Abstract 3292: Cardiac Dysfunction Induced By Chronic Restrain Stress Is Mediated By Opioid Receptors

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jinping Gao ◽  
Chu C Chua ◽  
Deling Yin ◽  
Hong Wang ◽  
Ronald C Hamdy ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Chronic Stress ◽  
Opioid Receptors ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Opioid Antagonist ◽  
Stroke Work ◽  
Ventricular Performance ◽  
Major Health Problem ◽  
Stressed Group

Psychological and physical stressors are a major health problem in our society. The effect of chronic stress on myocardial function has not been assessed. Our hypothesis is that chronic stress induces cardiac dysfunction and that its effect is mediated by activation of opioid receptors (OPR). Six week-old male ICR mice were restrained for 12 h with no food and water. This was followed by 12 h of rest with food and water provided ad labium. Unstressed (control) mice were kept in the original cage and were not given food and water during the stress period of the experimental group. Left ventricular performance was analyzed in mice anesthetized with 2% isoflurane using an ARIA pressure-volume conductance system (Millar Instruments). Our studies demonstrated for the first time that cardiac function was significantly depressed in restrained mice, as evidenced by a significant decrease in body weight (9%), heart rate (21%), stroke volume (38%), cardiac output (52%), ejection fraction (27%) and preload recruitable stroke work (43%). Systolic function (control vs. stressed group) (P<0.05), was 88 ± 2.2 vs. 68 ± 2.8 mmHg for end-systolic pressure, 6.1 ± 0.15 vs. 7.6 ± 0.15 μl for end-systolic volume, and 11,471 ± 913 vs. 5,860 ± 761 mmHg/s for +dP/dt. Diastolic function (control vs. stressed group) (P<0.05), was 2.9 ± 0.3 vs. 5.0 ± 0.5 mmHg for end-diastolic pressure, 17.1 ± 0.4 vs. 14.4 ± 0.5 μl for end-diastolic volume, 7,678 ± 419 vs. 4,195 ± 358 mmHg/s for -dP/dt, and 7.1 ± 0.5 vs. 10.8 ± 1.1 ms for tau (time constant of isovolumic relaxation). Peripheral vascular resistance (Ea) increased from 7.7 ± 0.2 in the control group to 9.8 ± 0.7 mmHg/μ l in the stressed group (P<0.05). Administration of an opioid antagonist naltrexone (8 mg/kg, i.p.) during each cycle of stress completely restored the cardiac function of stressed mice. Naltrexone alone had no effect on cardiac function in unstressed mice. These intriguing data suggest that opioid receptors are involved in the chronic stress-induced cardiac dysfunction and that treatment with an opioid antagonist can prevent this cardiac dysfunction.

scholarly journals TLR2 ligands attenuate cardiac dysfunction in polymicrobial sepsis via a phosphoinositide 3-kinase-dependent mechanism

2010 ◽  
Vol 298 (3) ◽  
pp. H984-H991 ◽  
Author(s):  
Tuanzhu Ha ◽  
Chen Lu ◽  
Li Liu ◽  
Fang Hua ◽  
Yulong Hu ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Rate Of Change ◽  
Stroke Work ◽  
Therapeutic Treatment ◽  
Phosphoinositide 3 Kinase ◽  
Dependent Mechanism ◽  
Tlr2 Ligands

Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. In the present study, we examined the effect of Toll-like receptor 2 (TLR2) ligands, peptidoglycan (PGN), and Pam3CSK4 (Pam3) on cardiac function in cecal ligation and puncture (CLP)-induced sepsis in mice. We also investigated whether the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is involved in the effect of TLR2 ligands on cardiac function in CLP mice. PGN was administered to C57B6/L mice 1 h before the induction of CLP. Sham surgically operated mice served as a control. Cardiac function indexes (rate of change in left ventricular pressure, stroke work, cardiac output, and ejection fraction) were examined by a microconductance pressure catheter. Cardiac function was significantly decreased 6 h after CLP-induced sepsis compared with sham-operated control. In contrast, PGN administration attenuated CLP-induced cardiac dysfunction. Importantly, the therapeutic treatment with Pam3 1 h after CLP also significantly attenuated cardiac dysfunction in CLP mice. However, the beneficial effect of TLR2 ligands on cardiac dysfunction in CLP-mice was abolished in TLR2-deficient mice. PGN administration significantly increased the levels of phospho-Akt and phospho-GSK-3β in the myocardium compared with the levels in untreated CLP mice. PI3K inhibition abolished the PGN-induced attenuation of cardiac dysfunction in CLP mice. In conclusion, these data demonstrate that the administration of TLR2 ligands, PGN, or Pam3 attenuates cardiac dysfunction in septic mice via a TLR2/PI3K-dependent mechanism. More significantly, Pam3 therapeutic treatment will have a potential clinical relevance.

