Despite promising data showing that circulating tumour DNA (ctDNA) dynamics during treatment can inform real-time tumour response and recurrence risk1, how best to translate these insights into actionable clinical decision-making remains unclear. Here we report results from the EP-STAR trial-a multi-centre, ctDNA-driven, risk-adapted, non-randomized phase II study ( NCT04072107 ; ClinicalTrials.gov) testing whether a risk-adaptive treatment (RAT) strategy guided by on-treatment ctDNA dynamics can meaningfully improve survival, using nasopharyngeal carcinoma as a model. Eligible patients were enrolled and began treatment with standard-of-care gemcitabine-cisplatin neoadjuvant chemotherapy (GP-NAC; the P in this abbreviation stands for platinum)2, followed by RAT or standard-of-care chemoradiotherapy guided by ctDNA clearance trajectory during GP-NAC. Protocol-eligible patients who did not receive RAT, drawn from a prospectively registered ctDNA biomarker cohort ( NCT03855020 )3, served as a non-randomized, contemporaneous no-RAT external cohort. The primary end-point was failure-free survival (FFS) in the RAT group. After a median follow-up of 47.3 months, the 3-year FFS was 89.1% (83.2-95.0%) in the RAT group (n = 110). Patients who received RAT showed significantly improved FFS (P = 0.003, log-rank test) compared with the no-RAT external cohort (hazard ratio = 0.41 [0.23-0.75]; P = 0.004, Cox regression model). The RAT strategy was well-tolerated with no treatment-related deaths. Collectively, these data show that a ctDNA-driven RAT paradigm could be a promising strategy to improve survival, challenging the conventional fixed-course, static treatment approach.

BACKGROUND:Right ventricular-pulmonary arterial uncoupling (RV-PAuc), assessed by the tricuspid annular plane systolic excursion-to-pulmonary artery systolic pressure (TAPSE/PASP) ratio, acts importantly to determine outcomes in both cardiovascular diseases (CVDs) and non-CVDs. OBJECTIVES:This study sought to evaluate the prognostic value of the TAPSE/PASP ratio across diseases, identify RV-PAuc-related risk factors, and explore an optimal cutoff for risk stratification and clinical application. METHODS:Two independent reviewers selected eligible studies, including 82 cohort studies with 32,482 patients for mortality endpoints and 17 observational studies with 4,615 participants for baseline TAPSE/PASP values for this meta-analysis (PROSPERO, CRD42024579107). Relative risk (RR) was calculated for mortality endpoints, and standard mean differences were used for comparisons. RESULTS:RV-PAuc was positively associated with mortality in both CADs and non-CADs (RR: 2.20 [95% CI: 2.02-2.40]; I2 = 81.6%]. Cutoff values ranged from 0.15 to 0.70 across conditions: pulmonary arterial hypertension (0.15-0.33), valvular heart disease (0.27-0.55), heart failure (0.33-0.60), cardiac amyloidosis (0.31-0.47), acute coronary syndrome (0.49-0.55), sepsis (0.39-0.50), COVID-19 (0.50-0.64), and other non-CVDs (0.63-0.70). The association remained significant at the 3 most commonly used cutoffs (0.31, 0.36, and 0.50), with heterogeneity eliminated only at 0.50. Except for body mass index, hypertension, and dyslipidemia, factors such as age (0.43-0.67), estimated glomerular filtration rate (0.31-0.60), atrial fibrillation (0.27-0.60), chronic kidney disease (0.34-0.40), coronary artery disease (0.27-0.37), type 2 diabetes (0.40-0.51), stroke, and chronic obstructive pulmonary disease were associated with RV-PAuc, with observed heterogeneity in TAPSE/PASP cutoff values. CONCLUSIONS:The TAPSE/PASP ratio is a potential prognostic marker for predicting mortality in CVDs and non-CVDs. Despite heterogeneity, a universal cutoff of ≤0.50 mm/mm Hg enhances its clinical applicability.

Nedaplatin (NDP), a cisplatin derivative, is widely employed in the treatment of solid tumours. Commonly reported adverse effects include hypersensitivity, myelosuppression and nephrotoxicity. To date, QT-interval prolongation and polymorphic ventricular tachyarrhythmia have not been attributed to NDP. A 41-year-old Asian woman was referred to our institution with abdominal pain, diarrhoea and vomiting. Percutaneous biopsy confirmed a diagnosis of high-grade serous carcinoma with widespread metastatic dissemination. She sequentially received a PD-1 inhibitor, paclitaxel and NDP. Twenty minutes after NDP infusion commenced she developed abdominal pain, palpitations, nausea and hypotension (68/39 mmHg). ECG disclosed marked QT prolongation, polymorphic ventricular tachycardia and Mobitz type I second-degree atrioventricular block. Advanced life-support measures were instituted immediately. Following withdrawal of the implicated agent and substitution with carboplatin, she remained asymptomatic during 48 h of monitoring. We report the case of marked QT-interval prolongation and polymorphic ventricular tachycardia temporally related to NDP administration. Clinicians should therefore monitor the electrocardiogram closely during NDP therapy, particularly in patients receiving polypharmacy.

