Transient pacing in pigs with complete heart block via myocardial injection of mRNA coding for the T-box transcription factor 18.

The adenovirus-mediated somatic transfer of the embryonic T-box transcription factor 18 (TBX18) gene can convert chamber cardiomyocytes into induced pacemaker cells. However, the translation of therapeutic TBX18-induced cardiac pacing faces safety challenges. Here we show that the myocardial expression of synthetic TBX18 mRNA in animals generates de novo pacing and limits innate and inflammatory immune responses. In rats, intramyocardially injected mRNA remained localized, whereas direct myocardial injection of an adenovirus carrying a reporter gene resulted in diffuse expression and in substantial spillover to the liver, spleen and lungs. Transient expression of TBX18 mRNA in rats led to de novo automaticity and pacemaker properties and, compared with the injection of adenovirus, to substantial reductions in the expression of inflammatory genes and in activated macrophage populations. In rodent and clinically relevant porcine models of complete heart block, intramyocardially injected TBX18 mRNA provided rate-adaptive cardiac pacing for one month that strongly correlated with the animal's sinus rhythm and physical activity. TBX18 mRNA may aid the development of biological pacemakers.

A Survey of Emerging Memory in a Microcontroller Unit.

In the era of widespread edge computing, energy conservation modes like complete power shutdown are crucial for battery-powered devices, but they risk data loss in volatile memory. Energy autonomous systems, relying on ambient energy, face operational challenges due to power losses. Recent advancements in emerging nonvolatile memories (NVMs) like FRAM, RRAM, MRAM, and PCM offer mature solutions to sustain work progress with minimal energy overhead during outages. This paper thoroughly reviews utilizing emerging NVMs in microcontroller units (MCUs), comparing their key attributes to describe unique benefits and potential applications. Furthermore, we discuss the intricate details of NVM circuit design and NVM-driven compute-in-memory (CIM) architectures. In summary, integrating emerging NVMs into MCUs showcases promising prospects for next-generation applications such as Internet of Things and neural networks.

Efficacy and safety of antiplatelet therapy in COVID-19: Insights from a meta-analysis of randomized controlled trials.

BACKGROUND: COVID-19 induces a pro-coagulant state with thrombotic events. This meta-analysis explores the efficacy and safety of antiplatelet-based therapy in COVID-19 patients through randomized controlled trials (RCTs). MATERIALS AND METHODS: A systematic literature search until March 10, 2023, identified 7 RCTs involving 23,415 inpatients. Of these, 11,891 received antiplatelet-based treatment, and 11,524 received placebo/other drugs. Statistical analysis was performed using Review Manager 5.4. RESULTS: The included trials involved patients with a mean age ranging from 54.3 to 62.0 years and a prevalence of hypertension ranging from 10.9 to 65.0% and coronary artery disease ranging from 3.2 to 32.7%. The pooled analysis showed no significant difference in overall mortality between groups (RR 1.0, 95% CI 0.99 - 1.01, p = 0.76). However, antiplatelet therapy significantly reduced major thrombotic events (RR 0.86, 95% CI 0.75 - 0.99, p = 0.04). Conversely, it increased major bleeding risks (RR 1.62, 95% CI 1.24 - 2.12, p = 0.0005). There was no significant difference in the incidence of invasive mechanical ventilation and respiratory death. CONCLUSION: Antiplatelet therapy does not confer mortality benefit in COVID-19 patients but lowers major thrombotic events while increasing major bleeding risks. Ongoing large RCTs will provide more information on the therapeutic value of this therapy.

A meta-analysis of randomized controlled trials of statin-based therapy in patients with COVID-19.

