scholarly journals Reversal of right ventricular failure by chronic α1A-subtype adrenergic agonist therapy

2019 ◽  
Vol 316 (1) ◽  
pp. H224-H232 ◽  
Author(s):  
Patrick M. Cowley ◽  
Guanying Wang ◽  
Philip M. Swigart ◽  
Anaha Raghunathan ◽  
Nikitha Reddy ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Right Ventricular ◽  
Therapeutic Target ◽  
Adrenergic Receptors ◽  
Chronic Stimulation ◽  
Pulmonary Artery Constriction ◽  
Rv Function ◽  
Fractional Shortening ◽  
Stimulation Of

Right ventricular (RV) failure (RVF) is a serious disease with no effective treatment available. We recently reported a disease prevention study showing that chronic stimulation of α1A-adrenergic receptors (α1A-ARs), started at the time of RV injury, prevented the development of RVF. The present study used a clinically relevant disease reversal design to test if chronic α1A-AR stimulation, started after RVF was established, could reverse RVF. RVF was induced surgically by pulmonary artery constriction in mice. Two weeks after pulmonary artery constriction, in vivo RV fractional shortening as assessed by MRI was reduced by half relative to sham-operated controls (25 ± 2%, n = 27, vs. 52 ± 2%, n = 13, P < 10−11). Subsequent chronic treatment with the α1A-AR agonist A61603 for a further 2 wk resulted in a substantial recovery of RV fractional shortening (to 41 ± 2%, n = 17, P < 10−7 by a paired t-test) along with recovery of voluntary exercise capacity. Mechanistically, chronic A61603 treatment resulted in increased activation of the prosurvival kinase ERK, increased abundance of the antiapoptosis factor Bcl-2, and decreased myocyte necrosis evidenced by a decreased serum level of cardiac troponin. Moreover, A61603 treatment caused increased abundance of the antioxidant glutathione peroxidase-1, decreased level of reactive oxygen species, and decreased oxidative modification (carbonylation) of myofilament proteins. Consistent with these effects, A61603 treatment resulted in increased force development by cardiac myofilaments, which might have contributed to increased RV function. These findings suggest that the α1A-AR is a therapeutic target to reverse established RVF. NEW & NOTEWORTHY Currently, there are no effective therapies for right ventricular (RV) failure (RVF). This project evaluated a novel therapy for RVF. In a mouse model of RVF, chronic stimulation of α1A-adrenergic receptors with the agonist A61603 resulted in recovery of in vivo RV function, improved exercise capacity, reduced oxidative stress-related carbonylation of contractile proteins, and increased myofilament force generation. These results suggest that the α1A-adrenergic receptor is a therapeutic target to treat RVF.

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.

scholarly journals The Association Between Notching of the Right Ventricular Outflow Tract Flow Velocity Doppler Envelope and Impaired Right Ventricular Function After Acute High-Altitude Exposure

2021 ◽  
Vol 12 ◽  
Author(s):  
Fangzhengyuan Yuan ◽  
Chuan Liu ◽  
Shiyong Yu ◽  
Shizhu Bian ◽  
Jie Yang ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Right Ventricular ◽  
Flow Velocity ◽  
Healthy Subjects ◽  
Right Ventricular Outflow Tract ◽  
Ventricular Outflow Tract ◽  
Tricuspid Annulus ◽  
Doppler Flow ◽  
The Right ◽  
Rv Function

IntroductionPulmonary artery pressure (PAP) is increased and right ventricular (RV) function is well preserved in healthy subjects upon exposure to high altitude (HA). An increase in PAP may trigger notching of the right ventricular outflow tract Doppler flow velocity envelope (RVOT notch), which is associated with impaired RV function in patients with pulmonary hypertension. However, whether HA exposure can induce RVOT notch formation and the subsequent impact on cardiac function in healthy subjects remains unclear.MethodsA total of 99 subjects (69 males and 30 females) with a median age of 25 years were enrolled in this study; they traveled from 500 to 4100 m by bus over a 2-day period. All subjects underwent a comprehensive physiological and echocardiographic examination 1 day before ascension at low altitude and 15 ± 3 h after arrival at HA. The RVOT notch was determined by the presence of a notched shape in the RVOT Doppler flow velocity envelope. The systolic PAP (SPAP) was calculated as Bernoulli equation SPAP = 4 × (maximum tricuspid regurgitation velocity)2+5 and mean PAP (mPAP) = 0.61 × SPAP+2. Cardiac output was calculated as stroke volume × heart rate. Pulmonary capillary wedge pressure (PCWP) was calculated as 1.9+1.24 × mitral E/e’. Pulmonary vascular resistance (PVR) was calculated as (mPAP-PCWP)/CO.ResultsAfter HA exposure, 20 (20.2%) subjects had an RVOT notch [notch (+)], and 79 (79.8%) subjects did not have an RVOT notch [notch (−)]. In the multivariate logistic regression analysis, the SPAP, right ventricular global longitude strain (RV GLS), and tricuspid E/A were independently associated with the RVOT notch. The SPAP, mPAP, PVR, standard deviations of the times to peak systolic strain in the four mid-basal RV segments (RVSD4), peak velocity of the isovolumic contraction period (ICV), and the peak systolic velocity (s’) at the mitral/tricuspid annulus were increased in all subjects. Conversely, the pulse oxygen saturation (SpO2), RV GLS, and tricuspid annulus plane systolic excursion (TAPSE)/SPAP were decreased. However, the increases of SPAP, mPAP, PVR, and RVSD4 and the decreases of SpO2, RV GLS, and TAPSE/SPAP were more pronounced in the notch (+) group than in the notch (−) group. Additionally, increased tricuspid ICV and mitral/tricuspid s’ were found only in the notch (−) group.ConclusionHA exposure-induced RVOT notch formation is associated with impaired RV function, including no increase in the tricuspid ICV or s’, reduction of RV deformation, deterioration in RV-pulmonary artery coupling, and RV intraventricular synchrony.

