Aim: The protective effects of inorganic nitrate in hypertensive patients remain uncertain. Therefore, this study investigated the associations of urinary nitrate with blood pressure, the prevalence of cardiovascular disease (CVD), and cardiovascular mortality among the hypertensive population. Methods: A total of 6,130 hypertensive adults from the 2005-2014 NHANES (The National Health and Nutrition Examination Survey) were included. Piecewise linear regression, logistic regression, and Cox proportional hazards regression models were performed to evaluate the associations of urinary nitrate with blood pressure, CVD prevalence, and cardiovascular mortality, respectively. Mediation and subgroup analyses were further conducted to explore the potential mechanisms and the consistency of the association between urinary nitrate and cardiovascular mortality. Results: Within the range of 0-4.40 mg/dL, an inverse linear correlation between urinary nitrate and systolic blood pressure (SBP) was observed [β = -0.60; 95% confidence interval (95%CI): -0.99 to -0.21; P < 0.001]. Higher urinary nitrate levels were associated with a reduced prevalence of heart failure [odds ratio (OR): 0.942; 95%CI: 0.905 to 0.981; P = 0.004] and lower cardiovascular mortality [hazard ratio (HR): 0.921; 95%CI, 0.867 to 0.977; P = 0.006]. Mediation analyses indicated that neither SBP nor baseline heart failure mediated the association between urinary nitrate and cardiovascular mortality. Subgroup analyses showed that the inverse association between urinary nitrate and cardiovascular mortality was modified by the presence of coronary heart disease. Conclusion: Among hypertensive individuals, higher urinary nitrate levels were associated with lower SBP, heart failure prevalence, and cardiovascular mortality. These findings suggest that urinary nitrate may serve as a potential biomarker for cardiovascular risk stratification.

BACKGROUND:Early identification of atrial fibrillation (AF) allows for timely interventions to reduce cardiovascular complications. Risk scores including C2HEST and CHA2DS2-VASc have limitations in capturing cardiovascular remodeling. Given the association among hypertension, cardiovascular remodeling, and AF, integrating echocardiographic and demographic parameters may improve AF risk assessment in hypertension. OBJECTIVE:We aimed to develop and validate a machine learning model integrating echocardiographic and demographic parameters to assess AF risk in hypertension. METHODS:This study included 48,571 hypertensive patients from 8 hospitals. AF was diagnosed based on electrocardiograms or medical records. Patients from The Second Affiliated Hospital of Chongqing Medical University (n = 40,811) were randomly divided into training and internal test sets (7:3), whereas patients from other hospitals (n = 7760) were split into early (2014-2019; n = 3648) and late temporal test sets (2020-2021; n = 4112). 8 machine learning models integrating echocardiographic and demographic parameters were developed and optimized via 10-fold cross-validation in the training set. The best-performing model was selected in the internal test set and further evaluated across all test sets using area under the receiver operating characteristic curve, calibration, and clinical utility. RESULTS:An extreme gradient boosting-based model achieved an area under the receiver operating characteristic curve of 0.875 in both internal test (95% confidence interval [CI], 0.861-0.888) and early temporal test sets (95% CI, 0.850-0.899) and 0.886 (95% CI, 0.865-0.904) in the late temporal test set, significantly outperforming C2HEST and CHA2DS2-VASc scores while maintaining calibration and clinical utility. CONCLUSION:An extreme gradient boosting-based model integrating echocardiographic and demographic parameters outperformed existing scores, offering a reliable tool for AF risk assessment in hypertension.

Previous studies have demonstrated that cardioversion of atrial fibrillation may alleviate atrial remodeling. We aimed to investigate whether left atrial (LA) tissue fibrosis assessed by LGE-MRI, may be reversed after conversion of persistent atrial fibrillation (PersAF) to sinus rhythm. Patients with PersAF underwent two LGE-MRI scans following cardioversion were prospectively recruited. LA fibrosis was categorized into core zone (IIR > 1.61) and border zone (0.97 Fifty-three patients were included. The area of the border [22.2 (11.8-37.0) vs. 18.1 (11.8-25.2) cm 2 , p = 0.037] and core zones [0.9±3.0 vs. 0.1±0.6 cm 2 , p = 0.010] decreased from baseline, along with reductions in LAV, increase of LA ejection fraction and strain. After multivariable adjustment, ΔLATEF was correlated with Δborder zone (r 2 =0.155, p = 0.015), baseline left ventricular mass and ΔLATEF was correlated with Δcore zone (r 2 =0.286, p <0.001). The cardiac reverse remodeling is not related with Δborder zone and Δcore zone. Atrial fibrosis improved concomitantly with LA shrinkage and enhanced LA function after PersAF to sinus rhythm. LA fibrotic reverse is an independent parameter compared with the traditional definition of cardiac reverse remodeling. The clinical implications warrant further investigation.