BACKGROUND:In the PLATINUM (ClinicalTrials.gov: NCT03984357) trial, nivolumab plus chemoradiotherapy sparing concurrent cisplatin demonstrated efficacy and safety in nasopharyngeal carcinoma (NPC). Herein, patient-reported outcomes (PROs) on quality of life (QoL), tolerability, and social reintegration are reported. METHODS:Patients with T4N1M0/T1-4N2-3M0 NPC were assessed for general and head-and-neck-specific QoL (using the European Organization for Research and Treatment of Cancer and the Functional Assessment of Cancer Therapy) and tolerability (using the PRO-specific Common Terminology Criteria for Adverse Events). Analyses included change over time, effect of the treatment phase on QoL, time-to-event analysis, and a comparison of PROs and clinician-reported outcomes (CROs) in toxicity. FINDINGS:Among 152 patients, 44.1% achieved social reintegration, and 51.3% were satisfied with their current life. Radiotherapy dominated QoL deterioration rather than induction chemotherapy (pooled mean difference, -18.51; 95% confidence interval [CI], -29.50 to -7.52; p = 0.001), and its removal dominated QoL improvement rather than that of nivolumab (pooled mean difference, -7.62; 95% CI, -10.05 to -5.19; p < 0.001). Patients without social reintegration had greater deterioration in speech (hazard ratio [HR], 0.60; 95% CI, 0.38 to 0.94; p = 0.027) and swallowing functions (HR, 0.59; 95% CI, 0.39 to 0.89; p = 0.011). Under-reporting of decreased appetite severity by CROs vs. by PROs in all three treatment phases was associated with poorer social reintegration (p = 0.002) and reduced failure-free survival (3 years, 86.1% vs. 95.0%; p = 0.021). CONCLUSIONS:Social reintegration is a practical composite indicator of favorable PROs in NPC. Interventions targeting speech, swallowing, and decreased appetite might promote better recovery. FUNDING:This study was funded by the Academician Workstation of Jun Ma (YSGZZ2024001), the Specific Research Fund of the Innovation Platform for Academicians of Hainan Province (YSPTZX202501), the National Natural Science Foundation of China (82573549, 82172870), the Guangdong Special Support Program for Young Top Talents (TZ09B0046), and the Guangzhou Science and Technology Program (2023A04J1786).

Importance With the programmed cell death protein 1 (PD-1) blockade toripalimab, omitting highly toxic concurrent cisplatin may be feasible for nasopharyngeal carcinoma (NPC) without compromising survival. Objective To evaluate the efficacy and safety of toripalimab incorporated into induction chemotherapy and radiotherapy, without concurrent cisplatin, for locoregionally advanced NPC. Design, Setting, and Participants Open-label, multicenter, randomized phase 3 clinical trial conducted from August 2021 to July 2022 at 13 hospitals in China, enrolling 532 patients with T4N1M0 or T1-4N2-3M0 NPC; 400 (75.2%) completed the trial per protocol. The final date of follow-up was March 21, 2025. Interventions Patients were randomly assigned to either the standard therapy group (n = 266), receiving toripalimab with gemcitabine-cisplatin induction chemotherapy and concurrent cisplatin-radiotherapy (100 mg/m(2) triweekly for 2 cycles), or the concurrent cisplatin-sparing group (n = 266), receiving the same regimen without concurrent cisplatin. The 17 cycles of toripalimab (240 mg triweekly) were distributed across the induction, radiotherapy, and adjuvant phases as 3, 3, and 11 cycles, respectively. Main Outcomes and Measures Coprimary end points were failure-free survival (noninferiority margin, 8%) and incidence of all-grade vomiting (superiority design). Secondary end points included overall survival, locoregional recurrence-free survival, distant metastasis-free survival, safety, tumor response, quality of life, and tolerability. Results In the 532 patients in the intention-to-treat population (median [IQR] age, 47 [39-54] years; 25.2% women), after a median follow-up of 37.0 (range, 4.0-50.0) months, the concurrent cisplatin-sparing group had a 3-year failure-free survival rate of 88.3% vs 87.6% in the standard therapy group, a difference of 0.7% (lower limit of the 1-sided 95% CI, -3.9%; P = .002 for noninferiority; stratified hazard ratio, 0.92 [95% CI, 0.66-1.79]; log-rank P = .73). In the safety analysis, the incidence of all-grade vomiting was significantly lower in the concurrent cisplatin-sparing group vs the standard therapy group (26.2% [68/260] vs 59.8% [156/261]; difference, 33.6% [1-sided 95% CI, 26.9%-infinity]; P < .001). Patient-reported quality of life (participation rate, 87.5%) and tolerability (participation rate, 94.7%) were better in the concurrent cisplatin-sparing group, primarily in gastrointestinal, functional, and global health status. Conclusions and Relevance In this phase 3 randomized clinical trial, among patients with locoregionally advanced NPC, toripalimab combination therapy without concurrent cisplatin was a feasible treatment with high efficacy in failure-free survival and low toxicity. Trial Registration ClinicalTrials.gov Identifier: NCT04907370