Humoral regulation of vascular resistance after 30 days of pulmonary artery constriction

1979 ◽  
Vol 236 (6) ◽  
pp. H866-H872 ◽  
Author(s):  
R. F. McNamara ◽  
P. G. Schmid ◽  
J. A. Schmidt ◽  
D. D. Lund ◽  
R. K. Bhatnagar
Keyword(s):  
Angiotensin Ii ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Vascular Resistance ◽  
Guinea Pigs ◽  
Ventricular Hypertrophy ◽  
Adrenergic Blockade ◽  
Flow Curves ◽  
Pulmonary Artery Constriction ◽  
Humoral Regulation

In an earlier study of guinea pigs with constriction of the pulmonary artery (PA) for 30 days, hindquarters' vascular resistance was maintained primarily by humoral mechanisms. In the present study, we investigated the contribution of circulating catecholamines, angiotensin II, and other constrictor stimuli to hindquarters' vascular resistance by observing vasodilator responses to specific competitive antagonists. Pressure-flow curves indicated vascular resistances in isolated, perfused, sympathectomized hindquarters of anesthetized guinea pigs. Phentolamine produced significantly greater (P less than 0.05) vasodilatation in animals with constriction of pulmonary artery than in sham animals [Sar1-Ala8]angiotensin II produced no vasodilation in either group. After alpha-adrenergic blockade, papaverine produced similar vasodilatation and similar final perfusion pressures in both groups. It appears that circulating catecholamines and augmented vasoconstrictor responsiveness to norepinephrine are totally responsible for the increased humoral regulation of vascular resistance in this experimental model of right ventricular hypertrophy.

scholarly journals Evaluation of right ventricle pulmonary artery coupling on right ventricular function in post operative tetralogy of Fallot patients underwent for pulmonary valve replacement

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Bhushan Sandeep ◽  
Xin Huang ◽  
Yuan Li ◽  
Xiaowei Wang ◽  
Long Mao ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Pulmonary Artery ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Ventricular Function ◽  
Right Ventricular Function ◽  
Pulmonary Valve ◽  
Primary Repair ◽  
Pulmonary Valve Replacement ◽  
Rv Function

Abstract Background To evaluate RV-PA coupling in post operative TOF patients with ventricular dilatation underwent for PVR and investigate the correlation between ventricular functions measuring Ea/Emax ratio using cardio magnetic resonance and the effect of surgical type at primary repair of TOF on coupling. Method RV-PA coupling was measured noninvasively by Ea/Emax ratio from CMRI and ECHO. From CMRI results the patients were divided in two groups, RV-PA coupling and RV-PA uncoupling. Ea/Emax ≤1 was considered for coupling patients and Ea/Emax > 1 for uncoupling patients. Results Ninety patients were uncoupled (Ea/Emax: 1.55 ± 0.46) and 45 were coupled (Ea/Emax: 0.81 ± 0.15). Out of 75 TAP repaired patients 60 were uncoupled RV-PV. In addition, higher pro-BNP is an important factor for uncoupled RV-PV (P = 0.001). CMR evaluation for right ventricular function between uncoupling and coupling were RVEDVi (196.65 ± 63.57 vs. 154.28 ± 50.07, P = 0.001), RVESVi (121.19 ± 51.47 vs. 83.94 ± 20.43, P = 0.001), RVSVi (67.19 ± 19.87 vs. 106.31 ± 33.44, P = 0.001), and RVEF (40.90 ± 8.73 vs. 54.63 ± 4.76, P = 0.001). The increased RVEDVi, RVESVi and RVSVi and decreased RVEF have significant correlation with Ea/Emax. Ea/Emax was also found positively correlated with RVEDVi (P = < 0.05, r = 0.35), RVESVi (P = < 0.001, r = 0.41) and negatively correlated with RVSVi (P = < 0.05, r = 0.22) and RVEF (P = < 0.05, r = 0.78). Conclusions Unfavorable RV-PA coupling is present in post operative TOF patients and it is affected by several factors. Our results explain a new concept of RV-PA interactions as a contributing mechanism for the observed decline in RV function.

