Impaired Right Ventricular-Pulmonary Arterial Coupling and Effect of Sildenafil in Heart Failure With Preserved Ejection Fraction: An Ancillary Analysis From the Phosphodiesterase-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) Trial.
ABSTRACT: Right ventricular (RV) dysfunction (RVD) is a poor prognostic factor in heart failure with preserved ejection fraction (HFpEF). The physiological perturbations associated with RVD or RV function indexed to load (RV-pulmonary arterial [PA] coupling) in HFpEF have not been defined. HFpEF patients with marked impairment in RV-PA coupling may be uniquely sensitive to sildenafil.In a subset of HFpEF patients enrolled in the Phosphodiesteas-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial, physiological variables and therapeutic effect of sildenafil were examined relative to the severity of RVD (tricuspid annular plane systolic excursion [TAPSE]) and according to impairment in RV-PA coupling (TAPSE/pulmonary artery systolic pressure) ratio. The prevalence of atrial fibrillation and diuretic use, n-terminal probrain natriuretic peptide levels, renal dysfunction, neurohumoral activation, myocardial necrosis and fibrosis biomarkers, and the severity of diastolic dysfunction all increased with severity of RVD. Peak oxygen consumption decreased and ventilatory inefficiency (VE/VCO2 slope) increased with increasing severity of RVD. Many but not all physiological derangements were more closely associated with the TAPSE/pulmonary artery systolic pressure ratio. Compared with placebo, at 24 weeks, TAPSE decreased, and peak oxygen consumption and VE/CO2 slope were unchanged with sildenafil. There was no interaction between RV-PA coupling and treatment effect, and sildenafil did not improve TAPSE, peak oxygen consumption, or VE/VCO2 in patients with pulmonary hypertension and RVD.HFpEF patients with RVD and impaired RV-PA coupling have more advanced heart failure. In RELAX patients with RVD and impaired RV-PA coupling, sildenafil did not improve RV function, exercise capacity, or ventilatory efficiency.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867.
Project description:BACKGROUND:Right ventriculo-arterial coupling (RV-PA) can be estimated by echocardiography using the ratio between tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) and it has prognostic value in the general heart failure (HF) population. We aimed to study the clinical correlates and prognostic value of RV-PA in HF patients undergoing cardiac resynchronization therapy (CRT). METHODS:We retrospectively studied 70 HF patients undergoing CRT implantation. RESULTS:RV-PA coupling was estimated by TAPSE/PASP ratio using baseline echocardiography. Non-response to CRT was defined as improvement of left ventricular ejection fraction < 5% in a follow-up echo 6-12 months after CRT. Those with lower TAPSE/PASP ratios (worse RV-PA coupling) had higher NT-proBNP concentrations and increased E/e' ratio. TAPSE/PASP ratio and PASP, but not TAPSE, predicted nonresponse to CRT with TAPSE/PASP ratio showing the best discriminative ability with a sensitivity of 76% and specificity of 71%. Among these parameters, PASP independently predicted all-cause mortality. CONCLUSIONS:RV-PA coupling estimated by TAPSE/PASP ratio was associated with established prognostic markers in HF. It numerically outperformed PASP and TAPSE in predicting the response to CRT. Our data suggest that this simple and widely available echocardiographic parameter conveys significant pathophysiological and prognostic meaning in HF patients undergoing CRT.
