Inhibition of heme oxygenase 1 alleviates thoracic aortic aneurysm via restoration of extracellular matrix.

BACKGROUND: Thoracic aortic aneurysm (TAA) is a silent but life-threatening cardiovascular disease. Heme oxygenase 1 (HO-1) plays an important role in the cardiovascular diseases but is poorly understood in TAA. This study aims at investigating the role of HO-1 in TAA. METHODS: Single-cell RNA sequencing, Western blot and histological assay were performed to identify specific cellular expression of HO-1 in both human and ß-aminopropionitrile (BAPN)-induced mice TAA. Zinc protoporphyrin (ZnPP), a pharmacological inhibitor of HO-1, was used to investigate whether inhibition of HO-1 could attenuate BAPN-induced TAA in rodent model. Histological assay, Western blot assay, and mRNA sequencing were further performed to explore the underlying mechanisms. RESULTS: Single-cell transcriptomic analyses of 113,800 thoracic aortic cells identified an increase of HO-1(+) macrophage in aneurysmal thoracic aorta from BAPN-induced TAA mice and TAA patients. Histological assay verified HO-1 overexpression in clinical TAA specimens, which was co-localized with CD68(+) macrophage. HO-1(+) macrophage was closely associated with pro-inflammatory response and immune activation. Inhibition of HO-1 through ZnPP significantly alleviated BAPN-induced TAA in mice and restored extracellular matrix (ECM) in vivo. Further experiments showed that ZnPP treatment suppressed the expression of matrix metalloproteinases (MMPs) in aneurysmal thoracic aortic tissues from BAPN-induced TAA mice, including MMP2 and MMP9. Macrophages from myeloid specific HO-1 knockout mice displayed weakened pro-inflammatory activity and ECM degradation capability. CONCLUSION: HO-1(+) macrophage subgroup is a typical hallmark of TAA. Inhibition of HO-1 through ZnPP alleviates BAPN-induced TAA in mice, which might work through restoration of ECM via suppressing MMP2 and MMP9 expression.

Systolic blood pressure time in target range and long-term outcomes in patients with ischemic cardiomyopathy.

BACKGROUND: The relationship between the degree of systolic blood pressure (SBP) control and outcomes remains unclear in patients with ischemic cardiomyopathy (ICM). Current control metrics may not take into account the potential effects of SBP fluctuations over time on patients. METHODS: This study was a post-hoc analysis of the surgical treatment of ischemic heart failure trial which enrolled 2,136 participants with ICM. Our SBP target range was defined as 110 to 130 mm Hg and the time in target range (TTR) was calculated by linear interpolation. RESULTS: A total of 1,194 patients were included. Compared with the quartile 4 group (TTR 77.87%-100%), the adjusted hazard ratios and 95% confidence intervals of all-cause mortality were 1.32 (0.98-1.78) for quartile 3 group (TTR 54.81%-77.63%), 1.40 (1.03-1.90) for quartile 2 group (TTR 32.59%-54.67%), and 1.53 (1.14-2.04) for quartile 1 group (TTR 0%-32.56%). Per 29.28% (1-SD) decrement in TTR significantly increased the risk of all-cause mortality (1.15 [1.04-1.26]). Similar results were observed in the cardiovascular (CV) mortality and the composite outcome of all-cause mortality plus CV rehospitalization, and in the subgroup analyses of either coronary artery bypass grafting or medical therapy, and different baseline SBP. CONCLUSIONS: In patients with ICM, the higher TTR was significantly associated with decreased risk of all-cause mortality, CV mortality and the composite outcome of all-cause mortality plus CV rehospitalization, regardless of whether the patient received coronary artery bypass grafting or medical therapy, and the level of baseline SBP. TTR may be a surrogate metric of long-term SBP control in patients with ICM.

Postoperative Dipping Patterns of Mean Arterial Pressure and Mortality After Coronary Artery Bypass Grafting.

