Automatic reorientation by deep learning to generate short-axis SPECT myocardial perfusion images.

BACKGROUND: Single photon emission computed tomography (SPECT) myocardial perfusion images (MPI) can be displayed both in traditional short-axis (SA) cardiac planes and polar maps for interpretation and quantification. It is essential to reorient the reconstructed transaxial SPECT MPI into standard SA slices. This study is aimed to develop a deep-learning-based approach for automatic reorientation of MPI. METHODS: A total of 254 patients were enrolled, including 226 stress SPECT MPIs and 247 rest SPECT MPIs. Fivefold cross-validation with 180 stress and 201 rest MPIs was used for training and internal validation; the remaining images were used for testing. The rigid transformation parameters (translation and rotation) from manual reorientation were annotated by an experienced nuclear cardiologist and used as the reference standard. A convolutional neural network (CNN) was designed to predict the transformation parameters. Then, the derived transform was applied to the grid generator and sampler in spatial transformer network (STN) to generate the reoriented image. A loss function containing mean absolute errors for translation and mean square errors for rotation was employed. A three-stage optimization strategy was adopted for model optimization: (1) optimize the translation parameters while fixing the rotation parameters; (2) optimize rotation parameters while fixing the translation parameters; (3) optimize both translation and rotation parameters together. RESULTS: In the test set, the Spearman determination coefficients of the translation distances and rotation angles between the model prediction and the reference standard were 0.993 in X axis, 0.992 in Y axis, 0.994 in Z axis, 0.987 along X axis, 0.990 along Y axis and 0.996 along Z axis, respectively. For the 46 stress MPIs in the test set, the Spearman determination coefficients were 0.858 in percentage of profusion defect (PPD) and 0.858 in summed stress score (SSS); for the 46 rest MPIs in the test set, the Spearman determination coefficients were 0.9 in PPD and 0.9 in summed rest score (SRS). CONCLUSIONS: Our deep learning-based LV reorientation method is able to accurately generate the SA images. Technical validations and subsequent evaluations of measured clinical parameters show that it has great promise for clinical use.

Ni(II)-Pyrazolate Framework Bearing a Metalated Schiff-Base Moiety for Electrocatalytic Hydrogen Evolution.

A robust and porous Ni-based metal-organic framework (MOF), NiL1, was assembled from Ni(II) ions and a dipyrazolate linker (L12-). A Ni(II)-anchored MOF catalyst Ni@NiL1-Sal has been successfully prepared by post-synthetic modification (PSM) condensation between NiL1 with salicylaldehyde, followed by chelation of Ni(II) ions by salicylaldimine as a secondary active site. Ni@NiL1-Sal with carbon black was found to exhibit enhanced electrocatalytic hydrogen evolution reaction (HER) performance (the smallest overpotential, 384 mV, and Tafel slope, 87 mV dec-1) when compared with primitive NiL1 and NiL1-Sal. Such improvement in HER highlights the creation of unambiguous secondary active sites as an avenue to the rational design of a functional MOF-based electrocatalyst.

Left Bundle Branch Pacing for Bradycardia in Non-obstructive Hypertrophic Cardiomyopathy Patients: Feasibility, Safety, and Effect.

PURPOSE: Left bundle branch pacing (LBBP) is as an innovative physiological pacing approach. The research on LBBP in non-obstructive hypertrophic cardiomyopathy (NOHCM) patients is scarce. This study aimed to assess the feasibility, safety, and effect of LBBP in bradycardia NOHCM patients with permanent pacemaker (PPM) implantation indication. METHODS: Thirteen consecutive patients with NOHCM who received LBBP were retrospectively enrolled as a hypertrophic cardiomyopathy (HCM) group. Following 1:3 matching, 39 patients without HCM were randomly matched as a control group. Echocardiographic index and pacing parameters were collected. RESULTS: The successful LBBP was achieved in 96.2% of all cases (50/52), and the success rate of the HCM group was 92.3% (12/13). In the HCM group, the paced QRS duration (from the pacing stimulus to QRS end) was 145.6±20.8 ms. The stimulus to left ventricular activation time (s-LVAT) was 87.4±15.2 ms. In the control group, the paced QRS duration was 139.4±17.2 ms, and the s-LVAT was 79.9±14.1 ms. During the implantation, R-wave sensing and the pacing threshold of the HCM group were significantly higher than the control group (20.2±10.5 vs 12.5±5.9 mV, P < 0.05; 0.8±0.3 vs 0.6±0.2V/0.4 ms, P < 0.05). In addition, the fluoroscopic duration and procedural duration were longer in the HCM group (14.8±8.3 vs 10.3±6.6min, P = 0.07; 131.8±50.5 vs 101.4±41.6 min, P < 0.05). The lead insertion depth was 15±2 mm in the HCM group, and no procedure-related complications occurred. During the 12-month follow-up, pacing parameters remained stable and were of no significance in the two groups. The cardiac function did not deteriorate, and the left ventricular outflow tract gradient (LVOTG) did not increase in the follow-up. CONCLUSION: LBBP might be feasible and safe for NOHCM patients with conventional bradycardia pacing indication, and there is no deterioration in cardiac function and LVOTG of patients with NOHCM.