With the programmed cell death protein 1 (PD-1) blockade toripalimab, omitting highly toxic concurrent cisplatin may be feasible for nasopharyngeal carcinoma (NPC) without compromising survival. To evaluate the efficacy and safety of toripalimab incorporated into induction chemotherapy and radiotherapy, without concurrent cisplatin, for locoregionally advanced NPC. Open-label, multicenter, randomized phase 3 clinical trial conducted from August 2021 to July 2022 at 13 hospitals in China, enrolling 532 patients with T4N1M0 or T1-4N2-3M0 NPC; 400 (75.2%) completed the trial per protocol. The final date of follow-up was March 21, 2025. Patients were randomly assigned to either the standard therapy group (n = 266), receiving toripalimab with gemcitabine-cisplatin induction chemotherapy and concurrent cisplatin-radiotherapy (100 mg/m2 triweekly for 2 cycles), or the concurrent cisplatin–sparing group (n = 266), receiving the same regimen without concurrent cisplatin. The 17 cycles of toripalimab (240 mg triweekly) were distributed across the induction, radiotherapy, and adjuvant phases as 3, 3, and 11 cycles, respectively. Coprimary end points were failure-free survival (noninferiority margin, 8%) and incidence of all-grade vomiting (superiority design). Secondary end points included overall survival, locoregional recurrence-free survival, distant metastasis–free survival, safety, tumor response, quality of life, and tolerability. In the 532 patients in the intention-to-treat population (median [IQR] age, 47 [39-54] years; 25.2% women), after a median follow-up of 37.0 (range, 4.0-50.0) months, the concurrent cisplatin–sparing group had a 3-year failure-free survival rate of 88.3% vs 87.6% in the standard therapy group, a difference of 0.7% (lower limit of the 1-sided 95% CI, −3.9%; P = .002 for noninferiority; stratified hazard ratio, 0.92 [95% CI, 0.66-1.79]; log-rank P = .73). In the safety analysis, the incidence of all-grade vomiting was significantly lower in the concurrent cisplatin–sparing group vs the standard therapy group (26.2% [68/260] vs 59.8% [156/261]; difference, 33.6% [1-sided 95% CI, 26.9%-∞]; P < .001). Patient-reported quality of life (participation rate, 87.5%) and tolerability (participation rate, 94.7%) were better in the concurrent cisplatin–sparing group, primarily in gastrointestinal, functional, and global health status. In this phase 3 randomized clinical trial, among patients with locoregionally advanced NPC, toripalimab combination therapy without concurrent cisplatin was a feasible treatment with high efficacy in failure-free survival and low toxicity. ClinicalTrials.gov Identifier: NCT04907370

Background The aim of this study was to characterize the burden of valvular heart disease (VHD)‐related heart failure (HF) in Group of 20 (G20) countries. Methods and Results Using data from the 2019 Global Burden of Disease Study, we estimated VHD‐related HF burdens (cases, age‐standardized prevalence rates, and years lived with disabilities rates) in G20 countries from 1990 to 2019 by age, sex, and sociodemographic index. The burden of VHD‐related HF increased in G20 countries from 1990 to 2019, exhibiting heterogeneity across VHD subtypes. In 2019, Italy, the United States, and the Russian Federation had the highest age‐standardized prevalence rates of nonrheumatic VHD‐related HF, whereas India, Brazil, and Mexico had the lowest. Rheumatic VHD‐related HF was most prevalent in China, India, and Italy, whereas the Republic of Korea, Brazil, and Turkey had the lowest. Nonrheumatic VHD‐related HF prevalence peaked among G20 countries in individuals ≥85 years of age, whereas rheumatic VHD‐related HF peaked in those 75 to 84 years of age in several countries, including China, India, the Russian Federation, Mexico, Argentina, and Turkey. Age‐standardized prevalence rates of nonrheumatic VHD‐related HF showed a decreasing trend, more pronounced in women, whereas rheumatic VHD‐related HF increased in both sexes, with a lower increase in men. Nonrheumatic VHD‐related HF burden correlated with age and sociodemographic index, whereas rheumatic VHD‐related HF burden was highest in middle sociodemographic index countries for those <75 years of age. Years lived with disabilities rates for VHD‐related HF represented about 9.0% of the overall burden across populations. Conclusions The increasing burden of VHD‐related HF in G20 countries highlights the need for timely interventions to mitigate this growing public health challenge.

