scholarly journals The SGLT2i Dapagliflozin Reduces RV Hypertrophy Independent of Changes in RV Pressure Induced by Pulmonary Artery Banding

2021 ◽  
Author(s):  
Kim Connelly ◽  
Ellen Wu ◽  
Aylin Visram ◽  
Mark K. Friedberg ◽  
Sri Nagarjun Batchu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Artery ◽  
Protein Expression ◽  
Right Ventricular ◽  
Sglt2 Inhibitor ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Pulmonary Artery Banding ◽  
Calcium Handling ◽  
Sglt2 Inhibition

Abstract Background— Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class might be similarly efficacious in the treatment and prevention of right heart failure has not been unexplored. Hypothesis: We hypothesized that SGLT2 inhibition would reduce the structural, functional and molecular responses to pressure overload of the right ventricle. Methods: Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (0.5mg/kg/day) or vehicle by oral gavage. After six weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses. Results: PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content and alteration in calcium handling protein expression (all p<0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, AMPkinase and LC3I/II ratio expression (all p<0.05). Significance: Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined.

scholarly journals The SGLT2i Dapagliflozin Reduces RV Hypertrophy Independent of Changes in RV Pressure Induced by Pulmonary Artery Banding

2021 ◽  
Author(s):  
Kim A Connelly ◽  
Ellen Wu ◽  
BSc Aylin Visram ◽  
Mark K. Friedberg ◽  
Sri Nagarjun Batchu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Artery ◽  
Protein Expression ◽  
Right Ventricular ◽  
Sglt2 Inhibitor ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Pulmonary Artery Banding ◽  
Calcium Handling ◽  
Sglt2 Inhibition

Abstract Background— Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class might be similarly efficacious in the treatment and prevention of right heart failure has not been unexplored.Hypothesis: We hypothesized that SGLT2 inhibition would reduce the structural, functional and molecular responses to pressure overload of the right ventricle.Methods: Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (1.5mg/kg/day) or vehicle by oral gavage. After six weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses.Results: PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content and alteration in calcium handling protein expression (all p<0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, AMPkinase and LC3I/II ratio expression (all p<0.05).Significance: Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined.

scholarly journals Pressure-overload hypertrophy of the developing heart reveals activation of divergent gene and protein pathways in the left and right ventricular myocardium

2013 ◽  
Vol 304 (5) ◽  
pp. H697-H708 ◽  
Author(s):  
Ingeborg Friehs ◽  
Douglas B. Cowan ◽  
Yeong-Hoon Choi ◽  
Kendra M. Black ◽  
Reanne Barnett ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Oxidative Phosphorylation ◽  
Protein Expression ◽  
Right Ventricular ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Macromolecular Complex ◽  
Transcript Expression ◽  
Expression Levels

Right ventricular (RV) and left ventricular (LV) myocardium differ in their pathophysiological response to pressure-overload hypertrophy. In this report we use microarray and proteomic analyses to identify pathways modulated by LV-aortic banding (AOB) and RV-pulmonary artery banding (PAB) in the immature heart. Newborn New Zealand White rabbits underwent banding of the descending thoracic aorta [LV-AOB; n = 6]. RV-PAB was achieved by banding the pulmonary artery ( n = 6). Controls ( n = 6 each) were sham-manipulated. After 4 (LV-AOB) and 6 (RV-PAB) wk recovery, the hearts were removed and matched RNA and proteins samples were isolated for microarray and proteomic analysis. Microarray and proteomic data demonstrate that in LV-AOB there is increased transcript expression levels for oxidative phosphorylation, mitochondria energy pathways, actin, ILK, hypoxia, calcium, and protein kinase-A signaling and increased protein expression levels of proteins for cellular macromolecular complex assembly and oxidative phosphorylation. In RV-PAB there is also an increased transcript expression levels for cardiac oxidative phosphorylation but increased protein expression levels for structural constituents of muscle, cardiac muscle tissue development, and calcium handling. These results identify divergent transcript and protein expression profiles in LV-AOB and RV-PAB and provide new insight into the biological basis of ventricular specific hypertrophy. The identification of these pathways should allow for the development of specific therapeutic interventions for targeted treatment and amelioration of LV-AOB and RV-PAB to ameliorate morbidity and mortality.