Influence of Light-EmittingDiode-Derived Blue Light Overexposure on Rat Ocular Surface.

We aim to investigate the effect of overexposure to blue light on the rat ocular surface and explore the potential mechanisms. 450 nm light-emitting diode (LED) derived light at 1000 lux was used to irradiate SD rats, 12 hours a day, for consecutive 28 days. Rats in the control group were exposed to 400 lux white light at the same time (in an indoor environment). Tear film breakup time (TBUT), tear volume, and corneal fluorescein staining scores were used to measure the changes to the ocular surface. Expressions of nuclear factor-κB (NF-κB), inhibitor-κB (I-κB), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured by real-time PCR, and the activation of the NF-κB pathway was detected by Western blotting, respectively. Cornea ultrastructure was examined by TEM and optical microscope on day 28. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB signaling pathway, was used to measure the inhibition of blue light injury. The above indexes were detected again when compared with the solvent-treated group. On day 28, compared with day 0, the TBUT of the blue light group was significantly shorter, and the score was significantly higher. The amount of tear secretion changed slightly with time. HE and PAS staining revealed significantly decreased corneal epithelial cell layers and increased goblet cells after 28-day irradiation of blue light. Disarranged stromal cells, vacuoles in the basal nuclei, and decreased desmosomes were also found in the blue light group. Significantly increased levels of NF-κB, IL-6, TNF-α, and the ratio of phosphorylated NF-κB p65 (pNF-κB p65) to total NF-κB p65 implied blue light-induced damage and pathway activation. In addition, PDTC significantly reduced the phosphorylation of NF-κB activated in blue light-treated corneas and alleviated the ocular surface changes caused by blue light. Finally, our results demonstrated that long-term blue light exposure in rats could cause ocular surface changes and manifest as dry eye. Inflammation and activation of the NF-κB pathway may play a role in the pathogenesis.

Utilizing Metal-Thiocatecholate Functionalized UiO-66 Framework for Photocatalytic Hydrogen Evolution Reaction.

Exploiting clean energy is essential for sustainable development and sunlight-driven photocatalytic water splitting represents one of the most promising approaches toward this goal. Metal-organic frameworks (MOFs) are competent photocatalysts owing to their tailorable functionality, well-defined structure, and high porosity. Yet, the introduction of the unambiguous metal-centered active site into MOFs is still challenging since framework motifs capable of anchoring metal ions firmly are lacking. Herein, the assembly using 1,4-dicarboxylbenzene-2,3-dithiol (H2 dcbdt) and Zr-Oxo clusters to give a thiol-functionalized UiO-66 type framework, UiO-66-dcbdt, is reported. The thiocatechols on the struts are allowed to capture transition metal (TM) ions to generate UiO-66-dcbdt-M (M  = Fe, Ni, Cu) with unambiguous metal-thiocatecholate moieties for photocatalytic hydrogen evolution reaction (HER). UiO-66-dcbdt-Cu is found the best catalyst exhibiting an HER rate of 4.18 mmol g-1  h-1  upon irradiation with photosensitizing Ru-polypyridyl complex. To skip the use of the external sensitizer, UiO-66-dcbdt-Cu is heterojunctioned with titanium dioxide (TiO2 ) and achieves an HER rate of 12.63 mmol g-1  h-1  (32.3 times that of primitive TiO2 ). This work represents the first example of MOF assembly employing H2 dcbdt as the mere linker followed by chelation with TM ions and undoubtedly fuels the rational design of MOF photocatalysts bearing well-defined active sites.

