Search

Purpose: This paper aims to present a unique perspective that emphasizes the intricate interplay between energy, dietary proteins, and amino acid composition, underscoring their mutual dependence for health-related considerations. Energy and protein synthesis are fundamental to biological processes, crucial for the sustenance of life and the growth of organisms., Methods and Results: We explore the intricate relationship between energy metabolism, protein synthesis, regulatory mechanisms, protein sources, amino acid availability, and autophagy in order to elucidate how these elements collectively maintain cellular homeostasis. We underscore the vital role this dynamic interplay has in preserving cell life., Conclusions: A deeper understanding of the link between energy and protein synthesis is essential to comprehend fundamental cellular processes. This insight could have a wide-ranging impact in several medical fields, such as nutrition, metabolism, and disease management.

Background: Many patients who have been suffering by Covid-19 suffer of long-Covid syndrome, with symptoms of fatigue and muscular weakness that characterize post-acute sequelae SARS-CoV-2 infection (PASC). However, there is limited knowledge about the molecular pathophysiology, and about the serum profile of these patients. Methods: We studied the blood serum profile of 75 selected patients, with previous confirmed Covid-19, 2 months after hospital discharge, who reported new-onset fatigue, muscle weakness and/or dyspnea not present prior to the virus infection and independently from concomitant diseases and/or clinical conditions. Results: All patients had very high serum concentrations of ferritin and D-Dimer. 87 and 72% of patients had clinically significant low levels of hemoglobin and albumin, respectively. Seventy three percentage had elevations in erythrocyte sedimentation rate and CRP. Twenty seven percentage had elevations in LDH. Conclusions: The co-existence of patient symptoms along with blood markers of coagulation, protein disarrangement and inflammation suggests ongoing alterations in the metabolism, promoting an inflammatory/hypercatabolic state which maintains a vicious circles implicated in the persistence of PASC. The persistence of altered D-Dimer levels raises the possibility of long-term risks of thromboembolic disease. All these markers levels should be accurately evaluated in the long-term follow-up, with individualized consideration for prophylactic nutritional, anti-inflammatory and/or anticoagulant therapy if indicated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pasini, Corsetti, Romano, Scarabelli, Chen-Scarabelli, Saravolatz and Dioguardi.)

Chronic heart failure (CHF) is a disease with important clinical and socio-economic ramifications. Malnutrition and severe alteration of the protein components of the body (protein disarrangements), common conditions in CHF patients, are independent correlates of heart dysfunction, disease progression, and mortality. Autophagy, a prominent occurrence in the heart of patients with advanced CHF, is a self-digestive process that prolongs myocardial cell lifespan by the removal of cytosolic components, such as aging organelles and proteins, and recycles the constituent elements for new protein synthesis. However, in specific conditions, excessive activation of autophagy can lead to the destruction of molecules and organelles essential to cell survival, ultimately leading to organ failure and patient death. In this review, we aim to describe the experimental and clinical evidence supporting a pathophysiological role of nutrition and autophagy in the progression of CHF. The understanding of the mechanisms underlying the interplay between nutrition and autophagy may have important clinical implications by providing molecular targets for innovative therapeutic strategies in CHF patients.

BACKGROUND In humans, wood dust is a carcinogen. Indeed, a strong association between wood dust and lung cancer risk has been reported in woodworkers, as well as in the general population. CASE REPORT The patient was a 58-year-old man with follicular B-cell lymphoma. In the 10 years preceding the cancer diagnosis, he lived within 1/4 mile of a paper mill, where wood was processed. Computed tomography of the chest, abdomen, and pelvis revealed right hilar, mediastinal, abdominal, and retroperitoneal lymphadenopathy, bilateral pleural effusions, and a large soft-tissue mass infiltrating the small bowel mesentery. Analysis of the pleural fluid revealed the presence of a web of thin filopodia-like filaments, which trapped clusters of mesothelial cells and atypical lymphocytes. Single tubular filaments, morphologically similar to tunneling nanotubes, were seen originating from atypical lymphocytes and reaching neighboring cells. Furthermore, long, thick, cylindrical fibers of unknown nature, probably from the external environment, were also observed. CONCLUSIONS Because the patient lived in an unhealthy environment for many years, the possibility that his clinical condition was related to exposure to toxic emissions should be entertained. Considered in this context, the foreign fibers in his pleural fluid could be a direct consequence of inhalation of contaminants in the polluted air.

