Generation of an induced pluripotent stem cell line (ESi107-A) from a transthyretin amyloid cardiomyopathy (ATTR-CM) patient carrying a p.Ser43Asn mutation in the TTR gene

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a life-threatening disease caused by the abnormal production of misfolded TTR protein by liver cells, which is then released systemically. Its amyloid deposition in the heart is linked to cardiac toxicity and progression toward heart failure. A human induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells (PBMCs) from a patient suffering familial transthyretin amyloid cardiomyopathy carrying a c.128G>A (p.Ser43Asn) mutation in the TTR gene. This iPSC line offers a useful resource to study the disease pathophysiology and a cell-based model for therapeutic discovery

Catheter-based intramyocardial injection of FGF1 or NRG1-loaded MPs improves cardiac function in a preclinical model of ischemia-reperfusion

Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemiareperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials

Acute L waves in heart failure

L waves are an unusual finding in the analysis of mitral valve pulsed-wave Doppler. This wave is recorded as flow between the left atrium and left ventricle during diastole, due to elevated left ventricular (LV) filling pressures.1---3 In this situation, triphasic mitral filling can be observed, with the presence of mid-diastolic L wave

Caracterización de la miocarditis por COVID-19 mediante resonancia magnética cardiaca

Desde su primera descripción en diciembre de 2019 en la ciudad de Wuhan (Hubei, China), un nuevo tipo de coronavirus mutado, llamado coronavirus 2 del síndrome respiratorio agudo grave (SARS-CoV-2), ha infectado a más de 3,6 millones de personas y ha causado más de 257.000 muertos en todo el mundo (hasta el 5 de mayo de 2020). Preocupa cada vez más que la afección respiratoria aguda que tiene lugar en la enfermedad coronavírica de 2019 (COVID-19) tenga fuerte relación con el daño cardiovascular. Los pacientes con COVID-19 corren el riesgo de sufrir arritmias cardiacas, síndromes coronarios agudos, eventos relacionados con insuficiencia cardiaca y miocarditis fulminante. La lesión miocárdica puede ocurrir en distintas fases de la COVID-19 (p. ej., fases viral, pulmonar, inflamatoria y de recuperación), incluso tardíamente tras el inicio de los síntomas

Combined catheter ablation and left atrial appendage closure as a hybrid procedure for the treatment of atrial fibrillation

Aims: Left atrial appendage (LAA) is the source of thrombi in up to 90% of patients with non-valvular atrial fibrillation (AF). Catheter ablation (CA) is an effective treatment for symptomatic AF and, in selected cases, LAA occlusion devices have been introduced as an alternative to oral anticoagulants (OACs). The safety and feasibility of combining CA and percutaneous LAA closure (LAAC) are unknown. Methods and results: Patients with symptomatic drug-refractory AF, CHADS2 score of ≥1, and CHA2DS2-VASc score ≥2 were included. Catheter ablation consisted in pulmonary vein isolation with or without roof line with radiofrequency and LAA was occluded with the Watchman or Amplatzer Cardiac Plug (ACP) devices guided by angiography and transoesophageal echocardiography. A total of 35 patients were included (71% male; 70 years). Median score was 3 on both CHA2DS2-VASc and HAS-BLED, 9% had prior stroke under OAC, and 48% had bleeding complications. Successful CA and device implantation were achieved in 97% of cases. The Watchman device was used in 29 patients and ACP in 6 patients. Periprocedural complications included three cases of cardiac tamponade. At 3 months, all patients met the criteria for successful sealing of the LAA. After a mean follow-up of 13 months (3-75), 78% of patients were free of arrhythmia recurrences and OAC was withheld in 97% of patients. Conclusions: The combination of CA and percutaneous LAAC in a single procedure is technically feasible in patients with symptomatic drug-refractory AF, high risk of stroke, and contraindications to OACs, although it is associated with a significant risk of major complications

Catheter-based intramyocardial injection of FGF1 or NRG1-loaded MPs improves cardiac function in a preclinical model of ischemia-reperfusion

Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemiareperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials

Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

Abstract. Cannabinoids are neuroprotective in models of neurodegenerative dementias. Their effects are mostly mediated through CB1 and CB2 receptor-dependent modulation of excitotoxicity, inflammation, oxidative stress, and other processes. We tested the effects of Sativex ® , a mixture of 9 -tetrahydrocannabinol and cannabidiol, acting on both CB1 and CB2 receptors, in parkin-null, human tau overexpressing (PK −/− /Tau VLW ) mice, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease. The animals received Sativex ® , 4.63 mg/kg, ip, daily, for one month, at six months of age, at the onset of the clinical symptoms. We evaluated the effects of Sativex ® on behavior, dopamine neurotransmission, glial activation, redox state, mitochondrial activity, and deposition of abnormal proteins. PK −/− /Tau VLW mice developed the neurological deficits, but those treated with Sativex ® showed less abnormal behaviors related to stress, less auto and hetero-aggression, and less stereotypy. Sativex ® significantly reduced the intraneuronal, MAO-related free radicals produced during dopamine metabolism in the limbic system. Sativex ® also decreased gliosis in cortex and hippocampus, increased the ratio reduced/oxidized glutathione in the limbic system, reduced the levels of iNOS, and increased those of complex IV in the cerebral cortex. With regard to tau and amyloid pathology, Sativex ® reduced the deposition of both in the hippocampus and cerebral cortex of PK −/− /Tau VLW mice and increased autophagy. Sativex ® , even after a short administration in animals with present behavioral and pathological abnormalities, improves the phenotype, the oxidative stress, and the deposition of proteins in PK −/− /Tau VLW mice, a model of complex neurodegenerative disorders

Myocardial work index in professional football players: A novel method for assessment of cardiac adaptation

: Background: The global myocardial work index (GWI), a novel, valid, and non-invasive method based on speckle-tracking echocardiography, could provide value for calculating left ventricular (LV) function and energy consumption in athletes. Materials and Methods: We prospectively analyzed a single-center cohort of Spanish First-Division football players who attended a pre-participation screening program from June 2020 to June 2021, compared to a control group. All the individuals underwent an electrocardiogram and echocardiography, including two-dimensional speckle tracking and 4D-echo. The study aimed to evaluate the feasibility of myocardial work in professional football players and its correlations with other echocardiographic parameters. Results: The study population comprised 97 individuals (49 professional players and 48 controls). The mean age was 30.48 ± 7.20 years old. The professional football players had significantly higher values of LVEDV (p < 0.001), LVESV (p < 0.001), LV-mass index (p = 0.011), PWTd (p = 0.023), and EA (p < 0.001) compared with the control group. In addition, the professional players had lower GCW (p = 0.003) and a tendency to show lower GWI values (p < 0.001). These findings could suggest that professional football players have more remodeling and less MW, related to their adaptation to intensive training. Significant differences in GLS (p = 0.01) and GWE (p = 0.04) were observed as a function of the septal thickness of the athletes. Irrespective of the MW variable, the parameters with better correlations across all the populations were SBP, DBP, and GLS. Conclusions: The GWI is a novel index to assess cardiac performance, with less load dependency than strain measurements. Future GWI analyses are warranted to understand myocardial deformation and other pathological differential diagnoses

A multimodal scaffold for SDF1 delivery improves cardiac function in a rat subacute myocardial infarct model

Ischemic heart disease is one of the leading causes of death worldwide. The efficient delivery of therapeutic growth factors could counteract the adverse prognosis of post-myocardial infarction (post-MI). In this study, a collagen hydrogel that is able to load and appropriately deliver pro-angiogenic stromal cell-derived factor 1 (SDF1) was physically coupled with a compact collagen membrane in order to provide the suture strength required for surgical implantation. This bilayer collagen-on-collagen scaffold (bCS) showed the suitable physicochemical properties that are needed for efficient implantation, and the scaffold was able to deliver therapeutic growth factors after MI. In vitro collagen matrix biodegradation led to a sustained SDF1 release and a lack of cytotoxicity in the relevant cell cultures. In vivo intervention in a rat subacute MI model resulted in the full integration of the scaffold into the heart after implantation and biocompatibility with the tissue, with a prevalence of anti-inflammatory and pro-angiogenic macrophages, as well as evidence of revascularization and improved cardiac function after 60 days. Moreover, the beneficial effect of the released SDF1 on heart remodeling was confirmed by a significant reduction in cardiac tissue stiffness. Our findings demonstrate that this multimodal scaffold is a desirable matrix that can be used as a drug delivery system and a scaffolding material to promote functional recovery after MI

Generation of an induced pluripotent stem cell line (ESi107-A) from a transthyretin amyloid cardiomyopathy (ATTR-CM) patient carrying a p.Ser43Asn mutation in the TTR gene

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a life-threatening disease caused by the abnormal production of misfolded TTR protein by liver cells, which is then released systemically. Its amyloid deposition in the heart is linked to cardiac toxicity and progression toward heart failure. A human induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells (PBMCs) from a patient suffering familial transthyretin amyloid cardiomyopathy carrying a c.128G>A (p.Ser43Asn) mutation in the TTR gene. This iPSC line offers a useful resource to study the disease pathophysiology and a cell-based model for therapeutic discovery