Abstract 13441: D-dimmer is a Predictor of Cancer Therapeutics-related Cardiac Dysfunction in Patients Treated With Cardiotoxic Chemotherapy

Background: D-dimer is a sensitive biomarker for cancer-associated thrombosis, but little is known about its significance on cancer therapeutics-related cardiac dysfunction (CTRCD). Methods and Results: Consequtive 202 patients planned for cardiotoxic chemotherapy (anthracyclines, monoclonal antibodies, tyrosine kinase inhibitors, and proteasome inhibitors) were enrolled and followed up for 12 months. Cancer types were as follows: breast cancer (n=112), lymphoma (n=37), ovarian or uterine cancer (n=18), leukemia (n=13), multiple myeloma (n=6), bone cancer (n=4), and others (n=12). All patients underwent echocardiography and blood test at baseline, 3-month, 6-month, and 12-month. The patients were divided into 2 groups based on the value of D-dimer (>1.5 μg/ml or ≦1.5 μg/ml) at baseline before chemotherapy: High D-dimer group (n=52) and Low D-dimer group (n=150). At baseline, left ventricular ejection fraction (LVEF), left ventricular end-systolic volume index, and B-type natriuretic peptide levels were similar between two groups. Time-dependent decrease in LVEF was observed after chemotherapy in high D-dimer group (baseline, 66±5%; 3-month, 63±7%; 6-month, 62±7%; 12-month 62±6%; P=0.005, figure), but not in low D-dimer group. Time-dependent increase in troponin I was similarly observed after chemotherapy in both groups. The occurrence of CTRCD was higher in high D-dimer group than in low D-dimer group (11.5% vs. 4.0%, P=0.048). When we set the cut-off value of baseline D-dimer at 1.65 μg/ml from ROC analysis, sensitivity, specificity, and area under the curve to predict CTRCD were 50%, 77%, and 0.679, respectively. Multivariable logistic analysis revealed that baseline D-dimer was an independent factor to predict the decrease in LVEF more than 10% after cardiotoxic chemotherapy (odds ratio 1.210, 95% confidence interval [1.020-1.440], P=0.025). Conclusion: Baseline D-dimer is a pivotal parameter to predict CTRCD.

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D-Dimer is a Predictive Factor of Cancer Therapeutics-Related Cardiac Dysfunction in Patients Treated With Cardiotoxic Chemotherapy

10.21203/rs.3.rs-900426/v1 ◽

2021 ◽

Author(s):

Masayoshi Oikawa ◽

Daiki Yaegashi ◽

Tetsuro Yokokawa ◽

Tomofumi Misaka ◽

Takamasa Sato ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Independent Predictor ◽

Cancer Therapeutics ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Multivariable Logistic Regression Analysis ◽

Ventricular Ejection Fraction ◽

Cancer Associated Thrombosis ◽

D Dimer

Abstract Background: D-dimer is a sensitive biomarker for cancer-associated thrombosis, but little is known about its significance on cancer therapeutics-related cardiac dysfunction (CTRCD). Methods: Consecutive 169 patients planned for cardiotoxic chemotherapy were enrolled and followed up for 12 months. All patients underwent echocardiography and blood test at baseline, as well as at 3-month, 6-month, and 12-month. Results: The patients were divided into 2 groups based on the level of D-dimer (> 1.65 µg/ml or ≦ 1.65 µg/ml) at baseline before chemotherapy: High D-dimer group (n = 37) and low D-dimer group (n = 132). Left ventricular ejection fraction (EF) decreased at 3-month and 6-month after chemotherapy in high D-dimer group (baseline, 65.2% [62.8%-71.4%]; 3-month, 62.9% [59.0%-67.7%]; 6-month, 63.1% [60.0%-67.1%]; 12-month, 63.3% [58.8%-66.0%], P = 0.03), but no change was observed in low D-dimer group. The occurrence of CTRCD within the 12-month follow-up period was higher in high D-dimer group than in low D-dimer group (16.2% vs. 4.5%, P = 0.0146). Multivariable logistic regression analysis revealed that high D-dimer level at baseline was an independent predictor of the development of CTRCD (odds ratio 3.93, 95% CI [1.00-15.82], P = 0.047). Conclusion: Elevated D-dimer is a pivotal biomarker to predict CTRCD.

