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Targeted inactivation of Cerberus like-2 leads to left ventricular cardiac hyperplasia and systolic dysfunction in the mouse.

ABSTRACT: Previous analysis of the Cerberus like 2 knockout (Cerl2-/-) mouse revealed a significant mortality during the first day after birth, mostly due to cardiac defects apparently associated with randomization of the left-right axis. We have however, identified Cerl2-associated cardiac defects, particularly a large increase in the left ventricular myocardial wall in neonates that cannot be explained by laterality abnormalities. Therefore, in order to access the endogenous role of Cerl2 in cardiogenesis, we analyzed the embryonic and neonatal hearts of Cerl2 null mutants that did not display a laterality phenotype. Neonatal mutants obtained from the compound mouse line Cer2-/-::Mlc1v-nLacZ24+, in which the pulmonary ventricle is genetically marked, revealed a massive enlargement of the ventricular myocardium in animals without laterality defects. Echocardiography analysis in Cerl2-/- neonates showed a left ventricular systolic dysfunction that is incompatible with a long lifespan. We uncovered that the increased ventricular muscle observed in Cerl2-/- mice is caused by a high cardiomyocyte mitotic index in the compact myocardium which is mainly associated with increased Ccnd1 expression levels in the left ventricle at embryonic day (E) 13. Interestingly, at this stage we found augmented left ventricular expression of Cerl2 levels when compared with the right ventricle, which may elucidate the regionalized contribution of Cerl2 to the left ventricular muscle formation. Importantly, we observed an increase of phosphorylated Smad2 (pSmad2) levels in embryonic (E13) and neonatal hearts indicating a prolonged TGF?s/Nodal-signaling activation. Concomitantly, we detected an increase of Baf60c levels, but only in Cerl2-/- embryonic hearts. These results indicate that independently of its well-known role in left-right axis establishment Cerl2 plays an important role during heart development in the mouse, mediating Baf60c levels by exerting an important control of the TGF?s/Nodal-signaling pathway.

SUBMITTER: Araujo AC

PROVIDER: S-EPMC4102536 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Targeted inactivation of Cerberus like-2 leads to left ventricular cardiac hyperplasia and systolic dysfunction in the mouse.

Araújo Ana Carolina AC Marques Sara S Belo José António JA

PloS one 20140717 7

Previous analysis of the Cerberus like 2 knockout (Cerl2-/-) mouse revealed a significant mortality during the first day after birth, mostly due to cardiac defects apparently associated with randomization of the left-right axis. We have however, identified Cerl2-associated cardiac defects, particularly a large increase in the left ventricular myocardial wall in neonates that cannot be explained by laterality abnormalities. Therefore, in order to access the endogenous role of Cerl2 in cardiogenes ...[more]

PMID: 25033293

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Project description:The relationship between fibroblast growth factor 21 (FGF21) and cardiovascular disease has been well established in recent studies. This study aimed to investigate the relationship between FGF21 and left ventricular systolic dysfunction and cardiac death.Two-dimensional echocardiography was used to measure the left ventricular ejection fraction (LVEF) to estimate left ventricular systolic function. The optimal cutoff of FGF21 for identifying left ventricular systolic dysfunction at baseline was analyzed via receiver operating characteristic (ROC) curves. The identification of different serum levels of FGF21 and their association with cardiac death was analyzed via Kaplan-Meier survival curves. Serum FGF21 level was measured by an enzyme-linked immunosorbent assay kit, and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level was determined by a chemiluminescent immunoassay.A total of 253 patients were recruited for this study at baseline. Patients were excluded if they lacked echocardiography or laboratory measurement data, and there were 218 patients enrolled in the final analysis. The average age was 66.32 ± 10.10 years. The optimal cutoff values of FGF21 and NT-pro-BNP for identifying left ventricular systolic dysfunction at baseline were 321.5 pg/mL and 131.3 ng/L, respectively, determined separately via ROC analysis. The areas under the curves were non-significant among FGF21, NT-pro-BNP and FGF21 + NT-pro-BNP as determined by pairwise comparisons. Both a higher serum level of FGF21 and a higher serum level of NT-pro-BNP were independent risk factors for left ventricular systolic dysfunction at baseline (odd ratio (OR) 3.138 [1.037-9.500], P = 0.043, OR 9.207 [2.036-41.643], P = 0.004, separately). Further Kaplan-Meier survival analysis indicated an association between both a higher serum level of FGF21 and a higher serum level of NT-pro-BNP with cardiac death in 5 years [RR 5.000 (1.326-18.861), P = 0.026; RR 9.643 (2.596-35.825), P = 0.009, respectively].Serum FGF21 level was significantly correlated with left ventricular systolic dysfunction at baseline. Patients with higher serum levels of FGF21 tended to suffer greater risks of cardiac death than patients with lower serum levels of FGF21. The identification of FGF21 and its relationship with left ventricular systolic function and cardiac death were non-inferior to NT-pro-BNP.

