The clinical implications of choroidal thickness combined with tear VEGFA in coronary artery disease.

OBJECTIVE: The purpose of this study was to evaluate the effect of choroidal thickness and tear vascular endothelial growth factor A (VEGFA) as biomarkers of coronary artery disease (CAD). METHODS: This study was a retrospective observational case-control trial. A total of 637 patients who underwent coronary angiography to assess their coronary artery status were included. The patients were divided into two groups: 200 people in the No CAD group and 437 people in the CAD group. We evaluated the choroidal thickness of the right foveal membrane in all patients through optical coherence tomography angiography examination. We also collected tear samples from patients to measure VEGFA. The ROC curve and its area under the curve (AUC) were used for analysis. RESULTS: The central foveal choroid in the No CAD group was significantly thicker than that in the CAD group (289.09 µm ± 38.41; 229.03 µm ± 33.44, P  < 0.01). The tear VEGFA in the CAD group was higher than that in the No CAD group (706.15 ng/mL ±â€…147.42; 419.66 ng/mL ±â€…105.85, P  < 0.01). Spearman analysis showed that the correlation between choroidal thickness and Gensini score was -0.7387 ( P  < 0.01). The correlation between tear VEGFA level and Gensini score was 0.8636 ( P  < 0.01). Taking choroidal thickness and tear VEGFA as independent variables, we obtained AUC = 0.9647 (95% CI 0.9506-0.9789, P  < 0.01) through binary logic regression and ROC curve analysis. CONCLUSION: The combination of choroidal thickness and tear VEGFA in patients can serve as a clinical marker of CAD and its severity.

Role of TMS5: staphylococcal multidrug-efflux protein QacA.

BACKGROUND: QacA, a main exporter mediating the multidrug-resistance of Staphylococcus aureus to a variety of antiseptics and disinfectants, possesses a topology of 14 alpha-helical transmembrane segments (TMS). Our study aimed to determine the importance and topology of amino acid residues in and flanking the cytoplasmic end of TMS5. METHODS: Site-directed mutagenesis was used to mutate 5 residues, including L146, A147, V148, W149 and S150, into cysteine. A minimum inhibitory concentration (MIC) and transport assay with or without N-ethylmaleimide (NEM) were performed to analyse the function of these mutants. RESULTS: All of the mutants showed comparable protein expression levels. MIC analysis suggested that mutant W149C showed low resistance levels to the drugs, but the mutations at L146, A147, V148, and S150C had little or no effect on the resistance level. And the results of the fluorimetric transport assay were in agreement with those of MIC analysis, that is to say, W149C did not allow transport to the substrates to be tested, while the other mutants retained significant transport ability. The reaction of the different mutant proteins with Fluorescein-NEM revealed that the mutant L146C was highly reactive with NEM; the W149C and S150C mutants were moderately reactive; A147C was barely reactive and V148C showed no reactivity. CONCLUSIONS: The study identified that residues W149 and S150 situated at the interface of the aqueous: lipid junction as functionally important residues, probably involved in the substrate binding and translocation of QacA.

Angiotensin-converting enzyme-2 overexpression improves atrial electrical remodeling through TRPM7 signaling pathway.

Atrial electrical remodeling is an important factor in the development and persistence of atrial fibrillation. The aim of this study was to examine the effects of atrial angiotensin-converting enzyme-2 overexpression on atrial electrical remodeling and to elucidate the molecular mechanisms underlying these effects. Twenty-eight male and female dogs were randomly divided into the following 4 groups: a sham-operation group, a control group, an adenovirus-enhanced green fluorescent protein (Ad-EGFP) gene group and an Ad-ACE2 gene group. All dogs in the Ad-EGFP and Ad-ACE2 groups were rhythmized at 450 bpm for 14 days. Two weeks later, all the dogs underwent thoracotomy and epicardial gene painting. On day 21 after gene transfer, all the animals were subjected to electrophysiological and molecular studies. AF induction rates and durations were significantly increased in the control and Ad-EGFP groups compared to the sham-operated and Ad-ACE2 groups. Transient receptor potential melastatin 7 (TRPM7) expression levels in the Ad-EGFP and control groups were significantly higher than those in the sham-operated and Ad-ACE2 groups. Basal [Mg2+]i was significantly decreased in siRNA transfected cells compared with control and non-silencing siRNA-transfected cells. Our results suggest that ACE2 overexpression suppresses atrial electrical remodeling and improves atrial function through the TRPM7 signaling pathway.

