. miRNAs are short non-coding RNA molecules of about 22 nucleotides, and their inhibitors are 8-15 nucleotides long plus a sugar-ring (LNA, locked nucleid acid) or cholesterol ending (AntagomiR). Modulation of miRNAs might serve as therapeutic targets through miRNA knockdown or overexpression via miRNA mimics. Due to their pleiotropic mode of action and the presence of individual miRNAs in a variety of tissues and cells, a local, target region-oriented application is important to achieve therapeutic effects and at the same time reducing adverse effects in other off-target organs and tissues. Due to their small size, the miRNA inhibitors are able to pass endothelial barrier at both arterial and venous sides of the bloodstream vessels. For these reasons, the gold standard administration route of miRNA modulators for therapeutic approaches of the left ventricle is the anterograde application into one or both coronary arteries via an over-the-wire (OTW) balloon. In this chapter we provide a comprehensive description of the anterograde application procedure in a large animal model such as pig. Of a particular note, this methodology is a standard procedure in catheter laboratories, a key characteristic that allows therapeutic translation from large animals to patients., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

An interplay between Ca 2+ /calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na + current (I NaL ) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform Na V 1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of Na V 1.8, we demonstrate that Na V 1.8 contributes to I NaL formation. In addition, we reveal a direct interaction between Na V 1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of Na V 1.8 and CaMKIIδc, we show that Na V 1.8-driven I NaL is CaMKIIδc-dependent and that Na V 1.8-inhibtion reduces diastolic SR-Ca 2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a Na V 1.8 knock-out is introduced. Cellular and in vivo experiments reveal reduced ventricular arrhythmias without changes in HF progression. Our work therefore identifies a proarrhythmic CaMKIIδc downstream target which may constitute a prognostic and antiarrhythmic strategy., (© 2021. The Author(s).)

Myocardial infarction (MI) occurs when coronary blood flow is decreased due to an obstruction/occlusion of the vessels, leading to myocardial death and progression to heart failure (HF). Cognitive impairment, anxiety, depression and memory loss are the most frequent mental health problems among patients with HF. The most common cause of cognitive decline is cardiac systolic dysfunction, which leads to reduced cerebral perfusion. Several in vivo and clinical studies provide information regarding the underlying mechanisms of HF in brain pathology. Neurohormonal activation, oxidative stress, inflammation, glial activation, dendritic spine loss and brain programmed cell death are all proposed as contributors of cognitive impairment in HF. Furthermore, several investigations into the effects of various medications on brain pathology utilizing MI models have been reported. In this review, potential mechanisms involving HF-associated cognitive impairment, as well as neuroprotective interventions in HF models, are discussed and summarized. In addition, gaps in the surrounding knowledge, including the types of brain cell death and the effects of cell death inhibitors in HF, are presented and discussed. This review provides valuable information that will suggest the potential therapeutic strategies for cognitive impairment in patients with HF., (© 2021 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Non-human primates (NHP) are valuable models for late translational pre-clinical studies, often seen as a last step before clinical application. The unique similarity between NHPs and humans is often the subject of ethical concerns. However, it is precisely this analogy in anatomy, physiology, and the immune system that narrows the translational gap to other animal models in the cardiovascular field. Cell and gene therapy approaches are two dominant strategies investigated in the research field of cardiac regeneration. Focusing on the cell therapy approach, several xeno- and allogeneic cell transplantation studies with a translational motivation have been realized in macaque species. This is based on the pressing need for novel therapeutic options for heart failure patients. Stem cell-based remuscularization of the injured heart can be achieved via direct injection of cardiomyocytes (CMs) or patch application. Both CM delivery approaches are in the late preclinical stage, and the first clinical trials have started. However, are we already ready for the clinical area? The present review concentrates on CM transplantation studies conducted in NHPs, discusses the main sources and discoveries, and provides a perspective about human translation. [ABSTRACT FROM AUTHOR]

Non-human primates (NHP) are valuable models for late translational pre-clinical studies, often seen as a last step before clinical application. The unique similarity between NHPs and humans is often the subject of ethical concerns. However, it is precisely this analogy in anatomy, physiology, and the immune system that narrows the translational gap to other animal models in the cardiovascular field. Cell and gene therapy approaches are two dominant strategies investigated in the research field of cardiac regeneration. Focusing on the cell therapy approach, several xeno- and allogeneic cell transplantation studies with a translational motivation have been realized in macaque species. This is based on the pressing need for novel therapeutic options for heart failure patients. Stem cell-based remuscularization of the injured heart can be achieved via direct injection of cardiomyocytes (CMs) or patch application. Both CM delivery approaches are in the late preclinical stage, and the first clinical trials have started. However, are we already ready for the clinical area? The present review concentrates on CM transplantation studies conducted in NHPs, discusses the main sources and discoveries, and provides a perspective about human translation. [ABSTRACT FROM AUTHOR]

