Chronic Right Ventricular Pressure Overload Research Articles

Characterizing the Spatiotemporal Transcriptomic Response of the Right Ventricle to Acute Pressure Overload.

This study analyzed microarray data of right ventricular (RV) tissue from rats exposed to pulmonary embolism to understand the initial dynamic transcriptional response to mechanical stress and compare it with experimental pulmonary hypertension (PH) models. The dataset included samples harvested from 55 rats at 11 different time points or RV locations. We performed principal component analysis (PCA) to explore clusters based on spatiotemporal gene expression. Relevant pathways were identified from fast gene set enrichment analysis using PCA coefficients. The RV transcriptomic signature was measured over several time points, ranging from hours to weeks after an acute increase in mechanical stress, and was found to be highly dependent on the severity of the initial insult. Pathways enriched in the RV outflow tracts of rats at 6 weeks after severe PE share many commonalities with experimental PH models, but the transcriptomic signature at the RV apex resembles control tissue. The severity of the initial pressure overload determines the trajectory of the transcriptomic response independent of the final afterload, but this depends on the location where the tissue is biopsied. Chronic RV pressure overload due to PH appears to progress toward similar transcriptomic endpoints.

Right heart response to different loading conditions - a comparison of chronic volume versus pressure overload using an integrated echocardiographic and invasive approach

Abstract Funding Acknowledgements Type of funding sources: None. Background. It is widely believed that right ventricular (RV) volume overload is better tolerated than RV pressure overload and this is mainly due to the preservation of or even an increase in RV longitudinal function in patients (pts) with RV volume overload. Conversely, patients with RV pressure overload experience an early decrease in radial shortening and the global RV performance is maintained due to a normal longitudinal function. The multiparametric assessment of RV function and RV-pulmonary artery (PA) coupling could offer a better understanding of the RV adaptive mechanisms in response to volume versus pressure overload. Purpose. To assess the right heart remodelling and function in different chronic loading conditions using an integrated echocardiographic and invasive approach. Methods. Thirty-nine patients with atrial septal defect (ASD) and 41 pts with pulmonary hypertension (PH) age and gender-matched were enrolled. The etiology of PH was idiopathic (14 pts), operated congenital heart disease (3), connective tissue disease (9), chronic thromboembolic PH (8) and other forms of arterial PH (7). Clinical parameters, B-type natriuretic peptide (BNP), RV function and pulmonary artery stiffness (PAS) echocardiographic parameters were assessed. RV-PA coupling was assessed using the TAPSE to systolic PA pressure ratio. A right heart catheterization was also performed and ASD pts with pulmonary vascular resistance >3 Wu and/or Qp/Qs ratio <1.5 were excluded. Results. PH pts were more symptomatic than pts with ASD (32 PH pts vs 6 ASD pts were in NYHA class III and IV, p < 0.001). ASD pts had lower BNP levels (lnBNP 4.24 ± 1.11 vs 5.49 ± 1.29, p < 0.001), similar right atrial (RA) area (26.6 ± 7.7 vs 27.8 ± 11.9 cm2, p = 0.61) and pressure (7.5 ± 4.2 vs 8.2 ± 5.9 mmHg), lower systolic (1.11 ± 0.13 vs 1.55 ± 0.50) and diastolic (1.21 ± 0.16 vs 1.50 ± 0.32) eccentricity index (p < 0.001) and better RV function parameters than PH pts (all p < 0.001): TAPSE (26 ± 5 vs 16 ± 3 mm), RV-free wall S wave (14.4 ± 2.5 vs 9.9 ± 2.1 cm/s), RV fractional area change (46 ± 8 vs 32 ± 8%), RV global longitudinal strain on 3 segments (-27.6 ± 5.0 vs -14.4 ± 6.0%) or 6 segments (-24.2 ± 4.3 vs -12.5 ± 4.9%). Also, ASD pts had less impaired PAS parameters (pulmonary compliance 4.03 ± 5.54 vs 1.53 ± 3.01 mm2/mmHg, p = 0.016; elastic modulus 167 ± 131 vs 594 ± 369 mmHg, p < 0.001; beta index 5.36 ± 3.77 vs 11.00 ± 6.39, p < 0.001) and better RV-PA coupling (0.60 ± 0.20 vs 0.19 ± 0.06 mm/mmHg, p < 0.001) than PH pts. The BNP levels significantly correlated with RA area, parameters of RV size and systolic function and RV-PA coupling in both groups, but invasively assessed PA pressure correlated with BNP levels only in ASD pts. Conclusions Patients with ASD as a model of chronic RV volume overload have not only preserved RV longitudinal function but also better global RV function, PAS and RV-PA coupling compared to pts with chronic RV pressure overload. The BNP levels are significantly more impaired in pts with chronic RV pressure overload.

