scholarly journals Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of Serca2

2014 ◽  
Vol 306 (7) ◽  
pp. H1018-H1024 ◽  
Author(s):  
N. T. Boardman ◽  
J. M. Aronsen ◽  
W. E. Louch ◽  
I. Sjaastad ◽  
F. Willoch ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Left Ventricular ◽  
Lv Function ◽  
Mechanical Function ◽  
Transport Mechanisms ◽  
Working Capacity ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Plasmic Reticulum ◽  
The Relationship

Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2 transports Ca2+ from the cytosol into the sarcoplasmic reticulum of cardiomyocytes and is essential for maintaining myocardial Ca2+ handling and thus the mechanical function of the heart. SERCA2 is a major ATP consumer in excitation-contraction coupling but is regarded to contribute to energetically efficient Ca2+ handling in the cardiomyocyte. Previous studies using cardiomyocyte-specific SERCA2 knockout (KO) mice have demonstrated that decreased SERCA2 activity reduces the Ca2+ transient amplitude and induces compensatory Ca2+ transport mechanisms that may lead to more inefficient Ca2+ transport. In this study, we examined the relationship between left ventricular (LV) function and myocardial O2 consumption (MV̇o2) in ex vivo hearts from SERCA2 KO mice to directly measure how SERCA2 elimination influences mechanical and energetic features of the heart. Ex vivo hearts from SERCA2 KO hearts developed mechanical dysfunction at 4 wk and demonstrated virtually no working capacity at 7 wk. In accordance with the reported reduction in Ca2+ transient amplitude in cardiomyocytes from SERCA2 KO mice, work-independent MV̇o2 was decreased due to a reduced energy cost of excitation-contraction coupling. As these hearts also showed a marked impairment in the efficiency of chemomechanical energy transduction (contractile efficiency, i.e, work-dependent MV̇o2), hearts from SERCA2 KO mice were found to be mechanically inefficient. This ex vivo evaluation of mechanical and energetic function in hearts from SERCA2 KO mice brings together findings from previous experimental and mathematical modeling-based studies and demonstrates that reduced SERCA2 activity not only leads to mechanical dysfunction but also to energetic dysfunction.

Cardiac dysfunction in terms of left ventricular mechanical work and energetics in hypothyroid rats

2002 ◽  
Vol 283 (2) ◽  
pp. H631-H641 ◽  
Author(s):  
Yoshimi Ohga ◽  
Susumu Sakata ◽  
Chikako Takenaka ◽  
Takehisa Abe ◽  
Tsuyoshi Tsuji ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Cardiac Dysfunction ◽  
Myocardial Oxygen Consumption ◽  
Left Ventricular ◽  
Mechanical Work ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Plasmic Reticulum ◽  
Heart Preparation ◽  
Whole Heart

We hypothesized that cardiac dysfunction in hypothyroidism is mainly caused by the impairment of Ca2+ handling in excitation-contraction coupling. To prove this hypothesis, we investigated left ventricular (LV) mechanical work and energetics without interference of preload and afterload in an excised, blood-perfused whole heart preparation from hypothyroid rats. We found that LV inotropism and lusitropism were significantly depressed, and these depressions were causally related to decreased myocardial oxygen consumption for Ca2+ handling and for basal metabolism. The oxygen costs of LV contractility for Ca2+ and for dobutamine in the hypothyroid rats did not differ from those in age-matched normal rats. The expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) significantly decreased and that of phospholamban significantly increased. The present results revealed that changes in LV energetics associated with decreased mechanical work in hypothyroid rats are mainly caused by the impairment of Ca2+ uptake via SERCA2. We conclude that the impairment of Ca2+ uptake plays an important role in the pathogenesis of cardiac dysfunction in hypothyroidism.

scholarly journals Remodeling of t-system and proteins underlying excitation-contraction coupling in aging versus failing human heart

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yankun Lyu ◽  
Vipin K. Verma ◽  
Younjee Lee ◽  
Iosif Taleb ◽  
Rachit Badolia ◽  
...  
Keyword(s):  
Heart Function ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Excitation Contraction Coupling ◽  
Transverse Tubular System ◽  
Contraction Coupling ◽  
Senescent Phenotype ◽  
Cellular Microstructure ◽  
T System

