The combination of supervised and unsupervised learning based risk stratification and phenotyping in pulmonary arterial hypertension-a long-term retrospective multicenter trial.

BACKGROUND: Accurate risk stratification in pulmonary arterial hypertension (PAH), a devastating cardiopulmonary disease, is essential to guide successful therapy. Machine learning may improve risk management and harness clinical variability in PAH. METHODS: We conducted a long-term retrospective observational study (median follow-up: 67 months) including 183 PAH patients from three Austrian PAH expert centers. Clinical, cardiopulmonary function, laboratory, imaging, and hemodynamic parameters were assessed. Cox proportional hazard Elastic Net and partitioning around medoid clustering were applied to establish a multi-parameter PAH mortality risk signature and investigate PAH phenotypes. RESULTS: Seven parameters identified by Elastic Net modeling, namely age, six-minute walking distance, red blood cell distribution width, cardiac index, pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide and right atrial area, constituted a highly predictive mortality risk signature (training cohort: concordance index = 0.82 [95%CI: 0.75 - 0.89], test cohort: 0.77 [0.66 - 0.88]). The Elastic Net signature demonstrated superior prognostic accuracy as compared with five established risk scores. The signature factors defined two clusters of PAH patients with distinct risk profiles. The high-risk/poor prognosis cluster was characterized by advanced age at diagnosis, poor cardiac output, increased red cell distribution width, higher pulmonary vascular resistance, and a poor six-minute walking test performance. CONCLUSION: Supervised and unsupervised learning algorithms such as Elastic Net regression and medoid clustering are powerful tools for automated mortality risk prediction and clinical phenotyping in PAH.

Riociguat in pulmonary hypertension and heart failure with preserved ejection fraction: the haemoDYNAMIC trial.

AIMS: The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. This study investigated the efficacy of chronic treatment with the oral soluble guanylate cyclase stimulator riociguat in patients with PH-HFpEF. METHODS AND RESULTS: The phase IIb, randomized, double-blind, placebo-controlled, parallel-group, multicentre DYNAMIC trial assessed riociguat in PH-HFpEF. Patients were recruited at five hospitals across Austria and Germany. Key eligibility criteria were mean pulmonary artery pressure ≥25 mmHg, pulmonary arterial wedge pressure >15 mmHg, and left ventricular ejection fraction ≥50%. Patients were randomized to oral treatment with riociguat or placebo (1:1). Patients started at 0.5 mg three times daily (TID) and were up-titrated to 1.5 mg TID. The primary efficacy endpoint was change from baseline to week 26 in cardiac output (CO) at rest, measured by right heart catheterization. Primary efficacy analyses were performed on the full analysis set. Fifty-eight patients received riociguat and 56 patients placebo. After 26 weeks, CO increased by 0.37 ± 1.263 L/min in the riociguat group and decreased by -0.11 ± 0.921 L/min in the placebo group (least-squares mean difference: 0.54 L/min, 95% confidence interval 0.112, 0.971; P = 0.0142). Five patients dropped out due to riociguat-related adverse events but no riociguat-related serious adverse event or death occurred. CONCLUSION: The vasodilator riociguat improved haemodynamics in PH-HFpEF. Riociguat was safe in most patients but led to more dropouts as compared to placebo and did not change clinical symptoms within the study period.

[Pulmonary hypertension associated with left heart disease (group 2)]. / Pulmonale Hypertonie assoziiert mit Linksherzerkrankungen (Gruppe 2).

