Takahide Arai

Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents

Although several cytokines and neurotrophic factors induce sympathetic neurons to transdifferentiate into cholinergic neurons in vitro, the physiological and pathophysiological roles of this remain unknown. During congestive heart failure (CHF), sympathetic neural tone is upregulated, but there is a paradoxical reduction in norepinephrine synthesis and reuptake in the cardiac sympathetic nervous system (SNS). Here we examined whether cholinergic transdifferentiation can occur in the cardiac SNS in rodent models of CHF and investigated the underlying molecular mechanism(s) using genetically modified mice. We used Dahl salt-sensitive rats to model CHF and found that, upon CHF induction, the cardiac SNS clearly acquired cholinergic characteristics. Of the various cholinergic differentiation factors, leukemia inhibitory factor (LIF) and cardiotrophin-1 were strongly upregulated in the ventricles of rats with CHF. Further, LIF and cardiotrophin-1 secreted from cultured failing rat cardiomyocytes induced cholinergic transdifferentiation in cultured sympathetic neurons, and this process was reversed by siRNAs targeting Lif and cardiotrophin-1. Consistent with the data in rats, heart-specific overexpression of LIF in mice caused cholinergic transdifferentiation in the cardiac SNS. Further, SNS-specific targeting of the gene encoding the gp130 subunit of the receptor for LIF and cardiotrophin-1 in mice prevented CHF-induced cholinergic transdifferentiation. Cholinergic transdifferentiation was also observed in the cardiac SNS of autopsied patients with CHF. Thus, CHF causes target-dependent cholinergic transdifferentiation of the cardiac SNS via gp130-signaling cytokines secreted from the failing myocardium.

G-CSF influences mouse skeletal muscle development and regeneration by stimulating myoblast proliferation

Granulocyte colony-stimulating factor and its receptor are needed for skeletal muscle development and injury-induced regeneration in mice.

Norepinephrine-induced nerve growth factor depletion causes cardiac sympathetic denervation in severe heart failure

In severe congestive heart failure (CHF), sympathetic overactivity correlates with the exacerbation of cardiac performance. To test the hypothesis that the cardiac sympathetic nerve density dramatically changes with the acceleration of circulating norepinephrine (NE) concentration, we investigated the temporal association of nerve growth factor (NGF) expression in the heart and cardiac sympathetic nerve density during the development of CHF in the continuous NE-infused rats. The animals were analyzed at 0-, 1-, 3-, 7-, 14-, and 28-day after implantation of osmotic pump at a rate of 0.05 mg/kg/hr. The cardiac performance was temporally facilitated in NE-exposed rats at 3-day in accordance with the sympathetic hyper-innervation induced by the augmentation of NGF mRNA expression in the heart. In NE-treated rats, left ventricular end-diastolic pressure was significantly increased after 7-day and marked left ventricular hypertrophy and systemic fluid retention were observed at 28-day. CHF-induced sympathetic overactivity further increased plasma NE concentration in NE-treated rats and finally reached to 16.1+/-5.6 ng/ml at 28-day (control level was 0.39+/-0.1 ng/ml, p<0.01). In the decompensated CHF rats at 28-day, the NGF mRNA expression was conspicuously reduced concomitant with the obvious nerve fiber loss confirmed by the immunostaining of nerve axonal marker, PGP9.5 and sympathetic neuron marker, tyrosine hydroxylase. This resulted in the attenuated tissue NE contents and the exacerbating cardiac performance. The cardiac sympathetic fiber loss was also confirmed in NE-exposed DBH (dopamine beta-hydroxylase)-Cre/Floxed-EGFP (enhanced green fluorescent protein) mice with severe CHF, in which sympathetic nerve could be traced by EGFP. Our results suggest that the cardiac sympathetic nerve density is strictly regulated by the NGF expression in the heart and long-exposure of high plasma NE concentration caused myocardial NGF reduction, following sympathetic fiber loss in severe CHF animals.

