Successful pharmaco-invasive approach using a lower alteplase dose and VA-ECMO support in high-risk pulmonary embolism: case report.

Despite the elevated mortality rates associated with high-risk pulmonary embolism (PE), this condition remains understudied. Data regarding the effectiveness and safety of invasive therapies such as venoarterial extracorporeal membrane oxygenation (VA-ECMO) in this patient population remains controversial. Here, we present the case of a 61-year-old male with high-risk PE associated with refractory cardiac arrest and cardiogenic shock who underwent a combination of extracorporeal cardiopulmonary resuscitation with VA-ECMO and pharmaco-invasive therapy (mechanical thrombi fragmentation plus lower alteplase dose), resulting in successful pulmonary reperfusion. After a prolonged in-hospital stay, the patient was discharged in stable condition.

Distinguishing pathophysiological features of heart failure with reduced and preserved ejection fraction: A comparative analysis of two mouse models.

Heart failure (HF) is a heterogeneous condition that can be categorized according to the left ventricular ejection fraction (EF) into HF with reduced (HFrEF) or preserved (HFpEF) EF. Although HFrEF and HFpEF share some common clinical manifestations, the mechanisms underlying each phenotype are often found to be distinct. Identifying shared and divergent pathophysiological features might expand our insights on HF pathophysiology and assist the search for therapies for each HF subtype. In this study, we evaluated and contrasted two new murine models of non-ischaemic HFrEF and cardiometabolic HFpEF in terms of myocardial structure, left ventricular function, gene expression, cardiomyocyte calcium handling, mitochondrial polarization and protein acetylation in a head-to-head fashion. We found that in conditions of similar haemodynamic stress, the HFrEF myocardium underwent a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation was greater in the HFpEF myocardium. We observed opposing features on calcium release, which was diminished in the HFrEF cardiomyocyte but enhanced in the HFpEF cardiomyocyte. Mitochondria were less polarized in both HFrEF and HFpEF cardiomyocytes, reflecting similarly impaired metabolic capacity. Hyperacetylation of cardiac proteins was observed in both models, but it was more accentuated in the HFpEF heart. Despite shared features, unique triggering mechanisms (neurohormonal overactivation in HFrEF vs. inflammation in HFpEF) appear to determine the distinct phenotypes of HF. The findings of the present research stress the need for further exploration of the differential mechanisms underlying each HF subtype, because they might require specific therapeutic interventions. KEY POINTS: The mechanisms underlying heart failure with either reduced (HFrEF) or preserved (HFpEF) ejection fraction are often found to be different. Previous studies comparing pathophysiological traits between HFrEF and HFpEF have been conducted on animals of different ages and strains. The present research contrasted two age-matched mouse models of non-ischaemic HFrEF and cardiometabolic HFpEF to uncover divergent and shared features. We found that upon similar haemodynamic stress, the HFrEF heart experienced a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation appeared to be greater in the HFpEF myocardium. Calcium release was diminished in the HFrEF cardiomyocyte and enhanced in the HFpEF cardiomyocyte. Mitochondria were comparably less polarized in both HFrEF and HFpEF myocytes. Hyperacetylation of proteins was common to both models, but stronger in the HFpEF heart. Casting light on common and distinguishing features might ease the quest for phenotype-specific therapies for heart failure patients.

Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor-associated lethal myocarditis in mice.

AIMS: Immune checkpoint inhibitors (ICIs) are antineoplastic drugs designed to activate the immune system's response against cancer cells. Evidence suggests that they may lead to immune-related adverse events, particularly when combined (e.g., anti-CTLA-4 plus anti-PD-1), sometimes resulting in severe conditions such as myocarditis. We aimed to investigate whether a previously sustained cardiac injury, such as pathological remodelling due to hypertension, is a prerequisite for ICI therapy-induced myocarditis. METHODS: We evaluated the cardiotoxicity of ICIs in a hypertension (HTN) mouse model (C57BL/6). Weekly doses were administered up to day 21 after the first administration. Our analysis encompassed the following parameters: (i) survival and cardiac pathological remodelling, (ii) cardiac function assessed using pressure-volume (PV)-loops, with brain natriuretic peptide (BNP) serving as a marker of haemodynamic dysfunction and (iii) cardiac inflammation (cytokine levels, infiltration, and cardiac antigen autoantibodies). RESULTS: After the first administration of ICI combined therapy, the treated HTN group showed a 30% increased mortality (P = 0.0002) and earlier signs of hypertrophy and pathological remodelling compared with the untreated HTN group. BNP (P = 0.01) and TNF-α (<0.0001) increased 2.5- and 1.7-fold, respectively, in the treated group, while IL-6 (P = 0.8336) remained unchanged. Myocarditis only developed in the HTN group treated with ICIs on day 21 (score >3), characterised by T cell infiltration and increased cardiac antigen antibodies (86% showed a titre of 1:160). The control group treated with ICI was unaffected in any evaluated feature. CONCLUSIONS: Our findings indicate that pre-existing sustained cardiac damage is a necessary condition for ICI-induced myocarditis.

