Efficacy and safety of sacubitril/valsartan after six months in patients with heart failure with reduced ejection fraction and asymptomatic hypotension

BACKGROUND It is not clear whether sacubitril/valsartan is beneficial for patients with heart failure(HF)with reduced ejec-tion fraction(HFrEF)and low systolic blood pressure(SBP).This study aimed to investigate the efficacy and tolerability of sacu-bitril/valsartan in HFrEF patients with SBP<100 mmHg.METHODS&RESULTS An observational study was conducted on 117 patients,40.2%of whom had SBP<100 mmHg wit-hout symptomatic hypotension,and 59.8%of whom had SBP≥100 mmHg in an optimized HF follow-up management system.At the 6-month follow-up,52.4%of patients with SBP<100 mmHg and 70.0%of those with SBP≥100 mmHg successfully rea-ched the target dosages of sacubitril/valsartan.A reduction in the concentration of N-terminal pro-B-type natriuretic peptide was similar between patients with SBP<100 mmHg and SBP≥100 mmHg(1627.5 pg/mL and 1340.1 pg/mL,respectively;P=0.75).The effect of sacubitril/valsartan on left ventricular ejection fraction was observed in both SBP categories,with a 10.8%increase in patients with SBP<100 mmHg(P<0.001)and a 14.0%increase in patients with SBP≥100 mmHg(P<0.001).The effects of sac-ubitril/valsartan on SBP were statistically significant and inverse across both SBP categories(P=0.001),with an increase of 7.5 mmHg in patients with SBP<100 mmHg and a decrease of 11.5 mmHg in patients with SBP≥100 mmHg.No statistically signi-ficant differences were observed between the two groups in terms of the occurrence of symptomatic hypotension,deteriorating re-nal function,hyperkalemia,angioedema,or stroke.CONCLUSIONS Within an optimized HF follow-up management system,sacubitril/valsartan exhibited excellent tolerability and prompted left ventricular reverse remodeling in patients with HFrEF who presented asymptomatic hypotension.

NQO1 Pro187Ser Polymorphism Confers to the Susceptibility of Prostate Cancer

Increasing epidemiological studies were recently performed to assess the relationship of NAD(P)H: quinine oxidoreductase 1 (NQO1) Pro187Ser polymorphism and the risk of prostate cancer (PCa) to yield inconsistent results. In this study, we aimed to generate large-scale evidence on whether NQO1 Pro187Ser polymorphism conferred to the susceptibility of PCa. The database of PubMed was comprehensively reviewed until September 12th, 2013, without any linguistic limitation. Meta-analysis was complied in the codominant, dominant, recessive and allele models by either fixed or random effect models. Odds ratios (OR) and 95% confidence intervals (95%CI) were calculated to evaluate the strength of the association between the two. Finally, six eligible studies with 717 cases and 1764 controls were included. In overall analyses, significant associations were found in the dominant (OR = 1.26, 95%CI = 1.04 - 1.52, P = 0.02), allele (OR = 1.20, 95%CI = 1.03 - 1.40, P = 0.02) and the heterozygous codominant (OR = 1.24, 95%CI = 1.02 - 1.52, P = 0.03) models. Also, significant results were found in the stratified analyses by Hardy-Weinberg equilibrium (HWE). Still, subgroup analysis showed an increased risk of PCa in Asian rather than Caucasian population. Besides, NQO Pro187Ser polymorphism correlated with a heightened risk of PCa in the hospital-based studies. Our study indicated that NQO1 functional Pro187Ser polymorphism could be a potentially genetic biomarker for the risk of PCa, especially in Asian population.

Stress Echocardiography for Chronic Coronary Syndrome:Clinical Practice Guidelines(2023)

In the context of the People's Republic of China,coronary artery disease(CAD)presents a sig-nificant clinical challenge,with over 11.3 mil-lion patients diagnosed.Traditionally,the diagnos-is of CAD has predominantly relied on invasive coronary angiography.[1]However,recent advances in clinical research have revealed a notable trend:a substantial 82% of patients subjected to such invas-ive diagnostics do not necessitate interventional therapy.

