Impact of empagliflozin on peak oxygen uptake in HFmrEF patients: a randomized controlled trial / 中华心血管病杂志

Objective: To evaluate the impact of empagliflozin on peak oxygen uptake (VO2peak) in patients with heart failure with mildly reduced ejection fraction (HFmrEF). Methods: In this randomized controlled trial, consecutive HFmrEF patients admitted to the Department of Cardiology of China-Japan Friendship Hospital from September 2019 to October 2020 were screened, and randomly assigned to empagliflozin group (EG) or conventional group (CG) using a random number table. The enrolled patients were treated according to the guidelines, and patients in the empagliflozin group received additional empagliflozin (10 mg, once a day, orally) on top of the conventional treatment. The primary end points were VO2peak at 6 months after treatment, and the secondary end points included other parameters of cardiopulmonary exercise test (CPET), 6-minute walking distance, N-terminal B-type pro-natriuretic peptide (NT-proBNP) level, and Kansas City Cardiomyopathy Questionnaire (KCCQ) score. Results: A total of 112 patients were included (mean age 69 (57, 78) years, 84 male (75.0%)). There were 55 cases in CG group and 57 cases in EG group. There were no significant differences in baseline data including age, sex, body mass index, left ventricular ejection fraction, systolic blood pressure, heart rate, estimated glomerular filtration rate, glycosylated hemoglobin, hemoglobin, NT-proBNP, daily dose of tolasemi, combined medication, CPET parameters, the proportion of New York Heart Association heart function Ⅲ/Ⅳ, history of coronary heart disease, history of hypertension, history of diabetes (all P>0.05). At 6 months after treatment, VO2peak was significantly higher in EG group than in CG group(P=0.023). VE/VCO2 slope was significantly lower in EG group than in CG group(P=0.034). Oxygen uptake efficiency slope was significantly higher in EG group than in CG group(P=0.038). The level of NT-proBNP was significantly lower in EG group than in CG group(P=0.020). Six-minute walking distance was significantly higher in EG group than in CG group(P=0.037). KCCQ score was significantly higher in EG group than in CG group(P=0.048). Exercise oscillatory ventilation decreased in both groups (1 case in each group, P>0.05). Conclusion: Empagliflozin can significantly improve VO2peak in patients with HFmrEF.

Meta-analysis on efficacy of PCI treatment or conservative treatment among patients with chronic total occlusions / 中华心血管病杂志

Objective: To compare the efficacy between percutaneous coronary intervention (PCI) and conservative medication treatment in chronic total occlusions (CTO) patients. Methods: It was a meta-analysis.Articles on drug therapy and PCI for complete coronary artery occlusion were retrieved from Pubmed, Embase and Web of Science databases. The search time was from the database construction to May 10, 2020, and the following search criteria were used for the search "chronic total occlusion" "percutaneous coronary intervention" and "medical therapy". References from searched literatures were also searched to identify more eligible studies. Randomized controlled trials (RCT) and cohort studies comparing efficacy of PCI versus oral medication as well as medication as initial therapy option for CTO patients with single or multiple lesions were included. The primary endpoints included all-cause death, cardiac death, recurrent myocardial infarction, re-revascularization, major adverse cardiac events (MACE) and stroke. Data were analyzed with ReviewManager5.3.0 software. Pooled effect size RR and 95%CI were calculated by randomization effect model. Heterogeneity was evaluated by I2. Bege test was used to evaluate publication bias. Subgroup analyses were performed for RCT and cohort studies. Results: A total of 1 079 articles were retrieved and 16 studies (RCT=4, cohort study=12) were included with 12 223 patients. Fourteen publications (RCT=4, cohort study=10) reported all-cause death post PCI and/or drug therapy. Results showed that risk of all-cause death was significantly lower in PCI group than in drug therapy group (RR=0.45,95%CI 0.39-0.53,P<0.001);subgroup analysis showed that risk of all-cause death was significantly lower in PCI group than in drug therapy group from cohort studies (RR=0.44,95%CI 0.38-0.52,P<0.001),but comparable in RCT (P=0.27). Thirteen studies (RCT=3, cohort study=10) reported cardiac death post PCI and/or drug therapy. Results showed that risk of cardiac death was significantly lower in PCI group than in drug therapy group (RR=0.44,95%CI 0.35-0.55,P<0.001);subgroup analysis showed that risk of cardiac death was significantly lower in PCI group than in drug therapy group in cohort studies (RR=0.43,95%CI 0.34-0.54,P<0.001),but not in RCT (P=0.25). Fourteen publications (RCT=4, cohort study=10) reported recurrent myocardial infarction post PCI and/or drug therapy. Results showed that risk of recurrent myocardial infarction was significantly lower in PCI group than in drug therapy group (RR=0.62,95%CI 0.44-0.88,P=0.007);subgroup analysis showed that risk of recurrent myocardial infarction was significantly lower in PCI group than in drug therapy group from cohort studies (RR=0.56,95%CI 0.40-0.78,P=0.000 5),but comparable in RCT (P=0.17). Fourteen publications (RCT=4, cohort study=10) reported re-revascularization post PCI and/or drug therapy. Results showed that risk of re-revascularization was comparable between PCI group and drug therapy group (P=0.91);subgroup analysis showed that risk of re-revascularization was comparable between PCI group and drug therapy group both in cohort study and RCT (P=0.60 and 0.41, respectively). Eleven publications (RCT=3, cohort study=8) reported MACE post PCI and/or drug therapy. Results showed that risk of MACE was significantly lower in PCI group than in drug therapy group (RR=0.74,95%CI 0.59-0.93,P=0.03);subgroup analysis showed that risk of MACE was significantly lower in PCI group than in drug therapy group in cohort studies (RR=0.72,95%CI 0.56-0.93,P=0.01), but not in RCT (P=0.8). Six publications (RCT=2, cohort study=4) reported stroke post PCI and/or drug therapy. Results showed that risk of stroke was comparable between PCI and drug therapy groups (RR=0.62,95%CI 0.32-1.20, P=0.15);subgroup analysis showed that risk of stroke was comparable between PCI and drug therapy groups both in cohort studies and RCT (P=0.48 and 0.32, respectively). Conclusion: Compared with oral drug therapy, PCI may have better efficacy for CTO patients based on results from this cohort study.

