Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

2018 ◽  
Vol 47 (5) ◽  
pp. 361-371 ◽  
Author(s):  
Qing Kuang ◽  
Ning Xue ◽  
Jing Chen ◽  
Ziyan Shen ◽  
Xiaomeng Cui ◽  
...  
Keyword(s):  
Renal Function ◽  
Hydrogen Sulfide ◽  
Cardiac Dysfunction ◽  
Mononuclear Cells ◽  
Troponin T ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Mrna Levels ◽  
Ventricular Ejection Fraction

Background: Chronic kidney disease (CKD) has been proposed to associate with decreased hydrogen sulfide (H2S) level. Nevertheless, the role of H2S in the pathogenesis of CKD has not been fully investigated. Our study aimed to investigate the plasma level of endogenous H2S in patients with different stages of CKD, and to identify the role of H2S in the progression of CKD and its relationship with cardiovascular diseases. Methods: A total of 157 non-dialysis CKD patients were recruited in our study, with 37 age- and sex-matched healthy individuals as control. Plasma concentration of H2S was measured with spectrophotometry. Sulfhemoglobin, the integration of H2S and hemoglobin, was characterized and measured by dual wavelength spectrophotometry. Serum levels of homocysteine (Hcy), cardiac troponin T (cTnT), and N-terminal pro B type natriuretic peptide were measured using automated analyzers. Conventional transthoracic echocardiography was performed and left ventricular ejection fraction (LVEF) was analyzed as a sensitive parameter of cardiac dysfunction. Results: The plasma H2S level (μmol/L) in CKD patients was significantly lower than those in healthy controls (7.32 ± 4.02 vs. 14.11 ± 5.24 μmol/L, p < 0.01). Plasma H2S level was positively associated with estimated glomerular filtration rate (eGFR; ρ = 0.577, p < 0.01) and negatively associated with plasma indoxyl sulfate concentration (ρ = –0.554, p < 0.01). The mRNA levels of cystathionine β-synthase and cystathionine γ-lyase, 2 catalytic enzymes of H2S formation, were significantly lower in blood mononuclear cells of CKD patients with respect to controls; however, the mRNA level of 3-mercaptopyruvate sulfurtransferase, as another H2S-producing enzyme, was significantly higher in CKD patients. The serum concentration of Hcy, acting as the substrate of H2S synthetase, was higher in the CKD group (p < 0.01). Specifically, the content of serum Hcy in CKD stages 3–5 patients was significantly higher than that in CKD stages 1–2, indicating an increasing trend of serum Hcy with the decline of renal function. Examination of ultrasonic cardiogram revealed a negative ­correlation between plasma H2S level and LVEF (ρ = –0.204, p < 0.05) in CKD patients. The H2S level also correlated negatively with cTnT concentration (ρ = –0.249, p < 0.01). Conclusions: Plasma H2S level decreased with the decline of eGFR, which may contribute to the cardiac dysfunction in CKD ­patients.

scholarly journals Role of B lymphocytes in the infarcted mass in patients with acute myocardial infarction

2021 ◽  
Vol 41 (2) ◽  
Author(s):  
Ana C.A. Casarotti ◽  
Daniela Teixeira ◽  
Ieda M. Longo-Maugeri ◽  
Mayari E. Ishimura ◽  
Maria E.R. Coste ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
B Lymphocytes ◽  
Troponin T ◽  
High Sensitivity ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Early Reperfusion ◽  
Ventricular Ejection Fraction ◽  
High Sensitivity Troponin T

