scholarly journals Structural and Biomechanical Adaptations of Right Ventricular Remodeling—In Pulmonary Arterial Hypertension—Reduces Left Ventricular Rotation During Contraction: A Computational Study

2019 ◽  
Vol 141 (5) ◽  
Author(s):  
Vitaly O. Kheyfets ◽  
Uyen Truong ◽  
Dunbar Ivy ◽  
Robin Shandas
Keyword(s):  
Right Ventricular ◽  
Structural Changes ◽  
Ventricular Remodeling ◽  
Computational Study ◽  
Functional Decline ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Apical Rotation ◽  
Gene And Protein Expression ◽  
Myocardial Fibers

Pulmonary hypertension (PH) is a degenerative disease characterized by progressively increased right ventricular (RV) afterload that leads to ultimate functional decline. Recent observational studies have documented a decrease in left ventricular (LV) torsion during ejection, with preserved LV ejection fraction (EF) in pediatric and adult PH patients. The objective of this study was to develop a computational model of the biventricular heart and use it to evaluate changes in LV torsion mechanics in response to mechanical, structural, and hemodynamic changes in the RV free wall. The heart model revealed that LV torsion and apical rotation were decreased when increasing RV mechanical rigidity and during re-orientation of RV myocardial fibers, both of which have been demonstrated in PH. Furthermore, structural changes to the RV appear to have a notable impact on RV EF, but little influence on LV EF. Finally, RV pressure overload exponentially increased LV myocardial stress. The computational results found in this study are consistent with clinical observations in adult and pediatric PH patients, which reveal a decrease in LV torsion with preserved LV EF. Furthermore, discovered causes of decreased LV torsion are consistent with RV structural adaptations seen in PH rodent studies, which might also explain suspected stress-induced changes in LV myocardial gene and protein expression.

scholarly journals Acute right ventricular pressure overload compromises left ventricular function by altering septal strain and rotation

2013 ◽  
Vol 115 (2) ◽  
pp. 186-193 ◽  
Author(s):  
Jason Chua ◽  
Wei Zhou ◽  
Jonathan K. Ho ◽  
Nikhil A. Patel ◽  
G. Burkhard Mackensen ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Circumferential Strain ◽  
Median Sternotomy ◽  
Radial Strain ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Rotational Dynamics ◽  
Time To Peak ◽  
End Diastolic Volume ◽  
Apical Rotation

While right ventricular (RV) dysfunction has long been known to affect the performance of left ventricle (LV), the mechanisms remain poorly defined. Recently, speckle-tracking echocardiography has demonstrated that preservation of strain and rotational dynamics is crucial to both LV systolic and diastolic function. We hypothesized that alteration in septal strain and rotational dynamics of the LV occurs during acute RV pressure overload (RVPO) and leads to decreased cardiac performance. Seven anesthetized pigs underwent median sternotomy and placement of intraventricular pressure-volume conductance catheters. Two-dimensional echocardiographic images and LV pressure-volume loops were acquired for offline analysis at baseline and after banding of the pulmonary artery to achieve RVPO (>50 mmHg) induced RV dysfunction. RVPO resulted in a significant decrease ( P < 0.05) in LV end-systolic elastance (50%), systolic change in pressure over change in time (19%), end-diastolic volume (22%), and cardiac output (37%) that correlated with decrease in LV global circumferential strain (58%), LV apical rotation (28%), peak untwisting (reverse rotation) rate (27%), and prolonged time to peak rotation (17%), while basal rotation was not significantly altered. RVPO reduced septal radial and circumferential strain, while no other segment of the LV midpapillary wall was affected. RVPO decreased septal radial strain on LV side by 27% and induced a negative radial strain from 28 ± 5 to −16 ± 2% on the RV side of the septum. The septal circumferential strain on both LV and RV side decreased by 46 and 50%, respectively, following RVPO ( P < 0.05). Our results suggest that acute RVPO impairs LV performance by primarily altering septal strain and apical rotation.

scholarly journals Pressure overload induced right ventricular remodeling is not attenuated by the anti-fibrotic agent pirfenidone

