Risk factors of preoperative myocardial injury in patients with gastrointestinal tumors.

BACKGROUND: Recent studies indicated that the prognosis of patients with gastrointestinal tumors is frequently influenced by its complications, notably myocardial injury. The main object is to investigate the occurrence and risk factors of myocardial injury in patients with gastrointestinal tumor. METHODS: 1126 patients who received gastrointestinal tumor related surgery from May 2018 to June 2020 in the Sixth Affiliated Hospital of Sun Yat-sen University were retrospectively collected and divided into the non-myocardial injury group and the myocardial injury group (high-sensitive cardiac troponin I (hs-cTnI) ≥ 0.028 ng/ml). The occurrence and risk factors of myocardial injury in patients with gastrointestinal tumor are analyzed. The influence of myocardial injury on the ICU detention time in gastrointestinal tumor patients is also studied. RESULTS: In total, 78 (6.93%) patients developed myocardial injuries. Compared with patients in the non-myocardial injury group, patients in the myocardial injury group have a higher prevalence of cardiovascular risk factors (including advanced age and higher smoking ratio), a higher prevalence of comorbidities (such as previous coronary artery disease, hypertension, atrium fibrillation and diabetes), and a higher rate of premedication (such as anticoagulation, ß-blocker, Angiotensin-converting enzyme inhibitor/Angiotensin II receptor blocker, and diuretic) (all with P-value < 0.05). In addition, patients in the myocardial injury group also presented with a higher revised cardiac risk index (Lee index), higher neutrophil granulocyte ratio, lower hemoglobin, and higher likelihood of impaired cardiac structure and function (all with P-value < 0.05). There was a trend of statistical significance in the ICU detention time between the myocardial injury group and the non-myocardial injury group (1[1,3] vs. 2[1,10], P = 0.064). In this study, there were 7 patients presented with clinical symptoms in the myocardial injury group (chest discomfort in 4 cases, non-compressive precordial chest pain in 1 case, dyspnea in 2 cases). In the multivariate analysis, advanced age, increased Lee index score, increased neutrophil granulocyte ratio, decreased left ventricular ejection fraction (LVEF), increased interventricular septum were independent risk factors for myocardial injury. CONCLUSION: In conclusion, advanced age, increased Lee index, increased neutrophil granulocyte ratio, decreased left ventricular ejection fraction, and increased ventricular septum were independent risk factors for preoperative myocardial injury in patients with gastrointestinal tumors. The proportion of clinical symptoms in gastrointestinal tumor patients with myocardial injury was low, indicating the necessity to closely monitor the cardiac status of individuals with gastrointestinal tumors.

Efficacy and Safety of Statins for Pulmonary Hypertension: A Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: Pulmonary hypertension (PH) is a serious disease, and treatment is a continuing challenge. Some in vitro and in vivo studies identified that statins were effective for PH. However, results of some randomised controlled trials (RCTs) have been controversial. The objective of our study was to clarify whether statins are effective and safe for pulmonary hypertension. METHODS: We systematically searched for eligible RCTs from PubMed, EMBASE, Web of Science, and the Cochrane Library during January 2016. Two reviewers independently extracted data. Standard mean differences (SMDs) and weighted mean differences (WMDs) with 95% confidence intervals (CIs) were estimated for continuous data (exercise capacity cardiac, pulmonary arterial pressure (PAP), cardiac index, and low-density lipoprotein (LDL)). Risk ratios (RRs) were estimated for dichotomous data (adverse events and clinical deterioration). RESULTS: A total of 496 patients from six RCTs were included. Low-density lipoprotein in the statin group decreased significantly compared with the placebo group (WMD = -22.79; 95% CI: -34.33 ∼ -11.24). However, we did not find a statistically significant effect on exercise capacity (SMD = 0.18; 95% CI: -0.34 - 0.71), PAP (WMD = -3.01; 95% CI: -8.68 - 2.65), or CI (WMD = -0.04; 95% CI: -0.15 - 0.23). Additionally, there was no difference between statins and placebo with respect to hepatic injury (RR: 1.12; 95% CI: 0.43 - 2.92), myalgia (RR: 0.81; 95% CI: 0.32 - 2.03), or clinical deterioration (RR: 0.98; 95% CI: 0.58 - 1.67). CONCLUSIONS: Statin treatment appears to be safe but may have no effect on PH.