Abstract 1213: Cardiac Overexpression of Epac1 in Transgenic Mice Protects Heart from Lipopolysaccharide-induced Cardiac Dysfunction and Inhibits JAK-STAT Pathway

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoshi Okumura ◽  
Yunzhe Bai ◽  
Meihua Jin ◽  
Sayaka Suzuki ◽  
Akiko Kuwae ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cyclic Amp ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Proinflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Stat Pathway

The sympathetic nervous system and proinflammatory cytokines are believed to play independent roles in the pathophysiology of heart failure. However, the recent identification of Epac (exchange protein activated by cyclic AMP), a new cyclic AMP-binding protein that directly activates Rap1, have implicated that there may be a potential cross talk between the sympathetic and cytokine signals. In order to examine the role of Epac in cytokine signal to regulate cardiac function, we have generated transgenic mice expressing the human Epac1 gene under the control of alpha-cardiac myosin heavy chain promoter (Epac1-TG), and examined their response in lipopolysaccharide (LPS)-induced cardiac dysfunction, a well established model for sepsis-induced cardiac dysfunction. Sepsis-induced cardiac dysfunction results from the production of proinflammatory cytokines. At baseline, left ventricular ejection fraction (LVEF) was similar (TG vs. NTG, 67±1.7 vs. 69±2.1%, n =7–9). The degree of cardiac hypertrophy (LV(mg)/tibia(mm)) was also similar at 3 months old (TG vs. NTG 4.0±0.1 vs. 4.2±0.1, n =5–6), but it became slightly but significantly greater in Epac1-TG at 5 month old (TG vs. NTG 4.9±0.1 vs. 4.4±0.1, p< 0.05, n =5–7). LPS (5mg/kg) elicited a significant and robust reduction of LVEF in both Epac1-TG and NTG, but the magnitude of this decrease was much less in Epac1-TG at 6 hr after injection (TG vs. NTG 48±2.4 vs. 57±1.8%, p< 0.01, n =6–9). At 24 hr after injection, cardiac function was restored to the baseline in both Epac1-TG and NTG. We also examined the activation of JAK-STAT pathway at 24 hr after injection. The tyrosine phosphorylation of STAT1 (Tyr701) and STAT3 (Tyr705) in LV, which is an indicator of STAT activation, was reduced to a greater degree in Epac1-TG by 31±8.8% ( p< 0.05, n =4) and 29±5.9% ( p< 0.05, n =7), respectively, relative to that in NTG. Taken together, Epac1 protects the heart from the cytokine-induced cardiac dysfunction, at least in part, through the inhibition of the JAK-STAT pathway, suggesting the beneficial role played by sympathetic signal to antagonize proinflammatory cytokine signal in heart failure.

Cardiac dysfunction in mice lacking cytochrome-c oxidase subunit VIaH

2002 ◽  
Vol 282 (2) ◽  
pp. H726-H733 ◽  
Author(s):  
Nina B. Radford ◽  
Bang Wan ◽  
Angela Richman ◽  
Lidia S. Szczepaniak ◽  
Jia-Ling Li ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Cardiac Dysfunction ◽  
Mechanical Performance ◽  
Left Ventricular ◽  
Mutant Mice ◽  
Stroke Work ◽  
Wild Type ◽  
Oxidase Subunit ◽  
End Diastolic Volume

Cytochrome -c oxidase subunit VIaH (COXVIaH) has been implicated in the modulation of COX activity. A gene-targeting strategy was undertaken to generate mice that lacked COXVIaH to determine its role in regulation of oxidative energy production and mechanical performance in cardiac muscle. Total COX activity was decreased in hearts from mutant mice, which appears to be a consequence of altered assembly of the holoenzyme COX. However, total myocardial ATP was not significantly different in wild-type and mutant mice. Myocardial performance was examined using the isolated working heart preparation. As left atrial filling pressure increased, hearts from mutant mice were unable to generate equivalent stroke work compared with hearts from wild-type mice. Direct measurement of left ventricular end-diastolic volume using magnetic resonance imaging revealed that cardiac dysfunction was a consequence of impaired ventricular filling or diastolic dysfunction. These findings suggest that a genetic deficiency of COXVIaH has a measurable impact on myocardial diastolic performance despite the presence of normal cellular ATP levels.

