Supplementation with Iron in Pulmonary Arterial Hypertension. Two Randomized Crossover Trials.

Rationale: Iron deficiency, in the absence of anemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin concentrations. The safety and benefit of parenteral iron replacement in this patient population is unclear. Objectives: To evaluate the safety and efficacy of parenteral iron replacement in PAH. Methods: In two randomized, double-blind, placebo-controlled 12-week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject) (1,000 mg or 15 mg/kg if weight <66.7 kg) or saline as placebo, and 17 patients in China received iron dextran (Cosmofer) (20 mg iron/kg body weight) or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by a serum ferritin <37 µg/L or iron <10.3 µmol/L or transferrin saturations <16.4%. Results: Both iron treatments were well tolerated and improved iron status. Analyzed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6-minute walk test) or cardiopulmonary hemodynamics, as assessed by right heart catheterization, cardiac magnetic resonance, or plasma NT-proBNP (N-terminal-pro hormone brain natriuretic peptide) at 12 weeks. Conclusions: Iron repletion by administration of a slow-release iron preparation as a single infusion to patients with PAH with iron deficiency without overt anemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).

Prognostic impact of right ventricular mass change in patients with idiopathic pulmonary arterial hypertension.

BACKGROUND: Compensatory remodelling i.e. increased right ventricular (RV) mass frequently occurs as an adaptive response to the chronic pressure overload to maintain contractile function. The prognostic value of the serial change in RV mass is unclear. AIM: The aim of our study was to examine the longitudinal changes in RV mass and survival in patients with idiopathic pulmonary arterial hypertension (IPAH). METHODS: Consecutive newly diagnosed IPAH patients >18 years old were prospectively recruited from a tertiary referral center. All recruited patients were maintained on guideline-based therapy and were followed up with echocardiography and cardiac magnetic resonance for 2 years. RESULTS: Serial measures of RV mass revealed that survivors appeared to have had a compensatory increase in RV mass, which constituted adaptive RV remodelling early in the disease process, which was not seen in those who died. (Hazard ratio of 0.932, 95% confidence interval 0.893-0.973, p = 0.001). CONCLUSION: This study shows that serial measurement of RV mass in IPAH patients provides prognostic information. RV mass regression is an ominous prognostic sign, which may predict early mortality in these patients.

Deep learning cardiac motion analysis for human survival prediction.

Motion analysis is used in computer vision to understand the behaviour of moving objects in sequences of images. Optimising the interpretation of dynamic biological systems requires accurate and precise motion tracking as well as efficient representations of high-dimensional motion trajectories so that these can be used for prediction tasks. Here we use image sequences of the heart, acquired using cardiac magnetic resonance imaging, to create time-resolved three-dimensional segmentations using a fully convolutional network trained on anatomical shape priors. This dense motion model formed the input to a supervised denoising autoencoder (4Dsurvival), which is a hybrid network consisting of an autoencoder that learns a task-specific latent code representation trained on observed outcome data, yielding a latent representation optimised for survival prediction. To handle right-censored survival outcomes, our network used a Cox partial likelihood loss function. In a study of 302 patients the predictive accuracy (quantified by Harrell's C-index) was significantly higher (p = .0012) for our model C=0.75 (95% CI: 0.70 - 0.79) than the human benchmark of C=0.59 (95% CI: 0.53 - 0.65). This work demonstrates how a complex computer vision task using high-dimensional medical image data can efficiently predict human survival.

Metabolic pathways associated with right ventricular adaptation to pulmonary hypertension: 3D analysis of cardiac magnetic resonance imaging.