Prognostic relevance of ventricular arrhythmias in surgical patients with gastrointestinal tumors.

BACKGROUND: Individuals diagnosed with gastrointestinal tumors are at an increased risk of developing cardiovascular diseases. Among which, ventricular arrhythmia is a prevalent clinical concern. This suggests that ventricular arrhythmias may have predictive value in the prognosis of patients with gastrointestinal tumors. AIM: To explore the prognostic value of ventricular arrhythmias in patients with gastrointestinal tumors receiving surgery. METHODS: We retrospectively analyzed data from 130 patients undergoing gastrointestinal tumor resection. These patients were evaluated by a 24-h ambulatory electrocardiogram (ECG) at the Sixth Affiliated Hospital of Sun Yat-sen University from January 2018 to June 2020. Additionally, 41 general healthy age-matched and sex-matched controls were included. Patients were categorized into survival and non-survival groups. The primary endpoint was all-cause mortality, and secondary endpoints included major adverse cardiovascular events (MACEs). RESULTS: Colorectal tumors comprised 90% of cases. Preoperative ambulatory ECG monitoring revealed that among the 130 patients with gastrointestinal tumors, 100 (76.92%) exhibited varying degrees of premature ventricular contractions (PVCs). Ten patients (7.69%) manifested non-sustained ventricular tachycardia (NSVT). The patients with gastrointestinal tumors exhibited higher PVCs compared to the healthy controls on both conventional ECG [27 (21.3) vs 1 (2.5), P = 0.012] and 24-h ambulatory ECG [14 (1.0, 405) vs 1 (0, 6.5), P < 0.001]. Non-survivors had a higher PVC count than survivors [150.50 (7.25, 1690.50) vs 9 (0, 229.25), P = 0.020]. During the follow-up period, 24 patients died and 11 patients experienced MACEs. Univariate analysis linked PVC > 35/24 h to all-cause mortality, and NSVT was associated with MACE. However, neither PVC burden nor NSVT independently predicted outcomes according to multivariate analysis. CONCLUSION: Patients with gastrointestinal tumors exhibited elevated PVCs. PVCs > 35/24 h and NSVT detected by 24-h ambulatory ECG were prognostically significant but were not found to be independent predictors.

The association of preoperative high-sensitivity cardiac troponin i and long-term outcomes in colorectal cancer patients received tumor resection surgery.

BACKGROUND: This study aimed to evaluate the association between preoperative hs-cTnI and long-term mortality and major adverse cardiovascular events (MACE) in colorectal cancer patients. METHODS: This single-center retrospective cohort study included 1105 consecutive colorectal cancer patients who received tumor resection surgery between January 2018 and June 2020. Inclusion criteria were an age ≥ 18 years and had been tested for hs-cTnI on admission within 7 days prior to tumor resection surgery. Exclusion criteria were emergent surgery, failure to received tumor resection surgery, hospital death, there was clinical evidence of unstable coronary artery disease or pulmonary embolism occurred before operation according to medical record. The primary endpoint was all-cause death. Secondary endpoint was major adverse cardiovascular events (MACE). RESULTS: A total of 1105 patients were enrolled: 1032 with normal hs-cTnI and 73 with elevated hs-cTnI. The mean follow-up was 24.4 ± 10.8 months, 176 patients died and 39 patients met MACE. In the elevated troponin group, 50%, 32.1% and 17.9% died from cancer, cardiovascular and other causes, while those in the normal troponin group were 75.7%, 2% and 22.3%, there was statistical difference between 2 groups (P < 0.001). Patients with elevated preoperative hs-cTnI had significantly higher mortality (P < 0.001) and more MACE (P < 0.001) compared with those with normal hs-cTnI. A propensity-matching analysis were performed, resulting in 151 patients with normal hs-cTnI and 60 patients with elevated hs-cTnI. The matched population had the similar results for all-cause death (P = 0.009) and MACE (P = 0.001). The results were consistent after further excluding 147 patients who had received chemoradiotherapy prior to surgery in subgroup analysis. The results of multivariate Cox regression analysis shown that hs-cTnI was one of the best predictors for all-cause death (hazard ratio [HR] 2.278; 95% confidence interval [CI] 1.19-4.361) and MACE (HR, 3.523; 95%CI, 1.477-8.403) in total populations, similar results were found in subgroup analysis. CONCLUSIONS: Colorectal cancer patients without myocardial ischemia manifestation but with elevated hs-cTnI prior to tumor resection surgery were at increased risk for long-term all-cause death and MACE, irrespective of whether they have received chemoradiotherapy prior to surgery.