Abstract Despite early reperfusion, patients with ST segment elevation myocardial infarction (STEMI) may present large myocardial necrosis and significant impairment of ventricular function. The present study aimed to evaluate the role of subtypes of B lymphocytes and related cytokines in the infarcted mass and left ventricular ejection fraction obtained by cardiac magnetic resonance imaging performed after 30 days of STEMI. This prospective study included 120 subjects with STEMI submitted to pharmacoinvasive strategy. Blood samples were collected in subjects in the first (D1) and 30th (D30) days post STEMI. The amount of CD11b+ B1 lymphocytes (cells/ml) at D1 were related to the infarcted mass (rho = 0.43; P=0.033), measured by cardiac MRI at D30. These B1 cells were associated with CD4+ T lymphocytes at D1 and D30, while B2 classic lymphocytes at day 30 were related to left ventricular ejection fraction (LVEF). Higher titers of circulating IL-4 and IL-10 were observed at D30 versus D1 (P=0.013 and P&lt;0.001, respectively). Titers of IL-6 at D1 were associated with infarcted mass (rho = 0.41, P&lt;0.001) and inversely related to LVEF (rho = −0.38, P&lt;0.001). After multiple linear regression analysis, high-sensitivity troponin T and IL-6 collected at day 1 were independent predictors of infarcted mass and, at day 30, only HDL-C. Regarding LVEF, high-sensitivity troponin T and high-sensitivity C-reactive protein were independent predictors at day 1, and B2 classic lymphocytes, at day 30. In subjects with STEMI, despite early reperfusion, the amount of infarcted mass and ventricular performance were related to inflammatory responses triggered by circulating B lymphocytes.

scholarly journals 614 Implantable cardiac monitors predict arrhythmic events in post-infarction patients with mildly reduced left ventricular ejection fraction

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Vincenzo Riverso ◽  
Antonio Curcio ◽  
Alessia Tempestini ◽  
Emilia De Luca ◽  
Sabrina La Bella ◽  
...  
Keyword(s):  
Remote Monitoring ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
St Segment ◽  
Group A ◽  
Group B

Abstract Aims Complications of acute myocardial infarction (MI) can be life-threatening leading to sudden cardiac death. While guidelines recommend prompt revascularization and prolonged intensive care hospitalization, predictors of major adverse cardiovascular outcomes are yet poorly understood. The role of implantable cardioverter-defibrillators, even in cases of non-sustained arrhythmias is still debated. To date, it is unknown how to follow-up patients with mild cardiac dysfunction after MI. Implantable cardiac monitors (ICMs) can be helpful for stratifying patients in the early discharge period, and remote monitoring might speed up arrhythmia recognition and treatment. We investigated the role of remote monitoring of ICMs to detect arrhythmic events in post-MI patients without overt cardiac dysfunction. Methods and results We enrolled 13 patients (9 males; 69.8 years) after either ST-segment (N = 7) or non-ST-segment elevation (N = 6) MI with a left ventricular ejection fraction (LVEF) &gt;35%, admitted to our coronary care unit for urgent revascularization between September 2019 and September 2021. Twelve patients underwent percutaneous myocardial revascularization, whereas one was treated with medical therapy only. All patients received an ICM during hospitalization according to echo and EKG parameters. We considered LVEF ≤ 40% as sole risk factor or LVEF between 40% and 50% in addition to either PQ length prolongation, or QRS widening, or pathologic heart rate variability, or non-sustained ventricular tachycardia/paroxysmal advanced second degree atrioventricular block. Patients with multiple revascularization procedures and several hospital admissions were excluded. Implanted ICM were frequently monitored both remotely and in-office when required. During follow-up, brady- and tachy-arrhythmias were recorded in four patients (30.8%). The remote monitoring of the ICM documented new-onset atrial fibrillation, high-degree atrioventricular block, severe bradycardia, and sustained ventricular tachycardia. Three patients required hospitalization and upgrade of the implanted device with pacemakers and cardioverter/defibrillator. For arrhythmic risk stratification, patients were divided into two subgroups; group A included patients with LVEF 40% associated with heart rate &gt; 60 b.p.m., PQ length &gt;160 ms and QRS width &gt;86 ms (N = 4); group B included patients with EF 41%/50%, PQ length &lt;159 and QRS width &lt;85 ms (N = 10). First group experienced more advanced rhythm disorders than group B (P &lt; 0.05). Device implantation was significantly higher in group A (P &lt; 0.05%). Conclusions OFF-label implementation of ICMs coupled with remote device monitoring may be effective for early detection of serious adverse cardiac rhythm alterations in patients after MI and LVEF higher than 35%. Further monitoring is ongoing for assessing the occurrence of multiple arrhythmias or their increased occurrence.