Blood pressure dipping patterns have long been considered to be associated with adverse events. We aimed to investigate whether dipping patterns of postoperative MAP were related to 90-day and hospital mortality in patients undergoing CABG. Four thousand three hundred ninety-one patients were classified into extreme dippers (night-to-day ratio of MAP ≤ 0.8), dippers (0.8 < night-to-day ratio of MAP ≤ 0.9), non-dippers (0.9 < night-to-day ratio of MAP ≤ 1), and reverse dippers (> 1). Compared with non-dippers, reverse dippers were at a higher risk of 90-day mortality (aHR = 1.58; 95% CI, 1.10-2.27) and hospital mortality (aOR = 1.97; 95% CI, 1.12-3.47). A significant interaction was observed between hypertension and dipping patterns (P for interaction = 0.02), with a significant increased risk of 90-day mortality in non-hypertensive reverse dippers (aHR = 1.90; 95% CI, 1.17-3.07) but not in hypertensive reverse dippers (aHR = 1.26; 95% CI, 0.73-2.19).

Development and validation of a postoperative bleeding complications prediction model in infective endocarditis.

OBJECTIVES: Bleeding complications are one of the most serious postoperative complications after cardiac surgery and are associated with high mortality, especially in patients with infective endocarditis (IE). Our objectives were to identify the risk factors and develop a prediction model for postoperative bleeding complications in IE patients. METHODS: The clinical data of IE patients treated from October 2013 to January 2022 were reviewed. Multivariate logistic regression analysis was used to evaluate independent risk factors for postoperative bleeding complications and develop a prediction model accordingly. The prediction model was verified in a temporal validation cohort. The performance of the model was evaluated in terms of its discrimination power, calibration, precision, and clinical utility. RESULTS: A total of 423 consecutive patients with IE who underwent surgery were included in the final analysis, including 315 and 108 patients in the training cohort and validation cohort, respectively. Four variables were selected for developing a prediction model, including platelet counts, systolic blood pressure, heart failure and vegetations on the mitral and aortic valves. In the training cohort, the model exhibited excellent discrimination power (AUC = 0.883), calibration (Hosmer-Lemeshow test, P = 0.803), and precision (Brier score = 0.037). In addition, the model also demonstrated good discrimination power (AUC = 0.805), calibration (Hosmer-Lemeshow test, P = 0.413), and precision (Brier score = 0.067) in the validation cohort. CONCLUSIONS: We developed and validated a promising risk model with good discrimination power, calibration, and precision for predicting postoperative bleeding complications in IE patients.

Long-term Outcomes After On-Pump vs Off-Pump Coronary Artery Bypass Grafting for Ischemic Cardiomyopathy.

BACKGROUND: A post-hoc analysis of the Surgical Treatment for Ischemic Heart Failure (STICH) trial was performed to evaluate the perioperative and long-term outcomes after off-pump vs on-pump coronary artery bypass graft surgery in patients with ischemic cardiomyopathy (coronary artery disease with left ventricular ejection fraction 35% or less). METHODS: Patients who underwent isolated coronary artery bypass graft surgery were enrolled from the STICH trial. Operative details, perioperative outcomes, and long-term outcomes were compared in a 1-to-2 propensity score matching cohort. The primary outcome was death from any cause. RESULTS: Among 768 included patients operated on between July 2002 and May 2007, 152 (19.8%) received off-pump and 616 (80.2%) received on-pump coronary artery bypass graft surgery. In the 1-to-2 matched cohort (152 off pump and 304 on pump), off pump was associated with a higher prevalence of multiple arterial grafting (17.1% vs 8.6%, P = .01) and incomplete revascularization (34.2% vs 17.1%, P < .001). The overall 30-day mortality (3.3% vs 5.3%, P = .34) was comparable between the two groups. After a median follow-up of 8.7 years, off-pump surgery was associated with a similar risk of death from any cause (hazard ratio 0.82; 95% confidence interval, 0.61 to 1.09), with comparable estimated all-cause mortality at 1 year (12.5% vs 11.9%), 5 years (32% vs 32.8%), and 10 years (51.4% vs 62.3%). No significant interaction was detected in the subgroup analyses of incomplete revascularization, multiple arterial grafting, and three-vessel disease. CONCLUSIONS: In patients with ischemic cardiomyopathy, off-pump coronary artery bypass graft surgery could be performed with comparable 30-day mortality and similar long-term survival, and appears to have a lower incidence of perioperative morbidities.

