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Stress imaging identifies ischemic myocardium by comparing hemodynamics during rest and hyperemic stress. Hyperemia affects multiple hemodynamic parameters in myocardium, including myocardial blood flow (MBF), myocardial blood volume (MBV), and venous blood oxygen levels (PvO 2 ). Cardiac T2 is sensitive to these changes and therefore is a promising non-contrast option for stress imaging; however, the impact of individual hemodynamic factors on T2 is poorly understood, making the connection from altered T2 to changes within the tissue difficult. To better understand this interplay, we performed T2 mapping and measured various hemodynamic factors independently in healthy pigs at multiple levels of hyperemic stress, induced by different doses of adenosine (0.14-0.56 mg/kg/min). T1 mapping quantified changes in MBV. MBF was assessed with microspheres, and oxygen consumption was determined by the rate pressure product (RPP). Simulations were also run to better characterize individual contributions to T2. Myocardial T2, MBF, oxygen consumption, and MBV all changed to varying extents between each level of adenosine stress (T2 = 37.6-41.8 ms; MBF = 0.48-1.32 mL/min/g; RPP = 6507-4001 bmp*mmHg; maximum percent change in MBV = 1.31%). Multivariable analyses revealed MBF as the dominant influence on T2 during hyperemia (significant β-values >7). Myocardial oxygen consumption had almost no effect on T2 (β-values <0.002); since PvO 2 is influenced by both oxygen consumption and MBF, PvO 2 changes detected by T2 during adenosine stress can be attributed to MBF. Simulations varying PvO 2 and MBV confirmed that PvO 2 had the strongest influence on T2, but MBV became important at high PvO 2 . Together, these data suggest a model where, during adenosine stress, myocardial T2 responds predominantly to changes in MBF, but at high hyperemia MBV is also influential. Thus, changes in adenosine stress T2 can now be interpreted in terms of the physiological changes that led to it, enabling T2 mapping to become a viable non-contrast option to detect ischemic myocardial tissue., (© 2021 John Wiley & Sons, Ltd.)

Treprostinil palmitil (TP) is a long-acting inhaled pulmonary vasodilator prodrug of treprostinil (TRE). In this study, TP was delivered by inhalation (treprostinil palmitil inhalation suspension, TPIS) in a rat Sugen 5416 (Su)/hypoxia (Hx) model of pulmonary arterial hypertension (PAH) to evaluate its effects on hemodynamics, pulmonary vascular remodeling, and cardiac performance and histopathology. Male Sprague-Dawley rats received Su (20 mg/kg, s.c), three weeks of Hx (10% O 2 ) and 5 or 10 weeks of normoxia (Nx). TPIS was given during the 5-10 week Nx period after the Su/Hx challenge. Su/Hx increased the mean pulmonary arterial blood pressure (mPAP) and right heart size (Fulton index), reduced cardiac output (CO), stroke volume (SV) and heart rate (HR), and increased the thickness and muscularization of the pulmonary arteries along with obliteration of small pulmonary vessels. In both the 8- and 13-week experiments, TPIS at inhaled doses ranging from 39.6 to 134.1 μg/kg, QD, dose-dependently improved pulmonary vascular hemodynamics, reduced the increase in right heart size, enhanced cardiac performance, and attenuated most of the histological changes induced by the Su/Hx challenge. The PDE5 inhibitor sildenafil, administered at an oral dose of 50 mg/kg, BID for 10 weeks, was not as effective as TPIS. These results in Su/Hx challenged rats demonstrate that inhaled TPIS may have superior effects to oral sildenafil. We speculate that the improvement of the pathobiology in this PAH model induced by TPIS involves effects on pulmonary vascular remodeling due to the local effects of TRE in the lungs., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Excessive myocardial oxygen consumption (MVO 2 ) is considered a limitation for catecholamines, termed oxygen cost of contractility. We hypothesize that increased MVO 2 induced by dobutamine is not directly related to contractility but linked to intermediary myocardial metabolism. Furthermore, we hypothesize that selective β 3 adrenergic receptor (β 3 AR) antagonism using L-748,337 prevents this. In an open-chest pig model, using general anesthesia, we assessed cardiac energetics, hemodynamics and arterial metabolic substrate levels at baseline, ½ hour and 6 hours after onset of drug infusion. Cardiac efficiency was assessed by relating MVO 2 to left ventricular work (PVA; pressure-volume area). Three groups received dobutamine (5 μg/kg/min), dobutamine + L-748,337 (bolus 50 μg/kg), or saline for time-matched controls. Cardiac efficiency was impaired over time with dobutamine infusion, displayed by persistently increased unloaded MVO 2 from ½ hour and 47% increase in the slope of the PVA-MVO 2 relation after 6 hours. Contractility increased immediately with dobutamine infusion ( dP / dt max ; 1636 ± 478 vs 2888 ± 818 mmHg/s, P < 0.05) and persisted throughout the protocol (2864 ± 1055 mmHg/s, P < 0.05). Arterial free fatty acid increased gradually (0.22 ± 0.13 vs 0.39 ± 0.30 mM, P < 0.05) with peak levels after 6 hours (1.1 ± 0.4 mM, P < 0.05). By combining dobutamine with L-748,337 the progressive impairment in cardiac efficiency was attenuated. Interestingly, this combined treatment effect occurred despite similar alterations in cardiac inotropy and substrate supply. We conclude that the extent of cardiac inefficiency following adrenergic stimulation is dependent on the duration of drug infusion, and β 3 AR blockade may attenuate this effect.

The mechanisms regulating immune cells recruitment into the heart during healing after an acute myocardial infarction (AMI) have major clinical implications. We investigated whether cholinergic stimulation with pyridostigmine, a cholinesterase inhibitor, modulates heart and spleen immune responses and cardiac remodeling after AMI in spontaneous hypertensive rats (SHRs). Male adult SHRs underwent sham surgery or ligation of the left coronary artery and were randomly allocated to remain untreated or to pyridostigmine treatment (40 mg/kg once a day by gavage). Blood pressure and heart rate variability were determined, and echocardiography was performed at day six after MI. The heart and spleen were processed for immunohistochemistry cellular analyses (CD3 + and CD4 + lymphocytes, and CD68 + and CD206 + macrophages), and TNF levels were determined at day seven after MI. Pyridostigmine treatment increased the parasympathetic tone and T CD4 + lymphocytes in the myocardium, but lowered M1/M2 macrophage ratio towards an anti-inflammatory profile that was associated with decreased TNF levels in the heart and spleen. Treatment with this cholinergic agent improved heart remodeling manifested by lower ventricular diameters and better functional parameters. In summary, cholinergic stimulation by pyridostigmine enhances the parasympathetic tone and induces anti-inflammatory responses in the heart and spleen fostering cardiac recovery after AMI in SHRs.

Doxorubicin (DOX) is an anticancer chemotherapy drug that is widely used in clinical practice. It is well documented that DOX impairs baroreflex responsiveness and left ventricular function and enhances sympathetic activity, cardiac sympathetic afferent reflexes and oxidative stress, which contribute to hemodynamic deterioration. Because resistance training (RT)-induced cardioprotection has been observed in other animal models, the objective of this study was to assess the effects of RT during DOX treatment on hemodynamics, arterial baroreflex, cardiac autonomic tone, left ventricular function and oxidative stress in rats with DOX-induced cardiotoxicity. Male Wistar rats were submitted to a RT protocol (3 sets of 10 repetitions, 40% of one-repetition maximum (1RM) of intensity, 3 times per week, for 8 weeks). The rats were separated into 3 groups: sedentary control, DOX sedentary (2.5 mg/kg of DOX intraperitoneal injection, once a week, for 6 weeks) and DOX + RT. After training or time control, the animals were anesthetized and 2 catheters were implanted for hemodynamic, arterial baroreflex and cardiac autonomic tone. Another group of animals was used to evaluate left ventricular function. We found that RT in DOX-treated rats decreased diastolic arterial pressure, heart rate, sympathetic tone and oxidative stress. In addition, RT increased arterial baroreflex sensitivity, vagal tone and left ventricular developed pressure in rats with DOX-induced cardiotoxicity. In summary, RT is a useful non-pharmacological strategy to attenuate DOX-induced cardiotoxicity.

Aims: During heart ischemia, the lack of oxygen in the myocardial cells causes pH and ion disturbances and cell death through opening mitochondrial permeability transition pores (mPTP). Considering the inhibitory effects of mitochondrial ATP-dependent potassium channels (mt-K ATP ) on these pores and anti-ischemic effects of morin, we hypothesized that it may exert its positive effects via activating mt-K ATP as well as its anti-oxidative effects., Main Methods: Isolated rat hearts were perfused by Krebs-Henseleit solution enriched with the morin (0.25, 0.5 and 1 mg/L) or 5-hydroxydecanoate (5-HD, a mt-K ATP blocker;100 μM) or both as needed 5 min before starting regional ischemia till the first 10 min of the reperfusion period. The reperfusion was developed with Krebs-Henseleit solution 60 or 120 min respectively for biochemical evaluations (lactate dehydrogenase and malondialdehyde level) or the assessment of myocardial infarct size. During the experiments, hemodynamic functions were recorded and cardiac arrhythmias were determined., Key Findings: Our findings demonstrated that morin reduced the infarct size. Also, morin perfusion could remarkably prevent the malondialdehyde over-production during ischemia. Total ventricular ectopic beats had the same significant changes as the malondialdehyde level, in both ischemia and reperfusion phases. Morin could also relatively improve the ischemia-induced hemodynamic dysfunction. All mentioned protective effects of morin were reversed by concomitant perfusion of 5-HD., Significance: Morin has protective effects against ischemic hearts through anti-oxidative effects. It also suggests a link between the cardioprotective effects of morin and mt-K ATP . However, additional studies are required to prove this preliminary hypothesis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Neural control of the heart is regulated by sympathetic and parasympathetic divisions of the autonomic nervous system, both opposing each other to maintain cardiac homeostasis via regulating heart rate, conduction velocity, force of contraction, and coronary blood flow. Sympathetic hyperactivity and diminished parasympathetic activity are the characteristic features of many cardiovascular disease states including hypertension, myocardial ischemia, and arrhythmias that result in heart failure. Restoring parasympathetic activity to the heart has recently been identified as the promising approach to treat such conditions. However, approaches that used vagal nerve stimulation have been shown to be unsuccessful in heart failure. This review focuses on novel chemogenetic approaches used to identify the cardioprotective nature of activating neural points along the vagal pathway (both central and peripheral) while being selectively therapeutic in heart failure and obstructive sleep apnea.

