Right Ventricular Pressure Load Research Articles

Reversal of right ventricular pressure loading improves biventricular function independent of fibrosis in a rabbit model of pulmonary artery banding.

Right ventricular (RV) pressure loading leads to RV and left ventricular (LV) dysfunction through RV hypertrophy, dilatation and fibrosis. Relief of RV pressure load improves RV function. However, the impact and mechanisms on biventricular reverse-remodelling and function are only partially characterized. We evaluated the impact of RV pressure overload relief on biventricular remodelling and function in a rabbit model of reversible pulmonary artery banding (PAB). Rabbits were randomized to three groups: (1) Sham-operated controls (n=7); (2) PAB (NDef, n=7); (3) PAB followed by band deflation (Def, n=5). Sham and NDef animals were sacrificed at 6weeks after PAB surgery. Def animals underwent PAB deflation at 6weeks and sacrifice at 9weeks. Biventricular geometry, function, haemodynamics, hypertrophy and fibrosis were compared between groups using echocardiography, magnetic resonance imaging, high-fidelity pressure-tipped catheters and histology. RV pressure loading caused RV dilatation, systolic dysfunction, myocyte hypertrophy and LV compression which improved after PAB deflation. RV end-diastolic pressure (RVEDP) decreased after PAB deflation, although remaining elevated vs. Sham. LV end-diastolic pressure (LVEDP) was unchanged following PAB deflation. RV and LV collagen volumes in the NDef and Def group were increased vs. Sham, whereas RV and LV collagen volumes were similar between NDef and Def groups. RV myocyte hypertrophy (r=0.75, P<0.001) but not collagen volume was related to RVEDP. LV myocyte hypertrophy (r=0.58, P=0.016) and collagen volume (r=0.56, P=0.031) correlated with LVEDP. In conclusion, relief of RV pressure overload improves RV and LV geometry, hypertrophy and function independent of fibrosis. The long-term implications of persistent fibrosis and increased biventricular filling pressures, even after pressure load relief, need further study. KEY POINTS: Right ventricular (RV) pressure loading in a pulmonary artery banding rabbit model is associated with RV dilatation, left ventricular (LV) compression; biventricular myocyte hypertrophy, fibrosis and dysfunction. The mechanisms and impact of RV pressure load relief on biventricular remodelling and function has not been extensively studied. Relief of RV pressure overload improves biventricular geometry in conjunction with improved RV myocyte hypertrophy and function independent of reduced fibrosis. These findings raise questions as to the importance of fibrosis as a therapeutic target.

Female rats are less prone to clinical heart failure than male rats in a juvenile rat model of right ventricular pressure load.

Sex is increasingly emerging as determinant of right ventricular (RV) adaptation to abnormal loading conditions. It is unknown, however, whether sex-related differences already occur in childhood. Therefore, this study aimed to assess sex differences in a juvenile model of early RV pressure load by pulmonary artery banding (PAB) during transition from pre to postpuberty. Rat pups (n = 57, 3 wk old, 30-45 g) were subjected to PAB or sham surgery. Animals were euthanized either before or after puberty (4 and 8 wk postsurgery, respectively). Male PAB rats demonstrated failure to thrive already after 4 wk, whereas females did not. After 8 wk, female PAB rats showed less clinical symptoms of RV failure than male PAB rats. RV pressure-volume analysis demonstrated increased end-systolic elastance after 4 wk in females only, and a trend toward preserved end-diastolic elastance in female PAB rats compared with males (P = 0.055). Histology showed significantly less RV myocardial fibrosis in female compared with male PAB rats 8 wk after surgery. Myosin heavy chain 7-to-6 ratio switch and calcineurin signaling were less pronounced in female PAB rats compared with males. In this juvenile rat model of RV pressure load, female rats appeared to be less prone to clinical heart failure compared with males. This was driven by increased RV contractility before puberty, and better preservation of diastolic function with less RV myocardial fibrosis after puberty. These findings show that RV adaptation to increased loading differs between sexes already before the introduction of pubertal hormones.NEW & NOTEWORTHY In this study, we describe sex differences in our unique weanling rat model of increased RV pressure load by pulmonary artery banding. We are the first to assess temporal sex-related differences in RV adaptation during pubertal development. Female rats show superior RV function and less diastolic dysfunction and fibrosis compared with male rats. These differences are already present before puberty, indicating that the differences in RV adaptation are not only determined by sex hormones.