BACKGROUND Urocortin (Ucn) is a member of the hypothalamic corticotrophin-releasing factor family and has been shown to reduce cell death in the heart caused by ischemia/reperfusion (I/R) injury. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor known to function as a pro-survival and anti-apoptotic factor, whose activation depends on a variety of cytokines, including IL-6. A recent study demonstrated that urocortin induced IL-6 release from cardiomyocytes in a CRF-R2-dependent manner, suggesting a possible link between CRF-R2 stimulation and STAT3 activation. MATERIAL AND METHODS Experimental work was carried out in HL-1 cardiac myocytes exposed to serum starvation for 16-24 h. RESULTS Ucn stimulation led to IL-6 expression and release from mouse atrial HL-1 cardiomyocytes. Ucn treatment led to rapid phosphorylation of JAK2, which was blocked by the protein synthesis inhibitor cycloheximide or the JAK inhibitor AG490. Urocortin treatment induced STAT3 phosphorylation at Y705 and S727 through transactivation of JAK2 in an IL-6-dependent manner, but had no effect on STAT1 activity. Kinase inhibition experiments revealed that urocortin induces STAT3 S727 phosphorylation through ERK1/2 and Y705 phosphorylation through Src tyrosine kinase. In line with this finding, urocortin failed to induce phosphorylation of Y705 residue in SYF cells bearing null mutation of Src, while phosphorylation of S727 residue was unchanged. CONCLUSIONS Here, we have shown that Ucn induces activation of STAT3 through diverging signaling pathways. Full understanding of these signaling pathways will help fully exploit the cardioprotective properties of endogenous and exogenous Ucn.

BACKGROUND Although originally described as a survival mechanism, it is unknown whether and to what extent autophagy is implicated in the terminal stages of heart failure. Here, we studied magnitude and evolution of autophagy in patients with intractable heart failure. MATERIAL AND METHODS Myocardial samples were obtained from 22 patients with ischemic cardiomyopathy and idiopathic dilated cardiomyopathy who were undergoing cardiac transplantation. Hearts from 11 patients who died from non-cardiac causes were used as control samples. Autophagy was evaluated by immunostaining with a monoclonal microtubule associated protein light chain 3 (LC3)-II antibody, while the relationship of autophagy with apoptosis and oncosis was assessed by double staining with TUNEL (terminal deoxynucleotidyl transferase - mediated deoxyuridine triphosphate nick end labeling) assay and complement 9 (C9) immunological staining, respectively. In addition, several necroptotic markers, including RIP1 and RIP3 (receptor interacting protein kinase 1 and 3), anti-C3 (cleaved-caspase-3), and anti-NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) were assessed by immunohistochemistry. RESULTS Anti-LC3-II staining was detected in 8.7±1.6% of the heart failure patient heart samples and in 1.2±0.3% of control patient heart samples. Vacuole formation started at one nuclear pole, before becoming bipolar and involving the cytosol. Subsequently, the autophagic process extended also to the nuclei, which underwent a progressive vacuolization and disintegration, assuming a peculiar "strawberry like appearance". Myocytes with extensive vacuole formation exhibited nuclear degeneration, which was associated with TUNEL, C3, C9, RIP1, and RIP3 positive staining. Conversely, myocytes with less extensive vacuole formation showed RIP1 and NF-κB positive staining, though not positivity for other cell death markers. CONCLUSIONS Autophagy was extensively detected in end-stage heart failure and its progression, resulted in secondary cell death, with occurrence of oncosis and necroptosis exceeding that of apoptosis. Conversely, activation of the RIP1/NF-κB pathway was associated with cell survival.

Background: Carfilzomib (CFZ) is a new proteasome inhibitor used for the treatment of multiple myeloma. Besides heart failure, angina and myocardial ischemia occurred following administration of CFZ, which is not contraindicated in patients with recent myocardial infarction/unstable angina excluded from the safety trials., Aim of Study: To test the effects of CFZ (10 -9 to 10 -7 mol/L) on vascular tone and reactivity in the isolated rabbit heart and aorta., Methods and Results: CFZ administered by bolus injection to the isolated heart increased coronary perfusion pressure (CPP) at all tested concentrations and mildly raised left ventricular pressure and heart rate, only at the highest concentration. Addition of CFZ directly into the organ bath increased the basal tone of isolated aortic strips with contraction plateau reached after 10min. This spasmogenic effect doubled following ablation of the endothelium. Pretreatment with CFZ amplified the vasospastic action exerted by KCl, noradrenaline (NA) and angiotensin II (A) on aortic strips, and impaired vasodilation following administration of nitroglycerin (NTG) and nifedipine (NFP) on the contraction plateau induced by KCl, NA and A. Aortic strips pretreated with CFZ exhibited impaired relaxation, as compared to untreated strips, following administration of acetylcholine (Ach), an endothelium-dependent vasodilating agent, on the plateau of NA contraction (p<0.05)., Conclusions: CFZ increased CPP, resting vasoconstricting tone and the spasmogenic effect of different agents. Preincubation with CFZ decreased the anti-spasmogenic activity of NTG and NFP, as well as reduced by over 50% the vasodilating effect of Ach, suggesting that CFZ can impair vasodilation via an endothelium dependent mechanism. Further studies are warranted to establish its clinical safety in patients with known CAD and prior history of coronary spasm., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Cancer and cardiovascular disease are the two leading causes of mortality worldwide. Evolving oncologic therapy, including the use of newer targeted agents, has led to an improvement in survival from childhood- and adult-onset cancers. Consequently, there has been a growing realization of cardiotoxic complications related to cancer therapy, with some complications manifesting over months to decades after completion of cancer treatment. This paper reviews cancer therapeutics-related cardiovascular toxicity and its manifestations, multimodality imaging techniques for surveillance and detection of this complication, and the current state of knowledge in this emerging field.