Cardiopulmonary functions such as respiratory depression, severe irritation, inflamed respiratory tract, hyperventilation and, tachycardia are the most affected ones when it comes to the riot control agent oleoresin capsicum (OC) exposure. However, no studies have been done to elucidate the mechanism underlying deterioration of the combined cardiopulmonary functions. Parameters such as acute respiratory, cardiac, parameters and ultrasonography (USG) measurements were investigated in an in vivo setup using Wistar rats at 1 h and 24 h post inhalation exposure to 2%, 6% and 10% OC, whereas, cell migration in rat peritoneal mast cells (RPMCs), metabolomics and eosinophil peroxidase (EPO) activity in bronchoalveolar lavage fluid (BALF) were investigated in an in vitro setup. Results obtained from electrophysiological recording indicated that OC exposure produces apnea and decrease in mean arterial pressure (MAP) was obtained from hemodynamic parameters whereas cardiac parameters assessment revealed increase in the level of cardiac output (CO) and decrease in stroke volume (SV) with recovery towards the post-exposure period. A decrease in the percentage area of certain fatty acid pathway metabolites in BALF appropriately linked the lung injury following OC exposure which was further cemented by increasing concentration of EPO. Histopathology and SEM also proved to be favorable techniques for the detection of OC induced physiological cardiac and pulmonary modifications respectively. Furthermore, Boyden chamber experiment established the chemoattractant property of OC. It may be concluded from the above studies that these newly reported facets may be utilized pharmacologically to mitigate cardiopulmonary adverse effects owing to OC exposure., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Sepsis is a global economic and health burden. Dipeptidyl peptidase 3 (DPP3) is elevated in the plasma of septic patients. The highest levels of circulating DPP3 (cDPP3) are found in non-survivor septic shock patients. The aim of this study was to evaluate the benefits of inhibiting cDPP3 by a specific antibody, Procizumab (PCZ), on cardiac function in an experimental model of sepsis, the caecal ligature and puncture (CLP) model. Rats were monitored by invasive blood pressure and echocardiography. Results are presented as mean ± SD, with p <0.05 considered significant. PCZ rapidly restored left ventricular shortening fraction (from 39 ± 4% to 51 ± 2% before and 30 min after PCZ administration (p = 0.004)). Cardiac output and stroke volume were higher in the CLP + PCZ group when compared to the CLP + PBS group (152 ± 33 mL/min vs 97 ± 25 mL/min (p = 0.0079), and 0.5 ± 0.1 mL vs 0.3 ± 1.0 mL (p = 0.009), respectively) with a markedly reduced plasma DPP3 activity (138 ± 70 U/L in CLP + PCZ group versus 735 ± 255 U/L (p = 0.048) in the CLP + PBS group). Of note, PCZ rapidly reduced oxidative stress in the heart of the CLP + PCZ group when compared to those of the CLP + PBS group (13.3 ± 8.2 vs 6.2 ± 2.5 UI, p = 0.005, 120 min after administration, respectively). Our study demonstrates that inhibition of cDPP3 by PCZ restored altered cardiac function during sepsis in rats., Competing Interests: AM reports personal fees from Orion, Servier, Otsuka, Philips, Sanofi, Adrenomed, Epygon and Fire 1 and grants and personal fees from 4TEEN4 Pharmaceuticals GmbH, Abbott and Sphingotec. BD and AB were invited to meetings in Hennigsdorf by 4TEEN4 Pharmaceuticals GmbH. AB is CEO and shareholder at 4TEEN4 Pharmaceuticals GmbH. KS and MK are employees of 4TEEN4 Pharmaceuticals GmbH. Other authors declared no potential conflicts of interest with respect to the research authorship and/or publication of this article. 4TEEN4 Pharmaceuticals GmbH holds patent rights on the DPP3 biomarker and humanized antibody Procizumab. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aim: The effects of polyamidoamine (PAMAM) dendrimers on the mammalian heart are not completely understood. In this study, we have investigated the effects of a sixth-generation cationic dendrimer (G6 PAMAM) on cardiac function in control and diabetic rat hearts following ischemia-reperfusion (I/R) injury., Methods: Isolated hearts from healthy non-diabetic (Ctr) male Wistar rats were subjected to ischemia and reperfusion (I/R). LV contractility and hemodynamics data were computed digitally whereas cardiac damage following I/R injury was assessed by measuring cardiac enzymes. For ex vivo acute exposure experiments, G6 PAMAM was administered during the first 10 mins of reperfusion in Ctr animals. In chronic in vivo studies, nondiabetic rats (Ctr) received either vehicle or daily i.p. injections of G6 PAMAM (40 mg/kg) for 4 weeks. Diabetic (D) animals received either vehicle or daily i.p. injections of G6 PAMAM (10, 20 or 40 mg/kg) for 4 weeks. The impact of G6 PAMAM on pacing-postconditioning (PPC) was also studied in Ctr and D rats., Results: In ex vivo studies, acute administration of G6 PAMAM to isolated Ctr hearts during reperfusion dose-dependently impaired recovery of cardiac hemodynamics and vascular dynamics parameters following I/R injury. Chronic daily i.p. injections of G6 PAMAM significantly (P<0.01) impaired recovery of cardiac function following I/R injury in nondiabetic animals but this was not generally observed in diabetic animals except for CF which was impaired by about 50%. G6 PAMAM treatment completely blocked the protective effects of PPC in the Ctr animals., Conclusion: Acute ex vivo or chronic in vivo treatment with naked G6 PAMAM dendrimer can significantly compromise recovery of non-diabetic hearts from I/R injury and can further negate the beneficial effects of PPC. Our findings are therefore extremely important in the nanotoxicological evaluation of G6 PAMAM dendrimers for potential clinical applications in physiological and pathological settings., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Babiker et al.)

Background: Optical coherence tomography (OCT) requires intracoronary injection of contrast media to remove blood from the field of view during image acquisition. Contrast injection may cause a temporal increase in intracoronary pressure. The aim of this study was to compare the intracoronary pressure during contrast injection between OCT and coronary angiography., Methods: We measured intracoronary pressure by using a pressure guidewire during contrast injection for OCT and angiography in 30 coronary arteries (mean fractional flow reserve = 0.90 ± 0.03). Contrast media was injected into coronary artery through the guiding catheter by using a mechanical injector pump., Results: Intracoronary pressure before contrast injection was similar between OCT and angiography (systolic pressure: 123 ± 18 mmHg vs. 122 ± 19 mmHg, p = 0.863). Intracoronary pressure was increased due to contrast injection in both OCT (systolic pressure: 123 ± 18 mmHg to 132 ± 18 mmHg, p < 0.001) and angiography (systolic pressure: 122 ± 19 mmHg to 128 ± 19 mmHg, p < 0.001). The increase in intracoronary pressure was slightly greater in OCT compared with angiography (absolute increase of systolic pressure: 9 ± 2 mmHg vs. 6 ± 1 mmHg, p < 0.001; and relative increase of systolic pressure: 8 ± 2% vs. 5 ± 1%, p < 0.001). Intracoronary pressure during contrast injection was not significantly different between OCT and angiography (systolic pressure: 132 ± 18 mmHg vs. 128 ± 19 mmHg, p = 0.831)., Conclusions: Contrast injection for OCT induced significant but small increase in intracoronary pressure compared with that for angiography., (Copyright © 2019. Published by Elsevier Ltd.)

Septic shock (SS) leads to a high mortality rate for sepsis patients. Norepinephrine (NE) is a preferred vasoactive agent in SS treatment. This study aimed to assess the effects of NE at different administration time and NE combined with SP treatment on the cardiac function and prognosis of SS.SS patients received NE treatment at different administration time and NE combined with SP treatment were enrolled in this study. The serum levels of cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP), ejection fraction (EF), and pressure-adjusted heart rate (PAR) value were analyzed to evaluate cardiac function. The 28-day survival information was collected and assessed using the Kaplan-Meier method and log-rank test.The cardiac function of SS patients was improved significantly by NE treatment, especially in the patients received NE at 2 h after fluid infusion, which evidenced by the increased BNP and cTnI levels and EF% and the decreased RAP. In the NE-2 h group, SS patients had a better 28-day survival rate compared with those patients in NE-1 h and -3 h groups. Furthermore, the significantly improved cardiac function and survival outcomes were found in patients received NE combined SP treatment.Taken together, this study results show that NE administration at 2 h after fluid infusion may be the optimal time point for the treatment of SS and NE combined with SP treatment can improve early cardiac dysfunction and 28-day survival outcomes in patients with SS.