Ventricular performance and myocardial water content during hemodilution in dogs

1978 ◽  
Vol 235 (6) ◽  
pp. H767-H775 ◽  
Author(s):  
G. A. Geffin ◽  
M. A. Vasu ◽  
D. D. O'Keefe ◽  
D. G. Pennington ◽  
A. J. Erdmann ◽  
...  
Keyword(s):  
Water Content ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Lv Function ◽  
Stroke Work ◽  
Ventricular Performance ◽  
End Diastolic Volume ◽  
Lv Mass ◽  
Right Heart Bypass ◽  
Water Gain

In dogs anesthetized with chloralose-urethan on right heart bypass, left ventricular (LV) performance was assessed at constant LV stroke work before and for up to 2.5 h after crystalloid hemodilution was established. Lowering the hematocrit from 43.3 +/- 1.3% to 13.6 +/- 1.7% (SE) did not significantly change LV end-diastolic pressure (LVEDP) initially. After 80 min LVEDP increased slightly by 1.7 +/- 0.6 cmH2O (P less than 0.05) at a stroke work of 17.3 +/- 2.3 g.m. The value of dP/dt did not change significantly throughout. When LV function curves were generated by increasing cardiac output, the stroke work attained at an LVEDP of 10 cmH2O decreased with hemodilution from 23.9 +/- 3.5 to 20.8 +/- 3.9 g.m (NS). LV wall water content increased with hemodilution, from which it could be calculated that there was an 18.6% increase in LV mass. Thus, despite an increase in LV external girth demonstrated by LV circumferential gauges, it is possible that increased wall thickness due to the water gain resulted in little change or an actual decrease in LV end-diastolic volume. Thus, profound hemodilution can be attained with only slight depression of LV performance.

scholarly journals Environmentally persistent free radicals decrease cardiac function and increase pulmonary artery pressure

2012 ◽  
Vol 303 (9) ◽  
pp. H1135-H1142 ◽  
Author(s):  
Sarah Mahne ◽  
Gin C. Chuang ◽  
Edward Pankey ◽  
Lucy Kiruri ◽  
Philip J. Kadowitz ◽  
...  
Keyword(s):  
Free Radicals ◽  
Left Ventricle ◽  
Cardiac Function ◽  
Left Ventricular Function ◽  
Ventricular Function ◽  
Diastolic Pressure ◽  
Silica Particles ◽  
Left Ventricular ◽  
Heme Oxygenase 1 ◽  
Stroke Work

Epidemiological studies have consistently linked inhalation of particulate matter (PM) to increased cardiac morbidity and mortality, especially in at risk populations. However, few studies have examined the effect of PM on baseline cardiac function in otherwise healthy individuals. In addition, airborne PM contain environmentally persistent free radicals (EPFR) capable of redox cycling in biological systems. The purpose of this study was to determine whether nose-only inhalation of EPFRs (20 min/day for 7 days) could decrease baseline left ventricular function in healthy male Sprague-Dawley rats. The model EPFR tested was 1,2-dichlorobenzene chemisorbed to 0.2-μm-diameter silica/CuO particles at 230°C (DCB230). Inhalation of vehicle or silica particles served as controls. Twenty-four hours after the last exposure, rats were anesthetized (isoflurane) and ventilated (3 l/min), and left ventricular function was assessed using pressure-volume catheters. Compared with controls, inhalation of DCB230 significantly decreased baseline stroke volume, cardiac output, and stroke work. End-diastolic volume and end-diastolic pressure were also significantly reduced; however, ventricular contractility and relaxation were not changed. DCB230 also significantly increased pulmonary arterial pressure and produced hyperplasia in small pulmonary arteries. Plasma levels of C-reactive protein were significantly increased by exposure to DCB230, as were levels of heme oxygenase-1 and SOD2 in the left ventricle. Together, these data show that inhalation of EPFRs, but not silica particles, decreases baseline cardiac function in healthy rats by decreasing cardiac filling, secondary to increased pulmonary resistance. These EPFRs also produced systemic inflammation and increased oxidative stress markers in the left ventricle.