Background: Klotho proteins (α- and β) are membrane-based circulating proteins that regulate cell metabolism, as well as the lifespan modulating activity of Fibroblast Growth Factors (FGFs). Recent data has shown that higher plasma circulating Klotho levels reduce cardiovascular risk, suggesting Klotho has a protective role in cardiovascular diseases. However, although so far it has been identified in various organs, it is unknown whether cardiomyocytes express Klotho and FGFs, and whether high cardiovascular risk could affect cardiac expression of Klotho, FGFs and other molecules., Methods: We selected 20 patients with an estimated 10-year high atherosclerotic cardiovascular disease and 10 age-matched control subjects with an estimated 10-year low risk undergone cardiac surgery for reasons other than coronary artery by-pass. In myocardial biopsies, we evaluated by immuno-histochemistry whether Klotho and FGFs were expressed in cardiomyocytes, and whether higher cardiovascular risk influenced the expression of other molecules involved in endoplasmic reticulum stress, oxidative stress, inflammation and fibrosis., Results: Only cardiomyocytes of patients with a higher cardiovascular risk showed lower expression of Klotho, but higher expressions of FGFs. Furthermore, higher cardiovascular risk was associated with increased expression of oxidative and endoplasmic reticular stress, inflammation and fibrosis., Conclusions: This study showed for the first time that Klotho proteins are expressed in human cardiomyocytes and that cardiac expression of Klotho is down-regulated in higher cardiovascular risk patients, while expression of stress-related molecules were significantly increased.

With each successive year, the number of Emergency Department (ED) visits related to illicit drug abuse has progressively increased. Cocaine is the most common illegal drug to cause a visit to the ED. Cocaine use results in a variety of pathophysiological changes with regards to the cardiovascular system, such as constriction of coronary vessels, dysfunction of vascular endothelium, decreased aortic elasticity, hemodynamic disruptions, a hypercoagulable state, and direct toxicity to myocardial and vascular tissue. The clinical course of patients with cocaine-induced chest pain (CCP) is often challenging, and electrocardiographic findings can be potentially misleading in terms of diagnosing a myocardial infarction. In addition, there is no current satisfactory study regarding outcomes of use of various pharmacological drug therapies to manage CCP. At present, calcium-channel blockers and nitroglycerin are two pharmacological agents that are advocated as first-line drugs for CCP management, although the role of labetalol has been controversial and warrants further investigation. We performed an extensive search of available literature through a large number of scholarly articles previously published and listed on Index Medicus. In this review, we put forward a concise summary of the current approach to a patient presenting to the ED with CCP and management of the clinical scenario. The purpose of this review is to summarize the understanding of cocaine's cardiovascular pathophysiology and to examine the current approach for proper evaluation and management of CCP.

Background: This study examined the acute effect of intravenous S-nitroso human serum albumin (S-NO-HSA) infusion on overall hemodynamics and oxidative stress in a chronic left-to-right shunt-induced pulmonary arterial hypertension model with right ventricle (RV) failure., Methods: An aortocaval fistula (pulmonary-to-systemic blood flow ratio [Qp/Qs] > 2.0) was surgically created in 50 male Wistar rats. After 10 weeks, they were randomly treated with S-NO-HSA (n = 20) or human serum albumin (HSA; n = 25) infusion (0.5 µmol/kg/h) for 60 minutes. A sham group (n = 10) received S-NO-HSA. RV contractility, RV-vascular coupling, and ventricular interdependence were assessed in vivo at different pre-loads by biventricular conductance catheters. Heart and lung biopsy specimens were obtained for determination of high-energy phosphates, oxidative stress (oxidized glutathione/reduced glutathione), and endothelial nitric oxide synthase protein expression., Results: S-NO-HSA, compared with HSA infusion, reduced RV afterload expressed by effective pulmonary arterial elastance (Ea; 0.49 ± 0.3 vs 1.2 ± 0.2 mm Hg/ml; p = 0.0005) and improved RV diastolic function (slope of end-diastolic pressure-volume relationship) as well as contractility indicated by slope of end-systolic pressure-volume relationship (Ees). Therefore an increase in efficiency of ventricular-vascular coupling (Ees/Ea) occurred after S-NO-HSA (0.35 ± 0.17 to 0.94 ± 0.21; p = 0.005), but not HSA infusion, leading to positive effect on ventricular interdependence with increased left ventricular stroke volume (56% ± 4% vs 19% ± 5%; p = 0.0013). S-NO-HSA, compared with HSA, treatment improved adenosine 5'-triphosphate (13.9 ± 1.1 vs 7.0 ± 1.8 µmol/g protein) and phosphocreatine (5.9 ± 3.3 vs 1.9 ± 0.6 µmol/g protein; p = 0.01) RV content and decreased the tissue oxidized glutathione/reduced glutathione ratio (p = 0.001)., Conclusions: S-NO-HSA reduces pulmonary hypertension and improves RV systolic and diastolic function and RV-arterial coupling, with a positive effect on ventricular interdependence by increasing energetic reserve and reducing oxidative stress., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is the most common clinically significant arrhythmia and conveys an increased risk of stroke, regardless of whether it is symptomatic. Despite multiple studies supporting an association between subclinical atrial tachyarrhythmias (ATs) detected by cardiac implantable electronic devices and increased risk of thromboembolic events, clinical intervention for device-detected AT remains sluggish, with some clinicians delaying treatment and instead opting for continued surveillance for additional or longer episodes. However, the 2014 updated clinical practice guidelines on AF recommend use of the CHA2DS2-VASc stroke risk score for nonvalvular AF, with oral anticoagulation recommended for scores ≥2, regardless of whether AF is paroxysmal, persistent, or permanent. This paper reviews the epidemiology of AF and mechanisms of stroke in AF, and discusses device-detected AF and its clinical implications., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Deep insight into the complex mechanisms of myocardial ischemia-reperfusion injury has been attained in the past years. Minocycline is a second-generation tetracycline with US FDA approval for clinical use in various infections. Lately, several noninfectious cytoprotective activities of minocycline have been discovered as well. There now exists encouraging evidence of its protective role in cardiovascular pathology and its activity against myocardial ischemia-reperfusion injury. In this article, an overview of the major mechanisms involved in myocardial ischemia-reperfusion injury is presented. This is followed by an analysis of the mechanisms by which minocycline exerts its cytoprotective role and of studies that have been conducted in order to analyze minocycline, along with a review of the scope and limitations of its role as a cytoprotective agent.