The Importance of Electrocardiography in Pediatric Patients with Pulmonary Arterial Hypertension in Follow- up

Background: Right Ventricular (RV) hypertrophy is an adaptive response to chronic RV pressure overload in patients with pulmonary hypertension. We investigated the relationships between RV hypertrophy indicators, including electrocardiography, the percentage oxygen saturation (SaO2%), body mass index (BMI), and blood uric acid levels in patients with a biventricular structure followed up for Pulmonary Arterial Hypertension (PAH). Materials and Methods: This retrospective study included 33 patients with confirmed systemic PAH, according to the catheterization and a negative vascular reactivity test result. Patients with single-ventricle physiology and Down’s syndrome who had undergone surgery were excluded. The data of blood chemistry, hemogram, ECG, and SaO2% were collected, thus, the BMI was calculated. The patients were categorized according to SaO2 values ( 90% [n=19]), BMI (18.5 [n=17] kg/m2), PAH status (primary [n=13] vs. secondary [n=20]), and treatment regime (combination therapy [n=16] vs. monotherapy [n=17]), and the data were compared among the groups. Results: Patients with SaO2 values of 90% differed only in terms of blood uric acid level, which was significantly higher in the patients with SaO2 9 mm indicating impaired capacity. These measured markers can be used to follow-up patients with PAH.

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

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. 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. 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.

Cardiac Magnetic Resonance Imaging-Based Right Ventricular Strain Analysis for Assessment of Coupling and Diastolic Function in Pulmonary Hypertension

ObjectivesThis study sought to compare cardiac magnetic resonance (CMR) imaging-derived right ventricular (RV) strain and invasively measured pressure-volume loop-derived RV contractility, stiffness, and afterload and RV-arterial coupling in pulmonary hypertension (PH). BackgroundIn chronic RV pressure overload, RV-arterial uncoupling is considered the driving cause of RV maladaptation and eventual RV failure. The pathophysiological and clinical value of CMR-derived RV strain relative to that of invasive pressure-volume loop-derived measurements in PH remains incompletely understood. MethodsIn 38 patients with PH, global RV CMR strain was measured within 24 h of diagnostic right heart catheterization and conductance (pressure-volume) catheterization. Associations were evaluated by correlation, multivariate logistic binary regression, and receiver operating characteristic analyses. ResultsLong-axis RV longitudinal and radial strain and short-axis RV radial and circumferential strain were −18.0 ± 7.0%, 28.9% [interquartile range (IQR): 17.4% to 46.6%]; 15.6 ± 6.2%; and −9.8 ± 3.5%, respectively. RV-arterial coupling (end-systolic [Eds]/arterial elastance [Ea]) was 0.76 (IQR: 0.47 to 1.07). Peak RV strain correlated with Ees/Ea, afterload (Ea), RV diastolic dysfunction (Tau), and stiffness (end-diastolic elastance [Eed]) but not with contractility (Ees). In multivariate analysis, long-axis RV radial strain was associated with RV-arterial uncoupling (Ees/Ea: <0.805; odds ratio [OR]: 5.50; 95% confidence interval [CI]: 1.50 to 20.18), whereas long-axis RV longitudinal strain was associated with increased RV diastolic stiffness (Eed: ≥0.124 mm Hg/ml; OR: 1.23; 95% CI: 1.10 to 1.51). The long-axis RV longitudinal strain-to-RV end-diastolic volume/body surface area ratio strongly predicted RV diastolic stiffness (area under receiver operating characteristic curve: 0.908). ConclusionsIn chronic RV overload, CMR-determined RV strain is associated with RV-arterial uncoupling and RV end-diastolic stiffness and represents a promising noninvasive alternative to current invasive methods for assessment of RV-arterial coupling and end-diastolic stiffness in patients with PH. (Right Ventricular Haemodynamic Evaluation and Response to Treatment [Rightheart I]; NCT03403868)

Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension.