AIMS: We sought to identify metabolic pathways associated with right ventricular (RV) adaptation to pulmonary hypertension (PH). We evaluated candidate metabolites, previously associated with survival in pulmonary arterial hypertension, and used automated image segmentation and parametric mapping to model their relationship to adverse patterns of remodelling and wall stress. METHODS AND RESULTS: In 312 PH subjects (47.1% female, mean age 60.8 ± 15.9 years), of which 182 (50.5% female, mean age 58.6 ± 16.8 years) had metabolomics, we modelled the relationship between the RV phenotype, haemodynamic state, and metabolite levels. Atlas-based segmentation and co-registration of cardiac magnetic resonance imaging was used to create a quantitative 3D model of RV geometry and function-including maps of regional wall stress. Increasing mean pulmonary artery pressure was associated with hypertrophy of the basal free wall (ß = 0.29) and reduced relative wall thickness (ß = -0.38), indicative of eccentric remodelling. Wall stress was an independent predictor of all-cause mortality (hazard ratio = 1.27, P = 0.04). Six metabolites were significantly associated with elevated wall stress (ß = 0.28-0.34) including increased levels of tRNA-specific modified nucleosides and fatty acid acylcarnitines, and decreased levels (ß = -0.40) of sulfated androgen. CONCLUSION: Using computational image phenotyping, we identify metabolic profiles, reporting on energy metabolism and cellular stress-response, which are associated with adaptive RV mechanisms to PH.

Short-Term Hemodynamic Effects of Apelin in Patients With Pulmonary Arterial Hypertension.

Apelin agonism causes systemic vasodilatation and increased cardiac contractility in humans, and improves pulmonary arterial hypertension (PAH) in animal models. Here, the authors examined the short-term pulmonary hemodynamic effects of systemic apelin infusion in patients with PAH. In a double-blind randomized crossover study, 19 patients with PAH received intravenous (Pyr1)apelin-13 and matched saline placebo during invasive right heart catheterization. (Pyr1)apelin-13 infusion caused a reduction in pulmonary vascular resistance and increased cardiac output. This effect was accentuated in the subgroup of patients receiving concomitant phosphodiesterase type 5 inhibition. Apelin agonism is a novel potential therapeutic target for PAH. (Effects of Apelin on the Lung Circulation in Pulmonary Hypertension; NCT01457170).

Fractal Analysis of Right Ventricular Trabeculae in Pulmonary Hypertension.

Purpose To measure right ventricular (RV) trabecular complexity by its fractal dimension (FD) in healthy subjects and patients with pulmonary hypertension (PH) and to assess its relationship with hemodynamic and functional parameters and future cardiovascular events. Materials and Methods This retrospective study used data acquired from May 2004 to October 2013 in 256 patients with newly diagnosed PH who underwent cardiac MRI, right-sided heart catheterization, and 6-minute walk distance testing, with median follow-up of 4.0 years. A total of 256 healthy control subjects underwent cardiac MRI only. Biventricular FD, volumes, and function were assessed on short-axis cine images. Reproducibility was assessed with the intraclass correlation coefficient, correlation between variables was assessed with the Pearson correlation test, and mortality prediction was compared by using uni- and multivariable Cox regression analyses. Results RV FD reproducibility had an intraclass correlation coefficient of 0.97 (95% confidence interval [CI]: 0.96, 0.98). RV FD was higher in patients with PH (median, 1.310; interquartile range [IQR], 1.281-1.341) than in healthy subjects (median, 1.264; IQR, 1.242-1.295; P < .001), with the greatest difference near the apex. RV FD was associated with pulmonary vascular resistance (r = 0.30, P < .001). At univariable Cox regression analysis, RV FD was a significant predictor of death (hazard ratio [HR], 1.256; 95% CI: 1.011, 1.560; P = .04); however, at multivariable analysis, RV FD did not enable prediction of survival independently of conventional parameters of RV remodeling (HR, 1.179; 95% CI: 0.871, 1.596; P = .29). Conclusion Fractal analysis of RV trabecular complexity is a highly reproducible measure of remodeling in patients with PH that is associated with afterload, although the gain in survival prediction over traditional markers is not significant. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Exercise cardiac MRI unmasks right ventricular dysfunction in acute hypoxia and chronic pulmonary arterial hypertension.