Project description:Right ventricular dysfunction (RVD) parameters are increasingly important features in heart failure with preserved ejection fraction (HFpEF). We sought to evaluate the prognostic impact of a progressive RVD staging system by combining the tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (TAPSE/PASP) ratio with functional tricuspid regurgitation (TR) severity. We prospectively included 1355 consecutive HFpEF patients discharged for acute heart failure (HF). Of them, in 471 (34.7%) patients, PASP could not be accurately measured, leaving the final sample size to be 884 patients. Patients were categorized as Stage 1: TAPSE/PASP ? 0.36 without significant TR; stage 2: TAPSE/PASP ? 0.36 with significant TR; stage 3: TAPSE/PASP < 0.36 without significant TR; and stage 4: TAPSE/PASP < 0.36 with significant TR. By the 1 year follow-up, 207 (23.4%) patients had died. We found a significant and graded association between RVD stages and mortality rates (15.8%, 25%, 31.2%, and 45.4% from stage 1 to stage 4, respectively; log-rank test, p < 0.001). After multivariable adjustment, and compared to stage 1, stages 3 and 4 were independently associated with mortality risk (HR: 1.8219; 95% CI 1.308-2.538; p < 0.001 and HR = 2.2632; 95% CI 1.540-3.325; p < 0.001, respectively). A RVD staging system, integrating TAPSE/PASP and TR, provides a comprehensive and widely available tool for risk stratification in HFpEF.
Project description:BACKGROUND:We hypothesized that echocardiographic indices of right ventricular to pulmonary artery (RV-PA) coupling were comparable to cardiac magnetic resonance imaging (CMRI)-derived RV volumetric indices in predicting disease severity in chronic pulmonary regurgitation (PR). METHODS:Patients with ? moderate PR (2003-2015) with and without prior CMRI scans were enrolled into the study cohort and validation cohort, respectively. Endpoint was to determine the association between noninvasive RV-PA coupling indices (tricuspid annular plane systolic excursion/right ventricular systolic pressure [TAPSE/RVSP] and fractional area change [FAC]/RVSP ratio) and markers of disease severity, and compared this association to that of CMRI-derived RV volumetric indices and markers of disease severity (peak oxygen consumption [VO2 ], NT-proBNP and atrial and/or ventricular arrhythmias). RESULTS:Of the 256 patients in the study cohort (age 33 ± 6 years), 187 (73%) had tetralogy of Fallot (TOF) while 69 (27%) had valvular pulmonic stenosis (VPS). TAPSE/RVSP (r = 0.73, P < .001) and FAC/RVSP (r = 0.78, P < .001) correlated with peak VO2 . Among the CMRI-derived RV volumetric indices analyzed, only right ventricular end-systolic volume index correlated with peak VO2 (r = -0.54, P < .001) and NT-proBNP (r = 0.51, P < .001). These RV-PA coupling indices were tested in the validation cohort of 218 patients (age 37 ± 9 years). Similar to the study cohort, TAPSE/RVSP (r = 0.59, P < .001) and FAC/RVSP (r = 0.70, P < .001) correlated with peak VO2 . TAPSE/RVSP (but not FAC/RVSP) was also associated with arrhythmia occurrence in both the study cohort and validation cohorts. CONCLUSION:Noninvasive RV-PA coupling may provide complementary prognostic data in the management of chronic PR. Further studies are required to explore this clinical tool.
Project description:BACKGROUND:Tricuspid annular systolic excursion (TAPSE) or velocities (s') and right ventricular (RV) end-systolic dimensions are predictors of outcome in patients with pulmonary hypertension (PH). We explored the value of combining peak s' and RV end-systolic area index (RVESAi) as a surrogate of RV-pulmonary artery (RV-PA) coupling in a large animal of precapillary PH as well as clinically. METHOD:The first experimental group included four control and four piglets with thromboembolic disease. RV-PA coupling was assessed by ventricular to arterial elastance ratio (Ees/Ea) at baseline, after esmolol and dobutamine administration. Echocardiographic metrics included s', TAPSE, fractional area change (RVFAC), and RVESAi. The findings were validated in six piglets with severe PH. Clinical cohorts were stable outpatients (n = 141) and acutely decompensated pulmonary arterial hypertension (n = 48). RESULTS:In the first experimental group, the best linear correlates of Ees/Ea were s' (R2 = .51, p < .001) and RVESAi (R2 = .50, p < .001), while RVFAC (R2 = .17, p = .01) and TAPSE showed weaker association (R2 = .21, p = .39). The ratio s'/RVESAi showed nominally but not significantly (higher) association with Ees/Ea (R2 = .58, p < .01). The association between changes in s'/RVESAi and Ees/Ea was strong (R2 = .56, p < .001). In more severe PH, Ees/Ea and changes in Ees/Ea correlated significantly with s'/RVESAi and changes in s'/RVESAi (R2 = .69; p < .001 and R2 = .64, p < .001, respectively). In the two clinical cohorts, the s'/RVESAi did not emerge as a stronger predictor of outcome than RVESAi. CONCLUSION:RV s'/RVESAi index represents a reasonable bedside-usable surrogate of RV-PA coupling and of its acute variations in PH. Its incremental prognostic value over end-systolic dimension alone remains to be proven.