Heart failure (HF), a complex clinical syndrome due to structural or functional disorder of the heart, is a major global health issue, with a prevalence of over 5.8 million in the USA alone, and over 23 million worldwide. As a leading cause of hospitalizations among patients aged 65 years or older, HF is a major consumer of healthcare resources, creating a substantial strain on the healthcare system. This paper discusses the epidemiology of HF, financial impact, and multifaceted predicaments in end-stage HF care. A search was conducted on the U.S. National Library of Medicine website (www.pubmed.gov) using keywords such as end-stage heart failure, palliative care, ethical dilemmas. Despite the poor prognosis of HF (worse than that for many cancers), many HF patients, caregivers, and clinicians are unaware of the poor prognosis. In addition, the unpredictable clinical trajectory of HF complicates the planning of end-of-life care, such as palliative care and hospice, leading to underutilization of such resources. In conclusion, ethical dilemmas in end-stage HF are numerous, embroiling not only the patient, but also the caregiver, healthcare team, and society.

A physiological sequence called autophagy qualitatively determines cellular viability by removing protein aggregates and damaged cytoplasmic constituents, and contributes significantly to the degree of myocardial ischemia-reperfusion (I/R) injury. This tightly orchestrated catabolic cellular 'housekeeping' process provides cells with a new source of energy to adapt to stressful conditions. This process was first described as a pro-survival mechanism, but increasing evidence suggests that it can also lead to the demise of the cell. Autophagy has been implicated in the pathogenesis of multiple cardiac conditions including myocardial I/R injury. However, a debate persists as to whether autophagy acts as a protective mechanism or contributes to the injurious effects of I/R injury in the heart. This controversy may stem from several factors including the variability in the experimental models and species, and the methodology used to assess autophagy. This review provides updated knowledge on the modulation and role of autophagy in isolated cardiac cells subjected to I/R, and the growing interest towards manipulating autophagy to increase the survival of cardiac myocytes under conditions of stress-most notably being I/R injury. Perturbation of this evolutionarily conserved intracellular cleansing autophagy mechanism, by targeted modulation through, among others, mammalian target of rapamycin (mTOR) inhibitors, adenosine monophosphate-activated protein kinase (AMPK) modulators, calcium lowering agents, resveratrol, longevinex, sirtuin activators, the proapoptotic gene Bnip3, IP3 and lysosome inhibitors, may confer resistance to heart cells against I/R induced cell death. Thus, therapeutic manipulation of autophagy in the challenged myocardium may benefit post-infarction cardiac healing and remodeling.

Objectives: The present study investigated the cardioprotective role of urocortin (Ucn) and its relationship with protein kinase C (PKC)ε and PKCδ in patients with (DMPs) and without (NDMPs) diabetes mellitus after on-pump cardiac surgery (OPCS). The molecular mechanisms responsible for the reported worse outcomes of DMP after OPCS remain unknown., Methods: Two sequential biopsy specimens were obtained from the right atrium of 27 DMPs and 22 NDMPs before and after cardiopulmonary bypass., Results: Postcardioplegic induction of Ucn in NDMPs (P<.01) was not observed in the DMPs, whose precardioplegic Ucn levels were 50% lower than those in the NDMPs (P<.05). In the NDMPs, cardioplegic arrest increased PKCε mRNA and protein (P<.05); overexpression of PKCδ was not seen. In contrast, DMPs showed increased PKCδ expression (P<.01), with no change in PKCε. Apoptosis was more than twofold greater in the postcardioplegic samples from the DMPs than in those from the NDMPs. The apoptotic myocytes were Ucn negative and exhibited nuclear relocation of PKCδ. Enhanced PKCε/mitochondrial co-localization was observed in viable, Ucn-positive, myocytes. The leakage of troponin I documented in the DMPs was greater than that in the NDMPs, although the difference was not statistically significant (P=.06). Furthermore, despite a similar incidence of perioperative acute myocardial infarction, the DMPs did not show postoperative improvement of systolic or diastolic function, although that was seen in the NDMPs (P<.05)., Conclusions: Cardioplegic arrest failed to induce in DMPs myocyte overexpression of Ucn or PKCε but was associated with induction and mitochondrial relocation of PKCδ, resulting in apoptosis. Failure to overexpress Ucn in the DMPs was associated with apoptosis and cardiac dysfunction and, thus, might contribute to worse postoperative outcomes., (Copyright © 2014 The American Association for Thoracic Surgery. All rights reserved.)