Balancing mitochondrial dynamics via increasing mitochondrial fusion attenuates infarct size and left ventricular dysfunction in rats with cardiac ischemia/reperfusion injury

2019 ◽  
Vol 133 (3) ◽  
pp. 497-513 ◽  
Author(s):  
Chayodom Maneechote ◽  
Siripong Palee ◽  
Sasiwan Kerdphoo ◽  
Thidarat Jaiwongkam ◽  
Siriporn C. Chattipakorn ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Cardiac Dysfunction ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Mitochondrial Fusion ◽  
Time Points

Abstract An uncontrolled balance of mitochondrial dynamics has been shown to contribute to cardiac dysfunction during ischemia/reperfusion (I/R) injury. Although inhibition of mitochondrial fission could ameliorate cardiac dysfunction, modulation of mitochondrial fusion by giving a fusion promoter at different time-points during cardiac I/R injury has never been investigated. We hypothesized that giving of a mitochondrial fusion promoter at different time-points exerts cardioprotection with different levels of efficacy in rats with cardiac I/R injury. Forty male Wistar rats were subjected to a 30-min ischemia by coronary occlusion, followed by a 120-min reperfusion. The rats were then randomly divided into control and three treated groups: pre-ischemia, during-ischemia, and onset of reperfusion. A pharmacological mitochondrial fusion promoter-M1 (2 mg/kg) was used for intervention. Reduced mitochondrial fusion protein was observed after cardiac I/R injury. M1 administered prior to ischemia exerted the highest level of cardioprotection by improving both cardiac mitochondrial function and dynamics regulation, attenuating incidence of arrhythmia, reducing infarct size and cardiac apoptosis, which led to the preservation of cardiac function and decreased mortality. M1 given during ischemia and on the onset of reperfusion also exerted cardioprotection, but with a lower efficacy than when given at the pre-ischemia time-point. Attenuating a reduction in mitochondrial fusion proteins during myocardial ischemia and at the onset of reperfusion exerted cardioprotection by attenuating mitochondrial dysfunction and dynamic imbalance, thus reducing infarct size and improving cardiac function. These findings indicate that it could be a promising intervention with the potential to afford cardioprotection in the clinical setting of acute myocardial infarction.

scholarly journals Cardiac Function in Uncomplicated Type 2 Diabetes Mellitus

2019 ◽  
Vol 18 (2) ◽  
pp. 211-215
Author(s):  
Bimal K Agrawal ◽  
Parul Jain ◽  
Saurabh Marwaha ◽  
Richa Goel ◽  
Himanshu D Kumar ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Diabetic Patients ◽  
Coronary Arterial Disease ◽  
Type 2 Dm

Objective: Diabetic cardiomyopathy (DC) is a myocardial disease characterized by myocyte hypertrophy, interstitial fibrosis, protein glycosylation and intra-myocardial micro-angiopathy due to prolonged exposure of myocardial tissues to hyperglycemia in diabetes mellitus (DM) patients. Alteration in cardiac function can be non-invasively assessed via echocardiography. The early recognition of cardiac dysfunction can prevent the symptomatic heart failure in DM patients. The study aimed at evaluating cardiac function in uncomplicated type 2 diabetes mellitus. Materials And Methods: Sixty Type 2 DM patients without any feature of the coronary arterial disease (CAD), hypertension, nephropathy and respiratory illness were enrolled in the study and compared with the sixty age matched healthy controls. Echocardiographic assessment was done in all subjects to evaluate the cardiac function. Results: Diastolic dysfunction was more common in diabetic patients when compared with normal healthy population. Systolic dysfunction progresses with age of the diabetic patient. Conclusion: Echocardiography is a simple noninvasive cost effective test for detecting cardiac dysfunction in Type 2 DM patients and should be applied to detect early Left ventricular(LV) dysfunction so that corrective measures may be initiated early and cardiac functions may be preserved for long. Bangladesh Journal of Medical Science Vol.18(2) 2019 p.211-215

