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.

Efectividad y seguridad de una estrategia de antiagregación plaquetaria simple tras cierre percutáneo de orejuela izquierda en pacientes con FA / Single antiplatelet therapy after left atrial appendage closure in patients with AF: safety and effectiveness

Introduction and objectives The optimal antithrombotic strategy following left atrial appendage closure (LAAC) is poorly defined in patients with nonvalvular atrial fibrillation. We assessed the safety and effectiveness of a single antiplatelet treatment (SAPT) strategy after LAAC in a population at high risk of ischemic and bleeding events. Methods This single-center, observational, prospective study included a consecutive cohort of patients who underwent LAAC using the LAmbre device (Lifetech Scientific, China) and who were discharged with SAPT. The primary outcome was a composite of stroke, systemic embolism, and device-related thrombosis during follow-up. Secondary endpoints were cardiovascular mortality and major bleeding events (BARC ≥3a). Clinical follow-up was performed at 1, 6, and 12 months and subsequently on an annual basis. Transesophageal echocardiography was performed at 1 and 12 months of follow-up. Results The study comprised 74 patients. The median age was 77 [72-83] years and 43% were women. The cohort exhibited a high prevalence of comorbidities and cardiovascular risk factors. The median CHA2DS2-VASc and HAS-BLED scores were 4 [3-6] and 4 [4-5], respectively. The median length of follow-up was 2.5 years (188 patients-year). During follow-up, device-related thrombosis occurred in 3 patients (4%). Ischemic stroke occurred in 1 patient (1.3%, rate 0.5%/y), representing a 90.9% relative risk reduction compared with the risk predicted by CHA2DS2-VASc. Major bleeding events occurred in 12 patients (16%, 6.4%/y), with a relative risk reduction of 26.4% of that predicted by HAS-BLED. Cardiovascular-related mortality was observed in 2 patients (2.7%). Conclusions SAPT appears to be a safe and effective treatment following LAAC in patients at high ischemic and hemorrhagic risk. Further studies are needed to confirm our findings (AU)

Introducción y objetivos Se desconoce cuál es la terapia antitrombótica óptima tras el cierre percutáneo de la orejuela izquierda (CPOI) en pacientes con fibrilación auricular no valvular. El objetivo de este estudio es analizar la efectividad y la seguridad de un régimen de tratamiento antiagregante plaquetario simple (TAPS) tras el CPOI en una población con alto riesgo isquémico y hemorrágico. Métodos Estudio observacional prospectivo que incluyó una cohorte consecutiva de pacientes a los que se realizó CPOI con dispositivo LAmbre (Lifetech Scientific, China) y que recibieron TAPS al alta. El evento primario fue un combinado de ictus, embolia sistémica y trombosis del dispositivo. Los eventos secundarios fueron mortalidad cardiovascular y hemorragia mayor (BARC ≥ 3a). Se realizó seguimiento clínico al mes y a los 6 y 12 meses y cada año después. Se realizó ecocardiograma transesofágico al mes y a los 12 meses. Resultados Se incluyó a 74 pacientes (el 43% mujeres) con una mediana de edad de 77 [intervalo intercuartílico, 72-83] años, que presentaban gran comorbilidad y factores de riesgo cardiovascular. Los valores de CHA2DS2-VASc y HAS-BLED fueron una mediana de 4 [3-6] y 4 [4-5] respectivamente. Durante el seguimiento (mediana, 2,5 años), 3 pacientes (4%) presentaron trombosis del dispositivo. Uno sufrió ictus isquémico (1,3%, 0,5%/año), lo que supone, según la incidencia esperada por CHA2DS2-VASc, una reducción del riesgo relativo del 90,9%. Sufrieron eventos hemorrágicos 12 pacientes (16%; 6,4%/año), una tasa el 26,4% menor que el riesgo HAS-BLED predicho. Se produjo la muerte cardiovascular de 2 pacientes (2,7%). Conclusiones Una estrategia de TAPS tras el CPOI parece ser una opción efectiva y segura para los pacientes con altos riesgos isquémico y hemorrágico. Se necesitan más estudios que corroboren nuestros resultados (AU)

Single antiplatelet therapy after left atrial appendage closure in patients with AF: safety and effectiveness.