Coupling of right ventricular (RV) contractility to afterload is maintained at rest in the early stages of pulmonary arterial hypertension (PAH), but exercise may unmask depleted contractile reserves. We assessed whether elevated afterload reduces RV contractile reserve despite compensated resting function using noninvasive exercise imaging. Fourteen patients with PAH (mean age: 39.1 yr, 10 women and 4 men) and 34 healthy control subjects (mean ageL 35.6 yr, 17 women and 17 men) completed real-time cardiac magnetic resonance imaging during submaximal exercise breathing room air. Control subjects were then also exercised during acute normobaric hypoxia (fraction of inspired O2: 12%). RV contractile reserve was assessed by the effect of exercise on ejection fraction. In control subjects, the increase in RV ejection fraction on exercise was less during hypoxia ( P = 0.017), but the response of left ventricular ejection fraction to exercise did not change. Patients with PAH had an impaired RV reserve, with half demonstrating a fall in RV ejection fraction on exercise despite comparable resting function to controls (PAH: rest 53.6 ± 4.3% vs. exercise 51.4 ± 10.7%; controls: rest 57.1 ± 5.2% vs. exercise 69.6 ± 6.1%, P < 0.0001). In control subjects, the increase in stroke volume index on exercise was driven by reduced RV end-systolic volume, whereas patients with PAH did not augment the stroke volume index, with increases in both end-diastolic and end-systolic volumes. From baseline hemodynamic and exercise capacity variables, only the minute ventilation-to-CO2 output ratio was an independent predictor of RV functional reserve ( P = 0.021). In conclusion, noninvasive cardiac imaging during exercise unmasks depleted RV contractile reserves in healthy adults under hypoxic conditions and patients with PAH under normoxic conditions despite preserved ejection fraction at rest. NEW & NOTEWORTHY Right ventricular (RV) reserve was assessed using real-time cardiac magnetic resonance imaging in patients with pulmonary arterial hypertension and in healthy control subjects under normobaric hypoxia, which has been previously associated with acute pulmonary hypertension. Hypoxia caused a mild reduction in RV reserve, whereas chronic pulmonary arterial hypertension was associated with a marked reduction in RV reserve.

Machine Learning of Three-dimensional Right Ventricular Motion Enables Outcome Prediction in Pulmonary Hypertension: A Cardiac MR Imaging Study.

Purpose To determine if patient survival and mechanisms of right ventricular failure in pulmonary hypertension could be predicted by using supervised machine learning of three-dimensional patterns of systolic cardiac motion. Materials and Methods The study was approved by a research ethics committee, and participants gave written informed consent. Two hundred fifty-six patients (143 women; mean age ± standard deviation, 63 years ± 17) with newly diagnosed pulmonary hypertension underwent cardiac magnetic resonance (MR) imaging, right-sided heart catheterization, and 6-minute walk testing with a median follow-up of 4.0 years. Semiautomated segmentation of short-axis cine images was used to create a three-dimensional model of right ventricular motion. Supervised principal components analysis was used to identify patterns of systolic motion that were most strongly predictive of survival. Survival prediction was assessed by using difference in median survival time and area under the curve with time-dependent receiver operating characteristic analysis for 1-year survival. Results At the end of follow-up, 36% of patients (93 of 256) died, and one underwent lung transplantation. Poor outcome was predicted by a loss of effective contraction in the septum and free wall, coupled with reduced basal longitudinal motion. When added to conventional imaging and hemodynamic, functional, and clinical markers, three-dimensional cardiac motion improved survival prediction (area under the receiver operating characteristic curve, 0.73 vs 0.60, respectively; P < .001) and provided greater differentiation according to difference in median survival time between high- and low-risk groups (13.8 vs 10.7 years, respectively; P < .001). Conclusion A machine-learning survival model that uses three-dimensional cardiac motion predicts outcome independent of conventional risk factors in patients with newly diagnosed pulmonary hypertension. Online supplemental material is available for this article.

Cardiopulmonary exercise testing demonstrates maintenance of exercise capacity in patients with hypoxemia and pulmonary arteriovenous malformations.

