Therapeutic effect of MG-132 on diabetic cardiomyopathy is associated with its suppression of proteasomal activities: roles of Nrf2 and NF-κB

2013 ◽  
Vol 304 (4) ◽  
pp. H567-H578 ◽  
Author(s):  
Yuehui Wang ◽  
Weixia Sun ◽  
Bing Du ◽  
Xiao Miao ◽  
Yang Bai ◽  
...  
Keyword(s):  
Therapeutic Effect ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Nuclear Accumulation ◽  
Left Ventricular Ejection ◽  
Heart Weight ◽  
Diabetic Mice ◽  
Antioxidant Genes ◽  
Antioxidative Function

MG-132, a proteasome inhibitor, can upregulate nuclear factor (NF) erythroid 2-related factor 2 (Nrf2)-mediated antioxidative function and downregulate NF-κB-mediated inflammation. The present study investigated whether through the above two mechanisms MG-132 could provide a therapeutic effect on diabetic cardiomyopathy in the OVE26 type 1 diabetic mouse model. OVE26 mice develop hyperglycemia at 2–3 wk after birth and exhibit albuminuria and cardiac dysfunction at 3 mo of age. Therefore, 3-mo-old OVE26 diabetic and age-matched control mice were intraperitoneally treated with MG-132 at 10 μg/kg daily for 3 mo. Before and after MG-132 treatment, cardiac function was measured by echocardiography, and cardiac tissues were then subjected to pathological and biochemical examination. Diabetic mice showed significant cardiac dysfunction, including increased left ventricular systolic diameter and wall thickness and decreased left ventricular ejection fraction with an increase of the heart weight-to-tibia length ratio. Diabetic hearts exhibited structural derangement and remodeling (fibrosis and hypertrophy). In diabetic mice, there was also increased systemic and cardiac oxidative damage and inflammation. All of these pathogenic changes were reversed by MG-132 treatment. MG-132 treatment significantly increased the cardiac expression of Nrf2 and its downstream antioxidant genes with a significant increase of total antioxidant capacity and also significantly decreased the expression of IκB and the nuclear accumulation and DNA-binding activity of NF-κB in the heart. These results suggest that MG-132 has a therapeutic effect on diabetic cardiomyopathy in OVE26 diabetic mice, possibly through the upregulation of Nrf2-dependent antioxidative function and downregulation of NF-κB-mediated inflammation.

scholarly journals Lingguizhugan decoction attenuates doxorubicin-induced heart failure in rats by improving TT-SR microstructural remodeling

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Xueping Li ◽  
Guangmin Xu ◽  
Shujun Wei ◽  
Baocheng Zhang ◽  
Huan Yao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular Ejection Fraction ◽  
Ejection Fraction ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
The Body ◽  
Ventricular Ejection ◽  
Left Ventricular Ejection ◽  
Heart Weight ◽  
Ventricular Ejection Fraction