(1) Background and Objective: MicroRNAs (miRs) are biomarkers for assessing the extent of cardiac remodeling after myocardial infarction (MI) and important predictors of clinical outcome in heart failure. Overexpression of miR-30d-5p appears to have a cardioprotective effect. The aim of the present study was to demonstrate whether miR-30d-5p could be used as a potential therapeutic target to improve post-MI adverse remodeling. (2) Methods and Results: MiR profiling was performed by next-generation sequencing to assess different expression patterns in ischemic vs. healthy myocardium in a rat model of MI. MiR-30d-5p was significantly downregulated (p < 0.001) in ischemic myocardium and was selected as a promising target. A mimic of miR-30d-5p was administered in the treatment group, whereas the control group received non-functional, scrambled siRNA. To measure the effect of miR-30d-5p on infarct area size of the left ventricle, the rats were randomized and treated with miR-30d-5p or scrambled siRNA. Histological planimetry was performed 72 h and 6 weeks after induction of MI. Infarct area was significantly reduced at 72 h and at 6 weeks by using miR-30d-5p (72 h: 22.89 ± 7.66% vs. 35.96 ± 9.27%, p = 0.0136; 6 weeks: 6.93 ± 4.58% vs. 12.48 ± 7.09%, p = 0.0172). To gain insight into infarct healing, scratch assays were used to obtain information on cell migration in human umbilical vein endothelial cells (HUVECs). Gap closure was significantly faster in the mimic-treated cells 20 h post-scratching (12.4% more than the scrambled control after 20 h; p = 0.013). To analyze the anti-apoptotic quality of miR-30d-5p, the ratio between phosphorylated p53 and total p53 was evaluated in human cardiomyocytes using ELISA. Under the influence of the miR-30d-5p mimic, cardiomyocytes demonstrated a decreased pp53/total p53 ratio (0.66 ± 0.08 vs. 0.81 ± 0.17), showing a distinct tendency (p = 0.055) to decrease the apoptosis rate compared to the control group. (3) Conclusion: Using a mimic of miR-30d-5p underlines the cardioprotective effect of miR-30d-5p in MI and could reduce the risk for development of ischemic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Purpose: Cardiac autonomic dysfunction is one of the main pillars of cardiovascular pathophysiology. The purpose of this review is to provide an overview of the current state of the art on the pathological remodeling that occurs within the autonomic nervous system with cardiac injury and available neuromodulatory therapies for autonomic dysfunction in heart failure. Methods: Data from peer-reviewed publications on autonomic function in health and after cardiac injury are reviewed. The role of and evidence behind various neuromodulatory therapies both in preclinical investigation and in-use in clinical practice are summarized. Results: A harmonic interplay between the heart and the autonomic nervous system exists at multiple levels of the neuraxis. This interplay becomes disrupted in the setting of cardiovascular disease, resulting in pathological changes at multiple levels, from subcellular cardiac signaling of neurotransmitters to extra-cardiac, extra-thoracic remodeling. The subsequent detrimental cycle of sympathovagal imbalance, characterized by sympathoexcitation and parasympathetic withdrawal, predisposes to ventricular arrhythmias, progression of heart failure, and cardiac mortality. Knowledge on the etiology and pathophysiology of this condition has increased exponentially over the past few decades, resulting in a number of different neuromodulatory approaches. However, significant knowledge gaps in both sympathetic and parasympathetic interactions and causal factors that mediate progressive sympathoexcitation and parasympathetic dysfunction remain. Conclusions: Although our understanding of autonomic imbalance in cardiovascular diseases has significantly increased, specific, pivotal mediators of this imbalance and the recognition and implementation of available autonomic parameters and neuromodulatory therapies are still lagging. [ABSTRACT FROM AUTHOR]

Ischemic heart failure (IHF) is a leading cause of morbidity and mortality worldwide, for which heart transplantation remains the only definitive treatment. IHF manifests from myocardial infarction (MI) that initiates tissue remodeling processes, mediated by mechanical changes in the tissue (loss of contractility, softening of the myocardium) that are interdependent with cellular mechanisms (cardiomyocyte death, inflammatory response). The early remodeling phase is characterized by robust inflammation that is necessary for tissue debridement and the initiation of repair processes. While later transition toward an immunoregenerative function is desirable, functional reorientation from an inflammatory to reparatory environment is often lacking, trapping the heart in a chronically inflamed state that perpetuates cardiomyocyte death, ventricular dilatation, excess fibrosis, and progressive IHF. Therapies can redirect the immune microenvironment, including biotherapeutic and biomaterial-based approaches. In this review, we outline these existing approaches, with a particular focus on the immunomodulatory effects of therapeutics (small molecule drugs, biomolecules, and cell or cell-derived products). Cardioprotective strategies, often focusing on immunosuppression, have shown promise in pre-clinical and clinical trials. However, immunoregenerative therapies are emerging that often benefit from exacerbating early inflammation. Biomaterials can be used to enhance these therapies as a result of their intrinsic immunomodulatory properties, parallel mechanisms of action (e.g., mechanical restraint), or by enabling cell or tissue-targeted delivery. We further discuss translatability and the continued progress of technologies and procedures that contribute to the bench-to-bedside development of these critically needed treatments. [ABSTRACT FROM AUTHOR]

Although heart failure (HF) is a clinical syndrome that becomes worse over time, certain cases can be reversed with appropriate treatments. While coronary artery spasm (CAS) is still underappreciated and may be misdiagnosed, ischemia due to coronary artery disease and CAS is becoming the single most frequent cause of HF worldwide. CAS could lead to syncope, HF, arrhythmias, and myocardial ischemic syndromes such as asymptomatic ischemia, rest and/or effort angina, myocardial infarction, and sudden death. Albeit the clinical significance of asymptomatic CAS has been undervalued, affected individuals compared with those with classic Heberden's angina pectoris are at higher risk of syncope, life-threatening arrhythmias, and sudden death. As a result, a prompt diagnosis implements appropriate treatment strategies, which have significant life-changing consequences to prevent CAS-related complications, such as HF. Although an accurate diagnosis depends mainly on coronary angiography and provocative testing, clinical characteristics may help decision-making. Because the majority of CAS-related HF (CASHF) patients present with less severe phenotypes than overt HF, it underscores the importance of understanding risk factors correlated with CAS to prevent the future burden of HF. This narrative literature review summarises and discusses separately the epidemiology, clinical features, pathophysiology, and management of patients with CASHF. [ABSTRACT FROM AUTHOR]