Pulmonary hypertension associated with left heart disease (PH-LHD) corresponds to group two of pulmonary hypertension according to clinical classification. Haemodynamically, this group includes isolated post-capillary pulmonary hypertension (IpcPH) and combined post- and pre-capillary pulmonary hypertension (CpcPH). PH-LHD is defined by an mPAP > 20 mmHg and a PAWP > 15 mmHg, pulmonary vascular resistance (PVR) with a cut-off value of 2 Wood Units (WU) is used to differentiate between IpcPH and CpcPH. A PVR greater than 5 WU indicates a dominant precapillary component. PH-LHD is the most common form of pulmonary hypertension, the leading cause being left heart failure with preserved (HFpEF) or reduced ejection fraction (HFmrEF, HFrEF), valvular heart disease and, less commonly, congenital heart disease. The presence of pulmonary hypertension is associated with increased symptom burden and poorer outcome across the spectrum of left heart disease. Differentiating between group 1 pulmonary hypertension with cardiac comorbidities and PH-LHD, especially due to HFpEF, is a particular challenge. Therapeutically, no general recommendation for the use of PDE5 inhibitors in HFpEF-associated CpcPH can be made at this time. There is currently no reliable rationale for the use of PAH drugs in IpcPH, nor is therapy with endothelin receptor antagonists or prostacyclin analogues recommended for all forms of PH-LHD.

Rapid Switch From Subcutaneous to Intravenous Treprostinil in Precapillary Pulmonary Hypertension by Pump Implantation.

ABSTRACT: Limited data are available on the transition from subcutaneous to intravenous prostacyclin in precapillary pulmonary hypertension. We performed a retrospective analysis of all patients who were switched from subcutaneous to intravenous treprostinil with an implantable infusion pump. We included 85 consecutive, clinically stable patients (mean age 66 years and range 16-85), who had been treated with subcutaneous treprostinil for mean 9 months (range 1-78) before pump implantation. An interdisciplinary expert panel defined standards for this procedure before the first implantation. As the first patient experienced a significant hypotensive episode indicating treprostinil overdose postoperatively, the time span to stop subcutaneous treprostinil was reduced to 60 minutes for all following patients. No events associated with the switch from subcutaneous to intravenous treprostinil were observed during postoperative hospital stay in 84 (98.8%) patients. Taking into account a likely depot effect of subcutaneous treprostinil patients can safely be switched to the intravenous route by the implantation of an infusion pump.

Regression of left atrial diameter after kidney transplantation is associated with prolonged survival: an observational study.

Renal transplantation reduces the dramatically elevated risk of cardiovascular death in dialysis patients. We previously showed that left atrial diameter before transplantation predicts cardiovascular and overall mortality. Now, we investigated the association of changes in cardiac morphology after transplantation and mortality. We retrospectively analyzed data from the Austrian transplant repository using multivariable Cox and competing risk models and multivariable logistic regression for the prediction of changes in cardiac morphology. We identified 414 patients with a median follow-up of 8 years and observed a significant progression of mean diameter of left atrium (LA), right atrium and right ventricle and a significant regression of left ventricle. Complete case analysis of 243 patients with a regression of initially enlarged LA diameter had a significantly lower risk of adjusted overall and cardiovascular mortality; hazard ratio (HR 0.45, 95% CI 0.30-0.69, P < 0.001, 124 deaths), and HR of 0.43 [95% CI 0.21-0.92, P = 0.029, 48 cardiovascular (CV) deaths], respectively. Only age at transplantation was significantly associated with regression of LA (OR 0.75, 95% CI 0.60-0.93, P = 0.007). Patients with regression of LA after kidney transplantation exhibited a lower overall and CV mortality risk. Besides age, peritoneal dialysis and antihypertensive therapy were mediators of LA regression.

Intravenous Treprostinil in Severe Inoperable Chronic Thromboembolic Pulmonary Hypertension Using Implantable Pumps-Single-Center Experience over More Than a Decade.

The management of chronic thromboembolic pulmonary hypertension has significantly changed over the last decade with the availability of both specific therapies and interventional treatments. In parallel, implantable pumps for intravenous administration of treprostinil have broadened the spectrum of continuous prostanoid infusion. We evaluated the course of 17 consecutive patients with inoperable chronic thromboembolic pulmonary hypertension treated with treprostinil by means of an implantable infusion pump between 2011 and 2023 at our center. Complications associated with the infusion system were rare, leading to 0.4 unplanned surgical interventions during 17,160 patient days. No additional safety signals were detected, and clinical benefits achieved with subcutaneous treprostinil before pump implantation could be maintained in all patients. No catheter-related infections or thromboembolic events were observed. Implantable infusion pumps offer an attractive alternative to subcutaneous treprostinil for patients intolerant to the subcutaneous route, including those with chronic thromboembolic pulmonary hypertension.

