Preprocedural features of patients under antihypertensive drugs may help identify responders to renal denervation: a hypothesis-generating study.

BACKGROUND: Renal denervation (RDN) is effective to lower systolic blood pressure (SBP) in essential hypertension. However, patient selection under medications remains an important unmet clinical need. METHODS: This multicenter study aimed at observing whether preprocedural features associated with increased renin-angiotensin-aldosterone activity influence RDN response. This study enrolled the patients who underwent RDN for uncontrolled hypertension. Medical records were reviewd and patients were divided into 2 groups depending by meeting any of the following conditions prior to RDN: (1) >10 mmHg of office SBP reduction after aldosterone inhibition, (2) aldosterone-renin ratio >30 or (3) slow flow on the renal angiogram. RDN responders were defined by a reduction in 24-hour mean ≥6 mmHg or by ≥1 class of antihypertensive drug withdraw. RESULTS: A total of 46 patients were enrolled, of which 27 (59%) were in control group A and 19 (41%) in group B. The baseline age, gender, office and 24-hour SBP (mean 140.0 ± 12.8 mmHg vs. 144.0 ± 16.5 mmHg, p = 0.577) were comparable, while the number of prescribed drug classes was fewer in group A (4.0 ± 1.3 vs. 4.9 ± 0.9, p = 0.014). The proportion patients with prescribed aldosterone antagonist or high aldosterone-renin ratios were higher in group B. At 12 months post RDN, the results were significantly better in group B in terms of mean change in office SBP (12.4 ± 23.5 mmHg vs. 29.9 ± 25.5 mmHg, p = 0.046) and the proportion of RDN responders (51.9% vs. 89.5%, p < 0.001). CONCLUSION: RDN was more effective in patients with any of 3 clinical indices.

Effect of CYP2C19 status on platelet reactivity in Taiwanese acute coronary syndrome patients switching to prasugrel from clopidogrel: Switch Study.

BACKGROUND/PURPOSE: Pharmacogenetics is a potential driver of the "East Asian paradox," in which East Asian acute coronary syndrome (ACS) patients receiving dual antiplatelet therapy (DAPT) with clopidogrel following percutaneous coronary intervention (PCI) demonstrate higher levels of platelet reactivity on treatment than Western patients, yet have lower ischemic risk and higher bleeding risk at comparable doses. However, the impact of pharmacogenetics, particularly regarding CYP2C19 genotype, on the pharmacodynamics of P2Y12 inhibitors has not been extensively studied in Taiwanese ACS patients as yet. METHODS: CYP2C19 genotyping and pharmacogenetic analysis was conducted on 102 subjects from the Switch Study, a multicenter, single-arm, open-label intervention study that examined the effects on platelet activity and clinical outcomes of switching from clopidogrel (75 mg daily) to low-dose prasugrel (3.75 mg daily) for maintenance DAPT after PCI in 203 Taiwanese ACS patients. RESULTS: Genotyping results revealed that 43.1% were CYP2C19 extensive metabolizers (EM), while 56.9% were reduced metabolizers (RM). After switching to prasugrel, mean P2Y12 reaction units (PRU) values were significantly reduced in both EM and RM populations, while the proportion of high on-treatment platelet reactivity (HPR) patients significantly declined in RM patients. No increase in bleeding risk after switching was observed during follow-up. Multivariate analysis indicated that for RM patients, low estimated glomerular filtration rate (eGFR) and low hemoglobin were associated with greater HPR risk on clopidogrel, but not after switching to prasugrel. CONCLUSION: Switching to low-dose prasugrel from clopidogrel reduced mean PRU levels and proportion of HPR patients, with more significant reduction in RM patients.

Application and Comparison of Different Prognostic Scoring Systems in Patients Who Underwent Cardiologist-Managed Percutaneous Cardiopulmonary Support.