Heart failure is a leading cause of morbidity and mortality, with relevant social and economic burden on global healthcare system. Although the development of novel diagnostic tools and the advance in therapies have deeply influenced the diagnosis and treatment of this disease, improving both prognosis and life expectancy of patients, hospitalization is still high, and mortality remains considerable. MicroRNAs are small endogenous RNA molecules that post‐transcriptionally regulate gene expression in both physiological and pathological processes. In recent years, microRNA have arisen as attractive therapeutic targets in the treatment of a wide spectrum of pathologies, including heart failure. In cardiac pathology, deregulation of microRNAs expression and function is associated to adverse outcome and heart failure progression. Circulating levels of specific microRNAs have emerged as useful biomarkers for the diagnosis of heart failure or as prognostic indicators. In the present review, we summarize the state of current research on the role of miRNAs as biomarkers for diagnosis and prognosis in patients with heart failure and their use as potential therapeutic targets for this condition. [ABSTRACT FROM AUTHOR]

Acute and chronic cardiac disorders predispose to alterations in cognitive performance, ranging from mild cognitive impairment to overt dementia. Although this association is well-established, the factors inducing and accelerating cognitive decline beyond ageing and the intricate causal pathways and multilateral interdependencies involved remain poorly understood. Dysregulated and persistent inflammatory processes have been implicated as potentially causal mediators of the adverse consequences on brain function in patients with cardiac disease. Recent advances in positron emission tomography disclosed an enhanced level of neuroinflammation of cortical and subcortical brain regions as an important correlate of altered cognition in these patients. In preclinical and clinical investigations, the thereby involved domains and cell types of the brain are gradually better characterized. Microglia, resident myeloid cells of the central nervous system, appear to be of particular importance, as they are extremely sensitive to even subtle pathological alterations affecting their complex interplay with neighboring astrocytes, oligodendrocytes, infiltrating myeloid cells, and lymphocytes. Here, we review the current evidence linking cognitive impairment and chronic neuroinflammation in patients with various selected cardiac disorders including the aspect of chronic neuroinflammation as a potentially druggable target. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is a cardiovascular disease (CVD) with high morbidity and mortality worldwide, often leading to adverse cardiac remodeling and heart failure, which is a serious threat to human life and health. The immune system makes an important contribution to the maintenance of normal cardiac function. In the disease process of MI, necrotic cardiomyocytes release signals that activate nonspecific immunity and trigger the action of specific immunity. Complex immune cells play an important role in all stages of MI progression by removing necrotic cardiomyocytes and tissue and promoting the healing of damaged tissue cells. With the development of biomaterials, cardiac patches have become an emerging method of repairing MI, and the development of engineered cardiac patches through the construction of multiple animal models of MI can help treat MI. This review introduces immune cells involved in the development of MI, summarizes the commonly used animal models of MI and the newly developed cardiac patch, so as to provide scientific reference for the accurate diagnosis and effective treatment of MI. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases and specifically heart failure (HF) impact global health and impose a significant economic burden on society. Despite current advances in standard of care, the risks for death and readmission of HF patients remain unacceptably high and new therapeutic strategies to limit HF progression are highly sought. In disease settings, persistent mechanical or neurohormonal stress to the myocardium triggers maladaptive cardiac remodelling, which alters cardiac function and structure at both the molecular and cellular levels. The progression and magnitude of maladaptive cardiac remodelling ultimately leads to the development of HF. Classical therapies for HF are largely protein-based and mostly are targeted to ameliorate the dysregulation of neuroendocrine pathways and halt adverse remodelling. More recently, investigation of novel molecular targets and the application of cellular therapies, epigenetic modifications, and regulatory RNAs has uncovered promising new avenues to address HF. In this review, we summarize the current knowledge on novel cellular and epigenetic therapies and focus on two non-coding RNA-based strategies that reached the phase of early clinical development to counteract cardiac remodelling and HF. The current status of the development of translating those novel therapies to clinical practice, limitations, and future perspectives are additionally discussed. [ABSTRACT FROM AUTHOR]

Despite significant advances in the diagnosis and treatment of cardiovascular diseases, recent calls have emphasized the unmet need to improve precision-based approaches in cardiovascular disease. Although some studies provide preliminary evidence of the diagnostic and prognostic potential of circulating coding and non-coding RNAs, the complex RNA biology and lack of standardization have hampered the translation of these markers into clinical practice. In this position paper of the CardioRNA COST action CA17129, we provide recommendations to standardize the RNA development process in order to catalyse efforts to investigate novel RNAs for clinical use. We list the unmet clinical needs in cardiovascular disease, such as the identification of high-risk patients with ischaemic heart disease or heart failure who require more intensive therapies. The advantages and pitfalls of the different sample types, including RNAs from plasma, extracellular vesicles, and whole blood, are discussed in the sample matrix, together with their respective analytical methods. The effect of patient demographics and highly prevalent comorbidities, such as metabolic disorders, on the expression of the candidate RNA is presented and should be reported in biomarker studies. We discuss the statistical and regulatory aspects to translate a candidate RNA from a research use only assay to an in-vitro diagnostic test for clinical use. Optimal planning of this development track is required, with input from the researcher, statistician, industry, and regulatory partners. [ABSTRACT FROM AUTHOR]