Effects of alprostadil in β-aminopropanitrile induced aortic dissection in a murine model / 中华心血管病杂志

Objective: To investigate the protective role of alprostadil on aortic dissection. Methods: 26 C57BL6 male mice were divided into control group (normal drinking water, n=13) and model group (1 g·kg-1·d-1 BAPN via drinking water, n=13). On day 14, mRNA expression of inflammatory-related genes as well as EP receptor families were detected by RT-PCR (n=6 each) and EP4 protein levels were determined by Western blot (n=7 each). Another 88 mice were divided into 3 groups: control group (n=22), model group (n=33) and treatment group (n=33). The mice in model group and treatment group were applied with BAPN (1 g·kg-1·d-1) via drinking water. The mice in treatment group received additional intraperitoneal injection with alprostadil (80 μg·kg-1·d-1) for 28 days. The mice in the control and model group received equal volume intraperitoneal injection with 0.9% saline respectively. The body weight and systolic blood pressure, the mortality and morbidity were monitored from the beginning until the designed end of the study. On day 28, the mice were sacrificed and aorta were fixed, embedded and sliced, followed by staining with HE and Victoria Blue. The distribution of EP4 was determined by immunohistochemistry in control (n=6) and model group (n=6). Furthermore, the concentration of PGE1 were tested among model (n=3) and treatment group (n=4). EP4 protein expression was determined in model group (n=7) and treatment group (n=6). Results: On day 14, mRNA expression level of MCP-1 ((2.74±1.55) vs. (1.00±0.49),<0.05) and MMP2((1.38±0.42) vs. (1.00±0.27), P<0.05) was significantly upregulated in model group compared with control group. Protein expression of EP4 receptor also increased in aorta in model group compared with control group (1.48±0.51 vs. 1.00±0.19, P<0.05). In the dissection area, the EP4 expression was also enriched compared with non-dissection area, particularly in endothelial cells and inflammatory cells on day 28. BAPN applied in drinking water (model and treatment groups) successfully induced the aortic dissection in mice, some mice died of the rupture. The elastic fibers were fractured, and the infiltrated immune cells were visible in dissected tissue. False lumen was formed. There was no dissection and death in the control group. Compared with control group, the morbidity and mortality rates were significantly increased in the model group (60.6%, 20/33, 30.3%, 10/33) and the treatment group (72.7%, 24/33, 24.2%, 8/33). The mortality and morbidity rates were similar between model and treatment groups. There is no difference in terms of SBP among three groups (P>0.05). Further study showed that after alprostadil injection, the blood concentration of PGE1 was increased in treatment group ((0.540±0.041 vs. 0.436±0.012)μmol/L, P<0.05). Besides, the EP4 receptor expression was downregulated in the treatment group compared to model group (0.60±0.30 vs. 1.00±0.20, P<0.05). Conclusion: EP4 expression is upregulated in BAPN induced aortic dissection mouse model. No protective effects are observed post alprostadil treatment in this model probably due to the reduced expression of EP4.