The risk profile change in patients with severe chronic thromboembolic pulmonary hypertension treated with subcutaneous treprostinil.

Chronic thromboembolic pulmonary hypertension (CTEPH) is successfully treatable with pulmonary endarterectomy (PEA), balloon pulmonary angioplasty, and medical therapy. Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management risk score (RRS) is able to predict long-term outcome in inoperable patients or in patients with residual PH after surgery. We performed a post hoc analysis of RRS in patients who were enrolled in the CTREPH study (NCT01416636), a randomized, double-blind clinical trial comparing high-dose and low-dose subcutaneous (SC) treprostinil in patients with severe CTEPH that was classified by an interdisciplinary CTEPH team as nonoperable, or as persistent or recurrent pulmonary hypertension after PEA. Baseline mean RRS was similar in both treatment groups (8.7 in high-dose arm vs. 8.6 in low-dose arm), but mean RRS change from baseline to Week 24 was greater in the high-dose treprostinil group than in the low-dose treprostinil group (-0.88 vs. -0.17). The difference in RRS change from baseline to Week 24 between high dose versus low dose was statistically significant with mean difference of -0.70 (95% confidence interval: -1.36 to -0.05, p = 0.0352), and was driven mainly by improvement of World Health Organization functional class and N-terminal pro-brain natriuretic peptide concentration. SC treprostinil therapy administered in standard dose had positive effect on the risk profile measured by RRS in patients with inoperable or persistent/recurrent severe CTEPH. Although our study was limited by the small sample size and post hoc nature, assessment of risk profile is of great importance to this particular patient population with very poor prognosis.

Assessment of right ventricular function using echocardiographic speckle tracking of the tricuspid annular motion: comparison with cardiac magnetic resonance.

BACKGROUND: Assessment of right ventricular (RV) function is difficult due to the complex shape of this chamber. Tricuspid annular plane systolic excursion (TAPSE) measured with M-mode echocardiography is frequently used as an index of RV function. However, its accuracy may be limited by ultrasound beam misalignment. We hypothesized that two-dimensional (2D) speckle tracking echocardiography (STE) could provide more accurate estimates of RV function. Accordingly, STE was used to quantify tricuspid annular displacement (TAD), from which RV longitudinal shortening fraction (LSF) was calculated. These STE derived indices were compared side-by-side with M-mode TAPSE measurements against cardiac magnetic resonance (CMR) derived RV ejection fraction (EF). METHODS: Echocardiography (Philips iE33, four-chamber view) and CMR (Siemens, 1.5 T) were performed on the same day in 63 patients with a wide range of RV EF (23-70% by CMR). TAPSE was measured using M-mode echocardiography. TAD and RV LSF were obtained using STE analysis (QLAB CMQ, Philips). TAPSE, TAD and RV LSF values were compared with RV EF obtained from CMR short axis stacks. RESULTS: STE analysis required <15 seconds and was able to track tricuspid annular motion in all patients as verified visually. Correlation between RV EF and TAD (0.61 free-wall, 0.65 septal) was similar to that with M-mode TAPSE (0.63). However, STE-derived RV LSF showed a higher correlation with CMR EF (r = 0.78). CONCLUSION: RV LSF measurement by STE is fast and easy to obtain and provides more accurate evaluation of RV EF than the traditional M-mode TAPSE technique, when compared to CMR reference. (Echocardiography 2012;29:19-24).

Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry.

OBJECTIVE: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. METHODS: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3-6 months) and collated via case report forms. RESULTS: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years. CONCLUSION: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH.

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry.

OBJECTIVE: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. METHODS: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. RESULTS: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2]). CONCLUSION: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified.

Quantification of left ventricular volumes using three-dimensional echocardiographic speckle tracking: comparison with MRI.