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.

The Hemodynamic Characteristics of Right Ventricle After Gradient Pulmonary Artery Banding in Rats

2020 ◽  
Author(s):  
Song Jiyang ◽  
Wan Nan ◽  
Shen Shutong ◽  
Wei Ying ◽  
Cao Yunshan
Keyword(s):  
Heart Failure ◽  
Pulmonary Artery ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Right Heart Failure ◽  
Therapeutic Strategies ◽  
Pulmonary Artery Banding ◽  
Right Heart ◽  
Pulmonary Arterial ◽  
The Right

Abstract Background: Right ventricular (RV) failure induced by sustained pressure overload is a major contributor to morbidity and mortality in several cardiopulmonary disorders. Reliable and reproducible animal models of RV failure are important in order to investigate disease mechanisms and effects of potential therapeutic strategies. To establish a rat model of RV failure perfectly, we observed the right ventricle and carotid artery hemodynamics characteristics in different degrees of pulmonary artery banding of rats of different body weights. Methods: Rats were subjected to 6 groups：control(0%, n=5)(pulmonary arterial banding 0%), PAB(1-30%, n=4)(pulmonary arterial banding1-30%), PAB(31-60%, n=6)(pulmonary arterial banding31-60%),PAB(61-70%, n=5)(pulmonary arterial bandin61-70%), PAB(71-80%,n=4)(pulmonary arterial banding71-80%), PAB(100%, n=3)(pulmonary arterial banding 100%). We measured the right ventricular pressure(RVP) by right heart catheterization when the pulmonary arterial was ligated. Results: The RVP gradually increased with increasing degree of banding, but when occlusion level exceeding 70%, high pressure state can be only maintained for a few minutes or seconds, and then the RVP drops rapidly until it falls below the normal pressure, which in Group F particularly evident.Conclusions: RVP have different reactions when the occlusion level is not the same, and the extent of more than 70% ligation is a successful model of acute right heart failure. These results may have important consequences for therapeutic strategies to prevent acute right heart failure.

Effect of right ventricular hypertrophy on infundibular pressure gradients in dogs

1965 ◽  
Vol 209 (3) ◽  
pp. 513-518
Author(s):  
Peter E. Blundell ◽  
John R. Tobin ◽  
H. J. C. Swan
Keyword(s):  
Pulmonary Artery ◽  
Pressure Gradient ◽  
Right Ventricular ◽  
Arteriovenous Fistula ◽  
Ventricular Hypertrophy ◽  
Pressure Overload ◽  
Volume Overload ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Artery Banding ◽  
Pressure Gradients

Right ventricular hypertrophy was produced in normal dogs: in six by means of pressure overload (pulmonary artery banding) and in six by means of volume overload (systemic arteriovenous fistula). A greater degree of hypertrophy resulted from the latter procedure. Right ventricular hypertrophy due to chronic pressure overload causes a greater degree of infundibular constriction and much higher pressure gradient than in normal animals or in animals with volume overload. Infundibular pressure gradients associated with severe hypertrophy due to volume overload are not significantly greater than those observed in normal dogs. Infundibular gradients are dominantly related to narrowing of the outflow tract.

scholarly journals Alleviation of Inflammation and Oxidative Stress in Pressure Overload-Induced Cardiac Remodeling and Heart Failure via IL-6/STAT3 Inhibition by Raloxifene

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Shengqi Huo ◽  
Wei Shi ◽  
Haiyan Ma ◽  
Dan Yan ◽  
Pengcheng Luo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Protein Expression ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Stat3 Signaling ◽  
H9c2 Myoblasts ◽  
And Oxidative Stress ◽  
Stat3 Inhibition

Background. Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial. Methods and Results. Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n = 6 , respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro, we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene. Conclusion. Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF.

