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Prof. Losano was born on July the 25th 1934, and he graduated in Medicine and Surgery on November 18th 1959. He started his university career in the early 60ties as “Assistente Volontario alla Cattedra di Fisiologia”. He was several times a Visiting Professor at the A.M. Dogliotti College of Medicine of the University of Liberia in Monrovia (Liberia), where he also served as Dean of the Medicine Faculty. In 1973 he was named full professor and he continued to work at Torino University until 2019 as Professor Emeritus.

During myocardial ischemia, timely reperfusion is critical to limit infarct area and the overall loss of cardiac contractile function. However, reperfusion further exacerbates the damage of the ischemic heart. This type of injury is known as ischemia-reperfusion injury (IRI). Ischemic conditioning is a procedure which consists of brief cycles of ischemia and reperfusion in order to protect the myocardium against IRI. Remote ischemic conditioning (RIC), namely transient brief episodes of ischemia at a remote site before a subsequent damaging ischemia/reperfusion procedure of the target organ (e.g., the heart), protects against IRI. However, how the stimulus of RIC is transduced from the remote organ to the ischemic heart is still unknown. Recently, extracellular vesicles (EVs) have been proposed to have a role in the RIC procedure. The endothelium releases EVs and is also one of the tissues mostly exposed to EVs during their journey to the target organ. Moreover, EVs may have important roles in angiogenesis and, therefore, in the remodeling of post-ischemic organs. Here we analyze how EVs may contribute to the overall cardioprotective effect and the implication of the endothelium and its EVs in RIC mediated acute cardioprotection as well as in angiogenesis.

Heart failure (HF) prevalence is increasing among the aging population, and the mortality rate remains unacceptably high despite improvements in therapy. Myocardial ischemia (MI) and, consequently, ischemia/reperfusion injury (IRI), are frequently the basis of HF development. Therefore, cardioprotective strategies to limit IRI are mandatory. Nanocarriers have been proposed as alternative therapy for cardiovascular disease. Controlled reoxygenation may be a promising strategy. Novel nanocarriers, such as cyclic nigerosyl-nigerose (CNN), can be innovative tools for oxygen delivery in a controlled manner. In this study we analyzed new CNN-based formulations as oxygen nanocarriers (O2-CNN), and compared them with nitrogen CNN (N2-CNN). These different CNN-based formulations were tested using two cellular models, namely, cardiomyoblasts (H9c2), and endothelial (HMEC) cell lines, at different concentrations. The effects on the growth curve during normoxia (21% O2, 5% CO2 and 74% N2) and their protective effects during hypoxia (1% O2, 5% CO2 and 94% N2) and reoxygenation (21% O2, 5% CO2 and 74% N2) were studied. Neither O2-CNN nor N2-CNN has any effect on the growth curve during normoxia. However, O2-CNN applied before hypoxia induces a 15–30% reduction in cell mortality after hypoxia/re-oxygenation when compared to N2-CNN. O2-CNN showed a marked efficacy in controlled oxygenation, which suggests an interesting potential for the future medical application of soluble nanocarrier systems for MI treatment.

In-depth characterization of heart-brain communication in critically ill patients with severe acute respiratory failure is attracting significant interest in the COronaVIrus Disease 19 (COVID-19) pandemic era during intensive care unit (ICU) stay and after ICU or hospital discharge. Emerging research has provided new insights into pathogenic role of the deregulation of the heart-brain axis (HBA), a bidirectional flow of information, in leading to severe multiorgan disease syndrome (MODS) in patients with confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Noteworthy, HBA dysfunction may worsen the outcome of the COVID-19 patients. In this review, we discuss the critical role HBA plays in both promoting and limiting MODS in COVID-19. We also highlight the role of HBA as new target for novel therapeutic strategies in COVID-19 in order to open new translational frontiers of care. This is a translational perspective from the Italian Society of Cardiovascular Researches., Graphical Abstract ga1

