Journal of Cardiovascular Translational Research

Apoptosis and inflammation of vascular endothelial cells (VECs) are the most important causes of deep vein thrombosis (DVT). cAMP response element binding protein 1 (CREB1) encodes a transcription factor that binds as a homodimer to the cAMP-responsive element and can promote inflammation. CREB1 is found to be upregulated in the plasma of patients with venous thromboembolism. However, the biological functions of CREB1 in DVT remain unknown. We evaluated the effect of CREB1 in a rat model of inferior vena cava (IVA) stenosis-induced DVT. IVC stenosis resulted in stable thrombus, inflammatory response and CREB1 upregulation, whereas CREB1 knockdown inhibited thrombus and inflammation in DVT rats. In vitro analysis showed that CREB1 knockdown inhibited VEC apoptosis. Mechanistically, CREB1 knockdown reduced Ribosomal protein L9 (RPL9) expression and blocked the NF-κB pathway. Therefore, CREB1 may become a potential therapeutic target of DVT prevention.

Non-invasive means of evaluating appropriate cardiac unloading remain to be established. We hypothesized that myocardial deformation assessed by echocardiographic speckle-tracking strain analysis can reliably estimate the degree of left ventricular (LV) unloading under mechanical circulatory support. A total of 24 Yorkshire pigs underwent Impella-mediated acute LV unloading 1–2 weeks after myocardial infarction (MI). Echocardiographic and invasive pressure-volume measurements were used to evaluate the degree of LV unloading. Pressure-volume analysis before and after LV unloading exhibited a significant decrease in stroke work (3399 ± 1440 to 1244 ± 659 mmHg ml, p < 0.001), suggesting reduced external cardiac work. Both longitudinal strain (− 14.6 ± 4.1% to − 10.6 ± 2.3%, p < 0.001) and circumferential strain (− 18.7 ± 6.1% to − 9.3 ± 3.5%, p < 0.001) decreased after LV unloading, and there were linear relationships between stroke work and echocardiographic longitudinal (r = − 0.61, p < 0.001) as well as circumferential strains (r = − 0.75, p < 0.001). Echocardiographic LV strain analysis offers a non-invasive assessment of LV unloading in subacute MI.

Left ventricular end-diastolic pressure (LVEDP) is an easily obtained, physiologically integrative measure of total LV function. LVEDP may be a useful prognostic measure in patients with acute myocardial infarction and utilised to guide medical therapy and assess risk for post myocardial infarction heart failure. To assess the utility of LVEDP as a prognostic measure in patients presenting with acute myocardial infarction. We performed an unrestricted search of electronic databases (1946 to March 2017) using a predefined search strategy. Publications were included if patients had an acute coronary syndrome and LVEDP was measured by cardiac catheterisation and included outcome data specifying major adverse cardiac events. Two reviewers performed independent study selection, data abstraction and quality assessment by using the Cochrane tool for randomised trials and the ROBINS-I tool for non-randomised studies. Our search identified 8637 patients in seven studies. In patients with elevated LVEDP and STEMI, there was a significantly increased risk of 30-day death (three studies, 5372 participants; RR 1.9; 95% CI 1.4–2.7; p < 0.001; I 2 = 35.3%) and heart failure (two studies, 2574 participants; RR 2.9; 95% CI 1.9–4.5; p = < 0.001; I 2 = 0.0%). There was no significant increase in risk of 30 day reinfarction (RR 1.25; 95% CI 0.77–2.1; p = 0.37; I 2 = 41.3%). Elevated LVEDP measured during cardiac catheterisation for acute myocardial infarction appears to be a predictor of heart failure and mortality.

Survival of transplanted hearts is often limited by cold ischemia time. Here, we assessed the effects of the small molecular compound TJ-M2010-5 on graft preservation. In a cardiac cold ischemia/reperfusion model, TJ-M2010-5 ameliorated myocardial ischemia/reperfusion injury (MIRI) in histidine-tryptophan-ketoglutarate (HTK) organ preservation solution. When applied in HTK solution and on donors/recipients respectively, TJ-M2010-5 exerted optimal effects when applied as an additive in the HTK solution. TJ-M2010-5-administered mice exhibited shorter rebeating time; higher beating score; stronger and more regular sinus heart rate; and amelioration of apoptosis, inflammatory reactions, and myocardial injury. Mechanistically, TJ-M2010-5 inhibited the expression of key molecules in the toll-like receptor (TLR) signaling pathway and affected downstream proteins by inhibiting myeloid differentiation factor 88 homodimerization, thereby decreasing myocardial injury. Thus, TJ-M2010-5 may exert protective effects against MIRI by blocking the TLR signaling pathway. Our findings may lead to novel approaches for organ preservation, thereby reducing organ abandonment and improving recipient prognosis. The role of the TLR signaling pathway in MIRI progress and operation procedure of the MIRI model in vivo are presented in a graphical abstract (Online Abstract Figure).