Background: Although the association of dietary nitrate intake and improved blood pressure and cardiovascular outcomes has been confirmed in healthy individuals and non-cardiovascular disease (CVD) population, it still remains uncertain whether the protective effect of inorganic nitrate remains significant in the hypertensive population. Methods: This study analyzed health data of 5,989 hypertensive participants based on the National Health and Nutrition Examination Survey (NHANES) database between 2005 and 2014. The correlation between urinary nitrate and blood pressure, the prevalence of CVD subtypes and cardiovascular mortality were assessed respectively. Mediating effect analysis and subgroup analysis was performed. Results: Within a range of 0-4.34 mg/dL, an inverse linear correlation between urinary nitrate and systolic blood pressure (SBP) was observed (β= -0.84; 95% CI -1.28, -0.41; P<0.001). The increase in urinary nitrate was associated with a decreased prevalence of heart failure (OR=0.914; 95% CI 0.859, 0.972; P=0.006). Urinary nitrate was inversely associated with cardiovascular mortality (HR=0.906; 95% CI 0.864, 0.951; P<0.001). Neither SBP nor coexisting heart failure at baseline mediated the association between urinary nitrate and cardiovascular mortality. Subgroup analysis showed that the inverse association between urinary nitrate and cardiovascular mortality was influenced by smoking, coexisting coronary heart disease and heart failure at baseline. Conclusions: In hypertensive individuals, an appropriate increase in urinary nitrate was associated with a reduction in SBP, a diminished incidence of heart failure, and a mitigated risk of cardiovascular mortality. These findings suggested urinary nitrate as a plausible marker for monitoring cardiovascular health.

Background Renal denervation (RDN) was still performed without any intra-procedural method for nerve mapping. Whether renal nerve stimulation (RNS) is an efficient way to identify renal autonomic innervation and optimize the strategy for RDN remain to be worthy for further exploration. Methods The characteristics of renal autonomic innervation at the sites with different blood pressure (BP) responses to RNS were explored. Then, dogs anatomically eligible for RDN were randomly assigned into elevated BP response ablation group, reduced BP response ablation group, and RNS-control group. The postoperative outcomes were measured at baseline and after 4 weeks follow-up. Results The proportion of afferent sensory nerve was higher at elevated BP response sites (ERS) than reduced BP response sites (RRS) and non-response sites (NRS) (P = 0.012 and P = 0.004). Conversely, the proportion of parasympathetic nerve at RRS was the highest (RRS vs. ERS, P = 0.017; RRS vs. NRS, P = 0.023). More importantly, there was a significant correlation between systolic blood pressure changes and the area ratios of afferent sensory and parasympathetic nerve (R = 0.859; P < 0.001). In addition, ablation at BP-elevation sites can result in a significant decrease in BP and plasma norepinephrine (NE) after 4 weeks (P = 0.002; P = 0.008), while ablation at BP-reduction sites can lead to significant increases in BP and plasma NE (P = 0.016; P = 0.033). Conclusions RNS is an effective method to identify renal autonomic innervation. It could not only help to identify optimal target sites, but also avoid ablation of sympathetic-inhibitory areas during RDN.

