Impact of Tolvaptan Combined with Low-Dose Dopamine in Heart Failure Patients with Acute Kidney Injury.

The impact of tolvaptan and low-dose dopamine on heart failure (HF) patients with acute kidney injury (AKI) remains uncertain from a clinical standpoint.HF patients with AKI were selected and divided in a 1:1 fashion into the dopamine combined with the tolvaptan group (DTG), the tolvaptan group (TG), and the control group (CG). According to the standard of care, TG received tolvaptan 15 mg orally daily for a week. DTG received combination treatment, including 7 consecutive days of dopamine infusion (2 µg/kg・minutes) and oral tolvaptan 15 mg. Venous blood and urine samples were taken before and after therapy. The primary endpoint was the cardiorenal serological index after 7 days of treatment.Sixty-five patients were chosen randomly for the DTG (22 patients), TG (20 patients), and CG (23 patients), which were similar before the treatment. The serum indexes related to cardiac function (N-terminal probrain natriuretic peptide and cardiac troponin I) in DTG were decreased, compared with TG and CG (P < 0.05). Furthermore, the serological markers of renal function (serum cystatin C, serum creatinine, and neutrophil gelatinase-associated lipocalin) in DTG were lower than those in TG and CG (P < 0.05). There was no significant difference in the incidence of adverse reactions among groups.Low-dose dopamine combined with tolvaptan can markedly improve patients' cardiac and renal function. This may be considered a new therapeutic method for HF patients with AKI.

Liraglutide does not increase heart rate of diabetic patients during acute myocardial infarction.

BACKGROUND: Glucagon-like peptide 1 receptor agonists have been shown to reduce all-cause and cardiovascular mortality in patients with Type 2 diabetes mellitus (T2DM). The probable increase in heart rate hinders its early usage in acute myocardial infarction patients. In our study, we aimed to find out whether the use of liraglutide in patients with acute myocardial infarction as early as at the time of hospitalization would increase the heart rate. METHODS: This was an observational retrospective study. From December 2020 to August 2021, 200 patients with acute myocardial infarction were included in our study and divided into three groups: T2DM + liraglutide group (n = 46), T2DM + non-liraglutide group (n = 42), and non-T2DM group (n = 112). The primary outcomes were the differences in heart rate. Secondary outcomes were differences in systolic and diastolic blood pressure. RESULTS: There were no significant differences in heart rate among the three groups at admission, the day before the first shot of liraglutide, and before discharge. There was also no significant difference in heart rate between diabetic patients with acute myocardial infarction and those on liraglutide during the hospital stay. And there were no differences of beta-blocker dosages among the three groups. Liraglutide did not affect the blood pressure during acute myocardial infarction. CONCLUSIONS: Liraglutide did not increase the heart rate in diabetic patients during acute myocardial infarction and did not lead to an increase in the dose of beta-blockers in the patients. It also had no effect on blood pressure and showed better efficacy in lowering glucose levels without additional hypoglycemic events.

Effects of adaptive left bundle branch-optimized cardiac resynchronization therapy: a single centre experience.

BACKGROUND: Adaptive cardiac resynchronization therapy (aCRT) is associated with improved clinical outcomes. Left bundle branch area pacing (LBBAP) has shown encouraging results as an alternative option for aCRT. A technique that can be accomplished effectively using LBBAP combined with coronary venous pacing (LOT-aCRT). We aimed to assess the feasibility and outcomes of LOT-aCRT. METHODS: LOT-aCRT, capable of providing two pacing modes, LBBAP alone or LBBAP combined with LV pacing, was attempted in patients with CRT indications. Patients were divided into two groups: those with LBBAP and LV pacing (LOT-aCRT) and those with conventional biventricular pacing (BVP-aCRT). RESULTS: A total of 21 patients were enrolled in the study (10 in the LOT-aCRT group, 11 in the BVP-aCRT group). In the LOT-aCRT group, the QRS duration (QRSd) via BVP was narrowed from 158.0 ± 13.0 ms at baseline to 132.0 ± 4.5 ms (P = 0.019) during the procedure, and further narrowed to 123.0 ± 5.7 ms (P < 0.01) via LBBAP. After the procedure, when LOT-aCRT implanted and worked, QRSd was further changed to 121.0 ± 3.8 ms, but the change was not significant (P > 0.05). In the BVP-aCRT group, BVP resulted in a significant reduction in the QRSd from 176.7 ± 19.7 ms at baseline to 133.3 ± 8.2 ms (P = 0.011). However, compared with LOT-aCRT, BVP has no advantage in reducing QRSd and the difference was statistically significant (P < 0.01). During 9 months of follow-up, patients in both groups showed improvements in the LVEF and NT-proBNP levels (all P < 0.01). However, compared with BVP-aCRT, LOT-aCRT showed more significant changes in these parameters (P < 0.01). CONCLUSIONS: The study demonstrates that LOT-aCRT is clinically feasible in patients with systolic heart failure and LBBB. LOT-aCRT was associated with significant narrowing of the QRSd and improvement in LV function.