Neural Crest–Derived Stem Cells Migrate and Differentiate Into Cardiomyocytes After Myocardial Infarction

Objective—We recently demonstrated that primitive neural crest–derived (NC) cells migrate from the cardiac neural crest during embryonic development and remain in the heart as dormant stem cells, with the capacity to differentiate into various cell types, including cardiomyocytes. Here, we examined the migration and differentiation potential of these cells on myocardial infarction (MI). Methods and Results—We obtained double-transgenic mice by crossing protein-0 promoter-Cre mice with Floxed–enhanced green fluorescent protein mice, in which the NC cells express enhanced green fluorescent protein. In the neonatal heart, NC stem cells (NCSCs) were localized predominantly in the outflow tract, but they were also distributed in a gradient from base to apex throughout the ventricular myocardium. Time-lapse video analysis revealed that the NCSCs were migratory. Some NCSCs persisted in the adult heart. On MI, NCSCs accumulated at the ischemic border zone area (BZA), which expresses monocyte chemoattractant protein-1 (MCP-1). Ex vivo cell migration assays demonstrated that MCP-1 induced NCSC migration and that this chemotactic effect was significantly depressed by an anti-MCP-1 antibody. Small NC cardiomyocytes first appeared in the BZA 2 weeks post-MI and gradually increased in number thereafter. Conclusion—These results suggested that NCSCs migrate into the BZA via MCP-1/CCR2 signaling and contribute to the provision of cardiomyocytes for cardiac regeneration after MI.

Evaluation of the learning curve for transcatheter aortic valve implantation via the transfemoral approach

BACKGROUND The aim of this study was to evaluate the learning curve in performing transfemoral TAVI (TF-TAVI). METHODS Between October 2006 and October 2013, 312 consecutive TF-TAVI cases performed by 6 interventional cardiologists, using the Edwards Sapien valve and 104 using the CoreValve, were included in the present analysis. Cumulative sum (CUSUM) failure analysis of combined 30-day safety endpoint was used to evaluate learning curves. RESULTS The CUSUM analysis revealed a learning curve regarding the occurrence of 30-day adverse events with an improvement after the initial 86 cases using the Edwards valve and 40 cases using the CoreValve. We divided the Edwards valve cases into two groups (early experience: Cases 1 to 86; late experience: Cases 87 to 312). The rate of 30-day mortality and 1-year mortality significantly decreased in the late experience group (17% to 7%, p=0.019; 34% to 21%, p=0.035, respectively). We divided the CoreValve cases into two groups (early experience: Cases 1 to 40; late experience: Cases 41 to 104). The rate of 30-day mortality and 1-year mortality significantly decreased in the late experience group (20% to 6%, p=0.033; 38% to 15%, p=0.040, respectively). The groups including both valves were also analyzed after propensity-matching (early [n=52] vs late [n=52]). This model also showed that 30-day and 1-year mortality rates were significantly lower in the late experience group (13% to 1%, p=0.028; 34% to 20%, p=0.042, respectively). CONCLUSIONS An appropriate level of experience is needed to reduce the complication rate and mortality in TF-TAVI.

Streamlining the learning process for TAVI: Insight from a comparative analysis of the OCEAN-TAVI and the massy registries

To facilitate the learning process of transcatheter aortic valve implantation (TAVI) in Japan, unique supporting systems (e.g., on‐site proctor and web‐based screening systems) have been developed. Nevertheless, little is known about real‐world clinical outcomes after TAVI in Japan compared with their European counterparts.

Impact of pre- and post-procedural anemia on the incidence of acute kidney injury and 1-year mortality in patients undergoing transcatheter aortic valve implantation (from the French Aortic National CoreValve and Edwards 2 [FRANCE 2] Registry)

The relationship between anemia, renal insufficiency, and the outcomes of TAVI patients has not been thoroughly studied. We aimed to evaluate the influence of pre‐ and post‐procedural anemia on the incidence of renal insufficiency, especially AKI, and on the outcomes of TAVI.

Comparison of multislice computed tomography findings between bicuspid and tricuspid aortic valves before and after transcatheter aortic valve implantation: CT Imaging of Bicuspid Valve before and after TAVI

This study sought to compare the multislice computed tomography (MSCT) characteristics of bicuspid aortic valves (BAV) and tricuspid aortic valves (TAV) before and after implantation of the CoreValve (Medtronic, Santa Rosa, California) or the Edwards SapienXT (Edwards Lifesciences, Irvine, CA).