BACKGROUND: Previous observational studies and meta-analyses have suggested that statins could be beneficial in reducing the risk of adverse clinical outcomes. This study is the first to conduct a meta-analysis of recently published randomized controlled clinical trials investigating the potential therapeutic benefits of statins for COVID-19. MATERIALS AND METHODS: A thorough search was conducted using databases such as PubMed and Embase until May 2023 to identify randomized controlled clinical trials investigating the use of statins in patients with COVID-19. Review Manager 5.4 was used to analyze the selected studies. RESULTS: Seven randomized controlled trials comprising a total of 2,370 patients were included in this study. Of these, 1,295 patients received statin therapy, while 1,075 received placebo or other drugs. All included studies were conducted on inpatients with an average age of 45 - 61 years, and the proportion of patients with diabetes and coronary heart disease was less than 30%. One study only included severely ill patients. Our results showed that statin treatment did not significantly reduce hospitalized patient mortality (11.5 vs. 13.4%, p = 0.94), the proportion of patients transferred to intensive care due to disease changes (14.2 vs. 11.2%, p = 0.41), or the proportion of patients requiring mechanical ventilation (5.3 vs. 7.9%, p = 0.71) compared to controls. However, the use of statins was associated with a slight increase in hospital stay. CONCLUSION: A critical appraisal of published randomized controlled trials on statin therapy in COVID-19 did not show any significant effect on mortality, the risk of transfer to intensive care, or mechanical ventilation.

A nomogram based on CHADS2 score for predicting atrial fibrillation recurrence after cryoballoon ablation.

BACKGROUND: As reported, CHADS2 scoring system moderately predicts the atrial fibrillation (AF) recurrence, a common event after cryoballoon ablation. We aimed to improve the diagnostic accuracy of the CHADS2 score by adding several routine auxiliary detection indicators into the scoring system and constructing a CHADS2 score-based nomogram to predict AF recurrence in patients with paroxysmal AF undergoing cryoballoon ablation. METHODS: Eighty-four patients with paroxysmal AF undergoing cryoballoon ablation were enrolled. Baseline characteristics were collected. The multivariable Cox proportional hazards model was used to identify the significantly related predictors of recurrence and to construct the nomogram whose performance was evaluated by the discrimination and calibration tests. RESULTS: Thirty-five patients developed AF recurrence after a mean follow up of 19.0 ± 15.77 months. In the Cox multivariate model, CHADS2 (>2) (hazard ratio [HR]: 2.38; 95% confidence interval [CI]: 1.14-4.98, p = .021) and albumin-to-globulin ratio (AGR) (HR: 2.49; 95% CI: 1.26-4.92, p < .008) were independent risk factors associated with AF recurrence. In addition to CHADS2 , AGR and red blood cell distribution width were used to construct the nomogram. As a result, the discrimination of the concordance index for the predictive model of AF recurrence was increased from 0.56 (95% CI: 0.494-0.632) to 0.712 (95% CI: 0.631-0.811). The 24-month one well matched the ideal 45° line among the calibration plots for 6, 12, and 24 months' recurrence-free survival. CONCLUSION: This novel easy-to-use CHADS2 score-based nomogram may be used to predict AF recurrence for patient of paroxysmal AF undergoing cryoballoon ablation. Further external validation is still needed.

Quantitative SERS sensing mediated by internal standard Raman signal from silica nanoparticles in flexible polymer matrix.

Attributed to poor signal uniformity and external interference, ultrasensitive surface-enhanced Raman spectroscopy (SERS) still faces difficulties in the reliable and quantitative detection of trace molecules. Here, a facile Ag/Si/sodium carboxy methyl cellulose (NaCMC) film with internal standard (IS) was promoted for quantitative determination of thiram. The effects of preparation conditions on SERS activity of the film were systematically investigated and then a flexible SERS substrate with high sensitivity and uniformity was fabricated. The enhancement factor was calculated to be 1.12 × 106 and SERS mapping was recorded with a relative standard deviation value of 19.8% by utilizing 4-mercaptobenzoic acid (4-MBA) as target molecule. Additionally, the dominant contribution of the IS from encapsulated Si nanoparticles (NPs) was confirmed in the quantitative assay of 4-MBA and thiram, facilitating attractive fitting coefficients (R2) as 0.991 and 0.998. Besides that, the proposed flexible film was conducted to scrub trace thiram from the surfaces of apple, orange, and cucumber, resulting in recoveries of 89%, 94%, and 91%. A smart and facile quantitative SERS substrate was developed here for monitoring trace biochemical molecules, verifying its potential utilizations in monitoring pesticide residues.

Angiotensin (ang) 1-7 inhibits ang II-induced atrial fibrosis through regulating the interaction of proto-oncogene tyrosine-protein kinase Src (c-Src) and Src homology region 2 domain-containing phosphatase-1 (SHP-1)).