Coronary Artery Complication in Kawasaki Disease and the Importance of Early Intervention : A Systematic Review and Meta-analysis.

Importance: The timing and selection of patients with Kawasaki disease for corticosteroid use to prevent coronary artery complications remain controversial. Objective: To evaluate the effect of corticosteroid therapy in KD. Data Sources: Databases of Medline, The Cochrane Library, and the Clinicaltrials.gov website until July 2015. We used the key words ["Kawasaki disease"] and ["steroid" OR "corticosteroid"] to retrieve potentially relevant studies in the databases of Medline, the Cochrane Library, and the Clinicaltrials.gov website until July 2015. Both English and non-English literature was identified. Titles and abstracts were reviewed by 2 authors (S.C. and Y.D.) to determine suitability for inclusion. Relevant articles were reassessed by reviewing the full text. Discrepancies in study inclusion were resolved by consensus (M.G.K.). Study Selection: Clinical studies that compared corticosteroids plus intravenous immunoglobulin (IVIG) therapy with IVIG therapy alone in treating patients with KD. Studies either using corticosteroids as initial therapy or as rescue therapy were included. Data Extraction and Synthesis: Investigators independently extracted the data information. Data were quantitatively synthesized using random-effects analysis. Main Outcomes and Measures: Rate of coronary artery abnormalities. Results: Sixteen comparative studies characterizing 2746 patients were analyzed. The duration of illness before corticosteroids therapy was significantly shorter in the initial corticosteroids subset than in the rescue corticosteroids subset. The rate of coronary artery abnormalities was significantly lower in adjunctive corticosteroids therapy than in IVIG therapy (odds ratio [OR], 0.424; 95% CI, 0.270-0.665). Meta-regression based on known variables demonstrated that the overall efficacy was negatively correlated with the duration of illness before corticosteroid therapy (P < .001). Subgroup analysis, including studies using corticosteroids plus IVIG as initial therapy, showed a more advantageous effect than IVIG alone regarding coronary artery abnormality prevention (OR, 0.320; 95% CI, 0.183-0.560), whereas this benefit was not found in a subgroup of studies using corticosteroids as rescue therapy. Further analysis found that patients predicted at baseline to be at high risk of IVIG resistance seemed to obtain the greatest benefit from adjunctive corticosteroid therapy regarding coronary artery abnormality prevention (OR, 0.240; 95% CI, 0.123-0.467). The fever duration was significantly reduced in the corticosteroids group. The favorable effects of corticosteroids were conferred without an increased risk of adverse events. Conclusions and Relevance: This study highlights the importance of timing to prevent coronary artery complication in treating KD. High-risk patients with KD benefit greatly from a timely and potent adjunctive corticosteroid therapy strategy.

Angiotensin-converting enzyme-2 overexpression improves atrial remodeling and function in a canine model of atrial fibrillation.

BACKGROUND: Atrial fibrosis is an important factor in initiating and maintaining atrial fibrillation. The purpose of this study was to test the hypothesis that atrial angiotensin-converting enzyme-2 (ACE2) overexpression might inhibit atrial collagen accumulation and improve atrial remodeling in a canine atrial pacing model. METHODS AND RESULTS: Thirty-two mongrel dogs of both genders were divided randomly into 4 groups: sham-operated, control, gene therapy with adenovirus-enhanced green fluorescent protein (Ad-EGFP), and gene therapy with Ad-ACE2. All of the dogs in the control, Ad-EGFP, and Ad-ACE2 groups were paced at 450 bpm for a period of 14 days. The dogs in the sham group were instrumented without pacing. After 2 weeks, all of the dogs underwent a thoracotomy operation and received epicardial gene painting. On post-gene transfer day 21, the animals underwent electrophysiology, histology, and molecular studies. The percentage of fibrosis in the Ad-ACE2 group was markedly lower than the percentage in the control and Ad-EGFP groups. Compared with the other groups, ACE2 expression was increased significantly in the Ad-ACE2 group. Compared with the sham and Ad-ACE2 groups, the expression levels of transforming growth factor-ß1 and Smad3 were significantly higher in the Ad-EGFP and control groups; however, the expression levels of Smad7 were lower in the atrial tissue as detected by Western blot and reverse transcription polymerase chain reaction. CONCLUSIONS: Our results demonstrate that the overexpression of ACE2 inhibits atrial collagen accumulation and improves left atrial remodeling and function in a canine model of atrial fibrillation. Thus, targeted gene ACE2 therapy provides a promising approach for the treatment of atrial fibrillation.