BACKGROUND: Temporary mechanical support, including percutaneous cardiopulmonary support (PCPS), is crucial for reversing patients' compromised hemodynamic function. Knowledge about whether cardiologists can directly manage patients receiving PCPS and about the predictive values of different prognostic scores is insufficient. METHODS: We examined the data and in-hospital mortality of 45 eligible patients receiving cardiologist-managed PCPS from July 2012 to January 2019 in our institute. We compared different prognostic scores [namely Survival After Veno-arterial ECMO (SAVE), modified SAVE, prEdictioN of Cardiogenic shock OUtcome foR acute myocardial infarction patients salvaGed by VA-ECMO (ENCOURAGE), and Sequential Organ Failure Assessment (SOFA) scores] through area under the receiver operating characteristic curve (AUC) analysis. RESULTS: The patients' mean age was 64.3 ± 11.3 years, and 71.1% were men. The overall in-hospital survival rate was 35.6%. Compared to survivors, nonsurvivors were more likely to have an ischemic etiology, cardiopulmonary resuscitation, and higher lactate levels. Survivors had higher SAVE (-5.9 vs. -11.4) and modified SAVE (4.2 vs. -7.1) scores than nonsurvivors (both p = 0.001), but SOFA (9.7 vs. 10.3) and ENCOURAGE (24.8 vs. 26.8) scores were similar (both p > 0.1). In multivariate models, only modified SAVE score remained statistically significant (hazard ratio: 0.96, 95% confidence interval: 0.93-1.00; p = 0.047). Modified SAVE score showed the best risk discrimination (AUC = 0.78). CONCLUSIONS: Establishing regular and continual training protocols can enable cardiologists to perform emergency PCPS (without on-site surgery) and daily care for patients with refractory cardiogenic shock. The modified SAVE score facilitates risk stratification and future decision-making processes.

Prasugrel switching from clopidogrel after percutaneous coronary intervention for acute coronary syndrome in Taiwanese patients: an analysis of safety and efficacy.

The recommended maintenance dose of prasugrel for East Asian populations (i.e., Japanese and Taiwanese) is 3.75 mg as part of dual antiplatelet therapy (DAPT) for the prevention of recurrent ischemia and stent thrombosis in acute coronary syndrome (ACS). This modified dosage regimen has been established in studies conducted in Japan; however, the efficacy and safety of switching from clopidogrel to prasugrel DAPT among Taiwanese patients remain to be explored. In this phase IV, multicenter, single-arm, open-label study, we evaluated the 4-week pharmacodynamic response, and the 48-week safety outcomes of prasugrel 3.75 mg after a switch from clopidogrel in Taiwanese ACS patients. A total of 203 prasugrel-naïve ACS patients (over 90% male) who had received post-PCI clopidogrel DAPT for at least 2 weeks were enrolled from ten medical centers in Taiwan and subsequently switched to prasugrel 3.75 mg DAPT. Four weeks after the switch, P2Y12 reaction unit (PRU) values were significantly decreased in the total cohort (mean - 18.2 ± 48.1; 95% confidence interval - 24.9 to - 11.5, p < 0.001), and there was an overall consistent antiplatelet response in the treated subjects. The proportion of patients with high on-treatment platelet reactivity (HPR; PRU > 208) dropped from 23.5 to 10% (p < 0.001). Female sex was associated with a greater PRU reduction with prasugrel, whereas HPR at baseline, age ≥ 65 years, and body mass index ≥ 25 best predicted HPR at Week 4. Throughout the 48-week treatment with prasugrel, the incidences of MACE (1.0%) and TIMI major bleeding (2.0%) were rather low, accompanying an acceptable safety profile of TIMI minor (6.4%) and non-major, non-minor clinically relevant bleeding (3.0%). Overall, switching to the maintenance dose of prasugrel (3.75 mg) was observed to be effective and well tolerated among post-PCI ACS patients in Taiwan. Clinical Trial Registration Number: NCT03672097.

Effects of carbenoxolone on flow-mediated vasodilatation in healthy adults.

