Pathophysiology Underlying the Bimodal Edema Phenomenon After Myocardial Ischemia/Reperfusion.

BACKGROUND Post-ischemia/reperfusion (I/R) myocardial edema was recently shown to follow a consistent bimodal pattern: an initial wave of edema appears on reperfusion and dissipates at 24 h, followed by a deferred wave that initiates days after infarction, peaking at 1 week. OBJECTIVES This study examined the pathophysiology underlying this post-I/R bimodal edematous reaction. METHODS Forty instrumented pigs were assigned to different myocardial infarction protocols. Edematous reaction was evaluated by water content quantification, serial cardiac magnetic resonance T2-mapping, and histology/immunohistochemistry. The association of reperfusion with the initial wave of edema was evaluated in pigs undergoing 40-min/80-min I/R and compared with pigs undergoing 120-min ischemia with no reperfusion. The role of tissue healing in the deferred wave of edema was evaluated by comparing pigs undergoing standard 40-min/7-day I/R with animals subjected to infarction without reperfusion (chronic 7-day coronary occlusion) or receiving post-I/R high-dose steroid therapy. RESULTS Characterization of post-I/R tissue changes revealed maximal interstitial edema early on reperfusion in the ischemic myocardium, with maximal content of neutrophils, macrophages, and collagen at 24 h, day 4, and day 7 post-I/R, respectively. Reperfused pigs had significantly higher myocardial water content at 120 min and T2 relaxation times on 120 min cardiac magnetic resonance than nonreperfused animals. Permanent coronary occlusion or high-dose steroid therapy significantly reduced myocardial water content on day 7 post-infarction. The dynamics of T2 relaxation times during the first post-infarction week were altered significantly in nonreperfused pigs compared with pigs undergoing regular I/R. CONCLUSIONS The 2 waves of the post-I/R edematous reaction are related to different pathophysiological phenomena. Although the first wave is secondary to reperfusion, the second wave occurs mainly because of tissue healing processes.S

Ischemic postconditioning fails to reduce infarct size in pig models of intermediate and prolonged ischemia

This study was funded by the Spanish Ministry of Science and Innovation (“RETOS 2019” grant No PID2019-107332RB-I00 to B.I). B.I is funded by the European Commission (ERC-CoG grant No 819775, and H2020-HEALTH grant No 945118). J.N. is recipient of a predoctoral grant (Jordi Soler Soler) through CIBERCV. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministry of Science and Innovation and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (CEX2020-001041-S).S

Metoprolol in Critically Ill Patients With COVID-19.

Severe coronavirus disease-2019 (COVID-19) can progress to an acute respiratory distress syndrome (ARDS), which involves alveolar infiltration by activated neutrophils. The beta-blocker metoprolol has been shown to ameliorate exacerbated inflammation in the myocardial infarction setting. The purpose of this study was to evaluate the effects of metoprolol on alveolar inflammation and on respiratory function in patients with COVID-19-associated ARDS. A total of 20 COVID-19 patients with ARDS on invasive mechanical ventilation were randomized to metoprolol (15 mg daily for 3 days) or control (no treatment). All patients underwent bronchoalveolar lavage (BAL) before and after metoprolol/control. The safety of metoprolol administration was evaluated by invasive hemodynamic and electrocardiogram monitoring and echocardiography. Metoprolol administration was without side effects. At baseline, neutrophil content in BAL did not differ between groups. Conversely, patients randomized to metoprolol had significantly fewer neutrophils in BAL on day 4 (median: 14.3 neutrophils/µl [Q1, Q3: 4.63, 265 neutrophils/µl] vs median: 397 neutrophils/µl [Q1, Q3: 222, 1,346 neutrophils/µl] in the metoprolol and control groups, respectively; P = 0.016). Metoprolol also reduced neutrophil extracellular traps content and other markers of lung inflammation. Oxygenation (PaO2:FiO2) significantly improved after 3 days of metoprolol treatment (median: 130 [Q1, Q3: 110, 162] vs median: 267 [Q1, Q3: 199, 298] at baseline and day 4, respectively; P = 0.003), whereas it remained unchanged in control subjects. Metoprolol-treated patients spent fewer days on invasive mechanical ventilation than those in the control group (15.5 ± 7.6 vs 21.9 ± 12.6 days; P = 0.17). In this pilot trial, intravenous metoprolol administration to patients with COVID-19-associated ARDS was safe, reduced exacerbated lung inflammation, and improved oxygenation. Repurposing metoprolol for COVID-19-associated ARDS appears to be a safe and inexpensive strategy that can alleviate the burden of the COVID-19 pandemic.Mr Clemente-Moragón is supported by a fellowship from the Ministerio de Ciencia e Innovación (FPU2017/01932). The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovación, and the Pro CNIC Foundation. Dr Ibáñez is supported by the European Commission (ERC-CoG grant No 819775) and by the Spanish Ministry of Science and Innovation (MCN; “RETOS 2019” grant No PID2019- 107332RB-I00). Dr Oliver is supported by funds from the Comunidad de Madrid Programa de Atracción de Talento (2017-T1/BMD-5185). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.S

Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity

Aims: Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. Methods and results: Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs. Conclusion: In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.Fil: Galán Arriola, Carlos. Centro de Investigacion Biomedica En Red.; EspañaFil: Villena Gutiérrez, Rocio. Centro de Investigacion Biomedica En Red.; EspañaFil: Higuero Verdejo, María I.. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: Díaz Rengifo, Iván A.. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: Pizarro, Gonzalo. Centro de Investigacion Biomedica En Red.; EspañaFil: López, Gonzalo J.. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: de Molina Iracheta, Antonio. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: Pérez Martínez, Claudia. Universidad de Leon. Facultad de Veterinaria; ArgentinaFil: García, Rodrigo Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: González Calle, David. Centro de Investigacion Biomedica En Red.; EspañaFil: Lobo, Manuel. Centro de Investigacion Biomedica En Red.; EspañaFil: Sánchez, Pedro L.. Centro de Investigacion Biomedica En Red.; EspañaFil: Oliver, Eduardo. Centro de Investigacion Biomedica En Red.; EspañaFil: Córdoba, Raúl. Hospital Fundacion Jimenez Diaz; EspañaFil: Fuster, Valentin. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: Sánchez González, Javier. No especifíca;Fil: Ibanez, Borja. Centro de Investigacion Biomedica En Red.; Españ

Intracoronary administration of allogeneic adipose tissue-derived mesenchymal stem cells improves myocardial perfusion but not left ventricle function, in a translational model of acute myocardial infarction

Background-¿Autologous adipose tissue-derived mesenchymal stem cells (ATMSCs) therapy is a promising strategy to improve post-myocardial infarction outcomes. In a porcine model of acute myocardial infarction, we studied the long-term effects and the mechanisms involved in allogeneic ATMSCs administration on myocardial performance. Methods and Results-¿Thirty-eight pigs underwent 50 minutes of coronary occlusion; the study was completed in 33 pigs. After reperfusion, allogeneic ATMSCs or culture medium (vehicle) were intracoronarily administered. Follow-ups were performed at short (2 days after acute myocardial infarction vehicle-treated, n=10; ATMSCs-treated, n=9) or long term (60 days after acute myocardial infarction vehicle-treated, n=7; ATMSCs-treated, n=7). At short term, infarcted myocardium analysis showed reduced apoptosis in the ATMSCs-treated animals (48.6 6% versus 55.9 5.7% in vehicle; P=0.017); enhancement of the reparative process with up-regulated vascular endothelial growth factor, granulocyte macrophage colony-stimulating factor, and stromal-derived factor-1a gene expression; and increased M2 macrophages (67.2 10% versus 54.7 10.2% in vehicle; P=0.016). In long-term groups, increase in myocardial perfusion at the anterior infarct border was observed both on day-7 and day-60 cardiac magnetic resonance studies in ATMSCs-treated animals, compared to vehicle (87.9 28.7 versus 57.4 17.7 mL/min per gram at 7 days; P=0.034 and 99 22.6 versus 43.3 14.7 22.6 mL/min per gram at 60 days; P=0.0001, respectively). At day 60, higher vascular density was detected at the border zone in the ATMSCs-treated animals (118 18 versus 92.4 24.3 vessels/mm2 in vehicle; P=0.045). Cardiac magnetic resonance-measured left ventricular ejection fraction of left ventricular volumes was not different between groups at any time point. Conclusions-¿In this porcine acute myocardial infarction model, allogeneic ATMSCs-based therapy was associated with increased cardioprotective and reparative mechanisms and with better cardiac magnetic resonance-measured perfusion. No effect on left ventricular volumes or ejection fraction was observed

