Antiarrhythmic and Anti-Inflammatory Effects of Sacubitril/Valsartan on Post-Myocardial Infarction Scar.

BACKGROUND: Sacubitril/valsartan (Sac/Val) is superior to angiotensin-converting enzyme inhibitors in reducing the risk of heart failure hospitalization and cardiovascular death, but its mechanistic data on myocardial scar after myocardial infarction (MI) are lacking. The objective of this work was to assess the effects of Sac/Val on inflammation, fibrosis, electrophysiological properties, and ventricular tachycardia inducibility in post-MI scar remodeling in swine. METHODS: After MI, 22 pigs were randomized to receive ß-blocker (BB; control, n=8) or BB+Sac/Val (Sac/Val, n=9). The systemic immune response was monitored. Cardiac magnetic resonance data were acquired at 2-day and 29-day post MI to assess ventricular remodeling. Programmed electrical stimulation and high-density mapping were performed at 30-day post MI to assess ventricular tachycardia inducibility. Myocardial samples were collected for histological analysis. RESULTS: Compared with BB, BB+Sac/Val reduced acute circulating leukocytes (P=0.009) and interleukin-12 levels (P=0.024) at 2-day post MI, decreased C-C chemokine receptor type 2 expression in monocytes (P=0.047) at 15-day post MI, and reduced scar mass (P=0.046) and border zone mass (P=0.043). It also lowered the number and mass of border zone corridors (P=0.009 and P=0.026, respectively), scar collagen I content (P=0.049), and collagen I/III ratio (P=0.040). Sac/Val reduced ventricular tachycardia inducibility (P=0.034) and the number of deceleration zones (P=0.016). CONCLUSIONS: After MI, compared with BB, BB+Sac/Val was associated with reduced acute systemic inflammatory markers, reduced total scar and border zone mass on late gadolinium-enhanced magnetic resonance imaging, and lower ventricular tachycardia inducibility.

Implantation of a double allogeneic human engineered tissue graft on damaged heart: insights from the PERISCOPE phase I clinical trial.

BACKGROUND: In preclinical studies, the use of double allogeneic grafts has shown promising results in promoting tissue revascularization, reducing infarct size, preventing adverse remodelling and fibrosis, and ultimately enhancing cardiac function. Building upon these findings, the safety of PeriCord, an engineered tissue graft consisting of a decellularised pericardial matrix and umbilical cord Wharton's jelly mesenchymal stromal cells, was evaluated in the PERISCOPE Phase I clinical trial (NCT03798353), marking its first application in human subjects. METHODS: This was a double-blind, single-centre trial that enrolled patients with non-acute myocardial infarction eligible for surgical revascularization. Seven patients were implanted with PeriCord while five served as controls. FINDINGS: Patients who received PeriCord showed no adverse effects during post-operative phase and one-year follow-up. No significant changes in secondary outcomes, such as quality of life or cardiac function, were found in patients who received PeriCord. However, PeriCord did modulate the kinetics of circulating monocytes involved in post-infarction myocardial repair towards non-classical inflammation-resolving macrophages, as well as levels of monocyte chemoattractants and the prognostic marker Meteorin-like in plasma following treatment. INTERPRETATION: In summary, the PeriCord graft has exhibited a safe profile and notable immunomodulatory properties. Nevertheless, further research is required to fully unlock its potential as a platform for managing inflammatory-related pathologies. FUNDING: This work was supported in part by grants from MICINN (SAF2017-84324-C2-1-R); Instituto de Salud Carlos III (ICI19/00039 and Red RICORS-TERAV RD21/0017/0022, and CIBER Cardiovascular CB16/11/00403) as a part of the Plan Nacional de I + D + I, and co-funded by ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER) and AGAUR (2021-SGR-01437).

La proteína meteorin-like se asocia a un perfil de mayor riesgo y predice un peor pronóstico en pacientes con IAMCEST / Meteorin-like protein is associated with a higher risk profile and predicts a worse outcome in patients with STEMI

Introducción y objetivos: La proteína meteorin-like (Metrnl) es una citocina implicada en la atenuación de la inflamación asociada a mal pronóstico en la insuficiencia cardiaca. En este estudio se evalúan los niveles circulantes de Metrnl y su valor pronóstico en el infarto agudo de miocardio con elevación del segmento ST (IAMCEST).Métodos: Se incluyó a pacientes con IAMCEST tratados con angioplastia primaria. Se determinaron los niveles de Metrnl en sangre periférica a las 12 horas del inicio de los síntomas. El criterio de evaluación primario fue muerte por cualquier causa o infarto de miocardio no mortal a 3 años.Resultados: Se estudiaron 381 pacientes (edad media 61 años, 21% mujeres, 8% clase Killip III/IV). Los niveles de Metrnl se asociaron con la edad, los factores de riesgo cardiovascular y la extensión de la enfermedad coronaria, pero también con complicaciones del infarto, especialmente insuficiencia cardíaca y shock cardiogénico. En la regresión multivariante de Cox Metrnl fue un predictor independiente del criterio de evaluación combinado (HR = 1,86; IC95%, 1,23-2,81; p=0,003). Además, los pacientes en el tercil más alto (> 491,6 pg/ml) presentaron mayor riesgo que en los terciles inferiores (HR = 3,24; IC95%, 1,92-5,44; p <0,001), incluso después de ajustar por edad, diabetes, paro cardíaco, clase Killip-Kimball III/IV, fracción de eyección y aclaramiento de creatinina (HR = 1,90; IC95%, 1,10-3,29; p=0,021).Conclusiones: En los pacientes con IAMCEST, los niveles circulantes de Metrnl se asocian con las complicaciones durante la fase aguda y predicen de forma independiente un peor pronóstico.(AU)