Project description:The prevalence and clinical significance of right ventricular (RV) systolic dysfunction (RVD) in patients with heart failure and preserved ejection fraction (HFpEF) are not well characterized.Consecutive, prospectively identified HFpEF (Framingham HF criteria, ejection fraction ?50%) patients (n=562) from Olmsted County, Minnesota, underwent echocardiography at HF diagnosis and follow-up for cause-specific mortality and HF hospitalization. RV function was categorized by tertiles of tricuspid annular plane systolic excursion and by semiquantitative (normal, mild RVD, or moderate to severe RVD) 2-dimensional assessment. Whether RVD was defined by semiquantitative assessment or tricuspid annular plane systolic excursion ?15 mm, HFpEF patients with RVD were more likely to have atrial fibrillation, pacemakers, and chronic diuretic therapy. At echocardiography, patients with RVD had slightly lower left ventricular ejection fraction, worse diastolic dysfunction, lower blood pressure and cardiac output, higher pulmonary artery systolic pressure, and more severe RV enlargement and tricuspid valve regurgitation. After adjustment for age, sex, pulmonary artery systolic pressure, and comorbidities, the presence of any RVD by semiquantitative assessment was associated with higher all-cause (hazard ratio=1.35; 95% confidence interval, 1.03-1.77; P=0.03) and cardiovascular (hazard ratio=1.85; 95% confidence interval, 1.20-2.80; P=0.006) mortality and higher first (hazard ratio=1.99; 95% confidence interval, 1.35-2.90; P=0.0006) and multiple (hazard ratio=1.81; 95% confidence interval, 1.18-2.78; P=0.007) HF hospitalization rates. RVD defined by tricuspid annular plane systolic excursion values showed similar but weaker associations with mortality and HF hospitalizations.In the community, RVD is common in HFpEF patients, is associated with clinical and echocardiographic evidence of more advanced HF, and is predictive of poorer outcomes.
Project description:OBJECTIVES:To evaluate the prognostic value of the ratio between tricuspid annular plane systolic excursion (TAPSE)-pulmonary artery systolic pressure (PASP) as a determinant of right ventricular to pulmonary artery (RV-PA) coupling in patients undergoing transcatheter aortic valve replacement (TAVI). BACKGROUND:RV function and pulmonary hypertension (PH) are both prognostically important in patients receiving TAVI. RV-PA coupling has been shown to be prognostic important in patients with heart failure but not previously evaluated in TAVI patients. METHODS:Consecutive patients with severe aortic stenosis who received TAVI from July 2011 through January 2016 and with comprehensive baseline echocardiogram were included. All individual echocardiographic images and Doppler data were independently reviewed and blinded to the clinical information and outcomes. Cox models quantified the effect of TAPSE/PASP quartiles on subsequent all-cause mortality while adjusting for confounders. RESULTS:A total of 457 patients were included with mean age of 82.8±7.2 years, left ventricular ejection fraction (LVEF) 54%±13%, PASP 44±17?mm Hg. TAPSE/PASP quartiles showed a dose-response relationship with survival. This remained significant (HR for lowest quartile vs highest quartile=2.21, 95%?CI 1.07 to 4.57, p=0.03) after adjusting for age, atrial fibrillation, LVEF, stroke volume index, Society of Thoracic Surgeons Predicted Risk of Mortality. CONCLUSION:Baseline TAPSE/PASP ratio is associated with all-cause mortality in TAVI patients as it evaluates RV systolic performance at a given degree of afterload. Incorporation of right-side unit into the risk stratification may improve optimal selection of patients for TAVI.