To verify whether Ang-(1-7) produces an antagonistic effect on Ang II-mediated atrial remodeling. Ang II-induced HL-1 cell model and a rat model of Ang II-induced atrial remodeling were constructed and intervened with Ang II Ang-(1-7), AngII +Ang-(1-7), Ang II+ c-Src specific inhibitor (SU6656), and Ang II + Ang-(1-7) + SSG (SHP-1/2 specific inhibitor, stibogluconate), respectively. The systolic blood pressure of the rat caudal artery was detected. And trial fibrosis was detected by Picrosirius red staining and Masson's trichrome staining. Expressions of transforming growth factor-ß (TGF-ß), tissue inhibitor of metalloproteinases 1 (TIMP1), Matrix metalloproteinase 2 (MMP-2), connective tissue growth factor (CTGF), galectin-3, α-smooth muscle actin (α-SMA), and collagen I/III were subjected to qPCR and western blot. Furthermore, SHP-1 binding to c-Src was verified by co-immunoprecipitation (Co-IP). Results showed that the expressions of TGF-ß, TIMP1, MMP-2, CTGF, α-SMA, galectin-3, and collagen I were increased markedly in the Ang II intervention group, and the expressions of p-ERK1/2, p-Akt, and p-p38MAPK were also increased dramatically. Ang-(1-7) or SU6656 addition could inhibit the action of Ang II factor, thereby minimizing the expressions of the previously described genes and proteins. Simultaneously, SSG supplement reversed the antagonistic effect of Ang-(1-7) on Ang II, and the latter elevated the blood pressure and induced atrial fibrosis in rats. Ang-(1-7) could reverse the changes related to Ang II-induced atrial fibrosis in rats. In conclusion, Ang-(1-7) antagonized Ang II-induced atrial remodeling by regulating SHP-1 and c-Src, thereby affecting the MAPKs/Akt signaling pathway.

Characteristics of Ang-(1-7)/Mas-Mediated Amelioration of Joint Inflammation and Cardiac Complications in Mice With Collagen-Induced Arthritis.

Objectives: Rheumatoid arthritis (RA) is a disabling disease with a high incidence that is regularly accompanied by cardiovascular complications. Several studies have suggested that renin-angiotensin-aldosterone system (RAAS) is closely associated with RA. The aim of this study was to investigate the mechanisms underlying Angiotensin-(1-7) [Ang-(1-7)] and its Mas receptor agonist (AVE0991) on joint inflammation and cardiac complications in a collagen-induced arthritis (CIA) model. Methods: Collagen type II was injected into DBA/1 mice to construct an arthritis model. CIA mice were treated with Ang-(1-7) (2.0 mg/kg intraperitoneally) and AVE0991 (3.0 mg/kg intraperitoneally). The serum levels of inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 ß, IL-6, and C-reactive protein (CRP)] were determined by ELISA. The mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) signaling pathways in joint tissues and the transforming growth factor (TGF)-ß/Smad pathway and levels of α-Smooth muscle action (SMA) and ß-myosin heavy chain (MHC) protein expression in cardiac tissues were assessed by western blots. The levels of TGF-ß/Smad pathway, α-SMA, and ß-MHC RNA in cardiac tissues were analyzed by real time-PCR. The levels of receptor activator of nuclear factor kappa ligand (RANKL) and promoting matrix metalloproteinase (MMP)-3 expression in the ankle joints were detected by immunohistochemistry and real time-PCR. Results: Ang-(1-7) and AVE0991 reduced the levels of inflammatory cytokines and inhibited the MAPKs and NF-κB signaling pathways in ankle joint tissues, reduced RANKL and MMP3 expression, and ameliorated local joint inflammation and bone destruction compared with the control group. In addition, Ang-(1-7) and AVE0991 attenuated the TGF-ß/Smad signaling pathway, reduced the levels of α-SMA and ß-MHC expression, and diminished inflammatory cell infiltration into the myocardial interstitium and myocardial interstitial fibrosis in the hearts of CIA mice. Conclusions: Ang-(1-7) alleviated joint damage caused by inflammation likely through the attenuation of NF-κB and MAPK pathways and ameliorated inflammation-induced cardiac fibrosis and activation of the TGF-ß/Smad pathway. Moreover, Ang-(1-7) was likely mediated through the Mas receptor. This study provides theoretical evidence for exploring novel clinical therapeutic approaches for RA and its cardiac complications.