2019 ◽  
Vol 9 (2) ◽  
pp. 204589401984865 ◽  
Author(s):  
Stine Andersen ◽  
Julie Birkmose Axelsen ◽  
Steffen Ringgaard ◽  
Jens Randel Nyengaard ◽  
Signe Holm Nielsen ◽  
...  
Keyword(s):  
Body Weight ◽  
Left Ventricle ◽  
Right Ventricular ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Volume Fraction ◽  
Pressure Overload ◽  
Wistar Rat ◽  
Left Ventricular ◽  
Reduced Body

Cardiac fibrosis contributes to the development of heart failure in pulmonary hypertension. We aimed to assess the development of fibrosis and the effects of treatment with the anti-fibrotic agent pirfenidone in pressure overload induced right ventricular (RV) failure. Wistar rat weanlings were randomized to pulmonary trunk banding (PTB) or sham surgery. One week after the procedure, PTB rats were randomized into two groups with either six weeks on standard chow or treatment with pirfenidone mixed in chow (700 mg/kg/day). RV hemodynamic effects were evaluated by echocardiography, cardiac magnetic resonance imaging (MRI), and pressure-volume measurements. Sections from the isolated RV, left ventricle, and septum were sampled systematically; stereological point grids and the nucleator were used to estimate volume of fibrosis and cardiac hypertrophy, respectively. PTB caused RV failure in all rats subjected to the procedure. The volume fraction of fibrosis in the RV increased threefold in PTB rats corresponding to a sixfold increase in total volume of RV fibrosis. Volume fraction of fibrosis and total volume of fibrosis also increased in the septum and in the left ventricle. Pirfenidone reduced body weight but did not improve RV hemodynamics or reduce cardiac fibrosis. RV cardiomyocyte profile area was increased twofold in PTB rats without any effect of pirfenidone. RV pressure overload after PTB induced not only RV but also septal and left ventricular fibrosis assessed by stereology. Treatment with pirfenidone reduced body weight but did not reduce the development of cardiac fibrosis or delay the progression of RV failure.

scholarly journals Angiotensin Receptor‐Neprilysin Inhibition Attenuates Right Ventricular Remodeling in Pulmonary Hypertension

2020 ◽  
Vol 9 (13) ◽  
Author(s):  
Danial Sharifi Kia ◽  
Evan Benza ◽  
Timothy N. Bachman ◽  
Claire Tushak ◽  
Kang Kim ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Ventricular Remodeling ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Angiotensin Receptor ◽  
Risk Of Death ◽  
Neprilysin Inhibitor ◽  
Neprilysin Inhibition

Background Pulmonary hypertension ( PH ) results in increased right ventricular ( RV ) afterload and ventricular remodeling. Sacubitril/valsartan (sac/val) is a dual acting drug, composed of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan, that has shown promising outcomes in reducing the risk of death and hospitalization for chronic systolic left ventricular heart failure. In this study, we aimed to examine if angiotensin receptor‐neprilysin inhibition using sac/val attenuates RV remodeling in PH . Methods and Results RV pressure overload was induced in Sprague–Dawley rats via banding the main pulmonary artery. Three different cohorts of controls, placebo‐treated PH , and sac/val‐treated PH were studied in a 21‐day treatment window. Terminal invasive hemodynamic measurements, quantitative histological analysis, biaxial mechanical testing, and constitutive modeling were employed to conduct a multiscale analysis on the effects of sac/val on RV remodeling in PH . Sac/val treatment decreased RV maximum pressures (29% improvement, P =0.002), improved RV contractile (30%, P =0.012) and relaxation (29%, P =0.043) functions, reduced RV afterload (35% improvement, P =0.016), and prevented RV ‐ pulmonary artery uncoupling. Furthermore, sac/val attenuated RV hypertrophy (16% improvement, P =0.006) and prevented transmural reorientation of RV collagen and myofibers ( P =0.011). The combined natriuresis and vasodilation resulting from sac/val led to improved RV biomechanical properties and prevented increased myofiber stiffness in PH (61% improvement, P =0.032). Conclusions Sac/val may prevent maladaptive RV remodeling in a pressure overload model via amelioration of RV pressure rise, hypertrophy, collagen, and myofiber reorientation as well as tissue stiffening both at the tissue and myofiber level.