Atrial fibrillation (AF) is the most common cardiac arrhythmia that can potentially result in stroke. Vitamin K antagonists (VKA) like warfarin were for many decades the only oral anticoagulants available for stroke prevention in patients with non-valvular atrial fibrillation (AF) at high risk of stroke. Recently, new oral anticoagulants (NOACS) have been introduced that act via direct inhibition of thrombin (dabigatran) or activated factor X (edoxaban, rivaroxaban and apixaban). Unlike VKAs, these anticoagulants do not require routine INR monitoring and posses favorable pharmacological properties. NOACs act rapidly, and have a stable and predictable dose-related anticoagulant effect with few clinically relevant drug-drug interactions. Phase III trials comparing these agents to warfarin for stroke prevention in patients with non-valvular AF demonstrated that they are at least as efficacious and safe as warfarin. Evolution of clinical guidelines to incorporate the new anticoagulants for stroke prevention in non-valvular AF may result in a reduction in the incidence of AF-related strokes. Safe and effective use of these new drugs in clinical practice requires understanding of their distinct pharmacological properties.

Introduction: Rewarming from deep hypothermic circulatory arrest (DHCA) produces calcium desensitization by troponin I (cTnI) phosphorylation which results in myocardial dysfunction. This study investigated the acute overall hemodynamic and metabolic effects of epinephrine and levosimendan, a calcium sensitizer, on myocardial function after rewarming from DHCA., Methods: Forty male Wistar rats (400 to 500 g) underwent cardiopulmonary bypass (CPB) through central cannulation and were cooled to a core temperature of 13°C to 15°C within 30 minutes. After DHCA (20 minutes) and CPB-assisted rewarming (60 minutes) rats were randomly assigned to 60 minute intravenous infusion with levosimendan (0.2 μg/kg/min; n = 15), epinephrine (0.1 μg/kg/min; n = 15) or saline (control; n = 10). Systolic and diastolic functions were evaluated at different preloads with a conductance catheter., Results: The slope of left ventricular end-systolic pressure volume relationship (Ees) and preload recruitable stroke work (PRSW) recovered significantly better with levosimendan compared to epinephrine (Ees: 85 ± 9% vs 51 ± 11%, P<0.003 and PRSW: 78 ± 5% vs 48 ± 8%, P<0.005; baseline: 100%). Levosimendan but not epinephrine reduced left ventricular stiffness shown by the end-diastolic pressure-volume relationship and improved ventricular relaxation (Tau). Levosimendan preserved ATP myocardial content as well as energy charge and reduced plasma lactate concentrations. In normothermia experiments epinephrine in contrast to Levosimendan increased cTnI phosphorylation 3.5-fold. After rewarming from DHCA, cTnI phosphorylation increased 4.5-fold in the saline and epinephrine group compared to normothermia but remained unchanged with levosimendan., Conclusions: Levosimendan due to prevention of calcium desensitization by cTnI phosphorylation is more effective than epinephrine for treatment of myocardial dysfunction after rewarming from DHCA.

Src tyrosine kinase family was recently identified as a novel upstream modulator of MAP kinase subfamily, p42/p44, whose activation is required for urocortin (Ucn)-mediated cardioprotection. Src kinase was also shown to reduce apoptosis in different cancer cell lines, enhancing phosphorylation and DNA binding affinity of signal transducer and activator of transcription (STAT)3. In order to evaluate the effects of Ucn on the activation status of different STAT family members, HL-1 cardiac cells were incubated with Ucn (10 nM) for increasing periods of time. STAT3 was rapidly phosphorylated at Tyr705, while neither phosphorylation at Ser727 nor induction of total STAT3 was observed. Pretreatment with PP2, a selective inhibitor of Src tyrosine kinase, reduced the pSTAT(-T705) phosphorylation and transcriptional activity induced by Ucn in a dose-dependent manner. Overexpression of STAT3 in HL-1 cardiac myocytes pretreated with Ucn reduced the magnitude of cell death as compared with Ucn treatment alone, while transfection of HL-1 cells with a STAT3 mutant functionally inactive, acting as a dominant negative (DN-STAT3), enhanced the extent of cell death in a dose-dependent manner. In line with this finding, in HL-1 cardiac myocytes overexpressing STAT3 treated with Ucn, addition of the Src kinase inhibitor PP2 reversed the cytoprotective effects of Ucn, proving that the cytoprotective effects of Ucn are also mediated via the Src-pSTAT(-T705) phosphorylation pathway. By immunocytochemistry, Ucn induced nuclear translocation of pST3-T705, which was inhibited by pretreatment with PP2. Together, these data strongly suggest that Ucn can mediate cardioprotection by activating the Src-pSTAT-T705 phosphorylation pathway.