Takotsubo syndrome (TTS) is a severe but reversible acute heart failure syndrome that occurs following high catecholaminergic stress. TTS patients are similar to those with acute coronary syndrome, with chest pain, dyspnoea and ST segment changes on electrocardiogram, but are characterised by apical akinesia of the left ventricle, with basal hyperkinesia in the absence of culprit coronary artery stenosis. The pathophysiology of TTS is not completely understood and there is a paucity of evidence to guide treatment. The mechanisms of TTS are thought to involve catecholaminergic myocardial stunning, microvascular dysfunction, increased inflammation and changes in cardiomyocyte metabolism. Here, we summarise the available literature to focus on the molecular basis for the pathophysiology of TTS to advance the understanding of the condition. [ABSTRACT FROM AUTHOR]

Alamandine (Ala) is the newest identified peptide of the renin-angiotensin system and has protective effect on myocyte hypertrophy. However, it is still unclear whether Ala can alleviate heart failure (HF). The aim of this study was to explore the effects of Ala on HF and the related cardiac fibrosis, and to probe the mechanism. HF model was induced by myocardial infarction (MI) in mice. Four weeks after MI, Ala was administrated by intraperitoneal injection for two weeks. Ala injection significantly improved cardiac dysfunction of MI mice in vivo. The cardiac fibrosis and the related biomarkers were attenuated after Ala administration in HF mice in vivo. The increases of collagen I, alpha-smooth muscle actin and transforming growth factor-beta induced by oxygen–glucose deprivation (OGD) in neonatal rat cardiac fibroblasts (NRCFs) were inhibited by Ala treatment in vitro. The biomarkers of apoptosis were elevated in NRCFs induced by OGD, which were attenuated after treating with Ala in vitro. The enhancement of oxidative stress in the heart of MI mice or in the NRCFs treated with OGD was suppressed by treating with Ala in vivo and in vitro. These effects of Ala were reversed by tBHP, an exogenous inducer of oxidative stress in vitro. These results demonstrated that Ala could alleviate cardiac dysfunction and attenuate cardiac fibrosis via inhibition of oxidative stress. [ABSTRACT FROM AUTHOR]

Most patients survive acute myocardial infarction (MI). Yet this encouraging development has certain drawbacks: heart failure (HF) prevalence is increasing and patients affected tend to have more comorbidities worsening economic strain on healthcare systems and impeding effective medical management. The heart's pathological changes in structure and/or function, termed myocardial remodelling, significantly impact on patient outcomes. Risk factors like diabetes, chronic obstructive pulmonary disease, female sex, and others distinctly shape disease progression on the 'road to HF'. Despite the availability of HF drugs that interact with general pathways involved in myocardial remodelling, targeted drugs remain absent, and patient risk stratification is poor. Hence, in this review, we highlight the pathophysiological basis, current diagnostic methods and available treatments for cardiac remodelling following MI. We further aim to provide a roadmap for developing improved risk stratification and novel medical and interventional therapies. [ABSTRACT FROM AUTHOR]

Aims Cardiac energetic impairment is a major finding in takotsubo patients. We investigate specific metabolic adaptations to direct future therapies. Methods and results An isoprenaline-injection female rat model (vs. sham) was studied at Day 3; recovery assessed at Day 7. Substrate uptake, metabolism, inflammation, and remodelling were investigated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography, metabolomics, quantitative PCR, and western blot (WB). Isolated cardiomyocytes were patch-clamped during stress protocols for redox states of NAD(P)H/FAD or [Ca2+]c, [Ca2+]m, and sarcomere length. Mitochondrial respiration was assessed by seahorse/Clark electrode (glycolytic and β-oxidation substrates). Cardiac 18F-FDG metabolic rate was increased in takotsubo (P  = 0.006), as was the expression of GLUT4-RNA/GLUT1/HK2-RNA and HK activity (all P  < 0.05), with concomitant accumulation of glucose- and fructose-6-phosphates (P  > 0.0001). Both lactate and pyruvate were lower (P  < 0.05) despite increases in LDH-RNA and PDH (P  < 0.05 both). β-Oxidation enzymes CPT1b-RNA and 3-ketoacyl-CoA thiolase were increased (P  < 0.01) but malonyl-CoA (CPT-1 regulator) was upregulated (P  = 0.01) with decreased fatty acids and acyl-carnitines levels (P  = 0.0001–0.02). Krebs cycle intermediates α-ketoglutarate and succinyl-carnitine were reduced (P  < 0.05) as was cellular ATP reporter dihydroorotate (P  = 0.003). Mitochondrial Ca2+ uptake during high workload was impaired on Day 3 (P  < 0.0001), inducing the oxidation of NAD(P)H and FAD (P  = 0.03) but resolved by Day 7. There were no differences in mitochondrial respiratory function, sarcomere shortening, or [Ca2+] transients of isolated cardiomyocytes, implying preserved integrity of both mitochondria and cardiomyocyte. Inflammation and remodelling were upregulated—increased CD68-RNA, collagen RNA/protein, and skeletal actin RNA (all P  < 0.05). Conclusion Dysregulation of glucose and lipid metabolic pathways with decreases in final glycolytic and β-oxidation metabolites and reduced availability of Krebs intermediates characterizes takotsubo myocardium. The energetic deficit accompanies defective Ca2+ handling, inflammation, and upregulation of remodelling pathways, with the preservation of sarcomeric and mitochondrial integrity. [ABSTRACT FROM AUTHOR]