Empagliflozin ameliorates cardiac dysfunction in heart failure mice via regulating mitochondrial dynamics.

Empagliflozin has cardioprotective effects in patients with heart failure (HF). However, the mechanism by which empagliflozin protects against HF remains controversial. Study aimed to evaluate the effect of empagliflozin on myocardial fibrosis and cardiac function in HF mice and its possible mechanism. C57BL/6 mice were induced with HF by ligation of the left anterior descending coronary artery. At 4 weeks postoperation, mice were randomly given normal saline or empagliflozin for 8 weeks. Echocardiography was used to assess cardiac function. Masson's staining, immunohistochemistry and Western blot analysis were used to detect the degree of myocardial fibrosis. Changes in mitochondria were detected by observing mitochondrial morphology, measuring mitochondrial dynamics-related proteins and analysing the levels of adenosine triphosphate (ATP), adenosine monophosphate (AMP) and adenosine diphosphate (ADP). The mitochondrial fission inhibitor, mdivi1, was used to detect the relationship between mitochondrial dysfunction and cardiac dysfunction in HF mice. HF led to myocardial fibrosis and cardiac dysfunction. However, treatment with empagliflozin reduced these effects. Empagliflozin inhibited mitochondrial fission and improved energy metabolic efficiency in HF mice by regulating the expression of mitochondrial dynamics-related proteins. Similarly, mdivi1 attenuated mitochondrial dysfunction and cardiac dysfunction by inhibiting mitochondrial fission in HF mice. Regulation of mitochondrial dynamics, especially inhibition of mitochondrial fission, may be a potential target for reducing cardiac damage in patients with HF. Empagliflozin improved myocardial fibrosis and cardiac dysfunction by modulating mitochondrial dynamics in HF mice. Thus, the cardiac protective effect of empagliflozin may be related to the normalization of mitochondria and the increase in ATP production.

Were economic evaluations well reported for the newly listed oncology drugs in China's national reimbursement drug list.

PURPOSE: To assess the reporting quality of published economic evaluations of the negotiated oncology drugs listed for China's 2020 National Reimbursement Drug List (NRDL). METHODS: A comprehensive search was conducted to identify economic evaluation studies of negotiated oncology drugs listed in China's 2020 NRDL using the PubMed/MEDLINE, Embase, Web of Science, CNKI, SinoMed, and WanFang Database up to March 31, 2021. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist scored the reporting quality between 0 and 100. A linear regression analysis was employed to examine the influence of various characteristics on the reporting quality scores. RESULTS: Eighty papers were included in the study, with the majority published during the past decade. Furthermore, more than half of the articles (57.5%, or 46 out of 80) were written in English. The average CHEERS score was 74.63 ± 12.75 and ranged from 43.48 to 93.75. The most inadequately reported items included choice of model, characterization of heterogeneity, and discussion, as well as currency, price date and conversion. Higher scores were associated with articles published from 2019 to 2021 and English publications. CONCLUSION: The economic evaluation studies of negotiated oncology drugs listed in 2020 NRDL had moderate reporting quality. The Chinese economic evaluation publications could improve the reporting quality if the CHEERS checklist is consistently implemented. Also, the Chinese journals maybe explore introducing a reporting standard for economic evaluations.

The dynamic changes of genes revealed that persistently overexpressed genes drive the evolution of cyflumetofen resistance in Tetranychus cinnabarinus.

Changes in gene expression are associated with the evolution of pesticide resistance in arthropods. In this study, transcriptome sequencing was performed in three different resistance levels (low, L; medium, M; and high, H) of cyflumetofen-resistant strain (YN-CyR). A total of 1 685 genes, including 97 detoxification enzyme genes, were upregulated in all three stages, of which 192 genes, including 11 detoxification enzyme genes, showed a continuous increase in expression level with resistance development (L to H). RNAi experiments showed that overexpression of 7 genes (CYP392A1, TcGSTd05, CCE06, CYP389A1, TcGSTz01, CCE59, and CYP389C2) is involved in the development of cyflumetofen resistance in Tetranychus cinnabarinus. The recombinant CYP392A1 can effectively metabolize cyflumetofen, while CCE06 can bind and sequester cyflumetofen in vitro. We compared two methods for rapid screening of resistance molecular markers, including short-term induction and one-time high-dose selection. Two detoxification enzyme genes were upregulated in the field susceptible strain (YN-S) by induction with LC20 of cyflumetofen. However, 16 detoxification enzyme genes were upregulated by one-time selection with LC80 of cyflumetofen. Interestingly, the 16 genes were overexpressed in all three resistance stages. These results indicated that 1 685 genes that were upregulated at the L stage constituted the basis of cyflumetofen resistance, of which 192 genes whose upregulation continued to increase were the main driving force for the development of resistance. Moreover, the one-time high-dose selection is an efficient way to rapidly obtain the resistance-related genes that can aid in the development of resistance markers and resistance management in mites. This article is protected by copyright. All rights reserved.