Soluble factors in COVID-19 mRNA vaccine-induced myocarditis causes cardiomyoblast hypertrophy and cell injury: a case report.

BACKGROUND: Inflammation affecting the heart and surrounding tissues is a clinical condition recently reported following COVID-19 mRNA vaccination. Assessing trends of these events related to immunization will improve vaccine safety surveillance and best practices for forthcoming vaccine campaigns. However, the causality is unknown, and the mechanisms associated with cardiac myocarditis are not understood. CASE PRESENTATION: After the first dose, we reported an mRNA vaccine-induced perimyocarditis in a young patient with a history of recurrent myocardial inflammation episodes and progressive loss of cardiac performance. We tested this possible inflammatory cytokine-mediated cardiotoxicity after vaccination in the acute phase (ten days), and we found a significant elevation of MCP-1, IL-18, and IL-8 inflammatory mediators. Still, these cytokines decreased considerably at the recovery phase (42 days later). We used the cardiomyoblasts cell line to test the effect of serum on cell viability, observing that serum from the acute phase reduced the cell viability to 75%. We did not detect this toxicity in cells when we tested serum from the patient in the recovery phase. We also tested serum-induced hypertrophy, a phenomenon in myocarditis and heart failure. We found that acute phase-serum has hypertrophy effects, increasing 25% of the treated cardiac cells' surface and significantly increasing B-type natriuretic peptide. However, we did not observe the hypertrophic effect in the recovery phase or sera from healthy controls. CONCLUSION: Our results opened the possibility of the inflammatory cytokines or serum soluble mediators as key factors for vaccine-associated myocarditis. In this regard, identifying anti-inflammatory molecules that reduce inflammatory cytokines could help avoid vaccine-induced myocardial inflammation.

Prevalence of Depression, Anxiety, Post-Traumatic Stress, and Insomnia Symptoms Among Frontline Healthcare Workers in a COVID-19 Hospital in Northeast Mexico.

OBJECTIVE: Frontline healthcare workers (FHCWs) exposed to COVID-19 patients are at an increased risk of developing psychological burden. This study aims to determine the prevalence of mental health symptoms and associated factors among Mexican FHCWs attending COVID-19 patients. METHODS: FHCWs, including attending physicians, residents/fellows, and nurses providing care to COVID-19 patients at a private hospital in Monterrey, Mexico, were invited to answer an online survey between August 28, and November 30, 2020. Symptoms of depression, anxiety, post-traumatic stress, and insomnia were evaluated with the Patient Health Questionnaire (PHQ)-9, Generalized Anxiety Disorder (GAD)-7, Impact of Event Scale-Revised (IES-R), and Insomnia Severity Index (ISI). Multivariate analysis was performed to identify variables associated with each outcome. RESULTS: 131 FHCWs, 43.5% attending physicians, 19.8% residents/fellows, and 36.6% nurses were included. The overall prevalence of depression, anxiety, post-traumatic stress, and insomnia was 36%, 21%, 23%, and 24% respectively. Multivariate analysis revealed that residents/fellows and nurses reported more depression and insomnia than attending physicians. Although not significant, residents/fellows were more likely to experience all symptoms than nurses. CONCLUSIONS: Mexican FHCWs, especially nurses and residents/fellows, experienced a significant psychological burden while attending to COVID-19 patients. Tailored interventions providing support to FHCWs during future outbreaks are required.

A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block CTLA-4, PD-1, or PD-L1 and induce the activation of the immune system against cancer. Despite the efficacy of ICIs, which has improved the oncotherapy for patients with a variety of malignancies, several immune-related adverse events (irAEs) have been described, including those affecting the heart. Cardiac irAEs after ICI therapies, including myocarditis, can become life-threatening, and their pathogenic mechanisms remain unclear. Here, a systematic analysis was performed regarding the potential immune mechanisms underlying cardiac irAEs based on the immune adverse events induced by the ICIs: 1) recruitment of CD4+ and CD8+ T cells, 2) autoantibody-mediated cardiotoxicity, and 3) inflammatory cytokines. Furthermore, the impact of dual therapies in ICI-induced cardiac irAEs and the potential risk factors are reviewed. We propose that self-antigens released from cardiac tissues or cancer cells and the severity/advancement of cancer disease have an important role in ICI cardiotoxicity.