AIMS: Although the utility of two-dimensional (2D) speckle tracking echocardiography (STE) to quantify left ventricular (LV) volume has been demonstrated, this methodology is limited by foreshortened views, geometric modelling, and the assumption that speckles can be tracked from frame to frame, despite their out of plane motion. To circumvent these limitations, a three-dimensional (3D) speckle tracking algorithm was recently developed. Our goal was to evaluate the accuracy of the new 3D-STE side by side with 2D-STE using cardiac magnetic resonance (CMR) as a reference. METHODS AND RESULTS: Apical two- and four-chamber views (A2C and A4C) and real-time 3D datasets (Toshiba Artida 4D System) obtained in 43 patients with a wide range of LV size and function were analysed to measure LV end-systolic and end-diastolic volumes (ESV and EDV) using 2D and 3D-STE techniques. Short-axis CMR images (Siemens 1.5T scanner) acquired on the same day were analysed to obtain ESV and EDV reference values using the method of disks approximation. Reproducibility of both STE techniques was assessed using repeated measurements. While 2D-STE correlated well with CMR (r: 0.72-0.88), it underestimated LV volumes with relatively large biases (10-30 mL) and wide limits of agreement (SD: 36-51 mL), with A2C-derived measurements being worse than A4C values. The 3D-STE measurements showed higher correlation with CMR (0.87-0.92), and importantly smaller biases (1-16 mL) and narrower limits of agreement (SD: 28-37 mL). In addition, 3D-STE showed lower inter- and intra-observer variability (11-14% and 12-13%), than 2D-STE (16-17% and 12-16%, respectively). CONCLUSION: This is the first study to validate the new 3D-STE technique for LV volume measurements and demonstrate its superior accuracy and reproducibility over previously used 2D-STE technique.

Long-term experience with implantable infusion pumps for intravenous treprostinil in pulmonary arterial hypertension-procedural safety and system-related complications.

Implantable pumps for intravenous treprostinil provide a promising option to overcome drawbacks of parenteral prostanoid administration with external pumps in pulmonary hypertension. We retrospectively analyzed 85 patients undergoing implantation in a single center since 2010. In our cohort, serious complications were rare, and flow rate increase over time warrants careful monitoring.

Subcutaneous treprostinil for the treatment of severe non-operable chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled trial.

BACKGROUND: Treprostinil, a prostacyclin analogue, is effective for the treatment of pulmonary arterial hypertension. However, information is scarce regarding treprostinil for treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to examine the efficacy and safety of subcutaneous treprostinil in this setting. METHODS: In this 24-week, randomised, double-blind controlled trial, we enrolled patients with CTEPH, classified as non-operable, or with persistent or recurrent pulmonary hypertension after pulmonary endarterectomy, in six European expert centres in Austria, Czech Republic, Germany, and Poland. Patients in WHO functional class III or IV with a 6-min walk distance of 150-400 m were randomly assigned at a 1:1 allocation ratio to continuous high-dose subcutaneous treprostinil (target dose around 30 ng/kg per min at week 12) or low-dose subcutaneous treprostinil (target dose around 3 ng/kg per min at week 12). The primary endpoint was the change from baseline in 6-min walk distance at week 24. All patients who received at least one dose of the study drug were included in the intention-to-treat efficacy and safety analyses based on assessment of adverse events. The trial was registered at ClinicalTrialsRegister.eu EudraCT number 2008-006441-10 and ClinicalTrials.gov, number NCT01416636. FINDINGS: From March 9, 2009, to June 9, 2016, 105 patients were enrolled with 53 (50%) patients randomly assigned to high-dose and 52 (50%) patients to low-dose subcutaneous treprostinil. At week 24, marginal mean 6-min walk distance improved by 44·98 m (95% CI 27·52 to 62·45) in the high-dose group, and by 4·29 m (95% CI -13·34 to 21·92) in the low-dose group (treatment effect 40·69 m, 95% CI 15·86 to 65·53, p=0·0016). 12 serious adverse events were reported in ten (19%) of 52 patients from the low-dose group and 16 serious adverse events were reported in nine (17%) of 53 patients from the high-dose group. The most common treatment-related adverse events in both groups were infusion site pain and other infusion site reactions. INTERPRETATION: Treatment with subcutaneous treprostinil was safe, and improved exercise capacity in patients with severe CTEPH. Subcutaneous treprostinil provides a parenteral treatment option for patients of WHO functional class III or IV and those who do not tolerate other therapies or need combination treatment. FUNDING: SciPharm Sàrl.

