Recapitulating aortic valve disease hemodynamics with a highly tunable bio-inspired soft robotic aortic sleeve

2021 ◽  
Author(s):  
Luca Rosalia ◽  
Caglar Ozturk ◽  
Yiling Fan ◽  
Jaume Coll-Font ◽  
Shi Chen ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Flow Patterns ◽  
Left Ventricular ◽  
Patient Specific ◽  
Congenital Defects ◽  
Lumped Parameter

Abstract Existing models of aortic stenosis (AS) are limited to inducing left ventricular pressure overload. As they have reduced control over the severity of aortic constriction, the clinical relevance of these models is largely hindered by their inability to mimic AS hemodynamics and recapitulate flow patterns associated with congenital valve defects, responsible for the accelerated onset and progression of AS. Here we report the development of a highly tunable bio-inspired soft robotic tool that enables the recapitulation of AS in a porcine model, in which customization of actuation patterns allows hemodynamic mimicry of AS and congenital aortic valve defects. In vitro and computational tools including lumped-parameter, finite element, and computational fluid dynamics platforms were developed to predict the hemodynamics induced by the bio-inspired soft robotic sleeve. The controllability of our in vivo model and its ability to replicate flow patterns of AS and congenital defects were demonstrated in swine through echocardiography, left ventricular catheterization, and magnetic resonance imaging. This work supports the use of soft robotics to simulate human physiology and disease, while paving the way towards the development of patient-specific models of AS and congenital defects that can guide clinical decisions to improve the management and treatment of these patients.

scholarly journals Cardiac fibroblasts acquire properties of matrifibrocytes in vitro and in mice with pressure overload-induced congestive heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K.M Herum ◽  
G Gilles ◽  
A Romaine ◽  
A.O Melleby ◽  
G Christensen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Funding Source ◽  
High Stiffness

Abstract Introduction Activation of cardiac fibroblasts (CFB) is a key step in development of fibrosis in the heart. It was recently shown that, in addition to the well-studied myofibroblast (myoFB) phenotype, activated cardiac fibroblasts can adopt a newly defined matrifibrocyte phenotype, characterized by expression of extracellular matrix (ECM) genes associated with bone, cartilage and tendon development. However, it is unknown whether matrifibrocytes exists in the pressure-overloaded fibrotic and failing heart, and whether substrate stiffness drives differentiation. Hypothesis Matrifibrocyte differentiation occurs in vitro during culturing of primary cardiac fibroblasts, and in vivo in response to left ventricular pressure overload. Methods Left ventricular pressure overload induced by o-ring aortic banding (ORAB) induced cardiac phenotypes of concentric hypertrophic remodelling and congestive heart failure. Primary CFB from adult mice were cultured on plastic or soft polyacrylamide hydrogels (4.5 kPa) for various times. mRNA expression of phenotypic markers were measured by RT-PCR. Presence of smooth muscle α-actin (SMA) fibers was determined by immunocytochemistry. Results ECM genes normally expressed in bone and cartilage (COMP, CILP-2, OPG and SCX) were upregulated in hypertrophic left ventricles of mice with congestive heart failure. The myoFB marker acta2 was increased 2 weeks after ORAB, returned to baseline at 4 weeks and increased again at 20 weeks when the left ventricle was dilating and failing, indicating that the myoFB phenotype is not permanent. In vitro, primary CFB upregulated bone/cartilage-associated ECM genes after 12 days of culturing on plastic. Acta2 mRNA and SMA protein levels peaked after 9 days in culture whereafter they declined, indicating a shift in phenotype. Culturing primary CFB on soft (4.5 kPa) hydrogels delayed, but did not prevent, myoFB differentiation while expression of bone/cartilage ECM genes was absent or low, indicating that high stiffness is a driver of the matrifibrocyte phenotype. Blockers of mechanotransduction, SB431542 (TGFβRI inhibitor), Y27623 (ROCK inhibitor) and cyclosporine A (calcineurin inhibitor), completely inhibited myoFB differentiation but upregulated several matrifibrocyte markers, indicating that distinct signaling pathways regulate myoFB and matrifibrocyte differentiation. Removing inhibitors re-induced myofibroblast markers in cells on plastic but not on soft gels consistent with high stiffness promoting myofibroblast differentiation. Conclusion Primary cardiac fibroblasts acquire characteristics of matrifibrocytes in vitro when cultured for long time on plastic and in vivo in left ventricles of mice with pressure overload-induced congestive heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): Marie Sklodowska-Curie Individual Fellowship