Safety of trastuzumab in women with HER2+ breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12522-e12522
Author(s):  
Somaira Nowsheen ◽  
Khaled Aziz ◽  
Jae Yoon Park ◽  
Hector R. Villarraga ◽  
Joerg Herrmann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cardiac Function ◽  
Cancer Patients ◽  
Cardiac Dysfunction ◽  
Physical Symptoms ◽  
Left Ventricular ◽  
Breast Cancer Patients ◽  
Her2 Breast Cancer ◽  
History Of ◽  
Normal Lvef

e12522 Background: Trastuzumab is widely used in management of HER2+ breast cancer patients. A known adverse effect of trastuzumab use is cardiac dysfunction, which can often be reversed with cessation of therapy. Our objectives were to 1) assess if trastuzumab can be safely administered to breast cancer patients with reduced cardiac function and 2) identify patient characteristics that predict susceptibility to trastuzumab-induced cardiac dysfunction. Methods: A retrospective analysis was performed on female patients seen at Mayo Clinic for HER2+ breast cancer and treated with trastuzumab for localized or metastatic disease between January 1, 2000 and August 31, 2015. Eligibility criteria included documentation of and results from at least one echocardiogram prior to and at least one after trastuzumab initiation. Left ventricular (LV) ejection fraction (EF) of 53% or more was considered normal. Any LVEF reduction of 10% or more was considered significant. Among patients with normal EF, age strata of < 45, 45-60, and > 60 at time of trastuzumab initiation were used to assess risk factors for clinically diagnosed cardiac dysfunction (defined as EF < 53 or abnormal strain and physical symptoms of heart failure (HF)). Results: We identified 335 women (mean age 53.3, with 25.3% age < 45, 44.5% age 45-60, and 30.1% age > 60) who had normal LVEF (median EF 64, range: 53-75) and 23 women (mean age 53.4, with 30.4% age < 45, 43.5% age 45-60, and 26.1% age > 60) who had low LVEF at baseline (median EF 52, range: 25-52). Approximately a third (34.3%) of women with normal LVEF prior to initiation of therapy had at least one subsequent echocardiogram showing a drop of 10% or a low LVEF ( < 53). Approximately a quarter (26%) of women with low LVEF at baseline had a 10% drop in LVEF. HF incidence increased with age. Predictive factors for trastuzumab-induced cardiac dysfunction were obesity and history of coronary artery disease (CAD) across all age strata, and chest irradiation (IR) for those aged 45-60 only. Conclusions: Our results suggest that trastuzumab can be administered in women with reduced cardiac function at no greater risk than in those with preserved cardiac function. Some women with no obesity, history of CAD, or history of chest IR may not need echocardiograms during trastuzumab therapy.

scholarly journals Loss of Bradykinin Signaling Does Not Accelerate the Development of Cardiac Dysfunction in Type 1 Diabetic Akita Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (8) ◽  
pp. 3536-3542 ◽  
Author(s):  
Adam R. Wende ◽  
Jamie Soto ◽  
Curtis D. Olsen ◽  
Karla M. P. Pires ◽  
John C. Schell ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Reactive Oxygen ◽  
Left Ventricular ◽  
Oxygen Species ◽  
Receptor Signaling ◽  
Genetic Ablation ◽  
Akita Mice

Bradykinin signaling has been proposed to play either protective or deleterious roles in the development of cardiac dysfunction in response to various pathological stimuli. To further define the role of bradykinin signaling in the diabetic heart, we examined cardiac function in mice with genetic ablation of both bradykinin B1 and B2 receptors (B1RB2R−/−) in the context of the Akita model of insulin-deficient type 1 diabetes (Ins2Akita/+). In 5-month-old diabetic and nondiabetic, wild-type and B1RB2R−/− mice, in vivo cardiac contractile function was determined by left-ventricular (LV) catheterization and echocardiography. Reactive oxygen species levels were measured by 2′-7′-dichlorofluorescein diacetate fluorescence. Mitochondrial function and ATP synthesis were determined in saponin-permeabilized cardiac fibers. LV systolic pressure and the peak rate of LV pressure rise and decline were decreased with diabetes but did not deteriorate further with loss of bradykinin signaling. Wall thinning and reduced ejection fractions in Akita mouse hearts were partially attenuated by B1RB2R deficiency, although other parameters of LV function were unaffected. Loss of bradykinin signaling did not increase fibrosis in Ins2Akita/+ diabetic mouse hearts. Mitochondrial dysfunction was not exacerbated by B1RB2R deficiency, nor was there any additional increase in tissue levels of reactive oxygen species. Thus, loss of bradykinin B2 receptor signaling does not abrogate the previously reported beneficial effect of inhibition of B1 receptor signaling. In conclusion, complete loss of bradykinin expression does not worsen cardiac function or increase myocardial fibrosis in diabetes.

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