Ischemia–reperfusion injury (IRI) is one of the biggest challenges for cardiovascular researchers given the huge death toll caused by myocardial ischemic disease. Cardioprotective conditioning strategies, namely pre- and post-conditioning maneuvers, represent the most important strategies for stimulating pro-survival pathways essential to preserve cardiac health. Conditioning maneuvers have proved to be fundamental for the knowledge of the molecular basis of both IRI and cardioprotection. Among this evidence, the importance of signal transducer and activator of transcription 3 (STAT3) emerged. STAT3 is not only a transcription factor but also exhibits non-genomic pro-survival functions preserving mitochondrial function from IRI. Indeed, STAT3 is emerging as an influencer of mitochondrial function to explain the cardioprotection phenomena. Studying cardioprotection, STAT3 proved to be crucial as an element of the survivor activating factor enhancement (SAFE) pathway, which converges on mitochondria and influences their function by cross-talking with other cardioprotective pathways. Clearly there are still some functional properties of STAT3 to be discovered. Therefore, in this review, we highlight the evidence that places STAT3 as a promoter of the metabolic network. In particular, we focus on the possible interactions of STAT3 with processes aimed at maintaining mitochondrial functions, including the regulation of the electron transport chain, the production of reactive oxygen species, the homeostasis of Ca2+and the inhibition of opening of mitochondrial permeability transition pore. Then we consider the role of STAT3 and the parallels between STA3/STAT5 in cardioprotection by conditioning, giving emphasis to the human heart and confounders.

Extracellular vesicles (EV) are emerging early markers of myocardial damage and key mediators of cardioprotection. Therefore, EV are becoming fascinating tools to prevent cardiovascular disease and feasible weapons to limit ischaemia/reperfusion injury. It is well known that metabolic syndrome negatively affects vascular and endothelial function, thus creating predisposition to ischemic diseases. Additionally, sex is known to significantly impact myocardial injury and cardioprotection. Therefore, actions able to reduce risk factors related to comorbidities in ischaemic diseases are required to prevent maladaptive ventricular remodelling, preserve cardiac function, and prevent the onset of heart failure. This implies that early diagnosis and personalised medicine, also related to sex differences, are mandatory for primary or secondary prevention. Here, we report the contribution of EV as biomarkers and/or therapeutic tools in comorbidities predisposing to cardiac ischaemic disease. Whenever possible, attention is dedicated to data linking EV to sex differences.

Extracellular vesicles (EVs) are promising therapeutic tools in the treatment of cardiovascular disorders. We have recently shown that EVs from patients with Acute Coronary Syndrome (ACS) undergoing sham pre-conditioning, before percutaneous coronary intervention (PCI) were cardio-protective, while EVs from patients experiencing remote ischemic pre-conditioning (RIPC) failed to induce protection against ischemia/reperfusion Injury (IRI). No data on EVs from ACS patients recovered after PCI are currently available. Therefore, we herein investigated the cardio-protective properties of EVs, collected after PCI from the same patients. EVs recovered from 30 patients randomly assigned (1:1) to RIPC (EV-RIPC) or sham procedures (EV-naive) (NCT02195726) were characterized by TEM, FACS and Western blot analysis and evaluated for their mRNA content. The impact of EVs on hypoxia/reoxygenation damage and IRI, as well as the cardio-protective signaling pathways, were investigated in vitro (HMEC-1 + H9c2 co-culture) and ex vivo (isolated rat heart). Both EV-naive and EV-RIPC failed to drive cardio-protection both in vitro and ex vivo. Consistently, EV treatment failed to activate the canonical cardio-protective pathways. Specifically, PCI reduced the EV-naive Dusp6 mRNA content, found to be crucial for their cardio-protective action, and upregulated some stress- and cell-cycle-related genes in EV-RIPC. We provide the first evidence that in ACS patients, PCI reprograms the EV cargo, impairing EV-naive cardio-protective properties without improving EV-RIPC functional capability.

Ischemic Heart Disease (IHD) is a clinical condition characterized by insufficient blood flow to the cardiac tissue, and the consequent inappropriate oxygen and nutrients supply and metabolic waste removal in the heart. In the last decade a broad scientific literature has underlined the distinct mechanism of onset and the peculiar progress of IHD between female and male patients, highlighting the estrogenic hormonal setting as a key factor of these sex-dependent divergences. In particular, estrogen-activated cardioprotective pathways exert a pivotal role for the microvascular health, and their impairment, both physiologically and pathologically driven, predispose to vascular dysfunctions. Aim of this review is to summarize the current knowledge on the estrogen receptors localization and function in the cardiovascular system, particularly focusing on sex-dependent differences in microvascular vs macrovascular dysfunction and on the experimental models that allowed the researchers to reach the current findings and sketching the leading estrogen-mediated cardioprotective mechanisms.