Adenovirus-mediated expression of hypoxia-inducible factor 1α double mutant converts neonatal cardiac fibroblasts into (cardio)myocyte phenotype.

Adenovirus-mediated expression of hypoxia-inducible factor 1α double mutant (pAd-HIF-1α-Ala564-Ala803) can be effectively transfected into bone marrow stem cells (MSCs) in the MSCs and cardiomyocytes co-culture system at normoxia to regulate the expression of downstream target genes of hypoxia-inducible factor 1α (HIF-1α), which in turn can promote MSC differentiation into cardiomyocytes. Fibroblasts share common characteristics with MSCs such as the morphology, phenotype and differentiation potential. Therefore, we further studied whether the pAd-HIF-1α-Ala564-Ala803 also can convert neonatal rat cardiac fibroblasts (NCFs) into (cardio)myocyte phenotype via regulating the downstream target genes of HIF-1α at normoxia. The immunostaining analysis showed that NCFs treated with pAd-HIF-1α-Ala564-Ala803 exhibited higher protein expression levels of smooth muscle α-actin (SMA, myocyte marker) and cardiac troponin T (cTnT, cardiomyocyte marker), compared with phosphate-buffered saline and pAd-LacZ treatments. The reverse transcription-polymerase chain reaction results showed that NCFs transfected with pAd-HIF-1α-Ala564-Ala803 augmented messenger RNA (mRNA) expression of transforming growth factor-ß1 (TGF-ß1), Smad4, NKx2.5, GATA4, myocardin, SMA and cTnT. The effects of HIF-1α-Ala564-Ala803 on NCFs were attenuated by pre-transfection of TGF-ß1 or myocardin small interference RNAs. Adult CFs transfected with pAd-HIF-1α-Ala564-Ala803 showed a lower protein expression of SMA but not cTnT without any change in the mRNA expression level of NKx2.5, myocardin. Therefore, NCFs but not adult CFs possess a similar differentiation potential to MSCs as evidenced by the fact that pAd-HIF-1α-Ala564-Ala803 can convert NCFs into (cardio)myocyte phenotype via regulating its downstream target genes.

The therapeutic effect and mechanism of Rapamycin combined with HO-3867 on monocrotaline-induced pulmonary hypertension in rats.

This study test was designed to investigate the possible modulatory effect of rapamycin combined with HO-3867 in monocrotaline(MCT)-induced pulmonary arterial hypertension in rats. We hypothesized that combined treatment with rapamycin and HO-3867 is superior to either alone in attenuating MCT-induced rat pulmonary arterial hypertension (PAH). Pulmonary arterial hypertension was induced by a single intraperitoneal injection of monocrotaline (60 mg/kg). 2 weeks later, rapamycin (2 mg/kg i.p.) and HO3867 (10 mg/kg i.h.) were administered daily, alone and in combination, for 2 weeks. Right ventricular systolic pressure, echocardiography were recorded and then rats were sacrificed. Histological analysis of pulmonary arteries medial wall thickness, right ventricular hypertrophy index (RVHI), the ratio of right ventricular to body weight, and collagen volume fraction (CVF) of right ventricular were performed. Moreover, the expression of t-STAT3, p-STAT3, t-Akt, p-Akt in lung and t-STAT3, p-STAT3, t-S6, p-S6 in right ventricular were examined. The result showed that combined treatment provided a considerable improvement toward maintaining hemodynamic changes, lung vascular remodeling as well as amending RV remodeling and function. Furthermore, Combined treatment can normalize the protein levels of two signal pathways in lung and heart tissue, where p-S6 or p-Akt significantly decreased compared to HO-3867 alone, or p-STAT3 significantly reduced compared to rapamycin alone. In conclusion, combined treatment with rapamycin and HO-3867 is superior to either alone in attenuating MCT-induced PAH in rats.