Notch3 Modulates Cardiac Fibroblast Proliferation, Apoptosis, and Fibroblast to Myofibroblast Transition via Negative Regulation of the RhoA/ROCK/Hif1α Axis.

Cardiac fibrosis is a common pathological process in multiple cardiovascular diseases, including myocardial infarction (MI). Abnormal cardiac fibroblast (CF) activity is a key event in cardiac fibrosis. Although the Notch signaling pathway has been reported to play a vital role in protection from cardiac fibrosis, the exact mechanisms underlying cardiac fibrosis and protection from it have not yet been elucidated. Similarly, Hif1α and the RhoA/ROCK signaling pathway have been shown to participate in cardiac fibrosis. The RhoA/ROCK signaling pathway has been reported to be an upstream pathway of Hif1α in several pathophysiological processes. In the present study, we aimed to determine the effects of notch3 on CF activity and its relationship with the RhoA/ROCK/Hif1α signaling pathway. Using in vitro experiments, we demonstrated that notch3 inhibited CF proliferation and fibroblast to myofibroblast transition (FMT) and promoted CF apoptosis. A knockdown of notch3 using siRNAs had the exact opposite effect. Next, we found that notch3 regulated CF activity by negative regulation of the RhoA/ROCK/Hif1α signaling pathway. Extending CF-based studies to an in vivo rat MI model, we showed that overexpression of notch3 by the Ad-N3ICD injection attenuated the increase of RhoA, ROCK1, ROCK2, and Hif1α levels following MI and further prevented MI-induced cardiac fibrosis. On the basis of these results, we conclude that notch3 is involved in the regulation of several aspects of CF activity, including proliferation, FMT, and apoptosis, by inhibiting the RhoA/ROCK/Hif1α signaling pathway. These findings are significant to further our understanding of the pathogenesis of cardiac fibrosis and to ultimately identify new therapeutic targets for cardiac fibrosis, potentially based on the RhoA/ROCK/Hif1α signaling pathway.

CHA2DS2-VASc Score for Identifying Patients at High Risk of Postoperative Atrial Fibrillation After Cardiac Surgery: A Meta-analysis.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery, resulting in an increased risk of morbidity and longer hospital stay. Pharmacologic prophylaxis has been recommended to improve the outcome in patients at high risk of developing POAF after cardiac surgery. Several studies have applied the CHA2DS2-VASc (Congestive heart failure, Hypertension Age [≥65 = 1 point, ≥75 = 2 points], Diabetes, and Stroke/transient ischemic attack (2 points)-vascular disease [peripheral arterial disease, previous myocardial infarction, aortic atheroma]) score in the risk stratification of POAF but yielded contradicting results. This study aims to determine the association between CHA2DS2-VASc score and POAF and further to explore its discriminative ability for the prediction of POAF. METHODS: We systematically searched the Medline, Embase, Cochrane library, and other data sources with key terms "CHA2DS2-VASc," "atrial fibrillation," and "cardiac surgery." Studies designed for CHA2DS2-VASc score in stratifying the risks of POAF in patients undergoing cardiac surgery were included. Statistical analyses were performed with R 3.5.1 and STATA 13.0. RESULTS: Seven hundred twenty-one studies were identified, of which 12 studies with 18,086 patients were finally included in our analysis. The CHA2DS2-VASc score was found to be an independent predictor of POAF after cardiac surgery (odds ratio, 1.46; 95% confidence interval [CI], 1.25-1.72) and exhibited a relatively strong specificity (0.70; 95% CI, 0.61-0.78) and sensitivity (0.72; 95% CI, 0.54-0.85) for predicting POAF. The bivariate model-based pooled area under the receiver operating curve was estimated to be 0.76 (95% CI, 0.72-0.79). CONCLUSIONS: The CHA2DS2-VASc score has relatively good performance in predicting POAF after cardiac surgery and may help identify the patients at high risk of POAF.

Engineered Cardiac Pacemaker Nodes Created by TBX18 Gene Transfer Overcome Source-Sink Mismatch.