To treat or not to treat pulmonary arteries: epinephrine provocation to unmask right ventricular load

BackgroundPulmonary artery stenosis (PAS) is common in congenital heart disease (CHD). The indication for treatment of PAS is primarily based on invasively measured pressure gradients. Anesthetics used during cardiac catheterization cause systemic and pulmonary hypotension. We hypothesize that this leads to underestimation of right ventricular (RV) pressure load and under treatment of PAS. The aim of this study is to describe the use of epinephrine to unmask RV pressure load in patients with PAS. MethodsAll cardiac catheterizations in which epinephrine was administered to evaluate RV load were included. There was an indication for treatment in case of a right to left ventricular (RV:LV) pressure ratio >0.6. The indication for treatment before and after epinephrine was evaluated to determine its role in clinical decision making. ResultsA total of 74 procedures were included. In all procedures the invasively measured LV pressure was below the awake blood pressure. At baseline, 33 patients had a RV:LV ratio >0.6. In 41 patients the baseline RV:LV ratio was <0.6. After epinephrine bolus, the LV pressure was raised up to the awake blood pressure. In 19 of the 41 patients without baseline indication, this resulted in a RV:LV ratio >0.6 thereby revealing the indication for treatment. No epinephrine related complications were registered. ConclusionThe hypotensive properties of anesthetics during cardiac catheterization may lead to underestimation of RV pressure load. Invasive pressure measurements should be performed under conditions similar to awake conditions. Epinephrine provocation prevented under treatment in 25% of our patients.

Abstract 14033: Inhibition of the Prolyl Isomerase Pin1 Improves Endothelial Function and Attenuates Vascular Remodelling in Pulmonary Hypertension by Inhibiting TGF-β Signalling

Introduction: Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-β (TGF-β) / bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-β/BMP signalling, endothelial cell dysfunction and vascular remodelling in PAH is unknown. Methods and Results: Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-β signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-β signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Conclusions: Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH-MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-β/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.

Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-\u03b2 signalling

Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl-prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-β/BMP signalling, endothelial cell dysfunction, and vascular remodelling in PAH is unknown. Here, we report that Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-β signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-β signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-β/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.

Asymmetric Regional Work Contributes to Right Ventricular Fibrosis, Inefficiency, and Dysfunction in Pulmonary Hypertension versus Regurgitation

Right ventricular (RV) pressure loading from pulmonary hypertension (PH) and volume loading from pulmonary regurgitation (PR) lead to RV dysfunction, a critical determinant of clinical outcomes, but their impact on regional RV mechanics and fibrosis is poorly characterized. The aim of this study was to test the hypothesis that regional myocardial mechanics and efficiency in RV pressure and volume loading are associated with RV fibrosis and dysfunction. Eight PH, six PR, and five sham-control rats were studied. The PH rat model was induced using Sugen5416, a vascular endothelial growth factor receptor 2 inhibitor, combined with chronic hypoxia. PR rats were established by surgical laceration of the pulmonary valve leaflets. Six (n=4) or 9 (n=4) weeks after Sugen5416 and hypoxia and 12weeks after PR surgery, myocardial strain and RV pressure were measured and RV pressure-strain loops generated. We further studied RV regional mechanics in 11 patients with PH. Regional myocardial work was calculated as the pressure-strain loop area (mm Hg ∙ %). Regional myocardial work efficiency was quantified through wasted work (ratio of systolic lengthening to shortening work). The relation of regional myocardial work to RV fibrosis and dysfunction was analyzed. In rats, PH and PR induced similar RV dilatation, but fractional area change (%) was lower in PH than in PR. RV lateral wall work was asymmetrically higher in PH compared with sham, while septal work was similar to sham. In PR, lateral and septal work were symmetrically higher versus sham. Myocardial wasted work ratio was asymmetrically increased in the PH septum versus sham. Fibrosis in the RV lateral wall, but not septum, was higher in PH than PR. RV fibrosis burden was linearly related to regional work and to measures of RV systolic and diastolic function but not to wasted myocardial work ratio. Patients with PH demonstrated similar asymmetric and inefficient regional myocardial mechanics. Asymmetric RV work and increased wasted septal work in experimental PH are associated with RV fibrosis and dysfunction. Future investigation should examine whether assessment of asymmetric regional RV work and efficiency can predict clinical RV failure and influence patient management.