CILP1 as a biomarker for right ventricular maladaptation in pulmonary hypertension

2020 ◽  
pp. 1901192
Author(s):  
Stanislav Keranov ◽  
Oliver Dörr ◽  
Leili Jafari ◽  
Christian Troidl ◽  
Christoph Liebetrau ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Protein Expression ◽  
Right Ventricular ◽  
Predictive Power ◽  
Pressure Overload ◽  
Serum Levels ◽  
Left Ventricular ◽  
Dilative Cardiomyopathy ◽  
Significant Difference ◽  
Rv Function

The aim of our study was to analyse the protein expression of cartilage intermediate layer protein 1 (CILP1) in a mouse model of right ventricular (RV) pressure overload and to evaluate CILP1 as a biomarker of cardiac remodelling and maladaptive RV function in patients with pulmonary hypertension (PH).Pulmonary artery banding was performed in 14 mice; another 9 mice underwent sham surgery. CILP1 protein expression was analysed in all hearts by western blotting and immunostaining. CILP1 serum concentrations were measured in 161 patients (97 with adaptive and maladaptive RV pressure overload caused by PH; 25 with left ventricular (LV) hypertrophy; 20 with dilative cardiomyopathy (DCM); 19 controls without LV or RV abnormalities)In mice, the amount of RV CILP1 was markedly higher after banding than after sham. Control patients had lower CILP1 serum levels than all other groups (p<0.001). CILP1 concentrations were higher in PH patients with maladaptive RV function than those with adaptive RV function (p<0.001), LV pressure overload (p<0.001), and DCM (p=0.003). CILP1 showed good predictive power for maladaptive RV in ROC analysis (AUC 0.79). There was no significant difference between the AUCs of CILP1 and NT-pro-BNP (AUC 0.82). High CILP1 (≥cut-off value for maladaptive RV of 4373 pg·mL−1) was associated with lower TAPSE/PASP ratios (p<0.001) and higher NT-pro-BNP levels (p<0.001).CILP1 is a novel biomarker of RV and LV pathological remodelling that is associated with RV maladaptation and ventriculoarterial uncoupling in patients with PH.

P5370Pulmonary pressure overload stimulates cardiac stem or progenitor cell-derived cardiac regeneration in the right ventricular area

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Kanda ◽  
T Nagai ◽  
N Kondou ◽  
K Tateno ◽  
M Hirose ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Progenitor Cell ◽  
Pressure Overload ◽  
Right Heart Failure ◽  
Left Ventricular ◽  
Free Wall ◽  
Right Heart ◽  
The Right

Abstract Introduction and purpose The number of patients with right heart failure due to pulmonary hypertension has been increasing. Although several drugs have reportedly improved pulmonary hypertension, no treatments have been established for decompensated right heart failure. The heart has an innate ability to regenerate, and cardiac stem or progenitor cells (e.g., side population [SP] cells) have been reported to contribute to the regeneration process. However, their contribution to right ventricular pressure overload has not been clarified. Here, this regeneration process was evaluated using a genetic fate-mapping model. Methods and results We used Cre-LacZ mice, in which more than 99.9% of the cardiomyocytes in the left ventricular field were positive for 5-bromo-4-chloro-3-indolyl-β-D-galactoside (X-gal) staining immediately after tamoxifen injection. Then, we performed either a pulmonary binding (PAB) or sham operation on the main pulmonary tract. In the PAB-treated mice, the right ventricular cavity was significantly enlarged (right-to-left ventricular [RV/LV] ratio, 0.24±0.04 in the sham group and 0.68±0.04 in the PAB group). Increased peak flow velocity in the PAB group (1021±80 vs 1351±62 mm/sec) was confirmed by echocardiography. One month after the PAB, the PAB-treated mice had more X-gal-negative (newly generated) cells than the sham mice (94.8±34.2 cells/mm2 vs 23.1±10.5 cells/mm2; p<0.01). The regeneration was biased in the RV free wall (RV free wall, 225.5±198.7 cells/mm2; septal area, 88.9±56.5/mm2; LV lateral area, 46.8±22.0/mm2; p<0.05). To examine the direct effects of PAB on the cardiac progenitor cells, bromodeoxyuridine was administered to the mice daily until 1 week after the PAB operation. Then, the hearts were isolated and SP cells were harvested. The SP cell population increased from 0.65±0.23% in the sham mice to 1.87% ± 1.18% in the PAB-treated mice. Immunostaining analysis revealed a significant increase in the number of BrdU-positive SP cells, from 11.6±2.0% to 44.0±18%, therefore showing SP cell proliferation. Conclusions Pulmonary pressure overload stimulated cardiac stem or progenitor cell-derived regeneration with a RV bias, and SP cell proliferation may partially contribute to this process. Acknowledgement/Funding JSPS KAKENHI Grant Number JP 17K17636, GSK Japan Research Grant 2016