The aim of this study was to investigate alterations in the intrarenal blood pressure (BP) regulation system after renal denervation (RDN) guided by renal nerve stimulation (RNS). Twenty-one dogs were randomized to receive RDN at strong (SRA group, n = 7) or weak (WRA group, n = 7) BP-elevation response sites identified by RNS or underwent RNS only (RNS-control, RSC, n = 7). After 4 weeks of follow-up, renal sympathetic components, the main components of renin-angiotensin system (RAS) and the major transporters involved in sodium and water reabsorption were assessed by immunohistochemical analysis. Compared with RSC treatment, RDN therapy significantly reduced renal norepinephrine and tyrosine hydroxylase levels, decreased the renin content and inhibited the onsite generation of angiotensinogen. Moreover, the expression of exciting axis components, including angiotensin-converting enzyme (ACE), angiotensin II and angiotensin II type-1 receptor, was downregulated, while protective axis components for the cardiovascular system, including ACE2 and Mas receptors, were upregulated in both WRA and SRA groups. Moreover, RDN reduced the abundance of aquaporin-1 and aquaporin-2 in kidneys. Although RDN had a minimal effect on overall NKCC2 expression, its activation (p-NKCC2) and directional enrichment in the apical membrane (mNKCC2) were dramatically blunted. All these changes were more obvious in the SRA group than WRA group. Selective RDN guided by RNS effectively reduced systemic BP by affecting the renal neurohormone system, as well as the sodium and water transporter system, and these effects at sites with a strong BP response were more superior.

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-β1 (TGF-β1) 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.

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.

OBJECTIVE:We sought to investigate and report a novel surgical technique of screws insertion and posterior surgical reduction, as well as explore its clinical results.METHODS:From September 2008 to September 2012, we treated 41 cases of unstable craniovertebral junction anomalies with a narrow C2 pedicle at our department. All patients underwent "posterior reduction and internal fixation of the occipital bone with superior or inferior articular process of C2 and lateral mass of C3 on the narrowed C2 pedicle side-for non-narrowed C2 pedicle side, the screw was only inserted into C2 pedicle without extending the fixation to C3 vertebrae-using a titanium screw-rod (plate) fixation system." The preoperative and postoperative atlantodens interval, Chamberlain line, McRae line, and cervicomedullary angle were all measured. In addition, the preoperative and postoperative Japanese Orthopedic Association score was used to evaluate the cervical myelopathy.RESULTS:A total of 134 screws were inserted into the C2 pedicle (30 screws), superior (35 screws) or inferior (17 screws) articular process of C2, and lateral mass of C3 (52 screws). There was a significant statistical difference between the preoperative and postoperative results in the reduction of the odontoid process, decompression of the upper cervical spinal cord and medulla, as well as the improvement of neurologic functions (P < 0.05). All patients have exhibited a major neurologic improvement and solid bony fusion.CONCLUSION:This novel surgical technique is safe, feasible, and effective for the treatment of unstable craniovertebral junction anomalies with a narrow C2 pedicle.

OBJECTIVETo investigate the effect of a single dose of ropivacaine combined with sufentanilfor thoracic paravertebral block (TPVB) on pain and enhanced recovery after surgery (ERAS) in patients undergoing video-assisted thoracosopic surgery.METHODSSixty patients undergoing video-assisted thoracosopic surgery were randomly divided into three groups to receive intravenous combined general anesthesia (group C), a single dose of ropivacainefor thoracic paravertebral block before surgery combined with intravenous and general anesthesia(group T1), or a single dose of ropivacaineand sufentanilfor thoracic paravertebral blockcombined with intravenous and general anesthesia (group T2). None of the patients used postoperative analgesia pump, and tramadol hydrochoride injection (100 mg) was given in cases with NRS scores > 4 after the surgery. The data were recorded including analgesics used for nerve block before the operation, intravenous dosage of sufentanilduring operation, total dose of sufentanilused (intravenous+nerve block), intravenous remifentanil dose during operation, NRS scores at 4, 6, 24, 48 h after the surgery, rescue analgesia in the first postoperative 24 h after surgery, ICU stay and hospital stay after the surgery.RESULTSCompared with those in group C, the intravenous sufentanildose, total sufentanildose, intravenous remifentanildose during operation, NRS scores at 4 and 6, 24 h, and ICU stay and hospital stay after the surgery were significantly decreased in groups T1 and T2 (P<0.05). The total dose of opioids during the operation and NRS scores at 4 and 6 h were significantly lower in group T2 than in group T1 (P<0.05), but the total dose of sufentanil, ICU stay and hospital stay were simialr between the two groups.CONCLUSIONA single dose of ropivacaine combined with sufentanilfor thoracic paravertebral blockbefore surgery can reduce the total dose opioids, produce the optimal analgesic effect, and promote postoperative recovery of the patients.