Mutations in the KCNK3 gene, which encodes for an outward-rectifier K+ channel, have been identified in patients suffering from pulmonary arterial hypertension (PAH), and constitute the first described channelopathy in PAH. In human PAH and experimental pulmonary hypertension (PH), we demonstrated that KCNK3 expression and function are severely reduced in pulmonary vascular cells, promoting PH-like phenotype at the morphologic and haemodynamic levels. Since KCNK3 channel is also expressed in both the human and rodent heart, we aimed to elucidate the pathophysiological role of KCNK3 channel in right ventricular (RV) hypertrophy (RVH) related to PH. Using whole-cell Patch-clamp technique, we demonstrated that KCNK3 is predominantly expressed in adult rat RV cardiomyocytes compared to the left ventricle cardiomyocytes and participates in the repolarizing phase of the RV action potential. We revealed a reduction in KCNK3 function prior to development of RVH and the rise of pulmonary vascular resistance. KCNK3 function is severely reduced in RV cardiomyocytes during the development of RVH in several rat models of PH (exposure to monocrotaline, chronic hypoxia, and Sugen/hypoxia) and chronic RV pressure overload (pulmonary artery banding). In experimental PH, we revealed a reduction in KCNK3 function before any rise in pulmonary vascular resistance and the development of RVH. KCNK3 mRNA level is also reduced in human RV tissues from PAH patients compared to non-PAH patients. In line with these findings, chronic inhibition of KCNK3 in rats with the specific inhibitor (A293) induces RV hypertrophy which is associated with the re-expression of foetal genes, RV fibrosis, RV inflammation, and subsequent loss of RV performance as assessed by echocardiography. Our data indicate that loss of KCNK3 function and expression is a hallmark of the RV hypertrophy/dysfunction associated with PH.

A rabbit model of progressive chronic right ventricular pressure overload.

Right ventricular (RV) failure from increased pressure loading is a frequent consequence of acquired and congenital heart diseases. However, the mechanisms involved in their pathophysiology are still unclear, and few data exist on RV pressure-loading models and early versus late effects on RV and left ventricular responses. We characterized a rabbit model of chronic RV pressure overload and early-late effects on biventricular function. Twenty-one New Zealand white rabbits were randomized into 3 groups: (i) sham, (ii) pulmonary artery (PA) banding (PAB) for 3 weeks (PAB3W) and (iii) PAB for 6 weeks (PAB6W). Progressive RV pressure overload was created by serial band inflation using an adjustable device. Molecular, echocardiographic and haemodynamic studies were performed. RV pressure overload was achieved with clinical manifestations of RV failure. Heart and liver weights were significantly higher after PAB. PAB-induced echocardiographic ventricular remodelling increased wall thickness and stress and ventricular dilation. Cardiac output (ml/min) (sham 172.4 ± 42.86 vs PAB3W 103.1 ± 23.14 vs PAB6W 144 ± 60.9, P = 0.0027) and systolic and diastolic functions decreased; with increased RV end-systolic and end-diastolic pressures (mmHg) (sham 1.6 ± 0.66 vs PAB3W 3.9 ± 1.8 vs PAB6W 5.2 ± 2.2, P = 0.0103), despite increased contractility [end-systolic pressure-volume relationship (mmHg/ml), sham 3.76 ± 1.76 vs PAB3W 12.21 ± 3.44 vs PAB6W 19.4 ± 6.88, P < 0.0001]. Functional parameters further worsened after PAB6W versus PAB3W. LV contractility increased in both the PAB groups, despite worsening of other invasive measures of systolic and diastolic functions. We describe a novel, unique model of chronic RV pressure overload leading to early biventricular dysfunction and fibrosis with further progression at 6 weeks. These findings can aid in guiding management.

Histologic and Hemodynamic Correlates of Right Ventricular Function in a Pressure Overload Model: a Study Using Three-Dimensional Speckle Tracking Echocardiography

The aim of our study was to assess the characterization of right ventricular (RV) deformation using three-dimensional (3D) speckle tracking echocardiography (STE) and association of 3D-STE indices with histologic and hemodynamic parameters in a chronic RV pressure overload animal model. Pulmonary artery banding (PAB) was used to induce RV pressure overload in seven beagles. 3D-STE, histologic and hemodynamic measurements were performed in PAB and sham-operated beagles 3 mo after PAB. RV longitudinal, radial and circumferential strain was measured from 3D-STE. Three mo after PAB, RV longitudinal strain was decreased; whereas radial and circumferential strain remained unchanged in PAB group. RV longitudinal strain was associated with interstitial fibrosis (r = −0.733) in the endocardial layer of the RV free wall. RV circumferential strain was related to dp/dtmax (r = 0.718). The significant correlations of RV 3D-STE indices with histologic and hemodynamic parameters indicate that 3D-STE may be a valuable tool for assessment of ventricular function in RV pressure overload.