WITHDRAWN: HMGB1 and COX2 are regulated during organ damage following obesity-induced hypertension in a metabolic syndrome mouse model.

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Therapeutic efficacy of catalpol against apoptosis in cardiomyocytes derived from human induced pluripotent stem cells.

Cardiac arrhythmia is an irregular heart rhythm that can lead to serious heart conditions and various organ disorders, and may cause sudden cardiac death. Catalpol belongs to the iridoid glycoside family and is highly abundant in Rehmannia glutinosa Libosch. The study included five groups such as group I (normal control), group II (treatment control), group III (low-dose treatment), group IV (medium-dose treatment) and group V (high-dose treatment). We investigated the therapeutic effects of catalpol on cardiac arrhythmia in human-induced pluripotent stem cells (iPSCs). Cell viability, lactate dehydrogenase (LDH) levels, lipid peroxidation, antioxidant activity, and caspase-3 and caspase-9 activities and protein levels were measured in normal control, treatment control, and treated (1, 10, and 100 µM) iPSC groups. Compared with the treatment control group, catalpol supplementation (1, 10, and 100 µM) increased iPSC cell viability by 7.5, 27.3, and 65.8%, respectively; reduced the LDH levels by 10.4, 31.3, and 75.2%, respectively; and reduced the lipid peroxidation levels by 7.7, 33.0, and 62.6%, respectively. The antioxidant levels were significantly higher in the treatment control group than in the normal control group. Catalpol (100 µM) reduced the caspase-3 and caspase-9 activities by more than 30% and increased expression of the corresponding proteins by more than 50%. These findings suggest that the naturally occurring iridoid glycoside catalpol is effective against aconitine-induced cardiac arrhythmia in iPSCs.

Berberine Attenuates Cholesterol Accumulation in Macrophage Foam Cells by Suppressing AP-1 Activity and Activation of the Nrf2/HO-1 Pathway.

Atherosclerosis is a chronic inflammation condition resulting from the interaction between lipoproteins, monocyte-derived macrophages, T lymphocytes, and other cellular elements in the arterial wall. Macrophage-derived foam cells play a key role in both early and advanced stage of atherosclerosis. Previous studies have shown that berberine could inhibit foam cell formation and prevent experimental atherosclerosis. However, its underlying molecular mechanisms have not been fully clarified. In this study, we explored the cholesterol-lowering effects of berberine in macrophage-derived foam cells and investigated its possible mechanisms in prevention and treatment of atherosclerosis. Here, we demonstrated that berberine could inhibit atherosclerosis in apolipoprotein E-deficient mice and induce cholesterol reduction as well as decrease the content of macrophages. Berberine can regulate oxLDL uptake and cholesterol efflux, thus suppresses foam cell formation. Mechanisms study showed that berberine can suppress scavenger receptor expression via inhibiting the activity of AP-1 and upregulate ATP-binding cassette transporter via activating Nrf2/HO-1 signaling in human macrophage. In summary, berberine significantly inhibits atherosclerotic disease development by regulating lipid homeostasis and suppressing macrophage foam cell formation.

Risk factor analysis of device-related infections: value of re-sampling method on the real-world imbalanced dataset.