Background: IL-17A and IL-17F are pro-inflammatory cytokines which induce the expression of several cytokines, chemokines and matrix metalloproteinases (MMPs) in target cells. IL-17 cytokines have recently attracted huge interest due to their pathogenic role in diseases such as arthritis and inflammatory bowel disease although a role for IL-17 cytokines in myocardial infarction (MI) has not previously been described., Methods: In vivo MI was performed by coronary artery occlusion in the absence or presence of a neutralizing IL-17 antibody for blocking IL-17 actions in vivo. IL-17 signaling was also assessed in isolated primary cardiomyocytes by Western blot, mRNA expression and immunostaining., Results: Expression of IL-17A, IL-17F and the IL-17 receptor (IL-17RA) were all increased following MI. Expression of several IL-17 target genes, including Cxcl1, Cxcl2, IL-1β, iNOS and IL-6 was also upregulated following MI. In addition, IL-17A promoted the expression of Cxcl1 and IL-6 in isolated cardiomyocytes in a MAPK and PI(3)K-dependent manner. IL-17A and ischaemia/reperfusion (I/R) injury were found to have an additive effect on Cxcl1 expression, suggesting that IL-17 may enhance myocardial neutrophil recruitment during MI. Moreover, protein levels of both IL-17R and IL-17A were enhanced following in vivo MI. Finally, blocking IL-17 signaling in vivo reduced the levels of apoptotic cell death markers following in vivo MI., Conclusions: These data imply that the expression of IL-17 cytokines and their receptor are elevated during myocardial I/R injury and may play a fundamental role in post infarct inflammatory and apoptotic responses., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

β-Adrenergic receptor antagonists (β-blockers) have been recognized for their cardioprotective properties, prompting use of these pharmacologic agents to become more mainstream in acute myocardial infarction (AMI) and congestive heart failure (CHF). Despite their popularity as a class, the ability to protect the myocardium varies significantly between different agents. Carvedilol is a non-selective β-blocker with α₁-adrenergic receptor antagonism properties. It is unique among β-blockers because in addition to improving exercise tolerance and its anti-ischemic properties secondary to a reduction in heart rate and myocardial contractility, carvedilol exerts other beneficial effects including: antioxidant effects; reduction in neutrophil infiltration; apoptosis inhibition; reduction of vascular smooth muscle migration; and improvement of myocardial remodeling post-AMI. These properties, documented in animal models and subsequent clinical trials, are consistent with established evidence demonstrating decreased morbidity and mortality in patients with CHF and post-AMI. This article reviews the role of carvedilol compared with other β-blockers in the treatment of CHF and post-AMI management.

All seven STAT proteins are expressed in the heart, and in this review we will focus on their contribution to cardiac physiology and to ischemic heart disease and its consequences. A substantial literature has focused on the roles of STAT1 and STAT3 in ischemic heart disease, where, at least in the acute phase, they appear to have a yin-yang relationship. STAT1 contributes to the loss of irreplaceable cardiac myocytes both by increasing apoptosis and by reducing cardioprotective autophagy. In contrast, STAT3 is cardioprotective, since STAT3-deficient mice have larger infarcts following ischemic injury, and a number of cardioprotective agents have been shown to act, at least partly, through STAT3 activation. STAT3 is also absolutely required for preconditioning-a process where periods of brief ischemia protect against a subsequent or previous prolonged ischemic episode. Prolonged activation of STAT3, however, is strongly implicated in the post-infarction remodeling of the heart which leads to heart failure, where, possibly together with STAT5, it augments activation of the renin-angiotensin system.