BACKGROUND: Patients with pulmonary arteriovenous malformations (PAVMs) are unusual because hypoxemia results from right-to-left shunting and not airway or alveolar disease. Their surprisingly well-preserved exercise capacity is not generally appreciated. METHODS: To examine why exercise tolerance is preserved, cardiopulmonary exercise tests were performed while breathing room air in 21 patients with radiologically proven PAVMs, including five restudied 3 to 12 months after embolization when their PAVMs had regressed. Where physiologic matching was demonstrable, comparisons were made with 12 healthy control subjects. RESULTS: The majority of patients achieved their predicted work rate despite a resting arterial oxygen saturation (SaO2) of 80% to 96%. Peak work rate and oxygen consumption (VO2) were no lower in patients with more hypoxemia. Despite higher SaO2 following embolization (median, 96% and 90%; P = .009), patients achieved similar work rates and similar peak VO2. Strikingly, treated patients reset to virtually identical peak oxygen pulses (ie, VO2 per heart beat) and in many cases to the same point on the peak oxygen pulse/work rate plot. The 21 patients had increased minute ventilation (VE) for given increases in CO2 production (VE/VCO2 slope), but perceived dyspnea was no greater than in the 12 control subjects or in the same patients before compared to after embolization comparison. Overall, work rate and peak VO2 were associated not with oxygenation parameters but with VE/VCO2 slope, BMI, and anaerobic threshold. CONCLUSIONS: Patients with hypoxemia and PAVMs can maintain normal oxygen delivery/VO2 during peak exercise. Following improvement of SaO2 by embolization, patients appeared to reset compensatory mechanisms and, as a result, achieved similar peak VO2 per heart beat and peak work rates.

Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension.

Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy.

The association of clinical outcome with right atrial and ventricular remodelling in patients with pulmonary arterial hypertension: study with real-time three-dimensional echocardiography.

AIMS: Right atrial (RA) dilatation may be important for patients' outcome in pulmonary arterial hypertension (PAH). The aim of this study was to examine the longitudinal RA and right ventricular (RV) remodelling in PAH patients using real-time three-dimensional echocardiography (3DE) and their relation to clinical outcome. METHODS AND RESULTS: Sixty-two consecutive PAH patients were studied and compared with a control group of 30 healthy volunteers. RA and RV sphericity indices were measured with 3DE. RV ejection fraction (RVEF), RA volume (RAvol), and the quantification of jet area of tricuspid regurgitation (TR) were measured. Two observers were used for reproducibility assessment. The geometrical change of RA and RV was assessed in relation to clinical outcome, as defined by the increase of functional class or admission to the hospital due to right heart failure. Over 1 year of follow-up, there was significant increase of RA sphericity index (0.85±0.16 vs. 1.2±0.24, P<0.01), RV dilatation (RV sphericity index 0.71±0.07 vs. 0.98±0.04, P<0.01), as well as deterioration of RV systolic function (RVEF 33±8.2 vs. 28±7.6%, P<0.01). Twenty-three patients (37%) had a clinical deterioration within 1 year. An increase of RA sphericity index>0.24 predicted clinical deterioration with a sensitivity of 96% and a specificity of 90% [area under the curve (AUC) 0.97]. RV sphericity index was less sensitive (70%) and specific (62%) in predicting clinical deterioration (AUC 0.649). The deterioration in RVEF had a sensitivity of 91.1% and a specificity of 35.3% (AUC 0.479) in predicting clinical deterioration. The dilatation of RA>14 mL over 1 year had high sensitivity at 82.6% but low specificity at 30.8% in predicting clinical deterioration. CONCLUSION: PAH leads to RA and RV dilatation and functional deterioration which are linked to an adverse clinical outcome. 3DE measurement of RA sphericity index may be a suitable index in predicting clinical deterioration of PAH patients.

Morphologic and functional remodeling of the right ventricle in pulmonary hypertension by real time three dimensional echocardiography.