scholarly journals First in vivo assessment of RAS-Q technology as lung support device for pulmonary hypertension

2020 ◽  
pp. 039139882095421
Author(s):  
Tom Verbelen ◽  
Michael Halwes ◽  
Bart Meyns
Keyword(s):  
Pulmonary Hypertension ◽  
Cardiac Output ◽  
Pulmonary Artery ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Pressure Ratio ◽  
Severe Pulmonary Hypertension ◽  
Fully Integrated ◽  
Arterial Blood

Objectives: To assess the in vivo hemodynamic effects on the pressure overloaded right ventricle of RAS-Q® technology, the world’s first gas exchanger with a fully integrated compliance. Methods: In six acute in vivo trials RAS-Q was implanted in sheep between the pulmonary artery and left atrium. Right ventricular pressure overload was induced by pulmonary artery banding. Pressures and flows were recorded in baseline, moderate and severe pulmonary hypertension conditions. In one trial, RAS-Q was benchmarked against the pediatric Quadrox-i®. Results: With 1.00 and 1.17 L/min, RAS-Q delivered 31% and 39% of the total cardiac output in moderate and severe pulmonary hypertension, respectively. Pulmonary artery pressures and mean pulmonary artery pressure/mean arterial blood pressure ratio successfully decreased, implying a successful right ventricular unloading. Cardiac output was restored to normal levels in both pulmonary hypertension conditions. With both devices in parallel, RAS-Q provided three times higher flow rates and a 10 times higher pressure relief, compared to the pediatric Quadrox-i. Conclusion: A gas exchanger with a fully integrated compliance better unloads the right ventricle compared to a non-compliant gas exchanger and it can restore cardiac output to normal levels in cases of severe pulmonary hypertension.

scholarly journals Identification of Long Noncoding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (15) ◽  
pp. 1464-1484 ◽  
Author(s):  
Junichi Omura ◽  
Karima Habbout ◽  
Tsukasa Shimauchi ◽  
Wen-Hui Wu ◽  
Sandra Breuils-Bonnet ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Therapeutic Target ◽  
Noncoding Rna ◽  
Pulmonary Artery Banding ◽  
Pulmonary Arterial ◽  
Rv Function

Background: Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly understood and as a consequence there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. Accumulating evidence indicates that long noncoding RNAs are powerful regulators of cardiac development and disease. Nonetheless, their implication in adverse RV remodeling in PAH is unknown. Methods: Expression of the long noncoding RNA H19 was assessed by quantitative PCR in plasma and RV from patients categorized as control RV, compensated RV or decompensated RV based on clinical history and cardiac index. The impact of H19 suppression using GapmeR was explored in 2 rat models mimicking RV failure, namely the monocrotaline and pulmonary artery banding. Echocardiographic, hemodynamic, histological, and biochemical analyses were conducted. In vitro gain- and loss-of-function experiments were performed in rat cardiomyocytes. Results: We demonstrated that H19 is upregulated in decompensated RV from PAH patients and correlates with RV hypertrophy and fibrosis. Similar findings were observed in monocrotaline and pulmonary artery banding rats. We found that silencing H19 limits pathological RV hypertrophy, fibrosis and capillary rarefaction, thus preserving RV function in monocrotaline and pulmonary artery banding rats without affecting pulmonary vascular remodeling. This cardioprotective effect was accompanied by E2F transcription factor 1-mediated upregulation of enhancer of zeste homolog 2. In vitro, knockdown of H19 suppressed cardiomyocyte hypertrophy induced by phenylephrine, while its overexpression has the opposite effect. Finally, we demonstrated that circulating H19 levels in plasma discriminate PAH patients from controls, correlate with RV function and predict long-term survival in 2 independent idiopathic PAH cohorts. Moreover, H19 levels delineate subgroups of patients with differentiated prognosis when combined with the NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels or the risk score proposed by both REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) and the 2015 European Pulmonary Hypertension Guidelines. Conclusions: Our findings identify H19 as a new therapeutic target to impede the development of maladaptive RV remodeling and a promising biomarker of PAH severity and prognosis.