Selective proximal renal denervation guided by autonomic responses evoked via high-frequency stimulation in a preclinical canine model.

BACKGROUND: Electric stimulation has been proved to be available to monitor the efficacy of renal denervation (RDN). This study was to evaluate the effectiveness of high-frequency stimulation (HFS)-guided proximal RDN. METHODS AND RESULTS: A total of 13 Chinese Kunming dogs were included and allocated to proximal RDN group (n=8) and control group (n=5). HFS (20 Hz, 8 V, pulse width 2 ms) was performed from proximal to distal renal artery in all dogs. Radiofrequency ablations were delivered in proximal RDN group and only at the proximal positive sites where systolic blood pressure (BP) increased ≥10 mm Hg during HFS. Postablation HFS was performed over the previously stimulated sites. BP, heart rate, and plasma norepinephrine were analyzed. In 8 denervated dogs, preablation HFS caused significant BP increases of 6.0±5.0/3.4±5.5, 16.9±11.7/11.1±8.5, and 17.1±8.4/8.5±5.3 mm Hg during the first, second, and third 20 s of HFS at the proximal positive sites. After ablation, these sites showed a negative response to postablation HFS with increases of BP by 1.3±3.0/1.0±2.5, 0.8±3.9/1.5±3.4, and 1.5±4.5/0.7±3.8 mm Hg. Of note, no radiofrequency applications were delivered at the positive sites of middle renal artery, repeated HFS increased BP only by 3.3±5.3/2.8±4.2, 5.3±6.6/3.8±4.7, and 2.9±4.6/1.3±3.2 mm Hg, failed to reproduce the previous BP increases of 6.2±5.6/5.3±4.4, 15.0±9.3/10.2±6.2, and 14.9±7.7/8.4±4.7 mm Hg. At 3 months, BP and plasma norepinephrine substantially decreased in proximal RDN group. Whereas controls showed minimal BP decreases and had similar plasma norepinephrine concentrations as baseline. CONCLUSIONS: Renal afferent nerves can be mapped safely, and HFS-guided targeted proximal RDN can achieve apparent BP reduction and sympathetic inhibition.

Comparison of Saline-Irrigated Catheter vs. Temperature-Controlled Catheter for Renal Denervation in a Canine Model.

BACKGROUND: The effectiveness of catheter-based renal denervation (RDN) remains controversial. Although the reasons for this have not yet been elucidated, ineffective denervation appears to be an important factor. The present study aimed to investigate the difference in RDN between a saline-irrigated catheter (SIC) and a temperature-controlled catheter (TCC). METHODS: Dogs (n = 6) from the Kunming province in Chinese were ablated; the SIC was introduced into the right renal artery, while the TCC was introduced into the left renal artery. After 6 months, histopathology and renal angiography were performed, and the change in neural density was evaluated using morphometric software. The average values of heart rate (HR), blood pressure (BP), and catecholamine metabolites were assessed at baseline and follow-up. RESULTS: Histopathology showed nerve demyelination and denaturation, as well as interstitial hyperplasia, although these changes were more pronounced when the SIC was used. The change in neural density was greater and ablation was deeper when the SIC was used. Intimal hyperplasia was greater when the TCC was used, whereas medial hyperplasia was greater when the SIC was used. A trend toward a decrease in HR, BP, metanephrine, and normetanephrine between baseline and follow-up was observed. CONCLUSIONS: Our findings suggest that SIC ablation results in more extensive neural degeneration, deeper penetration, and less extensive intimal hyperplasia than TCC ablation for RDN.