Regional Left Ventricular Systolic Function in Relation to the Cavity Geometry in Patients With Chronic Right Ventricular Pressure Overload

Circulation ◽  
1995 ◽  
Vol 91 (9) ◽  
pp. 2359-2370 ◽  
Author(s):  
Sheng-Jing Dong ◽  
Adrian P. Crawley ◽  
John H. MacGregor ◽  
Yael Fisher Petrank ◽  
Dale W. Bergman ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Systolic Function ◽  
Pressure Overload ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Ventricular Systolic Function

scholarly journals Delineating the molecular and histological events that govern right ventricular recovery using a novel mouse model of pulmonary artery de-banding

2019 ◽  
Vol 116 (10) ◽  
pp. 1700-1709 ◽  
Author(s):  
Mario Boehm ◽  
Xuefei Tian ◽  
Yuqiang Mao ◽  
Kenzo Ichimura ◽  
Melanie J Dufva ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Mouse Model ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Exercise Capacity ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Sequence Of Events ◽  
Reverse Remodelling ◽  
Rv Function

Abstract Aims The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload is unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodelling events. Methods and results Surgical pulmonary artery banding (PAB) around a 26-G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic, and vascular myocardial remodelling within 5 weeks of chronic RV pressure overload in mice. Gradual reduction of the afterload burden through PA band absorption (de-PAB)—after RV dysfunction and structural remodelling were established—initiated recovery of RV function (cardiac output and exercise capacity) along with rapid normalization in RV hypertrophy (RV/left ventricular + S and cardiomyocyte area) and RV pressures (right ventricular systolic pressure). RV fibrotic (collagen, elastic fibres, and vimentin+ fibroblasts) and vascular (capillary density) remodelling were equally reversible; however, reversal occurred at a later timepoint after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher Scientific, Waltham, MA, USA) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators, and apoptosis mediators as major cellular components underlying functional RV recovery. Conclusion We established a novel gradual de-PAB mouse model and used it to demonstrate that established pulmonary hypertension-associated RV dysfunction is fully reversible. Mechanistically, we link functional RV improvement to hypertrophic normalization that precedes fibrotic and vascular reverse-remodelling events.

Abstract 129: Transient Activation of AMPK Prior to Cardiac Pressure Overload Alleviates Fibrotic Accumulation and Functional Decline

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Erin L Reineke ◽  
George E Taffet ◽  
Jason T Kaelber ◽  
Heinrich Taegtmeyer ◽  
Mark L Entman ◽  
...  
Keyword(s):  
Metabolic Flux ◽  
Molecular Mechanisms ◽  
Functional Decline ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Metabolic Changes ◽  
Cardiac Stress ◽  
Molecular Change ◽  
Transient Activation

The multiple adaptive pathways activated during cardiac stress must communicate with each other for an efficient response; however, little is known about the molecular mechanisms underlying this coordination. During left ventricular pressure overload induced by transverse aortic constriction (TAC), an increase in metabolic flux to meet the ATP demand is the first molecular change observed in the heart. Following initial metabolic changes, there is genetic remodeling of the metabolic machinery and activation of other acute and long-term adaptive pathways to control hypertrophy, fibrosis, and contraction. In order to better understand how the early metabolic changes affect the activation and magnitude of the downstream pathways, we treated mice with the AMPK activator AICAR for 6 days prior to TAC and then monitored effects on the cardiac stress response for 4 weeks. This treatment was performed in both WT mice and in mice lacking cardiomyocyte expression of steroid receptor coactivator-2 (SRC-2 CKO), a model we have previously shown to be genetically similar to a stressed mouse and whose function declines rapidly in response to TAC. Interestingly, we found that this small transient treatment with AICAR is sufficient to blunt hypertrophy (20% reduction) and fibrotic accumulation (56% reduction) and prevent left ventricular dilation and pleural edema. Furthermore, AICAR treatment in the SRC-2 CKO animals was able to rescue the functional decline observed post-TAC. We are currently investigating the molecular pathways underlying these changes. Our results strongly suggest that there are very early events during cardiac stress that are key determinants in the ability of the heart to adapt and maintain function under stress, even in late stages post-stress. Disruption of these determinants can lead to rapid failure, whereas their promotion could hold a key for therapeutic intervention.