138 Background: Cisplatin-based concurrent chemoradiotherapy has long been regarded as the cornerstone of treatment for patients with locoregionally advanced nasopharyngeal carcinoma (LANPC) over two decades ago. However, the persistent issue of severe acute toxicities (54.0–61.0%) and late sequelae (9.2–11.4%) induced by concurrent cisplatin remains unresolved. Methods: In this single-arm, phase II clinical trial (PLATINUM study), patients with high-risk LANPC (T4N1M0 or T1–4N2–3M0) were recruited from 7 hospitals in China to receive intravenous nivolumab (360 mg once every 3 weeks for 3 cycles [Q3W x 3]) + induction chemotherapy (gemcitabine 1000 mg/m2 + cisplatin 80 mg/m2, Q3W x 3), followed by nivolumab (360 mg, Q3W x 3) + intensity-modulated radiotherapy (PGTVnx, 70Gy/33fx), and thereafter adjuvant nivolumab (480 mg, Q4W x 6). The primary end point was 3-year failure-free survival (FFS), defined as the time from enrollment to any disease failure or death. Secondary end points were overall survival, safety, and health-related quality-of-life (QoL) assessed by cellphone-based EORTC and FACT questionnaires. This trial was registered with ClinicalTrials.gov (NCT03984357). Results: Between April 2020 and October 2020, 152 patients (median [IQR] age, 49 [39–56] years; 18.4% women) were included. After a median follow-up of 43 months (92.6% alive patients ≥ 36 months), the 3-year FFS was 88.5% (95% CI, 83.4–93.8%) and the 3-year overall survival was 97.9%. Sixty (40.2%) patients had grade 3–4 acute treatment-related adverse events (trAEs) throughout treatment; 11 (7.2%) were associated with potential immunologic causes, mainly involving skin system (rash, 2.0%; dermatitis, 2.0%). A total of 123 patients completed all required treatment, including 6 cycles of adjuvant nivolumab, with an overall compliance rate of 80.9%. The incidences of grade 3–4 acute trAEs in the induction, radiotherapy, and adjuvant phases were 30.2%, 16.7%, and 6.0%, respectively; compliance rates, 95.4%, 96.5%, and 91.8%, respectively. Eight (5.2%) patients had grade 3–4 late trAEs, eg. hearing impaired (3.3%) and dry mouth (0.7%). No treatment-related death was observed. Patients had consistent worsening changes in general QoL from baseline between the radiotherapy and induction phases, except for the domains of global health status and physical function/well-being, which were more common during the radiotherapy phase. Conclusions: Nivolumab incorporated into induction chemotherapy followed by radiotherapy has a promising efficacy and low toxicity for high-risk LANPC patients. A phase 3 randomized clinical trial assessing PD-1 blockade plus this de-intensified radical chemoradiotherapy is underway (NCT04907370). Clinical trial information: NCT03984357 .

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with increased risks of stroke and other adverse outcomes. Aims: This study sought to determine whether the Essen Stroke Risk Score (ESRS) could predict the risks of adjudicated clinical outcomes in patients with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Methods: We evaluated associations of baseline ESRS with clinical outcomes by using the Cox proportional hazard model with competing risk regression. The diagnostic accuracy of the ESRS was assessed using the C-index and calibration data. Results: Of 3,441 HFpEF patients with a mean follow-up of 3.3 years, the risk of stroke ranged from 0.32% per year at an ESRS of 1 to 2 points to 1.71% per year at a score of >= 6 points. Each point increase in ESRS was associated with increased risks of primary composite outcome (hazard ratios [HRs] = 1.31; 95% confidence intervals [CIs]: 1.23-1.40; C-index = 0.68), stroke (HR = 1.33 [95% CI: 1.16-1.53]; C-index = 0.68), myocardial infarction (HR = 1.60 [95% CI: 1.40-1.83]; C-index = 0.75), HF hospitalization (HR = 1.30 [95% CI: 1.20-1.41]; C-index = 0.71), any hospitalization (HR = 1.20, 95% CI: 1.15-1.26; C-index = 0.68), cardiovascular death (HR = 1.32 [95% CI: 1.20-1.44]; C-index = 0.68), and all-cause death (HR = 1.37, [95% CI: 1.28-1.48]; C-index = 0.68). The calibration curves showed that the ESRS had a better agreement between predicted and observed stroke risks compared with the R2CHADS2, CHADS2, or CHA2DS2-VASC stroke scores. Conclusions: The ESRS had modest discriminatory abilities for predicting stroke as well as other adverse outcomes including myocardial infarction, hospitalization, and death in HFpEF patients. ESRS might have better calibration performance than R2CHADS2, CHADS2, or CHA2DS2-VASC in HFpEF at high risk for stroke.