Abstract 13144: Epsilon Waves on Electrocardiograms in Pulmonary Hypertensive Patients With and Without Right Ventricular Hypertrophy or Fibrosis: Comparison With Arrhythmogenic Right Ventricular Cardiomyopathy

Introduction: Epsilon waves on V1-3 leads are one of the specific ECG findings in patients with arrhythmogenic right ventricular (RV) cardiomyopathy (ARVC) that suggest the presence of RV conduction delay. Hypothesis: In patients with pulmonary hypertension (PH) due to RV pressure load, RV hypertrophy and fibrosis are frequently observed that may lead to RV conduction delay and epsilon waves. Methods: We retrospectively analyzed 43 PH patients (33 females, 55 ± 15 years, 31 chronic thromboembolic PH, seven idiopathic pulmonary arterial hypertension), with proven PH by right heart catheterization. On CT, RV fibrosis was defined as a contrast defect in the early phase and a conversely abnormal enhancement in the late phase. We also retrospectively analyzed 17 patients (11 males, 57 ± 17 years) with suspected ARVC who underwent cardiac CT. Of these, nine met 2010 ARVC task force criteria on cardiac CT. Results: All 9 ARVC patients (100%) had epsilon waves on ECG. In PH patients, 32 and 9 patients had RV hypertrophy and fibrosis, respectively. Of these, 4 patients had both. Among 32 PH patients with RV hypertrophy, 2 had complete right bundle branch block (RBBB) and 8 had incomplete RBBB. Of 22 PH patients with RV hypertrophy but without any RBBB, two (9%, P &lt; 0.01, compared with ARVC) had waves with abnormal small upward spikes after the QRS wave. These were more marked in lead II and aVF leads than in V1 and 2 leads, and were not typical epsilon waves, suggesting RV conduction delay shown in ARVC. Fourteen patients had a negative T wave in V1-3 leads (5 had only a V1 lead, one had only V1 and 2 leads, four had only V1-3 leads, and four only had V1-4 leads, respectively). Of nine PH patients with RV hypertrophy, one had complete RBBB and one had incomplete RBBB. Of seven PH patients with RV fibrosis but without any RBBB, none (0%, P &lt; 0.01, compared with ARVC) had epsilon waves in V1-3 leads; all seven had a negative T wave in V1-3 leads (three only had a V1 lead, one had only V1 and 2 leads, two had only V1-3 leads, and one had V1-4 leads). Conclusions: In PH patients with an organized RV myocardial change, such as RV hypertrophy and/or fibrosis, the frequency of epsilon waves was significantly less than those in ARVC. Epsilon waves seem not only to be caused by an organized RV myocardium but also by other factors.

Abstract 13068: Epsilon and Inverted T Waves in Right Side Precordial Leads in Pulmonary Hypertensive Patients With or Without Right Ventricular Hypertrophy or Fibrosis on Cardiac Computed Tomography

Introduction: Epsilon and inverted T waves on V1-3 leads are known as specific ECG findings in patients with arrhythmogenic right ventricular (RV) cardiomyopathy (ARVC), which suggests the presence of RV conduction delay. Right bundle branch block (RBBB) is often observed in ARVC. In patients with pulmonary hypertension (PH) due to RV pressure load, the occurrence of RV hypertrophy and fibrosis are frequently observed, which may also lead to the occurrence of RV conduction delay and epsilon waves. Hypothesis: We hypothesized that there were epsilon and inverted T waves in right side precordial leads on ECG in PH patients with RV hypertrophy and/or RV fibrosis, both confirmed on cardiac CT. Methods: We retrospectively analyzed 43 patients (33 females, 55 ± 15 years, 31 chronic thromboembolic PH, 7 idiopathic pulmonary arterial hypertension) with proven PH by right heart catheterization. On CT, RV fibrosis was defined as a contrast defect in the early phase and a conversely abnormal enhancement in the late phase. Results: 32 and 9 patients had RV hypertrophy and RV fibrosis, respectively; of these, 4 had both. Of 32 PH patients with RV hypertrophy, 2 had complete RBBB and 8 had incomplete RBBB. Of 22 PH patients with RV hypertrophy but without any RBBB, only one (5%) had typical epsilon waves and 2 (9%) had waves with abnormal small upward spikes after the QRS wave that were more marked in II and aVF leads than V1 and 2 leads; these were not typical epsilon waves. 14 had a negative T wave in V1-3 leads (5 had only a V1 lead, one had only V1 and 2 leads, 4 had only V1-3 leads, and 4 had V1-4 leads, respectively). Of 9 PH patients with RV hypertrophy, one had complete RBBB and one had incomplete RBBB. Of 7 PH patients with RV fibrosis but without any RBBB, none (0%) had epsilon waves in V1-3 leads. All 7 had a negative T wave in V1-3 leads (3 had only a V1 lead, one had only V1 and 2 leads, 2 had only V1-3 leads, and one had V1-4 leads). Conclusions: In a total of 37 PH participants with an organized RV myocardial change, such as RV hypertrophy and fibrosis confirmed on cardiac CT, only one (3%) had typical epsilon waves that are frequently found in patients with ARVC. The mechanism of epsilon waves occurring predominantly in V1-3 leads seems not only to be caused by an organised RV myocardium, but also by other factors.