Background: Ventricular remodeling is a major pathological process of normal heart failure. With the aging of society, poor diet control, social, psychological and other risk factors in our country, the incidence of myocardial infarction and hypertension is reported to increase yearly. Many treatment methods have effectively delayed the occurrence of ventricular remodeling. However, in order to prevent and delay the occurrence and development of ventricular remodeling, the new treatment strategy cannot be ignored., Methods: In this study, we used male C57BL/6 mice (8 weeks old), weight 23 g-27 g, SPF grade. According to the established methods of the research group, the left anterior descending branch of the coronary artery (LAD) was used to make the model of myocardial ischemia, and which was evaluated by the change of EF value in mice. The experiment included seven groups: sham operation group, model group, metoprolol group, puerarin group, tanshinone IIA group, tanshinone IIA: puerarin =1:1 group, tanshinone IIA: puerarin =1:2 group. The changes of cardiac function in each group were observed by echocardiography and hemodynamics after the drug delivery cycle was 3d, 7d, 14d and 28d. Detection of 3d serum enzyme indexes LDH, CK and CK-MB by automatic biochemical analyzer. The expression of CD11b, F4/80, Ly6C in cardiac tissues were detected by flow cytometry at 3d and 7d. The expression of IL-1β and TNF- α in serum were detected by ELISA. IL-1β, IL-6, IL-10, iNOS and other related genes were detected by RT-PCR method. HE, Masson staining and immunohistochemical staining were used to observe the changes of myocardial histomorphology in mice. We also examined the effects of different drug treatments on the proliferation and function of Raw264.7 cells, H9C2 cells and HUVECs. Western blot examined the effects of different drug treatments on the expression of inflammatory pathway related proteins TLR4 and C/EBP-β., Results: 1. Echocardiographic results showed that with the prolongation of ischemic time, the ejection fraction of the model group, the shortening rate of the short axis of the left ventricle, the flow rate of the outflow tract were significantly decreased, and the structure of the ventricle was significantly changed. Hemodynamic tests showed that the maximum and maximum rate of decline in the post-ischemia model group were significantly reduced, with increased systolic and diastolic volume, and a decrease in pressure difference. After treatment with drugs, all groups improved, but tanshinone IIA: puerarin = 1:1 group can significantly improve the above indicators after 28d of administration, which can effectively relieve the deterioration of cardiac function caused by acute myocardial infarction. 2. After administration for 3 and 7 days, the inflammatory cell CD11b monocytes and the F4/80 phenotype macrophages in heart tissue were detected by flow cytometry, and it was found that tanshinone IIA: puerarin = 1:1 can inhibit the release of inflammatory cells. The results of RT-PCR showed that the tanshinone IIA: puerarin = 1:1 group significantly improved the expression of inflammatory cytokines such as IL-1β, IL-6, IL-10, and iNOS. In the immunohistochemical analysis of iNOS and Arg-1, the tanshinone IIA and puerarin 1:1 treatment group was able to inhibit the expression of M1 macrophages in the early stage of inflammation and promote the expression of M2 macrophages. 3. The cardiac index increased significantly and the serum TGF-β increased after 28d. The combination of tanshinone IIA and puerarin could significantly reduce these indexes. HE, Masson, Sirius red and immunohistochemical staining were found in the combination of tanshinone IIA and puerarin can significantly reduce the structure of acute ischemic myocardial cell damage and interstitial edema, reduce collagen synthesis, and fibroblasts release, thereby inhibiting myocardial fibrosis and heart remodeling. 4. MTT assay showed a significantly greater proliferation of above two cells types treated with tanshinone IIA: puerarin =1:1 and more nodes and meshes were found in tanshinone IIA: puerarin =1:1 group compared with other groups. 5. The combination of tanshinone IIA and puerarin could regulate inflammation through inhibiting the expression of TLR4 protein, but up-regulating the expression of C/EBP-β protein., Conclusion: The combination of tanshinone IIA and puerarin inhibits the immersion of inflammatory cells. Improving hemodynamics by improving cardiac function, reducing the destruction of cardiac myocytes, reducing collagen synthesis, inhibiting myocardial fibrosis and ventricular remodeling. Through the whole experiment, tanshinone IIA: puerarin = 1:1 is the best., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Severe burn injury results in systemic disruption of metabolic regulations and impaired cardiac function. Restoration of hemodynamic homeostasis utilizing intravenous (IV) fluids is critical for acute care of the burn victim. However, the effects of burns and resuscitation on cardiomyocyte mitochondria are currently unknown. The purpose of this study is to determine cardiac mitochondrial function in a swine burn model with subsequent resuscitation using either crystalloids or colloids. Anesthetized Yorkshire swine ( n = 23) sustained 40% total body surface area burns and received IV crystalloids ( n = 11) or colloids ( n = 12) after recovery from anesthesia. Non-burned swine served as controls ( n = 9). After euthanasia at 48 h, heart tissues were harvested, permeabilized, and analyzed by high-resolution respirometry. Citrate synthase (CS) activity was measured, and Western blots were performed to quantify proteins associated with mitochondrial fusion (OPA1), fission (FIS1), and mitophagy (PINK1). There were no differences in state 2 respiration or maximal oxidative phosphorylation. Coupled complex 1 respiration decreased, while uncoupled state 4 O and complex II increased significantly due to burn injury, particularly in animals receiving colloids ( P < 0.05). CS activity and electron transfer coupling efficiency were significantly lower in burned animals, particularly with colloid treatment ( P < 0.05). Protein analysis revealed increased FIS1 but no differences in mitophagy in cardiac tissue from colloid-treated compared with crystalloid-treated swine. Taken together, severe burns alter mitochondrial respiration in heart tissue, which may be exacerbated by early IV resuscitation with colloids. Early IV burn resuscitation with colloids may require close hemodynamic observation. Mitochondrial stabilizing agents incorporated into resuscitation fluids may help the hemodynamic response to burn injury.

Background and Aims: Cardiovascular outcome trials have documented a strong benefit of sodium glucose cotransporter-2 inhibitors (SGLT2i) on the risk of hospitalization for heart failure (HF) in patients with type 2 diabetes (T2D) with or without established cardiovascular disease or prior history of HF. The mechanisms, however, are not entirely clear. We aimed to evaluate whether treatment with SGLT2i affected cardiac function using impedance cardiography (ICG) in a randomized placebo-controlled trial., Materials and Methods: Thirty-three patients with T2D were randomized to receive blind dapagliflozin 10 mg or matching placebo for 12-week on top of their ongoing glucose lowering medication regimen. Cardiac function was evaluated by resting ICG at baseline and at the end of the 12-week treatment period. ICG is a non-invasive technology based on the continuous measurement of thoracic electrical conductivity to process a cardiodynamic parameters related to fluid content, blood flow, cardiac function, and circulatory function. We also evaluated changes in glycaemic control, blood pressure, and body weight., Results: Thirty-one patients completed the study, 1 was excluded because ICG data was missing. Patients included in the final analysis were on average 63.4-year-old, with a known diabetes duration of 14.1 years and a baseline HbA1c of 8.2% (66 mmol/mol). 63.3% of patients had established cardiovascular disease (symptomatic or asymptomatic) and 36.7% had microangiopathy, but none had a prior history of HF. After 12 weeks, patients randomized to dapagliflozin, as compared to those randomized to placebo, showed improvements in HbA1c (- 1.2%; 13 mmol/mol), systolic blood pressure (- 3.7 mmHg), and body weight (- 3.3 kg). Based on ICG, in both groups, we detected no significant change in parameters of blood flow (stroke volume, cardiac output, cardiac index), systolic function (ejection fraction, acceleration and velocity indexes, systolic time ratio), circulatory function (systemic vascular resistance index), and fluid status (thoracic fluid content) after treatment., Conclusion: This is the first study exploring cardiac effects of SGLT2i using ICG in T2D. We observed no change in cardiac function parameters estimated by ICG in T2D patients who received dapagliflozin versus placebo for 12 weeks. Trial registration ClinicalTrial.gov NCT02327039. Registered 30 December 2014.

Non-invasive remote detection of cardiac and blood displacements is an important topic in cardiac telemedicine. Here we propose kino-cardiography (KCG), a non-invasive technique based on measurement of body vibrations produced by myocardial contraction and blood flow through the cardiac chambers and major vessels. KCG is based on ballistocardiography and measures 12 degrees-of-freedom (DOF) of body motion. We tested the hypothesis that KCG reliably assesses dobutamine-induced haemodynamic changes in healthy subjects. Using a randomized double-blinded placebo-controlled crossover study design, dobutamine and placebo were infused to 34 volunteers (25 ± 2 years, BMI 22 ± 2 kg/m², 18 females). Baseline recordings were followed by 3 sessions of increasing doses of dobutamine (5, 10, 20 μg/kg.min) or saline solution. During each session, stroke volume (SV) and cardiac output (CO) were determined by echocardiography and followed by a 90 s KCG recording. Measured linear accelerations and angular velocities were used to compute total Kinetic energy (iK) and power (Pmax). KCG sorted dobutamine infusion vs. placebo with 96.9% accuracy. Increases in SV and CO were correlated to iK (r = +0.71 and r = +0.8, respectively, p < 0.0001). Kino-cardiography, with 12-DOF, allows detecting dobutamine-induced haemodynamic changes with a high accuracy and present a major improvement over single axis ballistocardiography or seismocardiography.

