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. 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. 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. In patients with HFpEF and PH, riociguat was well tolerated, had no significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters. ClinicalTrials.gov; No.: NCT01172756; URL: www.clinicaltrials.gov.

Background—: The underlying pathophysiology of heart failure with preserved ejection fraction (HFPEF) is incompletely understood, but myocardial extracellular matrix accumulation is thought to play a major role. Our aims were to estimate myocardial extracellular matrix using cardiac magnetic resonance T1 mapping and to assess the relationship between pathobiology/pathophysiology and prognosis. Methods and Results—: Patients with suspected HFPEF (n=100) were enrolled in this prospective, observational study. Confirmatory diagnostic tests, cardiac magnetic resonance imaging including T1 mapping, and invasive hemodynamic assessments were performed at baseline. Sixty-one patients with confirmed HFPEF entered a longitudinal outcome-monitoring phase (mean, 22.9±5.0 months), during which 16 had a cardiac event. Cardiac magnetic resonance T1 time (hazard ratio, 0.99; 95% confidence interval, 0.98–0.99; P =0.046), left atrial area (hazard ratio, 1.08; 95% confidence interval, 1.03–1.13; P <0.01), and pulmonary vascular resistance (hazard ratio, 1.01; 95% confidence interval, 1.00–1.01; P =0.03) were significantly associated with cardiac events. Patients with T1 times below the median (<388.3 ms) were at greater risk of cardiac events than the rest of the group ( P <0.01). Extracellular matrix of left ventricular biopsies (n=9), quantified by TissueFAXS technology correlated with T1 time ( R =0.98; P <0.01). T1 time also correlated with right ventricular–pulmonary arterial coupling (pulmonary vascular resistance: R =−0.36; P <0.01; right ventricular ejection fraction: R =0.28; P =0.01). Conclusions—: In the present preliminary study, cardiac magnetic resonance postcontrast T1 time is associated with prognosis in HFPEF, suggesting postcontrast T1 as possible biomarker for HFPEF.

Current guidelines recommend right heart catheterisation (RHC) in symptomatic patients at risk of pre-capillary pulmonary hypertension (PH) with echocardiographic systolic pulmonary artery pressures ≥36 mmHg. Growing awareness for PH, a high prevalence of post-capillary PH and the inability to distinguish between pre- and post-capillary PH by echocardiography have led to unnecessary RHCs. The aim of our study was to assess whether standard noninvasive diagnostic procedures are able to safely exclude pre-capillary PH.Data from 251 patients referred for suspicion of pre-capillary PH were used to develop a noninvasive diagnostic decision tree. A prospectively collected data set of 121 consecutive patients was utilised for temporal validation.According to the decision tree, patients were stratified by the presence or absence of an electrocardiographic right ventricular strain pattern (RVS) and serum N-terminal brain natriuretic peptide (NT-proBNP) levels below and above 80 pg·mL⁻¹. In the absence of RVS and elevated NT-proBNP, none of the patients in the prospective validation cohort were diagnosed with pre-capillary PH by RHC. Combining echocardiography with the diagnostic algorithm increased specificity to 19.3% (p = 0.0009), while sensitivity remained at 100%.Employing ECG and NT-proBNP on top of echocardiography helps recognise one false positive case per five patients referred with dyspnoea and echocardiographic suspicion of PH, while not missing true pre-capillary PH.

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. 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. 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. A total of 114 consecutive patients with pulmonary hypertension associated with heart failure and preserved ejection fraction were randomized to receive riociguat (Rio) or placebo. Riociguat is an orally administered drug that stimulates soluble guanylate cyclase (sGC) directly, independent of nitric oxide, and also sensitizes sGC to endogenous nitric oxide. Stimulation of sGC results in an increase of the cyclic guanosine monophosphate (cGMP) concentration which leads to vasorelaxation. After 26 weeks, the primary efficacy endpoint—cardiac output (CO) at rest measured by right heart catheterization—improved significantly in response to riociguat, along with other haemodynamic parameters.

Tafamidis improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, it is not yet known whether tafamidis affects cardiac amyloid deposition and structural changes in the myocardium. We aimed to determine disease-modifying effects on myocardial amyloid progression and to identify imaging parameters that could be applied for specific therapy monitoring. ATTR-CM patients underwent serial cardiac magnetic resonance (CMR) imaging using T1 mapping techniques to derive extracellular volume (ECV). Patients receiving tafamidis 61 mg (n = 35) or 20 mg (n = 15) once daily showed stable measurements at follow-up (FU) {61 mg: 9.0 [interquartile range (IQR) 7.0–11.0] months, 20 mg: 11.0 (IQR 8.0–18.0) months} in left ventricular (LV) ejection fraction (LVEF; 61 mg: 47.6% vs. 47.5%, P = 0.935; 20 mg: 52.4% vs. 52.1%, P = 0.930), LV mass index (LVMI; 61 mg: 110.2 vs. 106.2 g/m², P = 0.304; 20 mg: 114.5 vs. 115.4 g/m², P = 0.900), and ECV (61 mg: 47.5% vs. 47.7%, P = 0.861; 20 mg: 56.7% vs. 57.5%, P = 0.759), whereas treatment-naïve ATTR-CM patients (n = 19) had clear signs of disease progression at the end of the observation period [12.0 (IQR 10.0–21.0) months; LVEF: 53.3% vs. 45.7%, P = 0.031; LVMI: 98.9 vs. 106.9 g/m², P = 0.027; ECV: 49.3% vs. 54.6%, P = 0.023]. Between-group comparison at FU revealed positive effects in tafamidis 61 mg-treated compared to treatment-naïve patients (LVEF: P = 0.035, LVMI: P = 0.036, ECV: P = 0.030), while those treated with 20 mg showed no difference in the above LV measurements when compared with treatment-naïve (P = 0.120, P = 0.287, P = 0.158). However, both treatment groups showed clinically beneficial effects compared to the natural course [61 mg, 6-min walk distance (6-MWD): P = 0.005, N-terminal prohormone of brain natriuretic peptide (NT-proBNP): P = 0.002; 20 mg, 6-MWD: P = 0.023, NT-proBNP: P = 0.003]. Tafamidis delays myocardial amyloid progression in ATTR-CM patients, resulting in structural, functional, and clinical benefits compared to the natural course. Serial CMR including measurement of ECV may be appropriate for disease-specific therapy monitoring.