Intracardiac Transplantation of Already Specifically Dedifferentiated Circulating CD34+ Cell Subsets Would Favor Post-Ischemic Myocardial Regeneration.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4175-4175
Author(s):  
Philippe R.G. Henon ◽  
Hanna Sovalat ◽  
Mario Ojeda-Uribe ◽  
Yazid Arkam ◽  
Nicolas Bischoff ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Phase I ◽  
Progenitor Cells ◽  
Cardiac Failure ◽  
Mononuclear Cells ◽  
Troponin T ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Cd34 Cells

Abstract Several groups, mainly from Germany and Japan, have recently conducted different phase-I clinical studies in which autologous bone marrow (BM) mononuclear cells (MNCs) were reinjected either directly in the ischemic area or intra-coronary in patients with severe post-infarct cardiac failure, resulting in a significant improvement of myocardium viability and/or reperfusion. However, besides “true” HSCs, BM-MNCs represent a mixture of mesenchymal progenitor cells, angioblasts, and maybe other progenitor cells, which does not allow to identify the type(s) of cells potentially responsible for improvement. Moreover, the obstructed coronary artery was always repermeabilized, which biases the evaluation of posttransplant myocardial reperfusion. We have personally chosen an other original approach using mobilized and purified circulating CD34+ cells. We and others have indeed demonstrated that mobilized CD34+cells were in fact subdivided into various subsets: of course, the most important (~75%) is the truly hematopoietic subset (CD34+/133+), of which a CD38− part is probably close to the very primitive HSC. But other smaller subsets are immunophenotypically characterized either as mature (CD34+/VEGFR-2+) or immature (CD34+/133+/VEGFR-2+) endothelial progenitor cells - thus potentially capable of neoangiogenesis -, or as muscle progenitors (Desmin+) and even more as cardiomyocytes (Troponin-T+). In a phase-I trial benefiting of the approval of the regional ethical committee, patients suffering of post-infarct cardiac failure are selected according to the following criteria: left ventricular ejection-fraction (LVEF) =35%; distinct area of left ventricular-wall akinesis determined by PetScan; candidates for coronary artery by-pass grafting (CABG), but without any repermeabilization of the coronary artery involved in the infarction; age =70 y. After a 6-days mobilization by G-CSF, circulating CD34+ cells are collected, then purified by immunomagnetism and immediately reinjected at d+7 during CABG, all around and within the infarcted area. The first evaluable patients well tolerated cell mobilization - and collection phases, as well as operative and post-operative periods. Three patients have presently a follow-up = 1 y post-transplantation. Two show a striking gain in LVEF (14 and 20% respectively) with an important improvement in myocardium viability, reperfusion and contractility, and finally in exercise capacity (from class IV to class I in New-York Association functional class). Although very encouraging, these results have to be confirmed in further patients.

scholarly journals N-Terminal Pro-B-Type Natriuretic Peptide after High-Dose Chemotherapy: A Marker Predictive of Cardiac Dysfunction?

2005 ◽  
Vol 51 (8) ◽  
pp. 1405-1410 ◽  
Author(s):  
Maria T Sandri ◽  
Michela Salvatici ◽  
Daniela Cardinale ◽  
Laura Zorzino ◽  
Rita Passerini ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Cardiac Dysfunction ◽  
High Dose Chemotherapy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
High Dose ◽  
Ventricular Ejection Fraction ◽  
Patients At Risk ◽  
Predictive Role

