Advanced hemodynamic and cluster analysis for identifying novel RV function subphenotypes in patients with pulmonary hypertension.

BACKGROUND: Quantifying right ventricular (RV) function is important to describe the pathophysiology of in pulmonary hypertension (PH). Current phenotyping strategies in PH rely on few invasive hemodynamic parameters to quantify RV dysfunction severity. The aim of this study was to identify novel RV phenotypes using unsupervised clustering methods on advanced hemodynamic features of RV function. METHODS: Participants were identified from the University of Arizona Pulmonary Hypertension Registry (n = 190). RV-pulmonary artery coupling (Ees/Ea), RV systolic (Ees), and diastolic function (Eed) were quantified from stored RV pressure waveforms. Consensus clustering analysis with bootstrapping was used to identify the optimal clustering method. Pearson correlation analysis was used to reduce collinearity between variables. RV cluster subphenotypes were characterized using clinical data and compared to pulmonary vascular resistance (PVR) quintiles. RESULTS: Five distinct RV clusters (C1-C5) with distinct RV subphenotypes were identified using k-medoids with a Pearson distance matrix. Clusters 1 and 2 both have low diastolic stiffness (Eed) and afterload (Ea) but RV-PA coupling (Ees/Ea) is decreased in C2. Intermediate cluster (C3) has a similar Ees/Ea as C2 but with higher PA pressure and afterload. Clusters C4 and C5 have increased Eed and Ea but C5 has a significant decrease in Ees/Ea. Cardiac output was high in C3 distinct from the other clusters. In the PVR quintiles, contractility increased and stroke volume decreased as a function of increased afterload. World Symposium PH classifications were distributed across clusters and PVR quintiles. CONCLUSIONS: RV-centric phenotyping offers an opportunity for a more precise-medicine-based management approach.

[Functional characterization of patients with isolated post-capillary or combined post-capillary and pre-capillary pulmonary hypertension]. / Funktionelle Charakterisierung von Patienten mit isoliert postkapillärer oder kombiniert post- und präkapillärer pulmonaler Hypertonie.

BACKGROUND: The World Conference on PH recommended differentiation of isolated postcapillary (Ipc) and combined post- and precapillary (Cpc) PH according to pulmonary vascular resistance alone. The aim of this study was the haemodynamic and functional characterization of patients diagnosed IpcPH and CpcPH according to the current recommendation of the latest World Symposium on Pulmonary Hypertension (PH) with an exploratory data analysis. METHODS: We evaluated all consecutive patients presenting at the PH outpatient clinic of Mission Medical Hospital from 2008-2015. All received a complete diagnostic work-up according to the guidelines. We analyzed data of patients with mPAP≥ 25 mmHg and pulmonary capillary wedge pressure (PCWP) > 15 mmHg. We compared anthropometric, hemodynamic and functional data of six-minute walking test (6 MWT), cardiopulmonary exercise testing (CPET) and echocardiography of patients with IpcPH and CpcPH. RESULTS: Out of 726 patients 58 showed a postcapillary PH: IpcPH: n = 20; CpcPH: n = 38. Patients with IpcPH had a significantly lower mPAP and PVR than patients with CpcPH. Cardiac index was lower in the Cpc-PH group compared to the IpcPH group. Functional capacity did not differ. CpcPH patients showed a higher right/left atrial area (RA/LA)-ratio. DISCUSSION AND CONCLUSION: Although CpcPH patients showed higher values of mPAP and PVR functional capacity was not worse than in patients with IpcPH. In patients with PH due to left heart disease an elevated RA/LA ratio may indicate CpcPH and invasive diagnostic work-up should be considered.

Development of the Pulmonary Hypertension Functional Classification Self-Report: a patient version adapted from the World Health Organization Functional Classification measure.

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by progressive limitations on physical activity, right heart failure, and premature death. The World Health Organization functional classification (WHO-FC) is a clinician-rated assessment used widely to assess PAH severity and functioning, but no equivalent patient-reported version of PAH symptoms and activity limitations exists. We developed a version of the WHO-FC for self-completion by patients: the Pulmonary Hypertension Functional Classification Self-Report (PH-FC-SR). METHODS: Semistructured interviews were conducted with three health care providers (HCPs) via telephone to inform development of the draft PH-FC-SR. Two rounds of semi-structured interviews were conducted with 14 US patients with a self-reported PAH diagnosis via telephone/online to elicit concepts and iteratively refine the PH-FC-SR. RESULTS: HCPs reported that the WHO-FC was a useful tool for evaluating patients' PAH severity over time and for making treatment decisions but acknowledged that use of the measure is subjective. Patients in round 1 interviews (n = 6) reported PAH symptoms, including shortness of breath (n = 6), fatigue (n = 5), syncope (n = 5), chest pains (n = 3), and dizziness (n = 3). Round 1 patients identified challenges with the original WHO-FC, including comprehensibility of clinical terms and overlapping descriptions of class II and III, and preferred the Draft 1 PH-FC-SR over the original WHO-FC. After minor changes were made to Draft 2, round 2 interviews (n = 8) confirmed patients understood the PH-FC-SR class descriptions, interpreting them consistently. CONCLUSIONS: The HCP and patient interviews identified and confirmed certain limitations inherent within the clinician-rated WHO-FC, including subjective assessment and overlapping definitions for class II and III. The PH-FC-SR includes patient-appropriate language, symptoms, and physical activity impacts relevant to patients with PAH. Future research is recommended to validate the PH-FC-SR and explore its correlation with the physician-assessed WHO-FC and other outcomes.

