Ventricular-pulmonary Arterial Coupling Research Articles

Non-invasive right ventriculo-arterial coupling as a rehospitalization predictor in dilated cardiomyopathy: A comparison of five different methods

Right ventricular (RV) pulmonary artery coupling (RVPAC) is a predictor of outcome in left-sided heart failure (HF). Several echocardiographic estimates for RVPAC have been proposed. This study aimed to compare multiple non-invasive methods to calculate RVPAC and to assess its prognostic role in patients with dilated cardiomyopathy (DCM). We prospectively enrolled 60 stable patients with DCM. RVPAC was estimated using five methods: as the tricuspid annular plane excursion/pulmonary artery systolic pressure (PASP) ratio; as the RV global longitudinal strain/PASP ratio; as the RV free wall strain (RVFW-LS)/PASP ratio; as the three-dimensional (3D) RV ejection fraction (RVEF)/PASP ratio; and as the 3D RV stroke volume (SV)/end-systolic volume (ESV) ratio. Patients were followed for a mean period of 18 (9) months for the endpoint of HF rehospitalizations. Twenty-nine patients (48%) reached the endpoint. All RVPAC estimates were more impaired in those patients reaching the endpoint (P <0.001 for all) and all predicted rehospitalizations in un-adjusted analysis. RVFW-LS/PASP and RVEF/PASP remained independent predictors of events, after adjustment for clinical and echocardiographic confounders. Using cut-offs obtained from receiver operating characteristic (ROC) analysis, we found that patients with RVFW-LS/PASP >-0.40 and patients with RVEF/PASP <1.30 had a higher risk of HF rehospitalization (log-rank P = 0.001 and P = 0.002, respectively). RVFW-LS/PASP and RVEF/PASP as non-invasive estimates of RVPAC are independent predictors of HF rehospitalization in patients with DCM.

Three-dimensional right ventriculo-arterial coupling as an independent determinant of severe heart failure symptoms in patients with dilated cardiomyopathy.

Right ventricular-pulmonary artery coupling (RVPAC) is a predictor of outcome in pulmonary hypertension. However, the role of this parameter in dilated cardiomyopathy (DCM) remains to be established. The aim of this study was to assess the contribution of RVPAC to the occurrence of severe heart failure (HF) symptoms in patients with DCM using three-dimensional (3D) echocardiography. We prospectively screened 139 outpatients with DCM, 105 of whom were enrolled and underwent 3D echocardiographic assessment. RVPAC was estimated non-invasively as the 3D right ventricular stroke volume (SV) to end-systolic volume (ESV) ratio. Severe HF symptoms were defined by New York Heart Association (NYHA) class III or IV. We evaluated differences in RVPAC across NYHA classes and the ability of RVPAC to predict severe symptoms. Mean left ventricular (LV) ejection fraction was 28±7%. Mean RVPAC was 0.77±0.30 and it was significantly more impaired with increasing symptom severity (p=0.001). RVPAC was the only independent determinant of severe HF symptoms, after adjusting for age, diuretic use, LV systolic function, LV diastolic function, and pulmonary artery systolic pressure (OR 0.035 [95% CI, 0.004-0.312], p=0.003). By receiver-operating characteristic analysis, the RVPAC cut-off value for predicting severely symptomatic status was 0.54 (area under the curve=0.712, p<0.001). 3D echocardiographic SV/ESV ratio is an independent correlate of severe HF symptoms in patients with DCM. 3D RVPAC might prove to be a useful risk stratification tool for these patients, should it be further validated in larger studies.

Abstract 10338: A Junctophilin-2-Mitofusin-2 Interaction Links T-Tubule Remodeling to Mitochondrial Dysfunction in Pulmonary Arterial Hypertension-Mediated Right Ventricular Failure

Introduction: Junctophilin-2 (JPH2) plays a crucial role in t-tubule structure/function and gene regulation in cardiomyocytes. In addition, JPH2 downregulation causes mitochondrial dysfunction and mitofusin-2 (MFN2) dysregulation, but the link between JPH2 and mitochondria is undetermined. Here, we investigated the hypothesis that a direct JPH2-MFN2 interaction is important for mitochondrial regulation and subsequent right ventricular (RV) function in pulmonary arterial hypertension (PAH). Methods and Results: Confocal microscopy revealed JPH2 and MFN2 colocalized at t-tubules in isolated cardiomyocytes. Immunoprecipitation demonstrated JPH2 and MFN2 interacted in RV extracts. Pulldown experiments showed JPH2 directly bound MFN2, and that the MFN2 binding domain was localized to the N-terminal third of JPH2. To probe the importance of the JPH2-MFN2 interaction for RV function, we compared the effects of treatment with AAV9-JPH2 to AAV9-GFP in monocrotaline-induced PAH. Consistent with its known role in t-tubule homeostasis, AAV9-JPH2 normalized RV t-tubule architecture. Interestingly, transmission electron microscopy showed AAV9-JPH2 corrected RV mitochondrial morphology. Immunoblots of RV extracts demonstrated AAV9-JPH2 increased JPH2 and MFN2 expression, which may underlie the restoration of mitochondrial morphology. At the organ level, AAV9-JPH2 reduced RV cardiomyocyte hypertrophy and RV fibrosis. AAV9-JPH2 increased tricuspid annular plane systolic excursion and RV free wall thickening as quantified by echocardiography. Pressure-volume loop analysis showed AAV9-JPH2 augmented RV ejection fraction and right ventricular-pulmonary arterial coupling and lowered RV end diastolic pressure and tau. Importantly, the improvements in RV systolic and diastolic function were independent of altering PAH severity as RV systolic pressure, effective arterial elastance, and pulmonary arterial small vessel remodeling were not altered with AAV9-JPH2. Conclusions: Disruption of the JPH2-MFN2 interaction may link altered t-tubule structure to mitochondrial dysfunction in the compromised RV. Strategies to increase JPH2 expression could have therapeutic value for RV failure.

