Left Atrium Assessment by Speckle Tracking Echocardiography in Cryptogenic Stroke: Seeking Silent Atrial Fibrillation

Enfermedad auricular; Fibrilación auricular; EcocardiografíaMalaltia auricular; Fibril·lació auricular; EcocardiografiaAtrial disease; Atrial fibrillation; EchocardiographySilent atrial fibrillation (AF) may be the cause of some cryptogenic strokes (CrS). The aim of the study was to analyse atrial size and function by speckle tracking echocardiography in CrS patients to detect atrial disease. Patients admitted to the hospital due to CrS were included prospectively. Echocardiogram analysis included left atrial ejection fraction (LAEF) and atrial strain. Insertable cardiac monitor was implanted, and AF was defined as an episode of ≥1 min in the first year after stroke. Left atrial enlargement was defined as indexed volume > 34 mL/m2. Seventy-five consecutive patients were included, aged 76 ± 9 years (arterial hypertension 75%). AF was diagnosed in 49% of cases. The AF group had higher atrial volume and worse atrial function: peak atrial longitudinal strain (PALs) 19.6 ± 5.7% vs. 29.5 ± 7.2%, peak atrial contraction strain (PACs) 8.9 ± 3.9% vs. 16.5 ± 6%, LAEF 46.8 ± 11.5% vs. 60.6 ± 5.2%; p < 0.001. AF was diagnosed in 20 of 53 patients with non-enlarged atrium, and in 18 of them, atrial dysfunction was present. The multivariate logistic regression analysis demonstrated an independent association between detection of AF and atrial volume, LAEF, and strain. Cut-off values were obtained: LAEF < 55%, PALs < 21.4%, and PACs < 12.9%. In conclusion, speckle tracking echocardiography in CrS patients improves silent atrial disease diagnosis, with or without atrial enlargement.This research was funded by Instituto de Salud Carlos III-FIS (Fondo de Investigación Sanitaria, PI13/01830)

TRPV4 Channels Promote Pathological, but Not Physiological, Cardiac Remodeling through the Activation of Calcineurin/NFAT and TRPC6

TRPV4 channels, which respond to mechanical activation by permeating Ca2+ into the cell, may play a pivotal role in cardiac remodeling during cardiac overload. Our study aimed to investigate TRPV4 involvement in pathological and physiological remodeling through Ca2+-dependent signaling. TRPV4 expression was assessed in heart failure (HF) models, induced by isoproterenol infusion or transverse aortic constriction, and in exercise-induced adaptive remodeling models. The impact of genetic TRPV4 inhibition on HF was studied by echocardiography, histology, gene and protein analysis, arrhythmia inducibility, Ca2+ dynamics, calcineurin (CN) activity, and NFAT nuclear translocation. TRPV4 expression exclusively increased in HF models, strongly correlating with fibrosis. Isoproterenol-administered transgenic TRPV4-/- mice did not exhibit HF features. Cardiac fibroblasts (CFb) from TRPV4+/+ animals, compared to TRPV4-/-, displayed significant TRPV4 overexpression, elevated Ca2+ influx, and enhanced CN/NFATc3 pathway activation. TRPC6 expression paralleled that of TRPV4 in all models, with no increase in TRPV4-/- mice. In cultured CFb, the activation of TRPV4 by GSK1016790A increased TRPC6 expression, which led to enhanced CN/NFATc3 activation through synergistic action of both channels. In conclusion, TRPV4 channels contribute to pathological remodeling by promoting fibrosis and inducing TRPC6 upregulation through the activation of Ca2+-dependent CN/NFATc3 signaling. These results pose TRPV4 as a primary mediator of the pathological response

Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS

Dilatación aórtica y miocardiopatía por sobrecarga de presión en el síndrome de Marfan: impacto del entrenamiento y del género