Trimethylamine N-oxide facilitates the progression of atrial fibrillation in rats with type 2 diabetes by aggravating cardiac inflammation and connexin remodeling

Diabetes is an independent risk factor for atrial fibrillation (AF). This study aimed to elucidate the pathophysiology of diabetes-related AF from the perspective of the gut microbial metabolite trimethylamine N-oxide (TMAO). In the present study, male rats received either a normal diet to serve as the control group or a high-fat diet/streptozotocin to induce type 2 diabetes mellitus. Then, diabetic rats were divided into two groups based on the presence or absence of 3,3-dimethyl-1-butanol (DMB, a specific TMAO inhibitor) in drinking water: the diabetic cardiomyopathy (DCM) group and the DCM + DMB group. Eight weeks later, compared with control rats, rats in the DCM group exhibited gut microbiota dysbiosis and systemic TMAO elevation. The inflammatory cytokines IL-1β, IL-6, and TNF-α were markedly increased in the atria of rats in the DCM group. Downregulated expression of connexin 40 and lateralized distribution of connexin 43 were also observed in the atria of DCM rats. AF inducibility was significantly higher in DCM rats than in control rats. Furthermore, DMB treatment effectively ameliorated atrial inflammation and connexin remodeling while markedly reducing plasma TMAO levels. DMB treatment also decreased the vulnerability of diabetic rats to AF. In conclusion, TMAO might promote atrial inflammation and connexin remodeling in the development of diabetes, which may play a key role in mediating diabetes-related AF. (AU)

Interventricular septum angle obtained from cardiac computed tomography for origin differentiation of outflow tract ventricular arrhythmia between left and right.

AIMS: Our objective was to explore whether the accuracy of the transitional zone index (TZI) for outflow tract ventricular arrhythmias (OT-VAs) origin is affected by cardiac rotation and the additive value of interventricular septum angle (IVSa) obtained from coronary computed tomography angiography (CCTA). METHODS: Standard 12-lead ECGs of OT-VAs with inferior axis in consecutive patients undergoing both CCTA examination and successful ablation were retrospectively analyzed. The IVSa was defined as an angle between the long axis of IVS and sagittal axis of the body from CCTA. RESULTS: 64 patients (31 men; mean age 54.2 ± 11.6 years) were enrolled. The OT-VAs exhibited right ventricular outflow tract origin in 46 (71.9%) patients and 36 (78.3%) were diagnosed correctly by TZI. The left ventricular outflow tract origin OT-VAs was observed in 18 (28.1%) patients and 16 (88.9%) were diagnosed correctly by TZI. The patients were then divided into TZI correct group (n = 52) and TZI incorrect group (n = 12). In the TZI incorrect group, 11/12 (91.7%) cases were R/S transition in lead V3 with the TZ score during premature ventricular contractions [2.8(2.5-3.4)], and the TZI between -1.5 and 0. The IVSa was significantly larger in the TZI incorrect group than correct group (52.0 ± 6.9° vs. 39.0 ± 6.1°; p < .0001). The IVSa ≥46° predicted TZI incorrect with 92% sensitivity, 94% specificity, and 94% accuracy. CONCLUSION: The IVSa is a novel cardiac rotation index that reliably improves TZI to differentiate the OT-VAs origin, especially for the OT-VAs with lead V3 R/S transition.

Trimethylamine N-oxide facilitates the progression of atrial fibrillation in rats with type 2 diabetes by aggravating cardiac inflammation and connexin remodeling.