Atrial fibrillation impairs dynamic right ventricular-pulmonary artery coupling and increases lung congestion during exercise in heart failure and preserved ejection fraction

Abstract Background Atrial fibrillation (AF) is common in patients with heart failure and preserved ejection fraction (HFpEF) and associated with left atrial (LA) myopathy, reduced exercise capacity and poor outcomes. However, the mechanisms underlying exercise intolerance in HFpEF with AF are not well-characterized. Purpose To test hypotheses that patients with HFpEF and AF (HFpEF-AF) would display greater acute impairments in right heart-pulmonary vascular coupling during exercise, leading to greater elevations in left and right heart filling pressures and increased lung congestion as compared to patients with HFpEF and no AF (HFpEF-no-AF) and control subjects free of heart failure and AF. As corollary hypotheses, we also posited that these changes would lead to greater ventricular interdependence during exercise in HFpEF-AF, and that pulmonary hypertension in HFpEF-AF was not simply ascribable to the LA dysfunction that accompanies AF, which would provide greater impetus to pursue restoration of sinus rhythm. Methods Subjects with HFpEF-AF (n=35), HFpEF-no-AF (n=85), and controls free of heart failure or AF (n=28) underwent cardiopulmonary exercise testing with invasive hemodynamic assessment and simultaneous echocardiography and lung ultrasound in a prospective study. Results As compared with controls and HFpEF-no-AF, subjects with HFpEF-AF displayed poorer left ventricular (LV) longitudinal strain, lower LA reservoir strain with greater LA volume at rest. With exercise, subjects with HFpEF-AF displayed more severe exercise-induced pulmonary hypertension, higher right atrial pressure (RAP) and more pronounced right ventricular-pulmonary vascular uncoupling. Peak oxygen consumption was lowest in patients with HFpEF-AF, coupled with greater limitations in cardiac output reserve and more severe increases in lung congestion and pulmonary vascular resistance (Figure 1). Dynamic ventricular interaction was greatest in HFpEF-AF, evidenced by greater increases in LV eccentricity index and RAP/PCWP (Figure 2) and less increase in LV transmural pressure compared with HFpEF-no-AF. In a sensitivity analysis, patients with HFpEF-AF displayed more severe pulmonary hypertension and pulmonary vascular disease compared to HFpEF-no-AF even after matching for the severity of LA remodeling and dysfunction. Conclusions Patients with AF and HFpEF display more severe abnormalities in pulmonary vascular reserve with exercise leading to greater lung congestion and enhanced exertional ventricular interdependence compared to patients with HFpEF-no-AF. While many of these differences appear attributable to LA dysfunction, the presence of AF is associated with more severe pulmonary vascular disease independent of LA myopathy, suggesting potential benefit from restoration of sinus rhythm even in the setting of LA myopathy. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): R01 HL128526

The Right Ventricular-Pulmonary Arterial Coupling and Diastolic Function Response to Therapy in Pulmonary Arterial Hypertension

Multiparametric risk assessment is used in pulmonary arterial hypertension (PAH) to target therapy. However, this strategy is imperfect because most patients remain at intermediate or high risk after initial treatment, with low risk being the goal. Metrics of right ventricular (RV) adaptation are promising tools that may help refine our therapeutic strategy. Does RV adaptation predict therapeutic response over time? We evaluated 52 incident treatment-naive patients with advanced PAH by catheterization and cardiac imaging longitudinally at baseline, follow-up 1 (∼3months), and follow-up 2 (∼18months). All patients received goal-directed therapy with parenteral treprostinil and/or combination therapy with treatment escalation if functional class I or II was not achieved. On the basis of their therapeutic response, patients were evaluated at follow-up 1 as nonresponders (died) or as responders, and again at follow-up 2 as super-responders (low risk) or partial responders (high/intermediate risk). Multiparametric risk was based on a simplified European Respiratory Society/European Society of Cardiology guideline score. RV adaptation was evaluated with the single-beat coupling ratio (Ees/Ea) and diastolic function with diastolic elastance (Eed). Data are expressed as mean ± SD or as OR (95%CI). Nine patients (17%) were nonresponders. PAH-directed therapy improved the European Respiratory Society low-risk score from 1 (2%) at baseline to 23 (55%) at follow-up 2. Ees/Ea at presentation was nonsignificantly higher in responders (0.9 ± 0.4) vsnonresponders (0.6 ± 0.4; P= .09) but could not be used to predict super-responder status at follow-up 2 (OR, 1.40 [95%CI, 0.28-7.0]; P= .84). Baseline RV ejection fraction and change in Eed were successfully used to predict super-responder status at follow-up 2 (OR, 1.15 [95%CI, 1.0-1.27]; P= .009 and OR, 0.29 [95%CI, 0.86-0.96]; P= .04, respectively). In patients with advanced PAH, RV-pulmonary arterial coupling could not discriminate irreversible RV failure (nonresponders) at presentation but showed a late trend to improvement by follow-up 2. Early change in Eed and baseline RV ejection fraction were the best predictors of therapeutic response.