Evolution, coronary artery bypass surgery and outcomes of right ventricular dysfunction in ischaemic cardiomyopathy.

OBJECTIVES: Whether the presence or evolution of right ventricular dysfunction (RVD) affects the prognosis and the therapeutic choice between coronary artery bypass grafting (CABG) or medical therapy alone in patients with ischaemic cardiomyopathy (ICM) remains unclear. We investigate the prognostic and therapeutic implications of RVD in patients with ICM. METHODS: Patients with baseline echocardiographic right ventricular (RV) assessment were included from the Surgical Treatment of Ischaemic Heart Failure trial. The primary outcome was all-cause mortality. RESULTS: Of 1212 patients enrolled in the Surgical Treatment of Ischaemic Heart Failure trial, 1042 patients were included, with 143 (13.7%) mild RVD and 142 (13.6%) moderate-to-severe RVD. After a median follow-up of 9.8 years, compared with patients with normal RV function, patients with RVD had a higher risk of mortality [mild RVD: adjusted hazard ratio (aHR) 1.32; 95% confidence interval (CI) 1.06-1.65; moderate-to-severe RVD: aHR, 1.75; 95% CI 1.40-2.19]. Among patients with moderate-to-severe RVD, CABG provided no additional survival benefits compared to medical therapy alone (aHR: 0.98; 95% CI: 0.67-1.43). Among 746 patients with pre- and post-therapeutic RV assessment, a gradient risk for death increased from patients with consistent normal RV function, to patients with recovery from RVD, new-onset RVD and persistent RVD. CONCLUSIONS: RVD was associated with a worse prognosis in patients with ICM, and CABG provided no additional survival benefits to patients with moderate-to-severe RVD. The evolution of RV function had important prognostic implications, which emphasized the importance of both pre- and post-therapeutic RV assessment.

Heterogeneous treatment effects of coronary artery bypass grafting in ischemic cardiomyopathy: A machine learning causal forest analysis.

OBJECTIVES: We aim to evaluate the heterogeneous treatment effects of coronary artery bypass grafting in patients with ischemic cardiomyopathy and to identify a group of patients to have greater benefits from coronary artery bypass grafting compared with medical therapy alone. METHODS: Machine learning causal forest modeling was performed to identify the heterogeneous treatment effects of coronary artery bypass grafting in patients with ischemic cardiomyopathy from the Surgical Treatment for Ischemic Heart Failure trial. The risks of death from any cause and death from cardiovascular causes between coronary artery bypass grafting and medical therapy alone were assessed in the identified subgroups. RESULTS: Among 1212 patients enrolled in the Surgical Treatment for Ischemic Heart Failure trial, left ventricular end-systolic volume index, serum creatinine, and age were identified by the machine learning algorithm to distinguish patients with heterogeneous treatment effects. Among patients with left ventricular end-systolic volume index greater than 84 mL/m2 and age 60.27 years or less, coronary artery bypass grafting was associated with a significantly lower risk of death from any cause (adjusted hazard ratio, 0.61; 95% CI, 0.45-0.84) and death from cardiovascular causes (adjusted hazard ratio, 0.63; 95% CI, 0.45-0.89). By contrast, the survival benefits of coronary artery bypass grafting no longer exist in patients with left ventricular end-systolic volume index 84 mL/m2 or less and serum creatinine 1.04 mg/dL or less, or patients with left ventricular end-systolic volume index greater than 84 mL/m2 and age more than 60.27 years. CONCLUSIONS: The current post hoc analysis of the Surgical Treatment for Ischemic Heart Failure trial identified heterogeneous treatment effects of coronary artery bypass grafting in patients with ischemic cardiomyopathy. Younger patients with severe left ventricular enlargement were more likely to derive greater survival benefits from coronary artery bypass grafting.

Bilateral internal thoracic artery coronary grafting: risks and benefits in elderly patients.