The crucial impact of iron deficiency definition for the course of precapillary pulmonary hypertension.

Imbalances of iron homeostasis are associated with an adverse clinical outcome of pulmonary hypertension (PH). Herein, we aimed to analyze the impact of iron deficiency (ID) in a real-life PH patient cohort according to different currently used ID definitions. In a retrospective study including 153 precapillary PH patients followed over a mean period of five years, iron deficiency was assessed according to five clinical definitions used in previous trials. The impact of ID on clinical, hematological and hemodynamic parameters was investigated. Depending on the different cutoff levels for serum ferritin and transferrin saturation, currently used ID definitions indicated a prevalence of either true or functional ID in 11 to 75 percent of PH patients. A good diagnostic accuracy was achieved by using the sTFRF/log ferritin (sTFRF) index, which identified 33 to 42 percent of PH patients as being iron deficient. The sTFRF index had the best prediction for the association between ID and clinical outcome. Iron deficient patients with precapillary PH had a significantly higher mortality as compared to non-iron deficiency subjects, which was true for both, PH patients with and without anemia. Although levels of the iron hormone hepcidin were rather affected by ID than by inflammation, they were not associated with the clinical course or mortality of PH subjects. To conclude, ID had a significant impact on the clinical course of precapillary PH patients. The appropriate use of robust biomarkers to define ID is a prerequisite to further evaluate the role of ID and the potential benefit of iron supplementation in precapillary PH patients.

Quantitative assessment of left ventricular size and function: side-by-side comparison of real-time three-dimensional echocardiography and computed tomography with magnetic resonance reference.

BACKGROUND: Cardiac CT (CCT) and real-time 3D echocardiography (RT3DE) are being used increasingly in clinical cardiology. CCT offers superb spatial and contrast resolution, resulting in excellent endocardial definition. RT3DE has the advantages of low cost, portability, and live 3D imaging without offline reconstruction. We sought to compare both CCT and RT3DE measurements of left ventricular size and function with the standard reference technique, cardiac MR (CMR). METHODS AND RESULTS: In 31 patients, RT3DE data sets (Philips 7500) and long-axis CMR (Siemens, 1.5 T) and CCT (Toshiba, 16-slice MDCT) images were obtained on the same day without beta-blockers. All images were analyzed to obtain end-systolic and end-diastolic volumes and ejection fractions using the same rotational analysis to eliminate possible analysis-related differences. Intertechnique agreement was tested through linear regression and Bland-Altman analyses. Repeated measurements were performed to determine intraobserver and interobserver variability. Both CCT and RT3DE measurements resulted in high correlation (r2 > 0.85) compared with CMR. However, CCT significantly overestimated end-diastolic and end-systolic volumes (26 and 19 mL; P < 0.05), resulting in a small but significant bias in ejection fraction (-2.8%). RT3DE underestimated end-diastolic and end-systolic volumes only slightly (5 and 6 mL), with no significant bias in EF (0.3%; P = 0.68). The limits of agreement with CMR were comparable for the 2 techniques. The variability in the CCT measurements was roughly half of that in either RT3DE or CMR values. CONCLUSIONS: CCT provides highly reproducible measurements of left ventricular volumes, which are significantly larger than CMR values. RT3DE measurements compared more favorably with the CMR reference, albeit with higher variability.

Intravenous treprostinil infusion via a fully implantable pump for pulmonary arterial hypertension.