Pulmonary artery banding is a relevant model to study the right ventricular remodeling and dysfunction that occurs in pulmonary arterial hypertension.

Right ventricular (RV) dysfunction determines mortality in patients with pulmonary arterial hypertension (PAH) and RV pressure loading. Experimental models commonly use Sugen hypoxia (SuHx)-induced PAH, monocrotaline (MCT)-induced PAH, or pulmonary artery banding (PAB). Because PAH models cannot interrogate RV effects or therapies independent of pulmonary vascular effects, we aimed to compare RV function and fibrosis in experimental PAB vs. PAH. Thirty rats were randomized to either sham controls, PAB, SuHx-, or MCT-induced PAH. RV pressures and function were assessed by high-fidelity pressure-tipped catheters and by echocardiography. RV myocyte hypertrophy, fibrosis, and capillary density were quantified from hematoxylin-eosin, picrosirius red-stained, and CD31-immunostained RV sections, respectively. RV pressures and the RV-to-left ventricular pressure ratio were significantly increased in all three groups to a similar degree (PAB 65 ± 17 mmHg, SuHx 72 ± 16 mmHg, and MCT 70 ± 12 mmHg) vs. controls (23 ± 2 mmHg, all P < 0.01). RV dilatation, hypertrophy, and fibrosis were similarly increased, and capillary density decreased, in the three models (RV fibrosis; PAB 13.3 ± 3.6%, SuHx 9.8 ± 3.0% and MCT 10.9 ± 2.4% vs control 5.5 ± 1.1%, all P < 0.05). RV function was similarly decreased in all models vs. controls. We observed comparable RV dilatation, hypertrophy, systolic and diastolic dysfunction, fibrosis, and capillary rarefaction in rat models of PAB, SuHx-, and MCT-induced PAH. These results suggest that PAB, when sufficiently severe, induces features of maladaptive RV remodeling and can be used to investigate RV pathophysiology and therapy effects independent of pulmonary vascular resistance.NEW & NOTEWORTHY Although animal models of pulmonary arterial hypertension and pressure loading are important to study right ventricular (RV) pathophysiology, pulmonary arterial hypertension models cannot interrogate RV responses independent of pulmonary vascular effects. Comparing three commonly used rat models under similar elevated RV pressure, we found that all models resulted in comparable maladaptive RV remodeling and dysfunction. Thus, these findings suggest that the pulmonary artery banding model can be used to investigate mechanisms of RV dysfunction in RV pressure overload and the effect of potential therapies.

Quantification of Biventricular Function and Morphology by Cardiac Magnetic Resonance Imaging in Mice with Pulmonary Artery Banding.

Right ventricular (RV) function and failure are major determinants of outcome in acquired and congenital heart diseases, including pulmonary hypertension. Assessment of RV function and morphology is complex, partly due to the complex shape of the RV. Currently, cardiac magnetic resonance (CMR) imaging is the golden standard for noninvasive assessment of RV function and morphology. The current protocol describes CMR imaging in a mouse model of RV pressure load induced by pulmonary artery banding (PAB). PAB is performed by placing a 6-0 suture around the pulmonary artery over a 23 G needle. The PAB gradient is determined using echocardiography at 2 and 6 weeks. At 6 weeks, the right and left ventricular morphology and function is assessed by measuring both end-systolic and end-diastolic volumes and mass by ten to eleven cine slices 1 mm thick using a 9.4 T magnetic resonance imaging scanner equipped with a 1,500 mT/m gradient. Representative results show that PAB induces a significant increase in RV pressure load, with significant effects on biventricular morphology and RV function. It is also shown that at 6 weeks of RV pressure load, cardiac output is maintained. Presented here is a reproducible protocol for the quantification of biventricular morphology and function in a mouse model of RV pressure load and may serve as a method for experiments exploring determinants of RV remodeling and dysfunction.

Impact of the Right Ventricular Sokolow-Lyon Index in Children with Idiopathic Pulmonary Arterial Hypertension.