Previous studies have shown that the transcription factor signal transducer and activator of transcription 1 (STAT1) activation is increased in primary cardiac myocytes exposed to simulated ischaemia/reperfusion injury. This promotes apoptotic cell death by enhancing the expression of pro-apoptotic proteins. Autophagy has been demonstrated to play a cardioprotective role in the heart following myocardial infarction (MI). We therefore investigated the role of STAT1 in the intact heart subjected to MI and examined the contribution of autophagy in modulating the protective effect of STAT1 after MI injury. STAT1-deficient hearts had significantly smaller infarcts than wild-type hearts and this correlated with increased levels of autophagy shown by light chain 3 (LC3)-I/LC3-II conversion, and up-regulation of Atg12 and Beclin 1. Moreover, pre-treatment with the autophagy inhibitor 3-methyladenine reversed the cardioprotection observed in the STAT1-deficient hearts. These results reveal a new function of STAT1 in the control of autophagy and indicate a cross-talk between the cardioprotective versus the damaging effects of STAT1 in the intact heart exposed to MI injury., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Autophagy is a regulated process for the degradation of cellular components that has been well conserved in eukaryotic cells. The discovery of autophagy-regulating proteins in yeast has been important in understanding this process. Although many parallels exist between fungi and mammals in the regulation and execution of autophagy, there are some important differences. The pre-autophagosomal structure found in yeast has not been identified in mammals, and it seems that there may be multiple origins for autophagosomes, including endoplasmic reticulum, plasma membrane and mitochondrial outer membrane. The maturation of the phagophore is largely dependent on 5'-AMP activated protein kinase and other factors that lead to the dephosphorylation of mammalian target of rapamycin. Once the process is initiated, the mammalian phagophore elongates and matures into an autophagosome by processes that are similar to those in yeast. Cargo selection is dependent on the ubiquitin conjugation of protein aggregates and organelles and recognition of these conjugates by autophagosomal receptors. Lysosomal degradation of cargo produces metabolites that can be recycled during stress. Autophagy is an important cellular safeguard during starvation in all eukaryotes; however, it may have more complicated, tissue specific roles in mammals. With certain exceptions, autophagy seems to be cytoprotective, and defects in the process have been associated with human disease.

Cardiovascular disease is a leading cause of death worldwide, particularly in Western societies. During an ischaemic insult, ventricular pressure from the heart is diminished as a result of cardiac myocyte death by necrosis and apoptosis. Autophagy is a process whereby cells catabolise intracellular proteins in order to generate ATP in times of stress such as nutrient starvation and hypoxia. Emerging evidence suggests that autophagy plays a positive role in cardiac myocyte survival during periods of cellular stress performing an important damage limitation function. By promoting cell survival, cardiac myocyte loss is reduced thereby minimising the potential of heart failure. In contrast, it has been reported that autophagy can also be a form of cell death. By considering the various animal models of autophagy, we examine the role of the Signal Transducers and Activator of Transcription (STAT) proteins in the autophagic response. Additionally we review the role of the tumour suppressor, p53 and its family member p73 and their potential role in the autophagic response.

Objective: We sought to prospectively evaluate long-term follow-up results of intracardiac echocardiography-aided transcatheter closure of interatrial shunts in adults., Background: Intracardiac echocardiography improves the safety and effectiveness of transcatheter device-based closure of interatrial shunts, but its impact on long-term follow-up is unknown., Methods: Over a 5-year period, we prospectively enrolled 258 consecutive patients (mean age 48 ± 19.1 years, 169 females) who had been referred to our centre for catheter-based closure of interatrial shunts. All patients were screened with transesophageal echocardiography before the operation. Eligible patients underwent intracardiac echocardiography study and attempted closure., Results: After intracardiac echocardiography study and measurements, 18 patients did not proceed to transcatheter closure due to unsuitable rims, atrial myxoma not diagnosed by preoperative transesophageal echocardiography or inaccurate transesophageal echocardiography measurement of defects more than 40 mm. The remaining 240 patients underwent transcatheter closure: transesophageal echocardiography-planned device type and size were modified in 108 patients (45%). Rates of procedural success, predischarge occlusion and complication were 100%, 94.2% and 5%, respectively. On mean follow-up of 65 ± 15.3 months, the follow-up occlusion rate was 96.5%. There were no cases of aortic/atrial erosion, device thrombosis or atrioventricular valve inferences., Conclusions: Intracardiac echocardiography-guided interatrial shunt transcatheter closure is safe and effective and appears to have excellent long-term results, potentially minimizing the complications resulting from incorrect device selection and sizing., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Minocycline is a semi-synthetic tetracycline that inhibits bacterial protein synthesis and hence is used for the treatment of many infectious diseases. Over the years, many other interesting properties of minocycline have been identified and been used to make patents which include anti-inflammatory, anti-apoptotic, matrix metalloproteinase inhibitor and free oxygen radical scavenger activity. Ischemia-reperfusion injury is a concern for almost every clinical specialty and minocycline seems to be an attractive cytoprotective agent that can ameliorate the damage due to these properties. Ischemia-reperfusion injury is a complex process and involves various pathways that lead to cell death. This review focuses on the body of evidence describing various proposed mechanisms of action of minocycline and its current experimental use in various animal models of ischemia-reperfusion injury.

The STAT3 transcription factor is well known to function as an anti-apoptotic factor, especially in numerous malignancies. Recently we showed that STAT3 is cytoprotective and that cells lacking STAT3 are more sensitive to oxidative stress. A key feature of oxidative stress involves activation of the DNA damage pathway. However, a role for STAT3 or its contribution in response to DNA damage has not been described. In the present study we show that cells lacking STAT3 are less efficient in repairing damaged DNA. Moreover, STAT3 deficient cells show reduced activity of the ATM-Chk2 and ATR-Chk1 pathways, both important pathways in sensing DNA damage. Finally we show that MDC1, a regulator of the ATM-Chk2 pathway and facilitator of the DNA damage response, is modulated by STAT3 at the transcriptional level. These findings demonstrate that STAT3 is necessary for efficient repair of damaged DNA, partly by modulating the ATM-Chk2 and ATR-Chk1 pathways., (© 2010 The Authors. International Journal of Experimental Pathology © 2010 International Journal of Experimental Pathology.)