The predictive value of high-sensitive troponin I for perioperative risk in patients undergoing gastrointestinal tumor surgery.

BACKGROUND: The incidence of cardiovascular events in perioperative period of gastrointestinal tumor surgery cannot be ignored, and studies have shown that level of postoperative troponin is related to the postoperative risk of non-cardiac surgery. However, the relationship between pre-operative troponin levels and perioperative risk of gastrointestinal tumor surgery is unclear. Thus, we aimed to evaluate the value of high-sensitive cardiac troponin I (hs-cTnI) prior to gastrointestinal tumor surgery for perioperative risk assessment. METHODS: In this retrospective cohort study, 1259 patients who underwent gastrointestinal tumor surgery and had been tested for hs-cTnI on admission within 7 days prior to surgery were retrospectively recruited from January 2018 to June 2020. The primary combined endpoint including in-hospital all-cause mortality, acute myocardial infarction, cardiac arrest or ventricular fibrillation and acute decompensated heart failure. The secondary endpoint included total hospital stay and requirement of intensive care treatment. FINDINGS: Compared with patients with normal hs-cTnI, those with elevated hs-cTnI (> 0·028 ng/ml) were more likely to experience the combined endpoint (28·2% versus 2·7%, P < 0·001) and there was also an increasing rate of in mortality in elevated hs-cTnI group (2·4% versus 0·3%, P = 0·057). The length of total hospital stay was significantly longer in patients with elevated hs-cTnI (24·8 ± 16·3 versus 19·5 ± 7·9, P = 0·003) and the number of patients requiring intensive care treatment was also higher (22·6% versus 4·2%, P < 0·001). The area under the ROC curve assessing hs-cTnI in predicting in-hospital mortality was 0·787 [95% confidence interval (CI) 0·612-0·963, P = 0·015] and for combined endpoint was 0·822 [95% CI 0·766-0·879, P < 0·001]. Hs-cTnI > 0·028 ng/ml was associated with significantly higher cardiovascular event rate in patients with the revised cardiac index ≤ 1. The positive likelihood ratio of hs-cTnI (> 0·028 ng/ml) for predicting combined endpoint reaches 10.5 in patients with Lee index = 0. In multivariate logistic analyses, hs-cTnI was one of the best predictors for the combined endpoint [odds ratio (OR) 5·924 (95%CI: 2·869-12·233), P < 0·001]. INTERPRETATION: Hs-cTnI provides powerful prognostic information for patients undergoing gastrointestinal tumor surgery, and therefore provides reliable prognostic information incremental to revised cardiac index.

[Effects of a recombinant adenovirus expressing human hypoxia-inducible factor 1α double-mutant on the in vitro differentiation of bone marrow mesenchymal stem cells to cardiomyocytes].

OBJECTIVE: To observe the effects of mutant hypoxia-inducible factor-1α (HIF-1α) adenovirus (Adeno-HIF-1α-Ala402-Ala564) on cardiomyocytes (CMCs) differentiation from the mesenchymal stem cells (MSCs) co-cultured with CMCs. METHODS: Following groups were studied: HIF-1α group (MSCs + CMCs + Ad-HIF-1α), LacZ group (MSCs + CMCs + Ad-LacZ), Sham group (MSCs + CMCs + PBS) and MSC + HIF-1α Group (MSCs + Ad-HIF-1α). MSCs were co-cultured with myocardial cells in proportion of MSCs:CMCs 1:2, after 24 hours, cells were infect with virus (MOI = 100) or treated with PBS, cardiac troponin (cTnT) expression in MSCs was detected 7 days post infection by immunochemical analysis, mRNA expression of HIF-1α, TGF-ß(1), Smad4, NKx2.5, GATA-4 was also detected by RT-PCR. RESULTS: HIF-1α increased MSCs differentiation to myocardial cells (differentiation rate 32.68% ± 6.52% vs. 8.28% ± 0.09% in the LacZ group and 10.25% ± 2.20% in the Sham group and 0.32% ± 0.05% in the MSC group (all P < 0.05 vs. HIF-1α group). mRNA expression of HIF, TGF-ß(1), Smad4, NKx2.5 and GATA-4 was also significantly upregulated in HIF-1α group all P < 0.05 vs. Sham group). CONCLUSION: HIF-1α promoted MSCs, co-cultured with myocardial cells, differentiating to cardiomyocytes via upregulating TGF-ß(1)/Smad4 signaling pathway.