Objective:To investigate whether exercise blood pressure (BP) was associated with cardiac structure and function independent of BP at rest.Methods:In the outpatients who underwent non-invasive cardiac exercising test and echocardiography at The First Affiliated Hospital of Sun Yat-Sen University between January 2019 and October 2020, collected the clinical data and retrospectively assessed the association of cardiac structure (i.e., left atrial internal diameter, interventricular septal wall thickness, left ventricular posterior wall thickness), diastolic function [i.e., the peak early-diastolic (E) and peak end-diastolic (A) transmission velocity, the mean early-diastolic myocardial velocity (e')], and systolic function (left ventricular ejection fraction) with 1-SD increment in BP during exercise and at rest, using multivariable regression analyses.Results:Among the 323 participants, age averaged (46.2±15.1) years. 40.2% (130/323) were men, and 13.6% (44/132) had coronary heart disease. With adjustments applied for gender, age, body mass index, coronary heart disease, and BP at rest, the association sizes with 1-SD increase in exercise systolic, and diastolic BP were 0.33 mm (P<0.001) / 0.33 mm (P<0.001) for interventricular septal wall thickness, and 0.32 mm (P<0.001) / 0.24 mm (P=0.004) for left ventricular posterior wall thickness, while the association sizes were non significant for the associations between indices of cardiac function and exercise systolic BP. After adjusted for gender, age, body mass index, coronary heart disease, and exercise BP, the association sizes with 1-SD increase in systolic BP at rest were 3.93 mm/s (P<0.001) for A peak and 0.46 (P=0.002) for E/e'. The association sizes with 1-SD increase in diastolic BP at rest were 2.91 mm/s (P=0.005) for A peak and -0.08 (P=0.002) for E/A, and 1-SD increase in systonic BP at rest were 0.26 mm for IVST (P=0.007), while there were no associations between indices of cardiac structure and systolic BP at rest with exception for interventricular septal wall thickness. After accounted for potential confounders, there was no association of left ventricular ejection fraction with BP during exercise and at rest.Conclusion:Exercise BP was mainly associated with cardiac structure independent of BP at rest, while BP at rest was mainly correlated with cardiac diastolic function independently of exercise BP.

Background Metabolic syndrome is a pre-diabetes condition that is associated with increased cardiovascular morbidity and mortality. We aimed to explore how exercise capacity, cardiac structure, and function were affected in patients with metabolic syndrome. Methods Outpatients with echocardiography and exercise stress test combined with impedance cardiography (ETT + ICGG) results available from Nov 2018 to Oct 2020 were retrospectively enrolled. Echocardiographic, ETT + ICG profiles, and exercise performance were compared between patients with metabolic syndrome and the ones without. Sensitivity analyses were performed excluding patients without established coronary heart disease and further 1:1 paired for age and gender, respectively. Multiple linear regression was used to find out related predictors for maximal metabolic equivalents (METs). Results Three hundred and twenty-third patients were included, among whom 97 were diagnosed as metabolic syndrome. Compared to patients without metabolic syndrome, echocardiography showed that patients with metabolic syndrome had a significantly lower E/A ratio (p < 0.001). Besides, they have larger left atrium, larger right ventricle, and thicker interventricular septum (all p < 0.001), but similar left ventricular ejection fraction (P = 0.443). ICG showed that patients with metabolic syndrome had significantly higher stroke volume at rest and maximum (p < 0.001), higher left cardiac work index at rest and maximum (p = 0.005), higher systemic vascular resistance (SVR) at rest (p < 0.001), but similar SVI (p = 0.888). During exercise, patients with metabolic syndrome had lower maximal METs (p < 0.001), and a higher proportion suffering from ST-segment depression during exercise (p = 0.009). Sensitivity analyses yielded similar results. As for the linear regression model, 6 independent variables (systolic blood pressure, BMI, E/A ratio, the height of O wave, the peak value of LCWi, and the baseline of SVR) had statistically significant effects on the maximal METs tested in exercise (R = 0.525, R2 = 0.246, P < 0.001). Conclusion Patients with metabolic syndrome had significant structural alteration, apparent overburden of left ventricular work index, pre-and afterload, which may be the main cause of impaired exercise tolerance.