The biological relevance of extracellular vesicles (EV) released in an ischemia/reperfusion setting is still unclear. We hypothesized that the inflammatory microenvironment prevents cardioprotection mediated by endothelial cell (EC)-derived extracellular vesicles. The effects of na&iuml, ve EC-derived EV (eEV) or eEV released in response to interleukin-3 (IL-3) (eEV-IL-3) were evaluated in cardiomyoblasts (H9c2) and rat hearts. In transwell assay, eEV protected the H9c2 exposed to hypoxia/reoxygenation (H/R) more efficiently than eEV-IL-3. Conversely, only eEV directly protected H9c2 cells to H/R-induced damage. Consistent with this latter observation, eEV, but not eEV-IL-3, exerted beneficial effects in the whole heart. Protein profiles of eEV and eEV-IL-3, established using label-free mass spectrometry, demonstrated that IL-3 drives changes in eEV-IL-3 protein cargo. Gene ontology analysis revealed that both eEV and eEV-IL-3 were equipped with full cardioprotective machinery, including the Nitric Oxide Signaling in the Cardiovascular System. eEV-IL-3 were also enriched in the endothelial-nitric oxide-synthase (eNOS)-antagonist caveolin-1 and proteins related to the inflammatory response. In vitro and ex vivo experiments demonstrated that a functional Mitogen-Activated Protein Kinase Kinase (MEK1/2)/eNOS/guanylyl-cyclase (GC) pathway is required for eEV-mediated cardioprotection. Consistently, eEV were found enriched in MEK1/2 and able to induce the expression of B-cell-lymphoma-2 (Bcl-2) and the phosphorylation of eNOS in vitro. We conclude that an inflammatory microenvironment containing IL-3 changes the eEV cargo and impairs eEV cardioprotective action.

Background Extracellular vesicles (EV) are recognized as carriers of relevant biological effects and have been identified as regulators of cell-to-cell communication contributing to several patho-physiological processes. These processes include angiogenesis/coagulation/tissue repair/inflammation. In ischemia/reperfusion (I/R) settings, along with the direct effects of the I/R itself, paracrine mechanisms associated with the activation of the inflammatory response, primary involving endothelial cells, are crucial drivers of both vessel and cardiomyocyte damage. Purpose Since in models of myocardial I/R injury the role of EV released from endothelial cells is still unclear, our hypothesis was to provide insight on this specific topic. To this end, naïve endothelial cell (EC)-derived EV (eEV) and eEV released in response to the pro-inflammatory cytokine interleukin-3 (IL-3) (eEV-IL-3) have been evaluated on different I/R models. Methods eEV were characterized by MACSPlex-Exosome-Kit and western blot analysis. For the in-vitro hypoxia-reoxygenation (H/R) experiments, H9c2 or EC were pretreated with eEV, eEV-IL-3 (1x104 EV/cell) or IL-3 (10ng/ml) for 2 hours and then exposed to hypoxia (1% O2, 5% CO2) for additional 2 hours in the presence of eEV, eEV-IL-3 or IL-3 and subsequently reoxygenated (21% O2 and 5% CO2) for 1 hour. To verify the effect of EC treated with eEV, eEV-IL-3 or IL-3 on H9c2 and subjected to H/R protocol, transwell assay was used. At the end of the H/R protocol, cell viability was assessed. For ex-vivo experiments, isolated rat hearts, pretreated with a buffer containing EV (from EC pretreated or not with IL-3), were subjected to 30 minutes global normothermic ischemia and 1 hour reperfusion. Triton infusion was also used as a model of endothelial damage. At the end of I/R, the infarct size was measured and expressed as a percentage of total left ventricular mass (LVM). The role of eNOS/guanylyl-cyclase/MEK1/2 pathways in mediating eEV biological effects was also evaluated using different inhibitors both in in-vitro and ex-vivo models. Finally, protein profiles of eEV and eEV-IL-3 were analyzed using label free mass spectrometry. Results eEV and eEV-IL-3 protect EC, but not H9c2 exposed to H/R protocol, while eEV, but not eEV-IL-3-treatment limits I/R injury in the rat heart. Rat hearts pre-treated with triton significantly avoid eEV-induced cardio-protection. Transwell assay showed a reduction of H9C2 mortality after treatment with both eEV and eEV-IL-3. Proteomic analysis revealed that MEK1/2 and the endothelial-NOS (eNOS)-antagonist caveolin-1 were differentially expressed in eEV and eEV-IL-3. The use of eNOS/guanylyl-cyclase/MEK1/2 inhibitors prevented eEV-induced cardio-protection. Conclusions These observations indicate that eEV, but not eEV-IL-3, have cardio-protective effects when given as preconditioning agents. We have also shown that the activation of eNOS/GC/MEK1/2 pathway is crucial for eEV-mediated cardio-protection. Funding Acknowledgement Type of funding source: None