Abstract 159: Ablation of the Hypertension Candidate Gene ATP2B1 Leads To Deficient Calcium Cycling, Systolic Dysfunction and Heart Failure Following Pressure Overload

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Nicholas P Stafford ◽  
Min Zi ◽  
Ludwig Neyses ◽  
Elizabeth J Cartwright
Keyword(s):  
Heart Failure ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Early Response ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Calcium Cycling ◽  
Lung Weight ◽  
Hypertrophic Growth ◽  
Ventricular Elastance

Mutations in ATP2B1 encoding the ubiquitous calcium extrusion pump Plasma Membrane Calcium ATPase 1 (PMCA1) have recently identified it as having the strongest association of any gene to hypertension, yet the role of PMCA1 in the pressure-overloaded heart is not known. To investigate this we generated a novel mouse line carrying cardiomyocyte-specific deletion of PMCA1 (PMCA1 cko ) and challenged them with transverse aortic constriction (TAC) alongside littermate ‘floxed’ controls (PMCA1 f/f ). After two weeks, echocardiographic analysis revealed signs of systolic dysfunction and left ventricular (LV) dilation in PMCA1 cko hearts as evidenced by reduced fractional shortening and increased diastolic diameter (both p<0.05), whilst function in PMCA1 f/f TAC controls remained preserved. This was accompanied by an increase in normalised lung weight in PMCA1 cko mice compared to sham operated and TAC controls (p<0.05) indicative of pulmonary congestion and a progression into LV failure, despite comparable hypertrophic growth amongst the two TAC cohorts. Hemodynamic analysis following LV catheterisation revealed contractility, as measured by left ventricular elastance (E es ), to be increased in controls after TAC (PMCA1 f/f TAC 12.69 ± 1.63 vs sham 7.02 ± 1.11 mmHg/μl, p<0.05), a change which was not reciprocated in knockout hearts (PMCA1 cko TAC 7.70 ± 1.19 vs sham 7.22 ± 1.55 mmHg/μl). To examine whether altered calcium handling could be the underlying cause of the observed phenotype, cardiomyocytes were isolated following one week TAC and loaded with Indo-1, prior to the onset of failure in PMCA1 cko hearts. Compatible with an increase in E es , systolic calcium levels were higher in PMCA1 f/f myocytes following pressure overload compared to sham controls (p<0.05), whilst PMCA1 cko TAC myocytes displayed equivalent peak calcium levels to their respective sham controls. These results suggest that PMCA1 may play a necessary role in enhancing calcium cycling during the early response to pressure overload, and that disrupting this gene may increase the susceptibility to heart failure under these conditions. This may provide first evidence of a novel genetic basis for the development of heart failure in a proportion of hypertensive patients.

Sign in / Sign up

Export Citation Format

Share Document