Background: We aimed to explore the value of combining real-time three-dimensional echocardiography (RT-3DE) and myocardial contrast echocardiography (MCE) in the left ventricle (LV) evaluating myocardial dysfunction in type 2 diabetes mellitus (T2DM) patients.Patients and Methods: A total of 58 T2DM patients and 32 healthy individuals were selected for this study. T2DM patients were further divided into T2DM without microvascular complications (n = 29) and T2DM with microvascular complications (n = 29) subgroups. All participants underwent RT-3DE and MCE. The standard deviation (SD) and the maximum time difference (Dif) of the time to the minimum systolic volume (Tmsv) of the left ventricle were measured by RT-3DE. MCE was performed to obtain the perfusion measurement of each segment of the ventricular wall, including acoustic intensity (A), flow velocity (β), and A·β.Results: There were significant differences in all Tmsv indices except for Tmsv6-Dif among the three groups (all P < 0.05). After heart rate correction, all Tmsv indices of the T2DM with microvascular complications group were prolonged compared with the control group (all P < 0.05). The parameters of A, β, and A·β for overall segments showed a gradually decreasing trend in three groups, while the differences between the three groups were statistically significant (all P < 0.01). For segmental evaluation of MCE, the value of A, β, and A·β in all segments showed a decreasing trend and significantly differed among the three groups (all P < 0.05).Conclusions: The RT-3DE and MCE can detect subclinical myocardial dysfunction and impaired myocardial microvascular perfusion. Left ventricular dyssynchrony occurred in T2DM patients with or without microvascular complications and was related to left ventricular dysfunction. Myocardial perfusion was reduced in T2DM patients, presenting as diffuse damage, which was aggravated by microvascular complications in other organs.

Notoginsenoside R1 (NGR1), the primary bioactive compound found in Panax notoginseng, is believed to have antihypertrophic and antiapoptotic properties, and has long been used to prevent and treat cardiovascular diseases. However, its potential role in prevention of diabetic cardiomyopathy remains unclear. The present study aimed to investigate the mechanism of NGR1 action in high glucose-induced cell injury. H9c2 cardiomyocytes were cultured in a high-glucose medium as an in-vitro model, and apoptotic cells were visualized using TUNEL staining. Expression of Nrf2 and HO-1 was measured using Western blotting or reverse transcription-quantitative PCR (RT-qPCR). The Nrf2 small interfering (si) RNA was transfected into cardiomyocytes using Opti-MEM containing Lipofectamine® RNAiMAX. NGR1 protected H9c2 cardiomyocytes from cell death, apoptosis and hypertrophy induced by high glucose concentration. Expression of auricular natriuretic peptide and brain natriuretic peptide was remarkably reduced in NGR1-treated H9C2 cells. Western blot analysis showed that high glucose concentration markedly inhibited AMPK, Nrf2 and HO-1, and this could be reversed by NGR1 treatment. However, the cardioprotective effect of NGR1 was attenuated by compound C, which reverses Nrf2 and HO-1 expression levels, suggesting that AMPK upregulates Nrf2 and HO-1 gene expression, protein synthesis and secretion. Transfection of H9C2 cells with Nrf2 siRNA markedly reduced the cardioprotective effect of NGR1 via reduced expression of HO-1. These results indicated that NGR1 attenuated high glucose-induced cell injury via AMPK/Nrf2 signaling and its downstream target, the HO-1 pathway. We conclude that the cardioprotective effects of NGR1 result from upregulation of AMPK/Nrf2 signaling and HO-1 expression in cardiomyocytes. Our findings suggest that NGR1 treatment might provide a novel therapy for diabetic cardiomyopathy.

Context Lower serum concentration of apolipoprotein A-I (ApoA-I) is causally associated with heart failure (HF) risk. Adenosine triphosphate-sensitive potassium channels (KATP), as gating channels coupling vascular reactivity and metabolism with ischemic protection, become a new potential target of management for HF. The KATP gene sequence is highly polymorphic and has a high degree of genetic heterogeneity. Objective This work aimed to determine whether KATP variants predict the risks of decreased ApoA-I concentration and its related HF. Methods A total of 634 individuals, including 317 patients with decreased ApoA-I concentration (< 120 mg/dL) and 317 counterpart participants (>= 120 mg/dL), were retrospectively selected. Five KATP variants were genotyped through the MassARRAY platform. Exosome-derived microRNAs (exo-miRs) expression profiles were identified by next-generation sequencing, and the top 10 differentially expressed (DE) exo-miRs were verified using quantitative polymerase chain reaction in a validation cohort of 240 individuals with decreased ApoA-I concentration. Results KATP rs141294036 was related to an increased risk of lower ApoA-I levels (adjusted odds ratio [OR] = 1.95, P = .002) and HF incidence (adjusted OR = 2.38, P = .009), especially heart failure with preserved ejection fraction (HFpEF; adjusted OR = 2.13, P = .015). After a median 48.6-month follow-up, participants carrying the CC genotype of rs141294036 were associated with an elevated HF rehospitalization risk (adjusted hazard ratio = 1.91, P = .005). Thirty-six exo-miRs were significantly DE between different genotypes of rs141294036 in participants with lower ApoA-I levels, but only 5 exo-miRs (miR-31-5p, miR-126-5p, miR-106a-5p, miR-378i, and miR-181c-5p) were further confirmed. Conclusion KATP rs141294036 was associated with increased risks of lower ApoA-I levels, HF incidence (especially HFpEF), and HF rehospitalization in those with the 5 confirmed exo-miRs and its related metabolic pathways.