Cardiotoxicity associated with immune checkpoint inhibitor therapy: a meta-analysis.

AIMS: This study aimed to estimate the incidence of cardiac immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs). METHODS AND RESULTS: First, we performed an ICI pharmacovigilance analysis, finding 4.2% of cardiac disorders, including myocarditis, for anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapies. Patients treated with anti-PD-1 antibodies presented a greater number of cardiac adverse events (AEs) than those treated with anti-CTLA-4 (69.4% vs. 20%). Then, we analysed the incidence and characteristics of cardiac irAEs in 1265 papers published prior to 31 August 2020. Of the 4751 patients studied, 1.3% presented cardiac irAEs, with myocarditis being the most frequent (50.8%); 15 patients died (24.6%) due to cardiac irAEs. Finally, we conducted a meta-analysis to determine cardiac irAEs in randomized clinical trials, identified through a systematic search from the ClinicalTrials.gov database, finding an incidence of 3.1% for ICI monotherapies, 5.8% for dual ICI therapies, 3.7% (irAEs/AEs) for ICIs plus chemotherapy, and cardiac AEs were reported in 2.5% of patients treated solely with chemotherapy. CONCLUSIONS: Our study provides precise data for the incidence of cardiac irAEs among patients using ICIs, where despite its low incidence, the high rate of mortality is an important issue to consider. ICIs induce mainly myocarditis at the first doses, and dual therapies seem to provoke higher rates of cardiac irAEs than monotherapies or ICIs plus chemotherapy.

What Is the Role of the Inflammation in the Pathogenesis of Heart Failure?

PURPOSE OF REVIEW: In heart failure, whether it is associated with reduced or preserved ejection fraction, the immune system is activated and contributes to heart remodeling and impaired function. RECENT FINDINGS: Studies indicate that cells of the immune system not only play a role in the pathology but are also critical regulators of heart function. Knowledge about the role of the immune system driving heart failure will lead to the development of new targets to this system, particularly in those patients that, despite the apparent wellness, relapse and worsen. In this review, we will address the diverse mechanisms that trigger inflammation and their impact on heart failure progression.

The role of B cells in heart failure and implications for future immunomodulatory treatment strategies.

Despite numerous demonstrations that the immune system is activated in heart failure, negatively affecting patients' outcomes, no definitive treatment strategy exists directed to modulate the immune system. In this review, we present the evidence that B cells contribute to the development of hypertrophy, inflammation, and maladaptive tissue remodelling. B cells produce antibodies that interfere with cardiomyocyte function, which culminates as the result of recruitment and activation of a variety of innate and structural cell populations, including neutrophils, macrophages, fibroblasts, and T cells. As B cells appear as active players in heart failure, we propose here novel immunomodulatory therapeutic strategies that target B cells and their products.

The Hospital Zambrano Hellion venous thromboembolism rapid response team (PREVENTION-team): Improving pulmonary embolism and deep venous thrombosis patient care / Equipo de respuesta rápida para tromboembolismo venoso del Hospital Zambrano Hellion (PREVENTION-Team): Mejorando el manejo del tromboembolismo pulmonar y trombosis venosa profunda

Abstract Background: Fast-track worldwide reperfusion programs improve outcomes in ST-elevation myocardial infarction and stroke. Similar programs called Program Evaluation and Review Technique (PERT) focus on submassive and massive pulmonary embolism (PE) excluding deep venous thrombosis (DVT). Methods: PREVENTION-team (Hospital Zambrano Hellion Venous Thromboembolism [VTE] Rapid Response). Primary objective: Fast-track stratification, diagnostics, and treatment (60-90 min) to improve proximal DVT and submassive and massive PE patients care. Secondary objectives: Increase diagnosis rate of low-risk PE and distal DVT; exploration of cause; long-term anticoagulation; identify high-risk profile for chronic complications; community-based support groups and patient education to extend the concept of the thrombosis-free hospital to thrombosis-free home. Structure and organization: The team includes cardiologists, vascular medicine, angiologist, echocardiographer, cardiovascular imaging, and interventional cardiologists. The team will be accessible 24 h a day, 7 days a week, 365 days a year, and base on previous national experience. The cardiology fellow on call will be responsible for activation and evaluation. We will design several tools to accelerate these processes. Risk stratification and therapeutic approach will be based on clinical presentation, echocardiogram, and biomarkers findings. According to PERT stratification based on resources and medical specialties, Hospital Zambrano Hellion has level 1 PERT. PREVENTION-team links physicians with different expertise, provide fast, efficient, and time-saving treatment, potentially saving lives and reducing bleeding and chronic complications in VTE patients. Finally, establishing a network in our hospital and health system to improve VTE patients care. To the best of our knowledge, this is the first rapid response team focused on VTE in Mexico.

