Differential changes in β-adrenoceptor signal transduction in left and right ventricles of infarcted ratsThis paper is one of a selection of papers published in this Special issue, entitled Second Messengers and Phosphoproteins—12th International Conference.

Although different experimental and clinical studies have revealed varying degrees of defects in β-adrenoceptors (β-ARs) during the development of heart failure, the mechanisms for differences in β-AR signal transduction between the left (LV) and right ventricle (RV) are not understood. Because biochemical alterations in the myocardium depend on the stage of heart disease, this study was undertaken to assess the status of β-ARs in the LV and RV at different stages of heart failure. Myocardial infarction was induced in rats by occluding the left coronary artery for 8 and 24 weeks. The β-AR signal transduction was monitored by measuring β1-AR density, the isoproterenol-induced positive inotropic effect, the increase in [Ca2+]i in cardiomyocytes, and the activation of adenylyl cyclase. The β-AR signal transduction parameters in the 8- and 24-week failing LV were depressed, whereas the RV showed upregulation at 8 weeks and downregulation at 24 weeks of these mechanisms. These results suggest that β-AR-mediated signal transduction in the LV and RV are differentially regulated and are dependent upon the stage of development of congestive heart failure due to myocardial infarction.

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Differential changes in left and right ventricular adenylyl cyclase activities in congestive heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.2.h884 ◽

1997 ◽

Vol 272 (2) ◽

pp. H884-H893 ◽

Cited By ~ 16

Author(s):

R. Sethi ◽

K. S. Dhalla ◽

R. E. Beamish ◽

N. S. Dhalla

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Congestive Heart Failure ◽

Left Ventricle ◽

Right Ventricle ◽

Adenylyl Cyclase ◽

Adrenergic Receptors ◽

The Status ◽

Left And Right ◽

The Right

The status of beta-adrenergic receptors and adenylyl cyclase in crude membranes from both left and right ventricles was examined when the left coronary artery in rats was occluded for 4, 8, and 16 wk. The adenylyl cyclase activity in the presence of isoproterenol was decreased in the uninfarcted (viable) left ventricle and increased in the right ventricle subsequent to myocardial infarction. The density of beta1-adrenergic receptors, unlike beta2-receptors, was reduced in the left ventricle, whereas no change in the characteristics of beta1- and beta2-adrenergic receptors was seen in the right ventricle. The catalytic activity of adenylyl cyclase was depressed in the viable left ventricle but was unchanged in the right ventricle. In comparison to sham controls, the basal, as well as NaF-, forskolin-, and 5'-guanylyl imidodiphosphate [Gpp(NH)p]-stimulated adenylyl cyclase activities were decreased in the left ventricle and increased in the right ventricle of the experimental animals. Opposite alterations in the adenylyl cyclase activities in left and right ventricles from infarcted animals were also seen when two types of purified sarcolemmal preparations were employed. These changes in adenylyl cyclase activities in the left and right ventricles were dependent on the degree of heart failure. Furthermore, adenosine 3',5'-cyclic monophosphate contents were higher in the right ventricle and lower in the left ventricle from infarcted animals injected with saline, isoproterenol, or forskolin in comparison to the controls. The results suggest differential changes in the viable left and right ventricles with respect to adenylyl cyclase activities during the development of congestive heart failure due to myocardial infarction.

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Myocardial infarction remodeling that progresses to heart failure: a signaling misunderstanding

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00131.2018 ◽

2018 ◽

Vol 315 (1) ◽

pp. H71-H79 ◽

Cited By ~ 16

Author(s):