Right Ventricular-Pulmonary Arterial Coupling in Patients With HF Secondary MR: Analysis From the COAPT Trial.

The aim of this study was to determine the prognostic impact of right ventricular (RV)-pulmonary arterial (PA) coupling in patients with heart failure (HF) with severe secondary mitral regurgitation (SMR) enrolled in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for HeartFailure Patients With Functional Mitral Regurgitation) trial. RV contractile function and PA pressures influence outcomes in patients with SMR, but the impact of RV-PA coupling in patients randomized to transcatheter edge-to-edge repair (TEER) vs guideline-directed medical therapy (GDMT) is unknown. RV-PA coupling was assessed by the ratio of RV free wall longitudinal strain derived from speckle-tracking echocardiography and noninvasively measured RV systolic pressure. Advanced RV-PA uncoupling was defined as RV free wall longitudinal strain/RV systolic pressure≤0.5%/mmHg. The primary endpoint was a composite of all-cause mortality or HF hospitalization at 24-month follow-up. A total of 372 patients underwent speckle-tracking echocardiography, and 70.2% had advanced RV-PA uncoupling. By multivariable analysis, advanced RV-PA uncoupling was strongly associated with an increased risk for the primary 24-month endpoint of death or HF hospitalization (HR: 1.87; 95% CI: 1.31-2.66; P=0.0005). A similar association was present for all-cause mortality alone (HR: 2.57; 95%CI: 1.54-4.29; P=0.0003). The impact of RV-PA uncoupling was consistent in patients randomized to TEER and GDMT alone. Compared with GDMT alone, the addition of TEER improved 2-year outcomes in patients with (48.0% vs 74.8%; HR: 0.51; 95%CI: 0.37-0.71) and those without (28.8% vs 47.8%; HR: 0.51; 95%CI: 0.27-0.97) advanced RV-PA uncoupling (Pinteraction=0.98). In the COAPT trial, advanced RV dysfunction assessed by RV-PA uncoupling was a powerful predictor of 2-year adverse outcomes in patients with HF and SMR. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for HeartFailure Patients With Functional Mitral Regurgitation [The COAPT Trial]; NCT01626079).

Reverse remodeling of tricuspid valve morphology and function in chronic thromboembolic pulmonary hypertension patients following pulmonary thromboendarterectomy: a cardiac magnetic resonance imaging and invasive hemodynamic study

BackgroundTo investigate changes in tricuspid annulus (TA) and tricuspid valve (TV) morphology among chronic thromboembolic pulmonary hypertension (CTEPH) patients before and 12 months after pulmonary thromboendarterectomy (PEA) and compare these findings to normal control subjects.Methods20 CTEPH patients and 20 controls were enrolled in the study. The patients were examined with echocardiography, right heart catherization and cardiac magnetic resonance imaging prior to PEA and 12 months after.ResultsRight atrium (RA) volume was significantly reduced from baseline to 12 months after PEA (30 ± 9 vs 23 ± 5 ml/m2, p < 0.005). TA annular area in systole remained unchanged (p = 0.11) and was comparable to controls. The leaflet area, tenting volume and tenting height in systole were significantly increased at baseline but decreased significantly with comparable values to controls after 12 months (p < 0.005). There was correlation between the changes of right ventricular-pulmonary artery coupling and changes of TV tenting height (r = − 0.54, p = 0.02), TV tenting volume (r = − 0.73, p < 0.001) and TV leaflet area (− 0.57, p = 0.01) from baseline to 12 months after PEA. Tricuspid regurgitation jet area/RA area was significantly (p < 0.01) reduced from baseline (30 ± 13%) to 12 months after PEA (9 ± 10%).ConclusionIn CTEPH patients selected for PEA, TV tenting height, volume and valve area are significantly increased whereas annulus size and shape are less affected. The alterations in TV morphology are fully reversed after PEA and correlates to improvements of right ventricular-pulmonary arterial coupling.

Right Ventricular-Pulmonary Arterial Coupling in Repaired Tetralogy of Fallot.

We assessed right ventricular (RV)-pulmonary arterial (PA) coupling in patients with repaired tetralogy of Fallot (TOF). Sixty patients (34 males) aged 18.6 ± 8.3years at 14.8 ± 7.4years after repair and 60 controls were studied. Two-dimensional, tissue Doppler and speckle tracking echocardiography and colour flow mapping were performed to assess RV end-systolic (ESA) and -diastolic areas, tricuspid valve Doppler and myocardial velocities, left ventricular (LV) and RV deformation and pulmonary (PR), tricuspid regurgitation (TR), respectively. The ratios of RV area change to ESA and peak tricuspid annular systolic (s) velocity to RV ESA indexed to body surface area reflected RV-PA coupling. Patients had greater RV areas and reduced tricuspid annular and myocardial velocities, LV and RV myocardial mechanics compared to controls (all p < 0.05). Both RV area change/ESA ratio and peak tricuspid annular s velocity/indexed RV ESA ratio were reduced in patients (all p < 0.001). Sixty-one and 100% of patients had, respectively, RV area change/ESA ratio and peak tricuspid annular s velocity/indexed RV ESA ratio < -2SD of controls. Indices of RV-PA coupling correlated positively with tricuspid myocardial velocities, LV and RV deformation and inversely with PR and TR (all p < 0.05). Multivariate analysis showed RV systolic strain rate, PR and TR as independent predictors of both RV-PA coupling indices, whilst age, gender and LV systolic strain were also predictors of peak tricuspid annular s velocity/indexed RV ESA ratio (all p < 0.05). In conclusion, RV-PA coupling is impaired and is associated with RV and LV mechanics and severity of PR and TR in patients with repaired TOF.