Diabetes is an independent risk factor for atrial fibrillation (AF). This study aimed to elucidate the pathophysiology of diabetes-related AF from the perspective of the gut microbial metabolite trimethylamine N-oxide (TMAO). In the present study, male rats received either a normal diet to serve as the control group or a high-fat diet/streptozotocin to induce type 2 diabetes mellitus. Then, diabetic rats were divided into two groups based on the presence or absence of 3,3-dimethyl-1-butanol (DMB, a specific TMAO inhibitor) in drinking water: the diabetic cardiomyopathy (DCM) group and the DCM + DMB group. Eight weeks later, compared with control rats, rats in the DCM group exhibited gut microbiota dysbiosis and systemic TMAO elevation. The inflammatory cytokines IL-1ß, IL-6, and TNF-α were markedly increased in the atria of rats in the DCM group. Downregulated expression of connexin 40 and lateralized distribution of connexin 43 were also observed in the atria of DCM rats. AF inducibility was significantly higher in DCM rats than in control rats. Furthermore, DMB treatment effectively ameliorated atrial inflammation and connexin remodeling while markedly reducing plasma TMAO levels. DMB treatment also decreased the vulnerability of diabetic rats to AF. In conclusion, TMAO might promote atrial inflammation and connexin remodeling in the development of diabetes, which may play a key role in mediating diabetes-related AF.

Hsa_circ_0016070/micro-340-5p Axis Accelerates Pulmonary Arterial Hypertension Progression by Upregulating TWIST1 Transcription Via TCF4/ß-Catenin Complex.

Background Hypoxia is considered a major leading cause of pulmonary hypertension (PH). In this study, the roles and molecular mechanism of circ_0016070 in PH were studied. Methods and Results The expression of circ_0016070 in serum samples, human pulmonary artery smooth muscle cells and hypoxia/monocrotaline-treated rats was determined by real-time quantitative polymerase chain reaction. Cell viability, migration, and apoptosis were analyzed by Cell Counting Kit-8, wound healing, flow cytometry, and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assays, respectively. The molecular interactions were validated using RNA immunoprecipitation, chromatin immunoprecipitation, and dual luciferase reporter assays. The levels of phenotype switch-related proteins were evaluated by Western blot and immunohistochemistry. The pathological characteristics were assessed using hematoxylin and eosin staining. circ_0016070 was highly expressed in the serum samples, hypoxia-induced pulmonary artery smooth muscle cells and pulmonary arterial tissues of PH rats. Downregulation of circ_0016070 ameliorated the excessive proliferation, migration, vascular remodeling, and phenotypic transformation but enhanced cell apoptosis in the PH rat model. In addition, micro (miR)-340-5p was verified as a direct target of circ_0016070 and negatively regulated TCF4 (transcription factor 4) expression. TCF4 formed a transcriptional complex with ß-catenin to activate TWIST1 (Twist family bHLH transcription factor 1) expression. Functional rescue experiments showed that neither miR-340-5p inhibition nor TWIST1 or TCF4 upregulation significantly impeded the biological roles of circ_0010670 silencing in PH. Conclusions These results uncovered a novel mechanism by which circ_0016070 play as a competing endogenouse RNA of miR-340-5p to aggravate PH progression by promoting TCF4/ß-catenin/TWIST1 complex, which may provide potential therapeutic targets for PH.

Reversible T-wave inversions during left bundle branch area pacing.

BACKGROUND: Our clinical observation found that T-wave inversions (TWIs) appeared during left bundle branch area pacing (LBBAP); however, the incidence and influencing factors were unclear. The study aimed to investigate the effects of LBBAP on T-wave and explore possible factors associated with TWIs. METHODS: This was a retrospective cohort study. An electrocardiogram (ECG) was acquired at baseline and after LBBAP. Baseline characteristics, ECG parameters, LBBAP parameters, and troponin T (TnT) levels were compared between the non-TWIs and TWIs groups. Multivariable logistic analyses were performed to adjust for potential confounders to identify the predictive factors of TWIs during LBBAP. RESULTS: A total of 398 consecutive patients who underwent successful LBBAP were assessed for inclusion between May 2017 and Jan 2021, and 264 (66.3%) patients had TWIs. The mean (standard deviation [SD]) baseline QRS duration (QRSd) was longer in the TWIs group compared to the non-TWIs group (125.9 [34.5] ms vs. 98.2 [18.1] ms; P <0.001). Multivariable logistic regression analysis suggested that QRSd >120 ms was an independent predictor for TWIs. TWIs were partially or com-pletely recovered in 151/172 (87.8%) patients during follow-up, the median (interquartile range [IQR]) follow-up duration was 10 days (7 days to 5.5 months). TWIs in patients with complete left bundle branch block (CLBBB) occurred more frequently in inferior wall leads (II, III, and aVF) and anterior wall leads (V1-V4) (P <0.05). Patients with complete right bundle branch block (CRBBB) were more prone to TWIs in high lateral wall leads (I and aVL) (P <0.05). There were no significant differences in TnT levels between the TWIs and non-TWIs groups. CONCLUSIONS: TWIs during LBBAP were clinically frequent and recoverable. QRSd >120 ms was independently associated with TWIs.