Every heartbeat originates from a tiny tissue in the heart called the sinoatrial node (SAN). The SAN harbors only ≈10 000 cardiac pacemaker cells, initiating an electrical impulse that captures the entire heart, consisting of billions of cardiomyocytes for each cardiac contraction. How these rare cardiac pacemaker cells (the electrical source) can overcome the electrically hyperpolarizing and quiescent myocardium (the electrical sink) is incompletely understood. Due to the scarcity of native pacemaker cells, this concept of source-sink mismatch cannot be tested directly with live cardiac tissue constructs. By exploiting TBX18 induced pacemaker cells by somatic gene transfer, 3D cardiac pacemaker spheroids can be tissue-engineered. The TBX18 induced pacemakers (sphTBX18) pace autonomously and drive the contraction of neighboring myocardium in vitro. TBX18 spheroids demonstrate the need for reduced electrical coupling and physical separation from the neighboring ventricular myocytes, successfully recapitulating a key design principle of the native SAN. ß-Adrenergic stimulation as well as electrical uncoupling significantly increase sphTBX18s' ability to pace-and-drive the neighboring myocardium. This model represents the first platform to test design principles of the SAN for mechanistic understanding and to better engineer biological pacemakers for therapeutic translation.

Selective Renal Denervation Guided by Renal Nerve Stimulation in Canine.

Renal nerve stimulation (RNS) can result in substantial blood pressure (BP) elevation, and the change was significantly blunted when repeated stimulation after ablation. However, whether RNS could provide a meaningful renal nerve mapping for identification of optimal ablation targets in renal denervation (RDN) is not fully clear. Here, we compared the antihypertensive effects of selective RDN guided by two different BP responses to RNS and explored the nerve innervations at these sites in Kunming dogs. Our data indicated that ablation at strong-response sites showed a more systolic BP-lowering effect than at weak-response sites (P=0.002), as well as lower levels of tyrosine hydroxylase and norepinephrine in kidney and a greater reduction in plasma norepinephrine (P=0.004 for tyrosine hydroxylase, P=0.002 for both renal and plasma norepinephrine). Strong-response sites showed a greater total area and mean number of renal nerves than weak-response sites (P=0.012 for total area and P<0.001 for mean number). Systolic BP-elevation response to RNS before RDN and blunted systolic BP-elevation to RNS after RDN were correlated with systolic BP changes at 4 weeks follow-up (R=0.649; P=0.012 and R=0.643; P=0.013). Changes of plasma norepinephrine and renal norepinephrine levels at 4 weeks were also correlated with systolic BP changes at 4 weeks (R=0.837, P<0.001 and R=0.927, P<0.001). These data suggest that selective RDN at sites with strong BP-elevation response to RNS could lead to a more efficient RDN. RNS is an effective method to identify the nerve-enriched area during RDN procedure and improve the efficacy of RDN.

Polymer-free drug-eluting stents versus permanent polymer drug-eluting stents: An updated meta-analysis.

BACKGROUND: Polymer-free drug-eluting stents (PF-DES) have been demonstrated comparable to permanent polymer drug-eluting stents (PP-DES) during long-term follow-up. As a critical component of drug-eluting stents, antiproliferative drugs may be a confounding factor for the results. Thus, we sought to compare the outcomes of these stents during long-term follow-up, especially in consideration of different stent platforms with the same drugs. METHODS: A systemic search was performed to identify the related randomized controlled trials comparing PF-DES with PP-DES. Primary outcomes included short (≤1 year) and long-term (>1 year) target lesion revascularization (TLR), short-term in-stent late luminal loss (LLL) and diameter stenosis (DS). Subgroup analyses stratified by the different platforms with the same proliferative drugs were conducted in TLR, LLL, and DS. Standardized mean differences (SMDs) and risk ratios (RRs) were estimated using fixed /random effects models RESULTS:: A total of 6927 patients extracted from 12 RCTs were enrolled in the meta-analysis. No differences were observed in clinical outcomes of short-term and long-term overall mortality, myocardial infarction and stent thrombosis and angiographic outcomes of short-term in-stent LLL and DS between PF-DES and PP-DES for patients with coronary artery lesions. Nevertheless, compared with PP-DES coated with the same proliferative drugs, PF-DES had significantly increased risks of in-stent LLL (SMD, 0.49; 95% confidence interval [CI], 0.25-0.72) and DS (SMD, 0.67; 95% CI, 0.27-1.07), and long-term TLR (RR, 1.64; 95% CI 1.13-2.39). There were no significant differences in other outcomes. CONCLUSIONS: Under the condition of using same antiproliferative drugs (paclitaxel or sirolimus) in different stent systems, PF-DES are associated with the increased risk of restenosis compared to PP-DES.