Urocortin is a 40 amino acid peptide of the corticotrophin-releasing factor (CRF) family that is synthesized and released by cardiac myocytes. Endogenous urocortin expression is increased during ischemia/reperfusion (I/R) and addition of exogenous urocortin reduces cell death caused by I/R injury. Studies have also showed that the protective action of urocortin is mediated by the activation of ERK1/2. We discovered that a non-receptor tyrosine kinase, Src, is involved in the urocortin-induced activation of ERK1/2 in mouse atrial HL-1 myocytes. The selective Src family kinase inhibitor, PP2, reduced the urocortin-induced phosphorylation of ERK1/2, and so did the expression of a dominant-negative mutant of Src in transfected HL-1 cells. Inhibition of Src by PP2 also reduced urocortin's protective effects in HL-1 cells after hypoxia/reoxygenation (H/R), as assessed by flow cytometry and caspase-3 activation assay. Titration studies indicated that as little as 10(-8)M urocortin was sufficient to induce Src activation. Maximal phosphorylation/activation of Src and ERK1/2 were both detected after 5 min incubation with urocortin. These effects of urocortin were largely mediated by CRF receptor-1, although a minor contribution of CRF receptor-2 cannot be excluded. Here we report for the first time that short-term treatment with urocortin causes rapid phosphorylation of Src, and that the urocortin-activated Src kinase serves as an upstream modulator of ERK1/2 activation, playing an essential role in urocortin-mediated cardioprotection., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

The urocortin (UCN) hormones UCN1 and UCN2 have been shown previously to confer significant protection against myocardial ischaemia/reperfusion (I/R) injury; however, the molecular mechanisms underlying their action are poorly understood. To further define the transcriptional effect of UCNs that underpins their cardioprotective activity, a microarray analysis was carried out using an in vivo rat coronary occlusion model of I/R injury. Infusion of UCN1 or UCN2 before the onset of reperfusion resulted in the differential regulation of 66 and 141 genes respectively, the majority of which have not been described previously. Functional analysis demonstrated that UCN-regulated genes are involved in a wide range of biological responses, including cell death (e.g. X-linked inhibitor of apoptosis protein), oxidative stress (e.g. nuclear factor erythroid derived 2-related factor 1/nuclear factor erythroid derived 2-like 1) and metabolism (e.g. Prkaa2/AMPK). In addition, both UCN1 and UCN2 were found to modulate the expression of a host of genes involved in G-protein-coupled receptor (GPCR) signalling including Rac2, Gnb1, Dab2ip (AIP1), Ralgds, Rnd3, Rap1a and PKA, thereby revealing previously unrecognised signalling intermediates downstream of CRH receptors. Moreover, several of these GPCR-related genes have been shown previously to be involved in mitogen-activated protein kinase (MAPK) activation, suggesting a link between CRH receptors and induction of MAPKs. In addition, we have shown that both UCN1 and UCN2 significantly reduce free radical damage following myocardial infarction, and comparison of the UCN gene signatures with that of the anti-oxidant tempol revealed a significant overlap. These data uncover novel gene expression changes induced by UCNs, which will serve as a platform to further understand their mechanism of action in normal physiology and cardioprotection.

A 56-year-old Caucasian male was admitted to our hospital with complaints of shortness of breath, joint aches, and chills in the absence of fever. During his hospitalization, he remained afebrile, but developed multiple episodes of bradycardia and intermittent second degree atrioventricular (AV) block, with both Wenckebach and Mobitz type II episodes. Laboratory evaluation demonstrated a chronically elevated amylase, without any significant electrolyte abnormalities. Abdominal computed tomography scan revealed prominence of the pancreatic head without any discrete pancreatic mass, suggestive of chronic pancreatitis. Pancreatic disorders, including acute pancreatitis or exacerbation of chronic pancreatitis, may be associated with intermittent transient AV block conduction abnormalities. Although the pathophysiology remains unclear, awareness of this entity is important for clinicians for appropriate management. Progression to more severe, permanent AV block necessitating permanent pacemaker implant to our knowledge has not been reported.

The small peptide urocortin (Ucn) has the ability to protect the heart by reducing cardiac cell loss during myocardial ischemia/reperfusion, and improving post-ischemic cardiac performance. Although its mechanism of action is not clearly defined, investigations have revealed that Ucn acts through several kinase pathways, and modulates a group of genes which synergistically minimize mitochondrial damage. Besides cardioprotection, most recent findings suggest a role for Ucn as a cardiac biomarker. Serum Ucn levels may be clinically useful to diagnose cases of mild sub-lethal ischemia, lacking elevation of cardiac enzymes and electrocardiogram changes. Infusion of Ucn may also help reduce the extent of the iatrogenic ischemic/reperfusion injury, associated with cardioplegic arrest.