Abstract Background: Chronic cardiac dysfunction may develop after administration of aggressive chemotherapy, sometimes leading to development of congestive heart failure (CHF). Recently, N-terminal pro-B-type natriuretic peptide (NT-proBNP) was implicated as a marker of CHF. In this study we evaluated the predictive role of NT-proBNP in patients treated with high-dose chemotherapy (HDC). Methods: NT-proBNP was measured after 62 chemotherapy treatments in 52 patients affected by aggressive malignancies. Blood samples were drawn before the start of HDC, at the end of HDC administration, and 12, 24, 36, and 72 h thereafter. In these patients, echocardiograms were performed regularly during a 1-year follow-up. Results: Seventeen patients (33%) had persistently increased NT-proBNP, 19 patients (36%) had only transient increases (concentrations went back to baseline at 72 h), and 16 (31%) had no increases [mean (SD) values at 72 h, 1163 (936) ng/L vs 185 (101) ng/L vs 39 (19) ng/L, respectively; P &lt;0.0001]. Only patients with persistently increased NT-proBNP had a significant worsening of the left ventricular diastolic indexes from baseline to 12 months [ratio of peak early to peak late flow velocities from 1.42 (0.33) to 0.78 (0.11); P &lt;0.0001; isovolumetric relaxation time from 90 (15) to 141 (26) ms; P &lt;0.0001; E-wave deceleration time from 162 (17) to 224 (32) ms; P = 0.0004] and of the left ventricular ejection fraction [from 62.8 (3.4)% to 45.6 (11.5)%; P &lt;0.0001]. Conclusions: Persistently increased NT-proBNP early after administration of HDC is strongly associated with development of cardiac dysfunction. This finding has important implications for identifying patients at risk of developing chemotherapy-induced cardiotoxicity.

Risk stratification in hf with mid-range LVEF: the role of cardiopulmonary exercise testing

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
B.M.L Rocha ◽  
G.J Lopes Da Cunha ◽  
P.M.D Lopes ◽  
P.N Freitas ◽  
F Gama ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Exercise Testing ◽  
Primary Endpoint ◽  
Prognostic Significance ◽  
Cardiopulmonary Exercise Testing ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Cardiopulmonary Exercise

Abstract Background Cardiopulmonary exercise testing (CPET) is recommended in the evaluation of selected patients with Heart Failure (HF). Notwithstanding, its prognostic significance has mainly been ascertained in those with left ventricular ejection fraction (LVEF) &lt;40% (i.e., HFrEF). The main goal of our study was to assess the role of CPET in risk stratification of HF with mid-range (40–49%) LVEF (i.e., HFmrEF) compared to HFrEF. Methods We conducted a single-center retrospective study of consecutive patients with HF and LVEF &lt;50% who underwent CPET from 2003–2018. The primary composite endpoint of death, heart transplant or HF hospitalization was assessed. Results Overall, 404 HF patients (mean age 57±11 years, 78.2% male, 55.4% ischemic HF) were included, of whom 321 (79.5%) had HFrEF and 83 (20.5%) HFmrEF. Compared to the former, those with HFmrEF had a significantly higher mean peak oxygen uptake (pVO2) (20.2±6.1 vs 16.1±5.0 mL/kg/min; p&lt;0.001), lower median minute ventilation/carbon dioxide production (VE/VCO2) [35.0 (IQR: 29.1–41.2) vs 39.0 (IQR: 32.0–47.0); p=0.002) and fewer patients with exercise oscillatory ventilation (EOV) (22.0 vs 46.3%; p&lt;0.001). Over a median follow-up of 28.7 (IQR: 13.0–92.3) months, 117 (28.9%) patients died, 53 (13.1%) underwent heart transplantation, and 134 (33.2%) had at least one HF hospitalization. In both HFmrEF and HFrEF, pVO2 &lt;12 mL/kg/min, VE/VCO2 &gt;35 and EOV identified patients at higher risk for events (all p&lt;0.05). In Cox regression multivariate analysis, pVO2 was predictive of the primary endpoint in both HFmrEF and HFrEF (HR per +1 mL/kg/min: 0.81; CI: 0.72–0.92; p=0.001; and HR per +1 mL/kg/min: 0.92; CI: 0.87–0.97; p=0.004), as was EOV (HR: 4.79; CI: 1.41–16.39; p=0.012; and HR: 2.15; CI: 1.51–3.07; p&lt;0.001). VE/VCO2, on the other hand, was predictive of events in HFrEF but not in HFmrEF (HR per unit: 1.03; CI: 1.02–1.05; p&lt;0.001; and HR per unit: 0.99; CI: 0.95–1.03; p=0.512, respectively). ROC curve analysis demonstrated that a pVO2 &gt;16.7 and &gt;15.8 mL/kg/min more accurately identified patients at lower risk for the primary endpoint (NPV: 91.2 and 60.5% for HFmrEF and HFrEF, respectively; both p&lt;0.001). Conclusions CPET is a useful tool in HFmrEF. Both pVO2 and EOV independently predicted the primary endpoint in HFmrEF and HFrEF, contrasting with VE/VCO2, which remained predictive only in latter group. Our findings strengthen the prognostic role of CPET in HF with either reduced or mid-range LVEF. Funding Acknowledgement Type of funding source: None