AbstractIt is well established that the aging heart progressively remodels towards a senescent phenotype, but alterations of cellular microstructure and their differences to chronic heart failure (HF) associated remodeling remain ill-defined. Here, we show that the transverse tubular system (t-system) and proteins underlying excitation-contraction coupling in cardiomyocytes are characteristically remodeled with age. We shed light on mechanisms of this remodeling and identified similarities and differences to chronic HF. Using left ventricular myocardium from donors and HF patients with ages between 19 and 75 years, we established a library of 3D reconstructions of the t-system as well as ryanodine receptor (RyR) and junctophilin 2 (JPH2) clusters. Aging was characterized by t-system alterations and sarcolemmal dissociation of RyR clusters. This remodeling was less pronounced than in HF and accompanied by major alterations of JPH2 arrangement. Our study indicates that targeting sarcolemmal association of JPH2 might ameliorate age-associated deficiencies of heart function.

scholarly journals Uric Acid, Oxidative Stress and Inflammation in Chronic Heart Failure with Reduced Ejection Fraction

2015 ◽  
Vol 23 (4) ◽  
pp. 397-406 ◽  
Author(s):  
Adriana Iliesiu ◽  
Alexandru Campeanu ◽  
Daciana Marta ◽  
Irina Parvu ◽  
Gabriela Gheorghe
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Uric Acid ◽  
Chronic Heart Failure ◽  
Ejection Fraction ◽  
Xanthine Oxidase ◽  
Left Ventricular ◽  
Paraoxonase 1 ◽  
Lv Function ◽  
The Relationship

Abstract Background. Oxidative stress (OS) and inflammation are major mechanisms involved in the progression of chronic heart failure (CHF). Serum uric acid (sUA) is related to CHF severity and could represent a marker of xanthine-oxidase activation. The relationship between sUA, oxidative stress (OS) and inflammation markers was assessed in patients with moderate-severe CHF and reduced left ventricular (LV) ejection fraction (EF). Methods. In 57 patients with stable CHF, functional NYHA class III, with EF<40%, the LV function was assessed by N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels and echocardiographically through the EF and E/e’ ratio, a marker of LV filling pressures. The relationship between LV function, sUA, malondialdehyde (MDA), myeloperoxidase (MPO), paraoxonase 1 (PON-1) as OS markers and high sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) as markers of systemic inflammation was evaluated. Results. The mean sUA level was 7.9 ± 2.2 mg/dl, and 61% of the CHF patients had hyperuricemia. CHF patients with elevated LV filling pressures (E/e’ ≥ 13) had higher sUA (8.6 ± 2.3 vs. 7.3 ± 1.4, p=0.08) and NT-proBNP levels (643±430 vs. 2531±709, p=0.003) and lower EF (29.8 ± 3.9 % vs. 36.3 ± 4.4 %, p=0.001). There was a significant correlation between sUA and IL-6 (r = 0.56, p<0.001), MDA (r= 0.49, p= 0.001), MPO (r=0.34, p=0.001) and PON-1 levels (r= −0.39, p= 0.003). Conclusion. In CHF, hyperuricemia is associated with disease severity. High sUA levels in CHF with normal renal function may reflect increased xanthine-oxidase activity linked with chronic inflammatory response.

scholarly journals Computational Investigation of Transmural Differences in Left Ventricular Contractility

2016 ◽  
Vol 138 (11) ◽  
Author(s):  
Hua Wang ◽  
Xiaoyan Zhang ◽  
Shauna M. Dorsey ◽  
Jeremy R. McGarvey ◽  
Kenneth S. Campbell ◽  
...  
Keyword(s):  
Myocardial Contractility ◽  
Ex Vivo ◽  
Experimental Studies ◽  
Contractile Force ◽  
Left Ventricular ◽  
Lv Function ◽  
Fe Model ◽  
Myocardial Layers ◽  
Best Fit