Alan J. Mouton ◽

Osvaldo J. Rivera ◽

Merry L. Lindsey

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Wound Healing ◽

Current Knowledge ◽

Healing Process ◽

Cell Types ◽

Left Ventricular ◽

Wound Healing Process ◽

The Status ◽

The Right

After myocardial infarction, remodeling of the left ventricle involves a wound-healing orchestra involving a variety of cell types. In order for wound healing to be optimal, appropriate communication must occur; these cells all need to come in at the right time, be activated at the right time in the right amount, and know when to exit at the right time. When this occurs, a new homeostasis is obtained within the infarct, such that infarct scar size and quality are sufficient to maintain left ventricular size and shape. The ideal scenario does not always occur in reality. Often, miscommunication can occur between infarct and remote spaces, across the temporal wound-healing spectrum, and across organs. When miscommunication occurs, adverse remodeling can progress to heart failure. This review discusses current knowledge gaps and recent development of the roles of inflammation and the extracellular matrix in myocardial infarction remodeling. In particular, the macrophage is one cell type that provides direct and indirect regulation of both the inflammatory and scar-forming responses. We summarize current research efforts focused on identifying biomarker indicators that reflect the status of each component of the wound-healing process to better predict outcomes.

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Improvement of cardiac function and β-adrenergic signal transduction by propionyl L-carnitine in congestive heart failure due to myocardial infarction

Coronary Artery Disease ◽

10.1097/00019501-200402000-00010 ◽

2004 ◽

Vol 15 (1) ◽

pp. 65-71 ◽

Cited By ~ 15

Author(s):

Rajat Sethi ◽

Xi Wang ◽

Roberto Ferrari ◽

Naranjan S. Dhalla

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Signal Transduction ◽

Congestive Heart Failure ◽

Cardiac Function

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Status of Prostacycline-Thromboxane System and Platelet Functional Activities in Patients with Acute Myocardial Infarction Depending on Stages of Heart Failure

Medicine Today ◽

10.3329/medtoday.v26i2.24227 ◽

2015 ◽

Vol 26 (2) ◽

pp. 83-87

Author(s):

AFM Sakhawat Hossain ◽

Brindaban Biswas ◽

Md Alfazzaman ◽

Mohammad Mohsin ◽

Md Mujibur Rahman

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Acute Myocardial Infarction ◽

Platelet Aggregation ◽

New England ◽

Medical Institute ◽

Functional Activities ◽

The Status ◽

Platelet Functions

Among possible pathogenic and adaptive mechanism of acute myocardial infarction and development of its complications, the system of prostanoids, particularly prostacycline-thromboxane system is of prime importance. But many questions relating the role of prostacycline-thromboxane system in pathogenesis of myocardial infarction associated with heart failure have studied insufficiently. The objective of this work is to study the ststus of prostacycline-thromboxane system in patients of acute myocardial infarction associated with heart failure and its correlation with the platelet functions depending on stages of heart failure. This study was performed in the department of Internal Medicine in Kharkov State Medical Institute, Ukraine in 1985-89. 120 patients with acute myocardial infarction leading to heart failure were studied. The status of prostacycline-thromboxane was considered by the level of stable metabolites of prostacycline and thromboxane - A2 as 6-keto-PGF and TXB2 respectively in venous plasma. 6-Keto-PGF-1a and TXB2 levels were determined by Radio-immunological method with the help of kits manufactured by the English Firm "New England Nuclear". To determine the platelet aggregation properties, the instrument "Bian-120" transmitter was used. It was established clinically that prostacycline- thromboxane activation depends on clinical features of myocardial infarction, i.e. its localization, depth, extension or affected size of MI, first attack or re-infarction. Maximum changes of prostacycline thromboxane system took place in extensive myocardial infarction which was expressed in increased level of TXB2 and significant change of prostanoid imbalance ratio. Parameters of platelet aggregation function and prostacycline thromboxane system were interrelated during heart failure, which were expressed by their changes in aggregation diagram.Medicine Today 2014 Vol.26(2): 83-87

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P5440Systolic/diastolic effects of chronic treatment with omecamtiv mecarbil in minipigs with post-myocardial infarction Heart Failure with reduced Ejection Fraction (HFrEF)

European Heart Journal ◽

10.1093/eurheartj/ehz746.0396 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

D Caillaud ◽

X Baudot ◽

L Gouraud ◽

L Lucats ◽

M P Pruniaux ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Ejection Fraction ◽