Introduction and objectives: Meteorin-like protein (Metrnl) is a cytokine involved in the attenuation of inflammation. In patients with heart failure, high levels of this biomarker are associated with a worse outcome. In this study, we evaluated the circulating levels and prognostic value of Metrnl in patients with ST-segment elevation myocardial infarction (STEMI).Methods: We enrolled STEMI patients undergoing primary percutaneous coronary intervention. Circulating Metrnl levels were measured in peripheral blood 12hours after symptom onset. The primary endpoint was a composite of all-cause mortality or nonfatal myocardial infarction (MI) at 3 years.Results: We studied 381 patients (mean age 61 years, 21% female, 8% Killip class III/IV). Metrnl levels were associated with age, cardiovascular risk factors and the extent of coronary artery disease, as well as with STEMI complications, particularly heart failure and cardiogenic shock. Multivariable Cox regression analysis revealed that Metrnl independently predicted all-cause death or nonfatal MI at 3 years (HR, 1.86; 95%CI, 1.23-2.81; P=.003). Moreover, patients in the highest tertile (> 491.6 pg/mL) were at higher risk for the composite endpoint than those in the lowest tertiles (HR, 3.24; 95%CI, 1.92-5.44; P <.001), even after adjustment by age, diabetes mellitus, cardiac arrest, Killip-Kimball III/IV class, left ventricular ejection fraction, and creatinine clearance (HR, 1.90; 95%CI, 1.10-3.29; P=.021).Conclusions: Circulating Metrnl levels are associated with complications during the acute phase of STEMI and independently predict a worse outcome in these patients.(AU)

Ingeniería tisular cardiaca y corazón bioartificial / Cardiac tissue engineering and the bioartificial heart

La insuficiencia cardiaca es la etapa final de muchas enfermedades cardiovasculares, como el infarto agudo de miocardio, y sigue siendo uno de los retos más atractivos para la medicina regenerativa debido a su alta incidencia y prevalencia. A lo largo de los últimos 20 años, la cardiomioplastia, basada en la administración aislada de células con capacidad regenerativa, ha focalizado la mayoría de estudios que han perseguido regenerar el corazón. No obstante, aunque esta terapia se ha mostrado factible en el ámbito clínico, el grado de regeneración del miocardio infartado y de mejoría de la función cardiaca es muy limitado. Ante tal escenario ha emergido la ingeniería tisular cardiaca como una novedosa tecnología basada en el uso de células con capacidad regenerativa, materiales biológicos y/o sintéticos, factores de crecimiento, diferenciación y proangiogénicos, y sistemas de registro online para inducir la regeneración de un órgano o tejido dañado. Un paso más, según algunos estudios pioneros realizados en animales, consiste en la generación de corazones bioartificiales de novo descelularizándolos y preservando sus estructuras de soporte para posteriormente repoblarlos con nuevo tejido muscular contráctil y vascular. Este nuevo abordaje comportaría, finalmente, el trasplante del corazón «reconstruido» restableciendo la función cardiaca del receptor (AU)

Heart failure is the end-stage of many cardiovascular diseases—such as acute myocardial infarction—and remains one of the most appealing challenges for regenerative medicine because of its high incidence and prevalence. Over the last 20 years, cardiomyoplasty, based on the isolated administration of cells with regenerative capacity, has been the focal point of most studies aimed at regenerating the heart. Although this therapy has proved feasible in the clinical setting, the degree of infarcted myocardium regenerated and of improved cardiac function are at best modest. Hence, tissue engineering has emerged as a novel technology using cells with regenerative capacity, biological and/or synthetic materials, growth, proangiogenic and differentiation factors, and online registry systems, to induce the regeneration of whole organs or locally damaged tissue. The next step, seen recently in pioneering animal studies, is de novo generation of bioartificial hearts by decellularization and preservation of supporting structures for their subsequent repopulation with new contractile, vascular muscle tissue. Ultimately, this new approach would entail transplantation of the “rebuilt” heart, reestablishing cardiac function in the recipient (AU)