[spa] Estudios recientes sugieren la existencia de una afectación miocárdica propia en el síndrome de Marfan (SM). Cabe mencionar que no hay datos sobre el potencial impacto diferencial del género en la manifestación de los signos de la miocardiopatía en SM, ni evidencia para apoyar el hecho de que el deporte con una carga mayor que baja siempre se haya desaconsejado en pacientes con el SM. Los objetivos son determinar si existe una respuesta funcional miocárdica anormal en el SM mediante la detección de la deformación miocárdica alterada y si ésta presenta patrones de deformación regional alterados típicos de los estados de incremento de postcarga. Evaluar el impacto del ejercicio físico en la dilatación de aorta ascendente y la miocardiopatía en el SM. Examinar diferencias de género en la presentación de dicha deformación alterada y los factores asociados a la misma. En el primer proyecto se han estudiado tres poblaciones: ratones de 4 y 9 meses de edad y pacientes humanos, con la medición de la presión arterial y la ecocardiografía avanzada con el Modo 2D, M y Doppler Tisular. El principal hallazgo fue la alta prevalencia de engrosamiento postsistólico (EPS) en el SM, detectado tanto en un modelo experimental murino como en una cohorte de pacientes con SM. En los ratones de 4 meses de edad, la presencia de EPS se asoció a la dilatación de la raíz aórtica a pesar de que no hubo diferencias estadísticamente significativas en la presión arterial entre el grupo de ratones con EPS y aquellos sin EPS. Curiosamente, los pacientes con EPS muestran una presión arterial sistólica más baja que los controles y se observa una asociación entre el aumento de la prevalencia de EPS y la dilatación aórtica en pacientes muy jóvenes. En el segundo proyecto se han analizado los ratones de 4 meses antes y después de la intervención en forma del programa del entreno físico controlado a moderada carga durante 5 meses. Los resultados evidencian que el ejercicio regular de intensidad moderada no acelera la tasa de dilatación aórtica, sino que más bien normaliza su progresión a valores comparables al observado en los animales sanos. Los ratones con SM del grupo entrenado mostraron un ligero aumento de la presión arterial sistólica, en comparación con los ratones sin SM. Sin embargo, vimos que, a pesar de este incremento en la presión arterial, hubo una menor dilatación aórtica y una menor hipertrofia de ventrículo izquierdo. En el tercer proyecto se han correlacionado los datos clínico-farmacológicos con los datos ecocardiográficos de los pacientes humanos según el sexo, revelando un claro impacto diferencial del género, siendo significativamente más frecuente el EPS en las mujeres, hecho asociado a que las mujeres reciben con menor frecuencia tratamiento con betabloqueadores y losartan, a pesar de que los diámetros aórticos y ventriculares son muy similares entre ambos géneros. Cabe destacar que la presión arterial es más alta en el caso de mujeres con EPS presente, en comparación con las que no presentan este signo. La alta prevalencia del EPS, tanto en ratones como en pacientes con SM, sugiere la existencia de miocardiopatía por sobrecarga de presión. Este marcador puede proporcionar una herramienta de detección y monitorización del remodelado cardíaco. En un modelo murino de SM, el ejercicio dinámico de intensidad moderada se asocia a una menor dilatación aórtica, menor hipertrofia cardíaca y menor frecuencia de EPS. La presencia de EPS se observa con mayor frecuencia en pacientes mujeres con SM que en pacientes de sexo masculino; sin embargo, las mujeres con SM reciben con menor frecuencia tratamiento vasodilatador a pesar de que su presión es significativamente más alta.[eng] Several studies have observed myocardial abnormalities in Marfan syndrome (MS). There are no data on the potential differential impact of gender on manifestation of the signs of cardiomyopathy in MS and the evidence is lacking to support the fact that sport with a load greater than low has always been discouraged in those patients. We postulate that patients with MS may have the ventricular myocardium more susceptible to afterload and therefore may develop greater segmental left ventricular (LV) wall stress heterogeneity due to underlying abnormal tissue of the arterial wall and/or myocardium. In the first project, three populations have been studied, 4- and 9-month-old mice and human patients. Main finding was the high prevalence of postsystolic thickening (PST) in MS and its association with aortic root dilatation, both in the experimental murine model and in a cohort of young patients. In the second project, the population of 4 month-old mice before and after the controlled physical training program at moderate load during 5 months have been analyzed. Regular exercise of moderate intensity does not accelerate the rate of aortic dilatation, but rather normalizes its progression. The third project reveals a clear differential impact of gender, the PST is significantly more frequent in women. This finding is associated with the fact that women receive treatment with beta-blockers and losartan less frequently, despite the fact that aortic and ventricular diameters are very similar between both genders. The high prevalence of the PST, both in mice and in patients with MS, suggests the finding of pressure overload cardiomyopathy. The PST can provide a tool for detection and monitoring of cardiac remodeling and support the decision to start preventive therapies in patients with MS, even with normal blood pressure levels. In a murine model of MS, moderate-intensity dynamic exercise is associated with less aortic dilation, less cardiac hypertrophy, and lower PST prevalence. The presence of PST is observed more frequently in female patients with MS than in male patients; however, women with MS receive vasodilator treatment less frequently despite the fact that their pressure is significantly higher

Prognosis of paradoxical low-flow low-gradient aortic stenosis: a severe, non-critical form, with surgical treatment benefits