Myocardial contractility of the left ventricle (LV) plays an essential role in maintaining normal pump function. A recent ex vivo experimental study showed that cardiomyocyte force generation varies across the three myocardial layers of the LV wall. However, the in vivo distribution of myocardial contractile force is still unclear. The current study was designed to investigate the in vivo transmural distribution of myocardial contractility using a noninvasive computational approach. For this purpose, four cases with different transmural distributions of maximum isometric tension (Tmax) and/or reference sarcomere length (lR) were tested with animal-specific finite element (FE) models, in combination with magnetic resonance imaging (MRI), pressure catheterization, and numerical optimization. Results of the current study showed that the best fit with in vivo MRI-derived deformation was obtained when Tmax assumed different values in the subendocardium, midmyocardium, and subepicardium with transmurally varying lR. These results are consistent with recent ex vivo experimental studies, which showed that the midmyocardium produces more contractile force than the other transmural layers. The systolic strain calculated from the best-fit FE model was in good agreement with MRI data. Therefore, the proposed noninvasive approach has the capability to predict the transmural distribution of myocardial contractility. Moreover, FE models with a nonuniform distribution of myocardial contractility could provide a better representation of LV function and be used to investigate the effects of transmural changes due to heart disease.

scholarly journals Left atrial appendage orifice area and morphology is closely associated with flow velocity in patients with nonvalvular atrial fibrillation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Lei Chen ◽  
Changjiang Xu ◽  
Wensu Chen ◽  
Chaoqun Zhang
Keyword(s):  
Atrial Fibrillation ◽  
Flow Velocity ◽  
Left Atrial ◽  
Left Atrial Appendage ◽  
Linear Regression Analysis ◽  
Left Ventricular ◽  
Atrial Appendage ◽  
Mechanical Function ◽  
Orifice Area ◽  
The Relationship

Abstract Background Thromboembolic events are the most serious complication of atrial fibrillation (AF), and the left atrial appendage (LAA) is the most important site of thrombosis in patients with AF. During the period of COVID-19, a non-invasive left atrial appendage detection method is particularly important in order to reduce the exposure of the virus. This study used CT three-dimensional reconstruction methods to explore the relationship between LAA morphology, LAA orifice area and its mechanical function in patients with non-valvular atrial fibrillation (NVAF). Methods A total of 81 consecutive patients with NVAF (36 cases of paroxysmal atrial fibrillation and 45 cases of persistent atrial fibrillation) who were planned to undergo catheter radiofrequency ablation were enrolled. All patients were examined by transthoracic echocardiography (TTE), TEE, and computed tomography angiography (CTA) before surgery. The LAA orifice area was obtained according to the images of CTA. According to the left atrial appendage morphology, it was divided into chicken wing type and non-chicken wing type. At the same time, TEE was performed to determine left atrial appendage flow velocity (LAAFV), and the relationship between the left atrial appendage orifice area and LAAFV was analyzed. Results The LAAFV in Non-chicken wing group was lower than that in Chicken wing group (36.2 ± 15.0 cm/s vs. 49.1 ± 22.0 cm/s, p-value < 0.05). In the subgroup analysis, the LAAFV in Non-chicken wing group was lower than that in Chicken wing group in the paroxysmal AF (44.0 ± 14.3 cm/s vs. 60.2 ± 22.8 cm/s, p-value < 0.05). In the persistent AF, similar results were observed (29.7 ± 12.4 cm/s vs. 40.8 ± 17.7 cm/s, p-value < 0.05). The LAAFV in persistent AF group was lower than that in paroxysmal AF group (34.6 ± 15.8 cm/s vs. 49.9 ± 20.0 cm/s, p-value < 0.001). The LAAFV was negatively correlated with left atrial dimension (R = − 0.451, p-value < 0.001), LAA orifice area (R= − 0.438, p-value < 0.001) and left ventricular mass index (LVMI) (R= − 0.624, p-value < 0.001), while it was positively correlated with LVEF (R = 0.271, p-value = 0.014). Multiple linear regression analysis showed that LAA morphology (β = − 0.335, p-value < 0.001), LAA orifice area (β = −  0.185, p-value = 0.033), AF type (β = − 0.167, p-value = 0.043) and LVMI (β = − 0.465, p-value < 0.001) were independent factors of LAAFV. Conclusions The LAA orifice area is closely related to the mechanical function of the LAA in patients with NVAF. The larger LAA orifice area and LVMI, Non-chicken wing LAA and persistent AF are independent predictors of decreased mechanical function of LAA, and these parameters might be helpful for better management of LA thrombosis.