Gap junctions play a key role in maintaining the functional integrity of the vascular wall. Using carbenoxolone (CBX) as a gap junction blocker, we aimed to assess the contribution of gap junctions in the vascular wall to flow-mediated vasodilatation (FMD) in healthy adults. Percentage FMD (%FMD) and circulating vasoactive molecules/activity, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), aldosterone, cortisol, plasma renin activity (PRA), and endothelin (ET-1), were measured in 25 healthy volunteers (mean age: 30.1 ± 5.4 yr; 14 males) before and after oral administration of CBX (100 mg). %FMD decreased after ingestion of CBX (9.71 ± 3.1 vs. 3.40 ± 2.0%; P < 0.0001). The levels of ANP, BNP, cortisol, and ET-1 remained stationary, while both PRA and aldosterone decreased (P < 0.005) after CBX ingestion. Blood pressure and heart rate were minimally changed by CBX. Inhibition of gap junctional communication by CBX impairs FMD in healthy persons, suggesting that physiologically, vascular gap junctions participate in the maintenance of FMD. CBX does not induce the release of vasoconstricting molecules or enhance vasoconstriction, suggesting that inhibition of gap junctional communication by CBX underlies the impairment of FMD. Therefore, administering CBX in FMD examination can be a way to follow the effect of gap junctions on endothelial function, but further work remains to verify the specificity of CBX effect.

Effect of Reducing Heart Rate on Outcomes in Patients With Reduced Ejection Fraction.

Since 1953, sinus tachycardia has been defined as a heart rate (HR) in sinus rhythm of >100 beats per minute (bpm). However, this number has never been formally evaluated, and no established threshold values for special groups, such as those with heart failure (HF) accompanied by a reduced ejection fraction (HFrEF). Herein, we provided evidence that lowering the HR of patients with HFrEF to <70 bpm with medications such as ivabradine improves outcomes. Numerous large-scale trials and smaller clinical studies have shown that reducing the HR in patients with HFrEF improves cardiovascular and overall outcomes. Evidence suggests that a HR of <70 bpm is appropriate for patients with HFrEF. Examination of HF registries indicates that in a large proportion of these patients the HR exceeds 80 bpm, and no consideration is given to lowering the HR, due in large part to lack of physician awareness of the benefits of a lower HR. Evidence indicates that the first-line medication for lowering HR in patients with HFrEF is ivabradine. In conclusion, the improved prognosis following appropriate HR management in patients with HFrEF suggest that the cut-off value for sinus tachycardia in these patients should be redefined as 75 bpm. Maintaining a HR of <70 bpm in patients with HFrEF is associated with improved cardiovascular and overall outcomes.

Computer-aided diagnosis of endobronchial ultrasound images using convolutional neural network.

BACKGROUND AND OBJECTIVE: In the United States, lung cancer is the leading cause of cancer death. The survival rate could increase by early detection. In recent years, the endobronchial ultrasonography (EBUS) images have been utilized to differentiate between benign and malignant lesions and guide transbronchial needle aspiration because it is real-time, radiation-free and has better performance. However, the diagnosis depends on the subjective judgment from doctors. In some previous studies, which using the grayscale image textures of the EBUS images to classify the lung lesions but it belonged to semi-automated system which still need the experts to select a part of the lesion first. Therefore, the main purpose of this study was to achieve full automation assistance by using convolution neural network. METHODS: First of all, the EBUS images resized to the input size of convolution neural network (CNN). And then, the training data were rotated and flipped. The parameters of the model trained with ImageNet previously were transferred to the CaffeNet used to classify the lung lesions. And then, the parameter of the CaffeNet was optimized by the EBUS training data. The features with 4096 dimension were extracted from the 7th fully connected layer and the support vector machine (SVM) was utilized to differentiate benign and malignant. This study was validated with 164 cases including 56 benign and 108 malignant. RESULTS: According to the experiment results, applying the classification by the features from the CNN with transfer learning had better performance than the conventional method with gray level co-occurrence matrix (GLCM) features. The accuracy, sensitivity, specificity, and the area under ROC achieved 85.4% (140/164), 87.0% (94/108), 82.1% (46/56), and 0.8705, respectively. CONCLUSIONS: From the experiment results, it has potential ability to diagnose EBUS images with CNN.

Autophagy mediates serum starvation-induced quiescence in nucleus pulposus stem cells by the regulation of P27.