BACKGROUND: The incidence of cardiac implantable electronic device infection (CIEDI) is low and usually belongs to the typical imbalanced dataset. We sought to describe our experience on the management of the imbalanced CIEDI dataset. METHODS: Database from two centers of patients undergoing device implantation from 2001 to 2016 were reviewed retrospectively. Re-sampling technique was used to improve the classifier accuracy. RESULTS: CIEDI was identified in 28 out of 4959 procedures (0.56%); a high imbalance existed in the sizes of the patient profiles. In univariate analyses, replacement procedure and male were significantly associated with an increase in CIEDI: (53.6% vs. 23.4, 0.8% vs. 0.3%, P < 0.01). Multivariate logistic regression analysis showed that gender (odds ratio, OR = 3.503), age (OR = 1.032), replacement procedure (OR = 3.503), and use of antibiotics (OR = 0.250) remained as independent predictors of CIEDI (all P < 0.05) after adjustment for diabetes, post-operation fever, and device style, device company. There were 616 under-sampled cases and 123 over-sampled cases in the analyzed cohort after re-sampling. The re-sampling and bootstrap results were robust and largely like the analysis results prior re-sampling method, while use of antibiotics lost the predicting capacity for CIEDI after re-sampling technique (P > 0.05). CONCLUSION: The application of re-sampling techniques can generate useful synthetic samples for the classification of imbalanced data and improve the accuracy of predicting efficacy of CIEDI. The peri-operative assessment should be intensified in male and aged patients as well as patients receiving replacement procedures for the risk of CIEDI.

Dual-specificity phosphatase 14 protects the heart from aortic banding-induced cardiac hypertrophy and dysfunction through inactivation of TAK1-P38MAPK/-JNK1/2 signaling pathway.

Dual-specificity phosphatase 14 (Dusp14), an important negative modulator of mitogen-activated protein kinase (MAPK) signaling pathways, has been implicated in inflammatory immune response, cancers, cell differentiation and proliferation. The role of Dusp14 in chronic pressure overload-induced cardiac hypertrophy has not been explored. Here we have shown that Dusp14-/- knockout mice and cardiac-specific Dusp14 transgenic mice were generated and subjected to aortic banding (AB) for 4 weeks. Our results demonstrated that genetic loss of Dusp14 significantly aggravated cardiac hypertrophy, fibrosis, ventricular dilation and dysfunction, whereas transgenic cardiac-specific Dusp14 overexpression significantly attenuated AB-induced cardiac dysfunction and remodeling. In vitro, adenoviral overexpression of constitutive Dusp14 blocked angiotensin II-induced hypertrophic growth of cardiomyocytes, while Dusp14 knockdown led to opposite effects. Mechanistically, excessive phosphorylation of TAK1, P38MAPK and JNK1/2 was evidenced in Dusp14-/- knockout mice post-AB and inactivation of TAK1-P38MAPK and -JNK1/2 signaling using TAK1 inhibitor 5Z-7-ox shares similar antihypertrophic effect as Dusp14 overexpression. Moreover, we show that Dusp14 directly interacted with TAK1. Results from present experiments indicate that Dusp14 protects the heart from AB-induced cardiac hypertrophy and dysfunction possibly through inactivation of TAK1-P38MAPK/-JNK1/2 signaling pathway. Future studies are warranted to test the feasibility of overexpressing Dusp14 as a therapeutic strategy to attenuate cardiac hypertrophy and failure.

Semaphorin 3a transfection into the left stellate ganglion reduces susceptibility to ventricular arrhythmias after myocardial infarction in rats.