Increased O2 cost of basal metabolism and excitation-contraction coupling in hearts from type 2 diabetic mice

2009 ◽  
Vol 296 (5) ◽  
pp. H1373-H1379 ◽  
Author(s):  
Neoma Boardman ◽  
Anne D. Hafstad ◽  
Terje S. Larsen ◽  
David L. Severson ◽  
Ellen Aasum
Keyword(s):  
Cardiac Metabolism ◽  
Therapeutic Benefit ◽  
Basal Metabolism ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Direct Measurements ◽  
The Difference ◽  
The Relationship ◽  
Type 2 Diabetic

We have reported previously that hearts from type 2 diabetic ( db/ db) mice show decreased cardiac efficiency due to increased work-independent myocardial O2 consumption (unloaded MV̇o2), indicating higher O2 use for nonmechanical processes such as basal metabolism (MV̇o2BM) and excitation-contraction coupling (MV̇o2ECC). Although alterations in cardiac metabolism and/or Ca2+ handling may contribute to increased energy expenditure in diabetic hearts, direct measurements of the O2 cost for these individual processes have not been determined. In this study, we 1) validate a procedure for measuring unloaded MV̇o2 directly (MV̇o2unloaded) and for determining MV̇o2BM and MV̇o2ECC separately in isolated perfused mouse hearts and 2) determine O2 cost for these processes in hearts from db/ db mice. Unloaded MV̇o2, extrapolated from the relationship between cardiac work (measured as pressure-volume area, PVA) and MV̇o2, was found to correspond with MV̇o2 measured directly in unloaded retrograde perfused hearts (MV̇o2unloaded). MV̇o2 in K+-arrested hearts was defined as MV̇o2BM; the difference between MV̇o2unloaded and MV̇o2BM represented MV̇o2ECC. This procedure was validated by demonstrating that elevations in perfusate fatty acid (FA) and/or Ca2+ concentrations resulted in changes in either MV̇o2BM and/or MV̇o2ECC. The higher MV̇o2unloaded in db/ db mice was due to both a higher MV̇o2BM and MV̇o2ECC. Elevation of glucose and insulin decreased FA oxidation and reduced both MV̇o2unloaded and MV̇o2BM. In conclusion, this study provides direct evidence that MV̇o2BM and MV̇o2ECC are elevated in diabetes and that acute metabolic interventions can have a therapeutic benefit in diabetic hearts due to a MV̇o2-lowering effect.

P5253Does regional myocardial strain by cardiac magnetic resonance feature tracking reflect scar in ischemic heart disease?

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
K Stathogiannis ◽  
V Mor-Avi ◽  
R Lang ◽  
A R Patel
Keyword(s):  
Cardiac Magnetic Resonance ◽  
Magnetic Resonance ◽  
Feature Tracking ◽  
Circumferential Strain ◽  
Myocardial Strain ◽  
Strain Analysis ◽  
Left Ventricular ◽  
Lv Function ◽  
Regional Strain ◽  
The Relationship