Association between lung ultrasound B-lines and exercise-induced pulmonary hypertension in patients with connective tissue disease.

Identification of elevation in pulmonary pressures during exercise may provide prognostic and therapeutic implications in patients with connective tissue disease (CTD). Interstitial lung disease (ILD) is common in CTD patients and subtle interstitial abnormalities detected by lung ultrasound could predict exercise-induced pulmonary hypertension (PH). Echocardiography and lung ultrasound were performed at rest and bicycle exercise in CTD patients (n=41) and control subjects without CTD (n=24). Ultrasound B-lines were quantified by scanning four intercostal spaces in the right hemithorax. We examined the association between total B-lines at rest and the development of exercise-induced PH during ergometry exercise. Compared to controls, the number of total B-lines at rest was higher in CTD patients (0 [0, 0] vs 2 [0, 9], P<.0001) and was correlated with radiological severity of ILD assessed by computed tomography (fibrosis score, r=.70, P<.0001). Pulmonary artery systolic pressure (PASP) was increased with ergometry exercise in CTD compared to controls (48 ± 14vs 35 ± 13mm Hg, P=.0006). The number of total B-lines at rest was highly correlated with higher PASP (r=.52, P<.0001) and poor right ventricular pulmonary artery coupling (tricuspid annular plane systolic excursion/PASP ratio, r=-.31, P=.01) during peak exercise. The number of resting B-lines predicted the development of exercise-induced PH with an area under the curve .79 (P=.0003). These data may suggest the value of a simple resting assessment of lung ultrasound as a potential tool for assessing the risk of exercise-induced PH in CTD patients.

Obesity, venous capacitance, and venous compliance in heart failure with preserved ejection fraction.

Circulating blood volume is functionally divided between the unstressed volume, which fills the vascular space, and stressed blood volume (SBV), which generates vascular wall tension and intravascular pressure. With decreases in venous capacitance, blood functionally shifts to the SBV, increasing central venous pressure and pulmonary venous pressures. Obesity is associated with both elevated venous pressure and heart failure with preserved ejection fraction (HFpEF). To explore the mechanisms underlying this association, we evaluated relationships between blood volume distribution, venous compliance, and body mass in patients with and without HFpEF. Subjects with HFpEF (n= 62) and non-cardiac dyspnoea (NCD) (n= 79) underwent invasive haemodynamic exercise testing with echocardiography. SBV was estimated (eSBV) from measured haemodynamic variables fit to a comprehensive cardiovascular model. Compared to NCD, patients with HFpEF displayed a leftward-shifted central venous pressure-dimension relationship, indicating reduced venous compliance. eSBV was 81% higher at rest and 69% higher during exercise in HFpEF than NCD (both P< 0.0001), indicating reduced venous capacitance. Despite greater augmented eSBV with exercise, the increase in cardiac output was reduced in HFpEF, suggesting operation on the plateau of the Starling curve. Exercise eSBV was directly correlated with higher body mass index (r=0.77, P< 0.0001) and inversely correlated with right ventricular-pulmonary arterial coupling (r=-0.57, all P< 0.0001). Patients with HFpEF display reductions in systemic venous compliance and increased eSBV related to reduced venous capacitance, abnormalities in right ventricular-pulmonary artery interaction, and increased body fat. These data provide new evidence supporting an important role of venous dysfunction in obesity-related HFpEF and suggest that therapies that improve venous function may hold promise to improve clinical status in this cohort.

Pulmonary Arterial Remodeling Is Related to the Risk Stratification and Right Ventricular-Pulmonary Arterial Coupling in Patients With Pulmonary Arterial Hypertension.

BackgroundPulmonary arterial (PA) stiffness has an essential contribution to the right ventricular (RV) failure pathogenesis. A comprehensive and multiparameter risk assessment allows predicting mortality and guiding treatment decisions in PA hypertension (PAH). We characterize PA remodeling with intravascular ultrasound (IVUS) in prevalent and stable patients with PAH according to the ESC/ERS risk table and analyze the RV-PA coupling consequences.MethodsTen control subjects and 20 prevalent PAH adult patients underwent right heart catheterization (RHC) with simultaneous IVUS study. We estimated cardiac index (CI), pulmonary vascular resistance, and compliance (PVR, PAC) by standard formulas. From IVUS and RHC data, PA diameter, wall thickness/luminal diameter ratio, and indexes of stiffness (pulsatility, compliance, distensibility, incremental elastic modulus - Einc-, and the stiffness index β) were measured. We evaluated RV-PA coupling by the ratio of tricuspid annular plane systolic excursion to systolic pulmonary arterial pressure (TAPSE/sPAP). The individual average risk was calculated by assigning a score of 1 (low-risk -LR-), 2 (intermediate-risk -IR-), and 3 (high-risk -HR-) for each of seven variables (functional class, six-minute walking test, brain natriuretic peptide, right atrial area and pressure, CI, and PA oxygen saturation) and rounding the average value to the nearest integer.ResultsAll PA segments interrogated showed increased vessel diameter, wall cross-sectional area (WCSA), and stiffness in patients with PAH compared to control subjects. 45% corresponded to LR, and 55% corresponded to IR PAH patients. The different measurements of PA stiffness showed significant correlations with TAPSE/sPAP (r = 0.6 to 0.76) in PAH patients. The IR group had higher PA stiffness and lower relative WCSA than LR patients (P < 0.05), and it is associated with a lower PAC and TAPSE/sPAP (P < 0.05).ConclusionIn prevalent PAH patients, the severity of proximal PA remodeling is related to the risk stratification and associated with PAC and RV-PA coupling impairment beyond the indirect effect of the mean PA pressure. The concomitant assessment of IVUS and hemodynamic parameters at diagnosis and follow-up of PAH patients could be a feasible and safe tool for risk stratification and treatment response of the PA vasculopathy during serial hemodynamic measurements.