OBJECTIVES: Parenteral prostanoids infused via external pumps are well-established pulmonary arterial hypertension (PAH) treatments. However, local side-effects and systemic infections restrict their use. The purpose of this study was to investigate the safety of a fully implantable treprostinil infusion pump (LENUS Pro®) in patients with PAH. METHODS: Thirty patients with PAH undergoing pump implantation (with stable PAH therapy for ≥3 weeks pre-implantation) were included in this prospective, multicenter, observational study (NCT01979822). Primary endpoints were predefined adverse events (AEs) during implantation, in-hospital and/or during 6-month follow-up. Refill-related AEs were a secondary endpoint. RESULTS: Twenty-nine patients completed 6-month follow-up (one underwent lung transplantation). During implantation, one pneumothorax (not requiring drainage) occurred. Four patients had an in-hospital AE (including one catheter revision). During 6-month follow-up, AEs were most frequent at the first refill (10); the most common AE was seroma around the pump. No infections occurred. One pump required replacement because of a defective septum caused by use of a non-approved refill needle (associated with extravasation). Apart from the extravasation, no refill-related AEs were recorded. Post hoc efficacy analyses showed significant improvements in functional class [number in functional class I/II/III/IV: 0/5/21/2 (baseline) versus 3/8/17/0 (6 months); p = 0.012] and 6-min walk distance (mean ± standard deviation: 407 ± 122 m versus 445 ± 127 m; n = 17; p = 0.014). CONCLUSIONS: This study supports use of a fully implantable treprostinil infusion pump in patients with PAH requiring parenteral prostanoids. Refills should be performed by specialized healthcare professionals at patients' homes or at experienced centers using approved equipment.

Evaluation of the pharmacoDYNAMIC effects of riociguat in subjects with pulmonary hypertension and heart failure with preserved ejection fraction : Study protocol for a randomized controlled trial.

BACKGROUND: The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFPEF) resulting in substantial morbidity and mortality. So far, neither established heart failure therapies nor pulmonary vasodilators have proven to be effective for this condition. Riociguat (Adempas®, BAY 63-2521), a stimulator of soluble guanylate cyclase, is a novel pulmonary and systemic vasodilator that has been approved for the treatment of precapillary forms of PH. With regard to postcapillary PH, the DILATE-1 study was a multicenter, double-blind, randomized, placebo-controlled single-dose study in subjects with PH associated with HFPEF. Although there was no significant change in the primary outcome measure, peak decrease in mean pulmonary artery pressure with riociguat versus placebo, riociguat significantly increased stroke volume without changing heart rate, pulmonary artery wedge pressure, transpulmonary pressure gradient or pulmonary vascular resistance. The present study is designed to test the efficacy of long-term treatment with riociguat in patients with PH associated with HFPEF. METHODS/STUDY DESIGN: The DYNAMIC study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical phase IIb trial evaluating the efficacy, safety and kinetics of riociguat in PH-HFPEF patients. The drug will be given over 26 weeks to evaluate the effects of riociguat versus placebo. The primary efficacy variable will be the change from baseline in cardiac output at rest, measured by right heart catheter after 26 weeks of study drug treatment. Additional efficacy variables will be changes from baseline in further hemodynamic parameters, changes in left and right atrial area, right ventricular volume, as well as right ventricular ejection fraction measured by cardiac magnetic resonance imaging, and changes from baseline in World Health Organization (WHO) class and N­terminal prohormone B­type natriuretic peptide (NT-proBNP). The trial was registered on 25 August 2014 (EudraCT Number: 2014-003055-60; www.clinicaltrialsregister.eu ).

Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study.

BACKGROUND: Deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling results from endothelial dysfunction and may underlie impaired cardiac relaxation in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) and pulmonary hypertension (PH). The acute hemodynamic effects of riociguat, a novel soluble guanylate cyclase stimulator, were characterized in patients with PH and HFpEF. METHODS: Clinically stable patients receiving standard HF therapy with a left ventricular ejection fraction > 50%, mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, and pulmonary arterial wedge pressure (PAWP) > 15 mm Hg at rest were randomized to single oral doses of placebo or riociguat (0.5, 1, or 2 mg). The primary efficacy variable was the peak decrease in mPAP from baseline up to 6 h. Secondary outcomes included hemodynamic and echocardiographic parameters, safety, and pharmacokinetics. RESULTS: There was no significant change in peak decrease in mPAP with riociguat 2 mg (n = 10) vs placebo (n = 11, P = .6). However, riociguat 2 mg significantly increased stroke volume (+9 mL [95% CI, 0.4-17]; P = .04) and decreased systolic BP (-12 mm Hg [95% CI, -22 to -1]; P = .03) and right ventricular end-diastolic area (-5.6 cm2 [95% CI, -11 to -0.3]; P = .04), without significantly changing heart rate, PAWP, transpulmonary pressure gradient, or pulmonary vascular resistance. Riociguat was well tolerated. CONCLUSIONS: In patients with HFpEF and PH, riociguat was well tolerated, had no significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01172756; URL: www.clinicaltrials.gov.