Dehydroepiandrosterone attenuates pulmonary artery and right ventricular remodeling in a rat model of pulmonary hypertension due to left heart failure.

AIM: Pulmonary hypertension due to left heart failure (PH-LHF) is the most common cause of pulmonary hypertension. However, therapies for PH-LHF are lacking. Therefore, we investigated the effects and potential mechanism of dehydroepiandrosterone (DHEA) treatment in an experimental model of PH-LHF. MAIN METHOD: PH-LHF was induced in rats via ascending aortic banding. The rats then received daily DHEA from Day 1 to Day 63 for the prevention protocol or from Day 49 to Day 63 for the reversal protocol. Other ascending aortic banding rats were left untreated to allow development of PH and right ventricular (RV) failure. Sham ascending aortic banding rats served as controls. KEY FINDING: Significant increases in mean pulmonary arterial pressure (mPAP) and right ventricular end-diastolic diameter (RVEDD) were observed in the PH-LHF group. Therapy with DHEA prevented LHF-induced PH and RV failure by preserving mPAP and preventing RV hypertrophy and pulmonary artery remodeling. In preexisting severe PH, DHEA attenuated most lung and RV abnormalities. The beneficial effects of DHEA in PH-LHF seem to result from depression of the STAT3 signaling pathway in the lung. SIGNIFICANT: DHEA not only prevents the development of PH-LHF and RV failure but also rescues severe preexisting PH-LHF.

The Effects and Mechanism of Atorvastatin on Pulmonary Hypertension Due to Left Heart Disease.

BACKGROUND: Pulmonary hypertension due to left heart disease (PH-LHD) is one of the most common forms of PH, termed group 2 PH. Atorvastatin exerts beneficial effects on the structural remodeling of the lung in ischemic heart failure. However, few studies have investigated the effects of atorvastatin on PH due to left heart failure induced by overload. METHODS: Group 2 PH was induced in animals by aortic banding. Rats (n = 20) were randomly divided into four groups: a control group (C), an aortic banding group (AOB63), an atorvastatin prevention group (AOB63/ATOR63) and an atorvastatin reversal group (AOB63/ATOR50-63). Atorvastatin was administered for 63 days after banding to the rats in the AOB63/ATOR63 group and from days 50 to 63 to the rats in the AOB63/ATOR50-63 group. RESULTS: Compared with the controls, significant increases in the mean pulmonary arterial pressure, pulmonary arteriolar medial thickening, biventricular cardiac hypertrophy, wet and dry weights of the right middle lung, percentage of PCNA-positive vascular smooth muscle cells, inflammatory infiltration and expression of RhoA and Rho-kinase II were observed in the AOB63 group, and these changes concomitant with significant decreases in the percentage of TUNEL-positive vascular smooth muscle cells. Treatment of the rats in the AOB63/ATOR63 group with atorvastatin at a dose of 10 mg/kg/day significantly decreased the mean pulmonary arterial pressure, right ventricular hypertrophy, pulmonary arteriolar medial thickness, inflammatory infiltration, percentage of PCNA-positive cells and pulmonary expression of RhoA and Rho-kinase II and significantly augmented the percentage of TUNEL-positive cells compared with the AOB63 group. However, only a trend of improvement in pulmonary vascular remodeling was detected in the AOB63/ATOR50-63 group. CONCLUSIONS: Atorvastatin prevents pulmonary vascular remodeling in the PH-LHD model by down-regulating the expression of RhoA/Rho kinase, by inhibiting the proliferation and increasing the apoptosis of pulmonary arterial smooth muscle cells, and by attenuating the inflammation of pulmonary arteries.