Unique mechanistic insights into the beneficial effects of angiotensin-(1-7) on the prevention of cardiac fibrosis: A metabolomic analysis of primary cardiac fibroblasts.

BACKGROUND: Cell metabolic pathways are highly conserved among species and change rapidly in response to drug stimulation. Therefore, we explore the effects of angiotensin-(1-7) in a primary cell model of cardiac fibrosis established in angiotensin II-stimulated cardiac fibroblasts via metabolomics analysis and further clarify the potential protective mechanism of angiotensin-(1-7). METHODS AND RESULTS: After exposing cardiac fibroblasts to angiotensin II and/or angiotensin-(1-7), 172 metabolites in these cells were quantified and identified by gas chromatography-mass spectrometry. The data were subsequently analyzed by orthogonal partial least squares discriminant analysis to shortlist biochemically significant metabolites associated with the antifibrotic action of angiotensin-(1-7). Seven significant metabolites were identified: 10,13-dimethyltetradecanoic acid, arachidonic acid, aspartic acid, docosahexaenoic acid (DHA), glutathione, palmitelaidic acid, and pyroglutamic acid. By metabolic network analysis, we found that these metabolites were involved in six metabolic pathways, including arachidonic acid metabolism, leukotriene metabolism, and the γ-glutamyl cycle. Since these metabolic pathways are related to calcium balance and oxidative stress, we further verified that angiotensin-(1-7) suppressed the abnormal extracellular calcium influx and excessive accumulation of intracellular reactive oxygen species (ROS) in angiotensin II-stimulated cardiac fibroblasts. Furthermore, we found that angiotensin-(1-7) suppressed the abnormal calcium- and ROS-dependent activation of calcium/calmodulin-dependent protein kinase II delta (CaMKIIδ), the increased expression of CaMKIIδ-related proteins (NADPH oxidase 4 (Nox4), cellular communication network factor 2 (CTGF), and p-ERK1/2), and excessive collagen deposition in vitro and in vivo. CONCLUSIONS: Angiotensin-(1-7) can ameliorate the angiotensin II-stimulated metabolic perturbations associated with cardiac fibroblast activation. These metabolic changes indicate that modulation of calcium- and ROS-dependent activation of CaMKIIδ mediates the activity of angiotensin-(1-7) against cardiac fibrosis. Moreover, pyroglutamic acid and arachidonic acid may be potential biomarkers for monitoring the antifibrotic action of angiotensin-(1-7).

The Impact of Renal Denervation on the Progression of Heart Failure in a Canine Model Induced by Right Ventricular Rapid Pacing.

Heart failure (HF) has been proposed as a potential indication of renal denervation (RDN). However, the mechanisms enabling RDN to attenuate HF are not well understood, especially the central effects of RDN. The aim of this study was to decipher the mode of operation of RDN in the treatment of HF using a canine model of right ventricular rapid pacing-induced HF. Accordingly, 24 Chinese Kunming dogs were randomly grouped to receive sham procedure (sham-operated group), bilateral RDN (RDN group), rapid pacing to induce HF (HF-control group), and bilateral RDN plus rapid pacing (RDN + HF group). Echocardiography, plasma brain natriuretic peptide (BNP), and norepinephrine (NE) concentrations of randomized dogs were measured at baseline and 4 weeks after interventions, followed by histological and molecular analyses. Twenty dogs completed the research successfully and were enrolled for data analyses. Results showed that the average optical density of renal efferent and afferent nerves were significantly lower in the RDN and RDN + HF groups than in the sham-operated group, with a significant reduction of renal NE concentration. Rapid pacing in the RDN + HF and HF-control groups, compared with the sham-operated group, induced a significant increase in left ventricular end-diastolic volume and decrease in left ventricular ejection fraction and correspondingly resulted in cardiac fibrosis and dysfunction. Cardiac fibrosis evaluated by Masson's trichrome staining and the expression of transforming growth factor-ß1 (TGF-ß1) were significantly higher in the HF-control group than in the sham-operated group, which were remarkably attenuated by the application of the RDN technique in the RDN + HF group. In terms of central renin-angiotensin system (RAS), the expression of angiotensin II (AngII)/angiotensin-converting enzyme (ACE)/AngII type 1 receptor (AT1R) in the hypothalamus of dogs in the HF-control group, compared with the sham-operated group, was upregulated and that of the angiotensin-(1-7) [Ang-(1-7)]/ACE2 was downregulated. Furthermore, both of them were significantly attenuated by the RDN therapy in the RDN + HF group. In conclusion, the RDN technique could damage renal nerves and suppress the cardiac remodeling procedure in canine with HF while concomitantly attenuating the overactivity of central RAS in the hypothalamus.