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Trastuzumab-Induced Cardiotoxicity: Clinical and Prognostic Implications of Troponin I Evaluation

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.3615 ◽

2010 ◽

Vol 28 (25) ◽

pp. 3910-3916 ◽

Cited By ~ 385

Author(s):

Daniela Cardinale ◽

Alessandro Colombo ◽

Rosalba Torrisi ◽

Maria T. Sandri ◽

Maurizio Civelli ◽

...

Keyword(s):

At Risk ◽

Cardiac Dysfunction ◽

Troponin I ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Trastuzumab Therapy ◽

Before And After ◽

Patients At Risk ◽

Prognostic Implications

Purpose Treatment of breast cancer with trastuzumab is complicated by cardiotoxicity in up to 34% of the patients. In most patients, trastuzumab-induced cardiotoxicity (TIC) is reversible: left ventricular ejection fraction (LVEF) improves after trastuzumab withdrawal and with, or sometimes without, initiation of heart failure (HF) therapy. The reversibility of TIC, however, is not foreseeable, and identification of patients at risk and of those who will not recover from cardiac dysfunction is crucial. The usefulness of troponin I (TNI) in the identification of patients at risk for TIC and in the prediction of LVEF recovery has never been investigated. Patients and Methods In total, 251 women were enrolled. TNI was measured before and after each trastuzumab cycle. LVEF was evaluated at baseline, every 3 months during trastuzumab therapy, and every 6 months afterward. In case of TIC, trastuzumab was discontinued, and HF treatment with enalapril and carvedilol was initiated. TIC was defined as LVEF decrease of > 10 units and below 50%. Recovery from TIC was defined as LVEF increase above 50%. Results TIC occurred in 42 patients (17%) and was more frequent in patients with TNI elevation (TNI+; 62% v 5%; P < .001). Twenty-five patients (60%) recovered from TIC. LVEF recovery occurred less frequently in TNI+ patients (35% v 100%; P < .001). At multivariate analysis, TNI+ was the only independent predictor of TIC (hazard ratio [HR], 22.9; 95% CI, 11.6 to 45.5; P < .001) and of lack of LVEF recovery (HR, 2.88; 95% CI,1.78 to 4.65; P < .001). Conclusion TNI+ identifies trastuzumab-treated patients who are at risk for cardiotoxicity and are unlikely to recover from cardiac dysfunction despite HF therapy.

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P1513 Myocardial work analysis is a potential novel tool to diagnose subclinical cardiac dysfunction in cirrhotic cardiomyopathy

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jez319.937 ◽

2020 ◽

Vol 21 (Supplement_1) ◽

Author(s):

A M Chitroceanu ◽

R C Rimbas ◽

S I Visoiu ◽

A E Balinisteanu ◽

M L Luchian ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Left Ventricular ◽