Adenovirus-mediated hypoxia-inducible factor 1alpha double-mutant promotes differentiation of bone marrow stem cells to cardiomyocytes.

The hypoxia-inducible factor 1alpha (HIF-1alpha) regulates transcriptional genes involved in cell proliferation, survival, and differentiation. Under normoxia, HIF-1alpha has a short half-life (t((1/2)) approximately 5 min) and low transcriptional activity. An HIF-1alpha mutant, produced by substitution of alanine (Ala) for proline (Pro) at position 564 and asparagine (Asp) at position 803, can prevent HIF-1alpha hydroxylation and results in a highly active form of HIF-1alpha (HIF-1alpha-Ala564-Ala803). We hypothesized that adenovirus (Ad)-mediated transfer of the active form of HIF-1alpha (pAd-HIF-1alpha-Ala564-Ala803) could effectively occur in bone marrow stem cells (MSCs) and promote MSC differentiation under normoxia. PCR-based site-specific mutagenesis was used to construct the Ad vector expressing HIF-1alpha-Ala564-Ala803. RT-PCR and immunostaining were used to study whether pAd-HIF-1alpha-Ala564-Ala803 affected MSC differentiation to cardiomyocyte (CMC). pAd-HIF-1alpha-Ala564-Ala803 exhibited higher transcriptional activity and stable HIF-1alpha protein expression. Under normoxia, an MSC-CMC co-culture treated with pAd-HIF1a-Ala564-Ala803 augmented TGF-beta(1), Smad4, NKx2.5, and GATA4 expression. Higher expression of cTnT and alpha-actinin was observed by immunostaining in MSCs, compared with the control and contrast groups. Adenovirus-mediated hypoxia-inducible factor 1alpha double-mutant, pAd-HIF-1alpha-Ala564-Ala803, can stably express HIF-1alpha and promote its downstream genes and MSC differentiation to CMC in the MSC-CMC co-culture system under normoxia.

Bone marrow derived stromal cells modified by adenovirus-mediated HIF-1alpha double mutant protect cardiac myocytes against CoCl2-induced apoptosis.

Bone marrow derived stromal cells (MSCs) can prevent the apoptosis of ischemic cardiomyocytes (CMCs). This anti-apoptosis activity may be related to an activation of the HIF-1alpha signal pathway in MSCs. Therefore, we investigated protective effects of an adenovirus (Ad)-mediated active form of HIF-1alpha (HIF-1alpha-Ala564-Ala803) modified MSCs on CMCs against CoCl(2)-induced apoptosis. At normoxia, pAd-HIF1alpha-Ala564-Ala803 exhibited a stable HIF-1alpha protein expression in MSCs. Compared with the single CMC culture, the TGF-beta1 level and the Bcl-2 expression were significantly increased, concomitant with a reduced expression of caspase-3, the LDH release and TUNEL-positive CMCs in CMC and MSC, beta-galactosidase (LacZ)-MSC or HIF-1alpha-Ala564-Ala803-MSC coculture exposed to CoCl(2). Furthermore, these effects were more prominent in CMC and HIF-1alpha-Ala564-Ala803-MSC coculture than in CMC and MSC or LacZ-MSC coculture exposed to CoCl(2). Pre-transfection of TGF-beta1-small interfering RNA (siRNA) effectively inhibited the TGF-beta1 level, resulting in a dramatic reduction in the Bcl-2 expression as well as an increased level of apoptosis in CMC and HIF-1alpha-Ala564-Ala803-MSC coculture exposure to CoCl(2), whereas pre-transfection of green fluorescent protein (GFP)-siRNA had no such effects. These data suggest that HIF1alpha-Ala564-Ala803 modified MSCs have better protective effects of CMCs against the CoCl(2)-induced apoptosis and these protective effects are at least partly TGF-beta1-mediated.