Potential impact of specific therapy on pregnant women with pulmonary arterial hypertension without cardiac shunt:a descriptive study in northern China

Background:Pregnancy in women with pulmonary arterial hypertension(PAH)is a fatal condition,despite the effectiveness of PAH-specific therapies.The coverage status and effect of specific therapies in pregnant patients with PAH without cardiac shunts in China remain unclear.To investigate this issue,we conducted a multicenter retrospective study in northern China.Methods:The study included 85 patients who were admitted to 4 clinical centers in Shandong Province between October 2010 and August 2020.Maternal endpoint events included(1)maternal death and/or(2)major adverse cardiac events,both occurring during pregnancy or within 6 weeks postpartum.Results:Although the overall mortality rate was encouraging(11.8%),the number of patients receiving PAH-specific therapies was extremely low(28.2%).Moreover,only 15.3%of patients received adequate duration of PAH-specific therapy(≥4 weeks)before delivery,and this subgroup showed the lowest major adverse cardiac events rate(7.7%)compared with that in the untreated(19.7%)and short-time treated groups(<4 weeks;54.5%).Conclusion:Pregnant patients with PAH without cardiac shunts face significantly increased mortality risks.Short-term PAH-specific therapy does not guarantee favorable maternal outcomes.Prepregnancy screening,early identification,and timely intervention are expected to improve maternal outcomes in pregnant women with PAH.

Measurement of left ventricular fluid dynamic parameters in healthy Chinese adults based on echocardiographic vector flow mapping

To the Editor:As we concerdered that there was barely any widely representative,recognized,and standardized echocardiographic vector flow mapping(VFM)method has been established for the observation and measurement of the blood flow in cardiac cavities in clinical practice,and there were no commonly accepted normal reference values for Chinese adults have been obtained till now,hindering the further promotion and application of this technology in clinical practice.Establishing normal reference values for echocardiographic VFM that can be widely accepted in clinical practice is of great significance for determining the normal or abnormal fluid dynamic status in the left ventricle(LV)chamber.

EFFECT OF ASPIRIN PLUS CLOPIDOGREL ON INFLAMMATORY MARKERS IN PATIENTS WITH NON-ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROME

Background Aspirin can inhibit inflammatory reactions and platelet aggregation, but little is known about the effects of the combination of aspirin plus clopidogrel, a new antiplatelet agent, on inflammation. The purpose of this study was to determine whether aspirin plus clopidogrel can further suppress inflammation in patients with non-ST-segment elevation acute coronary syndrome （NSTEACS）. Methods One hundred and fifteen patients with NSTEACS were randomized into two groups： group A （aspirin alone, n=58） and group B （aspirin plus clopidogrel, n=57）. Patients in group A received a loading dose of 300 mg aspirin, then 100 mg per day. The patients in group B received a loading dose of 300 mg aspirin and 300 mg clopidogrel, then 100 mg aspirin and 75 mg clopidogrel per day. Serum high sensitivity C-reactive protein （hs-CRP） and tumor necrosis factor-α （TNF-α ） were measured in all patients at baseline prior to any drug treatment after admission, and at 7 and 30 days after beginning drug treatment. Thirty healthy volunteers on no medications were enrolled as controls （group C）. Results Baseline levels of hs-CRP and TNF-α in group A and group B were significantly higher than those in group C. Seven days after administration, the levels of hs-CRP in both group A and group B decreased significantly [Group A： （6.15 ± 1.39） mg/L vs （9.18 ± 1.62） rag/L, P 〈0.01; Group B：（4.99 ± 1.62） mg/L vs （10.29 ± 1.47） rag/L, P〈0.01]. Similarly, levels of TNF-α in both groups decreased at 7 days compared to baseline [Group A： （90.99 ± 28.91） pg/ml vs （117.20 ± 37.13） pg/ml, P 〈0.01; Group B： （74.32± 21.83） pg/ml vs （115.27 ± 32.11） pg/ml, P 〈0.01]. Thirty days after administration, the levels of hs-CRP in both group A and group B decreased further to （3.49 ± 1.53） rag/L, and （2.40 ± 1.17） mg/L respectively （P 〈0.01 for both comparisons）. Levels of TNF-α in groups A and B also decreased significantly between 7 and 30 days, to 63.28 ± 29.01 pg/ml （group A） and （43.95 ± 17.10） pg/ml （group B; P 〈0.01 for both comparisons）. Significantly lower levels of hs-CRP and TNF-α were observed in group B compared to Group A at thirty days after initiating drug treatment （P 〈0.05）. Conclusions Aspirin plus clopidogrel treatment reduced levels of serum hs-CRP and TNF-α in patients with NSTEACS significantly more than aspirin alone. Because both aspirin and clopidogrel produce important anti-inflammatory effects, these results suggest the possibility that long-term treatment with aspirin plus clopidogrel may produce greater clinical benefits compared to treatment with aspirin alone.