INTRODUCTION AND OBJECTIVES: The optimal antithrombotic strategy following left atrial appendage closure (LAAC) is poorly defined in patients with nonvalvular atrial fibrillation. We assessed the safety and effectiveness of a single antiplatelet treatment (SAPT) strategy after LAAC in a population at high risk of ischemic and bleeding events. METHODS: This single-center, observational, prospective study included a consecutive cohort of patients who underwent LAAC using the LAmbre device (Lifetech Scientific, China) and who were discharged with SAPT. The primary outcome was a composite of stroke, systemic embolism, and device-related thrombosis during follow-up. Secondary endpoints were cardiovascular mortality and major bleeding events (BARC ≥3a). Clinical follow-up was performed at 1, 6, and 12 months and subsequently on an annual basis. Transesophageal echocardiography was performed at 1 and 12 months of follow-up. RESULTS: The study comprised 74 patients. The median age was 77 [72-83] years and 43% were women. The cohort exhibited a high prevalence of comorbidities and cardiovascular risk factors. The median CHA2DS2-VASc and HAS-BLED scores were 4 [3-6] and 4 [4-5], respectively. The median length of follow-up was 2.5 years (188 patients-year). During follow-up, device-related thrombosis occurred in 3 patients (4%). Ischemic stroke occurred in 1 patient (1.3%, rate 0.5%/y), representing a 90.9% relative risk reduction compared with the risk predicted by CHA2DS2-VASc. Major bleeding events occurred in 12 patients (16%, 6.4%/y), with a relative risk reduction of 26.4% of that predicted by HAS-BLED. Cardiovascular-related mortality was observed in 2 patients (2.7%). CONCLUSIONS: SAPT appears to be a safe and effective treatment following LAAC in patients at high ischemic and hemorrhagic risk. Further studies are needed to confirm our findings.

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.

Williams-Beuren syndrome (WBS) is a rare disorder that causes hyper-social behavior, intellectual disability, memory problems, and life-threatening overgrowth of the heart. Behavioral therapies can help improve the cognitive and social aspects of the syndrome and surgery is sometimes used to treat the effects on the heart, although often with limited success. However, there are currently no medications available to treat WBS. The endocannabinoid system ­ which consists of cannabis-like chemical messengers that bind to specific cannabinoid receptor proteins ­ has been shown to influence cognitive and social behaviors, as well as certain functions of the heart. This has led scientists to suspect that the endocannabinoid system may play a role in WBS, and drugs modifying this network of chemical messengers could help treat the rare condition. To investigate, Navarro-Romero, Galera-López et al. studied mice which had the same genetic deletion found in patients with WBS. Similar to humans, the male mice displayed hyper-social behaviors, had memory deficits and enlarged hearts. Navarro-Romero, Galera-López et al. found that these mutant mice also had differences in the function of the receptor protein cannabinoid type-1 (CB1). The genetically modified mice were then treated with an experimental drug called JZL184 that blocks the breakdown of endocannabinoids which bind to the CB1 receptor. This normalized the number and function of receptors in the brains of the WBS mice, and reduced their social and memory symptoms. The treatment also restored the animals' heart cells to a more normal size, improved the function of their heart tissue, and led to lower blood pressure. Further experiments revealed that the drug caused the mutant mice to activate many genes in their heart muscle cells to the same level as normal, healthy mice. These findings suggest that JZL184 or other drugs targeting the endocannabinoid system may help ease the symptoms associated with WBS. More studies are needed to test the drug's effectiveness in humans with this syndrome. Furthermore, the dramatic effect JZL184 has on the heart suggests that it might also help treat high blood pressure or conditions that cause the overgrowth of heart cells.

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] < 1.0 cm2) and normal left ventricular ejection fraction (LVEF). Patients were classified as: high-gradient (HG, mean gradient ≥ 40 mmHg), normal-flow low-gradient (NFLG, mean gradient < 40 mmHg, indexed systolic volume (SVi) > 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.

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.

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

Silent 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.

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 finding supports the use of PST as an indicator of myocardial damage and encourage searching for novel early preventive therapy.

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.

Impact of Preoperative Measurement of Right Heart Chambers in the Evaluation of Pulmonary Hypertension Following Aortic Valve Replacement.