Project description:Background: Transcatheter mitral valve repair (TMVR) is an effective therapy for high-risk patients with severe mitral regurgitation (MR) but heart failure (HF) readmissions and death remain substantial on mid-term follow-up. Recently, right ventricular (RV) to pulmonary arterial (PA) coupling has emerged as a relevant prognostic predictor in HF. In this study, we aimed to assess the prognostic value of tricuspid annular plane systolic excursion (TAPSE) to PA systolic pressure (PASP) ratio as a non-invasive measure of RV-to-PA coupling in patients undergoing TMVR with MitraClip (Abbott, CA, USA). Methods: Multicentre registry including 228 consecutive patients that underwent successful TMVR with MitraClip. The sample was divided in two groups according to TAPSE/PASP median value: 0.35. The primary combined endpoint encompassed HF readmissions and all-cause mortality. Results: Mean age was 72.5 ± 11.5 years and 154 (67.5%) patients were male. HF readmissions and all-cause mortality were more frequent in patients with TAPSE/PASP ? 0.35: Log-Rank 8.844, p = 0.003. On Cox regression, TAPSE/PASP emerged as a prognostic predictor of the primary combined endpoint, together with STS-Score. TAPSE/PASP was a better prognostic predictor than either TAPSE or PASP separately. Conclusions: TAPSE/PASP ratio appears as a novel prognostic predictor in patients undergoing MitraClip implantation that might improve risk stratification and candidate selection.
Project description:BACKGROUND:An elevated serum level of interleukin-6 (IL-6) in pulmonary arterial hypertension (PAH) patients results in a greater symptom burden and increased mortality; however, the mechanisms underlying these observations remain unclear. Because both pre-clinical and clinical data associate elevated IL-6 levels with impaired cardiac function, we hypothesized that the adverse effects of IL-6 in PAH result, in part, from right ventricular (RV) dysfunction. METHODS:We analyzed the relationship between IL-6 and RV function in 40 patients with PAH identified in our institutional PAH registry. Serum IL-6 levels was quantified by enzyme-linked immunoassay. RESULTS:PAH patients had higher IL-6 levels than age- and gender-matched controls. Circulating IL-6 levels correlated inversely with echocardiography-based measures of RV function and RV-pulmonary artery (RV-PA) coupling. When dividing PAH patients by median IL-6 level, patients with higher IL-6 had significantly worse RV function (fractional area change [FAC] 23 ± 12% vs 38 ± 11%, tricuspid annular plane systolic excursion [TAPSE] 1.3 ± 0.3 cm vs 2.1 ± 0.5 cm), impaired RV-PA coupling (0.6 ± 0.5%/mm Hg vs 0.9 ± 0.5%/mm Hg), higher right atrial pressure (13 ± 7 mm Hg vs 9 ± 5 mm Hg), reduced cardiac index (2.0 ± 0.5 liters/min/m2 vs 2.8 ± 1.0 liters/min/m2) and lower stroke volume (48 ± 20 ml vs 70 ± 28 ml). In contrast, the relationships between IL-6 and mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and pulmonary arterial compliance (PAC) were not significant. Finally, IL-6 was independently associated with RV function and RV-PA coupling after adjusting for static (PVR) and pulsatile (PAC) after-load on the RV. CONCLUSIONS:Serum IL-6 levels are independently associated with RV function and RV-PA coupling in PAH. Patients with higher IL-6 levels have more severe RV dysfunction and diminished RV-PA coupling despite a comparable severity of pulmonary vascular disease.