Objective: To explore the effect of the 6-minute walk test (6MWT) guided by non-invasive cardiac output on the rehabilitation of patients with knee osteoarthritis following artificial total knee arthroplasty. Methods: About 66 patients with knee osteoarthritis planned to undergo artificial total knee arthroplasty were included from March 2019 to October 2019, and randomly assigned to the intervention group or control group. Under the guidance of a clinical rehabilitation physician, orthopedic physician, and cardiologist, a home rehabilitation exercise program based on 6MWT and non-invasive cardiac output was formulated for patients with knee osteoarthritis. The participants of the intervention group conducted full rehabilitation training supervision and guidance through the WeChat platform to ensure their rehabilitation pieces of training were completed safely and effectively. As for the control group, patients were just given rehabilitation training manuals at the time of discharge and completed the training by themselves. Results: At 6 months post-operatively, 6-minute walk distance (413.88 ± 44.61 vs. 375.00 ± 40.53 m, P < 0.05), active metabolic equivalent (4.13 ± 0.29 vs. 3.88 ± 0.27, P < 0.05), stroke volume after 6MWT (114.97 ± 12.05 vs. 98.38 ± 16.43 ml, P < 0.05), and cardiac output (11.92 ± 1.68 vs. 9.79 ± 1.82 l/min, P < 0.05) of the intervention group were significantly higher than those of the control group. The symptom evaluation scores of the intervention group were also better than those of the control group. Conclusions: The multidisciplinary post-operative rehabilitation exercise training program is beneficial to the recovery of lower limb function and the improvement of exercise capacity after knee replacement, and it also helps to improve the non-invasive hemodynamic indicators related to the cardiac function of the patient. Clinical Trial Registration: http://www.chictr.org.cn/index.aspx.

Morphological change in retinal vessel diameters has been reported to be associated with negative cardiovascular outcomes, but its association with left ventricular diastolic dysfunction (LVDD) is not clear. This study aimed to examine the association between echocardiographic markers of LVDD and retinal vascular diameters, in untreated masked hypertension (MH). In this observational study, 105 MH patients without other cardiovascular risks were included (mean age 48.4 +/- 5.7, female 72.4%). All individuals underwent extensive clinical and laboratory investigations, including echocardiography, ambulatory blood pressure monitoring, and retinal vascular diameters measured by optical coherence tomography. In the group, LVDD was diagnosed in 36 participants evaluated by left ventricular volume index, E/A and E/e' ratio. Compared to non-LVDD, LVDD subjects displayed narrower retinal arteriolar diameter (139.1 +/- 33.8 vs 165.1 +/- 29.1; adjusted P = .007) and wider retinal venular diameter (237.9 +/- 42.2 vs 214.9 +/- 44.8; adjusted P = .045). Significant and independent associations were demonstrated for retinal arteriolar narrowing and E/A ratio (adjusted beta = 0.744, P = .031) and for retinal arteriolar diameter and E/e' ratio (adjusted beta = -0.158, P = .001) after controlling for age, gender, body mass index, ambulatory systolic blood pressure, low-density lipoprotein cholesterol, and retinal venular diameter. In untreated MH subjects, retinal arteriolar diameter, a marker of microvascular damage, was independently associated with echocardiographic markers of diastolic dysfunction. These findings might underscore the hypothesis that microvascular disease could contribute to cardiac remodeling.