Right ventricular (RV) hypertrophy is regarded as the adaptation on chronic RV pressure load in pulmonary hypertension. As the RV Sokolow-Lyon index (RVSLI) is an electrocardiographic marker of RV hypertrophy, we hypothesized that RVSLI might be able to reflect RV pressure load. Therefore, the purpose of this study was to characterize the diagnostic impact of the RVSLI in children with idiopathic pulmonary arterial hypertension (IPAH) in order to assess disease severity and to evaluate its value for the prediction of worse outcome. Forty-two children (aged 3-17years) with IPAH were included in this retrospective study. The follow-up after baseline examination was 59 ± 17months. Receiver-operating characteristic (ROC) curves and Kaplan-Meier analysis were used to discriminate a cut-off value of RVSLI and to assess its predictive value regarding morbidity and mortality. In 12/42 patients (29%) severe cardiovascular events (defined as death, lung transplantation, or Potts shunt) were observed (time to event 20 ± 22months). Patients with an event showed higher RVSLI values (3.6 ± 1.2mV vs. 2.6 ± 1.6mV; p < 0.05). ROC analysis discriminated an RVSLI of 2.1 as the best cut-off value (area under the ROC curve: 0.79, sensitivity: 0.91, specificity: 0.70, p < 0.05) to detect patients with high-risk PAH (mPAP/mSAP ratio > 0.75). Relative risk for a severe event with an index > 2.1mV was 1.76 (95% CI 1.21-3.20). Relative risk for death with RVSLI > 2.1mV was 2.01 (95% CI 1.61-4.80). Our study demonstrates a strong relationship between RVSLI and disease severity in children with IPAH. An RVSLI > 2.1mV at the time of first diagnosis is a predictor for patients at risk for cardiac events. As an adjunct to the usual diagnostic assessment this parameter may therefore contribute to the initial prognostic estimation.

Association of Right Ventricular Pressure and Volume Overload with Non-Ischemic Septal Fibrosis on Cardiac Magnetic Resonance.

BackgroundNon-ischemic fibrosis (NIF) on cardiac magnetic resonance (CMR) has been linked to poor prognosis, but its association with adverse right ventricular (RV) remodeling is unknown. This study examined a broad cohort of patients with RV dysfunction, so as to identify relationships between NIF and RV remodeling indices, including RV pressure load, volume and wall stress.Methods and ResultsThe population comprised patients with RV dysfunction (EF<50%) undergoing CMR and transthoracic echo within a 14 day (5±3) interval. Cardiac structure, function, and NIF were assessed on CMR. Pulmonary artery systolic pressure (PASP) was measured on echo. 118 patients with RV dysfunction were studied, among whom 47% had NIF. Patients with NIF had lower RVEF (34±10 vs. 39±9%; p = 0.01) but similar LVEF (40±21 vs. 39±18%; p = 0.7) and LV volumes (p = NS). RV wall stress was higher with NIF (17±7 vs. 12±6 kPa; p<0.001) corresponding to increased RV end-systolic volume (143±79 vs. 110±36 ml; p = 0.006), myocardial mass (60±21 vs. 53±17 gm; p = 0.04), and PASP (52±18 vs. 41±18 mmHg; p = 0.001). NIF was associated with increased wall stress among subgroups with isolated RV (p = 0.005) and both RV and LV dysfunction (p = 0.003). In multivariable analysis, NIF was independently associated with RV volume (OR = 1.17 per 10 ml, [CI 1.04–1.32]; p = 0.01) and PASP (OR = 1.43 per 10 mmHg, [1.14–1.81]; p = 0.002) but not RV mass (OR = 0.91 per 10 gm, [0.69–1.20]; p = 0.5) [model χ2 = 21; p<0.001]. NIF prevalence was higher in relation to PA pressure and RV dilation and was > 6-fold more common in the highest, vs. the lowest, common tertile of PASP and RV size (p<0.001).ConclusionAmong wall stress components, NIF was independently associated with RV chamber dilation and afterload, supporting the concept that NIF is linked to adverse RV chamber remodeling.

Carvedilol improves biventricular fibrosis and function in experimental pulmonary hypertension.