Volume Index ◽

Left Ventricular Ejection ◽

Lv Function ◽

Cirrhotic Cardiomyopathy ◽

Ventricular Ejection Fraction ◽

Work Index ◽

Constructive Work ◽

Global Work

Abstract Funding Acknowledgements This work was supported by a grant of Ministery of Research and Innovation, CNCS-UEFISCDI, project number PN-III-P1-1-TE-2016-0669, within PNCDI III Background Cirrhotic cardiomyopathy (CCM) is defined as systolic and/or diastolic cardiac dysfunction, associated with high preload and low afterload. Thus, assessment of cardiac dysfunction in these circumstances is still debatable. Left ventricular (LV) deformation is still load-dependent, and does not reflect directly myocardial energy consumption. Since myocardial work (MW)incorporates both deformation and afterload, it might be a better alternative for the assessment of LV function in CCM. Methods 80 subjects were assessed by 2D conventional and speckle tracking echocardiography (STE): 40 patients with liver cirrhosis (LC) (58 ± 8 years, 23 males), free of any cardiovascular disease or diabetes, and 40 age and gender matched normal, control subjects. Left ventricular ejection fraction (LVEF) and systolic/diastolic blood pressure (SBP/DBP) were measured. A new approach was used to evaluate myocardial work by 2DSTE: global constructive work (GCW), as the "positive" work of the heart; global wasted work (GWW), as the "negative" work of the heart; global work efficiency (GWE), as the GCW/(GCW + GWW) in %; and global work index (GWI), as the GCW added to GWW. E/E’ ratio, left atrial volume index (LAVi), and systolic pulmonary arterial pressure (sPAP) were also assessed. Results Patients with LC had significantly lower SBP/DBP than controls, with similar LVEF (Table). GCW and GWI were decreased in patients with LC, probably due to decrease in afterload, which shifts LV work to a lower level of energy. GWE and GWW were similar to controls. By segmental analysis (18 segments model), apical and mid antero-lateral segments were the first affected in terms of myocardial work, with higher WW, low WE, but without a compensatory increase in CW in other segments, suggesting a regional myocardial dysfunction. All patients with LC presented significantly elevated E/E’ ratio, LAVi, and sPAP, compared to controls (Table). Conclusion Myocardial global constructive work and global work index decrease in LC patients, compared to normal individuals, probably due to augmented peripheral vasodilatation. Apical and mid antero-lateral segments are the first affected. Assessment of global and regional MW might be a potential new tool to assess CCM, and to understand the relationship between LV remodeling and increased filling pressure under different loading conditions. Comparative myocardial work indices group SBP (mmHg) DBP LVEF (%) E/E’ LAVI sPAP GWI GWE (% ) GCW (mmHg % ) GWW (mmHg %) LC (40) 111 ±14 69 ± 12 59 ± 7 8.5 ± 2.5 45.9 ± 14.5 26 ± 9 1927 ± 379 95 ± 2 2068 ± 386 90.1 ± 49 Controls (40) 126 ± 14 76 ± 8 61 ± 7 7.5 ± 2.2 31.8 ± 6.8 21 ± 8 2123 ± 353 95± 2 2302 ± 335 94.4 ± 49 P value 0.001 0.004 0.3 0.05 0.001 0.009 0.01 0.9 0.005 0.7 Abstract P1513 Figure. Myocardial Work Cirrhotic Cardiomyopathy

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Prognostic Factors for Cancer Therapeutics-Related Cardiac Dysfunction in Breast Cancer Patients Treated with Current Anthracycline Regimens

10.21203/rs.3.rs-1084573/v1 ◽

2021 ◽

Author(s):

Koichi Egashira ◽

Daisuke Sueta ◽

Mai Tomiguchi ◽

Kaori Hidaka ◽

Lisa Goto-Yamaguchi ◽

...

Keyword(s):

Breast Cancer ◽

Prognostic Factors ◽

Cancer Patients ◽

Cumulative Dose ◽

Cardiac Dysfunction ◽

Cancer Therapeutics ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Breast Cancer Patients ◽

Ventricular Ejection Fraction

Abstract Background Anthracycline therapies cause myocardial damage and the onset of heart failure, depending on their doses. We investigated prognostic factors for cancer therapeutics-related cardiac dysfunction (CTRCD) in patients receiving modern anthracycline therapies. Methods Of 472 breast cancer patients with complete data treated with anthracycline, 8 were diagnosed with CTRCD. Results Multivariate regression analyses revealed that the anthracycline cumulative dose, concomitant use of molecular targeted drugs and a prechemotherapy left ventricular ejection fraction < 50% were independent and significant predictors of the onset of CTRCD. Conclusions Even in the modern era, the anthracycline cumulative dose is an independent risk factor for the onset of CTRCD.