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells following binding with the cell surface ACE2 receptors, thereby leading to coronavirus disease 2019 (COVID-19). SARS-CoV-2 causes viral pneumonia with additional extrapulmonary manifestations and major complications, including acute myocardial injury, arrhythmia, and shock mainly in elderly patients. Furthermore, patients with existing cardiovascular comorbidities, such as hypertension and coronary heart disease, have a worse clinical outcome following contraction of the viral illness. A striking feature of COVID-19 pandemics is the high incidence of fatalities in advanced aged patients: this might be due to the prevalence of frailty and cardiovascular disease increase with age due to endothelial dysfunction and loss of endogenous cardioprotective mechanisms. Although experimental evidence on this topic is still at its infancy, the aim of this position paper is to hypothesize and discuss more suggestive cellular and molecular mechanisms whereby SARS-CoV-2 may lead to detrimental consequences to the cardiovascular system. We will focus on aging, cytokine storm, NLRP3/inflammasome, hypoxemia, and air pollution, which is an emerging cardiovascular risk factor associated with rapid urbanization and globalization. We will finally discuss the impact of clinically available CV drugs on the clinical course of COVID-19 patients. Understanding the role played by SARS-CoV2 on the CV system is indeed mandatory to get further insights into COVID-19 pathogenesis and to design a therapeutic strategy of cardio-protection for frail patients.

Acute myocardial infarction causes lethal injury to cardiomyocytes during both ischaemia and reperfusion (IR). It is important to define the precise mechanisms by which they die in order to develop strategies to protect the heart from IR injury. Necrosis is known to play a major role in myocardial IR injury. There is also evidence for significant myocardial death by other pathways such as apoptosis, although this has been challenged. Mitochondria play a central role in both of these pathways of cell death, as either a causal mechanism is the case of mitochondrial permeability transition leading to necrosis, or as part of the signalling pathway in mitochondrial cytochrome c release and apoptosis. Autophagy may impact this process by removing dysfunctional proteins or even entire mitochondria through a process called mitophagy. More recently, roles for other programmed mechanisms of cell death such as necroptosis and pyroptosis have been described, and inhibitors of these pathways have been shown to be cardioprotective. In this review, we discuss both mitochondrial and mitochondrial‐independent pathways of the major modes of cell death, their role in IR injury and their potential to be targeted as part of a cardioprotective strategy. This article is part of a special Issue entitled ‘Mitochondria as targets of acute cardioprotection’ and emerged as part of the discussions of the European Union (EU)‐CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

In the last few decades extracellular vesicles (EVs), which include exosomes and microvesicles, have attracted significant interest in cardiovascular pathophysiology due to their intrinsic properties. Indeed, EVs by transferring their cargo, which contains miRNA, DNA, proteins and lipids, were found effective in preventive and regenerative medicine and in protecting the heart against an array of pathological conditions, including myocardial infarction and arrhythmias. EVs can attenuate cellular senescence, inflammation and myocardial injury. Cardiovascular structures may be targeted by circulating EVs derived by extra-cardiac cells and platelets, as well by EVs locally released from all major cardiovascular cell types, including endothelial cells, cardiomyocytes, macrophages and fibroblasts. Yet, EVs of cardiovascular origin can be also transferred to distant tissues by circulation. Therefore, EVs have been proposed not only as promising diagnostic tools (early disease biomarkers), but also as therapeutics. This review focuses on the protective effects exerted by EVs, released by different cell types in the cardiovascular system. Physical exercise is considered as a natural mechanism of EV production involved in preventive medicine. Particular attention will be devoted to describe the impact of EVs in cardioprotection after ischemia/reperfusion injury.

Metabolic syndrome, diabetes, and ischemic heart disease are among the leading causes of death and disability in Western countries. Diabetic cardiomyopathy is responsible for the most severe signs and symptoms. An important strategy for reducing the incidence of cardiovascular disease is regular exercise. Remote ischemic conditioning has some similarity with exercise and can be induced by short periods of ischemia and reperfusion of a limb, and it can be performed in people who cannot exercise. There is abundant evidence that exercise is beneficial in diabetes and ischemic heart disease, but there is a need to elucidate the specific cardiovascular effects of emerging and unconventional forms of exercise in people with diabetes. In addition, remote ischemic conditioning may be considered among the options to induce beneficial effects in these patients. The characteristics and interactions of diabetes and ischemic heart disease, and the known effects of exercise and remote ischemic conditioning in the presence of metabolic syndrome and diabetes, are analyzed in this brief review.