The Effect of Renal Denervation on Cardiac Diastolic Function in Patients with Hypertension and Paroxysmal Atrial Fibrillation.

Objective: Renal artery denervation (RDN) can treat hypertension and paroxysmal atrial fibrillation (PAF). Hypertension and PAF can affect cardiac diastolic function. The study aimed to evaluate the effect of RDN on cardiac diastolic function in patients with refractory hypertension and PAF. Methods: 190 consecutive patients with hypertension and PAF were recruited. The levels of NT-proBNP and metrics of echocardiography were measured before and after RDN in patients with refractory hypertension and PAF. The 190 patients were divided into the decreasing HR and nondecreasing HR group, the decreasing MAP and nondecreasing MAP group, the HFPEF group, and the normal diastolic function group, respectively. Results: Before RDN, the indices about cardiac diastolic function were out of the normal range. After RDN, the diastolic function improved in the indices of NT-proBNP, E/e', e'. The diastolic function about the indices of NT-proBNP, E/e', e' was improved in the decreasing HR group, the decreasing mean arterial pressure (MAP) group, and the HFPEF group, correspondingly compared to the nondecreasing HR group, the non-decreasing MAP group, and the preoperative normal diastolic function group. In the multivariate analysis, the MAP and HR were the only two indicators significantly associated with the improvement of diastolic function. Conclusion: RDN could improve the diastolic function in patients with refractory hypertension and PAF. Patients with HFPEF could receive benefits through RDN. It was speculated that RDN improved the diastolic function mainly through decreasing HR and MAP.

Prognostic Value of Time in Blood Pressure Target Range Among Patients With Heart Failure.

BACKGROUND: Blood pressure (BP) is a continuous and dynamic measure. However, standard BP control metrics may not reflect the variability in BP over time. OBJECTIVES: This study assessed the prognostic value of time in BP target range among hypertensive patients with heart failure (HF). METHODS: The authors performed a post hoc analysis of data from the TOPCAT (Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist) trial and the BEST (Beta-Blocker Evaluation of Survival Trial). Time in target range (TTR) for each patient was calculated using linear interpolation across the study period with the target range of systolic BP between 120 and 130 mm Hg. RESULTS: A total of 4,789 hypertensive patients (n = 1,654 from BEST and n = 3,135 from TOPCAT) were included. The cumulative incidences of primary endpoint (ie, cardiovascular death or HF hospitalization) were highest among the top quartile of TTR with a dose-dependent manner across quartiles (Ptrend <0.005). The top quartile of TTR was significantly associated with a lower risk of primary outcome using adjusted Cox regression model (HR: 0.71; 95% CI: 0.60-0.82), cardiovascular mortality (HR: 0.68; 95% CI: 0.55-0.84), HF hospitalization (HR: 0.70; 95% CI: 0.58-0.85), all-cause mortality (HR: 0.69; 95% CI: 0.58-0.83), and any hospitalization (HR: 0.76; 95% CI: 0.67-0.85). Further analyses using restricted cubic spline indicated a linear relationship between TTR and primary outcome. Similar patterns were observed in the individual trial. Sensitivity analyses generated consistent results while redefining target range as 110 to 130 mm Hg for systolic BP or 70 to 80 mm Hg for diastolic BP. CONCLUSIONS: TTR could independently predict major adverse cardiovascular events in hypertensive patients with HF.

Clinical benefit of systolic blood pressure within the target range among patients with or without diabetes mellitus: a propensity score-matched analysis of two randomized clinical trials.