Priorities in Cardio-Oncology Basic and Translational Science

Despite improvements in cancer survival, cancer therapy–related cardiovascular toxicity has risen to become a prominent clinical challenge. This has led to the growth of the burgeoning field of cardio-oncology, which aims to advance the cardiovascular health of cancer patients and survivors, through actionable and translatable science. In these Global Cardio-Oncology Symposium 2023 scientific symposium proceedings, we present a focused review on the mechanisms that contribute to common cardiovascular toxicities discussed at this meeting, the ongoing international collaborative efforts to improve patient outcomes, and the bidirectional challenges of translating basic research to clinical care. We acknowledge that there are many additional therapies that are of significance but were not topics of discussion at this symposium. We hope that through this symposium-based review we can highlight the knowledge gaps and clinical priorities to inform the design of future studies that aim to prevent and mitigate cardiovascular disease in cancer patients and survivors.</p

Fast T2 gradient-spin-echo (T2-GraSE) mapping for myocardial edema quantification: first in vivo validation in a porcine model of ischemia/reperfusion

BACKGROUND: Several T2-mapping sequences have been recently proposed to quantify myocardial edema by providing T2 relaxation time values. However, no T2-mapping sequence has ever been validated against actual myocardial water content for edema detection. In addition, these T2-mapping sequences are either time-consuming or require specialized software for data acquisition and/or post-processing, factors impeding their routine clinical use. Our objective was to obtain in vivo validation of a sequence for fast and accurate myocardial T2-mapping (T2 gradient-spin-echo [GraSE]) that can be easily integrated in routine protocols. METHODS: The study population comprised 25 pigs. Closed-chest 40 min ischemia/reperfusion was performed in 20 pigs. Pigs were sacrificed at 120 min (n = 5), 24 h (n = 5), 4 days (n = 5) and 7 days (n = 5) after reperfusion, and heart tissue extracted for quantification of myocardial water content. For the evaluation of T2 relaxation time, cardiovascular magnetic resonance (CMR) scans, including T2 turbo-spin-echo (T2-TSE, reference standard) mapping and T2-GraSE mapping, were performed at baseline and at every follow-up until sacrifice. Five additional pigs were sacrificed after baseline CMR study and served as controls. RESULTS: Acquisition of T2-GraSE mapping was significantly (3-fold) faster than conventional T2-TSE mapping. Myocardial T2 relaxation measurements performed by T2-TSE and T2-GraSE mapping demonstrated an almost perfect correlation (R(2) = 0.99) and agreement with no systematic error between techniques. The two T2-mapping sequences showed similarly good correlations with myocardial water content: R(2) = 0.75 and R(2) = 0.73 for T2-TSE and T2-GraSE mapping, respectively. CONCLUSIONS: We present the first in vivo validation of T2-mapping to assess myocardial edema. Given its shorter acquisition time and no requirement for specific software for data acquisition or post-processing, fast T2-GraSE mapping of the myocardium offers an attractive alternative to current CMR sequences for T2 quantification

New insights into anthracyline-induced cardiotoxicity

The increasing life expectancy of the population and the development of effective anticancer therapies result in a growing population of aged cancer survivors, which frequently have comorbidities for developing heart failure (HF). Anthracyclines are still first line treatment for many cancer types, but up to 10% of patients who received them develop some form of cardiotoxicity and subsequent HF. The trade-off between cancer and chronic HF is of massive psychological burden for patients, and of devastating economic consequences for healthcare systems.. Despite anthracyclines have been used since the 1960s, and their cardiotoxic effects known very early since they became standard of care, there are still several gaps and open questions regarding this frequent side effect. In particular, there is a need to gain scientific knowledge about early detection of anthracycline-induced cardiotoxicity, to better understand mechanisms leading to toxicity and cues about inter-individual vulnerability, and the identification of therapies that can prevent or treat this form of myocardial damage. The present thesis focuses on these 4 critical unresolved aspects by addressing the following objectives: 1) To identify the earliest non-invasive marker of anthracycline-induced cardiotoxicity; 2) to study the role of microcirculation damage as part of the cardiotoxicity effect of anthracyclines; 3) to study the interplay between cardiac hypertrophy and exposure to anthracyclines to induce cardiotoxicity; and 4) to test the effect of remote ischemic conditioning as a therapy to prevent anthracycline-induced cardiotoxicity. To reach these aims, we developed different swine models of anthracycline-induced cardiotoxicity and hypertrophy, and we used state of the art cardiac magnetic resonance imaging.N