BACKGROUND: Severe pulmonary hypertension (PH) in patients with aortic stenosis is related to poor prognosis following aortic valve replacement (AVR). Current European PH guidelines recommend adding two different echocardiographic signs to tricuspid regurgitation velocity (TRV) in PH estimation, classifying its probability as low (TRV ≤ 2.8 m/s), intermediate (TRV 2.9-3.4 m/s), and high (TRV > 3.4 m/s). The right ventricle is an important determinant of prognosis in PH. The goal of this study was to analyze the value of right atrial area > 18 cm2 and right ventricular/left ventricular ratio > 1 in the long-term prognosis following AVR, mainly in the intermediate probability group. METHODS: This study included 429 consecutive patients (mean age, 73 ± 8 years; 55% male) with a median follow-up of 4.25 years (completed in 98%). Patients were divided into low (n = 247), intermediate (n = 117), and high probability groups (n = 65). The intermediate probability group was divided into two subgroups: subgroup 2a (n = 27; TRV nonmeasurable or ≤ 2.8 m/s and two signs present) and subgroup 2b (n = 90; TRV 2.9-3.4 m/s, and none or only one sign present). RESULTS: Overall mortality rates during follow-up of the low, intermediate, and high probability groups were 24%, 32%, and 42%, respectively. High PH probability was an independent predictor of all-cause mortality (hazard ratio [HR], 1.82; 95% CI, 1.11-3.00), but the intermediate probability group did not reach significance following multivariate analysis (HR, 1.40; 95% CI, 0.91-2.16). When the intermediate probability group was divided into subgroups, the subgroup 2a mortality rate (56%) was higher than that of both subgroup 2b (24%; P = .002) and the low probability group (24%; P < .001). Following multivariate analysis, subgroup 2a showed a significantly higher mortality (HR, 2.13; 95% CI, 1.11-4.10) in contrast to subgroup 2b (HR, 1.24; 95% CI, 0.75-2.05), both compared with the low probability group. CONCLUSIONS: Incorporating measurement of the right cavities into the PH probability model in the assessment of long-term prognosis following AVR allowed better risk discrimination, especially in the intermediate probability group.

Fibroblast growth factor-21 protects against fibrosis in hypertensive heart disease.

FGF21 is an endocrine factor that contributes to multiple pathophysiological processes, mainly via its action as a metabolic regulator and cardioprotective agent. Recent studies have shown increased circulating FGF21 levels in hypertensive patients and in mouse models of hypertension. However, the relevance of FGF21 in hypertensive heart disease has not been addressed. Hypertension was induced by treating 4-month old WT and Fgf21-/- mice with angiotensin II (AngII) for 1 week, resulting in a similar increase in blood pressure in both genotypes. Plasma FGF21 levels and expression in heart and liver were significantly increased in hypertensive WT mice relative to controls, an effect that was associated with increased expression levels of ß-klotho specifically in the heart. Fgf21-/- mice developed a greater degree of hypertensive heart disease than WT mice, notably characterized by extensive cardiac dysfunction and fibrosis. In vitro and in vivo studies further showed that FGF21 exerted a marked protective effect against cardiac fibrosis. Finally, left ventricle biopsies from human hypertensive heart donors, especially those developing cardiomyopathy, showed a significant increase in FGF21expression compared with normotensive controls, a finding that was associated with significantly enhanced cardiac hypertrophy and fibrosis. We conclude that during hypertension, both systemic and cardiac-produced FGF21 are induced and act on the heart, protecting it from hypertensive heart disease. Thus, FGF21 acts as key factor in the fibrogenesis associated with hypertensive heart disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Redox stress in Marfan syndrome: Dissecting the role of the NADPH oxidase NOX4 in aortic aneurysm.