Left ventricular (LV) function influences outcomes in right ventricular (RV) failure. Carvedilol reduces mortality in LV failure and improves RV function in experimental pulmonary arterial hypertension (PAH). However, its impact on ventricular-ventricular interactions and LV function in RV afterload is unknown. We investigated effects of carvedilol on biventricular fibrosis and function in a rat model of persistent PAH. Rats were randomized into three groups: Sham controls, PAH, and PAH + carvedilol. Severe PAH was induced by 60 mg/kg subcutaneous monocrotaline. In the treatment group, oral carvedilol (15 mg/kg/day) was started 2 weeks after monocrotaline injection and continued for 3 weeks until the terminal experiment. Echocardiography and exercise performance were performed at baseline and repeated at the terminal experiment with hemodynamic measurements. LV and RV myocardium were analyzed for hypertrophy, fibrosis, and molecular signaling by protein and mRNA analysis. PAH and PAH + carvedilol rats experienced severely elevated pulmonary arterial pressures and RV hypertrophy. Despite similar RV systolic pressures, carvedilol reduced biventricular collagen content (RV fibrosis area; 13.4 ± 6.5 vs. 5.5 ± 2.7 %, p < 0.001) and expression of transforming growth factor-β1 (TGFβ1) (RV TGFβ1/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) ratio; 1.16 ± 0.39 vs. 0.57 ± 0.22, p < 0.01) and connective tissue growth factor (CTGF) (RV CTGF/GAPDH ratio; 0.49 ± 0.06 vs. 0.35 ± 0.17, p < 0.05). RV pro-apoptotic caspase-8 was increased in PAH compared to controls and was significantly reduced in both ventricles compared to PAH animals by carvedilol. Tissue effects were accompanied by improved biventricular systolic and diastolic performance and exercise treadmill distance (36 ± 30 vs. 80 ± 33 m, p < 0.05). In RV pressure-load, carvedilol improves biventricular fibrosis and function through abrogation of TGFβ1-CTGF signaling. • RV afterload caused biventricular injury and dysfunction through TGFβ1-CTGF signaling. • Carvedilol reduced biventricular TGFβ1-CTGF signaling, fibrosis, and apoptosis. • Carvedilol improved cardiac output and biventricular function. • Improved fibrosis and hemodynamics occurred despite persistent RV afterload.

Right heart morphology in elevated pulmonary artery pressure: relationship between echocardiographic and right heart catheterization data

Background When elevated pulmonary artery pressure (PAP) is assessed by echocardiography, right heart morphology is always considered. The goal of this study was to evaluate how right heart geometry changes with increasing right ventricular pressure load.Subjects and methods Data from patients undergoing transthoracic echocardiography with subsequent right heart catheterization within a time period of 6 months were retrospectively analysed. First, Spearman-rho coeffi cients between mean PAP and right heart parameters were calculated. Second, the population was divided into tertiles according to mean PAP and Kruskal-Wallis variance analysis between variables was performed.Results Fifty-four patients (23 female, median age 77 years, IQ range 63-83) were selected. Mean PAP (median 27 mmHg, IQ range 24-36), right atrial (RA) dilatation (median 1, IQ range 0-2), tricuspid insuffi ciency (TI) severity (median 1.5, IQ range 0-2) and right ventricular (RV) dilatation (median O, IQ range 0) were included. Signifi cant correlations with mean PAP were found for RA dilatation (ρ= 0.380; P= 0.005) and TI severity (ρ= 0.294; P= 0.032). No correlation with RV dilatation could be shown (ρ= 0.241; P= 0.081). Across the tertiles [(1) mean PAP ≤ 25 mmHg; (2) mean PAP 26-30 mmHg; (3) mean PAP ≥ 31 mmHg)], variance analysis showed a signifi cant increase in RA dilatation (P = 0.009) and TI severity (P = 0.040). No change in RV dilatation across groups was observed (P = 0.216).Conclusions RA dilatation and TI severity signifi cantly increase with increasing RV pressure load. No increase in RV dilatation was observed in the studied population. Hence, absence of RV dilatation does not exclude the presence of elevated PAP.

Sildenafil treatment in established right ventricular dysfunction improves diastolic function and attenuates interstitial fibrosis independent from afterload.

Right ventricular (RV) function is an important determinant of prognosis in congenital heart diseases, pulmonary hypertension, and heart failure. Preventive sildenafil treatment has been shown to enhance systolic RV function and improve exercise capacity in a model of fixed RV pressure load. However, it is unknown whether sildenafil has beneficial effects when treatment is started in established RV dysfunction, which is clinically more relevant. Our aim was to assess the effects of sildenafil treatment on RV function and fibrosis in a model of established RV dysfunction due to fixed afterload. Rats were subjected to pulmonary artery banding (PAB), which induced RV dysfunction after 4 wk, characterized by reduced exercise capacity, decreased tricuspid annular plane systolic excursion, and RV dilatation. From week 4 onward, 50% of rats were treated with sildenafil (100 mg·kg(-1)·day(-1), n = 9; PAB-SIL group) or vehicle (n = 9; PAB-VEH group). At 8 wk, exercise capacity was assessed using cage wheels, and RV function was assessed using invasive RV pressure-volume measurements under anesthesia. Sildenafil treatment, compared with vehicle, improved RV ejection fraction (44 ± 2% vs. 34 ± 2%, P < 0.05, PAB-SIL vs. PAB-VEH groups), reduced RV end-diastolic pressure (2.3 ± 0.5 vs. 5.1 ± 0.9 mmHg, P < 0.05), and RV dilatation (end-systolic volume: 468 ± 45 vs. 643 ± 71 μl, P = 0.05). Sildenafil treatment also attenuated RV fibrosis (30 ± 6 vs. 17 ± 3‰, P < 0.05) but did not affect end-systolic elastance, exercise capacity, or PKG or PKA activity. In conclusion, sildenafil improves RV diastolic function and attenuates interstitial fibrosis in rats with established RV dysfunction, independent from afterload. These results indicate that sildenafil treatment has therapeutic potential for established RV dysfunction.