Gene deficiency or pharmacological inhibition of PDCD4-mediated FGR signaling protects against acute kidney injury

Recent studies have shown that programmed cell death 4(PDCD4)modulates distinct signal transduction pathways in different pathological conditions.Despite acute and chronic immune responses elicited by ischemia contributing to the functional deterioration of the kidney,the contributions and mechanisms of PDCD4 in acute kidney injury(AKI)have remained unclear.Using two murine AKI models including renal ischemia/reperfusion injury(IRI)and cisplatin-induced AKI,we found that PDCD4 deficiency markedly ameliorated renal dysfunction and inflammatory responses in AKI mice.Consistently,upregulation of PDCD4 was also confirmed in the kidneys from patients with biopsy confirmed acute tubular necrosis from a retrospective cohort study.Moreover,we found that overexpression of Fgr,a member of the tyrosine kinase family,dramatically aggravated renal injury and counteracted the protective effects of PDCD4 deficiency in AKI mice.We discovered that FGR upregulated NOTCH1 expression through activating STAT3.Most importantly,we further found that systemic administration of ponatinib,a tyrosine kinase inhibitor,significantly ameliorated AKI in mice.In summary,we identified that PDCD4 served as an important regulator,at least in part,of FGR/NOTCH1-mediated tubular apoptosis and inflammation in AKI mice.Furthermore,our findings suggest that ponatinib-mediated pharmacologic targeting of this pathway had therapeutic potential for mitigating AKI.

Pitavastatin calcium improves endothelial function and delays the progress of atherosclerosis in patients with hypercholesterolemia

Background： Statins have proven efficacy in inhibiting the onset and progress of atherosclerosis. The effectiveness of pitavastatin in reversing carotid atherosclerosis associated with hypercholesterolemia （HC） is un-known. Objectives： To explore the simultaneous effects of pitavastatin calcium on brachial arterial flow-mediated vasodilatation （FMD）, carotid intima-media thickness （IMT）, and arterial stiffness （β）, three surrogate markers of ath-erosclerosis were studied in HC patients. Methods：A randomized, double-blind trial was performed with 40 HC sub-jects who fulfil ed the inclusion/exclusion criteria. Patients were given pitavastatin calcium 1 mg/d （Group 1） or 2 mg/d （Group 2） for 8 weeks. There were 20 patients in each group, and 30 gender-and age-matched healthy subjects as controls were recruited. FMD of the brachial artery, carotid IMT, and arterial stiffness indicated byβwere measured at baseline and at 8 weeks after starting pitavastatin calcium therapy using ultrasound techniques. Biochemical tests were also made on al subjects. Results： At baseline, higher total cholesterol （TC） and low-density lipoprotein cho-lesterol （LDL-C）, reduced FMD, and increasedβand IMT were observed in HC patients （P0.05）. Significant negative interactions between TC/LDL and FMD （P〈0.05–0.001）, positive interactions between TC and IMT （P=0.003） and between TC/LDL and β （P〈0.001–0.000） were found. Conclusions： Treatment with pitavastatin calcium exerted fa-vorable effects on endothelial function and arterial stiffness. It also improved carotid atherosclerosis in patients with HC.