Marfan syndrome (MFS) is characterized by the formation of ascending aortic aneurysms resulting from altered assembly of extracellular matrix fibrillin-containing microfibrils and dysfunction of TGF-ß signaling. Here we identify the molecular targets of redox stress in aortic aneurysms from MFS patients, and investigate the role of NOX4, whose expression is strongly induced by TGF-ß, in aneurysm formation and progression in a murine model of MFS. Working models included aortae and cultured vascular smooth muscle cells (VSMC) from MFS patients, and a NOX4-deficient Marfan mouse model (Fbn1C1039G/+-Nox4-/-). Increased tyrosine nitration and reactive oxygen species levels were found in the tunica media of human aortic aneurysms and in cultured VSMC. Proteomic analysis identified nitrated and carbonylated proteins, which included smooth muscle α-actin (αSMA) and annexin A2. NOX4 immunostaining increased in the tunica media of human Marfan aorta and was transcriptionally overexpressed in VSMC. Fbn1C1039G/+-Nox4-/- mice aortas showed a reduction of fragmented elastic fibers, which was accompanied by an amelioration in the Marfan-associated enlargement of the aortic root. Increase in the contractile phenotype marker calponin in the tunica media of MFS mice aortas was abrogated in Fbn1C1039G/+-Nox4-/- mice. Endothelial dysfunction evaluated by myography in the Marfan ascending aorta was prevented by the absence of Nox4 or catalase-induced H2O2 decomposition. We conclude that redox stress occurs in MFS, whose targets are actin-based cytoskeleton members and regulators of extracellular matrix homeostasis. Likewise, NOX4 have an impact in the progression of the aortic dilation in MFS and in the structural organization of the aortic tunica media, the VSMC phenotypic modulation, and endothelial function.

Cardiovascular Benefits of Moderate Exercise Training in Marfan Syndrome: Insights From an Animal Model.

BACKGROUND: Marfan syndrome (MF) leads to aortic root dilatation and a predisposition to aortic dissection, mitral valve prolapse, and primary and secondary cardiomyopathy. Overall, regular physical exercise is recommended for a healthy lifestyle, but dynamic sports are strongly discouraged in MF patients. Nonetheless, evidence supporting this recommendation is lacking. Therefore, we studied the role of long-term dynamic exercise of moderate intensity on the MF cardiovascular phenotype. METHODS AND RESULTS: In a transgenic mouse model of MF (Fbn1C1039G/+), 4-month-old wild-type and MF mice were subjected to training on a treadmill for 5 months; sedentary littermates served as controls for each group. Aortic and cardiac remodeling was assessed by echocardiography and histology. The 4-month-old MF mice showed aortic root dilatation, elastic lamina rupture, and tunica media fibrosis, as well as cardiac hypertrophy, left ventricular fibrosis, and intramyocardial vessel remodeling. Over the 5-month experimental period, aortic root dilation rate was significantly greater in the sedentary MF group, compared with the wild-type group (∆mm, 0.27±0.07 versus 0.13±0.02, respectively). Exercise significantly blunted the aortic root dilation rate in MF mice compared with sedentary MF littermates (∆mm, 0.10±0.04 versus 0.27±0.07, respectively). However, these 2 groups were indistinguishable by aortic root stiffness, tunica media fibrosis, and elastic lamina ruptures. In MF mice, exercise also produced cardiac hypertrophy regression without changes in left ventricular fibrosis. CONCLUSIONS: Our results in a transgenic mouse model of MF indicate that moderate dynamic exercise mitigates the progression of the MF cardiovascular phenotype.

Fgf21 is required for cardiac remodeling in pregnancy.

AIMS: Fibroblast growth factor-21 (Fgf21) is an endocrine factor that contributes to many physiological and pathological processes, mainly via its action as a metabolic regulator. Recent studies have shown that Fgf21 plays an important role in cardiac tissue. Pregnancy offers a physiological model of adaptive and reversible heart enlargement, but the molecular mechanisms underlying this cardiac hypertrophy are poorly understood. Therefore, the aim was to analyze the role of Fgf21 during late pregnancy, and assess the physiological relevance of Fgf21 for cardiac tissue during this process. METHODS AND RESULTS: Female mice and rats at day 18 of gestation and pregnant women in their third trimester were used as models of late pregnancy, and our results revealed that their plasma levels of Fgf21 were significantly increased relative to non-pregnant controls. Pregnant wild-type (wt) mice exhibited a PPARα (peroxisome proliferator-activated receptor-α)-dependent enhancement of Fgf21 expression in the liver and heart. Moreover, pregnancy altered the levels of Fgf21 receptor-1 (FGFR1) and ß-klotho, and activated intracellular Fgf21 signaling in the heart. Fgf21-/- mice did not develop the pregnancy-induced cardiac remodeling seen in wt mice. Furthermore, the hearts of Fgf21-/- mice exhibited reductions in their fatty acid oxidation levels, which may compromise cardiac function during pregnancy. CONCLUSIONS: During pregnancy, both systemic and cardiac-produced Fgf21 act on the heart, leading to the normal physiological cardiac changes that are associated with pregnancy. Thus, Fgf21 acts as an endocrine/autocrine factor required for cardiac remodeling response to gestation.