Effect of Dialysis on Antiplatelet Drug Efficacy in Uremic Patients with Coronary Heart Disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Coronary intervention therapy is the main treatment for uremic patients with coronary heart disease. The studies on whether dialysis reduces the efficacy of dual antiplatelet drugs are limited. The aim of this study was to examine the effect of dialysis on antiplatelet drugs in uremic patients with coronary heart disease.</p><p><b>METHODS</b>This study included 26 uremic patients who had undergone percutaneous coronary intervention in China-Japan Friendship Hospital from November 2015 to May 2017. We examined their thromboelastography results before and after hemodialysis. Self-paired t-tests were employed to analyze changes in the inhibition rate of platelet aggregation.</p><p><b>RESULTS</b>The mean inhibition rates of arachidonic acid-induced platelet aggregation before and after hemodialysis were 82.56 ± 2.79% and 86.42 ± 3.32%, respectively (t= -1.278, P= 0.213). The mean inhibition rates of adenosine diphosphate-induced platelet aggregation before and after hemodialysis were 67.87 ± 5.10% and 61.94 ± 5.90%, respectively (t = 1.425, P= 0.167). There was no significant difference in the inhibition rates of platelet aggregation before or after hemodialysis. These results also applied to patients with different sensitivity to aspirin and clopidogrel.</p><p><b>CONCLUSION</b>Dialysis did not affect the antiplatelet effects of aspirin and clopidogrel in uremic patients with coronary heart disease.</p>

Blood Pressure Targets in the Hypertensive Elderly / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>Hypertension is an important risk factor of cardiovascular disease and increases mortality in the elderly. However, the available medical evidences are both inconsistent and insufficient regarding establishing credible and useful blood pressure (BP) targets in the hypertensive elderly. This review summarizes the existing evidences used for establishing optimal BP targets for this patient population and points out some data inconsistencies which have added to the uncertainty.</p><p><b>DATA SOURCES</b>We conducted a search for the articles published in English in the PubMed database up to March 2017, with the keywords "hypertension," "elderly," "blood pressure," and "antihypertensive."</p><p><b>STUDY SELECTION</b>Articles that related to BP targeting in the hypertensive elderly were selected for this review.</p><p><b>RESULTS</b>The selected studies indicated that antihypertensive therapy can substantially reduce the risk of cardiovascular events and mortality, for a subset of the elderly (60 years or older) with systolic BP> 160 mmHg. Studies regarding more strict targets yielded mixed findings. For the very old and frail patients (80 years or older), there is a lack of evidence that optimal BP targets and intensive antihypertensives are helpful but in fact may be harmful.</p><p><b>CONCLUSIONS</b>There are solid evidences that patients who are 60-80 years old and in good health have benefited from lowering their BP to below 150/90 mmHg. If well tolerated, the BP target can be further lowered to below 140/90 mmHg. However, for the very old and frail, individualized and careful assessment is crucial. Antihypertensive treatment should be cautious and the adverse effect of drugs requires close monitoring as such treatment can be counterproductive.</p>

ADAMTS-1 expression in rat myocardium after ischemic preconditioning: age-associated differences / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>It has been found that cardiac protection afforded by ischemic preconditioning (IPC) is significantly reduced in the senescent myocardium. ADAMTS-1 (a disintesrin and metalloprotease with thrombospondin type 1 motifs) has been shown to inhibit angiogenesis in a variety of in vitro and in vivo assays. The aim of this study was to investigate the age-associated differences in ADAMTS-1 protein expression in rat myocardium after ischemic preconditioning.</p><p><b>METHODS</b>Sixty-four young (4 months) and old (24 months) male Sprague-Dawley rats were randomly assigned to an IPC group (40 rats) or a sham group (rats). A model of delayed IPC was induced and rats were sacrificed and myocardial samples were harvested from the ischemic-reperfused region for immunohistochemical detection of ADAMTS-1 at serial time points after IPC. A model of myocardial infarction was produced by ligation of the left anterior descending coronary artery in additional sets of young and old rats after sham or IPC procedures, then age-associated myocardial infarction survival after IPC was calculated.</p><p><b>RESULTS</b>ADAMTS-1 expression increased significantly in old rats compared to young rats (P < 0.05). The mean densities of ADAMTS-1 protein at 0, 6, 12, and 24 hours in young-IPC group after IPC were 0.05 ± 0.01, 0.13 ± 0.03, 0.16 ± 0.04, and 0.12 ± 0.03 vs. 0.07 ± 0.03, 0.20 ± 0.03, 0.24 ± 0.05, and 0.21 ± 0.04 in old-IPC group. IPC resulted in diminished survival rates (5/35 vs. 6/14, old-IPC group vs. old-sham group, P < 0.05), reduced left ventricular fractional shortening ((13.9 ± 2.8)% vs. (18.3 ± 2.3)%, P < 0.05) and increased the myocardial infarction size ((37.9 ± 3.2)% vs. (32.8 ± 5.1)%, P < 0.05) in the older rats.</p><p><b>CONCLUSIONS</b>Cardioprotection with IPC is attenuated in the older heart. ADAMTS-1 expression induced by IPC is greater in old rats. Over-expression of anti-angiogenic factors might be a potential mechanism behind reduced protection after IPC associated with aging.</p>