Rationale,design,and baseline characteristics of Chinese registry in early detection and risk stratification of coronary plaques(C-STRAT)study

To the Editor:Coronary computed tomographic angiography(CCTA)has been considered as one of the most important noninvasive imaging modalities in diagnosing coronary artery disease(CAD).[1]Modern scanner of CCTA can provide precise coronary atherosclerotic plaque information,showing improved diagnostic accuracy and sensitivity for identifying obstructive CAD with a preferable temporal and spatial resolution.Several studies have demonstrated the prognosis value of CCTA for the prediction of future adverse CAD events.

Analysis of phosphorylation sites on autophagy proteins

Autophagy is a lysosome-based degradation pathway,characterized by formation of a double-membrane vesicle named the autophagosome.During autophagy,various cargos are engulfed and delivered to lysosomes(or the vacuole in yeast)for degradation.It is an evolutionarily conserved pathway and plays important roles in various physiological and pathological conditions such as develop-ment,immunity,cancer and neuronal degeneration(Jiang and Mizushima,2014;Martin et al.,2014).

Photoacoustic characteristics of lipid-rich plaques under ultra-low temperature and formaldehyde treatment

Photoacoustic imaging(PAI)has been used to characterize the spatial and quantitative features of lipid-rich atherosclerotic plaques with high sensitivity and specificity.In this Letter,we first validate that the ultra-low temperature and formaldehyde treatment have no effect on photoacoustic characteristics of the artery samples.Comparative experiments between the PAI and histological results demonstrate that the ultra-low temperature or formaldehyde treatment has few effects on the PAI of the lipid-rich atherosclerotic plaques;the lipid relative concentration and the lipid percentage by PAI hold high correlation with histology.

Echocardiographic Measurements in Normal Chinese Adults(EMINCA)II focusing on left ventricular and left atrial size and function by three-dimensional echocardiography

Current guidelines encourage large studies in a diverse population to establish normal reference ranges for three-dimensional(3D)echocardiography for different ethnic groups.This study was designed to establish the normal values of 3D-left ventricular(LV)and left atrial(LA)volume and function in a nationwide,population-based cohort of healthy Han Chinese adults.A total of 1117 healthy volunteers aged 18–89 years were enrolled from 28 collaborating laboratories in China.Two sets of 3D echocardiographic instruments were used,and full-volume echocardiographic images were recorded and transmitted to a core laboratory for image analysis with a vendor-independent off-line workstation.Finally,866 volunteers(mean age of 48.4 years,402 men)were qualified for final analysis.Most parameters exhibited substantial differences between different sex and age groups,even after indexation by body surface area.The normal ranges of 3D-LV and 3D-LA volume and function differed from those recommended by the American Society of Echocardiography and the European Association of Cardiovascular Imaging guidelines,presented by the World Alliance Societies of Echocardiography(WASE)study,and from the 2D values in the EMINCA study.The normal reference values of 3D echocardiography-derived LV and LA volume and function were established for the first time in healthy Han Chinese adults.Normal ranges of 3D-LV and 3D-LA echocardiographic measurements stratified with sex,age,and race should be recommended for clinical applications.

An unusual anterior mitral leaflet perforation in a patient with no infective endocarditis:a case report

Background:Mitral valve perforation refers to the occurrence of cracks or openings in the structure of the mitral valve,allowing blood to escape through these gaps.Typically,this is caused by infective endocarditis and the most common site is the anterior leaflet.However,it is crucial to explore other potential causes of valve damage,particularly when conventional risk factors are not apparent.Case presentation:We present a case of a middle-aged male patient who developed mitral valve perforation because of aortic valve regurgitation in the absence of infective endocarditis.Conclusion:Exploring such rare cases contributes to a deeper understanding of valvular diseases and enhances clinical decision making for effective management.