La función de la aurícula izquierda está alterada en algunos pacientes con ictus criptogénico: potenciales implicaciones en su evaluación y tratamiento / Left atrial function is impaired in some patients with stroke of undetermined etiology: potential implications for evaluation and therapy

Introducción y objetivos: El 30% de los casos de ictus sigue siendo de etiología desconocida (criptogénicos). En un 20-28% de los pacientes con ictus inicialmente clasificados como criptogénicos, se detecta posteriormente fibrilación auricular paroxística. El objetivo de este estudio es analizar la función auricular izquierda de pacientes con ictus isquémico para identificar patrones asociados a la etiología cardioembólica y determinar si se puede observar tales patrones en individuos clasificados inicialmente como ictus criptogénicos. Métodos: Se incluyó una cohorte de pacientes hospitalizados por ictus isquémico remitidos a ecocardiografía transtorácica. Los neurólogos al cargo determinaron la etiología del ictus según la clasificación TOAST. Se evaluó la función contráctil de la aurícula izquierda utilizando ecocardiografía bidimensional para determinar su fracción de eyección, y mediante técnicas de deformación miocárdica (speckle tracking o rastreo de marcas) se determinó la onda a del strain rate (tasa de deformación). Se comparó la función de la aurícula izquierda entre los subgrupos etiológicos del ictus así como con un grupo de control de individuos sanos. Resultados: Se incluyó a 97 pacientes (de 67 ± 15 años) con ictus isquémico (el 16,5% aterotrombóticos, el 15,5% lacunares, el 11,3% cardioembólicos, el 5,1% de otra etiología determinada y el 51,1% criptogénicos) y 10 voluntarios sanos (de 63 ± 7 años). Se observó una disminución significativa de la fracción de eyección de la aurícula izquierda solo en los pacientes con ictus cardioembólico y criptogénico respecto al grupo de control (31,5 ± 17,2%, 40,2 ± 17,1% y 59,1 ± 8,4% respectivamente; p = 0,004). El strain-rate de la aurícula izquierda fue significativamente inferior en los pacientes con ictus cardioembólicos, criptogénicos o aterotrombóticos en comparación con el grupo control (-0,86 ± 0,49, -1,31 ± 0,56, -1,5 ± 0,47 y -2,37 ± 1,18 respectivamente; p < 0,001). Conclusiones: Los pacientes con ictus criptogénico que presentan una función auricular izquierda (fracción de eyección y strain) similar a la de los pacientes con ictus cardioembólico podrían estar clasificados de forma incorrecta, por lo que en ellos sería útil una monitorización electrocardiográfica prolongada. El análisis de la función auricular izquierda (fracción de eyección y strain) podría ser útil para identificar a los pacientes con ictus cardioembólico inicialmente mal clasificados como criptogénicos (AU)

Introduction and objectives: Stroke etiology remains undetermined in up to 30% of cases. Paroxysmal atrial fibrillation is found in 20% to 28% of patients with stroke initially classified as being of undetermined etiology. The aim of our study was to analyze left atrial function in ischemic stroke patients to identify patterns associated with cardioembolic etiology and to determine whether the patterns identified can be found in individuals initially classified as having a stroke of undetermined etiology. Methods: We studied a cohort of in-hospital ischemic stroke patients referred for transthoracic echocardiography. Treating neurologists determined stroke etiology based on the TOAST classification. Left atrial contractile function was assessed using 2-dimensional echocardiography to determine their ejection fraction and speckle tracking to measure left atrial strain rate: a-wave. Left atrial function was compared between stroke etiology subgroups and healthy controls. Results: Ninety-seven patients (aged 67 ± 15 years) with ischemic stroke (16.5% large-artery atherosclerosis, 15.5% small-vessel occlusion, 11.3% cardioembolic, 5.1% other determined etiology, 51.1% undetermined etiology) and 10 healthy volunteers (aged 63 ± 7 years) were included. Left atrial ejection fraction was significantly decreased only in patients with stroke of cardioembolic and undetermined etiology compared with the control group (31.5 ± 17.2%, 40.2 ± 17.1%, and 59.1 ± 8.4%, respectively; P = .004). The left atrial strain rate was significantly lower in patients with stroke caused by cardioembolic or undetermined etiology, or large-artery atherosclerosis compared with controls (−0.86 ± 0.49, −1.31 ± 0.56, −1.5 ± 0.47, −2.37 ± 1.18, respectively; P < .001). Conclusions: Patients with stroke of undetermined etiology with left atrial function (ejection fraction and strain) similar to that of cardioembolic stroke patients may be misclassified and could potentially benefit from prolonged electrocardiography monitoring. Left atrial function analysis (ejection fraction and strain) might help to identify potential cardioembolic sources in patients with stroke of undetermined etiology (AU)