Objectives: to determine the risk of mortality and need for aortic valve replacement (AVR) in patients with low-flow low-gradient (LFLG) aortic stenosis (AS). Methods: a longitudinal multicentre study including consecutive patients with severe AS (aortic valve area [AVA] 35 ml/m2) and LFLG (mean gradient < 40 mmHg, SVi ≤ 35 ml/m2). Results: of 1,391 patients, 147 (10.5%) had LFLG, 752 (54.1%) HG, and 492 (35.4%) NFLG. Echocardiographic parameters of the LFLG group showed similar AVA to the HG group but with less severity in the dimensionless index, calcification, and hypertrophy. The HG group required AVR earlier than NFLG (p < 0.001) and LFLG (p < 0.001), with no differences between LFLG and NFLG groups (p = 0.358). Overall mortality was 27.7% (CI 95% 25.3-30.1) with no differences among groups (p = 0.319). The impact of AVR in terms of overall mortality reduction was observed the most in patients with HG (hazard ratio [HR]: 0.17; 95% CI: 0.12-0.23; p < 0.001), followed by patients with LFLG (HR: 0.25; 95% CI: 0.13-0.49; p < 0.001), and finally patients with NFLG (HR: 0.29; 95% CI: 0.20-0.44; p < 0.001), with a risk reduction of 84, 75, and 71%, respectively. Conclusions: paradoxical LFLG AS affects 10.5% of severe AS, and has a lower need for AVR than the HG group and similar to the NFLG group, with no differences in mortality. AVR had a lower impact on LFLG AS compared with HG AS. Therefore, the findings of the present study showed LFLG AS to have an intermediate clinical risk profile between the HG and NFHG groups.AGu has received funding from the Spanish Ministry of Science, Innovation and Universities (IJC2018- 037349-I)

Importance of Tricuspid Regurgitation Velocity Threshold in Risk Assessment of Pulmonary Hypertension-Long-Term Outcome of Patients Submitted to Aortic Valve Replacement

Background: The upper physiological threshold for tricuspid regurgitation velocity (TRV) of 2.8 m/s proposed by the Pulmonary Hypertension (PH) guidelines had been questioned. The aim of this study was to evaluate the prognostic significance of preoperative PH in patients with aortic stenosis, long-term after valve replacement, using two different TRV thresholds (2.55 and 2.8 m/s). Methods: Four hundred and forty four patients were included (mean age 73 ± 9 years; 55% male), with a median follow-up of 5.8 years (98% completed). Patients were divided into three PH probability groups according to guidelines (low, intermediate and high) for both thresholds (TRV ≤ 2.8 m/s and TRV ≤ 2.55 m/s), using right atrial area>18 cm 2 and right ventricle/left ventricle ratio>1 as additional echocardiographic variables. Results: In patients with measurable TRV (n = 304), the low group mortality rate was 25% and 30%, respectively for 2.55 and 2.8 m/s TRV thresholds. The intermediate group with TRV > 2.55 m/s was an independent mortality risk factor (HR 2.04; 95% CI: 1.91 to 3.48, p = 0.01), in contrast to the intermediate group with TRV>2.8 m/s (HR 1.44; 95% CI: 0.89 to 2.32, p = 0.14). Both high probability groups were associated with an increased mortality risk, as compared to their respective low groups. When including all patients (with measurable and non-measurable TRV), both intermediate groups remained independently associated with an increased mortality risk: HR 1.62 (95% CI 1.11 to 2.35 p = 0.01) for the new cut-off point; and HR 1.43 (95% CI: 0.96 to 2.13, p = 0.07) for guidelines threshold. Conclusion: A TRV threshold of 2.55 m/s, together with right cavities measures, allowed a better risk assessment of patients with PH secondary to severe aortic stenosis, with or without tricuspid regurgitation

Importance of tricuspid regurgitation velocity threshold in risk assessment of pulmonary hypertension-long-term outcome of patients submitted to aortic valve replacement

Background: the upper physiological threshold for tricuspid regurgitation velocity (TRV) of 2.8 m/s proposed by the Pulmonary Hypertension (PH) guidelines had been questioned. The aim of this study was to evaluate the prognostic significance of preoperative PH in patients with aortic stenosis, long-term after valve replacement, using two different TRV thresholds (2.55 and 2.8 m/s). Methods: four hundred and forty four patients were included (mean age 73 ± 9 years; 55% male), with a median follow-up of 5.8 years (98% completed). Patients were divided into three PH probability groups according to guidelines (low, intermediate and high) for both thresholds (TRV ≤ 2.8 m/s and TRV ≤ 2.55 m/s), using right atrial area>18 cm2 and right ventricle/left ventricle ratio>1 as additional echocardiographic variables. Results: in patients with measurable TRV (n = 304), the low group mortality rate was 25% and 30%, respectively for 2.55 and 2.8 m/s TRV thresholds. The intermediate group with TRV > 2.55 m/s was an independent mortality risk factor (HR 2.04; 95% CI: 1.91 to 3.48, p = 0.01), in contrast to the intermediate group with TRV>2.8 m/s (HR 1.44; 95% CI: 0.89 to 2.32, p = 0.14). Both high probability groups were associated with an increased mortality risk, as compared to their respective low groups. When including all patients (with measurable and non-measurable TRV), both intermediate groups remained independently associated with an increased mortality risk: HR 1.62 (95% CI 1.11 to 2.35 p = 0.01) for the new cut-off point; and HR 1.43 (95% CI: 0.96 to 2.13, p = 0.07) for guidelines threshold. Conclusion: A TRV threshold of 2.55 m/s, together with right cavities measures, allowed a better risk assessment of patients with PH secondary to severe aortic stenosis, with or without tricuspid regurgitation