Patients with short bowel syndrome (SBS) on long-term home parenteral nutrition (HPN) chronically receive high fluid volumes directly into the right atrium (RA) through the superior vena cava. We retrospectively evaluated cardiac function measured by routine transthoracic echocardiography (TTE) in a population of 26 SBS patients on long-term HPN and compared their data on echocardiograph-derived right heart structure and function, with those of a control group of 26 patients also bearing a central venous catheter (CVC) for other reasons. Results showed that body weight and BMI were significantly higher in the control group. The echocardiographic estimate of RA pressure was higher in HPN patients than in controls ( p = 0.01). An increased estimate of RA pressure indicates the need to consider TTE in the follow-up of long-term HPN patients to detect functional impairment early.

Haemodynamic instability predisposes patients to cardiac complications in non-cardiac surgery. Esmolol, a short-acting cardioselective beta-adrenergic blocker might be efficient in perioperative cardiac protection, but could affect other vital organs, such as the kidneys, and post-discharge survival. We performed a systematic review on the use of esmolol for perioperative cardiac protection. We searched PubMed, Ovid Medline and Cochrane Central Register for Controlled trials. Eligible randomized controlled studies (RCTs) reported a perioperative esmolol intervention with at least one of the primary (major cardiac or renal complications during the first 30 postoperative days) or secondary (postoperative adverse effects and all-cause mortality) outcomes. We included 196 adult patients from three RCTs. Esmolol significantly reduced postoperative myocardial ischaemia, RR =0.43 [95% confidence interval, CI: 0.21-0.88], p = .02. No association with clinically significant bradycardia and hypotension compared to patients receiving control treatment could be confirmed (RR =7.4 [95% CI: 0.29-139.81], p = .18 and RR =2.21 [95% CI: 0.34-14.36], p = .41, respectively). No differences regarding other outcomes were observed. No study reported postoperative renal outcomes. Esmolol seems promising for the prevention of perioperative myocardial ischaemia. However, the association with bradycardia and hypotension remains unclear. Randomized trials investigating the effect of β1-selective blockade on clinically relevant outcomes and non-cardiac vital organs are warranted. Key messages Short-acting cardioselective esmolol seems efficient in the prevention of perioperative myocardial ischaemia. The possibly increased risk of bradycardia and hypotension with short-acting intravenous beta blockade could not be confirmed or refuted by available data. Future adequately powered trials investigating the effect of β1-selective blockade on clinically relevant outcomes and non-cardiac vital organs are warranted.

The effects of a natural complex of cytokines IL-1, IL-2, IL-6, TNF, MIF, and GTFβ on myocardial blood flow were studied under control conditions and during acute experimental aortal stenosis. Systemic administration of the cytokine complex under control conditions led to moderate impairment of the blood flow in the myocardium associated with plethora and perivascular edema. The number of functioning vessels in the myocardium significantly increased under these conditions, which reflected enhancement of the coronary blood flow. The comparison of the myocardial blood flow under conditions of acute heart overload alone and in combination with systemic administration of the cytokine complex revealed similar changes. In both cases, moderate plethora in all compartments of the vascular network, moderate perivascular edema, and moderate blood stasis in the myocardial capillaries were seen. The only difference the increase in the density of functioning capillaries that was significantly more pronounced after cytokine administration. These data indicate that the increase in the blood cytokine level induced dilatation of myocardial vessels and intensification of blood flow in normal and under conditions of acute hemodynamic heart overload. Against the background of pronounced vasodilatation, the dyscirculatory changes in the myocardium were moderate. It was assumed that the increase in the duration or frequency of hypercytokinemia episodes can induce more severe blood flow disturbances in the myocardium.

We investigated the effects of an injectable pimobendan solution (0.15 mg/kg) on cardiac function in healthy dogs. Fifteen dogs were divided into placebo, intravenous pimobendan injection, and subcutaneous pimobendan injection groups. In the placebo, the heart rate, systolic and end-diastolic left ventricular pressure (LVPs and LVEDP), and peak positive (max dP/dt) and negative (min dP/dt) first derivatives of the left ventricular pressure did not change for 60 min. After the intravenous pimobendan injection, LVEDP decreased significantly within 5 min, while the max dP/dt increased, and the effects continued until 60 min. In comparison, there were no hemodynamic changes after the subcutaneous pimobendan injection. This study demonstrates that injectable pimobendan induced a rapid inotropic effect and decreased the LVEDP in dogs.

The peroxisome proliferator-activated receptor-α (PPAR-α) controls the lipid and glucose metabolism and also affects inflammation, cell proliferation and apoptosis during cardiovascular disease. Raspberry ketone (RK) is a red raspberry (Rubusidaeus, Family-Rosaceae) plant constituent, which activates PPAR-α. This study was conducted to assess the cardioprotective action of RK against isoproterenol (ISO)-induced cardiotoxicity. Wistar rats were randomly divided into six groups (six rats/group). Rats were orally administered with RK (50, 100 and 200 mg/kg, respectively) and fenofibrate (standard, 80 mg/kg) for 28 days and ISO was administered (85 mg/kg, subcutaneously) on 27th and 28th day. Administration of ISO in rats significantly altered hemodynamic and electrocardiogram patterns, total antioxidant capacity, PPAR-α, and apolipoprotein C-III levels. These myocardial aberrations were further confirmed during infarct size, heart weight to body weight ratio and immunohistochemical assessments (caspase-3 and nuclear factor-κB). RK pretreatment (100 and 200 mg/kg) significantly protected rats against oxidative stress, inflammation, and dyslipidemia caused by ISO as demonstrated by change in hemodynamic, biochemical and histological parameters. The results so obtained were quite comparable with fenofibrate. Moreover, RK was found to have binding affinity with PPAR-α, as confirmed by docking analysis. PPAR-α expression and concentration was also found increased in presence of RK which gave impression that RK probably showed cardioprotection via PPAR-α activation, however direct binding study of RK with PPAR-α is needed to confirm this assumption., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The therapeutic use of cisplatin for the treatment of solid tumours is associated with organ toxicity. Amongst those, the cardiotoxicity is an occasional but very serious and severe side effect. To prevent or reduce these negative effects, many cisplatin analogues have been synthesized and evaluated in terms of being a less toxic and more effective agent. In present study, we examined the effects of cisplatin and its three analogues in the isolated rat heart to determine whether changes in the structure of the platinum complexes (changing of carrier ligands - ethylenediamine; 1,2-diaminocyclohexane; 2,2':6',2''-terpyridine) can influence their cardiotoxic effects. The results of our research indicate that the introduction of aromatic rings in the structure of the platinum complexes has a negative influence on the heart function. Conversely, the other two examined complexes had less negative effects on heart function compared to cisplatin. Our findings may be of interest for a possible synthetic strategy of introducing a carrier ligand that will exert a less cardiotoxic effect.

This study analyzes whether autonomic dysfunction precedes cardiometabolic alterations in spontaneously hypertensive rats (SHR) with fructose overload. Animals were randomly distributed into three groups: control, hypertensive and hypertensive with fructose overload. Fructose overload (100 g/L) was initiated at 30 days old, and the animals (n = 6/group/time) were evaluated after 7, 15, 30 and 60 days of fructose consumption. Fructose consumption reduced baroreflex sensitivity by day 7, and still induced a progressive reduction in baroreflex sensitivity over the time. Fructose consumption also increased TNFα and IL-6 levels in the adipose tissue and IL-1β levels in the spleen at days 15 and 30. Fructose consumption also reduced plasmatic nitrites (day 15 and 30) and superoxide dismutase activity (day 15 and 60), but increased hydrogen peroxide (day 30 and 60), lipid peroxidation and protein oxidation (day 60). Fructose consumption increased arterial pressure at day 30 (8%) and 60 (11%). Fructose consumption also induced a late insulin resistance at day 60, but did not affect glucose levels. In conclusion, the results show that baroreflex sensitivity impairment precedes inflammatory and oxidative stress disorders, probably by inducing hemodynamic and metabolic dysfunctions observed in metabolic syndrome.

The klotho gene, which encodes a single-pass transmembrane protein and a secreted protein, is expressed predominantly by the distal renal tubules and is related to calcium phosphorus metabolism, ion channel regulation, intracellular signaling pathways, and longevity. Klotho deficiency aggravates acute kidney injury and renal fibrosis. Exposure to nicotine also worsens kidney injury. Here, we investigated renal Klotho protein expression in a mouse model of chronic (28-day) nicotine exposure, in which mice received nicotine or vehicle (saccharine) in drinking water, comparing wild-type (WT) mice, klotho-haploinsufficient ( kl/+) mice, and their respective controls, in terms of the effects of that exposure. Nicotine exposure was associated with a significant decline in renal Klotho expression in WT and kl/+ mice as well as a reduction in the glomerular filtration rate in WT mice. Although plasma electrolytes were similar among the groups, fractional excretion of sodium was reduced in both nicotine-exposed groups. The nicotine-WT mice presented augmented baroreflex sensitivity to nitroprusside and augmented sympathetic cardiac modulation. However, nicotine- kl/+ mice presented higher plasma levels of urea and aldosterone together with a higher α-index (spontaneous baroreflex) and higher peripheral sympathetic modulation, as evaluated by spectral analysis. We can conclude that nicotine downregulates Klotho expression as well as that renal and autonomic responses to nicotine exposure are modified in kl/+ mice.