Resumen Antecedentes: Programas de reperfusión mejoraron la evolución en infarto con elevación del ST y accidente cerebrovascular embólico. Programas similares llamados PERT para TEP masiva o submasiva excluyen TVP. Métodos: Equipo PREVENTION (Hospital Zambrano Hellion Venous Thromboembolism Rapid Response). Objetivo primario: Estratificación, diagnóstico y tratamiento acelerado (60-90 minutos) para mejorar atención del TVP proximal y TEP masiva o submasiva. Objetivos secundarios: Incrementar diagnóstico de TEP de riesgo bajo y TVP distal; explorar causa; anticoagulación a largo plazo; perfil de riesgo alto para complicaciones crónicas; grupos de soporte en la comunidad y educación para pacientes, y extender el concepto de hospital libre de trombosis a hogar libre de trombosis. Estructura y organización: Incluye cardiólogos, medicina vascular, angiólogo, ecocardiografistas, imagen cardiovascular. Basado en experiencia nacional, el equipo estará accesible 24 horas del día, siete días de la semana, 365 días del año. El residente de cardiología realizará la activación y estratificación. Diseñamos herramientas para acelerar el proceso. La estratificación de riesgo y el abordaje terapéutico se basará en presentación clínica, hallazgos ecocardiograficos y biomarcadores. El Hospital Zambrano Hellion tiene nivel PERT 1 de acuerdo a la estratificación PERT basada en recursos y especialidades. Equipo-PREVENTION en TEV vincula médicos con diferentes capacidades, ofrece rápido y eficiente tratamiento para preservar vidas y reducir complicaciones hemorrágicas y crónicas. En nuestro hospital y sistema de salud establecer una sólida red de trabajo para mejorar la atención. Hasta nuestro conocimiento, en México este podría ser el primer equipo de respuesta rápida enfocado en TEV.

Resveratrol Prevents Right Ventricle Remodeling and Dysfunction in Monocrotaline-Induced Pulmonary Arterial Hypertension with a Limited Improvement in the Lung Vasculature.

Pulmonary arterial hypertension (PAH) is a life-threatening disease that is characterized by an increase in pulmonary vascular pressure, leading to ventricular failure and high morbidity and mortality. Resveratrol, a phenolic compound and a sirtuin 1 pathway activator, has known dietary benefits and is used as a treatment for anti-inflammatory and cardiovascular diseases. Its therapeutic effects have been published in the scientific literature; however, its benefits in PAH are yet to be precisely elucidated. Using a murine model of PAH induced by monocrotaline, the macroscopic and microscopic effects of a daily oral dose of resveratrol in rats with PAH were evaluated by determining its impact on the lungs and the right and left ventricular function. While most literature has focused on smooth muscle cell mechanisms and lung pathology, our results highlight the relevance of therapy-mediated improvement of right ventricle and isolated cardiomyocyte physiology in both ventricles. Although significant differences in the pulmonary architecture were not identified either micro- or macroscopically, the effects of resveratrol on right ventricular function and remodeling were observed to be beneficial. The values for the volume, diameter, and contractility of the right ventricular cardiomyocytes returned to those of the control group, suggesting that resveratrol has a protective effect against ventricular dysfunction and pathological remodeling changes in PAH. The effect of resveratrol in the right ventricle delayed the progression of findings associated with right heart failure and had a limited positive effect on the architecture of the lungs. The use of resveratrol could be considered a future potential adjunct therapy, especially when the challenges to making a diagnosis and the current therapy limitations for PAH are taken into consideration.

The Hospital Zambrano Hellion venous thromboembolism rapid response team (PREVENTION-team): Improving pulmonary embolism and deep venous thrombosis patient care.