Left Atrial Function Is Impaired in Some Patients With Stroke of Undetermined Etiology: Potential Implications for Evaluation and Therapy.

INTRODUCTION AND OBJECTIVES: Stroke etiology remains undetermined in up to 30% of cases. Paroxysmal atrial fibrillation is found in 20% to 28% of patients with stroke initially classified as being of undetermined etiology. The aim of our study was to analyze left atrial function in ischemic stroke patients to identify patterns associated with cardioembolic etiology and to determine whether the patterns identified can be found in individuals initially classified as having a stroke of undetermined etiology. METHODS: We studied a cohort of in-hospital ischemic stroke patients referred for transthoracic echocardiography. Treating neurologists determined stroke etiology based on the TOAST classification. Left atrial contractile function was assessed using 2-dimensional echocardiography to determine their ejection fraction and speckle tracking to measure left atrial strain rate: a-wave. Left atrial function was compared between stroke etiology subgroups and healthy controls. RESULTS: Ninety-seven patients (aged 67±15 years) with ischemic stroke (16.5% large-artery atherosclerosis, 15.5% small-vessel occlusion, 11.3% cardioembolic, 5.1% other determined etiology, 51.1% undetermined etiology) and 10 healthy volunteers (aged 63±7 years) were included. Left atrial ejection fraction was significantly decreased only in patients with stroke of cardioembolic and undetermined etiology compared with the control group (31.5±17.2%, 40.2±17.1%, and 59.1±8.4%, respectively; P=.004). The left atrial strain rate was significantly lower in patients with stroke caused by cardioembolic or undetermined etiology, or large-artery atherosclerosis compared with controls (-0.86±0.49, -1.31±0.56, -1.5±0.47, -2.37±1.18, respectively; P<.001). CONCLUSIONS: Patients with stroke of undetermined etiology with left atrial function (ejection fraction and strain) similar to that of cardioembolic stroke patients may be misclassified and could potentially benefit from prolonged electrocardiography monitoring. Left atrial function analysis (ejection fraction and strain) might help to identify potential cardioembolic sources in patients with stroke of undetermined etiology.

Evaluación del dolor torácico agudo mediante ecocardiografía de ejercicio y tomografía computarizada multidetectores / Exercise echocardiography and multidetector computed tomography for the evaluation of acute chest pain

Introducción y objetivos Un 4% de los pacientes con dolor torácico agudo y troponinas y electrocardiograma normales presentan eventos cardiacos adversos como consecuencia del síndrome coronario agudo no diagnosticado. El presente estudio compara la utilidad diagnóstica de la tomografía cardiaca y el ecocardiograma de ejercicio en pacientes con probabilidad baja-intermedia de enfermedad coronaria. Métodos Se incluyó prospectivamente a 69 sujetos con dolor torácico agudo y troponinas y electrocardiograma normales a los que se realizó una tomografía cardiaca y un ecocardiograma de ejercicio. Los pacientes con al menos una lesión ≥ 50% o una puntuación de calcio de Agatston ≥ 400 en la tomografía cardiaca, ecocardiograma de ejercicio positivo o con resultados no concluyentes ingresaron para completar estudio. Resultados: El síndrome coronario agudo se confirmó en 17 casos (24,6%), cifra inferior al 42% sospechado según los hallazgos de la tomografía cardiaca (p<0,05) y no significativamente diferente del 29% sospechado por el ecocardiograma de ejercicio (p=0,56). El ecocardiograma de ejercicio fue normal en el 37% de los casos con tomografía cardiaca patológica. La tomografía cardiaca proporcionó una sensibilidad superior (el 100 frente al 82,3%; p=0,21) pero una especificidad inferior (el 76,9 frente al 88,4%; p=0,12) que el ecocardiograma de ejercicio, aunque sin significación estadística. Un valor de corte de estenosis coronaria del 70% mejoró la especificidad de la tomografía cardiaca al 88,4% manteniendo la sensibilidad del 100%. Conclusiones: La tomografía cardiaca es una alternativa válida al ecocardiograma de ejercicio para el diagnóstico de síndrome coronario agudo en pacientes con probabilidad baja-intermedia de enfermedad coronaria. La combinación de ambas técnicas podría mejorar el diagnóstico