AIMS: Myocardial infarction (MI) induces neural remodelling of the left stellate ganglion (LSG), which may contribute to ischaemia-induced arrhythmias. The neural chemorepellent Semaphorin 3a (Sema3a) has been identified as a negative regulator of sympathetic innervation in the LSG and heart. We previously reported that overexpression of Sema3a in the border zone could reduce the arrhythmogenic effects of cardiac sympathetic hyperinnervation post-MI. This study investigated whether Sema3a overexpression within the LSG confers an antiarrhythmic effect after MI through decreasing extra- and intra-cardiac neural remodelling. METHODS AND RESULTS: Sprague-Dawley rats were subjected to MI, and randomly allocated to intra-LSG microinjection of either phosphate-buffered saline (PBS), adenovirus encoding green fluorescent protein (AdGFP), or adenovirus encoding Sema3a (AdSema3a). Sham-operated rats served as controls. Two weeks after infarction, MI-induced nerve sprouting and sympathetic hyperinnervation in the LSG and myocardium were significantly attenuated by intra-LSG injection with AdSema3a, as assessed by immunohistochemistry and western blot analysis of growth-associated protein 43 and tyrosine hydroxylase. This was also confirmed by sympathetic nerve function changes assessed by cardiac norepinephrine content. Additionally, intra-LSG injection with AdSema3a alleviated MI-induced accumulation of dephosphorylated connexin 43 in the infarct border zone. Furthermore, Sema3a overexpression in the LSG reduced the incidence of inducible ventricular tachyarrhythmia by programmed electrical stimulation post-MI, and arrhythmia scores were significantly lower in the AdSema3a group than in the PBS and AdGFP groups. CONCLUSION: Semaphorin 3a overexpression in the LSG ameliorates the inducibility of ventricular arrhythmias after MI, mainly through attenuation of neural remodelling within the cardiac-neuraxis.

Mitogen-activated protein kinase phosphatase-1: a critical phosphatase manipulating mitogen-activated protein kinase signaling in cardiovascular disease (review).

Mitogen-activated protein kinase (MAPK) cascades are important players in the overall representation of cellular signal transduction pathways, and the deregulation of MAPKs is involved in a variety of diseases. The activation of MAPK signals occurs through phosphorylation by MAPK kinases at conserved threonine and tyrosine (Thr-Xaa-Tyr) residues. The mitogen-activated protein kinase phosphatases (MKPs) are a major part of the dual-specificity family of phosphatases and specifically inactivate MAPKs by dephosphorylating both phosphotyrosine and phosphoserine/phosphothreonine residues within the one substrate. MAPKs binding to MKPs can enhance MKP stability and activity, providing an important negative-feedback control mechanism that limits the MAPK cascades. In recent years, accumulating and compelling evidence from studies mainly employing cultured cells and mouse models has suggested that the archetypal MKP family member, MKP-1, plays a pivotal role in cardiovascular disease as a major negative modulator of MAPK signaling pathways. In the present review, we summarize the current knowledge on the pathological properties and the regulation of MKP-1 in cardiovascular disease, which may provide valuable therapeutic options.

The antiproliferative effect of sildenafil on pulmonary artery smooth muscle cells is mediated via upregulation of mitogen-activated protein kinase phosphatase-1 and degradation of extracellular signal-regulated kinase 1/2 phosphorylation.

BACKGROUND: Pulmonary hypertension is a group of diseases comprising vascular constriction and by obstructive changes of the pulmonary vasculature. Phosphodiesterase type 5 inhibitors, e.g., sildenafil, can alleviate vascular remodeling in the monocrotaline pulmonary hypertension model in rats, and inhibit the proliferation of pulmonary vascular smooth muscle cells in vitro. We examined the ability of sildenafil to inhibit platelet-derived growth factor (PDGF)-induced proliferation of porcine pulmonary artery smooth muscle cells. METHODS: Pulmonary artery smooth muscle cell proliferation and cell cycle analysis were assessed by MTT assay and fluorescence-activated cell sorting. Western blotting was used to examine protein expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) and phosphorylation level of extracellular signal-regulated kinase (ERK1/2). RESULTS: PDGF increased cell proliferation and the percentage of cells in S phase. These effects were inhibited by pretreatment with sildenafil in a dose-dependent manner. Sildenafil (96 microM) also caused a 67% decrease in PDGF-stimulated ERK1/2 phosphorylation. Sildenafil inhibition of ERK1/2 was accompanied by a rapid induction of MKP-1. Inhibition of the cGMP-dependent kinase I alpha (cGK I alpha) using Rp-8-BrcGMPS (25 microM) blocked sildenafil-induced MKP-1 expression. Either vanadate (12.5 microM), a phosphatase inhibitor, or Rp-8-BrcGMPS abolished the inhibitory effect of sildenafil on PDGF-stimulated phosphorylation of ERK1/2 and restored PDGF-induced cell proliferation. CONCLUSION: This study indicates that sildenafil upregulates MKP-1 expression and promotes degradation of phosphorylation of ERK1/2, which suppresses the proliferation of pulmonary artery smooth muscle cells.