AIMS: Whether bilateral internal thoracic artery (BITA) grafting benefits elderly patients in coronary artery bypass grafting (CABG) remains unclear since they tend to have a limited life expectancy and severe comorbidities. We aim to evaluate the outcomes of BITA vs. single internal thoracic artery (SITA) grafting in elderly patients. METHODS AND RESULTS: A meta-analysis was performed by database searching until May 2021. Studies comparing BITA and SITA grafting among elderly patients were included. One randomized controlled trial, nine propensity score matching, and six unmatched studies were identified, with a total of 18 146 patients (7422 received BITA grafting and 10 724 received SITA grafting). Compared with SITA grafting, BITA grafting had a higher risk of deep sternal wound infection (DSWI) [odds ratio: 1.67; 95% confidence interval (CI): 1.22-2.28], and this risk could not be significantly reduced by the skeletonization technique. Meanwhile, BITA grafting was associated with a higher long-term survival [hazard ratio: 0.83; 95% CI: 0.77-0.90], except for the octogenarian subgroup. Reconstructed Kaplan-Meier survival curves revealed 4-year, 8-year, and 12-year overall survival rates of 85.5%, 66.7%, and 45.3%, respectively, in the BITA group and 79.3%, 58.6%, and 34.9%, respectively, in the SITA group. No significant difference was observed in early mortality, perioperative myocardial infarction, perioperative cerebral vascular accidents, or re-exploration for bleeding. CONCLUSION: Compared with SITA grafting, BITA grafting could provide a long-term survival benefit for elderly patients, although this benefit remained uncertain in octogenarians. Meanwhile, elderly patients who received BITA were associated with a higher risk of DSWI and such a risk could not be eliminated by the skeletonization technique.

Randomized evidence on graft patency after off-pump versus on-pump coronary artery bypass grafting: An updated meta-analysis.

BACKGROUND: The debate between off-pump CABG (OPCAB) and on-pump CABG (ONCAB) has been ongoing for decades. We aimed to provide a comprehensive update of the current randomized controlled trials (RCTs) in evaluating the graft patency of OPCAB versus ONCAB. MATERIALS AND METHODS: A literature search was conducted in PubMed, EMBASE, and the Cochrane Library databases until April 30, 2021. All RCTs from 2003 to 2020 comparing the results of graft patency between OPCAB and ONCAB were included. We compared the overall graft occlusion between the two groups, and subgroup analyses were conducted based on different types of conduits and target territories, crossover from off-pump to on-pump rate, and the length of follow-up. RESULTS: Sixteen RCTs were identified, with 5743 grafts in the OPCAB group and 5898 in the ONCAB group. OPCAB was associated with a higher risk of occlusion in the overall graft (RR: 1.31; 95% CI, 1.17-1.46), saphenous vein graft (SVG) (RR: 1.40; 95% CI, 1.23-1.59), grafts to left anterior descending (LAD) territory (RR: 1.52; 95% CI, 1.11-2.08) and left circumflex artery (LCX) territory (RR: 1.45; 95% CI, 1.19-1.76), while no significant difference was observed between the two groups in respect of arterial conduits and grafts to right coronary artery (RCA) territory. Furthermore, the lower crossover rate and longer length of follow-up appeared to reduce the association between OPCAB and lower graft patency. CONCLUSIONS: The current meta-analysis indicates that, compared with ONCAB, graft patency is poorer with OPCAB for overall grafts, SVG grafts, grafts to LAD and LCX territories, whereas the results remain comparable for arterial conduits and grafts to RCA territory.

Left ventricular volume change and long-term outcomes in ischaemic cardiomyopathy with or without surgical revascularisation: A post-hoc analysis of a randomised controlled trial.