目的:探究肾动脉近段交感神经去除术(肾动脉消融)治疗顽固性高血压的有效性和安全性.方法:40例顽固性高血压患者为研究对象,并随机分为全段消融组(全段组,21例)和近段消融组(近段组,1 9例).采用单极盐水灌注导管进行消融.随访至术后6个月,所有患者定期测量诊室血压,部分患者术前、术后6个月监测24 h动态血压.结果:与全段组相比,近段组左侧[(6±1):(3±0),P＜0.01]及右侧[(7±1):(3.2±0.2),P＜0.01]肾动脉消融位点数目均有减少.近段组总消融时间短于全段组[(331±32)s:(906±130)s,P＜0.01].全段组与近段组基线诊室血压分别为(178.0±13.5/101.7±9.1) mmHg与(179.8±10.8/103.9±9.0) mmHg(收缩压和舒张压均P＞0.05),术后6个月全段组与近段组诊室血压分别下降(-37.7±10.4/-20.4±7.3)mmHg和(-39.5±9.2/-21.9±8.2)mmHg(收缩压和舒张压均P＞0.05).两组各有14例患者在术前、术后6个月监测24 h动态血压,结果显示白天平均血压下降值低于诊室平均血压下降值[(-23.3±11.6/-14.2±6.2)mmHg:(-37.7±19.4/-20.4±7.3+mmHg,收缩压和舒张压均P＜0.001].未发现消融相关血管并发症.结论:对顽固性高血压肾动脉近段消融与全段消融有相似的效果及安全性.

The purpose of this study was to investigate whether atrial overexpression of angiotensin-converting enzyme 2 (ACE2) by homogeneous transmural atrial gene transfer can reverse atrial remodeling and its mechanisms in a canine atrial-pacing model. Twenty-eight mongrel dogs were randomly divided into four groups: Sham-operated, AF-control, gene therapy with adenovirus-enhanced green fluorescent protein (Ad-EGFP) and gene therapy with Ad-ACE2 (Ad-ACE2) (n = 7 per subgroup). AF was induced in all dogs except the Sham-operated group by rapid atrial pacing at 450 beats/min for 2 weeks. Ad-EGFP and Ad-ACE2 group then received epicardial gene painting. Three weeks after gene transfer, all animals except the Sham group underwent rapid atrial pacing for another 3 weeks and then invasive electrophysiological, histological and molecular studies. The Ad-ACE2 group showed an increased ACE2 and Angiotensin-(1–7) expression, and decreased Angiotensin II expression in comparison with Ad-EGFP and AF-control group. ACE2 overexpression attenuated rapid atrial pacing-induced increase in activated extracellular signal-regulated kinases and mitogen-activated protein kinases (MAPKs) levels, and decrease in MAPK phosphatase 1(MKP-1) level, resulting in attenuation of atrial fibrosis collagen protein markers and transforming growth factor-β1. Additionally, ACE2 overexpression also modulated the tachypacing-induced up-regulation of connexin 40, down-regulation of connexin 43 and Kv4.2, and significantly decreased the inducibility and duration of AF. ACE2 overexpression could shift the renin–angiotensin system balance towards the protective axis, attenuate cardiac fibrosis remodeling associated with up-regulation of MKP-1 and reduction of MAPKs activities, modulate tachypacing-induced ion channels and connexin remodeling, and subsequently reduce the inducibility and duration of AF.