Apelin: A novel prognostic predictor for atrial fibrillation recurrence after pulmonary vein isolation.

Apelin, the ligand for the APJ receptor, is involved in the pathogenesis of atrial fibrillation (AF). However, whether serum apelin can predict the recurrence of AF after pulmonary vein isolation (PVI) has not been determined.A prospective cohort study was performed in patients with AF (but without structural heart disease) who were undergoing first-time PVI. Serum apelin-12 was measured by enzyme-linked immunosorbent assay. Echocardiographic examination was performed at baseline, 3 months, and 6 months after PVI. Patients were followed up for 6 months after PVI, and the association between baseline apelin-12 and AF recurrence (early recurrence: within 3 months after ablation; late recurrence: 3-6 months after ablation) was analyzed.A total of 61 patients were included in the study. Baseline serum level of apelin-12 was significant lower in patients with early (median [interquartile range]: 1844 [1607-2061] vs 2197 [1895-2455] ng/L, P = .01) and late (1639 [1524-1853] vs 1923 [1741-2303] ng/L, P = .02) AF recurrence compared with patients without these events. Results of Cox stepwise multivariate analysis demonstrated that lower baseline apelin-12 (<2265 ng/L) was independently associated with increased AF recurrence within 6 months after PVI (P < .05). The specificity and positive predictive value of apelin-12 for AF recurrence were significantly higher than those of baseline N-terminal brain proBNP (60.4% vs 28.6%, P < .001; 58.8% vs 34.4%, P = .01), although the sensitivity and negative predictive value were similar.Reduced baseline serum apelin-12 may be an independent risk factor for the recurrence of AF after PVI in patients without structural heart disease.

Midregional pro-atrial natriuretic peptide is a superior biomarker to N-terminal pro-B-type natriuretic peptide in the diagnosis of heart failure patients with preserved ejection fraction.

OBJECTIVES: To explore that if mid-regional sequence of pro-A-type natriuretic peptide (MR-proANP) may have a good value of diagnosis in heart failure with preserved ejection fraction (HFpEF) compared with N-terminal pro-B-type natriuretic peptide (NT-proBNP). METHODS: Participants with cardiovascular disease who were enrolled in this study were divided into the nonheart failure (non-HF) group (n = 75), HFpEF group (n = 65), and HF with reduced ejection fraction (HFrEF) group (n = 50). The MR-proANP and NT-proBNP levels in plasma from all patients were measured by enzyme-linked immunosorbent assay. RESULTS: The plasma levels of MR-proANP and NT-proBNP in HFpEF and HFrEF groups were higher than those in non-HF group (P < .05). MR-proANP levels were significantly different (P < .05) in different New York Heart Association class patients with HFpEF. In the diagnostic analysis area under the curve of MR-proANP (0.844) was higher than that of NT-proBNP (0.518, P < .001). The left atrial volume index in the HFrEF group was higher than HFpEF group (P < .05); however, both of these groups had a higher index than non-HF group (P < .05). CONCLUSION: Results indicated that MR-proANP may be more sensitive and specific than NT-proBNP in diagnosing HFpEF. It may be used as a potential diagnostic biomarker in patients with HFpEF.

Angiotensin II upregulates fibroblast-myofibroblast transition through Cx43-dependent CaMKII and TGF-ß1 signaling in neonatal rat cardiac fibroblasts.