BACKGROUND: Recent guidelines recommended a systolic blood pressure (SBP) target of < 130 mmHg for patients with or without diabetes but without providing a lower bound. Our study aimed to explore whether additional clinical benefits remain at achieved blood pressure (BP) levels below the recommended target. METHODS: We performed a secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) among the non-diabetic population and the Action to Control Cardiovascular Risk in Diabetes BP (ACCORD-BP) trial among diabetic subjects. We used the propensity score method to match patients from the intensive BP group to those from the standard group in each trial. Individuals with different achieved BP levels from the intensive BP group were used as "reference." For each stratum, the trial-specific primary outcome (i.e., composite outcome of myocardial infarction (MI), acute coronary syndrome not resulting in MI, stroke, acute decompensated heart failure (HF), or cardiovascular death for SPRINT; non-fatal MI, non-fatal stroke, or cardiovascular death for ACCORD-BP) was compared by Cox regression. RESULTS: A non-linear association was observed between the mean achieved BP and incidence of composite cardiovascular events, regardless of treatment allocation. The significant treatment benefit for primary outcome remained at SBP 110-120 mmHg (hazard ratio, 0.59 [95% CI, 0.46, 0.76] for SPRINT; 0.67 [0.52, 0.88] for ACCORD-BP) and SBP 120-130 mmHg for SPRINT (0.47 [0.34, 0.63]) but not for ACCORD-BP (0.93 [0.70, 1.23]). The results were similar for the secondary outcomes including all-cause mortality, cardiovascular mortality, MI, stroke, and HF. Intensive BP treatment benefits existed among patients maintaining a diastolic BP of 60-70 mmHg but were less distinct. CONCLUSIONS: The treatment benefit persists at as low as SBP 110-120 mmHg irrespective of diabetes status. Achieved very low BP levels appeared to increase cardiovascular events and all-cause mortality.

Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor.

Insulin sensitivity progressively declines with age. Currently, the mechanism underlying age-associated insulin resistance remains unknown. Here, we identify membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) as a central regulator of insulin sensitivity during ageing. Ageing promotes MMP14 activation in insulin-sensitive tissues, which cleaves Insulin Receptor to suppress insulin signaling. MT1-MMP inhibition restores Insulin Receptor expression, improving insulin sensitivity in aged mice. The cleavage of Insulin Receptor by MT1-MMP also contributes to obesity-induced insulin resistance and inhibition of MT1-MMP activities normalizes metabolic dysfunctions in diabetic mouse models. Conversely, overexpression of MT1-MMP in the liver reduces the level of Insulin Receptor, impairing hepatic insulin sensitivity in young mice. The soluble Insulin Receptor and circulating MT1-MMP are positively correlated in plasma from aged human subjects and non-human primates. Our findings provide mechanistic insights into regulation of insulin sensitivity during physiological ageing and highlight MT1-MMP as a promising target for therapeutic avenue against diabetes.

Time to Clinical Benefit of Intensive Blood Pressure Lowering in Patients 60 Years and Older With Hypertension: A Secondary Analysis of Randomized Clinical Trials.

Importance: Recent guidelines recommend a systolic blood pressure (BP) goal of less than 150 mm Hg or even 130 mm Hg for adults aged 60 years or older. However, harms from intensive BP treatments occur immediately (eg, syncope, fall), and benefits for cardiovascular event reduction emerge over time. Therefore, harms with low chance of benefit need to be clearer, particularly for those with limited life expectancy. Objective: To estimate the time needed to potentially derive clinical benefit from intensive BP treatment in patients 60 years and older. Design, Setting, and Participants: This secondary analysis included individual patient data from published randomized clinical trials with 27 414 patients 60 years or older with hypertension. Patient-level survival data were reconstructed when the original data were not available. Published trials were identified by searching PubMed until October 15, 2021. Exposures: Intensive BP lowering vs standard BP lowering with the treat-to-target design. Main Outcomes and Measures: Major adverse cardiovascular event (MACE) defined by each trial, which was broadly similar with all trials including myocardial infarction, stroke, and cardiovascular mortality. Results: Six trials (original data from 2 trials and reconstructed data from 4 trials) with 27 414 participants (mean age, 70 years; 56.3% were women) were included in the analysis. Intensive BP treatment with a systolic BP target below 140 mm Hg was significantly associated with a 21% reduction in MACE (hazard ratio, 0.79; 95% CI, 0.71-0.88; P < .001). On average, 9.1 (95% CI, 4.0-20.6) months were needed to prevent 1 MACE per 500 patients with the intensive BP treatment (absolute risk reduction [ARR], 0.002). Likewise, 19.1 (95% CI, 10.9-34.2) and 34.4 (95% CI, 22.7-59.8) months were estimated to avoid 1 MACE per 200 (ARR, 0.005) and 100 (ARR, 0.01) patients, respectively. Conclusions and Relevance: In this analysis, findings suggest that for patients 60 years and older with hypertension, intensive BP treatment may be appropriate for some adults with a life expectancy of greater than 3 years but may not be suitable for those with less than 1 year.