Right Ventricular Pulmonary Artery Coupling and Mortality in Cardiac Intensive Care Unit Patients.

BackgroundImpaired right ventricular (RV) pulmonary artery coupling has been associated with higher mortality in patients with chronic heart disease, but few studies have examined this metric in critically ill patients. We sought to evaluate the association between RV pulmonary artery coupling, defined by the ratio of tricuspid annular peak systolic tissue Doppler velocity (TASV)/estimated RV systolic pressure (RVSP), and mortality in cardiac intensive care unit patients.Methods and ResultsUsing a database of unique cardiac intensive care unit admissions from 2007 to 2018, we included patients with TASV/RVSP ratio measured within 1 day of hospitalization. Hospital mortality was analyzed using multivariable logistic regression, and 1‐year mortality was analyzed using multivariable Cox proportional‐hazards analysis. We included 4259 patients with a mean age of 69±15 years (40.1% women). Admission diagnoses included acute coronary syndrome in 56%, heart failure in 52%, respiratory failure in 24%, and cardiogenic shock in 12%. The mean TASV/RVSP ratio was 0.31±0.14, and in‐hospital mortality occurred in 7% of patients. Higher TASV/RVSP ratio was associated with lower in‐hospital mortality (adjusted unit odds ratio, 0.68 per each 0.1‐unit higher ratio; 95% CI, 0.58–0.79; P<0.001) and lower 1‐year mortality among hospital survivors (adjusted unit hazard ratio, 0.83 per each 0.1‐unit higher ratio; 95% CI, 0.77–0.90; P<0.001). Stepwise decreases in hospital and 1‐year mortality were observed in each higher TASV/RVSP quintile. The TASV/RVSP ratio remained associated with mortality after adjusting for left ventricular systolic and diastolic function.ConclusionsA low TASV/RVSP ratio is associated with increased short‐term and long‐term mortality among cardiac intensive care unit patients, emphasizing importance of impaired RV pulmonary artery coupling as a determinant of poor prognosis. Further study is required to determine whether interventions to optimize RV pulmonary artery coupling can improve outcomes.

Synthesis of CT Imaging and Right Heart Catheterization Enables Single-Beat RV-PA Coupling Estimations in Heart Failure Patients

<h3>Purpose</h3> Right ventricular-pulmonary arterial (RV-PA) coupling has been shown to predict RV failure in PH patients. However, current clinical approaches require physiological assumptions which may be invalid in heart failure patients. We utilized functional CT and right heart catheterization (RHC) to construct single-beat pressure-volume (PV) loops, assess the impact of coupling assumptions, and compare impact on predicting patient outcomes. <h3>Methods</h3> Heart failure patients who underwent advanced therapy evaluation between since 9/2017 with ECG-gated contrast-enhanced CT scans and RHC within 14 days were enrolled. PV loops were generated via synchronizing CT-derived volume and RHC-derived pressure waveforms. A model using PV data and RV wall thickness was used to fit RV and PA elastance. We compared our approach to two clinical alternatives: volumetric approach, which estimates coupling as stroke volume / end-systolic volume (SV/ESV), and pressure adjusted approach, estimated as (SV * ESP) / (ESV * mPAP). The prognostic value of the coupling approaches was evaluated using a composite endpoint of heart transplant due to ventricular decompensation, VAD implantation with RV failure, or cardiac related death within 30 days. <h3>Results</h3> 22 patients met inclusion criteria and within 30 days, 7 had the composite endpoint (3 deaths, 2 RV failure post VAD, 2 transplants), and 15 did not (2 VAD with no RV failure, 13 no events). Compared to the single-beat PV-loop based approach, both the volumetric approach (75.2% reduction) and pressure-adjusted approach (45.6% reduction) underestimated coupling. PV-derived coupling was significantly (p<0.05) lower in patients with adverse outcomes (0.80±0.32) than in those free from adverse events (1.21±0.43), but volumetric and pressure-adjusted were not (p>0.05). <h3>Conclusion</h3> Functional CT and RHC can be used to derive single-beat measures of coupling and differentiate between patients with and without short-term adverse outcomes.