Isolated muscle metaboreflex activation with posthandgrip exercise ischemia (PEI) increases sympathetic nerve activity and partially maintains the exercise-induced increase in blood pressure, but a smaller heart rate (HR) response occurs. The cardiopulmonary baroreceptors, mechanically sensitive receptors that respond to changes in central blood volume and pressure, are strongly associated with changes in body position and upon activation elicit reflex sympathoinhibition. Here, we tested the hypothesis that postural changes modulate the sympathetically mediated cardiac response to PEI in humans. Beat-to-beat HR (electrocardiography) and blood pressure (finger photoplethysmography) were continuously measured, and cardiac function was assessed by echocardiography in 13 healthy men (21 ± 3 yr). After a 15-min rest period, 90-s static handgrip at 40% maximum voluntary contraction was performed followed by 3 min of PEI. Four trials were randomly conducted during either seated or supine position with and without β 1 -adrenergic blockade (25 mg atenolol). During PEI under control conditions, HR remained elevated from baseline in the seated [change (Δ): 4 ± 1 beats/min] but not in the supine (change: -1 ± 1 beats/min) position. Similarly, stroke volume and cardiac output were increased from baseline in the seated (∆13.0 ± 2.4 ml and ∆1.1 ± 0.2 l/min, respectively) but not in the supine (∆2.5 ± 2.9 ml and ∆0.13 ± 0.20 l/min, respectively) position. During β 1 -adrenergic blockade, HR, stroke volume, and cardiac output remained unchanged in both conditions. We conclude that sympathetically mediated cardiac responses to PEI are influenced by changes in body position. These findings indicated that muscle metaboreflex and cardiopulmonary baroreflex have an interactive influence on the neural control of cardiovascular function in humans. NEW & NOTEWORTHY In the present study, we demonstrated that muscle metaboreflex activation increases heart rate, stroke volume, and cardiac output in the seated position but not in the supine position and not after β 1 -adrenergic blockade. These findings indicate that sympathetically mediated cardiac responses to isolated muscle metaboreflex activation after exercise are modulated by central blood volume mobilization.

Protein quality control in cardiomyocytes is crucial to maintain cellular homeostasis. The accumulation of damaged organelles, such as mitochondria and misfolded proteins in the heart is associated with heart failure. During the process to identify novel mitochondria-specific autophagy (mitophagy) receptors, we found FK506-binding protein 8 (FKBP8), also known as FKBP38, shares similar structural characteristics with a yeast mitophagy receptor, autophagy-related 32 protein. However, knockdown of FKBP8 had no effect on mitophagy in HEK293 cells or H9c2 myocytes. Since the role of FKBP8 in the heart has not been fully elucidated, the aim of this study is to determine the functional role of FKBP8 in the heart. Cardiac-specific FKBP8-deficient (Fkbp8 -/- ) mice were generated. Fkbp8 -/- mice showed no cardiac phenotypes under baseline conditions. The Fkbp8 -/- and control wild type littermates (Fkbp8 +/+ ) mice were subjected to pressure overload by means of transverse aortic constriction (TAC). Fkbp8 -/- mice showed left ventricular dysfunction and chamber dilatation with lung congestion 1week after TAC. The number of apoptotic cardiomyocytes was dramatically elevated in TAC-operated Fkbp8 -/- hearts, accompanied with an increase in protein levels of cleaved caspase-12 and endoplasmic reticulum (ER) stress markers. Caspase-12 inhibition resulted in the attenuation of hydrogen peroxide-induced apoptotic cell death in FKBP8 knockdown H9c2 myocytes. Immunocytological and immunoprecipitation analyses indicate that FKBP8 is localized to the ER and mitochondria in the isolated cardiomyocytes, interacting with heat shock protein 90. Furthermore, there was accumulation of misfolded protein aggregates in FKBP8 knockdown H9c2 myocytes and electron dense deposits in perinuclear region in TAC-operated Fkbp8 -/- hearts. The data suggest that FKBP8 plays a protective role against hemodynamic stress in the heart mediated via inhibition of the accumulation of misfolded proteins and ER-associated apoptosis., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ginseng, a popular herbal remedy, is often used in combination with other drugs to achieve the maximum therapeutic response. Shenfu (SFI) and Shenmai injection (SMI) have been widely used to treat cardiovascular disease in China. Our study explored the cardiovascular protection of SFI and SMI in eNOS knockout mice to investigate the differences and similarities of the two ginseng-combinations. Transthoracic echocardiography was performed to evaluate the left ventricular structure and function at baseline and 3, 7, and 14 days after drug administration. Agilent Gene Expression microarrays were used to demonstrate the gene expression profiling of the thoracic aorta. Ingenuity Pathway Analysis was performed to evaluate the mechanism improved by SFI and SMI in eNOS knockout mice. Both SFI and SMI could modulate Gadd45 Signaling from TOP15 canonical pathways. Moreover, SFI showed a better effect in the early treatment stage and improved myocardial function via GATA4, GATA6 and COL3A1. Meanwhile, SMI exerted better protective effects at the chronic stage, which may be related to endothelium protection by VEGFA and ACE. The advantage of multi-target by drug combination in progression of complex diseases should be noticed. The appropriate adjustment of drug combination could lead to a better accurate medical care in clinic.

Curcumin, a phytochemical component derived from turmeric (Carcuma longa), has been extensively investigated because of its anti-inflammatory and anti-oxidative properties. Inflammation and oxidative stress play critical roles in posttraumatic cardiomyocyte apoptosis, which contributes to secondary cardiac dysfunction. This research was designed to identify the protective effect of curcumin on posttraumatic cardiac dysfunction and investigate its underlying mechanism. Noble-Collip drum was used to prepare a mechanical trauma (MT) model of rats, and the hemodynamic responses of traumatized rats were observed by ventricular intubation 12h after trauma. Myocardial apoptosis was determined through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activity assay. Tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS) generated by monocytes and myocardial cells were identified through enzyme-linked immunosorbent assay (ELISA), and the intracellular alteration of Ca 2+ in cardiomyocytes was examined through confocal microscopy. In vivo, curcumin effectively ameliorated MT-induced secondary cardiac dysfunction and significantly decreased the apoptotic indices of the traumatized myocardial cells. In vitro, curcumin inhibited TNF-α production by monocytes and reduced the circulating TNF-α levels. With curcumin pretreatment, ROS production and Ca 2+ overload in H9c2 cells were attenuated when these cells were incubated with traumatic plasma. Therefore, curcumin can effectively ameliorate MT-induced cardiac dysfunction mainly by inhibiting systemic inflammatory responses and by weakening oxidative stress reaction and Ca 2+ overload in cardiomyocytes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Sunitinib is an anti-cancer tyrosine kinase inhibitor associated with severe cardiotoxic adverse effects. Using rat Langendorff heart model and human acute myeloid leukaemia 60 (HL60) cell line we detected the involvement of protein kinase C (PKC) α during Sunitinib-induced cardiotoxicity and the effect of Sunitinib on cancer progression. The cardioprotective and anti-cancer properties of the A 3 adenosine receptor agonist 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) were investigated. The cardiac effect of Sunitinib (1µM) and IB-MECA (1nM) treatment was measured through haemodynamic and infarct size assessment. The cytotoxic effect of Sunitinib (0.1 - 10μM) and IB-MECA (10nM - 10μM) on HL60 cells was assessed using the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay technique. Myocardial injury associated microRNAs (miR-1, miR-27a, miR-133a and miR-133b) and cancer associated microRNAs (miR-15a, miR-16-1 and miR-155) were profiled by qRT-PCR in the cardiac tissue and HL60 cells, while phosphorylated PKCα levels were measured by Western Blot analysis. Sunitinib treatment increased infarct size and decreased left ventricular developed pressure and heart rate. Co-treatment of IB-MECA reversed the myocardial injury produced by Sunitinib administration. IB-MECA did not jeopardize the anti-cancer effect of Sunitinib in HL60 cells. The expression signature of the specific microRNAs in cardiac tissue and HL60 cells showed an altered expression profile when treated with Sunitinib and IB-MECA. pPKCα levels were increased by Sunitinib treatment in cardiac tissue and HL60 cells and co-administration of IB-MECA attenuated this increase in the cardiac tissue. This study reveals that A 3 adenosine receptor activation by IB-MECA attenuates Sunitinib-induced cardiotoxicity through the involvement of PKCα., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mechanical activity of the heart is adversely affected in metabolic syndrome (MetS) characterized by increased body mass and marked insulin resistance. Herein, we examined the effects of high carbohydrate intake on cardiac function abnormalities by evaluating in situ heart work, heart rate, and electrocardiograms (ECGs) in rats. MetS was induced in male Wistar rats by adding 32% sucrose to drinking water for 22-24 weeks and was confirmed by insulin resistance, increased body weight, increased blood glucose and serum insulin, and increased systolic and diastolic blood pressures in addition to significant loss of left ventricular integrity and increased connective tissue around myofibrils. Analysis of in situ ECG recordings showed a markedly shortened QT interval and decreased QRS amplitude with increased heart rate. We also observed increased oxidative stress and decreased antioxidant defense characterized by decreases in serum total thiol level and attenuated paraoxonase and arylesterase activities. Our data indicate that increased heart rate and a shortened QT interval concomitant with higher left ventricular developed pressure in response to β-adrenoreceptor stimulation as a result of less cyclic AMP release could be regarded as a natural compensation mechanism in overweight rats with MetS. In addition to the persistent insulin resistance and obesity associated with MetS, one should consider the decreased heart work, increased heart rate, and shortened QT interval associated with high carbohydrate intake, which may have more deleterious effects on the mammalian heart.