Abstract 285: Cardiac Inflammation and Fibrosis Induced by Heart Failure Are Reversed by Short-Duration Estrogen Therapy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Andrea Iorga ◽  
Rangarajan Nadadur ◽  
Salil Sharma ◽  
Jingyuan Li ◽  
Mansoureh Eghbali
Keyword(s):  
Heart Failure ◽  
Estrogen Therapy ◽  
Pressure Overload ◽  
Decompensated Heart Failure ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
In Vivo Model ◽  
Anti Inflammatory

Heart failure is generally characterized by increased fibrosis and inflammation, which leads to functional and contractile defects. We have previously shown that short-term estrogen (E2) treatment can rescue pressure overload-induced decompensated heart failure (HF) in mice. Here, we investigate the anti-inflammatory and anti-fibrotic effects of E2 on reversing the adverse remodeling of the left ventricle which occurs during the progression to heart failure. Trans-aortic constriction procedure was used to induce HF. Once the ejection fraction reached ∼30%, one group of mice was sacrificed and the other group was treated with E2 (30 αg/kg/day) for 10 days. In vitro, co-cultured neonatal rat ventricular myocytes and fibroblasts were treated with Angiotensin II (AngII) to simulate cardiac stress, both in the presence or absence of E2. In vivo RT-PCR showed that the transcript levels of the pro-fibrotic markers Collagen I, TGFβ, Fibrosin 1 (FBRS) and Lysil Oxidase (LOX) were significantly upregulated in HF (from 1.00±0.16 to 1.83±0.11 for Collagen 1, 1±0.86 to 4.33±0.59 for TGFβ, 1±0.52 to 3.61±0.22 for FBRS and 1.00±0.33 to 2.88±0.32 for LOX) and were reduced with E2 treatment to levels similar to CTRL. E2 also restored in vitro AngII-induced upregulation of LOX, TGFβ and Collagen 1 (LOX:1±0.23 in CTRL, 6.87±0.26 in AngII and 2.80±1.5 in AngII+E2; TGFβ: 1±0.08 in CTRL, 3.30±0.25 in AngII and 1.59±0.21 in AngII+E2; Collagen 1: 1±0.05 in CTRL.2±0.01 in AngII and 0.65±0.02 (p<0.05, values normalized to CTRL)). Furthermore, the pro-inflammatory interleukins IL-1β and IL-6 were upregulated from 1±0.19 to 1.90±0.09 and 1±0.30 to 5.29±0.77 in the in vivo model of HF, respectively, and reversed to CTRL levels with E2 therapy. In vitro, IL-1β was also significantly increased ∼ 4 fold from 1±0.63 in CTRL to 3.86±0.14 with AngII treatment and restored to 1.29±0.77 with Ang+E2 treatment. Lastly, the anti-inflammatory interleukin IL-10 was downregulated from 1.00±0.17 to 0.49±0.03 in HF and reversed to 0.67±0.09 in vivo with E2 therapy (all values normalized to CTRL). This data strongly suggests that one of the mechanisms for the beneficial action of estrogen on left ventricular heart failure is through reversal of inflammation and fibrosis.

scholarly journals Chronic interval exercise training prevents BKCa channel-mediated coronary vascular dysfunction in aortic-banded miniswine

2018 ◽  
Vol 125 (1) ◽  
pp. 86-96 ◽  
Author(s):  
T. Dylan Olver ◽  
Jenna C. Edwards ◽  
Brian S. Ferguson ◽  
Jessica A. Hiemstra ◽  
Pamela K. Thorne ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Vascular Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Preserved Ejection Fraction ◽  
Interval Exercise

Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Thus, the purpose of this study was to determine the therapeutic efficacy of chronic interval exercise training (IT) on large-conductance Ca2+-activated K+ (BKCa) channel-mediated coronary vascular function in heart failure. We hypothesized that chronic interval exercise training would attenuate pressure overload-induced impairments to coronary BKCa channel-mediated function. A translational large-animal model with cardiac features of HFpEF was used to test this hypothesis. Specifically, male Yucatan miniswine were divided into three groups ( n = 7/group): control (CON), aortic banded (AB)-heart failure (HF), and AB-interval trained (HF-IT). Coronary blood flow, vascular conductance, and vasodilatory capacity were measured after administration of the BKCa channel agonist NS-1619 both in vivo and in vitro in the left anterior descending coronary artery and isolated coronary arterioles, respectively. Skeletal muscle citrate synthase activity was decreased and left ventricular brain natriuretic peptide levels increased in HF vs. CON and HF-IT animals. A parallel decrease in NS-1619-dependent coronary vasodilatory reserve in vivo and isolated coronary arteriole vasodilatory responsiveness in vitro were observed in HF animals compared with CON, which was prevented in the HF-IT group. Although exercise training prevented BKCa channel-mediated coronary vascular dysfunction, it did not change BKCa channel α-subunit mRNA, protein, or cellular location (i.e., membrane vs. cytoplasm). In conclusion, these results demonstrate the viability of chronic interval exercise training as a therapy for central and peripheral adaptations of experimental heart failure, including BKCa channel-mediated coronary vascular dysfunction. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show that chronic interval exercise training can prevent BKCa channel-mediated coronary vascular dysfunction in a translational swine model of chronic pressure overload-induced heart failure with relevance to human HFpEF.

Hypotensive mechanism of [Leu13]motilin in dogs in vivo and in vitro

1998 ◽  
Vol 76 (12) ◽  
pp. 1103-1109 ◽  
Author(s):  
Takeshi Iwai ◽  
Hiroyuki Nakamura ◽  
Hisanori Takanashi ◽  
Kenji Yogo ◽  
Ken-Ichi Ozaki ◽  
...  
Keyword(s):  
Mesenteric Artery ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Gastric Antrum ◽  
Ventricular Pressure ◽  
High Dose ◽  
Aortic Blood Flow ◽  
Arterial Blood

The effects of [Leu13]motilin were examined in vivo after its intravenous administration into anesthetized dogs and in vitro with isolated preparations of canine mesenteric artery. [Leu13]Motilin (0.1-10 nmol·kg-1, i.v.) induced both strong and clustered phasic contractions in the gastric antrum and duodenum. At doses of over 1 nmol·kg-1, [Leu13]motilin also produced transient decreases in arterial blood pressure, left ventricular pressure, maximum rate of rise of left ventricular pressure, and total peripheral resistance, and an increase in aortic blood flow and heart rate. A selective motilin antagonist, GM-109 (Phe-cyclo[Lys-Tyr(3-tBu)-betaAla]betatrifluoroacetate), completely abolished the gastric antrum and duodenal motor responses induced by [Leu13]motilin. In contrast, hypotension induced by [Leu13]motilin (1 nmol·kg-1) was unchanged in the presence of GM-109. In isolated mesenteric artery preparations precontracted with U-46619 (10-7 M), [Leu13]motilin (10-8-10-5 M) induced an endothelium-dependent relaxation, and this was inhibited by a pretreatment with Nomega-nitro-L-arginine, a competitive inhibitor of NO synthase (10-4 M). A high dose (10-4 M) of GM-109 slightly decreased [Leu13]motilin-induced relaxation, and shifted the concentration-response curve of [Leu13]motilin to the right. However, the pA2 value (4.09) of GM-109 for [Leu13]motilin in the present study was conspicuously lower than that previously demonstrated in the rabbit duodenum (7.37). These results suggest that [Leu13]motilin induces hypotension via the endothelial NO-dependent relaxation mechanism and not through the receptor type that causes upper gastrointestinal contractions.Key words: motilin, gastrointestinal motility, hypotension, hemodynamics, anesthetized dog, mesenteric artery, endothelium, nitric oxide.