Abstract Background Lingguizhugan decoction (LGZG), an ancient Chinese herbal formula, has been used to treat cardiovascular diseases in eastern Asia. We investigated whether LGZG has protective activity and the mechanism underlying its effect in an animal model of heart failure (HF). Methods A rat model of HF was established by administering eight intraperitoneal injections of doxorubicin (DOX) (cumulative dose of 16 mg/kg) over a 4-week period. Subsequently, LGZG at 5, 10, and 15 mL/kg/d was administered to the rats intragastrically once daily for 4 weeks. The body weight, heart weight index (HWI), heart weight/tibia length ratio (HW/TL), and serum BNP level were investigated to assess the effect of LGZG on HF. Echocardiography was performed to investigate cardiac function, and H&E staining to visualize myocardial morphology. Myocardial ultrastructure and T-tubule-sarcoplasmic reticulum (TT-SR) junctions were observed by transmission electron microscopy. The JP-2 protein level was determined by Western blotting. The mRNA level of CACNA1S and RyR2 and the microRNA-24 (miR-24) level were assayed by quantitative RT-PCR. Results Four weeks after DOX treatment, rats developed cardiac damage and exhibited a significantly increased BNP level compared with the control rats (169.6 ± 29.6 pg/mL versus 80.1 ± 9.8 pg/mL, P < 0.001). Conversely, LGZG, especially at the highest dose, markedly reduced the BNP level (93.8 ± 17.9 pg/mL, P < 0.001). Rats treated with DOX developed cardiac dysfunction, characterized by a strong decrease in left ventricular ejection fraction compared with the control (58.5 ± 8.7% versus 88.7 ± 4.0%; P < 0.001). Digoxin and LGZG improved cardiac dysfunction (79.6 ± 6.1%, 69.2 ± 2.5%, respectively) and preserved the left ventricular ejection fraction (77.9 ± 5.1, and 80.5 ± 4.9, respectively, P < 0.01). LGZG also improved the LVEDD, LVESD, and FS and eliminated ventricular hypertrophy, as indicated by decreased HWI and HW/TL ratio. LGZG attenuated morphological abnormalities and mitochondrial damage in the myocardium. In addition, a high dose of LGZG significantly downregulated the expression of miR-24 compared with that in DOX-treated rats (fold change 1.4 versus 3.4, P < 0.001), but upregulated the expression of JP-2 and antagonized DOX-induced T-tubule TT-SR microstructural remodeling. These activities improved periodic Ca2+ transients and cell contraction, which may underly the beneficial effect of LGZG on HF. Conclusions LGZG exerted beneficial effects on DOX-induced HF in rats, which were mediated in part by improved TT-SR microstructural remodeling.

Abstract P173: Caloric Restriction Attenuates Diabetic Cardiomyopathy Through the Recruitment of the Antioxidant System

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Maayan Waldman ◽  
Keren Cohen ◽  
Michael Arad ◽  
Nader G Abraham ◽  
Michal Laniado-Schwartzman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Caloric Restriction ◽  
Diabetic Cardiomyopathy ◽  
Diabetic Heart ◽  
Heart Weight ◽  
Internal Diameter ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Antioxidant Genes ◽  
Obesity And Diabetes

Introduction: Insulin resistance negatively impacts the diabetic heart in various ways, that include impaired insulin-mediated glucose uptake and a reduction in intracellular signalling. Diabetic cardiomyopathy is independent of coronary artery disease and is characterized by increased oxidative stress and extensive fibrotic changes, leading to increased myocardial stiffness and the development of diastolic dysfunction. Caloric restriction (CR) is cardioprotective mainly through its catabolic activity and increased insulin sensitivity. We examined the effect of CR on the development of diabetic cardiomyopathy and changes in oxidative stress and antioxidant genes. Methods: Leptin resistant (db/db) mice suffer from obesity and diabetes. Mice were treated for 4 weeks with angiotensin II (AT) to induce severe cardiomyopathy. Mice under CR were fed 90% of their normal food intake for 2 weeks and 65% for an additional 2 weeks. Each group consisted of 5-6 animals. Results: CR attenuated obesity and the cardiomyopathy phenotype in diabetic mice. CR reduced body weight and heart weight in diabetic mice when compared to control animals (33.7±7.9g vs.44 ±5.9g; 0.137±0.023g vs. 0.17±0.02g respectively, p<0.05); and lowered blood glucose (576±167mg/dL vs 702.5±309 mg/dL, p<0.05). Echocardiography indicated that CR attenuated the hypertrophic phenotype in the diabetic mice when compared to control animals (LV internal diameter 3.34±0.46mm vs. 4.06±0.36mm, p<0.01). Diabetic mice treated with AT suffer from oxidative stress as evident in a 110% increase in serum MDA levels (p<0.011), a reduction of 81% in adiponectin (p<0.001) and 65% in PGC-1α (p<0.0046) mRNA levels in cardiac tissue of diabetic mice compared to WT mice. The attenuation of diabetic cardiomyopathy after CR was accompanied by a reduction in serum MDA levels (p<0.028) and an increase in cardiac adiponectin, HO-1 and PGC-1α levels (p<0.05). Conclusion: These results indicate that a short term CR attenuated the development of AT induced diabetic cardiomyopathy through the activation of the adiponectin- PGC-1α- HO-1-axis. This appears to be a critical module in protecting the diabetic heart from the development of cardiomyopathy.