Project description:BackgroundThe term "end stage" has been used to describe hypertrophic cardiomyopathy (HCM) with left ventricular systolic dysfunction (LVSD), defined as occurring when left ventricular ejection fraction is <50%. The prognosis of HCM-LVSD has reportedly been poor, but because of its relative rarity, the natural history remains incompletely characterized.MethodsData from 11 high-volume HCM specialty centers making up the international SHaRe Registry (Sarcomeric Human Cardiomyopathy Registry) were used to describe the natural history of patients with HCM-LVSD. Cox proportional hazards models were used to identify predictors of prognosis and incident development.ResultsFrom a cohort of 6793 patients with HCM, 553 (8%) met the criteria for HCM-LVSD. Overall, 75% of patients with HCM-LVSD experienced clinically relevant events, and 35% met the composite outcome (all-cause death [n=128], cardiac transplantation [n=55], or left ventricular assist device implantation [n=9]). After recognition of HCM-LVSD, the median time to composite outcome was 8.4 years. However, there was substantial individual variation in natural history. Significant predictors of the composite outcome included the presence of multiple pathogenic/likely pathogenic sarcomeric variants (hazard ratio [HR], 5.6 [95% CI, 2.3-13.5]), atrial fibrillation (HR, 2.6 [95% CI, 1.7-3.5]), and left ventricular ejection fraction <35% (HR, 2.0 [95% CI, 1.3-2.8]). The incidence of new HCM-LVSD was ?7.5% over 15 years. Significant predictors of developing incident HCM-LVSD included greater left ventricular cavity size (HR, 1.1 [95% CI, 1.0-1.3] and wall thickness (HR, 1.3 [95% CI, 1.1-1.4]), left ventricular ejection fraction of 50% to 60% (HR, 1.8 [95% CI, 1.2, 2.8]-2.8 [95% CI, 1.8-4.2]) at baseline evaluation, the presence of late gadolinium enhancement on cardiac magnetic resonance imaging (HR, 2.3 [95% CI, 1.0-4.9]), and the presence of a pathogenic/likely pathogenic sarcomeric variant, particularly in thin filament genes (HR, 1.5 [95% CI, 1.0-2.1] and 2.5 [95% CI, 1.2-5.1], respectively).ConclusionsHCM-LVSD affects ?8% of patients with HCM. Although the natural history of HCM-LVSD was variable, 75% of patients experienced adverse events, including 35% experiencing a death equivalent an estimated median time of 8.4 years after developing systolic dysfunction. In addition to clinical features, genetic substrate appears to play a role in both prognosis (multiple sarcomeric variants) and the risk for incident development of HCM-LVSD (thin filament variants).

Project description:PurposeTo determine whether left ventricular (LV) extracellular volume (ECV) expansion is associated with atrial fibrillation (AF) or AF-mediated LV systolic dysfunction (LVSD) while minimizing the influence of biologic and imaging methodologic confounders.Materials and methodsThis study examined the prevalence of LV ECV expansion in 137 patients with AF (mean age, 62 years ± 11 [standard deviation]; 92 male patients and 45 female patients; 83 paroxysmal and 54 persistent) who underwent preablation cardiovascular MRI. Biologic confounders were minimized by measuring the ECV fraction and excluding patients with severe LV hypertrophy, defined as wall thickness greater than 1.5 cm. Imaging confounders were minimized by using an arrhythmia-insensitive-rapid (AIR) cardiac T1 mapping pulse sequence. Other cardiac functional parameters, including LV ejection fraction (LVEF) and left atrial end-diastolic volume indexed to body surface area, were assessed using cine cardiovascular MRI. A substudy was conducted in 32 patients with no AF (mean age, 54 years ± 16) in sinus rhythm to establish control values and convert these values between the AIR sequence and literature-based modified Look-Locker inversion recovery (MOLLI) values.ResultsThe mean ECV was not significantly different (P > .05) between patients with AF with a normal LVEF (24.5% ± 2.8; n = 107), patients with AF with LVSD (24.5% ± 2.5; n = 30), and patients with no AF (24.4% ± 3.8; n = 32), but there was a significant interaction between ECV and CHA2DS2-VASc score (P = .045). Compared with the literature data obtained from healthy control patients scanned using MOLLI, 99.3% of patients with AF had ECV below the fibrosis cutoff point (32.8% when converted from MOLLI T1 mapping to AIR T1 mapping), including a subset of patients with AF (n = 28) with low CHA2DS2-VASc score (0/1 for men/women).ConclusionStudy results suggest that an LV ECV expansion is not associated with AF or AF-mediated LVSD. Supplemental material is available for this article. © RSNA, 2020See also the commentary by Stillman in this issue.

Dataset Information

Targeted inactivation of Cerberus like-2 leads to left ventricular cardiac hyperplasia and systolic dysfunction in the mouse.

Publications

Targeted inactivation of Cerberus like-2 leads to left ventricular cardiac hyperplasia and systolic dysfunction in the mouse.

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