Intermittent outpatient administration of levosimendan improves right ventricular-pulmonary arterial coupling in ambulatory patients with advanced heart failure

Abstract Funding Acknowledgements Type of funding sources: None. Background Intermittent infusions of levosimendan in an outpatient setting have been associated with improved symptoms and reduced hospitalizations in patients with advanced heart failure (HF). Little is known on the potential effect of intermittent levosimendan infusions on right ventricle (RV)-pulmonary arterial (PA) coupling in ambulatory patients with advanced HF. Purpose Aim of the present study was to explore the effects of intermittent levosimendan infusions on the ratio between tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PAPs), an echocardiographic measure of RV/PA coupling, in ambulatory patients with advanced HF, and on left ventricular arterial coupling (VAC), expressed as the relationship between arterial elastance (Ea) and ventricular elastance (Ees). Methods 17 ambulatory patients with advanced HF treated with intermittent levosimendan (6-hour intravenous infusion, 0.2 ug/kg/min without bolus) received baseline clinical, biochemical and echocardiographic evaluation and changes in TAPSE/PAPs ratio were assessed from baseline to 48 hours after the infusion, based on the pharmacokinetic profile of levosimendan. VAC, expressed as Ea/Ees ratio, was obtained by a calculator (iElastance) designed for non-invasive single beat measure of end-systolic Ees and Ea according to Chen"s method. Results After 48 hours from levosimendan infusion, there was a significant improvement of TAPSE/PAPs ratio (p = 0.04), stroke voume (SV) (p = 0.05) and cardiac output (CO)(p = 0.04). We observed a significant reduction of Ea (p = 0.007) and of Ees (p = 0.01) and a non significant improvement of VAC (p = 0.4)(Tab.1). Conclusion. Our results show that an intermittent 6-hour levosimendan infusion at 0.2 ug/kg/min improves after 48 hours RV-PA coupling, SV, CO, Ea and Ees in ambulatory patients with advanced HF. Further studies including more patients are necessary to confirm these preliminary findings. Tab.1 Baseline 48h afterlevosimendan infusion p value NT-proBNP (pg/mL) 5607 ± 4300 3868 ± 3856 &amp;lt;0.001 LVEF (%) 24.1 ± 7.7 25.7 ± 7.3 0.5 SV (mL) 36.8 ± 12.4 46.1 ± 14.8 0.05 CO (L/min)36.8 ± 12.4 2.6 ± 0.7 3.2 ± 0.9 0.05 TAPSE/PAPs (mm/mmHg) 0.38 ± 0.13 0.49 ± 0.16 0.04 Ea (mmHg/mL/m2) 2.9 ± 0.9 2.1 ± 0.6 0.007 Ees (mmHg/mL/m2) 1.3 ± 0.4 1.0 ± 0.2 0.01 VAC 2.2 ± 0.6 2.0 ± 0.4 0.4

Tsantan Sumtang Restored Right Ventricular Function in Chronic Hypoxia-Induced Pulmonary Hypertension Rats.

Background: Tsantan Sumtang originated from Four Tantras, which consisted of Choerospondias axillaris (Roxb.) B. L. Burtt and A. W. Hill, Santalum album L., and Myristica fragrans Houtt. The three herbs are in ratio 1:1:1. This medication is widely used for cardiovascular diseases. Aims: The purpose of this study was to explore the effect of Tsantan Sumtang on right ventricular (RV) function in hypoxia-induced pulmonary hypertension (HPH) rats and investigate the underlying mechanism. Methods: Sixty male Sprague-Dawley (SD) rats were divided into control, hypoxia, and hypoxia + Tsantan Sumtang (1.0, 1.25, and 1.5 g•kg−1•d−1) groups. Chronic hypoxia was induced by putting the rats inside a hypobaric chamber for four weeks and adjusting the inner pressure and oxygen content to match an altitude of 4500 m. Echocardiography was used to assess RV function and right ventricular-pulmonary arterial (RV-PA) coupling. The physiological parameters of the animals were also evaluated. Morphological characteristics of RV were assessed by hematoxylin and eosin (H&E) staining and TEM. Masson’s trichrome staining, immunohistochemical staining, western blotting, and TUNEL assay were used to assess fibrosis and apoptosis levels. The antioxidant and anti-apoptosis properties of Tsantan Sumtang were also evaluated. The effect of Tsantan Sumtang on ROCK signaling pathway was evaluated using real-time quantitative PCR and western blotting. Results: We established an HPH rat model as indicated by the significant increases in the physiological parameters of the rats. Tsantan Sumtang showed a significant cardiac-protective function and an improved effect on RV-PA coupling. Moreover, Tsantan Sumtang treatment inhibited fibrosis and alleviated apoptosis and oxidative stress in RV. In terms of mechanism, Tsantan Sumtang reduced the expression of ROCK (ROCK1, ROCK2) in RV, inhibited cardiac remodeling-related transcription factors (NFATc3, P-STAT3), and regulated apoptosis-related proteins. Conclusion: Tsantan Sumtang was able to restore RV function, improve RV-PA coupling, recover hemodynamic and hematological indexes, and protect RV against structural maladaptive remodeling in the HPH rats. These findings demonstrated that Tsantan Sumtang protects the function of RV in HPH rats. The antioxidant and anti-apoptosis properties of Tsantan Sumtang may be responsible for inhibiting the ROCK signaling pathway.