Background Hypertension is a multifactorial and chronic cardiovascular condition whose complications are responsible for worldwide morbidity and mortality. An increasing body of experimental data, recognize low-grade inflammation as a basic process in hypertension onset and development since there is a strong contribution of both the innate and the adaptive immune system according to the so-called Danger-Model. In this contest, NLRP3 inflammasome represents a key signaling platform as demonstrated by its implication in several hypertension-associated conditions, such as vascular smooth muscle remodeling and proliferation. This intracellular receptor is activated by Pathogenassociated molecular pattern molecules/damage-associated molecular pattern molecules signals and its mechanism of action converges on the final production of caspase-1 and, consequently, of the proinflammatory cytokines IL-1β and IL-18. Objective The aim of the present work was to point out the role of the NLRP3 inflammasome complex in the hypertensive pathology and to describe it as a new potential therapeutic target. Method A systematic review of the literature data related to NLRP3 and hypertension correlation has been performed. Results Numerous and well-designed experiments demonstrate that the inflammasome plays a crucial role in essential and high-salt dependent hypertension, as well as in preeclampsia, in pulmonary hypertension, and in its related secondary disorders; its mechanism includes both a central nervous and a peripheral modulation of the inflammatory pathways. To date, research is trying to design inflammasome antagonists or equivalent inhibition strategies. Conclusion The inflammasome represents a leading promoter of hypertensive inflammation opening new perspective in the field of the clinical approach in this pathology.

Aim: To assess functional effects of silica nanoparticles (SiO2-NPs) on human mesenchymal stem cell (hMSC) cardiac integration potential. Methods: SiO2-NPs were synthesized and their internalization effects on hMSCs analyzed with particular emphasis on interaction of hMSCs with the cardiac environment Results: SiO2-NP internalization affected the area and maturation level of hMSC focal adhesions, accounting for increased in vitro adhesion capacity and augmented engraftment in the myocardial tissue upon cell injection in infarcted isolated rat hearts. SiO2-NP treatment also enhanced hMSC expression of Connexin-43, favoring hMSC interaction with cocultured cardiac myoblasts in an ischemia-like environment. Conclusion: These findings provide strong evidence that SiO2-NPs actively engage in mediating biological effects, ultimately resulting in augmented hMSC acute cardiac integration potential.

International audience; Catestatin (CST), a fragment of Chromogranin-A, exerts angiogenic, arteriogenic, vasculogenic and cardioprotective effects. CST is a very promising agent for revascularization purposes, in "NOOPTION" patients. However, peptides have a very short half-life after administration and must be conveniently protected. Fibronectin-coated pharmacologically active microcarriers (FN-PAM), are biodegradable and biocompatible polymeric microspheres that can convey mesenchymal stem cell (MSCs) and therapeutic proteins delivered in a prolonged manner. In this study, we first evaluated whether a small peptide such as CST could be nanoprecipitated and incorporated within FN-PAMs. Subsequently, whether CST may be released in a prolonged manner by functionalized FN-PAMs (FN-PAM-CST). Finally, we assessed the effect of CST released by FN-PAM-CST on the survival of MSCs under stress conditions of hypoxia-reoxygenation. An experimental design, modifying three key parameters (ionic strength, mixing and centrifugation time) of protein nanoprecipitation, was used to define the optimum condition for CST. An optimal nanoprecipitation yield of 76% was obtained allowing encapsulation of solid CST within FN-PAM-CST, which released CST in a prolonged manner. In vitro, MSCs adhered to FN-PAMs, and the controlled release of CST from FN-PAM-CST greatly limited hypoxic MSC-death and enhanced MSC-survival in post-hypoxic environment. These results suggest that FN-PAM-CST are promising tools for cell-therapy.

Background Neuregulin1 (Nrg1) and its receptors ErbB are crucial for heart development and for adult heart structural maintenance and function and Nrg1 has been proposed for heart failure treatment. Infarct size is the major determinant of heart failure and the mechanism of action and the role of each ErbB receptor remain obscure, especially in the post-ischemic myocardium. We hypothesized that Nrg1 and ErbB are affected at transcriptional level early after ischemia/reperfusion (I/R) injury, and that the protective postconditioning procedure (PostC, brief cycles of ischemia/reperfusion carried out after a sustained ischemia) can influence this pathway. Methods and results The Langendorff's heart was used as an ex-vivo model to mimic an I/R injury in the whole rat heart; after 30min of ischemia and 2h of reperfusion, with or without PostC, Nrg1 and ErbB expression were analysed by quantitative real-time PCR and Western blot. While no changes occur for ErbB2, ErbB4 and Nrg1, an increase of ErbB3 expression occurs after I/R injury, with and without PostC. However, I/R reduces ErbB3 protein, whereas PostC preserves it. An in vitro analysis with H9c2 cells exposed to redox-stress indicated that the transient over-expression of ErbB3 alone is able to increase cell survival (MTT assay), limiting mitochondrial dysfunction (JC-1 probe) and apoptotic signals (Bax/Bcl-2 ratio). Conclusions This study suggests ErbB3 as a protective factor against death pathways activated by redox stress and supports an involvement of this receptor in the pro-survival responses.