Effect of ischemia preconditioning on pro- and anti- angiogenic molecule expression and functional arteries formation / 中华心血管病杂志

<p><b>OBJECTIVE</b>to observe the effect of ischemia preconditioning (IPC) on the expression of pro-angiogenic VEGF, PDGF and anti-angiogenic ADAMTS-1, and arteriogenesis.</p><p><b>METHODS</b>rat heart IPC model was made by 4 circles of occluding the LAD for 6 min followed by 6 min of reperfusion. The expression of VEGF, PDGF-B and ADAMTS-1 in the ischemic area was examined with immunohistochemistry at 6, 12 and 24 h after IPC. IPC plus myocardial infarction model was induced by LAD ligation 24 h after IPC, 14 days later, the anti-SM-α-actin antibody was used to detect the mature neovascularization in the border of the infracted area.</p><p><b>RESULTS</b>VEGF, PDGF-B and ADAMTS-1 were significantly upregulated in the ischemic area in IPC group compared with the control group (P < 0.05). Density of mature arteries was also significantly increased in IPC plus MI group than that in MI group (P < 0.05).</p><p><b>CONCLUSION</b>IPC promoted the formation of mature new arteries which may be modulated by upregulating VEGF, PDGF-B, and ADAMTS-1 expressions.</p>

Ischemia preconditioning attenuated myocardial ischemia via upregulating the expression of adiponectin in rat / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate whether adiponectin plays a role in the protection of myocardium in the rat myocardial ischemia preconditioning (IPC) model.</p><p><b>METHOD</b>Infarct size was measured by Masson's Trichrome staining, the expression of protein and mRNA of adiponectin at 0, 6, 12 and 24 h after IPC was examined by immunohistochemistry and quantitative real time RT-PCR, plasma levels of adiponectin at above mentioned four time points after IPC were detected by ELISA in IPC and MI rats.</p><p><b>RESULT</b>Infarct size was smaller in IPC than in MI rats (20% ± 2% vs. 31% ± 3%, P < 0.05). The expression of adiponectin mRNA at 6 h and 12 h after IPC was 2.2 and 2.1 times higher than in Sham rats at respective time points (P < 0.05). Immunohistochemistry staining evidenced increased adiponectin expression in the ischemic area and weak expression of adiponectin in non-ischemic area (P < 0.05). Compared to the sham group, the plasma level of adiponectin increased significantly at 0, 6 and 12 h after IPC (0 h: 7.40 ± 0.47 vs. 10.90 ± 1.74; 6 h: 8.18 ± 1.41 vs. 10.98 ± 1.74; 12 h: 6.97 ± 1.02 vs. 9.31 ± 0.96, P < 0.05).</p><p><b>CONCLUSION</b>IPC reduced infarction size, upregulated the myocardial expression of adiponectin at mRNA and protein levels, and increased plasma adiponectin concentration, suggesting that the adiponectin may play a critical role in the protective effect of IPC.</p>

Pharmacokinetics of rapamycin-eluting stents in miniswine coronary model / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The results of clinical trials of rapamycin-eluting stents reduce restenosis have been quite promising. The main purpose of this study was to characterize the in vivo pharmacokinetics of high dose rapamycin (Rapa)-eluting stents in a miniswine coronary model.</p><p><b>METHODS</b>Ten miniswines underwent placement of 18 high dose Rapa-eluting stents in the left anterior descending and right coronary arteries. At the planned times of the 1.5th, 12th, 24th hour, 3th, 7th and 28th day, the animals (n = 1, 1, 2, 2, 2, and 2, respectively) were euthanized after completion of coronary angiography. Blood samples were obtained at 0, 10, 20, 30 minutes; 1, 2, 6, 24 hours; and 3, 7, 28 days to determine systemic Rapa levels. Rapa levels in whole blood, arterial wall, heart, renal and liver tissues were determined by high-performance liquid chromatography/mass spectroscopy.</p><p><b>RESULTS</b>Peak whole blood concentration (Cmax), time to peak concentration (tmax), elimination half-life (t1/2beta), area under the curve (AUC), and apparent systemic clearance (Cl/F) were (10.91 +/- 1.28) ng/ml, (2.0 +/- 0.2) hours, (7.25 +/- 0.63) hours, (1.15 +/- 0.11) ng x h x ml(-1), and (180 +/- 12) ml x h(-1) x kg(-1), respectively. More than 95% Rapa detected is localized in the coronary artery surrounding the stent and heart.</p><p><b>CONCLUSION</b>Stent-based delivery of Rapa via a copolymer stent is feasible and safe. This strategy holds promise for the prevention of stent restenosis.</p>