Cardiac interstitium is a complex and dynamic environment, vital for normal cardiac structure and function. Telocytes are active cellular players in regulating main events that feature myocardial homeostasis and orchestrating its involvement in heart pathology. Despite the great amount of data suggesting (microscopically, proteomically, genetically, etc.) the implications of telocytes in the different physiological and reparatory/regenerative processes of the heart, understanding their involvement in realizing the heart's mature cytoarchitecture is still at its dawn. Our scrutiny of the recent literature gave clearer insights into the implications of telocytes in the WNT signaling pathway, but also TGFB and PI3K/AKT pathways that, inter alia, conduct cardiomyocytes differentiation, maturation and final integration into heart adult architecture. These data also strengthen evidence for telocytes as promising candidates for cellular therapies in various heart pathologies. [ABSTRACT FROM AUTHOR]

Aims  Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and in the absence of culprit coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS. Methods and results  miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal), cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavβ subunit), RGS4 (regulator of G-protein signalling 4), and G-protein subunit Gβ (GNB1) as underlying these effects. Conclusion miR-16 and miR-26a sensitize the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future. [ABSTRACT FROM AUTHOR]

microRNAs (miRNA, miRs) play crucial roles in cardiovascular disease regulating numerous processes, including inflammation, cell proliferation, angiogenesis, and cell death. Herein, we present an updated and comprehensive overview of the functional involvement of miRs in the regulation of cardiomyocyte death, a central event in acute myocardial infarction, ischemia/reperfusion, and heart failure. Specifically, in this systematic review we are focusing on necrosis, apoptosis, and autophagy. [ABSTRACT FROM AUTHOR]

Genetic cardiomyopathies are disorders of the cardiac muscle, most often explained by pathogenic mutations in genes encoding sarcomere, cytoskeleton, or ion channel proteins. Clinical phenotypes such as heart failure and arrhythmia are classically treated with generic drugs, but aetiology‐specific and targeted treatments are lacking. As a result, cardiomyopathies still present a major burden to society, and affect many young and older patients. The Translational Committee of the Heart Failure Association (HFA) and the Working Group of Myocardial Function of the European Society of Cardiology (ESC) organized a workshop to discuss recent advances in molecular and physiological studies of various forms of cardiomyopathies. The study of cardiomyopathies has intensified after several new study setups became available, such as induced pluripotent stem cells, three‐dimensional printing of cells, use of scaffolds and engineered heart tissue, with convincing human validation studies. Furthermore, our knowledge on the consequences of mutated proteins has deepened, with relevance for cellular homeostasis, protein quality control and toxicity, often specific to particular cardiomyopathies, with precise effects explaining the aberrations. This has opened up new avenues to treat cardiomyopathies, using contemporary techniques from the molecular toolbox, such as gene editing and repair using CRISPR‐Cas9 techniques, antisense therapies, novel designer drugs, and RNA therapies. In this article, we discuss the connection between biology and diverse clinical presentation, as well as promising new medications and therapeutic avenues, which may be instrumental to come to precision medicine of genetic cardiomyopathies. [ABSTRACT FROM AUTHOR]

Protein kinase A (PKA) is a central regulator of cardiac performance and morphology. Myocardial PKA activation is induced by a variety of hormones, neurotransmitters, and stress signals, most notably catecholamines secreted by the sympathetic nervous system. Catecholamines bind β-adrenergic receptors to stimulate cAMP-dependent PKA activation in cardiomyocytes. Elevated PKA activity enhances Ca2+ cycling and increases cardiac muscle contractility. Dynamic control of PKA is essential for cardiac homeostasis, as dysregulation of PKA signalling is associated with a broad range of heart diseases. Specifically, abnormal PKA activation or inactivation contributes to the pathogenesis of myocardial ischaemia, hypertrophy, heart failure, as well as diabetic, takotsubo, or anthracycline cardiomyopathies. PKA may also determine sex-dependent differences in contractile function and heart disease predisposition. Here, we describe the recent advances regarding the roles of PKA in cardiac physiology and pathology, highlighting previous study limitations and future research directions. Moreover, we discuss the therapeutic strategies and molecular mechanisms associated with cardiac PKA biology. In summary, PKA could serve as a promising drug target for cardioprotection. Depending on disease types and mechanisms, therapeutic intervention may require either inhibition or activation of PKA. Therefore, specific PKA inhibitors or activators may represent valuable drug candidates for the treatment of heart diseases. [ABSTRACT FROM AUTHOR]

Objective. Heart failure and ventricular remodeling after acute myocardial infarction (AMI) are important factors affecting the prognosis of patients. Therefore, we expected to explore the therapeutic target of AMI by studying the effect of death-associated protein kinase 1 (DAPK1) on AMI rat model. Materials and Methods. We used male Sprague-Dawley rats to make AMI model, and after 1, 3, 7, and 14 d, we detect the success rate of modeling and the expression change of DAPK1 through 2, 3, 5-triphenyl tetrazolium chloride staining, myocardial injury markers detection, echocardiographic detection, and histological experiment. In addition, we determined the effect of DAPK1 on AMI by subcutaneous injection of the DAPK1 inhibitor (TC-DAPK 6). The effect of DAPK1 on cardiomyocytes has also been verified in cell experiments on H9c2 cells. Results. The expression of DAPK1 in AMI rats was significantly higher than that in sham group, and it increased with time. The expression of inflammatory factors (interleukin- (IL-) 1β, IL-6, and tumor necrosis factor-α) in AMI rats treated by TC-DAPK 6 was reduced. In addition, TC-DAPK 6 also reduced the activity of malonaldehyde and increased the activities of superoxide dismutase, glutathione, and catalase. The expression of antioxidant molecules such as peroxiredoxin1/4 and glutathione peroxidase1/3 was also promoted by TC-DAPK 6. In H9c2 cells, TC-DAPK 6 also reduced its oxidative stress level. Conclusions. The increase of DAPK1 may be related to the pathogenesis of AMI. DAPK1 inhibitors protect cardiomyocytes from AMI-induced myocardial injury by reducing levels of inflammation and oxidative stress in myocardial tissue and cells. [ABSTRACT FROM AUTHOR]