The protection from ischaemia‐reperfusion‐associated myocardial infarction worsening remains a big challenge. We produced a bioartificial 3D cardiac patch with cardioinductive properties on stem cells. Its multilayer structure was functionalised with clinically relevant doses of adenosine. We report here the first study on the potential of these cardiac patches in the controlled delivery of adenosine into the in vivo ischaemic‐reperfused pig heart. A Fourier transform infrared chemical imaging approach allowed us to perform a characterisation, complementary to the histological and biochemical analyses on myocardial samples after in vivo patch implantation, increasing the number of investigations and results on the restricted number of pigs (n = 4) employed in this feasibility step. In vitro tests suggested that adenosine was completely released by a functionalised patch, a data that was confirmed in vivo after 24 hr from patch implantation. Moreover, the adenosine‐loaded patch enabled a targeted delivery of the drug to the ischaemic‐reperfused area of the heart, as highlighted by the activation of the pro‐survival signalling reperfusion injury salvage kinases pathway. At 3 months, though limited to one animal, the used methods provided a picture of a tissue in dynamic conditions, associated to the biosynthesis of new collagen and to a non‐fibrotic outcome of the healing process underway. The synergistic effect between the functionalised 3D cardiac patch and adenosine cardioprotection might represent a promising innovation in the treatment of reperfusion injury. As this is a feasibility study, the clinical implications of our findings will require further in vivo investigation on larger numbers of ischaemic‐reperfused pig hearts.

Metaboreflex is a reflex triggered during exercise or postexercise muscle ischemia (PEMI) by metaboreceptor stimulation. Typical features of metaboreflex are increased cardiac output (CO) and blood pressure. Patients suffering from metabolic syndrome display hemodynamic abnormalities, with an exaggerated systemic vascular resistance (SVR) and reduced CO response during PEMI-induced metaboreflex. Whether patients with type 2 diabetes mellitus (DM2) have similar hemodynamic abnormalities is unknown. Here we contrast the hemodynamic response to PEMI in 14 patients suffering from DM2 (age 62.7 ± 8.3 yr) and in 15 age-matched controls (CTLs). All participants underwent a control exercise recovery reference test and a PEMI test to obtain the metaboreflex response. Central hemodynamics were evaluated by unbiased operator-independent impedance cardiography. Although the blood pressure response to PEMI was not significantly different between the groups, we found that the SVR and CO responses were reversed in patients with DM2 as compared with the CTLs (SVR: 392.5 ± 549.6 and −14.8 ± 258.9 dyn·s−1·cm−5; CO: −0.25 ± 0.63 and 0.46 ± 0.50 l/m, respectively, in DM2 and in CTL groups, respectively; P < 0.05 for both). Of note, stroke volume (SV) increased during PEMI in the CTL group only. Failure to increase SV and CO was the consequence of reduced venous return, impaired cardiac performance, and augmented afterload in patients with DM2. We conclude that patients with DM2 have an exaggerated vasoconstriction in response to metaboreflex activation not accompanied by a concomitant increase in heart performance. Therefore, in these patients, blood pressure response to the metaboreflex relies more on SVR increases rather than on increases in SV and CO. NEW & NOTEWORTHY The main new finding of the present investigation is that subjects with type 2 diabetes mellitus have an exaggerated vasoconstriction in response to metaboreflex activation. In these patients, blood pressure response to the metaboreflex relies more on systemic vascular resistance than on cardiac output increments.

Pulmonary vascular damage is a rare but possible complication of treatment with chemotherapeutic agents or bone marrow transplantation. The main clinical manifestations involving the pulmonary vessels are the development of pulmonary arterial hypertension or pulmonary veno-occlusive disease. In this chapter we describe the main mechanisms underlying the development of this form of toxicity, the screening algorithm, and its clinical management.