Abstract 89: 17beta-Estradiol-activated Estrogen Receptors Attenuate Cardiac Fibrosis Through Inhibition of Collagen I and III Expression in Female Hearts

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Elke Dworatzek ◽  
Shokoufeh Mahmoodzadeh ◽  
Christina Westphal ◽  
Daniela Fliegner ◽  
Vera Regitz-Zagrosek
Keyword(s):  
Estrogen Receptors ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Collagen I ◽  
Sham Operation ◽  
Female Rat ◽  
Female Mice ◽  
Gene And Protein Expression

Objectives: Female pressure-overloaded hearts show less fibrosis compared with males. 17β-Estradiol (E2) attenuates cardiac fibrosis in female mice. Whether this is mediated by direct E2-effects on collagen synthesis is still unknown. Therefore, we investigated the role of E2 and estrogen receptors (ER) on collagen I and III expression and analyzed involved mechanisms. Methods: Female C57BL/6J mice (7 weeks) underwent sham operation, ovariectomy (OVX), OVX with E2-supplementation (390mg E2-containing pellets) or placebo. After 2 weeks, animals underwent transverse aortic constriction (TAC) or sham surgery. Mice were sacrificed after 9 weeks. Collagen amount, collagen I and III protein in left ventricular tissue were detected by Sirius Red and antibody staining, respectively. Gene and protein expression were determined by quantitative Real-Time PCR and Western blot. Adult female rat cardiac fibroblasts were treated with E2 (10 -8 M), vehicle, ERα- and β-agonists (10 -7 M) for 24h or pre-treated with PD98059 for 1h. ER binding to the collagen I and III promoter was analyzed by chromatin immunoprecipitation assays. Findings: In female OVX mice, undergoing TAC surgery, E2-supplementation significantly reduced collagen deposition, collagen I and III mRNA and protein levels in comparison with mice without E2. In female rat cardiac fibroblasts, E2 significantly down-regulated collagen I and III mRNA and protein level. Specific ER-agonist-treatment showed that E2-mediated regulation of collagen I and III expression was mediated via activation of ERα, but not ERβ. Further, upon E2-treatment, ERα was phosphorylated at Ser118, which occurred by E2-induced activation of ERK1/2 signaling. Furthermore, we could show that ERα and ERβ bind to two putative half-palindromic estrogen response elements within the collagen I and III promoter in female cardiac fibroblasts. Conclusion: E2 inhibits cardiac collagen I and III mRNA and protein in female mice under pressure overload. Data from rat female cardiac fibroblasts suggest that this is mediated via E2-activated ERK1/2 signaling and ERα, which binds with ERβ to the collagen I and III promoter. Understanding of how E2/ER attenuate collagen I and III expression in pathological hypertrophy may improve therapy.

scholarly journals Noninvasive Detection of Early Metabolic Left Ventricular Remodeling in Systemic Hypertension

Cardiology ◽  
2015 ◽  
Vol 133 (3) ◽  
pp. 157-162 ◽  
Author(s):  
Yasmin S. Hamirani ◽  
Bijoy K. Kundu ◽  
Min Zhong ◽  
Andrew McBride ◽  
Yinlin Li ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Pressure Overload ◽  
Positron Emission Tomography Imaging ◽  
Left Ventricular ◽  
Systemic Hypertension ◽  
Myocardial Glucose Uptake ◽  
Positron Emission ◽  
Metabolic Remodeling

Objectives: Hypertension (HTN) is a common cause of left ventricular hypertrophy (LVH). Sustained pressure overload induces a permanent myocardial switch from fatty-acid to glucose metabolism. In this study, we tested the hypothesis that metabolic remodeling, characterized by increased myocardial glucose uptake, precedes structural and functional remodeling in HTN-induced LVH. Methods: We recruited 31 patients: 11 with HTN only, 9 with HTN and LVH and 11 normotensive controls without LVH. Transthoracic echocardiography was performed to assess the function, mass, wall thickness and diastolic function of the left ventricle. Positron emission tomography imaging was performed, and the rate of myocardial 2-deoxy-2-[18F]fluoro-D-glucose uptake, Ki, was determined using a 3-compartment kinetic model. Results: The mean Ki values were significantly higher in HTN patients than in those with HTN and LVH (p < 0.001) and in controls (p = 0.003). The unexpected decrease in Ki with LVH may be secondary to a decreased Ki with diastolic dysfunction (DD), 0.039 ± 0.032 versus 0.072 ± 0.013 (p = 0.004). There was also a significant stepwise decrease in Ki with increasing DD grade (p = 0.04). Conclusion: Glucose metabolic remodeling is detectable in hypertensive patients before the development of LVH. Furthermore, lower glucose uptake rates are observed in patients with DD. The mechanism for this last finding requires further investigation.

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