BACKGROUND: Adult stem cells exist in a quiescent state (G0) within the in vivo niche; the loss of quiescence often leads to a decrease in the number and function of adult stem cells, impairing tissue regeneration and repair. Endogenous repair by nucleus pulposus-derived stem cells has recently shown promising regenerative potential for the treatment of intervertebral disc degeneration (IDD). However, the number and function of nucleus pulposus stem cells (NPSCs) declined throughout the process of IDD. This effect may have a specific relationship with quiescence. However, the biology of the quiescent NPSCs has not been reported. METHODS: First, we established an in vitro model for NPSC quiescence with serum starvation. The induction of G0 was confirmed by flow cytometry analyses of dual staining with Hoechst 33342 and Pyronin Y, immunofluorescent staining with Ki67 and Western blot analysis of P27 expression. NPSCs were cultured under serum starvation conditions for a long time period (21 days). To examine the functional phenotype of quiescent NPSCs, the cells were reactivated with 10% serum and differentiated into osteogenic and chondrogenic lineages in vitro. The number of colony-forming units was also estimated. To elucidate the role of autophagy in the quiescence of NPSCs, we activated and inhibited autophagy in starved cells with rapamycin and chloroquine, respectively. Then, the expression of P27 was evaluated by Western blot analysis, and the immunofluorescence of Ki67 was assessed. Finally, we assessed the role of P27 siRNA in NPSC quiescence by flow cytometry analyses and 5-ethynyl-20-deoxyuridine incorporation assays under normal and serum-starved conditions. RESULTS: NPSC quiescence was induced by 48 h of serum starvation, and they maintained quiescence for up to 21 days. Upon reactivation with serum, the quiescent NPSCs re-entered the cell cycle and exhibited enhanced clonogenic self-renewal, osteogenic differentiation and chondrogenic differentiation potentials compared to control NPSCs under normal culture conditions. We also found that autophagy underlay serum starvation-induced NPSC quiescence. Further study demonstrated that autophagy mediated the quiescence of NPSCs by regulating P27. CONCLUSIONS: Serum starvation efficiently induces quiescence in NPSCs. Quiescent NPSCs maintain stem cell properties. Our study reveals that autophagy plays a role in maintaining NPSC quiescence and that autophagy mediates the quiescence of NPSCs by regulating P27. We conclude that the induction of quiescence in cultured NPSCs provides a useful model for the analysis of mechanisms that might be relevant to the biology of NPSCs in vivo.

Inhibition of the Notch1 Pathway Promotes the Effects of Nucleus Pulposus Cell-Derived Exosomes on the Differentiation of Mesenchymal Stem Cells into Nucleus Pulposus-Like Cells in Rats.

Stem cell therapies for intervertebral disc degeneration have been demonstrated as a promising strategy. Previous studies have shown that human nucleus pulposus cell- (NPC-) derived exosomes can induce the differentiation of mesenchymal stem cells (MSCs) into NP-like cells in vitro. However, the mechanism of MSC differentiation into NP-like cells with the induction of NPC exosomes is still unclear. Here, we verified the induction effects of NPC exosomes on the differentiation of MSCs into NP-like cells. In addition, the Notch1 pathway was downregulated in this process. Then, DAPT and soluble Jagged1 (SJAG) were applied to inhibit or enhance the expression of the Notch1 pathway, respectively, resulting in the upregulation or downregulation of collagen II, aggrecan, and Sox9 in MSCs. Knocking down of Notch1 protein facilitated the effects of NPC exosomes on the differentiation of MSCs into NP-like cells. NPC exosomes were more effective than an indirect coculture system in terms of the differentiation of MSCs into NP-like cells. Inhibition of NPC exosome secretion with Rab27a siRNA prevented the induction effects of an indirect coculture system on the differentiation of MSCs into NP-like cells. Transwell migration assays revealed that NPC exosomes could promote the migration of MSCs. Taken together, the Notch1 pathway was negatively associated with the differentiation of MSCs into NP-like cells with the treatments of NPC exosomes. Inhibition of the Notch1 pathway facilitates NPC exosome-induced differentiation of MSCs into NP-like cells in vitro. NPC exosomes play a key role in the differentiation of MSCs into NP-like cells in an indirect coculture system of NPCs and MSCs.