Ischemic stroke imparts elevated risk of heart failure though the underlying mechanisms remain poorly described. We aimed to characterize the influence of cerebral ischemic injury on cardiac function using multimodality molecular imaging to investigate brain and cardiac morphology and tissue inflammation in two mouse models of variable stroke severity. Transient middle cerebral artery occlusion (MCAo) generated extensive stroke damage (56.31 ± 40.39 mm3). Positron emission tomography imaging of inflammation targeting the mitochondrial translocator protein (TSPO) revealed localized neuroinflammation at 7 days after stroke compared to sham (3.8 ± 0.8 vs 2.6 ± 0.7 %ID/g max, p < 0.001). By contrast, parenchyma topical application of vasoconstrictor endothelin-1 did not generate significant stroke damage or neuroinflammatory cell activity. MCAo evoked a modest reduction in left ventricle ejection fraction at both 1 weeks and 3 weeks after stroke (LVEF at 3 weeks: 54.3 ± 5.7 vs 66.1 ± 3.5%, p < 0.001). This contractile impairment was paralleled by elevated cardiac TSPO PET signal compared to sham (8.6 ± 2.4 vs 5.8 ± 0.7%ID/g, p = 0.022), but was independent of leukocyte infiltration defined by flow cytometry. Stroke size correlated with severity of cardiac dysfunction (r = 0.590, p = 0.008). Statistical parametric mapping identified a direct association between neuroinflammation at 7 days in a cluster of voxels including the insular cortex and reduced ejection fraction (ρ = − 0.396, p = 0.027). Suppression of microglia led to lower TSPO signal at 7 days which correlated with spared late cardiac function after MCAo (r = − 0.759, p = 0.029). Regional neuroinflammation early after cerebral ischemia influences subsequent cardiac dysfunction. Total body TSPO PET enables monitoring of neuroinflammation, providing insights into brain–heart inter-organ communication and may guide therapeutic intervention to spare cardiac function post-stroke. [ABSTRACT FROM AUTHOR]

Alterations of RNA editing that affect the secondary structure of RNAs can cause human diseases. We therefore studied RNA editing in failing human hearts. Transcriptome sequencing showed that adenosine-to-inosine (A-to-I) RNA editing was responsible for 80% of the editing events in the myocardium. Failing human hearts were characterized by reduced RNA editing. This was primarily attributable to Alu elements in introns of protein-coding genes. In the failing left ventricle, 166 circRNAs were upregulated and 7 circRNAs were downregulated compared to non-failing controls. Most of the upregulated circRNAs were associated with reduced RNA editing in the host gene. ADAR2, which binds to RNA regions that are edited from A-to-I, was decreased in failing human hearts. In vitro, reduction of ADAR2 increased circRNA levels suggesting a causal effect of reduced ADAR2 levels on increased circRNAs in the failing human heart. To gain mechanistic insight, one of the identified upregulated circRNAs with a high reduction of editing in heart failure, AKAP13, was further characterized. ADAR2 reduced the formation of double-stranded structures in AKAP13 pre-mRNA, thereby reducing the stability of Alu elements and the circularization of the resulting circRNA. Overexpression of circAKAP13 impaired the sarcomere regularity of human induced pluripotent stem cell-derived cardiomyocytes. These data show that ADAR2 mediates A-to-I RNA editing in the human heart. A-to-I RNA editing represses the formation of dsRNA structures of Alu elements favoring canonical linear mRNA splicing and inhibiting the formation of circRNAs. The findings are relevant to diseases with reduced RNA editing and increased circRNA levels and provide insights into the human-specific regulation of circRNA formation. [ABSTRACT FROM AUTHOR]

Cardiac alterations are frequently observed after acute neurological disorders. Takotsubo syndrome (TTS) represents an acute heart failure syndrome and is increasingly recognized as part of the spectrum of cardiac complications observed after neurological disorders. A systematic investigation of TTS patients with neurological disorders has not been conducted yet. The aim of the study was to expand insights regarding neurological disease entities triggering TTS and to investigate the clinical profile and outcomes of TTS patients after primary neurological disorders. The International Takotsubo Registry is an observational multicenter collaborative effort of 45 centers in 14 countries (ClinicalTrials.gov, identifier NCT01947621). All patients in the registry fulfilled International Takotsubo Diagnostic Criteria. For the present study, patients were included if complete information on acute neurological disorders were available. 2402 patients in whom complete information on acute neurological status were available were analyzed. In 161 patients (6.7%) an acute neurological disorder was identified as the preceding triggering factor. The most common neurological disorders were seizures, intracranial hemorrhage, and ischemic stroke. Time from neurological symptoms to TTS diagnosis was ≤ 2 days in 87.3% of cases. TTS patients with neurological disorders were younger, had a lower female predominance, fewer cardiac symptoms, lower left ventricular ejection fraction, and higher levels of cardiac biomarkers. TTS patients with neurological disorders had a 3.2-fold increased odds of in-hospital mortality compared to TTS patients without neurological disorders. In this large-scale study, 1 out of 15 TTS patients had an acute neurological condition as the underlying triggering factor. Our data emphasize that a wide spectrum of neurological diseases ranging from benign to life-threatening encompass TTS. The high rates of adverse events highlight the need for clinical awareness. [ABSTRACT FROM AUTHOR]