Objective To investigate the effect of angiotensin-converting enzyme 2(ACE2)over-expression on ventricular remodeling in rat model of acute myocardial infarction(AMI)and the related mechanisms.Methods Totally 75male SpragueDawley rats were randomly divided into five groups(n=15):Sham group,AMI group,AMI+normal saline(AMI+NS) group,AMI+adenovirus-EGFP(AMI+AdEGFP)group,and AMI+adenovirus-ACE2(AMI+AdACE2)group.AMI models were established by ligating the left anterior descending coronary artery of rats.Rats in the AMI+NS,AMI+AdEGFP and AMI+AdACE2groups received intramyocardial injection of NS,AdEGFP and AdACE2in five different infarction border zones,respectively.Rats in the Sham and AMI groups received no injection intervention.Four weeks later,left ventricular end-diastolic pressure(LVEDP)and heart weight/body weight(HW/BW)were examined.Myocardial structure changes and collagen deposition were evaluated histopathologically.The expression of angiotensin(Ang)Ⅱ(AngⅡ),Ang-(1-7)and α-smooth muscle actin(α-SMA)proteins was assessed by immunohistochemical staining.The relative protein expression of ACE2,Src homology 2domain-containing protein tyrosine phosphatase 1(SHP-1),ERK1/2,p-ERK1/2,p38,p-p38,α-SMA and transforming growth factorβ1(TGF-β1)was measured by Western blotting analysis.Results(1)Compared with the other four groups,the protein expression levels of ACE2 and Ang-(1-7)were significantly increased in myocardial tissues in AMI+AdACE2group(P0.05).(2)Compared with the Sham group,LVEDP,the values of HW/BW,collagen deposition,and the expression levels of AngⅡ,Ang-(1-7),SHP-1,p-ERK1/2/ERK1/2,p-p38/p38,α-SMA and TGF-β1were all signficantly upgraded in AMI,AMI+NS and AMI+AdEGFP groups(P0.05).(3)Compared with AMI,AMI+NS and AMI+AdEGFP groups,the expression levels of Ang-(1-7)and SHP-1were significantly increased in AMI+AdACE2group(P0.05);while p-ERK1/2/ERK1/2,p-p38/p38,α-SMA and TGF-β1protein expression levels were significantly decreased in AMI+AdACE2group(P0.05).Conclusion This study suggests that over-expression of ACE2can improve ventricular fibrosis and ameliorate ventricular remodeling after myocardial infarction in rats,which may be due to that ACE2increases SHP-1protein expression,and the latter negatively regulates renin-angiotensin system(RAS)and mitogen-activated protein kinases(MAKPs)pathway.

Purpose The purpose of this study was to compare the efficacy of focused ultrasound circumferential pulmonary vein ablation (CPVa) and BOX ablation (BOXa) in an acute atrial fibrillation (AF) model. Methods Twenty mongrel dogs were divided into either CPVa or BOXa groups. CPV or BOX focused ultrasonic ablation was conducted in each group after successful establishment of the AF model. Before-and-after ablation left atrial effective refractory period (LAERP), AF inducibility, and induced AF lasting time were measured in both groups. Results The LAERP after AF model establishment was significantly shorter than that before establishment (102 ± 10 vs. 140 ± 10 ms, p < 0.01, in the CPVa group; 105 ± 8 vs. 139 ± 11 ms, p < 0.01, in the BOXa group). The AF inducibility after ablation was significantly lower than that before ablation in the two groups (98% vs. 28%, p < 0.01, in the CPVa group; 97% vs.14%, p < 0.01, in the BOXa group), and the induced AF lasting time after ablation was significantly shorter than that before ablation in both groups (233 ± 40 vs. 70 ± 29 s, p < 0.01, in the CPVa group; 240 ± 41 vs. 34 ± 22 s, p < 0.01, in the BOXa group). On intergroup comparison, AF inducibility and induced AF lasting time after ablation were significantly lower/shorter in the BOXa group than those in the CPVa group (14% vs. 28%, p = 0.021; 34 ± 22 vs. 70 ± 29 s, p = 0.048, respectively). Conclusions In the experimental AF model, the epicardial focused ultrasound BOX ablation may be more effective to prevent the recurrence of AF compared with the CPV approach.

BACKGROUNDThe electrophysiological characteristics of the Marshall potential is important in ligament of Marshall (LOM) ablation.METHODS AND RESULTSMarshall potential was recorded under sinus rhythm and left atrial appendage (LAA) pacing and in the first randomly selected 5 dogs (Group 1), LOM ablation was performed. Histological examination was performed in the remaining 10 dogs, which were subdivided according to the results (Groups 2, 3). During LAA pacing in Group 2, the AM interval was prolonged or shortened, whereas in Group 3 it was prolonged (125+/-9 vs 80+/-6 ms, P=0.043, when the pacing rate =350) (126+/-9 vs 80+/-6 ms, P=0.0442, when the pacing rate =450). The Marshall potential was separated from the atrial electrogram by LAA pacing in Groups 2 and 3. There was no significant difference in the AM interval during sinus rhythm and right atrial appendage pacing.CONCLUSIONSMarshall potential has different forms on electrograms, including a prolonged AM interval, which presents with LAA pacing. This finding might be useful in LOM ablation.