Si-Miao-Yong-An Decoction alleviates thromboangiitis obliterans by regulating miR-548j-5p/IL-17A signaling pathway

Thromboangiitis obliterans(TAO)is a rare,chronic,progressive,and segmental inflammatory disease characterized by a high rate of amputation,significantly compromising the quality of life of patients.Si-Miao-Yong-An decoction(SMYA),a tradition-al prescription,exhibits anti-inflammatory,anti-thrombotic,and various other pharmacological properties.Clinically,it was fully proved to be effective for TAO therapy,but the specific therapeutic effect of SMYA on TAO has been unknown.Thus,deep unveiling the mechanism of SMYA in TAO for identifying clinical therapeutic targets is extremely important.In this study,we observed elev-ated levels of IL-17A in the peripheral blood mononuclear cells(PBMCs)of TAO patients,whereas the expression of miR-548j-5p was significantly decreased.A negative correlation between the levels of miR-548j-5p and IL-17A was also demonstrated.In vitro ex-periments showed that overexpression of miR-548j-5p led to a decrease in IL-17A levels,whereas downregulation of miR-548j-5p showed the opposite effect.Using a dual luciferase assay,we confirmed that miR-548j-5p directly targets IL-17A.Furthermore,serum containing SMYA effectively decreased IL-17A levels by increasing the expression of miR-548j-5p.More importantly,the results of in vivo tests indicated that SMYA mitigated the development of TAO by inhibiting IL-17A through the upregulation of miR-548j-5p in vascular tissues.In conclusion,SMYA significantly enhances the expression of miR-548j-5p,thereby reducing the levels of the target gene IL-17A and alleviating TAO.Our research not only identifies novel targets and pathways for the clinical diagnosis and treatment of TAO but also advances the innovation in traditional Chinese medicine through the elucidation of the SMYA/miR-548j-5p/IL-17A regulatory axis in the pathogenesis of TAO.

NPRC deletion mitigated atherosclerosis by inhibiting oxidative stress, inflammation and apoptosis in ApoE knockout mice

Previous studies suggested a beneficial effect of natriuretic peptides in animal models of cardiovascular disease,but the role of natriuretic peptide receptor C(NPRC)in the pathogenesis of atherosclerosis(AS)remains unknown.This study was designed to test the hypothesis that NPRC may promote AS lesion formation and instability by enhancing oxidative stress,inflammation,and apoptosis via protein kinase A(PKA)signaling.ApoE^(−/−)mice were fed chow or Western diet for 12 weeks and NPRC expression was significantly increased in the aortic tissues of Western diet-fed mice.Systemic NPRC knockout mice were crossed with ApoE^(−/−)mice to generate ApoE^(−/−)NPRC^(−/−)mice,and NPRC deletion resulted in a significant decrease in the size and instability of aortic atherosclerotic lesions in ApoE^(−/−)NPRC^(−/−)versus ApoE^(−/−)mice.In addition,endothelial cell-specific NPRC knockout attenuated atherosclerotic lesions in mice.In contrast,endothelial cell overexpression of NPRC aggravated the size and instability of atherosclerotic aortic lesions in mice.Experiments in vitro showed that NPRC knockdown in human aortic endothelial cells(HAECs)inhibited ROS production,pro-inflammatory cytokine expression and endothelial cell apoptosis,and increased eNOS expression.Furthermore,NPRC knockdown in HAECs suppressed macrophage migration,cytokine expression,and phagocytosis via its effects on endothelial cells.On the contrary,NPRC overexpression in endothelial cells resulted in opposite effects.Mechanistically,the anti-inflammation and anti-atherosclerosis effects of NPRC deletion involved activation of cAMP/PKA pathway,leading to downstream upregulated AKT1 pathway and downregulated NF-κB pathway.In conclusion,NPRC deletion reduced the size and instability of atherosclerotic lesions in ApoE^(−/−)mice via attenuating inflammation and endothelial cell apoptosis and increasing eNOS expression by modulating cAMP/PKA-AKT1 and NF-κB pathways.Thus,targeting NPRC may provide a promising approach to the prevention and treatment of atherosclerosis.