Abstract 266: Phosphodiesterase 9A Deficiency Does Not Attenuate Chronic-hypoxic Pulmonary Hypertension

Background: Phosphodiesterase (PDE) inhibition is a cornerstone of therapy for pulmonary arterial hypertension. A novel role for PDE9A in natriuretic peptide-mediated left ventricular cyclic guanosine monophosphate (cGMP) signaling and remodeling has recently been described. Since cGMP-signaling can promote vaso-relaxation and prevent vascular smooth muscle cell proliferation and cardiac myocyte hypertrophy, we hypothesized that PDE9A deficiency would attenuate right ventricular (RV) and pulmonary vascular remodeling during chronic RV pressure overload. Methods: Chronic-hypoxic pulmonary hypertension (CH-PH) was induced in mice lacking PDE9A expression ( Pde9a -/- ) and wild-type littermates ( Pde9a +/+ ) by exposure to normobaric hypoxia (FiO2 = 10%) for 3 weeks. RV systolic pressures were measured to quantify PH, and RV hypertrophy was quantified as the ratio of RV free wall mass to LV/septal mass (RV/LV+S). Heart, lung, and serum were flash frozen for biochemical analyses. Results: In wild-type mice, exposure to chronic hypoxia resulted in significant increases in RV pressure (30 ± 2.4 vs. 20 ± 3.2 mm Hg; P = 0.0006) and RV hypertrophy (0.34 ± 0.04 vs. 0.25 ± 0.02; P &lt; 0.0001). Serum ANP levels were increased 5-fold with CH-PH ( P = &lt;0.0001), associated with a 72% reduction in lung Npr3 receptor expression (responsible for ANP clearance; P &lt; 0.0001) but no increase in RV Nppa expression. After 3 weeks of CH-PH, tissue levels of cGMP were not increased in lung (993 ± 502 pg/mg vs. 667 ± 210 pg/mg; P = 0.27) or RV (47 ± 18 pg/mg vs. 49 ± 13 pg/mg; P = 0.88) homogenates. Accordingly, serine-239 phosphorylation of vasodilatory-stimulated phosphoprotein (VASP; a surrogate for protein kinase G activation) was not increased by CH-PH in lung or RV. Expression of Pde9a RNA was not increased by CH-PH in lung or RV. Pde9a -/- mice did not have attenuated CH-PH induced increases in RVH ( P = 0.27, 2-way ANOVA) or RVSP ( P = 0.23, 2-way ANOVA) when compared to Pde9a +/+ mice. In both Pde9a -/- and Pde9a +/+ mice, CH-PH was associated with significant increases in lung PDE5A expression. Conclusions: In a murine model of chronic RV pressure overload, PDE9A deficiency does not attenuate RV remodeling or PH, despite robust increases in circulating natriuretic peptide levels.

Regional septal hinge-point injury contributes to adverse biventricular interactions in pulmonary hypertension.

Death and morbidity in pulmonary arterial hypertension (PAH) are often due to right ventricular (RV) failure and associated left ventricular (LV) dysfunction. We investigated regional myocardial remodeling and function as the basis for adverse ventricular‐ventricular interactions in experimental chronic RV pressure overload. Two distinct animal models were studied: A rabbit model of increased RV pressure‐load through progressive pulmonary artery banding A rat model of monocrotaline (MCT)‐induced pulmonary arterial hypertension (PAH). Regional myocardial function was assessed by speckle‐tracking strain echocardiography and ventricular pressures measured by catheterization before termination. Regional RV and LV myocardium was analyzed for collagen content, apoptosis and pro‐fibrotic signaling gene and protein expression. Although the RV developed more fibrosis than the LV; in both models the LV was substantially affected. In both ventricles, particularly the LV, fibrosis developed predominantly at the septal hinge‐point regions in association with decreased regional and global circumferential strain, reduced global RV and LV function and up‐regulation of regional transforming growth factor‐β1 (TGF β1) and apoptosis signaling. A group of PAH rats who received the TGF β blocker SB431542 showed improved RV function and reduced regional hinge‐point myocardial fibrosis. RV pressure‐loading and PAH lead to biventricular TGF β1 signaling, fibrosis and apoptosis, predominantly at the septal hinge‐point regions, in association with regional myocardial dysfunction. This suggests that altered geometry and wall stress lead to adverse RV‐LV interactions through the septal hinge‐points to induce LV fibrosis and dysfunction.

