Excessive left ventricular trabeculation does not promote cardiac dysfunction in asymptomatic middle aged and older individuals with preserved cardiac function: an analysis from the Multi-Ethnic Study of Atherosclerosis

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.

Download Full-text

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

Circulation ◽

10.1161/circ.116.suppl_16.ii_741-c ◽

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.

Download Full-text

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

Clinical Science ◽

10.1042/cs20190014 ◽

2019 ◽

Vol 133 (3) ◽

pp. 497-513 ◽

Cited By ~ 22

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.

Download Full-text

Cardiac Function in Uncomplicated Type 2 Diabetes Mellitus

Bangladesh Journal of Medical Science ◽

10.3329/bjms.v18i2.40687 ◽

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

Download Full-text

Safety of trastuzumab in women with HER2+ breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e12522 ◽

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.

Download Full-text

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

Endocrinology ◽

10.1210/en.2010-0256 ◽

2010 ◽

Vol 151 (8) ◽

pp. 3536-3542 ◽

Cited By ~ 12

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.

Download Full-text

Necrostatin-1 reduces cardiac and mitochondrial dysfunction in prediabetic rats

Journal of Endocrinology ◽

10.1530/joe-21-0134 ◽

2021 ◽

Author(s):

Nattayaporn Apaijai ◽

Kewarin Jinawong ◽

Kodchanan Singhanat ◽

Thidarat Jaiwongkam ◽

Sasiwan Kerdphoo ◽

...

Keyword(s):

Blood Pressure ◽

Cardiac Function ◽

Mitochondrial Dysfunction ◽

Cardiac Dysfunction ◽

Left Ventricular ◽

Mitochondrial Fusion ◽

Metabolic Parameters ◽

Vehicle Group ◽

Mitochondrial Dynamic ◽

Autonomic Imbalance

High fat diet (HFD) consumption induces prediabetes and left ventricular dysfunction through many pathways including the cell death pathway, necroptosis. Although benefits of necroptosis inhibitor (necrostatin-1 or Nec-1) in the brain of prediabetic rats have been shown, the effects of Nec-1 on cardiac autonomic function, blood pressure, and cardiac function, and the mechanisms involved have not been investigated. Male Wistar rats were fed with either a normal diet (n=8) or HFD (n=24) for 12 weeks to induce prediabetes. Prediabetic rats were randomly assigned into 3 interventional groups (n=8/group): 1) vehicle, 2) Nec-1 (1.65 mg/kg, sc injection), and 3) metformin (300 mg/kg, oral gavage feeding). Treatments lasted for 8 weeks. Normal saline was given to the vehicle group and a non-interventional group. Metabolic parameters, cardiac function and biochemical parameters were assessed. Prediabetic rats exhibited peripheral metabolic impairment as indicated by increased body weight, hyperinsulinemia with euglycemia, and dyslipidemia. Prediabetic rats also exhibited cardiac autonomic imbalance, high blood pressure, cardiac dysfunction, cardiac mitochondrial dysfunction, mitochondrial dynamic imbalance, and increased necroptosis and apoptosis. Treatment with Nec-1 did not affect peripheral metabolic parameters, however it effectively reduced cardiac autonomic imbalance, blood pressure, and cardiac dysfunction via reduced cardiac inflammation, necroptosis, mitochondrial dysfunction, and increased mitochondrial fusion. Treatment with metformin reduced peripheral metabolic impairment and cardiac dysfunction via decreased cardiac mitochondrial dysfunction, mitochondrial dynamic imbalance, and apoptosis. In summary, Nec-1 directly suppressed necroptosis, cardiac mitochondrial dysfunction, and increased mitochondrial fusion independent to peripheral metabolic function, leading to an improvement in cardiac function in prediabetic rats.

Download Full-text

Abstract 519: Talin is Required for Normal Adult Heart Function

Circulation Research ◽

10.1161/res.127.suppl_1.519 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Yoshitake Cho ◽