During an ST-elevation myocardial infarction (STEMI), the myocardium undergoes a prolonged period of ischaemia. Reperfusion therapy is essential to minimize cardiac injury but can paradoxically cause further damage. Experimental procedures to limit ischaemia and reperfusion (IR) injury have tended to focus on the cardiomyocytes since they are crucial for cardiac function. However, there is increasing evidence that non-cardiomyocyte resident cells in the heart (as discussed in a separate review in this Spotlight series) as well as circulating cells and factors play important roles in this pathology. For example, erythrocytes, in addition to their main oxygen-ferrying role, can protect the heart from IR injury via the export of nitric oxide bioactivity. Platelets are well-known to be involved in haemostasis and thrombosis, but beyond these roles, they secrete numerous factors including sphingosine-1 phosphate (S1P), platelet activating factor, and cytokines that can all strongly influence the development of IR injury. This is particularly relevant given that most STEMI patients receive at least one type of platelet inhibitor. Moreover, there are large numbers of circulating vesicles in the blood, including microvesicles and exosomes, which can exert both beneficial and detrimental effects on IR injury. Some of these effects are mediated by the transfer of microRNA (miRNA) to the heart. Synthetic miRNA molecules may offer an alternative approach to limiting the response to IR injury. We discuss these and other circulating factors, focussing on potential therapeutic targets relevant to IR injury. Given the prevalence of comorbidities such as diabetes in the target patient population, their influence will also be discussed. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

Despite advances in supportive and protective therapy for myocardial function, heart failure caused by various clinical conditions, including cardiomyopathy due to antineoplastic therapy, remains a major cause of morbidity and mortality. Because of the limitations associated with current therapies, investigators have been searching for alternative treatments that can effectively repair the damaged heart and permanently restore its function. Damage to the heart can result from both traditional chemotherapeutic agents, such as anthracyclines, and new targeted therapies, such as trastuzumab. Because of this unresolved issue, investigators are searching for alternative therapeutic strategies. In this article, we present state-of-the-art technology with regard to the genomic and epigenetic mechanisms underlying cardiotoxicity and cardioprotection, the role of anticancer in influencing the redox (reduction/oxidation) balance and the function of stem cells in the repair/regeneration of the adult heart. These findings, although not immediately transferable to clinical applications, form the basis for the development of personalized medicine based on the prevention of cardiotoxicity with the use of genetic testing. Proteomics, metabolomics and investigations on reactive oxygen species-dependent pathways, particularly those that interact with the production of NO and energy metabolism, appear to be promising for the identification of early markers of cardiotoxicity and for the development of cardioprotective agents. Finally, autologous cardiac stem and progenitor cells may represent future contributions in the field of myocardial protection and recovery in the context of antiblastic therapy.

COVID-19 (coronavirus disease 2019) pandemic due to infection with SARS-CoV-2 has led to the death of thousands of adults worldwide. It is now clear that the hyper-inflammatory response triggered by SARS-CoV-2 plays a major role in disease severity and lethality of the infection. Macrophages are innate immune cells that sense and respond to infections by producing a plethora of inflammatory molecules and by interacting with other inflammatory cells. Therefore, macrophages may be diriment on eliminating pathogens and promoting organ repair. However, macrophages can be a major player of the so called cytokine storm and may be damaging to the tissues. It is believed that macrophage activation syndrome is induced by SARS-CoV to be lethal. Surprisingly and fortunately few children die from COVID-19. For instance, in Italy, out of more than 30.000 deaths for COVID-19, three are children. Therefore, we must wonder why? Are macrophages different in children compared to adults? In my opinion they are different. It has been demonstrated that macrophages populate the lung in three "developmental waves", and it has been suggested that similar waves may be observed in other important organs, such as the heart and kidney. It is most likely that macrophages heterogeneity is involved in determining the severity. There are no doubts that macrophages are important in determining life or death in these patients. Comparing macrophages of children with those of adults with different degrees of disease severity is, therefore, mandatory.

Acute obstruction of a coronary artery causes myocardial ischaemia and if prolonged, may result in an ST-segment elevation myocardial infarction (STEMI). First-line treatment involves rapid reperfusion. However, a highly dynamic and co-ordinated inflammatory response is rapidly mounted to repair and remove the injured cells which, paradoxically, can further exacerbate myocardial injury. Furthermore, although cardiac remodelling may initially preserve some function to the heart, it can lead over time to adverse remodelling and eventually heart failure. Since the size of the infarct corresponds to the subsequent risk of developing heart failure, it is important to find ways to limit initial infarct development. In this review, we focus on the role of the innate immune system in the acute response to ischaemia-reperfusion (IR) and specifically its contribution to cell death and myocardial infarction. Numerous danger-associated molecular patterns are released from dying cells in the myocardium, which can stimulate pattern recognition receptors including toll like receptors and NOD-like receptors (NLRs) in resident cardiac and immune cells. Activation of the NLRP3 inflammasome, caspase 1, and pyroptosis may ensue, particularly when the myocardium has been previously aggravated by the presence of comorbidities. Evidence will be discussed that suggests agents targeting innate immunity may be a promising means of protecting the hearts of STEMI patients against acute IR injury. However, the dosing and timing of such agents should be carefully determined because innate immunity pathways may also be involved in cardioprotection. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