Background: Whether the association between post-therapeutic left ventricular volume change and long-term outcomes in ischaemic cardiomyopathy is influenced by the performance of coronary artery bypass grafting (CABG) remains unclear. We sought to perform a post-hoc analysis of the Surgical Treatment of Ischaemic Heart Failure (STICH) trial to investigate this association in patients treated with medical therapy (MED) with or without CABG. Methods: From July 24, 2002, to May 5, 2007, 1212 patients with ischaemic cardiomyopathy were enrolled in the STICH trial (NCT00023595) from 99 sites in 22 countries, and were randomly assigned to undergo CABG plus MED or MED alone. We completed a post-hoc analysis of this trial. Patients with paired left ventricular end-systolic volume index (ESVI) measured at baseline and 4-months were included in our analysis. The association between change in ESVI from baseline to 4-months and cardiovascular mortality or all-cause mortality was assessed in MED arm and CABG plus MED arm. Findings: 523 patients were included, with 291 (55.6%) assigned to MED arm and 232 (44.4%) to CABG plus MED arm. At a 4-month follow-up, ESVI reduction was more likely to occur among patients undergoing CABG plus MED. After a median follow-up of 10.3 years, for each 26% (1- standard deviation) decrement in ESVI, it was associated with a 22% lower risk of cardiovascular mortality (HR 0.78; 95% CI, 0.65-0.94) and 19% lower risk of all-cause mortality (HR 0.81; 95% CI, 0.69-0.95) in MED arm, whereas this association was not shown in CABG plus MED arm (cardiovascular mortality: HR 0.90; 95%CI, 0.74-1.10; all-cause mortality: HR 0.93; 95%CI, 0.79-1.09). A 16% reduction in ESVI was determined to be the most appropriate threshold of change in ESVI in the MED arm. Interpretation: In patients with ischaemic cardiomyopathy, left ventricular volume change was associated with long-term prognosis after medical therapy alone, whereas was likely not an optimal benchmark for evaluating the survival benefits associated with CABG. A more than 16% reduction in ESVI might assist in therapeutic efficacy assessment and prognostic evaluation in medically treated patients. Funding: National Natural Science Foundation of China; Natural Science Funds of Guangdong Province.

Notopterol Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rat.

Introduction: Current targeted pulmonary arterial hypertension (PAH) therapies have improved lung hemodynamics, cardiac function, and quality of life; however, none of these have reversed the ongoing remodeling of blood vessels. Considering notopterol, a linear furocoumarin extracted from the root of traditional Chinese medicine Qiang-Huo (Notopterygium incisum), had shown the antiproliferative and anti-inflammatory properties in previous studies, we hypothesized that it could play a role in ameliorating PAH. Methods: In vivo, we conducted monocrotaline (MCT) induced PAH rats and treated them with notopterol for 3 weeks. Then, the rats were examined by echocardiography and RV catheterization. The heart and lung specimens were harvested for the detection of gross examination, histological examination and expression of inflammatory molecules. In vitro, human pulmonary arterial smooth muscle cells (HPASMCs) were treated with notopterol after hypoxia; then, cell proliferation was assessed by cell counting kit-8 and Edu assay, and cell migration was detected by wound healing assays. Results: We found that notopterol improved mortality rate and RV function while reducing right ventricular systolic pressure in MCT-induced PAH rats. Furthermore, notopterol reduced right ventricular hypertrophy and fibrosis, and it also eased pulmonary vascular remodeling and MCT-induced muscularization. In addition, notopterol attenuated the pro-inflammatory factor (IL-1ß, IL-6) and PCNA in the lungs of PAH rats. For the cultured HPASMCs subjected to hypoxia, we found that notopterol can inhibit the proliferation and migration of HPASMCs. Conclusion: Our studies show that notopterol exerts anti-inflammatory and anti-proliferative effects in the pulmonary arteries, which may contribute to prevention of PAH.

Mitral Valve Surgery in Patients With Rheumatic Heart Disease: Repair vs. Replacement.

Background: High morbidity and mortality caused by rheumatic heart disease (RHD) are global burdens, especially in low-income and developing countries. Whether mitral valve repair (MVP) benefits RHD patients remains controversial. Thus, we performed a meta-analysis to compare the perioperative and long-term outcomes of MVP and mitral valve replacement (MVR) in RHD patients. Methods and Results: A systematic literature search was conducted in major databases, including Embase, PubMed, and the Cochrane Library, until 17 December 2020. Studies comparing MVP and MVR in RHD patients were retained. Outcomes included early mortality, long-term survival, freedom from reoperation, postoperative infective endocarditis, thromboembolic events, hemorrhagic events, and freedom from valve-related adverse events. Eleven studies that met the inclusion criteria were included. Of a total of 5,654 patients, 1,951 underwent MVP, and 3,703 underwent MVR. Patients who undergo MVP can benefit from a higher long-term survival rate (HR 0.72; 95% CI, 0.55-0.95; P = 0.020; I 2 = 44%), a lower risk of early mortality (RR 0.62; 95% CI, 0.38-1.01; P = 0.060; I 2 = 42%), and the composite outcomes of valve-related adverse events (HR 0.60; 95% CI, 0.38-0.94; P = 0.030; I 2 = 25%). However, a higher risk of reoperation was observed in the MVP group (HR 2.60; 95% CI, 1.89-3.57; P<0.001; I 2 = 4%). Patients who underwent concomitant aortic valve replacement (AVR) in the two groups had comparable long-term survival rates, although the trend still favored MVP. Conclusions: For RHD patients, MVP can reduce early mortality, and improve long-term survival and freedom from valve-related adverse events. However, MVP was associated with a higher risk of reoperation. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=228307.