Abstract 16434: IL-6 Signaling is Crucial for Cardiomyocyte Hypertrophy and Left Ventricular Dysfunction Induced by Pressure Overload

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Lin Zhao ◽  
Guangming Cheng ◽  
Yanjuan Yang ◽  
Anweshan Samanta ◽  
Rizwan R Afzal ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Lv Function ◽  
Ang Ii ◽  
Adult Cardiomyocytes

Introduction: Interleukin-6 (IL-6), a proinflammatory cytokine, has been implicated in ischemic cardiac pathologies. Very little is currently known regarding the role of IL-6 signaling in pathological cardiomyocyte hypertrophy and LV dysfunction. Hypothesis: We hypothesized that IL-6 signaling plays a central role in cardiomyocyte hypertrophy and exerts a deleterious impact on LV remodeling induced by pressure overload. Methods: In vitro, adult cardiomyocytes from C57BL/6 (WT, control) and IL-6 knockout (KO) mice were stimulated by IL-6 and pro-hypertrophic agent angiotensin II (Ang II). The expression of hypertrophy markers and related signaling molecules were examined by real-time quantitative RT-PCR. In vivo, weight-matched male WT and IL-6 KO mice underwent transverse aortic constriction (TAC) or a sham procedure. Serial echocardiograms and a terminal hemodynamic study were performed. Results: After exposure to IL-6 and hypertrophic agonists, the expression of hypertrophy related genes, BNP, GATA-4, αSK actin, and β-MHC increased significantly in WT cardiomyocytes (Fig). These effects were significantly attenuated in IL-6 knockout cardiomyocytes (Fig), indicating an essential role of IL-6 in cardiomyocyte hypertrophy. In vivo, the worsening in LV contraction as well as relaxation after TAC was significantly attenuated in IL-6 KO mice, indicating superior preservation of LV function in the setting of pressure overload in the absence of IL-6 signaling. Conclusions: The protection against Ang II-induced hypertrophy observed in IL-6 KO adult cardiomyocytes in vitro, and in hearts of IL-6 KO mice after TAC in vivo illustrates a crucial role played by IL-6 in pathogenesis of pressure overload-induced LV hypertrophy. Modulation of IL-6 signaling may have preventive therapeutic potential for countless hypertensive patients at risk for LV hypertrophy and failure.

Computer Simulation of Coronary Flow Waveforms during Caval Occlusion

2009 ◽  
Vol 48 (02) ◽  
pp. 113-122 ◽  
Author(s):  
D. Neglia ◽  
G. Ferrari ◽  
F. Bernini ◽  
M. Micalizzi ◽  
A L’Abbate ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cardiovascular System ◽  
Coronary Flow ◽  
Coronary Circulation ◽  
Left Ventricular Pressure ◽  
Aortic Pressure ◽  
Left Ventricular ◽  
Lumped Parameter ◽  
Flow Waveforms

Summary Objectives: Mathematical modeling of the cardiovascular system is a powerful tool to extract physiologically relevant information from multi-parametric experiments. The purpose of the present work was to reproduce by means of a computer simulator, systemic and coronary measurements obtained by in vivo experiments in the pig. Methods: We monitored in anesthetized open-chest pig the phasic blood flow of the left descending coronary artery, aortic pressure, left ventricular pressure and volume. Data were acquired before, during, and after caval occlusion.Inside the software simulator (CARDIOSIM©) of the cardiovascular system, coronary circulation was modeled in three parallel branching sections. Both systemic and pulmonary circulations were simulated using a lumped parameter mathematical model. Variable elastance model reproduced Starling’s law of the heart. Results: Different left ventricular pressure-volume loops during experimental caval occlusion and simulated cardiac loops are presented. The sequence of coronary flow-aortic pressure loops obtained in vivo during caval occlusion together with the simulated loops reproduced by the software simulator are reported. Finally experimental and simulated instantaneous coronary blood flow waveforms are shown. Conclusions: The lumped parameter model of the coronary circulation, together with the cardiovascular system model, is capable of reproducing the changes during caval occlusion, with the profound shape deformation of the flow signal observed during the in vivo experiment. In perspectives, the results of the present model could offer new tool for studying the role of the different determinants of myocardial perfusion, by using the coronary loop shape as a “sensor” of ventricular mechanics in various physiological and pathophysiological conditions.