While heart transplantation (HTX) is the definitive therapy of heart failure, donor shortage is emerging. Pharmacological activation of soluble guanylate cyclase (sGC) and increased cGMP-signalling have been reported to have cardioprotective properties. Gemfibrozil has recently been shown to exert sGC activating effects in vitro. We aimed to investigate whether pharmacological preconditioning of donor hearts with gemfibrozil could protect against ischemia/reperfusion injury and preserve myocardial function in a heterotopic rat HTX model. Donor Lewis rats received p.o. gemfibrozil (150 mg/kg body weight) or vehicle for 2 days. The hearts were explanted, stored for 1 h in cold preservation solution, and heterotopically transplanted. 1 h after starting reperfusion, left ventricular (LV) pressure-volume relations and coronary blood flow (CBF) were assessed to evaluate early post-transplant graft function. After 1 h reperfusion, LV contractility, active relaxation and CBF were significantly (p < 0.05) improved in the gemfibrozil pretreated hearts compared to that of controls. Additionally, gemfibrozil treatment reduced nitro-oxidative stress and apoptosis, and improved cGMP-signalling in HTX. Pharmacological preconditioning with gemfibrozil reduces ischemia/reperfusion injury and preserves graft function in a rat HTX model, which could be the consequence of enhanced myocardial cGMP-signalling. Gemfibrozil might represent a useful tool for cardioprotection in the clinical setting of HTX surgery soon.

The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ANG II) receptor antagonists in patients with heart failure secondary to reduced ejection fraction (HFrEF) are felt to result from prevention of the adverse effects of ANG II on systemic afterload and renal homeostasis. However, ANG II can activate the sympathetic nervous system, and part of the beneficial effects of ACE inhibitors and ANG II antagonists may result from their ability to inhibit such activation. We examined the acute effects of the ACE inhibitor captopril (25 mg, n = 9) and the ANG II receptor antagonist losartan (50 mg, n = 10) on hemodynamics as well as total body and cardiac norepinephrine spillover in patients with chronic HFrEF. Hemodynamic and neurochemical measurements were made at baseline and at 1, 2, and 4 h after oral dosing. Administration of both drugs caused significant reductions in systemic arterial, cardiac filling, and pulmonary artery pressures ( P < 0.05 vs. baseline). There was no significant difference in the magnitude of those hemodynamic effects. Plasma concentrations of ANG II were significantly decreased by captopril and increased by losartan ( P < 0.05 vs. baseline for both). Total body sympathetic activity increased in response to both captopril and losartan ( P < 0.05 vs. baseline for both); however, there was no change in cardiac sympathetic activity in response to either drug. The results of the present study do not support the hypothesis that the acute inhibition of the renin-angiotensin system has sympathoinhibitory effects in patients with chronic HFrEF., (Copyright © 2017 the American Physiological Society.)

Metabonomics/metabolomics is a rapid technology for comprehensive profiling of small molecule metabolites in cells, tissues, or whole organisms, the application of which has led to understanding pathophysiologic mechanisms of cardiometabolic diseases, defining predictive biomarkers for those diseases, and also assessing the efficacious effects of incident drugs. In this study, proton nuclear magnetic resonance (NMR)-based metabonomics was employed to identify the metabolic changes in rat plasma caused by myocardial ischemia-reperfusion injury (MIRI), and to compare the metabolic regulatory differences between traditional Chinese medicine Wenxin Keli (WXKL) and Western medicine verapamil. The results revealed that energy-substrate metabolism were significantly disturbed by ischemia-reperfusion (I/R) in myocardium and bulk of the key metabolites could be further modulated by verapamil and/or WXKL. Lipid metabolism and amino acid transamination occurred mainly following the treatment of verapamil, whereas glucose oxidation and BCAA degradation were prominently ameliorated by WXKL to content the energy demands of heart. Moreover, both WXKL and verapamil improved the secretions of taurine and ketone bodies to overcome the oxidative stress and the shortage of energy sources induced by ischemia-reperfusion.

Treatment with beta-blockers appears to show inferior reduction in central versus peripheral blood pressure. We aimed to examine simultaneous changes in central and peripheral blood pressure, vascular resistance, cardiac function and arterial stiffness during beta-blockade. Haemodynamics were investigated after 3 weeks of bisoprolol treatment (5 mg/day) in a double-blind, randomized, placebo-controlled cross-over trial in never-treated 16 Caucasian males with grade I-II primary hypertension using continuous tonometric pulse wave analysis and whole-body impedance cardiography. Bisoprolol decreased radial (134/80 versus 144/89 mmHg) and aortic blood pressure (122/80 versus 130/90 mmHg) and heart rate (57 versus 68 beats/min) when compared with placebo (p < 0.05 for all). Ejection duration (336 versus 316 ms) and stroke volume (109 versus 98 ml) were increased (p < 0.01 for all), while cardiac output was not significantly changed (6.2 versus 6.6 l/min). Bisoprolol decreased pulse wave velocity (7.8 versus 8.9 m/s, p < 0.001), but after adjustment for blood pressure, the decrease was not significant (8.16 versus 8.52 m/s, p = 0.464). The treatment reduced pulse pressure amplification from central to peripheral circulation (30 versus 38%, p = 0.002). No differences were observed in systemic vascular resistance, augmentation index, aortic characteristic impedance or total arterial stiffness after bisoprolol versus placebo. Bisoprolol decreased central and peripheral blood pressure and pulse wave velocity in male individuals with grade I to grade II hypertension. The decrease in pulse wave velocity was related to the antihypertensive effect. Reduced pulse pressure amplification indicates that peripheral blood pressure was reduced more efficiently than central blood pressure., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

This study has investigated the role of the α 2 -adrenoceptor subtypes involved in the inhibition of the cardiac sympathetic outflow induced by intravenous (i.v) infusions of agmatine. Therefore, we analysed the effect of an i.v. bolus injections of the selective antagonists BRL 44408 (300μg/kg; α 2A ), imiloxan (3000μg/kg; α 2B ), and JP-1302 (300μg/kg; α 2C ) given separately, and their combinations: BRL 44408 plus Imiloxan, JP 1302 plus imiloxan, BRL 44408 plus JP-1302, BRL 44408 plus imiloxan plus JP-1302 on the cardiac sympatho-inhibition of agmatine. Also, the effect of the combination BRL 44408 plus JP-1302 plus AGN 192403 (3000μg/kg; I 1 antagonist) was evaluated. In this way, i.v. infusions of 1000μg/kg min of agmatine, but not 300, inhibited the tachycardic response induced by electrical stimulation. Furthermore, the antagonists used or their combinations had no effect on the electrically-induced tachycardic response. On the other hand, the inhibitory response of agmatine was: (1) partially antagonized by BRL 44408 or JP-1302 given separately, a similar response was observed when we administered their combination with imiloxan, but not by imiloxan alone, (2) antagonized in greater magnitude by the combination BRL 44408 plus JP-1302 or the combination BRL 44408 plus imiloxan plus JP-1302, and (3) abolished by the combination BRL 44408 plus JP-1302 plus AGN 192403. Taken together, these results demonstrate that the α 2A - and α 2C -adrenoceptor subtypes and I 1 -imidazoline receptors are involved in the inhibition of the cardiac sympathetic outflow induced by agmatine., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of this study was to prove whether albumin-derived perfluorocarbon-based nanoparticles (capsules) can operate as a novel artificial oxygen carrier in a rat Langendorff-heart perfusion model. Hearts perfused with capsules showed increased left ventricular pressure and rate pressure product compared to hearts perfused with pure Krebs-Henseleit (KH)-buffer. The capsules prevented the myocardium from functional fail when in their absence a noxious ischemia was observed. Capsules did not change rheological properties of KH-buffer and could repeatedly reload with oxygen. This albumin-derived perfluorocarbon-based artificial oxygen carrier preserved the function of rat hearts due to the transport of oxygen in a satisfactory manner. Because of these positive results, the functionality of the applied capsules should be verified in living animals.

Hemorrhage impairs myocardial contractile function and decreases oxygen delivery. This study investigates how polymerized bovine hemoglobin (PolyHb) solutions affect cardiac function after resuscitation from hemorrhagic shock (HS). Hamsters were hemorrhaged and resuscitated with PolyHb at 8.5 g/dL and 11.5 g/dL. Left ventricle (LV) function was assessed during shock and resuscitation using a miniaturize conductance catheter. PolyHb resuscitation had no beneficial effects in cardiac function; it increased cardiac afterload and systemic vascular resistance (SVR) of 46 and 116% for 8.5 and 11.5 g/dL, respectively. Study findings indicate that preclinical evaluation of cardiac function is essential to develop safe and efficacious alternatives to blood transfusion.