scholarly journals P670 RV function in adult patients with repaired tetralogy of Fallot: assessment by three-dimensional echocardiography, comparison to CMR findings and relationship to pulmonary artery distensibility

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
L Capotosto ◽  
N Galea ◽  
M Francone ◽  
L Marchitelli ◽  
G Tanzilli ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Speckle Tracking ◽  
Speckle Tracking Echocardiography ◽  
Three Dimensional ◽  
Pulmonary Regurgitation ◽  
Dimensional Echocardiography ◽  
Three Dimensional Echocardiography ◽  
Rv Function

Abstract Purpose The purpose of this study was to examine right ventricular (RV) function by three-dimensional speckle-tracking echocardiography (3DSTE) in patients after correction of tetralogy of Fallot (TF), the accuracy of 3DSTE compared to cardiovascular magnetic resonance (CMR) findings and assess pulmonary arterial (PA) distensibility in order to achieve a more comprehensive understanding of the matching between RV performance and PA load. Methods Twenty-one patients (mean age 39 ± 16 years) with repaired TF and twenty-one age-matched healthy subjects selected as controls were studied. CMR findings were available in 14 patients. RV volumes, RV ejection fraction (RVEF) and RV longitudinal and circumferential strains were calculated by three-dimensional echocardiography and three-dimensional speckle tracking echocardiography. The main pulmonary artery was interrogated by color, pulsed, and continuous-wave Doppler. Pulmonary regurgitation (PR) was assessed by color-flow mapping and graded as none, mild, or greater than mild using the measurement of the regurgitant jet width in relation to the outflow tract diameter. Right pulmonary artery (PA) was visualized from suprasternal view by two-dimensional echocardiography. Tissue Doppler Imaging (TDI) mode was activated in B-mode imaging to examine arterial motion, then mode was changed to color-mode with the beam line aligned perpendicular to the superior and inferior walls of the right PA. PA distensibility and strain were determined. Data analysis was performed offline. Results Overall, 3D RVEF and RV longitudinal strain were reduced in TF patients compared to the control group. Nine patients had moderate or moderate-to-severe PR. PA strain and distensibility were decreased (p = 0.003) compared with controls, both in the presence and absence of PR. PA strain had a positive correlation with RVEF (r = 0.79, p &lt; 0.005) and RV strain (r = 0.82, p &lt; 0.001). RV end-diastolic and end-systolic volumes by 3DE correlated with the respective parameters by CMR (r = 0.88,p &lt; 0.001 and r = 0.87,p &lt; 0.005 respectively). Patients with moderate-to-severe PR had more prominent PA strain changes (p = 0.02). Conclusions Three-dimensional right ventricular ejection fraction and RV strain are impaired in patients with repaired TF, in agreement with CMR data. Reduced PA strain is associated with reduced RV 3DSTE parameters and is more pronounced in the presence of pulmonary regurgitation.

Determinants of pulmonary arterial flow variation during respiration

1984 ◽  
Vol 56 (5) ◽  
pp. 1237-1245 ◽  
Author(s):  
M. R. Pinsky
Keyword(s):  
Pulmonary Artery ◽  
Right Ventricular ◽  
Opposite Effect ◽  
Arterial Flow ◽  
Positive Pressure ◽  
Electromagnetic Flow Probe ◽  
Pulmonary Arterial ◽  
Intermittent Positive Pressure Breathing ◽  
The Relationship ◽  
Rv Function

We characterize the determinants of pulmonary arterial flow ( Qpa ) variation during spontaneous breathing ( SPONT ) and matched tidal volume intermittent positive-pressure breathing (IPPB) in 14 pentobarbital-anesthetized closed-chest canine preparations in which Qpa is measured by an electromagnetic flow probe around the pulmonary artery. Pressures are recorded from the juxtacardiac pleural space (Ppl), right atrium (Pra), and pulmonary artery. Spontaneous inspiratory efforts increase transmural Pra (Pra - Ppl) and right ventricular stroke volume ( SVRV ) but decreases Pra, whereas IPPB inspiration has the opposite effect. However, the relationship between instantaneous changes in SVRV and transmural Pra during SPONT and IPPB define a common “instantaneous” right ventricular (RV) function curve independent of mode of ventilation or phase or respiratory cycle, and this curve is similar to one generated by volume infusion measured at end expiration. Pulmonary vascular resistance changes during ventilation are small (less than 15%) and do not affect RV performance as noted by similar instantaneous RV function curves for SPONT and IPPB with Mueller and Valsalva maneuvers, respectively. Thus variations in Qpa during ventilation represent matched changes in RV filling pressure induced by phasic changes in venous return.

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