Systolic and diastolic unloading by mechanical support of the acute vs the chronic pressure overloaded right ventricle

Right ventricular (RV) mechanical support is well described in cases of sudden increase in RV afterload. In cases of chronic RV pressure overload (e.g., pulmonary arterial hypertension), it has rarely been described. The pulmonary artery was banded in 18 sheep. In the acute group (n = 9), we immediately implanted a Synergy Pocket Micro-Pump. Blood was withdrawn from the right atrium to the pulmonary artery. In the chronic group (n = 9), this pump was implanted 8 weeks after banding. Hemodynamics and pressure-volume loops were recorded before and 15 minutes after pump activation. Low-flow RV mechanical support significantly improved arterial blood pressure in both groups, but cardiac output only in the acute group. Intrinsic RV contractility was not affected. The RV contribution to the total right-sided cardiac output was 54% ± 8 in the acute group vs 10% ± 13 in the chronic group (p < 1.10-5), indicating a more profound unloading in the latter. Diastolic unloading (reflected by decreases in central venous pressure, end-diastolic pressure and volume, and ventricular capacitance) was successful in both groups. Decreases in pressure-volume area and RV peak pressure reflected successful systolic unloading only in the chronic group. Low-flow RV mechanical support improved arterial blood pressure in both conditions but caused a more profound unloading in the chronic group. Diastolic unloading was successful in both groups, but systolic unloading was successful only in the chronic group. The potential use of low-flow mechanical support for a chronic pressure overloaded right ventricle warrants further research to assess its long-term effects.

Right Ventricular Systolic Function Responses to Acute and Chronic Pulmonary Hypertension: Assessment with Myocardial Deformation

The distinction between right ventricular (RV) dysfunction due to an acute etiology (pulmonary embolism [PE]) or chronic afterload (pulmonary arterial hypertension [PAH]) has important therapeutic implications. The aim of this study was to test the hypothesis that RV remodeling would alter RV free wall strain (RVFWS) and differentiate chronic from acute RV afterload. In this retrospective study, patients with PE (n=45) who underwent echocardiography within 48hours of computed tomographic pulmonary angiography were matched 1:1 for age, gender, and pulmonary artery systolic pressure with patients with PAH (n=45) and a larger unmatched PAH control group (n=116). RV function was evaluated with end-diastolic area, fractional area change (FAC), and RVFWS by two-dimensional speckle-tracking. The ability of RVFWS to distinguish acute from chronic RV dysfunction was assessed using receiver operating characteristic curves, and its incremental value was sought with stepwise models. RV end-diastolic area, FAC, and RVFWS were significantly impaired in patients with PE (P<.001), with no significant differences in other clinical variables. In matched patients, receiver operating characteristic curve analysis revealed that RVFWS had significantly better discriminative power than the McConnell sign (P=.02), with a cutoff of -17.9%, sensitivity of 87.5%, specificity of 62.5%, and an area under the curve of 0.76. Sequential logistic regression demonstrated an incremental and independent benefit of using RVFWS to predict acute PE versus chronic PAH (P=.01). Observer concordance was superior for RVFWS compared with FAC (P<.01). RVFWS is more predictive than RV end-diastolic area and less variable than FAC in distinguishing acute from chronic RV pressure overload. RVFWS adds incremental and independent information to standard measures of RV function in assessing the acuity of pulmonary hypertension.

Structural and mechanical adaptations of right ventricle free wall myocardium to pressure overload.