New insights into anthracycline-induced cardiotoxicity

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 21-02-2020El incremento de la esperanza de vida en la población así como el desarrollo de nuevas terapias efectivas contra el cáncer han dado lugar a un aumento en la población de supervivientes de cáncer en edad avanzada; los cuales, frecuentemente presentan comorbilidades que predisponen al desarrolo de insuficiencia cardiaca. las antraciclinas son una primera opción para numerosos tipos de cánceres, pero cerca del 10 % de los pacientes que las reciben desarrollan alguna forma de cardiotoxicidad y posterior desarrollo de insuficiencia cardíaca. El "intercambio" del cáncer a la insuficiencia cardíaca supone una pesada carga psicológica para los pacientes y tiene consecuencias económocas devastadoras para los sistemas de salud. A pesar de que las antraciclinas se han utilizado desde la década de 1960, y sus efectos cardiotóxicos se conocieron poco después de convertirse en el estándar de muchos protocolos de quimioterapia, todavía hay varias lagunas y preguntas abiertas con respecto a este efecto secundario tan frecuente. En particular, es necesario obtener conocimiento científico sobre la detección temprana de la cardiotoxicidad inducida por antraciclinas, para comprender mejor los mecanismos que conducen a este daño así como las señales sobre la vulnerabilidad inter-individual y la identificación de terapias que puedan prevenir o tratar esta forma de daño miocárdico. La presente tesis se enfoca en estos 4 aspectos críticos no resueltos, abordando para ello los siguientes objetivos: 1) Indentificar el marcador más temprano de cardiotoxicidad mediante técnicas de imagen no invasivas; 2) estudiar el papel del daño en la microcirculación como parte de esta cardiotoxicidad; 3) estudiar la interacción entre la hipertrofia cardiaca y la exposición a antraciclinas; y 4) evaluar el efecto del precondicionamiento remoto isquémico como terapia para prevenir la cardiotoxicidad inducida por antraciclinas. Para lograr estos objetivos, desarrollamos diferentes modelos porcinos de cardiotoxicidad y utilizamos la tecnología de la resonancia magnética cardiaca.The increasing life expectancy of the population and the development of effective anticancer therapies result in a growing population of aged cancer survivors, which frequently have comorbidities for developing heart failure (HF). Anthracyclines are still first line treatment for many cancer types, but up to 10% of patients who received them develop some form of cardiotoxicity and subsequent HF. The trade-off between cancer and chronic HF is of massive psychological burden for patients, and of devastating economic consequences for healthcare systems.. Despite anthracyclines have been used since the 1960s, and their cardiotoxic effects known very early since they became standard of care, there are still several gaps and open questions regarding this frequent side effect.In particular, there is a need to gain scientific knowledge about early detection of anthracycline-induced cardiotoxicity, to better understand mechanisms leading to toxicity and cues about inter-individual vulnerability, and the identification of therapies that can prevent or treat this form of myocardial damage. The present thesis focuses on these 4 critical unresolved aspects by addressing the following objectives: 1) To identify the earliest non-invasive marker of anthracycline-induced cardiotoxicity; 2) To study the role of microcirculation damage as part of the cardiotoxicity effect of anthracyclines; 3) to study the interplay between cardiac hypertrophy and exposure to anthracyclines to induce cardiotoxicity; and 4) to test the effect of remote ischemic conditioning as a therapy to prevent anthracycline-induced cardiotoxicity. To reach these aims, we developed different swine models of anthracycline-induced cardiotoxicity and hypertrophy, and we used state of the art cardiac magnetic resonance imaging

The quest for the mechanism responsible for the cardiovascular benefits of novel antidiabetic agents.

B.Ibáñez is supported by the European Commission (H2020-HEALTH grant Nº 945118 and ERC-CoG grant Nº 819775) and by the Spanish Ministry of Science and Innovation (MCN; ‘RETOS 2019’ grant Nº PID2019-107332RB-I00), and by the Spanish Society of Cardiology. The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovación, and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (CEX2020-001041-S).S