The aims of this study were to assess the right ventricle in different causes of pulmonary hypertension (PH) and to assess the changes of the tricuspid apparatus during this remodeling. The functional and morphologic changes of the right ventricle and the tricuspid apparatus in relation to different causes of PH remain elusive. A total of 141 consecutive patients were prospectively recruited, of whom 55 had pulmonary arterial hypertension (PAH), 32 had chronic thromboembolic disease (CTED), and 34 had PH secondary to mitral regurgitation (MR). Twenty age- and gender-matched healthy volunteers were also studied to serve as controls. Real-time 3-dimensional echocardiography was used to assess right ventricular (RV) volumes and tricuspid valve mobility. Overall, RV diastolic volumes were greater and RV ejection fractions lower in patients with PAH compared to those with CTED and MR (186.4 ± 48.8 vs 113.5 vs 109.4 ml, p < 0.001, and 33.2% vs 36.8% vs 66.8%, p < 0.001, respectively). Among the 3 PH groups, tricuspid valve mobility was most restricted in the CTED group and least restricted in the MR group. Tricuspid tenting volume was greater in the CTED and PAH groups than in the MR group (p < 0.01). Most patients with PAH (54.6%) had at least moderate tricuspid regurgitation, while in the CTED group, most (59.4%) had mild and only 37.5% had moderate tricuspid regurgitation (p < 0.01). Conversely, patients with MR (85%) had only mild tricuspid regurgitation. There was no correlation between RV systolic pressures and the RV ejection fraction or tenting volume. In conclusion, this study demonstrates that different causes of PH may lead to diverse RV remodeling, with the most adverse remodeling being in patients with PAH. In addition, changes of the tricuspid apparatus also differed, with the most adverse effects seen in patients with CTED.

Endothelin receptor antagonists for pulmonary arterial hypertension: rationale and place in therapy.

The last decade has seen significant advances in the understanding and treatment of pulmonary arterial hypertension (PAH). Three main pathways, involving endothelin, nitric oxide, and prostacyclin, have been identified in its pathogenesis and these have all led to the development of therapies in current use. While the nitric oxide and prostacyclin pathways require augmentation, the endothelin system is overactive in PAH, with increased endothelin synthesis and receptor expression and, therefore, requires blockade. There are two known endothelin receptors. The type A receptor, expressed in pulmonary artery media, mediates vasoconstriction and remodeling, whereas the function of the type B receptor is more complex. Like the type A receptor, the type B receptor mediates vasoconstriction and remodeling effects when expressed on smooth muscle cells and (myo)fibroblasts, yet functions to clear endothelin from the circulation and induce release of endogenous nitric oxide and prostacyclin, when activated in the pulmonary artery endothelium. Consequently, it is not clear from in vitro data whether the optimal strategy is to block only the type A receptor or both receptors. Phase III clinical studies show clear short-term physiologic benefit with both dual and selective endothelin blockade in PAH. Longer-term experience with bosentan, a dual receptor antagonist, has shown improved outcomes compared with historic control data and comparable survival to intravenous prostacyclin therapy. The newer selective blockers, sitaxsentan and ambrisentan, appear to have similar short-term efficacy, but long-term data are as yet either lacking or unpublished. They may be less hepatotoxic than bosentan, although long-term follow-up of patients receiving bosentan has shown this is not a significant problem. On the basis of available evidence, the endothelin receptor antagonists have become first-line therapy for patients with PAH, except in the most severely affected who still require treatment with intravenous prostacyclin. Although their use as part of combination therapy with other agents is widespread, the evidence for this is not as robust, but appropriate investigation is underway.

New therapeutic agents for pulmonary vascular disease.

The improved understanding of the pathophysiology of pulmonary vascular diseases over the last decade has brought with it significant changes in disease management. Newer therapies have targeted the cardinal features of pulmonary hypertension, which include pulmonary vasoconstriction and vascular remodelling. In addition to prostacyclin, which had been the mainstay of therapy until recently, other available drugs include other prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase inhibitors. This review will discuss some of the evidence for their use and will look towards the future in the search of treatments that may ultimately modify and even reverse the disease process.