Postsystolic thickening is a potential new clinical sign of injured myocardium in marfan syndrome.

The mechanisms leading to cardiac remodeling in Marfan syndrome (MFS) are a matter of debate since it could be either due to structural dysfunction of the myocardial extracellular matrix or to increased afterload caused by the dilated aorta. We aim to characterize the presence of abnormal myocardial function in MFS and to investigate its potential association with increased afterload. Aorta, left ventricle (LV) and the postsystolic thickening (PST) were analyzed in echocardiography in Fbn1C1039G/+ mice and in patients with MFS in comparison with wild type (WT) mice and healthy humans. PST was more frequent in MFS than in WT mice (p< 0.05). MFS mice with PST showed larger aorta than those without PST. Patients with MFS showed larger aorta, poorer LV function and a higher prevalence of PST (56%) than did the healthy controls (23%); p= 0.003. Blood pressure was similar. The higher prevalence of PST in an experimental murine model and in MFS patients, regardless of systemic arterial pressure, suggests an increased afterload on the LV myocardium. This fnding supports the use of PST as an indicator of myocardial damage and encourage searching for novel early preventive therap

Left Atrial Appendage Closure with a New Occluder Device : Efficacy, Safety and Mid-Term Performance

The LAmbre TM device is a novel system designed for left atrial appendage closure (LAAC). First registries showed a high rate of device implantation success. However, few mid-term results are available. We present our 1- and 12-month follow-up results for this device. This prospective, single-center registry included consecutive patients with nonvalvular atrial fibrillation who underwent LAAC with the LAmbre TM device. Transesophageal echocardiography (TEE) was performed at 1-month follow-up. In total, 55 patients were included. The population was elderly (75 ± 9.4 years), with a high proportion of comorbidities. The mean CHADS-VASc and HAS-BLED scores were 4.6 ± 1.6 and 3.9 ± 1.0, respectively. Previous history of a major bleeding event was present in 37 patients (67.3%). Procedural success was achieved in 54 patients (98.2%). Device success was achieved in 100% of patients in whom device implantation was attempted (54 patients). Major in-hospital device-related complications included mortality of one patient (1.8%) and pericardial tamponade in two patients (3.6%); the incidence of stroke was 0%. No thrombus or significant leaks (≥5 mm) were observed on 1-month TEE. At 12 months, adverse events were overall death (1.8%), transient ischemic attack/ischemic stroke (1.8%), and major bleeding events (Bleeding Academic Research Consortium (BARC) 3a and 3c; 11%). In this high-risk population, the LAmbre TM device seems to be a safe and effective option for LAAC with a remarkable mid-term performance

Left atrial appendage closure with a new occluder device: efficacy, safety and mid-term performance

The LAmbreTM device is a novel system designed for left atrial appendage closure (LAAC). First registries showed a high rate of device implantation success. However, few mid-term results are available. We present our 1- and 12-month follow-up results for this device. This prospective, single-center registry included consecutive patients with nonvalvular atrial fibrillation who underwent LAAC with the LAmbreTM device. Transesophageal echocardiography (TEE) was performed at 1-month follow-up. In total, 55 patients were included. The population was elderly (75 ± 9.4 years), with a high proportion of comorbidities. The mean CHA2DS2-VASc and HAS-BLED scores were 4.6 ± 1.6 and 3.9 ± 1.0, respectively. Previous history of a major bleeding event was present in 37 patients (67.3%). Procedural success was achieved in 54 patients (98.2%). Device success was achieved in 100% of patients in whom device implantation was attempted (54 patients). Major in-hospital device-related complications included mortality of one patient (1.8%) and pericardial tamponade in two patients (3.6%); the incidence of stroke was 0%. No thrombus or significant leaks (≥5 mm) were observed on 1-month TEE. At 12 months, adverse events were overall death (1.8%), transient ischemic attack/ischemic stroke (1.8%), and major bleeding events (Bleeding Academic Research Consortium (BARC) 3a and 3c; 11%). In this high-risk population, the LAmbreTM device seems to be a safe and effective option for LAAC with a remarkable mid-term performance