Background: Despite the emerging evidence on beneficial effects of probiotics on the cardiovascular system, their impact on the management of ischemic heart diseases and its possible mechanism have not been elucidated., Methods: Four viable probiotics bacterial strains, including Bifidobacterium breve, Lactobacillus casei, Lactobacillus bulgaricus and Lactobacillus acidophilus, at the concentrations of 2×106 colony-forming units/ml were orally administered to the rats daily for 14 days before the induction of infarct-like myocardial injury using isoproterenol. Subsequently, 24 h after myocardial injury, the right carotid artery and the left ventricle were catheterized for recording blood pressure and cardiac parameters. At the end of the experiment, the heart was removed for the evaluation of histopathological and biochemical parameters, as well as tumor necrosis factor-alpha (TNF-α) assay., Results: The induction of acute myocardial injury resulted in significant (P≤0.01) left ventricular (LV) dysfunction, as shown by an increase in LV end-diastolic pressure and a decrease in LV dp/dt max, LV dp/dt min, LV systolic pressure, and blood pressure, as compared with normal rats. Pretreatment with viable probiotics significantly reduced lipid peroxidation and TNF-α level and improved cardiac function (P<0.01)., Conclusion: This study shows that viable probiotics have a cardioprotective effect on infarct-like myocardial injury through suppressing TNF-α and oxidative stress damage in a rat model. Probiotic supplements may be used as a new option for prophylaxis in patients at the risk of ischemic heart disease in future.

Urotensin II and its receptor are thought to be involved in various cardiovascular diseases such as heart failure, pulmonary hypertension and atherosclerosis. Since the regulation of the urotensin II/urotensin II receptor offers a great potential for therapeutic strategies related to the treatment of cardiovascular diseases, the study of selective and potent antagonists for urotensin II receptor is more fascinating. This study was designed to determine the potential therapeutic effects of a newly developed novel urotensin II receptor antagonist, N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)benzo[b]thiophene-3-carboxamide (KR-36996), in experimental models of heart failure. KR-36996 displayed a high binding affinity (Ki=4.44±0.67nM) and selectivity for urotensin II receptor. In cell-based study, KR-36996 significantly inhibited urotensin II-induced stress fiber formation and cellular hypertrophy in H9c2 UT cells. In transverse aortic constriction-induced cardiac hypertrophy model in mice, the daily oral administration of KR-36996 (30mg/kg) for 14 days significantly decreased left ventricular weight by 40% (P<0.05). In myocardial infarction-induced chronic heart failure model in rats, repeated echocardiography and hemodynamic measurements demonstrated remarkable improvement of the cardiac performance by KR-36996 treatment (25 and 50mg/kg/day, p.o.) for 12 weeks. Moreover, KR-36996 decreased interstitial fibrosis and cardiomyocyte hypertrophy in the infarct border zone. These results suggest that potent and selective urotensin II receptor antagonist could efficiently attenuate both cardiac hypertrophy and dysfunction in experimental heart failure. KR-36996 may be useful as an effective urotensin II receptor antagonist for pharmaceutical or clinical applications., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Rosuvastatin, a potent HMG-CoA reductase inhibitor, is cholesterol-lowering drugs and reduce the risk of myocardial infarction and stroke. This study is to explore whether rosuvastatin improves outcomes after cardiac arrest in rats. Male Sprague-Dawley rats were subjected to 8min of cardiac arrest (CA) by asphyxia and randomly assigned to three experimental groups immediately following successful resuscitation: Sham; Control; and Rosuvastatin. The survival, hemodynamics, myocardial function, neurological outcomes and apoptosis were assessed. The 7-d survival rate was greater in the rosuvastatin treated group compared to the Control group (P=0.019 by log-rank test). Myocardial function, as measured by cardiac output and ejection fraction, was significantly impaired after CA and notably improved in the animals treated with rosuvastatin beginning at 60min after return of spontaneous circulation (ROSC) (P<0.05). Moreover, rosuvastatin treatment significantly ameliorated brain injury after ROSC, which was characterized by the increase of neurological function scores, and reduction of brain edema in cortex and hippocampus (P<0.05). Meanwhile, the levels of cardiac troponin T and neuron-specific enolase and the caspase-3 activity were significantly decreased in the Rosuvastatin group when compared with the Control group (P<0.05). In conclusion, rosuvastatin treatment substantially improves the 7-d survival rate as well as myocardial function and neurological outcomes after ROSC., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The immunosuppressant drug cyclosporine A (CSA) improves survivability in endotoxemia and offsets associated loss in vascular reactivity and hypotension. We tested the hypothesis that central phosphoinositide-3-kinase (PI3K)/soluble guanylate cyclase (sGC)/mitogen activated protein kinases (MAPKs) cascade modulates the CSA counteraction of endotoxic hypotension and cardiac autonomic dysfunction. The effects of pharmacologic inhibition of these molecular substrates in central pools on CSA interaction with cardiovascular responses evoked by lipopolysaccharide (LPS) were evaluated in conscious rats. CSA (10mg/kg) reversed the LPS-evoked (i) hypotension and tachycardia, (ii) decreases in time and spectral measures of heart rate variability (HRV), and (iii) increases in serum TNFα and IL-6. These CSA effects disappeared after intracisternal (i.c.) administration of ODQ (sGC inhibitor) but not wortmannin (PI3K inhibitor). When used alone, ODQ or wortmannin abolished the LPS-evoked hypotension and tachycardia, but had no effect on the concomitant reductions in HRV. We also report that the reversal by CSA of LPS hypotension disappeared after treatment with i.c SB203580 (MAPK p38 inhibitor) or PD98059 (MAPK ERK inhibitor), in contrast to little effect for SP600125 (MAPK JNK inhibitor). Alternatively, the CSA amelioration of LPS-evoked reductions in HRV was abolished in presence of SP600125 or PD98059, but not SB203580. The single exposure to SP600125 reduced the decreases in blood pressure, but not HRV, caused by LPS whereas SB203580 produced the exact opposite effects. Together, while central sGC/MAPKs circuits modulate the CSA counteraction of endotoxic manifestations, the recruitment of individual MAPKs into this interaction depends on the nature of the cardiovascular response., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: We documented the dependence of ethanol (EtOH)-evoked myocardial dysfunction on estrogen (E 2 ), and our recent estrogen receptor (ER) blockade study, in proestrus rats, implicated ERα signaling in this phenomenon. However, a limitation of selective pharmacological loss-of-function approach is the potential contribution of the other 2 ERs to the observed effects because crosstalk exists between the 3 ERs. Here, we adopted a "regain"-of-function approach (using selective ER subtype agonists) to identify the ER subtype(s) required for unraveling the E 2 -dependent myocardial oxidative stress/dysfunction caused by EtOH in conscious ovariectomized (OVX) rats., Methods: OVX rats received a selective ERα (PPT), ERβ (DPN), or GPER (G1) agonist (10 μg/kg; i.v.) or vehicle 30 minutes before EtOH (1.0 g/kg; infused i.v. over 30 minutes) or saline, and the hemodynamic recording continued for additional 60 minutes. Thereafter, left ventricular tissue was collected for conducting ex vivo molecular/biochemical studies., Results: EtOH had no hemodynamic effects in OVX rats, but reduced the left ventricular contractility index, dP/dt max , and MAP after acute ERα (PPT) or ERβ (DPN) activation. These responses were associated with increases in the phosphorylation of ERK1/2 and eNOS, and in reactive oxygen species (ROS) and malondialdehyde (MDA) levels in the myocardium. GPER activation (G1) only unraveled a modest EtOH-evoked hypotension and elevation in myocardial ROS. PPT enhanced catalase, DPN reduced ALDH2, while G1 had no effect on the activity of either enzyme, and none of the agonists influenced alcohol dehydrogenase or CYP2E1 activities in the myocardium. Blood EtOH concentration (96.0 mg/dl) was significantly reduced following ERα (59.8 mg/dl) or ERβ (62.9 mg/dl), but not GPER (100.3 mg/dl), activation in EtOH-treated OVX rats., Conclusions: ERα and ERβ play major roles in the E 2 -dependent myocardial dysfunction caused by EtOH by promoting combined accumulation of cardiotoxic (ROS and MDA) and cardiodepressant (NOS-derived NO) molecules in female myocardium., (Copyright © 2016 by the Research Society on Alcoholism.)

Background and Objectives: This study was aimed to examine how inotropic effects of intravenously injected epinephrine change thoracic impedance measurements and to reveal the possible effects of this change on other hemodynamic parameters by using the technique of impedance cardiography., Methods: 10 male Wistar Albino rats were divided into two equal groups: control and epinephrine. 0.2 mg/kg of epinephrine was administered to the rats in the epinephrine group via the tail vein. All hemodynamic parameters obtained by impedance cardiography [the base impedance (Z0), the maximum rate of change in impedance (dZmax/dt), the left ventricular ejection time (LVET), stroke volume (SV), cardiac output (CO), contractility index (IC), thoracic fluid content (TFC), heart rate (HR)] were recorded using the EBI 100C, DA 100 and ECG modules in the BIOPAC MP100 system., Results: CO (p ≤ 0.05), HR (p ≤ 0.001), dZmax/dt (p ≤ 0.05) and IC (p ≤ 0.05) increased statistically significantly in the epinephrine group compared to the control group. However, LVET (p ≤ 0.001) decreased statistically significantly in the epinephrine group compared to the control group., Conclusion: Tachycardia was detected in the epinephrine group. There was an inverse correlation between LVET and dZmax/dt and IC. This is based on the fact that epinephrine increases inotropic effect (Tab. 2, Fig. 4, Ref. 30).