Rebuttal: Comparison of multislice computed tomography findings between bicuspid and tricuspid aortic valves before and after transcatheter aortic valve implantation

Aims This study sought to compare the multislice computed tomography (MSCT) characteristics of bicuspid aortic valves (BAV) and tricuspid aortic valves (TAV) before and after implantation of the CoreValve (Medtronic, Santa Rosa, California) or the Edwards SapienXT (Edwards Lifesciences, Irvine, CA). Methods and Results From March 2009 to March 2013, a total of 67 TAVI patients who had both pre- and post-procedural MSCT were studied. Eleven patients underwent TAVI in BAV with the CoreValve (n = 6) or SapienXT (n = 5) and 56 patients underwent TAVI in TAV with the CoreValve (n = 38) or SapienXT (n = 18). The BAV group was similar to the TAV group except for a higher pre-procedural mean pressure gradient (53.1 ± 17.4 vs. 48.8 ± 20.4 mm Hg, P = 0.03), a larger annulus perimeter (89.3 ± 9.0 vs. 81.8 ± 8.1 mm, P = 0.03) and a higher aortic valve calcium volume (1262.7 ± 396.0 vs. 556.4 ± 461.9 mm3, P < 0.01). In the CoreValve group, post-procedural mean pressure gradient was significantly higher in the BAV group (11.0 ± 2.6 vs. 8.2 ± 2.8 mm Hg, P = 0.04) and a smaller valve area/pre-annulus area ratio was observed at each level of the prosthesis (base of the stent frame 81.7% ± 14.9% vs. 94.7% ± 15.0%, P = 0.06, annulus level 74.3% ± 16.7% vs. 89.9% ± 10.5%, P = 0.03, leaflet level 64.6% ± 13.1% vs. 81.2% ± 13.2%, P < 0.01). This was not observed in the Edwards group. Conclusions Compared to TAV, patients with BAV have higher gradients, larger annulus perimeters and more calcified valves. Higher post procedural gradient and valve underexpansion were frequently observed after CoreValve implantation. Further MSCT study is required to demonstrate the efficacy of TAVI in BAV.

Comparison of Edwards SAPIEN 3 versus SAPIEN XT in transfemoral transcatheter aortic valve implantation: Difference of valve selection in the real world.

BACKGROUND The SAPIEN 3 (S3; Edwards Lifescience, Irvine, CA, USA) is a new-generation percutaneous aortic valve with better profile, more precise handling and positioning, designed to reduce the risk of post-procedural paravalvular aortic leak (PVL). The aim of this study was to compare the S3 valve and SAPIEN XT valve (SXT). METHODS The last 89 transfemoral transcatheter aortic valve implantation (TAVI) cases using SXT were compared to the first 111 cases using the S3. RESULTS Patient age and logistic EuroSCORE were similar (83.1 years vs 83.0 years and 18.2% vs 16.6%) in the S3 and SXT groups, respectively as were other baseline characteristics. The ratio of valve diameter/calculated annulus average diameter (CAAD) by multi-detector row computed tomography was significantly lower in the S3 group (1.06 vs 1.09, p<0.001) as was the annular area oversizing percentage (11.3% vs 20.5%, p<0.001). Furthermore, a smaller valve was selected in S3 cases with borderline CAAD compared to SXT cases. Nevertheless, the frequency of paravalvular aortic leakage (PVL) ≥2 tended to be reduced in the S3 group (5% vs 9%, p=0.339). The rate of major vascular complications was significantly lower with S3 (3% vs 12%, p=0.013). In addition, 30-day mortality was significantly lower in the S3 group (0% vs 5%, p=0.044). CONCLUSIONS Although TAVI using S3 tended to be carried out with a less oversized valve compared to TAVI using SXT, the frequency of post-procedural PVL ≥2 tended to be lower in the S3 group. The outcomes including vascular complications and 30-day mortality showed a trend in favor of the S3 group.