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Detecting early onset of anthracyclines-induced cardiotoxicity using a novel panel of biomarkers in West-Virginian population with breast cancer

Scientific Reports ◽

10.1038/s41598-021-87209-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hari Vishal Lakhani ◽

Sneha S. Pillai ◽

Mishghan Zehra ◽

Benjamin Dao ◽

Maria Tria Tirona ◽

...

Keyword(s):

Breast Cancer ◽

Left Ventricular Ejection Fraction ◽

Ejection Fraction ◽

Cardiac Dysfunction ◽

Early Onset ◽

Troponin I ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Circulating Mirnas ◽

Ventricular Ejection Fraction

AbstractCardiotoxic manifestation associated with breast cancer treatment by anthracycline regimen increases patients’ susceptibility to myocardial injury, reduction in left ventricular ejection fraction and complications associated with heart failure. There is currently no standardized, minimally invasive, cost effective and clinically verified procedure to monitor cardiotoxicity post-anthracycline therapy initiation, and to detect early onset of irreversible cardiovascular complications. This study aims to create a panel of novel biomarkers and circulating miRNAs associated with cardiotoxicity, further assessing their correlation with cardiac injury specific markers, troponin I and T, and demonstrate the development of cardiac dysfunction in breast cancer patients. Blood obtained from West Virginian females clinically diagnosed with breast cancer and receiving anthracyclines showed upregulated level of biomarkers and circulating miRNAs after 3 and 6 months of chemotherapy initiation with increased levels of cardiac troponin I and T. These biomarkers and miRNAs significantly correlated with elevated troponins. Following 6 months of anthracycline-regimens, 23% of the patient population showed cardiotoxicity with reduced left ventricular ejection fraction. Our results support the clinical application of plasma biomarkers and circulating miRNAs to develop a panel for early diagnosis of chemotherapy related cardiac dysfunction which will enable early detection of disease progression and management of irreversible cardiac damage.

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Comparison of the Levels of Cardiac Troponin I in Patients with Duchenne and Becker Muscular Dystrophies to Assess Cardiac Dysfunction

10.21203/rs.3.rs-154169/v1 ◽

2021 ◽

Author(s):

Hiroshi Yamaguchi ◽

Hiroyuki Awano ◽

Tetsushi Yamamoto ◽

Masafumi Matsuo ◽

Kazumoto Iijima

Keyword(s):

Cardiac Dysfunction ◽

Cardiac Troponin ◽

Myocardial Injury ◽

Troponin I ◽

Genetic Modifier ◽

Becker Muscular Dystrophy ◽

Left Ventricular ◽

Cardiac Troponin I ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction

Abstract Background: Cardiac troponin I (cTnI), uniquely expressed in the myocardium, is a marker for acute myocardial injury. Its clinical significance in Duchenne and Becker muscular dystrophy (DMD and BMD) and its relation to alpha-actinin-3 (ACTN3) genotype as a genetic modifier of cardiomyopathy are still unknown.Methods and Results: Overall, 529 and 131 serum cTnI values of 127 DMD and 47 BMD patients, respectively, were reviewed. cTnI elevation was generally observed in the second decade of life. Both cTnI levels and the proportion of abnormal cTnI levels were significantly higher in DMD patients than in BMD patients (age range: 1< years ≤10 and 10< years ≤18 and 10< years ≤18, respectively). Decreased left ventricular ejection fraction was observed after cTnI elevation in both populations. cTnI levels by age in DMD patients with ACTN3 null genotype tended to increase highly and early.Conclusions: Myocardial injury indicated by cTnI was more common and severe in DMD patients than in BMD patients. cTnI elevation preceding cardiac dysfunction may represent an early phase of cardiomyopathy progression and may be a biomarker for early detection of cardiomyopathy in DMD and BMD patients. The ACTN3 null genotype may be a risk factor for early myocardial injury.