Right ventricular (RV) failure in response to pulmonary hypertension (PH) is a severe disease that remains poorly understood. PH-induced pressure overload leads to changes in the RV free wall (RVFW) that eventually results in RV failure. While the development of computational models can benefit our understanding of the onset and progression of PH-induced pressure overload, detailed knowledge of the underlying structural and biomechanical events remains limited. The goal of the present study was to elucidate the structural and biomechanical adaptations of RV myocardium subjected to sustained pressure overload in a rat model. Hemodynamically confirmed severe chronic RV pressure overload was induced in Sprague-Dawley rats via pulmonary artery banding. Extensive tissue-level biaxial mechanical and histomorphological analyses were conducted to assess the remodeling response in the RV free wall. Simultaneous myofiber hypertrophy and longitudinal re-orientation of myo- and collagen fibers were observed, with both fiber types becoming more highly aligned. Transmural myo- and collagen fiber orientations were co-aligned in both the normal and diseased state. The overall tissue stiffness increased, with larger increases in longitudinal vs. circumferential stiffness. The latter was attributed to longitudinal fiber re-orientation, which increased the degree of anisotropy. Increased mechanical coupling between the two axes was attributed to the increased fiber alignment. Interestingly, estimated myofiber stiffness increased while the collagen fiber stiffness remained unchanged.The increased myofiber stiffness was consistent with clinical results showing titin-associated increased sarcomeric stiffening observed in PH patients. These results further our understanding of the underlying adaptive and maladaptive remodeling mechanisms and may lead to improved techniques for prognosis, diagnosis, and treatment for PH.

Abstract 18046: miR-21 is a Biomarker for Fibrosis and the Progression to Right Ventricular Systolic Failure in a Model of Pulmonary Volume and Pressure Overload

Introduction: Severe pulmonary insufficiency (PI) in combination with moderate pulmonary stenosis (PS) is a common long-term complication after repair of congenital heart diseases such as tetralogy of Fallot, causing progressive right ventricular (RV) dilation and failure. We characterize the physiologic and molecular characteristics of the first murine model of combined RV volume and pressure overload (PI/PS). Methods: Physiologic data was compared between sham controls and PI/PS at 1 and 3 mos. Histopathology and gene, microRNA (miR) and protein expression were assessed in the RV free wall. Plasma miR expression was assessed in children with severe PI/moderate PS vs controls (n=4). Results: Data are presented as sham vs. PI/PS at 1 and 3 mos (*p&lt;0.05). Mice developed diastolic heart failure at 1 mo progressing to systolic heart failure by 3 mos: restrictive RV filling (E/A ratio) (0.7±0.1 vs. 2.1±0.9 and 1.9±0.4*) and elevated RV end-diastolic pressure (2.7±0.3 vs. 7.8±2, and 8.5±2 mmHg*); followed by decreased RV outflow tract shortening (44±2 vs. 39±6 and 29±6%*) and exercise capacity (32±1.1 vs. 28±1.6 and 22±1.9 min*). RV fibrosis increased over time (0 vs. 4.0±2, 3.9±0.2%* sham vs 1 and 3 mos) along with pSMAD/total SMAD expression (0.2±0.1 vs. 0.4±0.1 and 0.6±0.1*), ANP expression (25±15 and 60±27* fold at 1 and 3 mos) and tissue miR-21 expression (2.7±0.3 and 2.9±0.6 fold). However, plasma miR-21 was upregulated with diastolic heart failure and switched to being downregulated with the development of systolic heart failure (2.6±1 and -1.8 ±0.2 fold). Finally, plasma miR-21 expression from children with severe PI/moderate PS at the time of pulmonary valve replacement was downregulated compared to controls (FC -3.6±1.2). Conclusion: We describe a novel murine model of chronic RV volume and pressure overload which recapitulates many aspects of the clinical disease. Gene and protein expression changes suggest enhanced miR-21 and TGF-β signaling as a mediator of RV fibrosis. miR-21 may serve as a novel biomarker of RV fibrosis, with a decline in expression heralding the need for valve replacement. This model provides investigators with a new tool for further evaluation of a form of RV failure unique to children with repaired congenital heart disease.

Abstract 18727: Right Ventricular Pressure Overload is More Important than Volume Overload in Producing Contralateral Ventricular Dysfunction: A Congenital Heart Disease Model