Introduction and objectives Up to 4% of patients with acute chest pain, normal electrocardiogram, and negative troponins present major adverse cardiac events as a result of undiagnosed acute coronary syndrome. Our aim was to compare the diagnostic performance of multidetector computed tomography and exercise echocardiography in patients with a low-to-intermediate probability of coronary artery disease. Methods We prospectively included 69 patients with acute chest pain, normal electrocardiogram, and negative troponins who underwent coronary tomography angiography and exercise echocardiography. Patients with coronary stenosis ≥ 50% or Agatston calcium score ≥ 400 on coronary tomography angiography or positive exercise echocardiography, or with inconclusive results, were admitted to rule out acute coronary syndrome. Results: An acute coronary syndrome was confirmed in 17 patients (24.6%). This was lower than the suspected 42% based on coronary tomography angiography (P < .05) and not significantly different than the suspected 29% based on the results of exercise echocardiography (P = .56). Exercise echocardiography was normal in up to 37% of patients with pathological findings on coronary tomography angiography. The latter technique provided a higher sensitivity (100% vs 82.3%; P = .21) but lower specificity (76.9% vs 88.4%; P=.12) than exercise echocardiography for the diagnosis of acute coronary syndrome, although without reaching statistical significance. Increasing the stenosis cutoff point to 70% increased the specificity of coronary tomography angiography to 88.4%, while maintaining high sensitivity. Conclusions: Coronary tomography angiography offers a valid alternative to exercise echocardiography for the diagnosis of acute coronary syndrome among patients with low-to-intermediate probability of coronary artery disease. A combination of both techniques could improve the diagnosis of acute coronary síndrome

Exercise echocardiography and multidetector computed tomography for the evaluation of acute chest pain.

INTRODUCTION AND OBJECTIVES: Up to 4% of patients with acute chest pain, normal electrocardiogram, and negative troponins present major adverse cardiac events as a result of undiagnosed acute coronary syndrome. Our aim was to compare the diagnostic performance of multidetector computed tomography and exercise echocardiography in patients with a low-to-intermediate probability of coronary artery disease. METHODS: We prospectively included 69 patients with acute chest pain, normal electrocardiogram, and negative troponins who underwent coronary tomography angiography and exercise echocardiography. Patients with coronary stenosis ≥ 50% or Agatston calcium score ≥ 400 on coronary tomography angiography or positive exercise echocardiography, or with inconclusive results, were admitted to rule out acute coronary syndrome. RESULTS: An acute coronary syndrome was confirmed in 17 patients (24.6%). This was lower than the suspected 42% based on coronary tomography angiography (P<.05) and not significantly different than the suspected 29% based on the results of exercise echocardiography (P=.56). Exercise echocardiography was normal in up to 37% of patients with pathological findings on coronary tomography angiography. The latter technique provided a higher sensitivity (100% vs 82.3%; P=.21) but lower specificity (76.9% vs 88.4%; P=.12) than exercise echocardiography for the diagnosis of acute coronary syndrome, although without reaching statistical significance. Increasing the stenosis cutoff point to 70% increased the specificity of coronary tomography angiography to 88.4%, while maintaining high sensitivity. CONCLUSIONS: Coronary tomography angiography offers a valid alternative to exercise echocardiography for the diagnosis of acute coronary syndrome among patients with low-to-intermediate probability of coronary artery disease. A combination of both techniques could improve the diagnosis of acute coronary syndrome.