Major changes have occurred in these last years in heart failure (HF) management. Landmark trials and the 2021 European Society of Cardiology guidelines for the diagnosis and treatment of HF have established four classes of drugs for treatment of HF with reduced ejection fraction: angiotensin‐converting enzyme inhibitors or an angiotensin receptor‐neprilysin inhibitor, beta‐blockers, mineralocorticoid receptor antagonists, and sodium‐glucose co‐transporter 2 inhibitors, namely, dapagliflozin or empagliflozin. These drugs consistently showed benefits on mortality, HF hospitalizations, and quality of life. Correction of iron deficiency is indicated to improve symptoms and reduce HF hospitalizations. AFFIRM‐AHF showed 26% reduction in total HF hospitalizations with ferric carboxymaltose vs. placebo in patients hospitalized for acute HF (P = 0.013). The guanylate cyclase activator vericiguat and the myosin activator omecamtiv mecarbil improved outcomes in randomized placebo‐controlled trials, and vericiguat is now approved for clinical practice. Treatment of HF with preserved ejection fraction (HFpEF) was a major unmet clinical need until this year when the results of EMPEROR‐Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic HFpEF) were issued. Compared with placebo, empagliflozin reduced by 21% (hazard ratio, 0.79; 95% confidence interval, 0.69 to 0.90; P < 0.001), the primary outcome of cardiovascular death or HF hospitalization. Advances in the treatment of specific phenotypes of HF, including atrial fibrillation, valvular heart disease, cardiomyopathies, cardiac amyloidosis, and cancer‐related HF, also occurred. Coronavirus disease 2019 (COVID‐19) pandemic still plays a major role in HF epidemiology and management. All these aspects are highlighted in this review. [ABSTRACT FROM AUTHOR]

Up-regulation of Circ-INSR can thus significantly safeguard the heart against mitochondrial damage and the consequent cardiotoxicity induced by the anticancer drug doxorubicin. Up-regulation of Circ-INSR can thus significantly safeguard the heart against mitochondrial damage and the consequent cardiotoxicity induced by the anticancer drug doxorubicin. In agreement with this, doxorubicin induced a down-regulation of Circ-INSR, and the loss of Circ-INSR correlated with mitochondrial damage, cardiomyocyte death, and eventually heart dysfunction in both rodents and humans. [Extracted from the article]

An interplay between Ca2+/calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na+ current (INaL) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform NaV1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of NaV1.8, we demonstrate that NaV1.8 contributes to INaL formation. In addition, we reveal a direct interaction between NaV1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of NaV1.8 and CaMKIIδc, we show that NaV1.8-driven INaL is CaMKIIδc-dependent and that NaV1.8-inhibtion reduces diastolic SR-Ca2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a NaV1.8 knock-out is introduced. Cellular and in vivo experiments reveal reduced ventricular arrhythmias without changes in HF progression. Our work therefore identifies a proarrhythmic CaMKIIδc downstream target which may constitute a prognostic and antiarrhythmic strategy. In heart failure, increased CaMKII activity is decisively involved in arrhythmia formation. Here, the authors introduce the neuronal sodium channel NaV1.8 as a CaMKII downstream target as its specific knock-out reduces arrhythmias and improves survival in a CaMKII-overexpressing mouse model. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease and subsequent heart failure threaten global health and impose a huge economic burden on society. MicroRNA-132 (miR-132), a regulatory RNA ubiquitously expressed in the cardiovascular system, is up-or down-regulated in the plasma under various cardiac conditions and may serve as a potential diagnostic or prognostic biomarker. More importantly, miR-132 in the myocardium has been demonstrated to be a master regulator in many pathological processes of ischemic or nonischemic heart failure in the past decade, such as myocardial hypertrophy, fibrosis, apoptosis, angiogenesis, calcium handling, neuroendocrine activation, and oxidative stress, through downregulating target mRNA expression. Preclinical and clinical phase 1b studies have suggested antisense oligonucleotide targeting miR-132 may be a potential therapeutic approach for ischemic or nonischemic heart failure in the future. This review aims to summarize recent advances in the physiological and pathological functions of miR-132 and its possible diagnostic and therapeutic potential in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Purpose of Review: To examine the use of positron emission tomography (PET) for imaging post-infarct myocardial inflammation and repair. Recent Findings: Dysregulated immune responses after myocardial infarction are associated with adverse cardiac remodelling and an increased likelihood of ischaemic heart failure. PET imaging utilising novel tracers can be applied to visualise different components of the post-infarction inflammatory and repair processes. This approach could offer unique pathophysiological insights that could prove useful for the identification and risk-stratification of individuals who would ultimately benefit most from emerging immune-modulating therapies. PET imaging could also bridge the clinical translational gap as a surrogate measure of drug efficacy in early-stage clinical trials in patients with myocardial infarction. The use of hybrid PET/MR imaging, in particular, offers the additional advantage of simultaneous in vivo molecular imaging and detailed assessment of myocardial function, viability and tissue characterisation. Summary: Further research is needed to realise the true clinical translational value of PET imaging after myocardial infarction. [ABSTRACT FROM AUTHOR]

Purpose of Review: Current therapeutic strategies to mitigate heart failure progression after myocardial infarction involve support of endogenous repair through molecular targets. The capacity for repair varies greatly between individuals. In this review, we will assess how cardiac PET/CT enables precise characterization of early pathogenetic processes which govern ventricle remodeling and progression to heart failure. Recent Findings: Inflammation in the first days after myocardial infarction predicts subsequent functional decline and can influence therapy decisions. The expansion of anti-inflammatory approaches to improve outcomes after myocardial infarction may benefit from noninvasive characterization using imaging. Novel probes also allow visualization of fibroblast transdifferentiation and activation, as a precursor to ventricle remodeling. Summary: The expanding arsenal of molecular imaging agents in parallel with new treatment options provides opportunity to harmonize diagnostic imaging with precision therapy. [ABSTRACT FROM AUTHOR]

The article presents the impact of Covid-19 on global health and economy. Topics include heart failure (HF) prevalence remaining high worldwide with significant sex-related and regional differences in the presentation, management, and outcomes; and Diastolic dysfunction, left atrial enlargement, elevated left atrial pressure, and pulmonary hypertension being common in the patients.