Intro: It is known that right ventricular (RV) contractile failure predisposes the left ventricle (LV) to failure. Animal models in an acute setting indicate this phenomenon is due predominantly to RV volume overload causing both changes in LV geometry and suboptimal LV filling. We investigated the relative importance of chronic RV pressure versus volume overload in producing LV dysfunction using d-transposition of the great vessels with an atrial switch (TGA, RV pressure overload) and repaired tetralogy of Fallot with severe pulmonary valve insufficiency (ToF, RV volume overload) as model systems. Methods: We performed a single center retrospective analysis of cardiac magnetic resonance imaging (MRI) data. All adult patients with TGA and ToF who had useful MRI data were screened. Included ToF patients had pulmonary insufficiency without residual pulmonary or infundibular stenosis. Included TGA patients had mild or less aortic or tricuspid regurgitation. We assessed MRI derived LV and RV volume measurements. Correlations were assessed using Pearson’s correlation coefficient. Differences between correlation coefficients were assessed using a Fischer r to z transformation. Results: 32 TGA and 46 ToF patients met enrollment criteria with 35 and 72 MRIs respectively having data adequate for analysis. The groups were similar in terms of sex (58 versus 51% male) and age (29.6 +/- 6.0 versus 31.0 +/- 9.7) respectively. Patients with TGA demonstrated a strong correlation between RV and LV systolic function based on ejection fraction (EF) r=0.75. They also demonstrated a strong correlation between RV end-diastolic volume indexed to body surface area (EDVi) and LV EF (r=-0.56). Although there was a trend toward increased RV EDVi in patients with ToF (119ml/m2 versus 101ml/m2 for TGA p=0.11), ToF patients had a weaker correlation between RV and LV EF (r=0.46; p=0.02 compared to TGA) and a very weak correlation between RV EDVi and LV EF (r=-0.21). Conclusions: The present data indicate that in the chronic setting, RV pressure rather than volume overload is of greater importance in producing LV dysfunction, implicating shared muscle fibers, neurohumoral milieu, or relative unloading of the LV as playing a greater role in this process.

Biventricular structural and functional responses to aortic constriction in a rabbit model of chronic right ventricular pressure overload

Chronic right ventricular (RV) pressure overload results in pathologic RV hypertrophy and diminished RV function. Although aortic constriction has been shown to improve systolic function in acute RV failure, its effect on RV responses to chronic pressure overload is unknown. Adjustable vascular banding devices were placed on the main pulmonary artery and descending aorta. In 5 animals (sham group), neither band was inflated. In 9 animals (PAB group), only the pulmonary arterial band was inflated, with adjustments on a weekly basis to generate systemic or suprasystemic RV pressure at 28 days. In 9 animals, both pulmonary arterial and aortic devices were inflated (PAB + AO group), the pulmonary arterial band as for the PAB group and the aortic band adjusted to increase proximal systolic blood pressure by approximately 20 mm Hg. Effects on the functional performance were assessed 5 weeks after surgery by conductance catheters, followed by histologic and molecular assessment. Contractile performance was significantly improved in the PAB + AO group versus the PAB group for both ventricles. Relative to sham-operated animals, both banding groups showed significant differences in myocardial histologic and molecular responses. Relative to the PAB group, the PAB + AO group showed significantly decreased RV cardiomyocyte diameter, decreased RV collagen content, and reduced RV expression of endothelin receptor type B, matrix metalloproteinase 9, and transforming growth factor β genes. Aortic constriction in an experimental model of chronic RV pressure overload not only resulted in improved biventricular systolic function but also improved myocardial remodeling. These data suggest that chronically increased left ventricular afterload leads to a more physiologically hypertrophic response in the pressure-overloaded RV.

Ventricular Geometry, Strain, and Rotational Mechanics in Pulmonary Hypertension

We tested the hypothesis that right ventricular (RV) pressure overload affects RV function and further influences left ventricular (LV) geometry, which adversely affects LV twist mechanics and segmental function. Echocardiographic images were prospectively acquired in 44 patients (age, 46+/-12 years; 82% women) with evidence of pulmonary hypertension (estimated pulmonary artery systolic pressure, 71+/-23 mm Hg) and in 44 age- and gender-matched healthy subjects. Patients with intrinsic LV diseases were excluded. RV lateral wall longitudinal strain (LS) and interventricular septal (IVS) LS were reduced in the pulmonary hypertension group compared with control subjects (-15.9+/-7.6% versus -25.5+/-6.1%, P<0.001; and -17.3+/-4.4% versus -20.2+/-3.9%, P=0.002, respectively), whereas LV lateral wall LS was preserved. RV lateral wall LS and IVS LS, but not LV lateral wall LS, correlated with pulmonary artery systolic pressure (r=0.56, P<0.01; r=0.32, P<0.01) and LV eccentricity index (r=0.57, P<0.01; r=0.57, P<0.01). IVS and LV lateral wall circumferential strain (CS) were both reduced in the pulmonary hypertension group. Although IVS CS and LV lateral wall CS correlated with pulmonary artery systolic pressure and LV eccentricity index, after adjustment of CS for LV eccentricity index, differences between groups persisted for IVS CS (P<0.01) but not LV lateral wall CS (P=0.09). LV torsion was decreased in patients with pulmonary hypertension compared with control subjects (9.6+/-4.9 degrees versus 14.7+/-4.9 degrees , P<0.001). LV torsion inversely correlated with pulmonary artery systolic pressure (r=-0.39, P<0.01) and LV eccentricity index (r=-0.3, P<0.01). LV untwisting rates were similar in both groups (P=0.7). Chronic RV pressure overload directly affects RV longitudinal systolic deformation. RV pressure overload further influences IVS and LV geometry, which impairs LV torsion and segmental LS and CS, more for the IVS than for the free wall of the LV.