Background: Extracorporeal cardiopulmonary resuscitation (E-CPR) is increasingly used as a rescue method in the management of cardiac arrest and provides the opportunity to rapidly induce therapeutic hypothermia. The survival after a cardiac arrest is related to post-arrest cardiac function, and the application of therapeutic hypothermia post-arrest is hypothesized to improve cardiac outcome. The present animal study compares normothermic and hypothermic E-CPR considering resuscitation success, post-arrest left ventricular function and magnitude of myocardial injury., Methods: After a 15-min untreated ventricular fibrillation, the pigs (n = 20) were randomized to either normothermic (38 °C) or hypothermic (32-33 °C) E-CPR. Defibrillation terminated ventricular fibrillation after 5 min of E-CPR, and extracorporeal support continued for 2 h, followed by warming, weaning and a stabilization period. Magnetic resonance imaging and left ventricle pressure measurements were used to assess left ventricular function pre-arrest and 5 h post-arrest. Myocardial injury was estimated by serum concentrations of cardiac TroponinT and Aspartate transaminase (ASAT)., Results: E-CPR resuscitated all animals and the hypothermic strategy induced therapeutic hypothermia within minutes without impairment of the resuscitation success rate. All animals suffered a severe global systolic left ventricular dysfunction post-arrest with 50-70% reductions in stroke volume, ejection fraction, wall thickening, strain and mitral annular plane systolic excursion. Serum concentrations of cardiac TroponinT and ASAT increased considerably post-arrest. No significant differences were found between the two groups., Conclusions: Two-hour therapeutic hypothermia during E-CPR offers an equal resuscitation success rate, but does not preserve the post-arrest cardiac function nor reduce the magnitude of myocardial injury, compared to normothermic E-CPR. Trial registration FOTS 4611/13 registered 25 October 2012.

In the past two decades, titanium dioxide nanoparticles (TiO 2 NPs) have been extensively used in medicine, food industry and other daily life, while their possible interactions with the their influence and human body on human health remain not well understood. Thus, the study was designed to examine whether long-term exposure to TiO 2 NPs cause myocardial dysfunction which is involved in cardiac lesions and alter expression of genes and proteins involving inflammatory response in the mouse heart. The findings showed that intragastric feeding for nine consecutive months with TiO 2 NPs resulted in titanium accumulation, infiltration of inflammatory cells and apoptosis of heart, reductions in net increases of body weight, cardiac indices of function (LV systolic pressure, maximal rate of pressure increase over time, maximal rate of pressure decrease over time and coronary flow), and increases in heart indices, cardiac indices of function (LV end-diastolic pressure and heart rate) in mice. TiO 2 NPs also decreased ATP production in the hearts. Furthermore, TiO 2 NPs increased expression of nuclear factor-κB, interleukin-lβ and tumour necrosis factor-α, and reduced expression of anti-inflammatory cytokines including suppressor of cytokine signaling (SOCS) 1 and SOCS3 in the cardiac tissue. These results suggest that TiO 2 NPs may modulate the cardiac function and expression of inflammatory cytokines. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2917-2927, 2016., (© 2016 Wiley Periodicals, Inc.)

This study shows that in spontaneously hypertensive rats (SHR) of 14-weeks-old, the sympathetically-induced, but not noradrenaline-induced tachycardic response are higher than age-matched Wistar normotensive rats. Furthermore, in SHR the sympathetically-induced tachycardic response was: (1) unaffected by moxonidine (3μg/kgmin); (2) partially inhibited by B-HT 933 (30μg/kgmin), both at the lowest doses; and (3) completely inhibited by the highest doses of B-HT 933 (100μg/kgmin), moxonidine (10μg/kgmin) or agmatine (1000 and 3000μg/kgmin) while the noradrenaline-induced tachycardic responses remained unaffected by the above compounds, except by 3000μg/kgmin agmatine. In SHR, 300μg/kg rauwolscine failed to block the sympatho-inhibition to 100μg/kgmin B-HT 933 or 10μg/kgmin moxonidine, but 1000μg/kg rauwolscine abolished, partially antagonized, and did not modify the sympatho-inhibition to the highest doses of B-HT 933, moxonidine, and agmatine, respectively, 3000μg/kg AGN 192403 or 300μg/kg BU224 given alone had no effect in the moxonidine- or agmatine-induced sympatho-inhibition, and the combination rauwolscine plus AGN 192403 but not plus BU224, abolished the sympatho-inhibition to the highest doses of moxonidine and agmatine. In conclusion, the sympathetically-induced tachycardic responses in SHR are inhibited by moxonidine and agmatine. The inhibition of moxonidine is mainly mediated by prejunctional α 2 -adrenoceptors and to a lesser extent by I 1 -imidazoline receptors, while the inhibition of agmatine is mediated by prejunctional α 2 -adrenoceptors and I 1 -imidazoline receptors at the same extent. Notwithstanding, the inhibitory function of α 2 -adrenoceptors seems to be altered in SHR compared with Wistar normotensive rats., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aims: Hemodynamic instability occurs following cardiac arrest and is associated with high mortality during the post-cardiac period. Urocortin is a novel peptide and a member of the corticotrophin-releasing factor family. Urocortin has the potential to improve acute cardiac dysfunction, as well as to reduce the myocardial damage sustained after ischemia reperfusion injury. The effects of urocortin in post-cardiac arrest myocardial dysfunction remain unclear., Methods and Results: We developed a preclinical cardiac arrest model and investigated the effects of urocortin. After cardiac arrest induced by 6.5 min asphyxia, male Wistar rats were resuscitated and randomized to either the urocortin treatment group or the control group. Urocortin (10 μg/kg) was administrated intravenously upon onset of resuscitation in the experimental group. The rate of return of spontaneous circulation (ROSC) was similar between the urocortin group (76%) and the control group (72%) after resuscitation. The left ventricular systolic (dP/dt40) and diastolic (maximal negative dP/dt) functions, and cardiac output, were ameliorated within 4 h after ROSC in the urocortin-treated group compared to the control group (P<0.01). The neurological function of surviving animals was better at 6 h after ROSC in the urocortin-treated group (p = 0.023). The 72-h survival rate was greater in the urocortin-treated group compared to the control group (p = 0.044 by log-rank test). Cardiomyocyte apoptosis was lower in the urocortin-treated group (39.9±8.6 vs. 17.5±4.6% of TUNEL positive nuclei, P<0.05) with significantly increased Akt, ERK and STAT-3 activation and phosphorylation in the myocardium (P<0.05)., Conclusions: Urocortin treatment can improve acute hemodynamic instability as well as reducing myocardial damage in post-cardiac arrest myocardial dysfunction., Competing Interests: The authors have declared that no competing interests exist.

Background: Accumulating evidence suggests a cardioprotective role of pacing postconditioning (PPC) maneuvers in animal models and more recently in humans. The procedure however remains to be optimized and its interaction with physiological systems remains to be further explored. The renin angiotensin system (RAS) plays a dual role in ischemia/reperfusion (I/R) injury. The interaction between RAS and PPC induced cardiac protection is however not clearly understood. We have recently demonstrated that angiotensin (1-7) via Mas receptor played a significant role in PPC mediated cardiac protection against I/R injury., Objective: The objective of this study was to investigate the role of angiotensin converting enzyme (ACE)-chymase-angiotensin II (Ang II)-angiotensin receptor 1 (AT1) axes of RAS in PPC mediated cardiac protection., Methods: Isolated rat hearts were subjected to I/R (control) or PPC in the presence or absence of Ang II, chymostatin (inhibitor of locally produced Ang II), ACE blocker (captopril) or AT1 antagonist (irbesartan). Hemodynamics data was computed digitally and infarct size was determined histologically using TTC staining and biochemically by measuring creatine kinase (CK) and lactate dehydrogenase levels., Results: Cardiac hemodynamics were significantly (P<0.001) improved and infarct size and cardiac enzymes were significantly (P<0.001) reduced in hearts subjected to PPC relative to hearts subjected to I/R injury. Exogenous administration of Ang II did not affect I/R injury or PPC mediated protection. Nonetheless inhibition of endogenously synthesized Ang II protected against I/R induced cardiac damage yet did not block or augment the protective effects of PPC. The administration of AT1 antagonist did not alleviate I/R induced damage. Interestingly it abrogated PPC induced cardiac protection in isolated rat hearts. Finally, PPC induced protection and blockade of locally produced Ang II involved enhanced activation of ERK1/2 and Akt components of the reperfusion injury salvage kinase (RISK) pathway., Conclusions: This study demonstrate a novel role of endogenously produced Ang II in mediating I/R injury and highlights the significance of AT1 signaling in PPC mediated cardiac protection in isolated rodents hearts ex vivo. The interaction between Ang II-AT1 and PPC appears to involve alterations in the activation state of ERK1/2 and Akt components of the RISK pathway., Competing Interests: The authors have declared that no competing interests exist.

Exposure to polycyclic aromatic hydrocarbons (PAH) negatively impacts exercise performance in fish species but the physiological modifications that result in this phenotype are poorly understood. Prior studies have shown that embryonic and juvenile mahi-mahi (Coryphaeus hippurus) exposed to PAH exhibit morphological abnormalities, altered cardiac development and reduced swimming performance. It has been suggested that cardiovascular function inhibited by PAH exposure accounts for the compromised exercise performance in fish species. In this study we used in-situ techniques to measure hemodynamic responses of young adult mahi-mahi exposed to PAH for 24h. The data indicate that stroke volume was reduced 44% in mahi-mahi exposed to 9.6±2.7μgl -1 geometric mean PAH (∑PAH) and resulted in a 39% reduction in cardiac output and a 52% reduction in stroke work. Maximal change in pressure over change in time was 28% lower in mahi-mahi exposed to this level of ∑PAH. Mean intraventricular pressures and heart rate were not significantly changed. This study suggests exposure to environmentally relevant PAH concentrations impairs aspects of cardiovascular function in mahi-mahi., (Copyright © 2016 Elsevier B.V. All rights reserved.)