Background: Fast-track worldwide reperfusion programs improve outcomes in ST-elevation myocardial infarction and stroke. Similar programs called Program Evaluation and Review Technique (PERT) focus on submassive and massive pulmonary embolism (PE) excluding deep venous thrombosis (DVT). Methods: PREVENTION-team (Hospital Zambrano Hellion Venous Thromboembolism [VTE] Rapid Response). Primary objective: Fast-track stratification, diagnostics, and treatment (60-90 min) to improve proximal DVT and submassive and massive PE patients care. Secondary objectives: Increase diagnosis rate of low-risk PE and distal DVT; exploration of cause; long-term anticoagulation; identify high-risk profile for chronic complications; community-based support groups and patient education to extend the concept of the thrombosis-free hospital to thrombosis-free home. Structure and organization: The team includes cardiologists, vascular medicine, angiologist, echocardiographer, cardiovascular imaging, and interventional cardiologists. The team will be accessible 24 h a day, 7 days a week, 365 days a year, and base on previous national experience. The cardiology fellow on call will be responsible for activation and evaluation. We will design several tools to accelerate these processes. Risk stratification and therapeutic approach will be based on clinical presentation, echocardiogram, and biomarkers findings. According to PERT stratification based on resources and medical specialties, Hospital Zambrano Hellion has level 1 PERT. PREVENTION-team links physicians with different expertise, provide fast, efficient, and time-saving treatment, potentially saving lives and reducing bleeding and -chronic complications in VTE patients. Finally, establishing a network in our hospital and health system to improve VTE patients care. To the best of our knowledge, this is the first rapid response team focused on VTE in Mexico.

Antecedentes: Programas de reperfusión mejoraron la evolución en infarto con elevación del ST y accidente cerebrovascular embólico. Programas similares llamados PERT para TEP masiva o submasiva excluyen TVP. Métodos: Equipo PREVENTION (Hospital Zambrano Hellion Venous Thromboembolism Rapid Response). Objetivo primario: Estratificación, diagnóstico y tratamiento acelerado (60-90 minutos) para mejorar atención del TVP proximal y TEP masiva o submasiva. Objetivos secundarios: Incrementar diagnóstico de TEP de riesgo bajo y TVP distal; explorar causa; anticoagulación a largo plazo; perfil de riesgo alto para complicaciones crónicas; grupos de soporte en la comunidad y educación para pacientes, y extender el concepto de hospital libre de trombosis a hogar libre de trombosis. Estructura y organización: Incluye cardiólogos, medicina vascular, angiólogo, ecocardiografistas, imagen cardiovascular. Basado en experiencia nacional, el equipo estará accesible 24 horas del día, siete días de la semana, 365 días del año. El residente de cardiología realizará la activación y estratificación. Diseñamos herramientas para acelerar el proceso. La estratificación de riesgo y el abordaje terapéutico se basará en presentación clínica, hallazgos ecocardiograficos y biomarcadores. El Hospital Zambrano Hellion tiene nivel PERT 1 de acuerdo a la estratificación PERT basada en recursos y especialidades. Equipo-PREVENTION en TEV vincula médicos con diferentes capacidades, ofrece rápido y eficiente tratamiento para preservar vidas y reducir complicaciones hemorrágicas y crónicas. En nuestro hospital y sistema de salud establecer una sólida red de trabajo para mejorar la atención. Hasta nuestro conocimiento, en México este podría ser el primer equipo de respuesta rápida enfocado en TEV.

Mitochondrial Hyperacetylation in the Failing Hearts of Obese Patients Mediated Partly by a Reduction in SIRT3: The Involvement of the Mitochondrial Permeability Transition Pore.