Echocardiographic evaluation of pulmonary hypertension, right ventricular function, and right ventricular-pulmonary arterial coupling in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) patients are at increased risk for developing cardiovascular disease, including right heart failure. The evaluation of right ventricle (RV) using the relationship between tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic pressure (RVSP) is of clinical prognostic relevance. Mild echocardiographic pulmonary hypertension (ePH) has been associated with worse RV function. The aim of this study was to evaluate RV function as measured by TAPSE to RVSP ratio in rheumatoid arthritis patients compared to matched healthy controls. A case-control study with 67 RA patients aged 40 to 75 years that fulfilled the 2010 ACR/EULAR criteria and 45 matching controls was included. A transthoracic echocardiogram was performed to all patients. TAPSE was measured as the distance traveled from end-diastole to end-systole. RVSP was calculated using the modified Bernoulli equation. Comparisons were done using Chi-square and Mann-Whitney's U test or Student's t test. Patients with RA had significantly reduced ventricular function (TAPSE 23 [21-25] vs 25 [23-26], p = 0.033) and TAPSE/RVSP ratio was significantly lower in RA-patients than controls (TAPSE to RVSP ratio 0.809 [0.67-1.01] vs 0.933 [0.79-1.11], p = 0.009). RA-patients with mild ePH had similar RV function, evaluated by TAPSE, in comparison to RA-patients with normal RVSP. RA-patients had worse RV function measured by TAPSE and worse TAPSE/RVSP ratio than controls. Also, RA-patients with mild ePH had reduced right ventricular-pulmonary arterial coupling in comparison with patients with RA and normal RVSP. These echocardiographic findings could justify aggressive treatment for these patients and assess their evolution. Key Points • Right ventricular (RV) function and RV coupling with the pulmonary artery (RV-PA coupling) were worse in patients with RA in comparison to healthy controls. • Values of right ventricular systolic pressure (RVSP) were similar between RA-patients and non-RA controls. • Prevalence of normal RVSP, mild echocardiographic pulmonary hypertension (ePH), and pulmonary hypertension was similar between RA-patients and non-RA matched controls •Patients with RA and mild ePH had reduced RV-PA coupling in comparison with RA-patients with normal RVSP.

Non-invasive assessment of right ventriculo-arterial coupling in dilated cardiomyopathy – insights from 3D echocardiography

Abstract Background Right ventricular-pulmonary artery coupling (RVPAC) reflects the mechanical efficiency of the interaction between the right ventricle (RV) and the pulmonary circulation unit. Although it has been traditionally assessed with right heart catheterisation (RHC), modern imaging techniques enable the non-invasive estimation of the RVPAC, which proved to correlate well with measurements derived from RHC. Methods We used three-dimensional (3D) echocardiography to study 88 consecutive patients (60.4±13.4 years, 69 men) with dilated cardiomyopathy (DCM) and left ventricular ejection fraction&amp;lt;40% and we measured the RV volumes and RV ejection fraction (RVEF) using dedicated software. 15 healthy individuals served as controls. RVPAC was estimated non-invasively as the ratio between the RV end-systolic volume and stroke volume. Right-sided heart failure was defined as either elevated jugular venous pressure, pedal oedema or congestive hepatomegaly. Results Patients with DCM showed larger RV end-diastolic volume (163±60.9 ml vs. 91.3±13.2 ml; p&amp;lt;0.0001), as well as larger RV end-systolic volume (97.3±43.2 ml vs. 39.8±7.2 ml; p&amp;lt;0.0001) than healthy controls. The patients in the study group showed lower RVEF: 41.5±8.5% vs. 56.5±3.6% (p&amp;lt;0.0001). Non-invasive RVPAC was 1.53±0.60 in DCM patients vs. 0.78±0.11 in controls (p&amp;lt;0.0001). RVPAC had an excellent negative correlation with RVEF, both in DCM patients (r=−0.96, p&amp;lt;0.0001) and in controls (r=−0.99, p&amp;lt;0.0001). Patients with no signs of right-sided heart failure had lower RVPAC (1.38±0.45) than patients with at least one sign of right heart failure (1.90±0.72, p=0.03). Patients with mild symptoms of heart failure (NYHA classes 1 or 2) showed lower RVPAC (1.37±0.48) than DCM patients with severe heart failure (NYHA classes 3 or 4): 1.79±0.68 (p=0.003). Conclusions 3D echocardiography provides useful insights in the functional assessment of the cardiopulmonary unit. Non-invasive RVPAC is impaired in patients with DCM, and it is more impaired when signs of right-sided heart failure are present. Severe symptoms are associated with more pronounced decoupling of the RV and the pulmonary circulation. The prognostic significance of non-invasive RVPAC in a disease primarily involving the left ventricle remains to be clarified. Funding Acknowledgement Type of funding source: Other. Main funding source(s): This work was supported by CREDO Project - ID: 49182, financed through the SOP IEC -A2-0.2.2.1-2013-1 cofinanced by the ERDF

Right ventriculo-pulmonary arterial uncoupling and poor outcomes in pulmonary arterial hypertension.