Load Dependency of Right Ventricular Performance Is a Major Factor to be Considered in Decision Making Before Ventricular Assist Device Implantation

Left ventricular assist devices (LVADs) provide better outcome than biventricular devices, but it is a challenge to predict the impact of LV mechanical unloading on postoperative right ventricular (RV) function preoperatively. We assessed the load dependency in RV performance before and after LVAD implantation aiming to improve preoperative decision making. Laboratory, echocardiography, and right heart catheterization data collected from 205 patients before LVAD implantation were tested for relationship with postoperative RV function. Comparing patients with different time-course of RV function after LVAD implantation, we found significant differences (P<0.01) in preoperative RV end-diastolic short-/long-axis and long-axis/length-area ratios, tricuspid annulus peak systolic velocity, RV peak longitudinal global systolic strain rate, systolic pressure gradient between RV and right atrium (ΔPRV-RA), tricuspid regurgitation velocity-time integral, and pulmonary arterial pressure between patients with and without postoperative RV failure. High predictive values for postoperative RV failure were found for end-diastolic short-/long-axis ratio ≥ 0.6, tricuspid annulus peak systolic velocity <8 cm/s, and peak systolic longitudinal strain rate <0.6/s in patients with maximum ΔPRV-RA <35 mm Hg. These parameters also seemed predictive for RV failure in patients with tricuspid regurgitation grade >2 and pulmonary arterial pressure <50 mm Hg. End-diastolic short-/long-axis ratio <0.6, tricuspid annulus peak systolic velocity ≥ 8 cm/s, and peak systolic longitudinal strain rate ≥ 0.6 in patients with maximum ΔPRV-RA ≥ 35 mm Hg showed high predictive values for postoperative freedom from RV failure. The RV load adaptation index seemed particularly predictive for RV function after LVAD implantation. RV geometry and velocity of contraction before LVAD implantation become more predictive for postoperative RV function and can improve decision making before VAD implantation if preoperative RV pressure load and tricuspid regurgitation are also considered.

Exercise Stress Echocardiographic Assessment of Outflow Tract and Ventricular Function in Patients With an Obstructed Right Ventricular-to-Pulmonary Artery Conduit After Repair of Conotruncal Heart Defects

This study assessed right ventricular (RV) and RV outflow tract (RVOT) function and pressure in response to exercise in patients with an obstructed RV-pulmonary artery (PA) conduit using exercise stress echocardiography (ESE) to evaluate these parameters. RV-PA conduits inevitably develop stenosis and/or regurgitation over time. Assessment of conduit obstruction only at rest may not reveal the extent of physiologic perturbation related to RV pressure loading. Patients with a stenotic RV-PA conduit who were being considered for transcatheter pulmonary valve placement were approached prospectively. ESE was performed and ventricular images were obtained at rest and at peak exercise. Forty patients (median age 17 years) were enrolled. Most patients had tetralogy of Fallot (63%) and were in New York Heart Association class II (59%). Exercise stress echocardiographic images were adequate in 38 patients (95%). With exercise there was a significant increase in maximum instantaneous RVOT gradient from rest (59 vs 96 mm Hg, p <0.001); exercise-induced change in RVOT gradient correlated with global RV strain at rest (r = -0.3, p = 0.05). Compared to measurements at rest there were significant increases in median peak longitudinal strain of the left ventricular free wall, interventricular septum, and global left ventricular strain at peak exercise. There were no significant changes in median RV strain at peak exercise (RV free wall -14.3 [-26, -8] at rest vs -15.2 [-27, -3] at peak exercise, p = 0.87; global RV strain -13.9 [-32, -9] vs -15.1 [-23, -6], p = 0.11). In conclusion, using ESE it was possible to evaluate abnormal ventricular function and conduit dysfunction at peak exercise in patients with an obstructed RV-PA conduit.