Chronic Pulmonary Artery Pressure Elevation Is Insufficient to Explain Right Heart Failure

The most important determinant of longevity in pulmonary arterial hypertension is right ventricular (RV) function, but in contrast to experimental work elucidating the pathobiology of left ventricular failure, there is a paucity of data on the cellular and molecular mechanisms of RV failure. A mechanical animal model of chronic progressive RV pressure overload (pulmonary artery banding, not associated with structural alterations of the lung circulation) was compared with an established model of angioproliferative pulmonary hypertension associated with fatal RV failure. Isolated RV pressure overload induced RV hypertrophy without failure, whereas in the context of angioproliferative pulmonary hypertension, RV failure developed that was associated with myocardial apoptosis, fibrosis, a decreased RV capillary density, and a decreased vascular endothelial growth factor mRNA and protein expression despite increased nuclear stabilization of hypoxia-induced factor-1alpha. Induction of myocardial nuclear factor E2-related factor 2 and heme-oxygenase 1 with a dietary supplement (Protandim) prevented fibrosis and capillary loss and preserved RV function despite continuing pressure overload. These data brought into question the commonly held concept that RV failure associated with pulmonary hypertension is due strictly to the increased RV afterload.

Right Atrial and Ventricular Adaptation to Chronic Right Ventricular Pressure Overload

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. 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). 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.

Usefulness of magnetic resonance imaging dobutamine stress in asymptomatic and minimally symptomatic patients with decreased cardiac reserve from congenital heart disease (complete and corrected transposition of the great arteries and subpulmonic obstruction)

We explored the effect of dobutamine stress and its possible clinical implications in different groups of asymptomatic patients with chronic right ventricular (RV) pressure overload due to congenital heart disease. Forty-seven asymptomatic and minimally symptomatic patients with chronic RV pressure overload were studied: 24 patients with systemic right ventricles (16 surgically corrected transposition of the great arteries (TGA) (Mustard or Senning), 8 congenitally corrected TGA), 23 patients with chronic pressure overloaded subpulmonic right ventricles, and 11 age- and sex-matched healthy volunteers. Magnetic resonance imaging (MRI) was performed both at baseline and during dobutamine stress to determine RV volumes and ejection fraction. At baseline, RV ejection fraction in patients with surgically corrected TGA was significantly lower than in controls (58 ± 10% vs 70 ± 8%, p = 0.02). During dobutamine stress, RV ejection fraction increased significantly in controls and patient groups except for patients with pressure overloaded subpulmonic right ventricles. RV stroke volume increased in controls (21 ± 21%, p = 0.008); RV stroke volume remained unchanged in patients with congenitally corrected TGA and surgically corrected TGA (2 ± 17%, p = NS; −8 ± 29%, p = NS). A significant RV stroke volume decrease was observed in patients with subpulmonic right ventricles (−15 ± 16%, p = 0.0002). The changes in RV stroke volume were accompanied by a significant decrease in RV end-diastolic volume (−13 ± 14%, p = 0.001) in patients with subpulmonic right ventricles and in patients with surgically corrected TGA (−23 ± 16%, p = 0.0001). In controls and in patients with congenitally corrected TGA there was no change in RV end-diastolic volume (3 ± 15%, p = NS; −5 ± 11%, p = NS). There is a clear heterogeneity in response to MRI dobutamine stress between different groups of patients with chronic RV pressure overload. Our data suggest impaired filling in surgically corrected TGA and decreased contractility in patients with chronic pressure overloaded subpulmonic right ventricles. Dobutamine stress MRI may facilitate follow-up of RV (dys)function in patients with chronic RV pressure overload due to congenital heart disease.