Right ventricular function critically affects the prognosis of patients with pulmonary arterial hypertension. We aimed to analyze the prognostic value of right ventricular indices calculated using magnetic resonance imaging and right heart catheterization metrics in pulmonary arterial hypertension. We retrospectively collected data from 57 Japanese patients with pulmonary arterial hypertension and 18 controls and calculated six indices of right ventricular function: two indices of contractility (end-systolic elastance calculated with right ventricular maximum pressure and with magnetic resonance imaging metrics); two indices of right ventricular–pulmonary arterial coupling (end-systolic elastance/arterial elastance calculated with the pressure method (end-systolic elastance/arterial elastance (P)) and with the volume method (end-systolic elastance/arterial elastance (V)); and two indices of right ventricular diastolic function (stiffness (β) and end-diastolic elastance). We compared the indices between controls and patients with pulmonary arterial hypertension and examined their prognostic role. In patients with pulmonary arterial hypertension, end-systolic elastance (right ventricular maximum pressure) was higher (pulmonary arterial hypertension 0.94 (median) vs control 0.42 (mmHg/mL), p < 0.001), end-systolic elastance/arterial elastance (V) was lower (pulmonary arterial hypertension 0.72 vs control 1.69, p < 0.001), and β and end-diastolic elastance were significantly higher than those in the controls. According to the log-rank test, end-systolic elastance/arterial elastance (P) and end-diastolic elastance were significantly associated with the composite event rate. According to the multivariate Cox regression analysis, decreased end-systolic elastance/arterial elastance (P) was associated with a higher composite event rate (hazard ratio 11.510, 95% confidence interval: 1.954–67.808). In conclusion, an increased right ventricular contractility, diastolic dysfunction, and a trend of impaired right ventricular–pulmonary arterial coupling were observed in our pulmonary arterial hypertension cohort. According to the multivariate outcome analysis, a decreased end-systolic elastance/arterial elastance (P), suggestive of impaired right ventricular–pulmonary arterial coupling, best predicted the pulmonary arterial hypertension-related event.

Elevated pulmonary arterial elastance and right ventricular uncoupling are associated with greater mortality in advanced heart failure

The objectives of this study were to describe right ventricular-pulmonary arterial elastance coupling hemodynamic phenotypes and their frequency in patients with advanced heart failure and to evaluate the association of elastance-based indices with all-cause mortality, cardiac transplantation, and left ventricular assist device therapy. This study included 175 patients with heart failure undergoing right heart catheterization to evaluate candidacy for advanced therapies and 21 healthy controls. We modified a single-beat approach to elastance to account for the magnitude of pulmonary arterial pressure and estimated right ventricular end-systolic elastance (Ees), pulmonary arterial elastance (Ea), and the Ees:Ea ratio. We defined elevated pulmonary arterial load as an Ea > 0.5 mmHg/ml, and ventriculo-arterial uncoupling as an Ees:Ea < 0.8. We evaluated associations between Ees, Ea, and Ees:Ea with all-cause mortality and composite event-free survival using multivariable Cox proportional-hazard models, adjusted for age and sex. All 21 controls had Ea ≤ 0.5 mmHg/ml and Ees:Ea ≥ 0.8. Of 175 patients with heart failure, 63% had Ea > 0.5 mmHg/ml. Ees:Ea was lower in patients than in controls (p < 0.001), and 47% of the patients demonstrated Ees:Ea < 0.8, including 8% with normal Ea. In median follow-up of 2.2 (0.8-4.6) years, 53 died, 37 received cardiac transplantation, and 33 received a left ventricular assist device. By multivariable analysis, Ea (hazard ratios [HR]: 2.01, 95% CI 1.18-3.41) and Ees:Ea (HR: 0.46, 95% CI: 0.26-0.82) were independently associated with mortality, whereas Ees was not. Right ventricular-pulmonary vascular coupling is frequently impaired in heart failure and associated with greater mortality. Elevated pulmonary arterial elastance is associated with greater mortality even when coupling is preserved.

P1511 Comparison between echocardiographic right ventricular-pulmonary arterial coupling and right ventricular longitudinal strain to identify pulmonary hypertension in heart failure

Abstract Background Both the ratio between tricuspid annular plane systolic excursion (TAPSE) and doppler estimated systolic pulmonary artery pressure (SPAP) and right ventricular longitudinal strain (RVSL) have been proposed as sensitive measures of RV contractile function and demonstrate important prognostic implications in heart failure (HF). However, a comparison between measurements to discern pulmonary hypertension (PH) in heart failure has not been adequately explored. Methods Consecutive subjects undergoing right heart catheterization (RHC) and simultaneous echocardiography to evaluate HF were enrolled. Subjects with atrial fibrillation, recent acute coronary syndrome and poor diagnostic images were excluded. RV-PA coupling was assessed based on the ratio between invasively derived RV elastance and arterial elastance (Ees/Ea) and correlated with TAPSE/RVSP and speckle-tracking derived RVSL. ROC analysis was performed to identify PH, defined as invasive PA mean pressure ≥25mmHg. Results 99 subjects were analysed (age: 59 ± 14; 49% female). Both TAPSE/RVSP (r = 0.47; p &amp;lt; 0.001) and RVSL (r = 0.48; p &amp;lt; 0.001) demonstrated significant associations with invasive Ees/Ea. TAPSE/RVSP was significantly lower in PH when compared with non-PH subjects (0.42 ± 0.27 vs 0.65 ± 0.34mm/mmHg; p &amp;lt; 0.001) and demonstrated strong differentiating ability (AUC = 0.80) for PH. RVSL, however, did not significantly differ between groups (p &amp;gt; 0.05). Conclusions Both TAPSE/RVSP and RVSL demonstrate significant association with invasive measures of RV-PA coupling. The stronger ability of TAPSE/RVSP to distinguish PH as compared with RVSL may be attributed to the lower load-dependency of this measure.