Abstract Background Cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) is the gold standard for detection of myocardial scar. We hypothesized that CMR Feature Tracking (FT)-derived regional myocardial strain may reflect the presence of scar and could thus potentially be used instead of LGE imaging. Purpose The aim of this study was to determine the relationship between FT-derived regional myocardial strain and LGE in patients with coronary artery disease (CAD). Methods Seventy-five patients with CAD and typical ischemic LGE patterns on CMR (1.5T) were included (mean age 60±12 years, 70% males). Myocardial strain analysis and LGE identification were performed using dedicated commercial software. Scar was defined by presence of LGE in the same area of the myocardium in both short- and long-axis views. Peak systolic regional longitudinal and circumferential strain (RLS, RCS) values were calculated in the region of interest corresponding to the LGE area and also in a non-LGE myocardial region as a reference in each patient. These comparisons were repeated for a subgroup of 36 patients with left ventricular (LV) ejection fraction (EF) <40% to determine whether the relationship between strain and LGE holds in the presence of reduced LV function, when strain measurements may be altered as a reflection of reduced LVEF itself. Results Both global longitudinal and circumferential strain values were abnormal (−12.8±5.1% and −11.4±4.1%, respectively), reflecting LV dysfunction in this CAD cohort (EF = 40±16%). The magnitude of both RLS and RCS was significantly reduced in areas of LGE, compared to those without LGE: RLS −10.0±5.8% versus −20.4±7.5% (p<0.001); RCS −10.1±5.3±% versus −18.9±7.5%, respectively (p<0.001). Same pattern was noted in the reduced EF subgroup: RLS −8.0±4.7% versus −16.9±6.6% (p<0.001), RCS −7.7±4.3±% versus −16.0±7.9%, respectively (p<0.001). The figure depicts 2 representative cases in long and short axis views, LGE detection and concomitant regional strain analysis. LGE and regional strain analysis. Conclusion Reduced magnitude of regional longitudinal and circumferential strain by CMR-FT correlates with presence of LGE. Pending further validation, this finding may constitute the basis for detection of scar without contrast enhanced imaging, and would result in reduced cost, scan time and risk associated with gadolinium. Acknowledgement/Funding ARP: Research support (software) from Neosoft and Philips

Abstract 57: Platelet Extracellular-signal-regulated Kinase 5 is a Redox Switch which Regulates Myocardial Infarct Expansion via Matrix Metalloproteinases

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Scott J Cameron ◽  
Sara K Ture ◽  
Deanne Mickelsen ◽  
Enakshi Chakrabarti ◽  
Kristina L Modjeski ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Ex Vivo ◽  
Myocardial Infarct ◽  
Left Ventricular ◽  
Fluorescent Imaging ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Dependent Manner ◽  
Platelet Receptor

Background: Dysregulated platelet activation in an ischemic microvascular environment may play a role in myocardial infarction (MI). Platelet receptor signaling is well-characterized, but mechanisms of receptor-independent activation, such as by reactive oxygen species (ROS) generated in ischemic conditions, are less well understood. We discovered that ERK5, a nuclear protein which is ROS-activated in others cells, is abundantly present in platelets. We investigated whether ERK5 could regulate platelet activation and thrombosis in healthy and diseased states. Methods: Human and mouse platelets were stimulated with agonists including ADP, U46619, TRAP, convulxin, or ROS (H 2 O 2 or 5% O 2 ). ERK5 activity was assessed by immunoblotting. Platelet activation was assessed via fluorescent-activated cell sorting (FACS) for P-selectin or activated GPIIb/IIIa. Intravascular thrombus (pulmonary embolus) or mesenteric thrombus (oxidative injury) formation was assessed by ex vivo fluorescent imaging and in vivo intravital microscopy, respectively. MI was performed in wild-type (WT) and in platelet specific ERK5 deficient (ERK5 -/- ) mice by LAD coronary artery ligation. Left ventricular (LV) function was determined by echocardiography. Matrix metalloproteinase (MMP) activity was determined by in-gel zymography. Results: Human and platelet ERK5 was activated by ROS and via the thrombin and thromboxane receptors, but not via the purinergic or collagen receptors. Murine in vivo thrombosis was regulated by platelet ERK5 only if the injury involved oxidative stress. MI in mice promoted sustained platelet activation over one week in an ERK5-dependent manner. Following MI, platelet ERK5 -/- mice had less reactive platelets, less platelet MMP activity and thromboxane production, attenuated MMP activity in the LV, less remodeling with smaller infarcts, and enhanced myocardial systolic performance. Conclusions: ERK5 is an ischemic sensor in platelets which regulates ongoing platelet activation after MI as well as remodeling via myocardial microvasculature. These observations may explain ischemic microvascular aberrations like the no-reflow phenomenon following percutaneous coronary intervention, suggesting a novel pharmacologic target.

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