Tong-xin-luo capsule inhibits left ventricular remodeling in spontaneously hypertensive rats by enhancing PPAR-γ expression and suppressing NF-κB activity

Background Tong-xin-luo capsule （TXL）, used as a traditional Chinese herb, offeres a therapeutic potential for treatment of cardiovascular diseases. It has been shown to exert a variety of pharmacological effects, including antihypertensive effects, and is able to improve ventricular remodeling. However, the mechanisms of its action are not completely understood. The aim of this study was to evaluate the molecular mechanisms of Tong-xin-luo capsule on left ventricular remodeling in spontaneously hypertensive rats （SHR）. Methods Sixteen eight-week-old SHRs were randomized into an SHR group （n=8） and a TXL group （n=8） that were given Tong-xin-luo capsule （1.5 mg·kg^-1·d^-1）. Eight Wistar Kyoto （WKY） rats fed with 0.9% NaCl served as the control group （WKY group）. Systolic blood pressure （BP）, body weight and heart rate were monitored once every two weeks. Ventricular remodeling was detected by histopathological examination. Nuclear factor kappa B P65 （NF-κB P65） and peroxisome proliferators activated receptor y （PPAR-γ） protein and phosphorylated inhibitor kappa a （IκBα） protein were detected by immunohistochemistry and western blot respectively. The physical interaction of the P65-P50 heterodimer with IκBα and NF-κB were measured by co-immunoprecipitation. PPAR-γ mRNA, collagen Ⅰ mRNA and collagen Ⅲ mHNA were measured by real-time PCR.Results TXL inhibited NF-κB P65 expression and ventricular remodeling and suppressed the activation of NF-κB compared with the SHR group （P〈0.01, P〈0.05）. TXL reduced IκBα phosphorylation, increased expression of PPAR-γ protein and enhanced the physical interaction of the P65-P50 heterodimer with IκBα. The mRNA expression of PPAR-γ was enhanced but the mRNA expression of collagen Ⅰ mRNA and collagen Ⅲ mRNA were suppressed by TXL. Conclusions In spontaneously hypertensive rats, TXL could inhibit ventricular remodeling induced by hypertension, and the inhibitory effect might be associated with the process of TXL increasing the expression of PPAR-γ that could result in the inhibition of the activation of NF-κB.

Plasma biomarkers and plaque strain predict long-term cardiovascular events in patients with acute coronary syndrome

To test whether circulating and intracoronary biomarkers and coronary plaque strain have additive values to Global Registry of Acute Coronary Events(GRACE) score for predicting long-term cardiovascular events in ACS patients. One hundred ACS patients were enrolled and the GRACE score and plasma levels and intracoronary gradients of a number of biomarkers were measured. Coronary plaque burden and morphology in non-critical stenotic plaques were determined by intravascular ultrasound(IVUS) technique, and the maximal shear strain(SSmax) and maximal area strain(ASmax) were determined by intravascular ultrasound elastography(IVUSE) technique. Patients were followed for cardiovascular events and the predictive values of clinical characteristics, plasma biomarkers and plaque parameters were compared with GRACE score, and the incremental values of these measurements to the GRACE score were assessed. GRACE score, plasma biomarkers and plaque strain were independent predictors of cardiovascular events. Combination of GRACE score, plasma biomarkers and plaque strains significantly improved the predictive value of the GRACE score alone with the receiver-operating characteristic area increased from0.457 to 0.667(P=0.014). The combination of circulating and intracoronary biomarkers, plaque strain and GRACE score provides a better predictive tool than GRACE score alone in patients with ACS.