Ruixia Li ◽

Ana M Manso ◽

Robert S Ross

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Cardiac Dysfunction ◽

Cardiac Development ◽

Heart Function ◽

Left Ventricular ◽

Mass Spectrometry Analysis ◽

Adult Heart ◽

Spectrometry Analysis ◽

Functional Changes

Talin (Tln) is a component of muscle costameres that links integrins to other components of the cellular cytoskeleton and plays an important role in maintaining the cellular integrity of cardiac myocytes (CM). There are two talin genes, Tln1 and Tln2, expressed in the heart. Tln1 is ubiquitously expressed, and Tln2 is dominantly expressed in CM. In our previous study, we show that the global deletion of Tln2 in mice (T2KO) caused no structural or functional changes in the heart, presumably because CM Tln1 became up-regulated. However, we found that mice lacking both CM Tln1 and Tln2 exhibit cardiac dysfunction by 4 weeks (w) of age with 100% mortality by 6 months (m), showing Tln plays an essential role in cardiac development and in maintaining cardiac function. In this study, we produced a tamoxifen (Tamo)-inducible mouse model in which Tln1 could be explicitly reduced in the adult CM (T1icKO), and then generate T1icKO:T2KO (T1/2dKO), so that the function of Tln could be assessed in the postnatal heart. T2KO and Tln1/2dKO mice were injected with Tamo at 8w. Echocardiograms were performed to evaluate cardiac function up to 8w post-Tamo injection. While T2KO mice showed normal cardiac function, T1/2dKO exhibited a gradual decrease in function post-Tamo injection. At 8w post-Tamo injection, T1/2dKO mice showed cardiac hypertrophy, fibrosis, and heart failure. To understand the mechanism by which deletion CM talin leads to cardiac dysfunction, left ventricular tissue protein lysates from T2KO and T1/2dKO mice at 4w post-Tamo when cardiac function (echo) and structure were preserved in dKO. The protein lysates were subjected to quantitative mass spectrometry analysis. We found there are 1,100 proteins differentially expressed in T2KO and T1/2dKO hearts. Pathway analysis was performed, and the results showed that proteins involved in vesicle transport, protein folding, and innate immunity are most up-regulated in the T1/2dKO heart. Taken together, our results show that Tln is required for maintaining proper cardiac function in the adult heart. The deletion of Tln in CM results in the up-regulation of multiple intracellular pathways, and we are currently studying the role of each pathway in the pathogenesis of heart failure induced by CM Tln deletion.

Download Full-text

Inhibition of vascular peroxidase alleviates cardiac dysfunction and apoptosis induced by ischemia–reperfusion

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y2012-066 ◽

2012 ◽

Vol 90 (7) ◽

pp. 851-862 ◽

Cited By ~ 4

Author(s):

Ting-Ting Li ◽

Yi-Shuai Zhang ◽

Lan He ◽

Bin Liu ◽

Rui-Zheng Shi ◽

...

Keyword(s):

Cardiac Function ◽

Cardiac Dysfunction ◽

Isolated Heart ◽

Ischemia Reperfusion ◽

Left Ventricular Pressure ◽

Left Ventricular ◽

Ventricular Pressure ◽

Clinical Value ◽

Pharmacologic Inhibition

Myeloperoxidase (MPO) is involved in myocardial ischemia–reperfusion (IR) injury and vascular peroxidase (VPO) is a newly identified isoform of MPO. This study was conducted to explore whether VPO is involved in IR-induced cardiac dysfunction and apoptosis. In a rat Langendorff model of myocardial IR, the cardiac function parameters (left ventricular pressure and the maximum derivatives of left ventricular pressure and coronary flow), creatine kinase (CK) activity, apoptosis, VPO1 activity were measured. In a cell (rat-heart-derived H9c2 cells) model of hypoxia–reoxygenation (HR), apoptosis, VPO activity, and VPO1 mRNA expression were examined. In isolated heart, IR caused a marked decrease in cardiac function and a significant increase in apoptosis, CK, and VPO activity. These effects were attenuated by pharmacologic inhibition of VPO. In vitro, pharmacologic inhibition of VPO activity or silencing of VPO1 expression significantly suppressed HR-induced cellular apoptosis. Our results suggest that increased VPO activity contributes to IR-induced cardiac dysfunction and inhibition of VPO activity may have the potential clinical value in protecting the myocardium against IR injury.

Download Full-text

Impact of subclinical hypothyroidism treatment in systolic and diastolic cardiac function

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302011000700005 ◽

2011 ◽

Vol 55 (7) ◽

pp. 460-467 ◽

Cited By ~ 10

Author(s):

Ricardo Mendes Martins ◽

Regina Helena Alves Fonseca ◽

Marta Maria Turano Duarte ◽

Vaneska Spinelli Reuters ◽

Márcia Martins Ferreira ◽

...

Keyword(s):

Cardiac Function ◽

Subclinical Hypothyroidism ◽

Positive Impact ◽

Left Ventricular ◽

Controlled Study ◽

Slight Reduction ◽

Middle Aged ◽

Double Blind ◽

Significant Deterioration ◽

One Year

OBJECTIVE: To evaluate the effects of levothyroxine (L-T4) replacement in echocardiographic parameters of middle-aged women with subclinical hypothyroidism (SH). SUBJECTS AND METHODS: This was a randomized, double-blind, placebo-controlled study. Echocardiographic evaluation was carried out at baseline and one year after restoration of euthyroidism. Thirty-three women with SH were assigned to one of two groups (L-T4 or placebo). RESULTS: The two groups had similar basal characteristics. There was a significant deterioration of left ventricular Tei index after one year of placebo use, which differed from the effect of L-T4 replacement (+0.086 ± 0.092 vs. -0.014 ± 0.012; p = 0.047). There was also a slight reduction in cardiac output and cardiac index with placebo use, which was not different from L-T4 effect. CONCLUSION: Results suggest a positive impact of L-T4 replacement in cardiac function of middle-aged women with SH.

Download Full-text