Project description:BACKGROUND:The ratios of tricuspid annular plane systolic excursion (TAPSE)/echocardiographically measured systolic pulmonary artery pressure (PASP), fractional area change/invasively measured mean pulmonary artery pressure, right ventricular (RV) area change/end-systolic area, TAPSE/pulmonary artery acceleration time, and stroke volume/end-systolic area have been proposed as surrogates of RV-arterial coupling. The relationship of these surrogates with the gold standard measure of RV-arterial coupling (invasive pressure-volume loop-derived end-systolic/arterial elastance [Ees/Ea] ratio) and RV diastolic stiffness (end-diastolic elastance) in pulmonary hypertension remains incompletely understood. We evaluated the relationship of these surrogates with invasive pressure-volume loop-derived Ees/Ea and end-diastolic elastance in pulmonary hypertension. METHODS:We performed right heart echocardiography and cardiac magnetic resonance imaging 1 day before invasive measurement of pulmonary hemodynamics and single-beat RV pressure-volume loops in 52 patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. The relationships of the proposed surrogates with Ees/Ea and end-diastolic elastance were evaluated by Spearman correlation, multivariate logistic regression, and receiver operating characteristic analyses. Associations with prognosis were evaluated by Kaplan-Meier analysis. RESULTS:TAPSE/PASP, fractional area change/mean pulmonary artery pressure, RV area change/end-systolic area, and stroke volume/end-systolic area but not TAPSE/pulmonary artery acceleration time were correlated with Ees/Ea and end-diastolic elastance. Of the surrogates, only TAPSE/PASP emerged as an independent predictor of Ees/Ea (multivariate odds ratio: 18.6; 95% CI, 0.8-96.1; P=0.08). In receiver operating characteristic analysis, a TAPSE/PASP cutoff of 0.31 mm/mm?Hg (sensitivity: 87.5% and specificity: 75.9%) discriminated RV-arterial uncoupling (Ees/Ea <0.805). Patients with TAPSE/PASP <0.31 mm/mm?Hg had a significantly worse prognosis than those with higher TAPSE/PASP. CONCLUSIONS:Echocardiographically determined TAPSE/PASP is a straightforward noninvasive measure of RV-arterial coupling and is affected by RV diastolic stiffness in severe pulmonary hypertension. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT03403868.
Project description:PURPOSE:To evaluate the influence of riociguat on World Health Organization functional class (WHO FC), 6-min walk distance (6MWD), right heart remodeling, and right ventricular-pulmonary arterial (RV-PA) coupling in patients with idiopathic pulmonary arterial hypertension (IPAH) who are treatment-naïve or who have failed to achieve treatment goals with sildenafil therapy. METHODS:Twenty patients with IPAH were enrolled: 12 had not previously received PAH-targeted therapy (treatment-naïve subgroup) and 8 had been receiving sildenafil therapy but failed to achieve treatment goals; on entering this pilot study these 8 patients were switched from sildenafil to riociguat therapy (treatment-switch subgroup). Patients received riociguat individually dose-adjusted up to a maximum of 2.5 mg three times daily. After 12 weeks, patients were assessed for WHO FC, 6MWD, right heart remodeling, and RV-PA coupling. RESULTS:Riociguat significantly improved WHO FC in treatment-naïve patients (from 0/4/8/0 patients in WHO I/II/III/IV at baseline to 1/6/5/0 at week 12) and in treatment-switch patients (from 0/4/4/0 patients in WHO I/II/III/IV at baseline to 1/4/3/0 at week 12). Additionally, treatment-naïve and treatment-switch patients showed significant improvements at week 12 versus baseline in 6MWD (increases of +?76.8 m and +?71.6 m, respectively), RV systolic function, and RV-PA coupling. CONCLUSION:These results support the proven efficacy of riociguat in patients with IPAH, including treatment-naïve patients and those switching to riociguat following failure to achieve treatment goals with sildenafil, and suggest that it may be possible to delay disease progression in this patient group.