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.

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.

Norepinephrine and dobutamine improve cardiac index equally by supporting opposite sides of the heart in an experimental model of chronic pulmonary hypertension

2021 ◽  
Author(s):  
Janus Adler Hyldebrandt ◽  
Nikolaj Bøgh ◽  
Camilla Omann Christensen ◽  
Peter Agger
Keyword(s):  
Pulmonary Hypertension ◽  
Cardiac Index ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Left Ventricular ◽  
Ventricular Contractility ◽  
End Diastolic Volume ◽  
Chronic Pulmonary Hypertension ◽  
Blood Pressures ◽  
The Right

Abstract Background: Pulmonary hypertension is a significant risk factor in patients undergoing surgery. The combined effects of general anaesthesia and positive pressure ventilation can aggravate this condition and cause increased pulmonary blood pressures, reduced systemic blood pressures and ventricular contractility. Although perioperative use of inotropic support or vasopressors is almost mandatory for these patients, preference is disputed. In this study, we investigated the effects of norepinephrine and dobutamine and their ability to improve the arterio-ventricular relationship and haemodynamics in pigs suffering from chronic pulmonary hypertension.Method: Pulmonary hypertension was induced in five pigs by banding the pulmonary artery at 2–3 weeks of age. Six pigs served as controls. After 16 weeks of pulmonary artery banding, the animals were re-examined under general anaesthesia using biventricular conductance catheters and a pulmonary artery catheter. After baseline measurements, the animals were exposed to both norepinephrine and dobutamine infusions in incremental doses, with a stabilizing period in between the infusions. The hypothesis of differences between norepinephrine and dobutamine with incremental doses was tested using repeated two-way ANOVA and Bonferroni multiple comparisons post-test. Results: At baseline, pulmonary artery banded animals had increased right ventricular pressure (+39%, p=0.04), lower cardiac index (-23% p=0.04), lower systolic blood pressure (-13%, p=0.02) and reduced left ventricular end-diastolic volume (-33%, p=0.02). When incremental doses of norepinephrine and dobutamine were administered, the right ventricular arterio-ventricular coupling was improved only by dobutamine (p<0.05). Norepinephrine increased both left ventricular end-diastolic volume and left ventricular contractility to a greater extent (p<0.05) in pulmonary artery banded animals. While the cardiac index was improved equally by norepinephrine and dobutamine treatments in pulmonary artery banded animals, norepinephrine had a significantly greater effect on mean arterial pressure (p<0.05) and diastolic arterial pressure (p<0.05).Conclusion: While norepinephrine and dobutamine improved cardiac index equally, it was obtained in different manners. Dobutamine significantly improved the right ventricular function and the arterio-ventricular coupling. Norepinephrine increased systemic resistance, thereby improving arterial pressures and left ventricular systolic function by maintaining left ventricular end-diastolic volume.

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.

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

Osteopontin and galectin-3 as biomarkers of maladaptive right ventricular remodeling in pulmonary hypertension

2021 ◽  
Author(s):  
Stanislav Keranov ◽  
Oliver Dörr ◽  
Leili Jafari ◽  
Christoph Liebetrau ◽  
Till Keller ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Dilated Cardiomyopathy ◽  
Ventricular Hypertrophy ◽  
Ventricular Remodeling ◽  
Left Ventricular ◽  
Potential Biomarker ◽  
Lv Remodeling ◽  
Galectin 3 ◽  
Right Ventricular Remodeling

Aim: This study assessed the utility of osteopontin (OPN) and galectin-3 (Gal-3) as biomarkers of maladaptive right ventricular remodeling in pulmonary hypertension (PH). Materials & methods: We examined plasma levels of OPN and Gal-3 in patients with PH (n = 62), dilated cardiomyopathy (n = 34), left ventricular hypertrophy (LVH; n = 47), and controls without right ventricle (RV) or LV abnormalities (n = 38). Results: OPN and Gal-3 levels were higher in PH, dilated cardiomyopathy and LVH than in the controls. OPN concentrations in PH patients with maladaptive RV were significantly higher than in those with adaptive RV. Gal-3 did not differentiate between adaptive and maladaptive RV remodeling in PH. OPN and Gal-3 levels did not correlate with parameters of LV remodeling. Conclusion: OPN is a potential biomarker of RV maladaptation.

scholarly journals Pulmonary Hypertension Related to Left-Sided Cardiac Pathology

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Todd L. Kiefer ◽  
Thomas M. Bashore
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Pressure Overload ◽  
Therapeutic Strategies ◽  
Left Ventricular ◽  
Right Ventricular Failure ◽  
Valve Disease ◽  
Ventricular Failure ◽  
Cardiac Pathology ◽  
Pathologic Processes

Pulmonary hypertension (PH) is the end result of a variety of diverse pathologic processes. The chronic elevation in pulmonary artery pressure often leads to right ventricular pressure overload and subsequent right ventricular failure. In patients with left-sided cardiac disease, PH is quite common and associated with increased morbidity and mortality. This article will review the literature as it pertains to the epidemiology, pathogenesis, and diagnosis of PH related to aortic valve disease, mitral valve disease, left ventricular systolic and diastolic dysfunction, and pulmonary veno-occlusive disease. Moreover, therapeutic strategies, which focus on treating the underlying cardiac pathology will be discussed.

scholarly journals Right Atrial and Ventricular Adaptation to Chronic Right Ventricular Pressure Overload

Circulation ◽  
2005 ◽  
Vol 112 (9_supplement) ◽  
Author(s):  
Sydney L. Gaynor ◽  
Hersh S. Maniar ◽  
Jeffrey B. Bloch ◽  
Paul Steendijk ◽  
Marc R. Moon
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Right Atrium ◽  
Systolic Function ◽  
Pressure Overload ◽  
Right Atrial ◽  
Chronic Pulmonary Hypertension ◽  
The Right ◽  
Conduit Function

Background— Increased mortality in patients with chronic pulmonary hypertension has been associated with elevated right atrial (RA) pressure. However, little is known about the effects of chronic right ventricular (RV) pressure overload on RA and RV dynamics or the adaptive response of the right atrium to maintain RV filling. Methods and Results— In 7 dogs, RA and RV pressure and volume (conductance catheter) were recorded at baseline and after 3 months of progressive pulmonary artery banding. RA and RV elastance (contractility) and diastolic stiffness were calculated, and RA reservoir and conduit function were quantified as RA inflow with the tricuspid valve closed versus open, respectively. With chronic pulmonary artery banding, systolic RV pressure increased from 34±7 to 70±17 mm Hg ( P <0.001), but cardiac output did not change ( P >0.78). RV elastance and stiffness both increased ( P <0.05), suggesting preserved systolic function but impaired diastolic function. In response, RA contractility improved (elastance increased from 0.28±0.12 to 0.44±0.13 mm Hg/mL; P <0.04), and the atrium became more distensible, as evidenced by increased reservoir function (49±14% versus 72±8%) and decreased conduit function (51±14% versus 28±8%; P <0.002). Conclusions— With chronic RV pressure overload, RV systolic function was preserved, but diastolic function was impaired. To compensate, RA contractility increased, and the atrium became more distensible to maintain filling of the stiffened ventricle. This compensatory response of the right atrium likely plays an important role in preventing clinical failure in chronic pulmonary hypertension.

Sign in / Sign up

Export Citation Format

Share Document