scholarly journals The role of neurohormonal blockers in the primary prevention of acute-, early-, and late-onset anthracycline-induced cardiotoxicity

2020 ◽  
Vol 72 (1) ◽  
Author(s):  
Ahmed Ayuna ◽  
Nik Abidin
Keyword(s):  
Primary Prevention ◽  
Myocardial Injury ◽  
Troponin I ◽  
Late Onset ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Main Body ◽  
Converting Enzyme Inhibitors ◽  
Ventricular Ejection Fraction

Abstract Background Anthracycline-induced cardiotoxicity has been classified based on its onset into acute, early, and late. It may have a significant burden on the quality and quantity of life of those exposed to this class of medication. Currently, there are several ongoing debates on the role of different measures in the primary prevention of cardiotoxicity in cancer survivors. Our article aims to focus on the role of neurohormonal blockers in the primary prevention of anthracycline-induced cardiotoxicity, whether it is acute, early, or late onset. Main body of the abstract PubMed and Google Scholar database were searched for the relevant articles; we reviewed and appraised 15 RCTs, and we found that angiotensin-converting enzyme inhibitors (ACEI) and B-blockers were the most commonly used agents. Angiotensin II receptor blockers (ARBs) and mineralocorticoid receptor antagonists (MRAs) were used in a few other trials. The follow-up period was on the range of 1–156 weeks (mode 26 weeks). Left ventricular ejection fraction (LVEF), left ventricular diameters, and diastolic function were assessed by either echocardiogram or occasionally by cardiac magnetic resonance imaging (MRI). The occurrence of myocardial injury was assessed by troponin I. It was obvious that neurohormonal blockers reduced the occurrence of LVEF and myocardial injury in 14/15 RCTs. Short conclusion Beta-blockers, especially carvedilol and ACEI, especially enalapril, should be considered for the primary prevention of acute- and early-onset cardiotoxicity. ARB and MRA are suitable alternatives when patients are intolerant to ACE-I and B-blockers. We recommend further studies to explore and establish the role of neurohormonal blockers in the primary prevention of the acute-, early-, and late-onset cardiotoxicity.

scholarly journals Effects of peak time of myocardial injury biomarkers on mid-term outcomes of patients undergoing OPCABG

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bo Hu ◽  
Fei Gao ◽  
Mengwei Lv ◽  
Ban Liu ◽  
Yu Shi ◽  
...  
Keyword(s):  
Myocardial Injury ◽  
Cox Regression ◽  
Troponin T ◽  
Artery Bypass ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Peak Time ◽  
Clinical Trial Registry ◽  
Ventricular Ejection Fraction ◽  
The Impact