Abstract 3184: Dynamics of Mitral Complex Geometry During Left Ventricular Pressure Overload: in Vivo Experimental Study by Real-time 3D Echocardiography

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Ryotaro Yamada ◽  
Nozomi Watanabe ◽  
Teruyoshi Kume ◽  
Miwako Tsukiji ◽  
Kikuko Obase ◽  
...  
Keyword(s):  
Surface Area ◽  
Complex Geometry ◽  
Statistical Significance ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Mitral Annulus ◽  
Left Ventricular ◽  
Functional Mitral Regurgitation ◽  
Aortic Banding

Background: Functional mitral regurgitation (MR) occurs as a consequence of regional or global left ventricular (LV) dysfunction despite a structurally normal mitral valve (MV). Degree of MV coaptation should be an important parameter in the assessment of functional MR. Purpose: We sought to investigate the change of MV coaptation and to clarify relationship between MV coaptation and development of MR in LV pressure overload. Methods: Using a canine model, LV pressure overload was induced by staged aortic banding (60 to 120mmHg). Echocardiographic examinations were performed before and during the banding. Degree of MR was evaluated by tracing the color jet MR area (MR area). By using a novel software system (RealView TM ) for 3D quantification, mitral annulus (MA) area, tenting volume, tenting length and 3D tenting surface area were analyzed. MA and surface of MV was manually traced both at the onset of MV closure [O] and at the maximum MV closure [M]. Coaptation index was calculated by the difference in 3D tenting surface area at O and at M devided by that at O. Results: MA area was gradually increased during banding ( p < 0.01). Tenting length and tenting volume tended to increase during banding but they did not reach statistical significance (tenting length; p = 0.17, tenting volume; p = 0.12). MR area increased with decrease in coaptation index (Figure ). The best cutoff value of the coaptation index to predict presence of MR was calculated as 0.24, giving a sensitivity of 82 % and specificity of 86 %. Conclusions: During aortic banding, MA dilated and coaptation of the MV decreased with apparent leaflet tenting. Coptation index might be able to predict the appearance of functional MR.

Abstract 462: Cardiac-specific LMCD1/dyxin-knockout in Mice Blunts Pressure Overload-induced Activation of Calcineurin Signaling

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Lucia S Kilian ◽  
Jakob Voran ◽  
Nesrin Schmiedel ◽  
Katharina Stiebeling ◽  
Julika Richter ◽  
...  
Keyword(s):  
Protein Level ◽  
Heart Function ◽  
Pressure Overload ◽  
Protective Role ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Mrna Levels

We and others have shown that LMCD1 expression levels are upregulated in various in vitro and in vivo models of hypertrophy and that LMCD1 is necessary and sufficient to induce cardiomyocyte hypertrophy in vitro . We successfully generated a new mouse line with a conditional cardiac knockout of LMCD1. We performed echocardiographic, morphometric, and molecular analysis in these LMCD1-deficient and appropriate control-mice under basic conditions as well as 14 days after transverse aortic banding (TAC)-induced left ventricular (LV) pressure overload. Our aim was to investigate the hypothesis of potential beneficial effects of LMCD1-downregulation in vivo . These knockout (KO)-mice revealed under basic conditions a significant reduction of LMCD1 in the heart to <10% on protein level compared to control (WT)-mice (females and males n=5 each, p<0.001), while anatomic and functional parameters of the heart as well as LMCD1 levels in all other tested organs remained unchanged. Sham-operated KO-mice also showed significantly reduced level of LMCD1 in the LV compared to Sham-operated WT-mice (protein level <20%, p<0.001, n=8). No significant increase of LMCD1 in TAC- compared to Sham-operated KO-mice was found. TAC-operated KO-mice showed no significant differences in heart anatomy and function when compared to TAC-operated WT-mice. However, we determined a consistent trend toward improved heart function (ejection fraction and fractional shortening). Furthermore, TAC-operated KO-mice showed reduced activation of the fetal gene program in LV-tissue compared to TAC-operated WT-mice: mRNA levels of the hypertrophic markers NppA, NppB, and Rcan1-4 were all decreased (WT-TAC n=8 vs. KO-TAC n=10: NppA 8.5±2.0 vs. 5.1±1.5, p<0.05; NppB 1.9±0.2 vs. 1.7±0.3, p=0.093; Rcan1-4 6.0±0.2 vs. 3.2 vs. 0.7, p<0.05), suggesting a protective role of LMCD1-knockout. The reduction of calcineurin (CnA)-responsive Rcan1-4 specifically suggests a protective role of LMCD1-knockout in CnA-dependent signaling. Taken together, our preliminary data reveals protective effects of LMCD1-knockout against TAC-induced hypertrophic signaling. Ongoing experiments focus on effects of LMCD1-knockout on apoptosis and fibrosis and its role in Angiotensin-induced hypertrophy.