Aims Cardiac microRNA-132-3p (miR-132) levels are increased in patients with heart failure (HF) and mechanistically drive cardiac remodelling processes. CDR132L, a specific antisense oligonucleotide, is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. The aim of the current clinical Phase 1b study was to assess safety, pharmacokinetics, target engagement, and exploratory pharmacodynamic effects of CDR132L in patients on standard-of-care therapy for chronic ischaemic HF in a randomized, placebo-controlled, double-blind, dose-escalation study (NCT04045405). Methods and results Patients had left ventricular ejection fraction between ≥30% and <50% or amino terminal fragment of pro-brain natriuretic peptide (NT-proBNP) >125 ng/L at screening. Twenty-eight patients were randomized to receive CDR132L (0.32, 1, 3, and 10 mg/kg body weight) or placebo (0.9% saline) in two intravenous infusions, 4 weeks apart in four cohorts of seven (five verum and two placebo) patients each. CDR132L was safe and well tolerated, without apparent dose-limiting toxicity. A pharmacokinetic/pharmacodynamic dose modelling approach suggested an effective dose level at ≥1 mg/kg CDR132L. CDR132L treatment resulted in a dose-dependent, sustained miR-132 reduction in plasma. Patients given CDR132L ≥1 mg/kg displayed a median 23.3% NT-proBNP reduction, vs. a 0.9% median increase in the control group. CDR132L treatment induced significant QRS narrowing and encouraging positive trends for relevant cardiac fibrosis biomarkers. Conclusion This study is the first clinical trial of an antisense drug in HF patients. CDR132L was safe and well tolerated, confirmed linear plasma pharmacokinetics with no signs of accumulation, and suggests cardiac functional improvements. Although this study is limited by the small patient numbers, the indicative efficacy of this drug is very encouraging justifying additional clinical studies to confirm the beneficial CDR132L pharmacodynamic effects for the treatment of HF. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Keywords: non-coding RNA; microRNAs; lncRNAs; cardiac regeneration and development; cardiovascular disease; circRNA EN non-coding RNA microRNAs lncRNAs cardiac regeneration and development cardiovascular disease circRNA 1 3 3 01/05/22 20220103 NES 220103 Introduction Cardiovascular diseases are the most common cause of death worldwide (Roth et al., [9]). Later, they focus on their role in the setting of cardiomyocyte biology, cardiovascular diseases, and a possible therapeutic potential in this field. The role of miRNAs in cardiac differentiation, cardiomyocyte proliferation, cardiac reprogramming, and cardiomyocyte survival is described in detail, since this class of ncRNAs was the first discovered and many studies have been conducted since then. Non-coding RNA, microRNAs, lncRNAs, cardiac regeneration and development, cardiovascular disease, circRNA. [Extracted from the article]

The article discusses the study "CDR132L Improves Systolic and Diastolic Function in a Large Animal Model of Chronic Heart Failure," by S. Batkai and colleagues, that was published within the issue. The study assessed the safety and efficacy of CDR132L, a synthetic lead-optimized oligonucleotide inhibitor of miR-132, in a porcine model of chronic heart failure triggered by closed chest balloon-induced myocardial infarction.

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The potential life-threatening consequences of catecholamine use for emergency circulatory support in Takotsubo cardiomyopathy-related acute heart failure is a major challenge in cardiovascular emergences. In their recent work in BMC Cardiovascular Disorders Ansari U. et al. demonstrated the harmful effects of catecholamines on the outcome of patients with Takotsubo cardiomyopathy. Concerning this matter we emphasize the usefulness of speckle-tracking-derived echocardiography for early recognition of an acute phase of a Takotsubo syndrome in order to avoid the deleterious effects of a catecholamine therapy in patients with Takotsubo-associated acute heart failure. [ABSTRACT FROM AUTHOR]

Under physiological circumstances, there is an exquisite balance between reactive oxygen species (ROS) production and ROS degradation, resulting in low steady-state ROS levels. ROS participate in normal cellular function and in cellular homeostasis. Oxidative stress is the state of a transient or a persistent increase of steady-state ROS levels leading to disturbed signaling pathways and oxidative modification of cellular constituents. It is a key pathophysiological player in pathological hypertrophy, pathological remodeling, and the development and progression of heart failure. The heart is the metabolically most active organ and is characterized by the highest content of mitochondria of any tissue. Mitochondria are the main source of ROS in the myocardium. The causal role of oxidative stress in heart failure is highlighted by gene transfer studies of three primary antioxidant enzymes, thioredoxin, and heme oxygenase-1, and is further supported by gene therapy studies directed at correcting oxidative stress linked to metabolic risk factors. Moreover, gene transfer studies have demonstrated that redox-sensitive microRNAs constitute potential therapeutic targets for the treatment of heart failure. In conclusion, gene therapy studies have provided strong corroborative evidence for a key role of oxidative stress in pathological remodeling and in the development of heart failure. [ABSTRACT FROM AUTHOR]