BACKGROUND/AIMS: Cyclophilin D (CypD) mediates the mitochondrial permeability transition pore (mPTP) opening that contributes to mitochondrial dysfunction. CypD is regulated by its acetylation/deacetylation state that depends on Sirtuin-3 (SIRT3) mitochondrial deacetylase. Since obesity and metabolic syndrome decrease SIRT3 activity and expression, we tested the hypothesis that CypD hyperacetylation promotes mitochondrial dysfunction under this pathophysiological state, which is associated with ventricular dysfunction and heart failure. METHODS: Myocardial tissue samples from patients with left ventricular heart failure, with either obesity or normal weight, were processed for the expression of SIRT3 and acetylation profile by Western Blot (WB). In addition, a rat model of obesity and metabolic syndrome induced by 30% (w/v) of sucrose was conducted. The WB analysis was used to determine the levels of mitochondrial expression of SIRT3, Adenine Nucleotide Translocator (ANT), CypD and the acetylation profile, as well as immunoprecipitation to establish the acetylation levels of CypD. Mitochondrial function was assessed by oxygen consumption analysis and maximum Ca2+ retention capacity. Oxidative stress was assessed by aconitase activity, protein carbonyl and thiol groups content. RESULTS: SIRT3 expression in the biopsies of the failing human hearts showed a 46% decrease in the expression levels of obese patients in comparison to the non-obese patients (p=0.0219). Remarkably, body mass index was associated with protein acetylation (0.627; p = 0.035), suggesting that the acetylation profiles of the failing hearts of obese patients are partly mediated by a reduction in SIRT3, which is also associated with higher BNP levels, indicating a more severe ventricular dysfunction (-0.636; p = 0.043). Accordingly, obese rats demonstrated a SIRT3 mitochondrial expression decrease of 22% concomitantly with a hyperacetylated mitochondrial profile, including CypD. Cardiac mitochondria from obese animals were 2.5-fold more prone to mPTP opening than the controls. CONCLUSION: Our results indicate that obesity reduces SIRT3 expression and that CypD hyperacetylation increases mPTP opening, suggesting that the activation of SIRT3 might be a potential target to decrease ventricular dysfunction and slow the progression of heart failure.

Phase II clinical trial testing the safety of a humanised monoclonal antibody anti-CD20 in patients with heart failure with reduced ejection fraction, ICFEr-RITU2: study protocol.

INTRODUCTION: Chronic heart failure with reduced ejection fraction (HFrEF) treatment targets neurohormonal inhibition; however, our experimental observations and the recent clinical evidence in myocardial infarction and heart transplant patients support the anti-inflammatory pathway as a potential novel therapeutic target. Therefore, we aimed to assess the safety of human monoclonal antibody-CD20 (rituximab) in patients with HFrEF. METHODS AND ANALYSIS: We designed this protocol according to the Standard Protocol Items: Recommendations for Interventional Trials guidelines as a phase II, single-centred, single group and prospective clinical trial. We hypothesise that the use of a monoclonal antibody, rituximab, could be a potentially safe new agent in HFrEF management. We will include patients with EF≤40%, New York Heart Association functional class III/IV and unresponsive to standard treatment. We will use a dosing regimen (1000 mg) previously applied to post-transplant patients and patients with rheumatoid arthritis with favourable results, aiming to provide supplementary evidence of safety in patients with HFrEF. We designed strategies tailored to preserving the integrity of patient safety. The date of study initiation will be 29th of May 2019. ETHICS AND DISSEMINATION: The following protocol was approved by IRB committees, and as a requirement, all patients need to sign an informed consent form before being subjected to any procedure prior to the initiation of the study. We are aware that the trial will be run in patients who due to their cardiovascular functional class, have reserved prognosis, with no known therapy that leads to improvement. Hence, this trial searches to establish the safety of an alternative strategy in ameliorating prognosis. Regardless of the study outcomes, whether favourable or not, they will be published. If a favourable outcome is evidenced, it will prompt performing a phase III, efficacy-based study. TRIAL REGISTRATION NUMBER: The trial was approved by the IRB (CONBIOÉTICA-19-CEI-011-20161017 and COFEPRIS-17-CI-19-039-003), and registered at Clinicaltrials.gov (NCT03332888; Pre-Results).

Temporal Frame of Immune Cell Infiltration during Heart Failure Establishment: Lessons from Animal Models.

Heart failure (HF) is a cardiovascular syndrome characterized by maladaptive changes with an underlying inflammatory mediated pathogenesis. Nevertheless, current therapy is aimed at the heart workload and neurohormonal axis; thus, prognosis remains poor. To continue improving treatment, we rely on murine models for a better understanding of HF pathophysiology. Among them, pressure overload HF (PO-HF) animal models are a common strategy. Development of PO-HF is characterized by monocyte infiltration, which orchestrates a cascade of events leading to sustained inflammation and maladaptive changes. Here, we divide the PO-HF model progression into four phases and describe the inflammatory, structural, and gene expression profiles. This division is relevant due to its similarities with clinical hypertensive heart disease progression to HF. Evidence shows improvement in hemodynamic and other local parameters by altering the inflammatory response in a specific immune response at a specific point of time. Thus, it is relevant to focus on the time-dependent immune response interaction in order to provide more effective therapy. This review summarizes the pathogenesis of PO-HF murine models, highlighting the inflammatory events in a time frame view. By this approach, we expect to provide researchers with a better understanding of the intertwining time-dependent events that occur in PO-HF.