Transesophageal echocardiography and intraoperative phlebotomy during surgical repair of coarctation of aorta in a patient with atrial septal defect, moderately severe mitral regurgitation and severe pulmonary hypertension

Acute left ventricular (LV) or right ventricular (RV) dysfunction during repair of coarctation of aorta (CoA) is rare. Well-developed collateral circulation between branches of both the subclavian arteries (SCAs) and upper descending thoracic aorta decompress LV and prevents acute rise in afterload. An adult patient presented for CoA repair. On chest X-ray, rib notching was not seen. Magnetic Resonance Imaging showed about 7 mm long CoA distal to the origin of left common carotid artery. Reconstruction images of distal arch and descending thoracic aorta showed origin of both the SCAs from CoA segment. Transthoracic echocardiography showed 1.3 cm atrial septal defect (ASD), left to right shunt, moderately severe mitral regurgitation (MR), dilated RV, and severe pulmonary artery hypertension (PH). During cardiac catheterization, the peak gradient across CoA was 60 mmHg. On aortic-root angiography, both the common carotids and the distal arch opacified simultaneously, the CoA segment and the distal aorta opacified a little later. Both the SCAs were filling retrograde. A unique anatomy in which aortic-clamping proximal to CoA and both the SCAs would increase flow to spinal-cord as clamping of the SCAs will stop stealing of blood into the CoA but potentially increase LV afterload, MR, left to right shunt across ASD and RV volume and pressure load depending on the magnitude of flow across the CoA. The increases in LV afterload, MR, and RV afterload and volume overload were managed by controlled phlebotomy and fine-tuned by manipulating inhaled isoflurane concentration whereas the Transesophageal echocardiography (TEE) monitored and guided the management.

Impact of pressure load caused by right ventricular outflow tract obstruction on right ventricular volume overload in patients with repaired tetralogy of Fallot

In correction of tetralogy of Fallot (TOF), surgical strategies to minimize right ventricular outflow tract (RVOT) enlargement have recently been preferred. However, we may be confronted with residual pulmonary stenosis (PS) combined with pulmonary regurgitation (PR), and how the pressure load affects these patients is not evident. We compared 51 patients with PR and significant PS (PR with PS group) with 87 patients with PR without significant PS (PR group) using echocardiography and cardiac magnetic imaging. We evaluated the differences in parameters derived by magnetic resonance imaging between the 2 groups and the influence of the pressure load on right ventricular (RV) volume and function. Although the PR fraction was similar between the 2 groups, the PR with PS group showed significantly smaller RV end-diastolic volume (136.7 ± 26.5 mL/m(2) vs 151.2 ± 34.7 mL/m(2); P = .01), RV end-systolic volume (68.1 ± 23.7 mL/m(2) vs 80.2 ± 27.5 mL/m(2); P = .01), and slightly better RV ejection fraction (51.1% ± 9.8% vs 47.6% ± 8.9%; P = .03) than the PR group. For influence of the pressure load, PR fraction (r = -0.18, P = .03), RV end-diastolic volume (r = -0.25, P = .003), and RV end-systolic volume (r = -0.24, P = .005) were decreased as peak pressure gradient of PS was higher. Linear regression analysis revealed that both PR fraction and peak pressure gradient of PS were independent predictors for RV volume. Our study demonstrated that the RV pressure load prevented RV dilatation from chronic PR without systolic dysfunction. It is suggested that a proper relief of RVOT obstruction with acceptable residual stenosis is more advantageous than aggressive RVOT enlargement in the long-term outcome of repaired TOF.

The Left Ventricle Responds to Acute Graded Elevation of Right Ventricular Afterload by Augmentation of Twist Magnitude and Untwist Rate

The right and left ventricles share the interventricular septum, which mechanically transmits pressure gradients. The aim of this study was to investigate how acute mild or moderate right ventricular (RV) afterload affects left ventricular (LV) function. In 14 open-chest pigs (mean weight, 43 ± 4 kg) with preserved pericardium, acute mild (>35 and ≤50 mm Hg) and moderate (>50 and ≤60 mm Hg) RV pressure loading conditions were induced by constriction of the pulmonary artery. Hemodynamic parameters and LV twist and untwist were evaluated under each condition. From baseline to mild and moderate RV afterload, the mean RV systolic pressure increased from 31.0 ± 4.3 to 41.1 ± 2.7 and 52.7 ± 3.4 mm Hg (P < .001), while LV twist magnitudes increased from 15.4 ± 5.1° to 18.5 ± 3.1° and 19.8 ± 5.0° (P= .004), respectively. Absolute values of LV untwist rate increased from -116.9 ± 64.9°/sec to -160.0 ± 53.3°/sec and -169.1 ± 47.0°/sec, respectively (P= .001). After adjusting for all variables, only the ratio of the early and atrial components of mitral inflow and RV outflow tract acceleration time was significantly associated with the LV twist magnitude and LV untwist rate. In an acute setting, the left ventricle responds to suddenly elevated RV afterload and decreased RV stroke volume by promptly increasing its twist magnitude and untwist rate.