scholarly journals Cellular Interplay and Cytokine Hierarchy Cause Pathological Cardiac Hypertrophy in RAF1-Mutant Noonan Syndrome

2017 ◽  
Author(s):  
Jiani C. Yin ◽  
Mathew J. Platt ◽  
Xixi Tian ◽  
Xue Wu ◽  
Peter H. Backx ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Noonan Syndrome ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Neutralizing Antibody ◽  
Cell Types ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy

AbstractNoonan syndrome (NS) is caused by mutations in RAS/ERK pathway genes, and is characterized by craniofacial, growth, cognitive and cardiac defects. NS patients with kinase-activating RAF1 alleles typically develop pathological left ventricular hypertrophy (LVH), which is reproduced in Raf1L613V/+ knock-in mice. Here, using inducible Raf1L613V expression, we show that LVH results from the interplay of cardiac cell types. Cardiomyocyte Raf1L613V enhances Ca2+ sensitivity and cardiac contractility without causing hypertrophy. Raf1L613V expression in cardiomyocytes or activated fibroblasts exacerbates pressure overload-evoked fibrosis. Endothelial/endocardial (EC) Raf1L613V causes cardiac hypertrophy without affecting contractility. Co-culture and neutralizing antibody experiments reveal a cytokine (TNF/IL6) hierarchy in Raf1L613V-expressing ECs that drives cardiomyocyte hypertrophy in vitro. Furthermore, post-natal TNF inhibition normalizes the increased wall thickness and cardiomyocyte hypertrophy in vivo. We conclude that NS cardiomyopathy involves cardiomyocytes, ECs, and fibroblasts, TNF/IL6 signaling components represent potential therapeutic targets, and abnormal EC signaling might contribute to other forms of LVH.

scholarly journals Enhanced basal contractility but reduced excitation-contraction coupling efficiency and β-adrenergic reserve of hearts with increased Cav1.2 activity

2010 ◽  
Vol 299 (2) ◽  
pp. H519-H528 ◽  
Author(s):  
Mingxin Tang ◽  
Xiaoying Zhang ◽  
Yingxin Li ◽  
Yinzheng Guan ◽  
Xiaojie Ai ◽  
...  
Keyword(s):  
Cardiac Contractility ◽  
Coupling Efficiency ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Adrenergic System ◽  
Adrenergic Stimulation ◽  
Pressure Maximum ◽  
Fractional Shortening

Cardiac remodeling during heart failure development induces a significant increase in the activity of the L-type Ca2+ channel (Cav1.2). However, the effects of enhanced Cav1.2 activity on myocyte excitation-contraction (E-C) coupling, cardiac contractility, and its regulation by the β-adrenergic system are not clear. To recapitulate the increased Cav1.2 activity, a double transgenic (DTG) mouse model overexpressing the Cavβ2a subunit in a cardiac-specific and inducible manner was established. We studied cardiac (in vivo) and myocyte (in vitro) contractility at baseline and upon β-adrenergic stimulation. E-C coupling efficiency was evaluated in isolated myocytes as well. The following results were found: 1) in DTG myocytes, L-type Ca2+ current ( ICa,L) density, myocyte fractional shortening (FS), peak Ca2+ transients, and sarcoplasmic reticulum (SR) Ca2+ content (caffeine-induced Ca2+ transient peak) were significantly increased (by 100.8%, 48.8%, 49.8%, and 46.8%, respectively); and 2) cardiac contractility evaluated with echocardiography [ejection fraction (EF) and (FS)] and invasive intra-left ventricular pressure (maximum dP/d t and −dP/d t) measurements were significantly greater in DTG mice than in control mice. However, 1) the cardiac contractility (EF, FS, dP/d t, and −dP/d t)-enhancing effect of the β-adrenergic agonist isoproterenol (2 μg/g body wt ip) was significantly reduced in DTG mice, which could be attributed to the loss of β-adrenergic stimulation on contraction, Ca2+ transients, ICa,L, and SR Ca2+ content in DTG myocytes; and 2) E-C couplng efficiency was significantly lower in DTG myocytes. In conclusion, increasing Cav1.2 activity by promoting its high-activity mode enhances cardiac contractility but decreases E-C coupling efficiency and the adrenergic reserve of the heart.

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