Association of Post-operative Systolic Blood Pressure Variability With Mortality After Coronary Artery Bypass Grafting.

Background: Blood pressure variability (BPV) has long been considered a risk factor for cardiovascular events. We aimed to investigate whether post-operative systolic BPV was associated with early and late all-cause mortality in patients undergoing coronary artery bypass grafting (CABG). Methods: Clinical variables and blood pressure records within the first 24 h in the post-operative intensive care unit stay from 4,509 patients operated on between 2001 and 2012 were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. BPV was measured as the coefficient of the variability of systolic blood pressure, and we compared patients in the highest quartile with patients in the other three quartiles. Results: After full adjustment, patients in the highest quartile of BPV were at a higher risk of intensive care unit mortality (OR = 2.02, 95% CI: 1.11-3.69), 30-day mortality (OR = 1.92, 95% CI: 1.22-3.02), and 90-day mortality (HR = 1.64, 95% CI: 1.19-2.27). For 2,892 patients with a 4-year follow-up, the association between a higher post-operative BPV and the risk of 4-year mortality was not significant (HR = 1.17, 95% CI: 0.96-1.42). The results were supported by the comparison of survival curves and remained generally consistent in the subgroup analyses and sensitivity analyses. Conclusions: Our findings demonstrated that in patients undergoing CABG, a higher post-operative BPV was associated with a higher risk of early mortality while the association was not significant for late mortality. Post-operative BPV can support doctors in identifying patients with potential hemodynamic instability and making timely clinical decisions.

Preoperative serum albumin: a promising indicator of early mortality after surgery for infective endocarditis.

BACKGROUND: Despite novel improvements in the diagnosis and treatment of infective endocarditis (IE), there has been no significant improvement in the survival rate of IE, which indicates that many details still need to be optimized in the preoperative assessment. We sought to evaluate preoperative serum albumin as a biomarker for predicting early mortality after IE surgery. METHODS: Between October 2013 and June 2019, patients with a definite diagnosis of IE were enrolled in this study. Patients' albumin levels at admission were used as the preoperative albumin levels. Restricted cubic spline and multivariate logistic regression analyses were performed to evaluate the relationship between albumin and early mortality. Receiver operating characteristic curve analyses were performed to assess the role of albumin in predicting early mortality and compare the predictive capacity of traditional models with models that included albumin. RESULTS: Of the 276 IE patients, 20 (7.2%) died in hospital or within 30 days of surgery. Hypoalbuminemia (an albumin level <3.5 g/dL) was present in 109 (39.5%) patients. The multivariate logistic regression analysis showed that preoperative albumin was inversely associated with early mortality [adjusted odds ratio (OR) =0.22 per 1 g/dL, 95% confidence interval (CI): 0.07-0.65, P=0.006] after full adjustment. Preoperative albumin had value in predicting early mortality [area under the curve (AUC) =0.72, 95% CI: 0.61-0.84; P<0.01]. After adding albumin to the European System for Cardiac Operative Risk Evaluation (EuroSCORE) and Charlson score, the predictive ability of the model was further improved (EuroSCORE II: AUC =0.55; 95% CI: 0.42-0.67 to AUC =0.72; 95% CI: 0.61-0.84; Charlson score: AUC =0.73; 95% CI: 0.64-0.83 to AUC =0.78; 95% CI: 0.68-0.88). CONCLUSIONS: Preoperative serum albumin is inversely associated with early mortality after IE surgery, and is a promising prognostic indicator in preoperative risk stratification assessments of IE patients.