Abstract Background With the development of cardiac surgery techniques, myocardial injury is gradually reduced, but cannot be completely avoided. Myocardial injury biomarkers (MIBs) can quickly and specifically reflect the degree of myocardial injury. Due to various reasons, there is no consensus on the specific values of MIBs in evaluating postoperative prognosis. This retrospective study was aimed to investigate the impact of MIBs on the mid-term prognosis of patients undergoing off-pump coronary artery bypass grafting (OPCABG). Methods Totally 564 patients undergoing OPCABG with normal courses were included. Cardiac troponin T (cTnT) and creatine kinase myocardial band (CK-MB) were assessed within 48 h before operation and at 6, 12, 24, 48, 72, 96 and 120 h after operation. Patients were grouped by peak values and peak time courses of MIBs. The profile of MIBs and clinical variables as well as their correlations with mid-term prognosis were analyzed by univariable and multivariable Cox regression models. Result Continuous assessment showed that MIBs increased first (12 h after surgery) and then decreased. The peak cTnT and peak CK-MB occurred within 24 h after operation in 76.8% and 67.7% of the patients respectively. No significant correlation was found between CK-MB and mid-term mortality. Delayed cTnT peak (peak cTnT elevated after 24 h after operation) was correlated with lower creatinine clearance rate (69.36 ± 21.67 vs. 82.18 ± 25.17 ml/min/1.73 m2), body mass index (24.35 ± 2.58 vs. 25.27 ± 3.26 kg/m2), less arterial grafts (1.24 ± 0.77 vs. 1.45 ± 0.86), higher EuroSCORE II (2.22 ± 1.12 vs.1.72 ± 0.91) and mid-term mortality (26.5 vs.7.9%). Age (HR: 1.067, CI: 1.006–1.133), left ventricular ejection fraction (HR: 0.950, CI: 0.910–0.993), New York Heart Association score (HR: 1.839, CI: 1.159–2.917), total venous grafting (HR: 2.833, CI: 1.054–7.614) and cTnT peak occurrence within 24 h (HR: 0.362, CI: 0.196–0.668) were independent predictors of mid-term mortality. Conclusion cTnT is a better indicator than CK-MB. The peak value and peak occurrence of cTnT are related to mid-term mortality in patients undergoing OPCABG, and the peak phases have stronger predictive ability. Trial registration: Chinese Clinical Trial Registry, ChiCTR2000033850. Registered 14 June 2020, http://www.chictr.org.cn/edit.aspx?pid=55162&htm=4.

Trastuzumab-Associated Cardiac Adverse Effects in the Herceptin Adjuvant Trial

2007 ◽  
Vol 25 (25) ◽  
pp. 3859-3865 ◽  
Author(s):  
Thomas M. Suter ◽  
Marion Procter ◽  
Dirk J. van Veldhuisen ◽  
Michael Muscholl ◽  
Jonas Bergh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Adverse Effects ◽  
Cancer Patients ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Breast Cancer Patients ◽  
Ventricular Ejection Fraction ◽  
Neo Adjuvant Chemotherapy

Purpose The purpose of this analysis was to investigate trastuzumab-associated cardiac adverse effects in breast cancer patients after completion of (neo)adjuvant chemotherapy with or without radiotherapy. Patients and Methods The Herceptin Adjuvant (HERA) trial is a three-group, multicenter, open-label randomized trial that compared 1 or 2 years of trastuzumab given once every 3 weeks with observation in patients with HER-2–positive breast cancer. Only patients who after completion of (neo)adjuvant chemotherapy with or without radiotherapy had normal left ventricular ejection fraction (LVEF ≥ 55%) were eligible. A repeat LVEF assessment was performed in case of cardiac dysfunction. Results Data were available for 1,693 patients randomly assigned to 1 year trastuzumab and 1,693 patients randomly assigned to observation. The incidence of trastuzumab discontinuation due to cardiac disorders was low (4.3%). The incidence of cardiac end points was higher in the trastuzumab group compared with observation (severe congestive heart failure [CHF], 0.60% v 0.00%; symptomatic CHF, 2.15% v 0.12%; confirmed significant LVEF drops, 3.04% v 0.53%). Most patients with cardiac dysfunction recovered in fewer than 6 months. Patients with trastuzumab-associated cardiac dysfunction were treated with higher cumulative doses of doxorubicin (287 mg/m2 v 257 mg/m2) or epirubicin (480 mg/m2 v 422 mg/m2) and had a lower screening LVEF and a higher body mass index. Conclusion Given the clear benefit in disease-free survival, the low incidence of cardiac adverse events, and the suggestion that cardiac dysfunction might be reversible, adjuvant trastuzumab should be considered for treatment of breast cancer patients who fulfill the HERA trial eligibility criteria.

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.

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