There are currently 25 new clinical cellular therapy trials in progress for cardiovascular disease in the US, and a similar number ongoing in Europe. The lack of standardization in cell isolation, preparation, storage, and time and localization of delivery, present clear hurdles to this growing field. This emphasizes the need for an organized task force to work closely with the FDA to agree upon standardized methods with the end result being improvements in patient care and enhanced knowledge in the field.

Dexmedetomidine (DEX) is clinically used for sedation of patients in intensive care, which also has been shown to have a strong anti-inflammatory effect on a variety of diseases. Parthanatos is a newly discovered form of programmed cell death. Here, we aimed to explore whether DEX protects cardiomyocytes from parthanatos in chronic heart failure (CHF). The levels of malondialdehyde (MAD), total superoxide dismutase (SOD), and adenosine triphosphate (ATP) were measured by corresponding detection kits. CHF mice model was established by transverse aortic constriction (TAC). PARP-1 expression in cardiac tissues of wild-type CHF mice was evaluated by immunohistochemistry. Flow cytometry was used to detect the effect of N-methyl-N′-nitro-N′-nitrosoguanidine (MNNG) on cell death. Masson trichrome staining and hematoxylin and eosin staining were conducted in cardiac tissues to evaluate the histological changes. TUNEL and caspase-1 double-staining and caspase-1 and NLRP3 double-staining were conducted in cardiac tissues to evaluate the effect of DEX on cell death in vivo. The relative expression of parthanatos and NLRP3 inflammasome-related proteins was evaluated by western blotting. MNNG induced parthanatos in mouse HL-1 cardiomyocytes. MNNG-induced parthanatos was promoted by ROS production and NLRP3 inflammasome activation. DEX treatment suppressed MNNG-induced parthanatos via NLRP3 inflammasome activation mediated by ROS. Importantly, DEX inhibited pathological changes and parthanatos in CHF mice. DEX suppressed the ROS/NLRP3 signaling pathway in CHF mice. DEX inhibited parthanatos in cardiomyocytes and in CHF mice by regulating the ROS-mediated NLRP3 inflammasome activation. The PARP-1 activation and NLRP3 inflammasome activation induced by MNNG was inhibited by DEX treatment, thus the generation of ROS was further inhibited, suggesting the inhibitory effect of DEX treatment on parthanatos in cardiomyocytes.

The splanchnic vascular compartment is the major reservoir for intravascular blood volume, and dysregulation of the compartment was implicated in a series of cardiovascular conditions. We explored feasibility and effectiveness of an implantable cuff system on the greater splanchnic nerve (GSN) in healthy canines for short- and long-term neuromodulation to affect the circulation. Five mongrel hounds underwent minimally invasive right-sided unilateral GSN cuff placement. All animals underwent same day GSN stimulation and repeat stimulation at 9–30 days. Stimulation parameter optimization was conducted both acutely and chronically. Parameters ranged from 1–250 Hz, 0.25 mA–35 mA, 0.1–0.5 ms, and 30-s pulse duration. Two animals were survived for 9 days and 3 animals for 30 days. Stimulation of the right GSN increased mean arterial blood pressure by 36.9 mmHg ± 13.4 (p < 0.0001), central venous pressure by 6.9 mmHg ± 1.7 (p < 0.0001), and mean pulmonary arterial pressure by 6.3 mmHg ± 2.0 (p < 0.0001). Peak effects were observed within 30 s, and magnitude of effects was comparable between stimulation cycles (p = 0.4). Stimulation-induced changes in hemodynamics were independent of afferent nerve fibers (pain response) or the adrenal gland. Necropsy showed no evidence of nerve damage on histologic studies up to 30 days after implantation. GSN stimulation via an implanted nerve cuff provided a reproducible and rapid method to increase arterial, central venous, and pulmonary arterial pressures. The neuromodulation cuff was well tolerated and elicited a response up to 30 days after implantation. The clinical application of GSN stimulation as a tool to change central and peripheral cardiovascular hemodynamics needs to be explored.

The porcine intra-abdominal heterotopic heart transplantation model allows for the assessment of immunologic effects on cardiac transplantation without relying on the allograft to maintain hemodynamic support for the animal. Historically, allograft function and histology is monitored by physical exam, echocardiogram evaluation, percutaneous core biopsy, and open biopsy. We performed transvenous endomyocardial biopsies in three pigs that had undergone heterotopic heart implantation. We describe the procedure to be feasible and reproducible, and that histologic results from these biopsies correlated with those from corresponding tissue collected by surgical dissection at the time of allograft explantation. The ability to perform endomyocardial biopsies in the heterotopic heart transplantation model allows for serial non-invasive monitoring of allograft histology.