In cardiac fibroblasts, angiotensin II (Ang II) can increase connexin 43 (Cx43) expression and promote calmodulin-dependent protein kinase II (CaMKII) activation. Cx43 overexpression is crucial for the fibroblast-myofibroblast transition. The main purpose of the present study was to investigate the role of CaMKII in regulating Cx43 expression and to determine whether the CaMKII/Cx43 pathway is essential for controlling fibroblast activation and differentiation. In vivo, 4 weeks of Ang II infusion enhanced CaMKII activation but reduced Cx43 expression in hearts undergoing fibrosis remodeling, while in cultured neonatal rat fibroblasts, CaMKII activation upregulated Cx43 expression via transforming growth factor-beta1 (TGF-ß1). CaMKII inhibition by Ang-(1-7) or autocamtide 2-related inhibitory peptide reversed the Ang II-induced changes in Cx43 expression and attenuated Ang II-induced upregulation of alpha smooth muscle actin and TGF-ß1 in both Ang II-infused rats and cultured fibroblasts. Based on the in vivo and in vitro experimental results, CaMKII plays a pivotal role in the Ang II-mediated fibroblast-myofibroblast transition by modulating the expressions of TGF-ß1 and Cx43. We conclude that Ang II mediates the fibroblast-myofibroblast transition partially via the Ang II/CaMKII/TGF-ß1/Cx43 signaling pathway.

Blood pressure elevation response to radiofrequency energy delivery: one novel predictive marker to long-term success of renal denervation.

BACKGROUND: Previous studies showed that radiofrequency energy delivery of the renal artery could induce an immediate and substantial blood pressure (BP)-elevation response, which might be indicative of the increase in central sympathetic nervous activity. OBJECTIVE: The current study was to investigate whether the presence of BP-elevation response to radiofrequency energy delivery can serve as a surrogate to predict BP reduction following renal artery sympathetic denervation (RDN). METHOD: Data were collected on 67 patients undergoing RDN for drug-resistant hypertension. The BP-elevation response to radiofrequency application was defined as elevation of SBP by at least 10 mmHg during radiofrequency energy delivery. The extent of BP reduction at 1, 3, 6, 12 months after RDN were analyzed. Multivariable linear regression analysis of baseline and procedural characteristics was performed to identify the determinants of BP reduction after RDN. RESULTS: Ten patients (14.9%) were classified as nonresponders to radiofrequency delivery and showed significantly lower BP reduction compared with responders. The SBP reductions of radiofrequency delivery responders vs. nonresponders were 31.2 ±â€Š8.6 vs. 11.4 ±â€Š8.6 mmHg, 36.3 ±â€Š10.0 vs. 14.6 ±â€Š10.6 mmHg, 39.9 ±â€Š9.9 vs. 15.2 ±â€Š8.8 mmHg, and 40.0 ±â€Š8.7/13.5 ±â€Š5.8 mmHg (P < 0.001 for all) at 1, 3, 6, and 12 months, respectively. On multiple linear regression analysis, higher baseline office SBP, the presence of BP-elevation response to radiofrequency energy delivery, and especially larger number of BP-elevation response points, were independent predictors of SBP reduction at 6-month and 12-month follow-up. CONCLUSION: Baseline SBP and BP-elevation response during radiofrequency ablation, as well as larger positive response points to radiofrequency energy delivery could be an effective intraprocedural predictive markers to long-term procedural success of RDN.

ICG: a wiki-driven knowledgebase of internal control genes for RT-qPCR normalization.

Real-time quantitative PCR (RT-qPCR) has become a widely used method for accurate expression profiling of targeted mRNA and ncRNA. Selection of appropriate internal control genes for RT-qPCR normalization is an elementary prerequisite for reliable expression measurement. Here, we present ICG (http://icg.big.ac.cn), a wiki-driven knowledgebase for community curation of experimentally validated internal control genes as well as their associated experimental conditions. Unlike extant related databases that focus on qPCR primers in model organisms (mainly human and mouse), ICG features harnessing collective intelligence in community integration of internal control genes for a variety of species. Specifically, it integrates a comprehensive collection of more than 750 internal control genes for 73 animals, 115 plants, 12 fungi and 9 bacteria, and incorporates detailed information on recommended application scenarios corresponding to specific experimental conditions, which, collectively, are of great help for researchers to adopt appropriate internal control genes for their own experiments. Taken together, ICG serves as a publicly editable and open-content encyclopaedia of internal control genes and accordingly bears broad utility for reliable RT-qPCR normalization and gene expression characterization in both model and non-model organisms.