Healthy Volunteers ◽

Chronic Treatment ◽

Positive Inotropic Effect ◽

Post Myocardial Infarction ◽

Inotropic Effect ◽

Reduced Ejection Fraction ◽

Omecamtiv Mecarbil

Abstract Background Omecamtiv mecarbil (OM), a novel myosin ATPase activator, is currently developed for the treatment of Heart Failure with reduced Ejection Fraction (HFrEF). Phase I in healthy volunteers and patients showed that the positive inotropic effect of OM was associated with an impairment of diastolic function as assessed by change in E peak, e' wave and E/e' ratio. Purpose The diastolic impact of chronic treatment with OM has not been described yet. This study investigates the balance between positive inotropic effect and the diastolic impairment after chronic treatment with OM in a post-myocardial infarction (Post-MI) swine model of HFrEF. Methods HFrEF was induced in minipigs after myocardial infarction caused by a 150-min left anterior descending (LAD) artery occlusion performed under angiography. HFrEF minipigs were treated with OM at 3 mg/kg PO BID for 15 days (n=4), a dose known to increase systolic ejection time (SET) by ∼50 ms as achieved in healthy volunteers and patients at plasma levels between 200–300 ng/ml. Echocardiogram was performed before and after 15 days of treatment with OM. An additional echocardiogram was conducted 7 days after the last administration. Results One year after MI, minipigs displayed increased left ventricular end-diastolic volume index (LVEDVi 151±3.7ml/m2 vs 100±8.9ml/m2 before infarction) and decreased LVEF (42±2.5% vs 68±4.4% before infarction) associated with a pseudo-normal mitral pattern. A two-week treatment with OM increased SET by 64ms (p<0.0001 vs before treatment) and EF to 49±3.8% (p=0.07 vs before treatment) as well as it improved SVi by 13%. This inotropic effect was associated with a decrease of mitral E peak (p=0.01 vs before treatment) and e' waves, and with the prolongation of deceleration time (p<0.05 vs before treatment). OM treatment was associated with marked reduction of LVEDVi to 117±13.2ml/m2 (p<0.05 vs before treatment) concomitant with a ∼20% increase in diastolic septum and posterior wall thicknesses. None of these systolic or diastolic effects remained 7 days post OM treatment completion. Conclusion Similarly to clinical description, OM treatment increased LVEF and SVi principally through extension of SET. It provides positive inotropic effects associated with diastolic impairment resulting in impaired ventricular filling as assessed by LVEDVi decrease and the thickening of ventricular wall in diastole. Whether this profile will allow a beneficial reverse remodeling, needs to be investigated in a longer chronic study. Acknowledgement/Funding Sanofi sponsored study

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Wenxin-Keli Regulates the Calcium/Calmodulin-Dependent Protein Kinase II Signal Transduction Pathway and Inhibits Cardiac Arrhythmia in Rats with Myocardial Infarction

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/464508 ◽

2013 ◽

Vol 2013 ◽

pp. 1-15 ◽

Cited By ~ 16

Author(s):

Yanwei Xing ◽

Yonghong Gao ◽

Jianxin Chen ◽

Haiyan Zhu ◽

Aiming Wu ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Signal Transduction ◽

Protein Kinase ◽

Signal Transduction Pathway ◽

Treated Group ◽

Transduction Pathway ◽

Dependent Protein Kinase ◽

Group A ◽

Dependent Protein

Wenxin-Keli (WXKL) is a Chinese herbal compound reported to be of benefit in the treatment of cardiac arrhythmia, cardiac inflammation, and heart failure. Amiodarone is a noncompetitive inhibitor of theα- andβ-adrenergic receptors and prevents calcium influx in the slow-response cells of the sinoatrial and atrioventricular nodes. Overexpression of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in transgenic mice results in heart failure and arrhythmias. We hypothesised that administration of WXKL and amiodarone can reduce the incidence of arrhythmias by regulating CaMKII signal transduction. A total of 100 healthy Sprague Dawley rats were used in the study. The rats were randomly divided into four groups (a sham group, a myocardial infarction (MI) group, a WXKL-treated group, and an amiodarone-treated group). A myocardial infarction model was established in these rats by ligating the left anterior descending coronary artery for 4 weeks. Western blotting was used to assess CaMKII, p-CaMKII (Thr-286), PLB, p-PLB (Thr-17), RYR2, and FK binding protein 12.6 (FKBP12.6) levels. The Ca2+content in the sarcoplasmic reticulum (SR) and the calcium transient amplitude were studied by confocal imaging using the fluorescent indicator Fura-4. In conclusion, WXKL may inhibit heart failure and cardiac arrhythmias by regulating the CaMKII signal transduction pathway similar to amiodarone.