BACKGROUND:Exercise capacity is evaluated using the 6-minute walk test (6MWT) in various cardiovascular diseases. Bevacizumab (BEV) has been associated with significant risk of cardiovascular complications. The aim of this study was to investigate BEV-related influences on cardiac hemodynamic response to 6MWT.METHODS:We prospectively studied 24 patients with intestinal carcinoma to assess the hemodynamic response during 6MWT, of whom eight underwent BEV treatment. Obtained data was analyzed to identify hemodynamic differences between BEV and non-BEV treated patients.RESULTS:Twenty-four patients with stage IV intestinal carcinoma consented to assessment after the completion of three cycles of BEV-combined chemotherapy (age, 46.4±16.7 years) or standard chemotherapy alone (age, 56.4±13.7 years). In comparison with non-BEV treated patients, BEV-treated patients walked less (484.3±42.4 vs. 503.0±48.2, P=0.339). These two groups manifested similar hemodynamic response during the 6MWT. The change of hemodynamic parameters at 1 minute after completion of 6MWT was defined as hemodynamic parameter recovery. BEV-treated patients had significantly lower change of left cardiac work index (LCWi), cardiac index (CI), cardiac output (CO) and stroke volume (SV) after 6MWT. Interestingly, in BEV-treated patients CI change after 6MWT was predominantly related to the decrease in SV instead of heart rate (HR) as suggested by a higher standardized beta coefficient (0.883 vs. 0.657) and semi-partial correlations (0.821 vs. 0.677).CONCLUSIONS:Estimation of hemodynamic response to 6MWT is feasible, and may provide useful information of myocardial damage in BEV-treated patients.

Transcribed ultraconserved regions (T-UCRs) are a novel class of long noncoding RNAs transcribed from UCRs, which exhibit 100% DNA sequence conservation among humans, mice, and rats. However, whether T-UCRs regulate cardiac hypertrophy remains unclear. We aimed to explore the effects of T-UCRs on cardiac hypertrophy. First, we performed long noncoding RNA microarray analysis on hearts of mice subjected to sham surgery or aortic banding and found that the T-UCR uc.323 was decreased significantly in mice with aortic banding-induced cardiac hypertrophy. In vitro loss- and gain-of-function experiments demonstrated that uc.323 protected cardiomyocytes against hypertrophy induced by phenylephrine. Additionally, we discovered that mammalian target of rapamycin 1 contributed to phenylephrine-induced uc.323 downregulation and uc.323-mediated cardiomyocyte hypertrophy. We further mapped the possible target genes of uc.323 through global microarray mRNA expression analysis after uc.323 knockdown and found that uc.323 regulated the expression of cardiac hypertrophy-related genes such as CPT1b (Carnitine Palmitoyl transferase 1b). Then, chromatin immunoprecipitation proved that EZH2 (enhancer of zeste homolog 2) bound to the promoter of CPT1b via H3K27me3 (trimethylation of lysine 27 of histone H3) to induce CPT1b downregulation. And overexpression of CPT1b could block uc.323-mediated cardiomyocyte hypertrophy. Finally, we found that uc.323 deficiency induced cardiac hypertrophy. Our results reveal that uc.323 is a conserved T-UCR that inhibits cardiac hypertrophy, potentially by regulating the transcription of CPT1b via interaction with EZH2.

Aim: Protein-energy malnutrition and cardiovascular (CV) disease predisposes patients with end-stage renal disease (ESRD) on dialysis to a high risk of early death, but the prognostic value of prealbumin (PAB) and echocardiographic indices in ESRD patients treated with maintenance peritoneal dialysis (PD) remains unclear. Methods: A total of 211 PD patients (mean age 49.2 ± 15.4 years, 51.7% male) were prospectively studied. PAB and echocardiography parameters were recorded at baseline. Follow-up (mean ± SD: 33.7 ± 17.3 months) was conducted based on hospital records, clinic visits, and telephone reviews, to record death events and their causes. Results: In the Cox proportional hazards model, PAB and the echocardiographic parameters listed below were found to be optimal predictors of all-cause mortality: PAB (p = 0.003), aortic root diameter (ARD) (p = 0.004), interventricular septum end-diastolic thickness (IVSd) (p = 0.046), and left ventricular end-diastolic diameter index (LVEDDI) (p = 0.029). Of the above-mentioned factors, PAB (p = 0.018), ARD (p = 0.031), and IVSd (p = 0.037) were independent predictors of CV mortality in PD patients. Of note, malnutrition, degradation of the aorta, and myocardial hypertrophy are also known death risk factors in the general population. The all-cause mortality and CV death rate significantly increased as the number of risk factors increased, reaching values as high as 40 and 22% in patients who had all of the risk factors, i.e., abnormal PAB, ARD, and IVSd (p < 0.001 and p = 0.011). Conclusion: In PD patients, low serum PAB and abnormal echocardiographic parameters together were significantly associated with all-cause mortality and CV death, independently of other risk factors. These risk factors for death in PD are similar to those in the general population. Noticeably, the combination of echocardiographic parameters and PAB could provide additional predictive value for mortality in PD patients. In light of these findings, more studies in an optimal model containing PAB and echocardiographic parameters for the prediction of outcomes in ESRD are required.