FUNCTIONAL RESILIENCE OF C57BL/6J MOUSE HEART TO DIETARY FAT OVERLOAD

2021 ◽  
Author(s):  
Satya Murthy Tadinada ◽  
Eric T. Weatherford ◽  
Greg V. Collins ◽  
Gourav Bhardwaj ◽  
Jesse Cochran ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
High Fat Diet ◽  
Saturated Fat ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Mouse Heart ◽  
High Fat ◽  
Ventricular Ejection Fraction

Molecular mechanisms underlying cardiac dysfunction and subsequent heart failure in diabetic cardiomyopathy are incompletely understood. Initially we intended to test the role of GRK2, a potential mediator of cardiac dysfunction in diabetic cardiomyopathy, but found that control animals on HFD did not develop cardiomyopathy. Cardiac function was preserved in both wildtype and GRK2 knockout animals fed high fat diet as indicated by preserved left ventricular ejection fraction (LVEF) although heart mass was increased. The absence of cardiac dysfunction led us to rigorously evaluate the utility of diet-induced obesity to model diabetic cardiomyopathy in mice. Using pure C57BL/6J animals and various diets formulated with different sources of fat- lard (32% saturated fat, 68% unsaturated fat) or hydrogenated coconut oil (95% saturated fat), we consistently observed left ventricular hypertrophy, preserved LVEF and preserved contractility measured by invasive hemodynamics in animals fed high fat diet. Gene expression patterns that characterize pathological hypertrophy were not induced but a modest induction of various collagen isoforms and matrix metalloproteinases were observed in heart with high fat diet feeding. PPARa-target genes that enhance lipid utilization such as Pdk4, CD36, AcadL and Cpt1b were induced, but mitochondrial energetics were not impaired. These results suggest while long-term fat feeding in mice induces cardiac hypertrophy and increases cardiac fatty acid metabolism, it may not be sufficient to activate pathological hypertrophic mechanisms that impair cardiac function or induce cardiac fibrosis. Thus, additional factors that are currently not understood may contribute to the cardiac abnormalities previously reported by many groups.

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.

Abstract 137: Deficiency of Senescence Marker Protein 30 Exacerbates Doxorubicin-Induced Cardiac Dysfunction in Mice

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Makiko Miyata ◽  
Satoshi Suzuki ◽  
Tomofumi Misaka ◽  
Shu-ichi Saitoh ◽  
Yasuchika Takeishi
Keyword(s):  
Cardiac Dysfunction ◽  
Protective Role ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Marker Protein ◽  
Morphological Examination ◽  
Protective Function ◽  
Ventricular Ejection Fraction ◽  
Wide Range ◽  
Oxidative Effects