The role of ROS/RNS signaling in cardiovascular functions and diseases is increasingly emerging in the last decades. The involvement of ROS/RNS in the control of a large number of cardiovascular functions like the regulation of the vascular tone, the control of blood pressure or myocyte excitation-contraction coupling and force development has been broadly investigated and in part clarified. On the other hand, many efforts have been focused in clarifying the redox mechanisms involved in cardiovascular diseases like ischemia/reperfusion injury, diabetes-associated cardiovascular dysfunctions, atherosclerosis or hypertension, just to mention the major ones. However, in most cases the two levels of investigation remain separate and not interlaced, failing in the attempt to provide a unified vision of the pathophysiologic mechanisms of cardiovascular diseases. The major aim of the Research Topic has been to collect original papers and review articles dealing with the issue from basic to translation research point of views. The topic includes contributions that highlight different interesting aspects of cardiovascular biology with an integrated approach useful for the development of new ideas and advancements in the field of redox signaling in the control of normal cardiovascular functions and their disruption in diseases.

Mitochondria play a pivotal role in cardioprotection. Here we report some fundamental studies which considered the role of mitochondrial components (connexin 43, mitochondrial KATP channels and mitochondrial permeability transition pore) in postconditioning cardioprotection. We briefly discuss the role of mitochondria, reactive oxygen species and gaseous molecules in postconditioning. Also the effects of anesthetics - used as cardioprotective substances - is briefly considered in the context of postconditioning. The role of mitochondrial postconditioning signaling in determining the limitation of cell death is underpinned. Issues in clinical translation are briefly considered. The aim of the present mini-review is to discuss in a historical perspective the role of main mitochondria mechanisms in cardiac postconditioning.

The incidence of obesity and diabetes is increasing rapidly worldwide. Obesity and metabolic syndrome are strictly linked and represent the basis of different cardiovascular risk factors, including hypertension and inflammatory processes predisposing to ischemic heart disease, which represent the most common causes of heart failure. Recent advances in the understanding of ischemia/reperfusion mechanisms of injury and mechanisms of cardioprotection are briefly considered. Resistance to cardioprotection may be correlated with the severity of obesity. The observation that heart failure obese patients have a better clinical condition than lean heart failure patients is known as “obesity paradox”. It seems that obese patients with heart failure are younger, making age the most important confounder in some studies. Critical issues are represented by the "obesity paradox” and heart failure exacerbation by inflammation. For heart failure exacerbation by inflammation, an important role is played by NLRP3 inflammasome, which is emerging as a possible target for heart failure condition. These critical issues in the field of obesity and cardiovascular diseases need more studies to ascertain which metabolic alterations are crucial for alleged beneficial and deleterious effects of obesity.

Molecular chaperones are stress proteins that allow the correct folding or unfolding as well as the assembly or disassembly of macromolecular cellular components. Changes in expression and post-translational modifications of chaperones have been linked to a number of age- and stress-related diseases including cancer, neurodegeneration, and cardiovascular diseases. Redox sensible post-translational modifications, such as S-nitrosylation, glutathionylation and phosphorylation of chaperone proteins have been reported. Redox-dependent regulation of chaperones is likely to be a phenomenon involved in metabolic processes and may represent an adaptive response to several stress conditions, especially within mitochondria, where it impacts cellular bioenergetics. These post-translational modifications might underlie the mechanisms leading to cardioprotection by conditioning maneuvers as well as to ischemia/reperfusion injury. In this review, we discuss this topic and focus on two important aspects of redox-regulated chaperones, namely redox regulation of mitochondrial chaperone function and cardiac protection against ischemia/reperfusion injury.

Traditional chemotherapeutics are essential tools in the management of cancer patients. Nevertheless, these drugs are burdened by some degree of cardiovascular toxicity. Anthracycline-induced toxicity has been historically the most studied, but also the use of other drugs can be limited by a certain risk of cardiac and vascular toxicities. Here we acknowledge the main mechanistic insights, and we describe the different aspects of cardiotoxicity of these drugs, highlighting the different cellular compartments and cardiovascular components affected.