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265 Incidence, determinants and prognostic relevance of HS-troponin and natriuretic peptides elevation at admission in hospitalized COVID-19 pneumonia patients

European Heart Journal Supplements ◽

10.1093/eurheartj/suaa198 ◽

2020 ◽

Vol 22 (Supplement_N) ◽

pp. N65-N79

Author(s):

Luca Arcari ◽

Michelangelo Luciano ◽

Luca Cacciotti ◽

Maria Beatrice Musumeci ◽

Valerio Spuntarelli ◽

...

Keyword(s):

Hospital Mortality ◽

Natriuretic Peptides ◽

Multivariable Analysis ◽

Left Ventricular ◽

Cardiac Biomarkers ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Good Ability ◽

Myocardial Involvement ◽

D Dimer

Abstract Aims myocardial involvement in the course of Coronavirus disease 2019 (COVID-19) pneumonia has been reported, though not fully characterized yet. Aim of the present study is to undertake a joint evaluation of hs-Troponin and natriuretic peptides (NP) in patients hospitalized for COVID-19 pneumonia. Methods and results in this multicenter observational study, we analyzed data from n = 111 COVID-19 patients admitted to dedicated “COVID-19” medical units. Hs-Troponin was assessed in n = 103 patients and NP in n = 82 patients on admission; subgroups were identified according to values beyond reference range. increased hs-Troponin and NP were found in 38% and 56% of the cases respectively. As compared to those with normal cardiac biomarkers, these patients were older, had higher prevalence of cardiovascular diseases (CVD) and more severe COVID-19 pneumonia by higher CRP and D-dimer and lower PaO2/FIO2. Two-dimensional echocardiography performed in a subset of patients (n = 24) showed significantly reduced left ventricular ejection fraction in patients with elevated NP only (p = 0.02), whereas right ventricular systolic function (tricuspid annular plane systolic excursion) was significantly reduced both in patients with high hs-Troponin and NP (p = 0.022 and p = 0.03 respectively). On multivariable analysis, independent associations were found of hs-Troponin with age, PaO2/FIO2 and D-dimer (B = 0.419, p = 0.001; B=-0.212, p = 0.013 and B = 0.179, p = 0.037 respectively), and of NP with age and previous CVD (B = 0.480, p < 0.001 and B = 0.253, p = 0.001 respectively). In patients with in-hospital mortality (n = 23, 21%) hs-Troponin and NP were both higher (p = 0.001 and p = 0.002 respectively), while increasing hs-troponin and NP were associated with worse in-hospital prognosis [OR 4.88 (95% CI 1.9-12.2), p = 0.001 (adjusted OR 3.1 (95% CI 1.2-8.5), p = 0.025) and OR 4.67 (95% CI 2-10.8), p < 0.001 (adjusted OR 2.89 (95% CI 1.1-7.9), p = 0.04) respectively]. Receiver operator characteristic curves showed good ability of hs-Troponin and NP in predicting in-hospital mortality (AUC = 0.869 p < 0.001 and AUC = 0.810, p < 0.001 respectively). Conclusion myocardial involvement at admission is common in COVID-19 pneumonia and associated to worse prognosis, suggesting a role for cardiac biomarkers assessment in COVID-19 risk stratification. Independent associations of hs-Troponin with markers of disease severity and of NP with underlying CVD might point towards existing different mechanisms leading to their elevation in this setting.

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

The Egyptian Heart Journal ◽

10.1186/s43044-020-00090-0 ◽

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.

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Trastuzumab-Associated Cardiac Adverse Effects in the Herceptin Adjuvant Trial

Journal of Clinical Oncology ◽

10.1200/jco.2006.09.1611 ◽

2007 ◽

Vol 25 (25) ◽

pp. 3859-3865 ◽

Cited By ~ 378

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.

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

Circulation ◽

10.1161/circ.116.suppl_16.ii_246-b ◽

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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