Background: Senescence marker protein 30 (SMP30) was originally identified as an aging marker protein in the rat liver. The expression of SMP30 decreases with aging androgen-independently. Doxorubicin (DOX) has been used as a potent anticancer agent, but serious cardiotoxicity precludes its use in a wide range of patients. SMP30 may have anti-oxidative and anti-apoptosis functions in several organs, but functional role of SMP30 has not been rigorously examined in the heart. We hypothesized that SMP30 has cardio-protective function by anti-aging and anti-oxidant effects on DOX-induced cardiac dysfunction. Method and Results: Male SMP30 knockout (SMP30KO) and age-matched littermate male wild-type (WT) mice at 12-14 weeks of age were given intraperitoneal injections of DOX (20 mg/kg) or saline. Seven days after DOX injection, echocardiography revealed that left ventricular ejection fraction in DOX-treated SMP30KO mice was more severely reduced than in DOX-treated WT mice (40.9 ± 3.1% vs. 46.9 ± 4.9%, P<0.01). Morphological examination of myocardial sections showed fibrotic change in DOX-treated SMP30KO mice significantly increased compared to DOX-treated WT mice (3.2 ± 0.5% vs. 1.3 ± 0.2%, P<0.01). Generation of reactive oxygen species assessed by dihydroethidium staining was greater in DOX-treated SMP30KO mice than DOX-treated WT mice (166.9 ± 8.6% vs. 131.6 ± 5.8%, P<0.01). Moreover, apoptotic signaling pathways such as caspase-3 activity (1.8 ± 0.1% vs. 1.1 ± 0.2%, P<0.01), bax/bcl-2 ratio (2.4 ± 0.3% vs.1.6 ± 0.2%, P<0.05) and phosphorylation activity of c-Jun N-terminal kinase (1.6 ± 0.3 vs. 1.0 ± 0.1, P<0.05) were significantly elevated in the SMP30KO mice compared with WT mice after DOX injection. The numbers of TUNEL-positive nuclei in the myocardium were higher in DOX-treated SMPKO mice than in DOX-treated WT mice (0.15 ± 0.02% vs. 0.08 ± 0.01%, P<0.01). Conclusions: The results of this study demonstrated that DOX-induced cardiotoxicity is aggravated in SMP30KO mice by exacerbating of superoxide generation, leading to enhanced apoptosis of cardiomyocytes. SMP30 has a cardio-protective role by anti-apoptotic and anti-oxidative effects in DOX-induced cardiotoxicity.

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

2010 ◽  
Vol 28 (25) ◽  
pp. 3910-3916 ◽  
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.

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.

Abstract 13246: The Impact of Body-Mass Index Trajectories During Early Adulthood on Cardiac Mechanics in Middle Age: The CARDIA Study

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sadiya S Khan ◽  
Sanjiv J Shah ◽  
Kiang J Liu ◽  
Cora E Lewis ◽  
Christina Shay ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Young Adulthood ◽  
Cardiac Dysfunction ◽  
Middle Age ◽  
Cardiac Mechanics ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
The Impact ◽  
Baseline Bmi

Introduction: Obesity is a risk factor for left ventricular dysfunction and incident heart failure. We hypothesized that baseline body mass index (BMI) and trajectories in weight change through young adulthood are associated with abnormal cardiac mechanics in middle age. Methods: We examined 2,735 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study. BMI was calculated at exam years 0, 2, 5, 7, 10, 15, 20, 25. 2D echo was performed with speckle-tracking analysis. Left ventricular ejection fraction (LVEF) and global longitudinal, circumferential, and radial strain (GLS, GCS, GRS, respectively) were measured at y25. Group-based modeling with latent class analysis (PROC TRAJ) was used to identify trajectories in relative changes in BMI (% change in BMI from baseline at each exam). Linear regression examined associations between baseline BMI and trajectory of BMI change and absolute GLS, GCS, and GRS at y25 adjusting for demographics, risk factors, and echo parameters. Results: Mean age at baseline was 25±4 years. Baseline BMI at y0 was significantly associated with mean GLS at y25 (p=0.01), but not GRS or GCS. We identified 4 distinct trajectories of relative BMI change: stable weight (36% of sample), mild increase (40%), moderate increase (18%), and major increase (6%) in weight (Figure). At y25, there was no difference in LVEF across the 4 BMI trajectory groups (P=NS). After adjustment for clinical variables and baseline BMI, absolute GLS was lower in groups with BMI increases (overall P<0.001). GRS and GCS were not significantly different between the groups. Conclusion: In conclusion, baseline BMI and increases in BMI during young adulthood are significantly associated with the presence of subclinical cardiac dysfunction in middle age despite normal EF. This novel characterization of BMI trajectories across young adulthood may assist in improving understanding of the impact of weight gain and obesity on cardiac dysfunction.

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

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Masayoshi Oikawa ◽  
Daiki Yaegashi ◽  
Tetsuro Yokokawa ◽  
Tomofumi Misaka ◽  
Takamasa Sato ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Troponin I ◽  
Uterine Cancer ◽  
Cancer Therapeutics ◽  
Left Ventricular ◽  
Time Dependent ◽  
Volume Index ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
D Dimer

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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