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Differential Alterations in Left and Right Ventricular G-Proteins in Congestive Heart Failure due to Myocardial Infarction

Journal of Molecular and Cellular Cardiology ◽

10.1006/jmcc.1998.0778 ◽

1998 ◽

Vol 30 (11) ◽

pp. 2153-2163 ◽

Cited By ~ 17

Author(s):

Rajat Sethi ◽

Vijayan Elimban ◽

Donald Chapman ◽

Ian M.C. Dixon ◽

Naranjan S. Dhalla

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Congestive Heart Failure ◽

Right Ventricular ◽

G Proteins ◽

Left And Right

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Impact of concomitant impairments of the left and right ventricular myocardial strain on the prognoses of patients with ST-elevation myocardial infarction

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeab090.094 ◽

2021 ◽

Vol 22 (Supplement_2) ◽

Author(s):

LAI Wei ◽

HENG Ge ◽

JUN Pu

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Coronary Artery ◽

Predictive Power ◽

Independent Predictor ◽

Cardiovascular Death ◽

Cerebrovascular Events ◽

St Elevation ◽

Left And Right

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): the National Key Research and Development Program of China OnBehalf Renji Hospital Affiliated to Medical College of Shanghai Jiaotong University Background The impact of concomitant impairments of left and right ventricular (LV and RV) strain on the long-term prognosis of acute ST-elevation myocardial infarction (STEMI) is not clear. Methods We analyzed CMR images and followed up 420 first STEMI patients from the EARLY Assessment of MYOcardial Tissue Characteristics by CMR in STEMI (EARLY-MYO-CMR) registry (NCT03768453). These patients received timely primary percutaneous coronary intervention (PCI) within 12h and CMR examination within 1 week (median,5 days; range, 2-7 days) after infarction. Global longitudinal strain (GLS), global radial strain (GRS), and global circumferential strain (GCS) of both ventricles were measured based on CMR cine images. Conventional CMR indexes were also assessed. Primary clinical outcome was composite major adverse cardiac and cerebrovascular events (MACCEs) including cardiovascular death, re-infarction, re-hospitalization for heart failure and stroke. Results During follow-up (median: 52 months, interquartile range: 29–78 months), 80 patients experienced major adverse cardiac and cerebrovascular events (MACCEs) including cardiovascular death, re-infarction, heart failure, and stroke. LV-GCS > -11.20% was an independent predictor of MACCEs (P < 0.001). The impairment of RV strain was found in 177 patients (42.14%), including 37.8% of patients with left anterior descending occlusions, 37.5% with left circumflex occlusions, and 51.5% with right coronary artery occlusions. Although none of the three individual RV strain measurements, the RV-GLS, RV-GRC and RV-GCS, was independently associated with the risk of MACCEs, patients who had RV-GRS ≤ 38.79% in addition to an impaired LV-GCS however were more likely to experience MACCEs than patients with decreased LV-GCS alone (log rank P = 0.010). Moreover, the addition of RV-GRS to LV-GCS improved the predictive power for MACCEs compared to the predictive power of LV-GCS alone (continuous NRI: 0.327; 95% CI: 0.095 - 0.558; P = 0.006). Finally, Tobacco use (P = 0.003), right coronary artery involvement (P = 0.002), and LV-GCS > -11.20% (P = 0.012) were found to be independent risk factors of RV-GRS impairment. Conclusions Impairment of the RV strain is prevalent in infarctions occurring at all cardiac locations. While LV-GCS is an independent predictor of long-term MACCEs, the concomitant impairment of RV-GRS results in a worsened prognosis. Combination assessment of both LV and RV strain indexes could improve risk stratification of STEMI patients.

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