Real-time 3D echocardiographic quantification of left atrial volume: multicenter study for validation with CMR.

OBJECTIVES: We studied in a multicenter setting the accuracy and reproducibility of 3-dimensional echocardiography (3DE)-derived measurements of left atrial volume (LAV) using new, dedicated volumetric software, side by side with 2-dimensional echocardiography (2DE), using cardiac magnetic resonance (CMR) imaging as a reference. BACKGROUND: Increased LAV is associated with adverse cardiovascular outcomes. Although LAV measurements are routinely performed using 2DE, this methodology is limited because it is view dependent and relies on geometric assumptions regarding left atrial shape. Real-time 3DE is free of these limitations and accordingly is an attractive alternative for the evaluation of LAV. However, few studies have validated 3DE-derived LAV measurements against an accepted independent reference standard, such as CMR imaging. METHODS: We studied 92 patients with a wide range of LAV who underwent CMR (1.5-T) and echocardiographic imaging on the same day. Images were analyzed to obtain maximal and minimal LAV: CMR images using standard commercial tools, 2DE images using a biplane area-length technique, and 3DE images using Tomtec LA Function software. Intertechnique comparisons included linear regression and Bland-Altman analyses. Reproducibility of all 3 techniques was assessed by calculating the percentage of absolute differences in blinded repeated measurements. Kappa statistics were used to compare 2DE and 3DE classification of normal/enlarged against the CMR reference. RESULTS: 3DE-derived LAV values showed higher correlation with CMR than 2DE measurements (r = 0.93 vs. r = 0.74 for maximal LAV; r = 0.88 vs. r = 0.82 for minimal LAV). Although 2DE underestimated maximal LAV by 31 ± 25 ml and minimal LAV by 16 ± 32 ml, 3DE resulted in a minimal bias of -1 ± 14 ml for maximal LAV and 0 ± 21 ml for minimal LAV. Interobserver and intraobserver variability of 2DE and 3DE measurements of maximal LAV were similar (7% to 12%) and approximately 2 times higher than CMR (4% to 5%). 3DE classified enlarged atria more accurately than 2DE (kappa: 0.88 vs. 0.71). CONCLUSIONS: Compared with CMR reference, 3DE-derived LAV measurements are more accurate than 2DE-based analysis, resulting in fewer patients with undetected atrial enlargement.

Three-dimensional analysis of regional left ventricular endocardial curvature from cardiac magnetic resonance images.

PURPOSE: Left ventricular (LV) remodeling is usually assessed using global changes in LV volume. We hypothesized that three-dimensional analysis of regional endocardial curvature from magnetic resonance images could provide clinically useful information on localized LV remodeling. We tested this approach by investigating regional differences in endocardial curvature in normal and hypokinetic ventricles. MATERIALS AND METHODS: Images were obtained in 44 patients with normal LV function (NL, N=14), dilated cardiomyopathy (DCM, N=15) or ischemic heart disease (IHD, N=15). Local surface curvedness, normalized to take into account instantaneous LV size (C(n)), was calculated throughout the cardiac cycle and compared between segment groups: NL (N=401), IHD (N=92) and DCM (N=255). RESULTS: In all normal segments, C(n) gradually increased during systole and then decreased during diastole. While both maximum and minimum values of C(n) were comparable in the basal and midventricular segments, they were significantly higher in the four apical segments and highest in the apical cap. In addition, percent change in C(n) was higher in mid and apical compared to basal segments (P<.05). At all LV levels, C(n) values in DCM segments were lower (P<.05) than in NL and IHD segments, which were similar. In contrast, percent change in C(n) was significantly lower in both IHD and DCM segments compared to NL. CONCLUSION: Three-dimensional analysis of LV endocardial curvature yielded quantitative information on regional ventricular shape consistent with the known pathophysiology, supporting its potential clinical usefulness in the evaluation of LV remodeling.