Clinical Outcomes of Permanent Left Bundle Branch Area Pacing in Patients With Left Bundle Branch Block and Left Ventricular Ejection Fraction >35 vs. ≤35.

Aims: The present study aimed to compare the effects of left bundle branch area pacing (LBBAP) on cardiac function and clinical outcomes in patients with left bundle branch block (LBBB) and left ventricular ejection fraction (LVEF) >35 vs. ≤35%. Methods and Results: Thirty-six consecutive patients with LBBB and LVEF <50% were enrolled. All patients were followed up for a mean of 6 months. The successful LBBAP was defined as a paced QRS complex presented as right bundle branch block (RBBB) morphology and QRSd < 130 ms. Echocardiography parameters, pacing parameters and clinical outcomes were collected. The successful LBBAP was achieved in 77.8% of all cases (28/36). In LVEF > 35% group (70 ± 8 years, 9 male), the success rate was 81.0% (17/21). QRSd significantly decreased from 174 ± 23 ms to 108 ± 13 ms (P < 0.001). The pacing threshold and R-wave amplitude were 0.6 ± 0.2 V @ 0.5 ms and 12 ± 7 mV, respectively. In LVEF ≤ 35% group (69 ± 5 years, 9 male), the success rate was 73.3% (11/15) with QRSd decreasing from 188 ± 25 ms to 107 ± 11 ms (P < 0.001). The hyperresponders to LBBAP (functional recovery and LVEF ≥ 50%) in LVEF > 35% group was 52.9%, which were almost twice of that in LVEF ≤ 35% group (33.3%). Whether patients had LBBAP or left ventricular septal pacing (LVSP), patients in the LVEF > 35% group showed significantly lower incidence of heart failure hospitalizations or death from any cause (hazard ratio in LVEF > 35% group, 0.22; 95%CI, 0.06 to 0.75, P = 0.011). Conclusions: LBBAP can significantly shorten the QRSd and improve cardiac function in LBBB patients with either LVEF > 35 or ≤ 35%. LBBAP should be considered as an effective therapy for preventing the deterioration of cardiac function in early-stage heart failure patients with LBBB and LVEF > 35%.

Body weight regulation via MT1-MMP-mediated cleavage of GFRAL.

GDNF-family receptor a-like (GFRAL) has been identified as the cognate receptor of growth/differentiation factor 15 (GDF15/MIC-1), considered a key signaling axis in energy homeostasis and body weight regulation. Currently, little is known about the physiological regulation of the GDF15-GFRAL signaling pathway. Here we show that membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) is an endogenous negative regulator of GFRAL in the context of obesity. Overnutrition-induced obesity increased MT1-MMP activation, which proteolytically inactivated GFRAL to suppress GDF15-GFRAL signaling, thus modulating the anorectic effects of the GDF15-GFRAL axis in vivo. Genetic ablation of MT1-MMP specifically in GFRAL+ neurons restored GFRAL expression, resulting in reduced weight gain, along with decreased food intake in obese mice. Conversely, depletion of GFRAL abolished the anti-obesity effects of MT1-MMP inhibition. MT1-MMP inhibition also potentiated GDF15 activity specifically in obese phenotypes. Our findings identify a negative regulator of GFRAL for the control of non-homeostatic body weight regulation, provide mechanistic insights into the regulation of GDF15 sensitivity, highlight negative regulators of the GDF15-GFRAL pathway as a therapeutic avenue against obesity and identify MT1-MMP as a promising target.