The Evolution in Nomenclature, Diagnosis, and Classification of Pulmonary Hypertension.

The current description of pulmonary hypertension is a testament to the physicians and scientists who dedicated their lives to furthering understanding of the pulmonary circulation. This has spanned a millennium, from ancient Egyptian descriptions of human anatomy to the current molecular and hemodynamic phenotyping of pulmonary hypertension. The recent Sixth World Symposium on Pulmonary Hypertension is a direct result of these discoveries and reflects an evolution in a classification scheme that has spanned half a century. This provides a framework for future directions related to therapeutics and mechanisms of disease.

The prevalence and clinical outcome of supraventricular tachycardia in different etiologies of pulmonary hypertension.

PURPOSE: Patients with pulmonary hypertension (PH) frequently suffer from supraventricular tachycardias (SVT). The main purpose of our study was to identify the cumulative incidence of SVT in patients with different etiologies of PH. The secondary objective was to analyse the clinical impact of SVT. METHODS: We retrospectively studied the prevalence of SVT and the clinical outcome in 755 patients (41% males; 60 ± 15 years; mean follow-up 3.8 ± 2.8 years) with PH of different etiologies. The prevalence of SVT was analysed separately in isolated pre-capillary PH (Ipc-PH) and in patients with combined post- and pre-capillary PH (Cpc-PH). RESULTS: The prevalence of SVT in the Ipc-PH group (n = 641) was 25% (n = 162). The most prevalent arrhythmias were atrial fibrillation followed by a typical atrial flutter (17% and 4.4% of all Icp-PH patients). An excessive prevalence of SVT was found in patients with pulmonary arterial hypertension associated with congenital heart disease (35%, p = 0.01). Out of the overall study population, Cpc-PH was present in 114 (15%) patients. Patients with Cpc-PH manifested a higher prevalence of SVT than subjects with Ipc-PH (58; 51% vs. 162; 25%; p <0.0001) and were more likely to have persistent or permanent atrial fibrillation (38; 29% vs. 61; 10%; p <0.0001). Parameters significantly associated with mortality in a multivariate analysis included age, male gender, functional exercise capacity and right atrial diameter (p < 0.05). Neither diagnosis of SVT nor type of arrhythmia predicted mortality. CONCLUSIONS: The study detected a significant prevalence of SVT in the population of PH of different origins. Different spectrum and prevalence of arrhythmia might be expected in different etiologies of PH. Patients with an elevated post-capillary pressure showed a higher arrhythmia prevalence, predominantly due to an excessive number of atrial fibrillations. The diagnosis of SVT was not associated with mortality.

Pulmonary Hypertension: A Brief Guide for Clinicians.

Pulmonary hypertension (PH) is classified into 5 clinical subgroups: pulmonary arterial hypertension (PAH), PH due to left-sided heart disease, PH due to chronic lung disease, chronic thromboembolic PH (CTEPH), and PH with an unclear and/or multifactorial mechanisms. A range of underlying conditions can lead to these disorders. Overall, PH affects approximately 1% of the global population, and over half of patients with heart failure may be affected. Cardiologists are therefore likely to encounter PH in their practice. Routine tests in patients with symptoms and physical findings suggestive of PH include electrocardiography, chest radiography, and pulmonary function tests. Transthoracic echocardiography is used to estimate the probability of PH. All patients with suspected or confirmed PH, without confirmed left-sided heart or lung diseases, should have a ventilation-perfusion scan to exclude CTEPH. Right-sided heart catheterization is essential for accurate diagnosis and classification. All patients with PAH or CTEPH must be referred to a specialist center. Surgical pulmonary endarterectomy is the treatment of choice for eligible patients with CTEPH. Targeted treatments (phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, prostacyclin analogues, and prostacyclin receptor agonists) are licensed for patients with PAH. The soluble guanylate cyclase stimulator riociguat is the only licensed targeted therapy for patients with inoperable or persistent/recurrent CTEPH. Management of PH resulting from left-sided heart disease primarily involves treatment of the underlying condition.

Which Functional Classification Scale is Optimal for Children with Pulmonary Hypertension (PAH)?

Functional status assessed by the WHO-FC scale derived from adults is a known prognostic factor for pulmonary hypertension. Data on the usefulness of the Panama-FC scale in assessing children with pulmonary hypertension are limited. The study was performed to compare functional status results (WHO-FC and Panama-FC) and to assess the usefulness of these scales in various clinical situations. The reliability of the Panama-FC questionnaire method for facilitating patient evaluation was also examined. 26 functional status assessments (7 in disease progression/after treatment intensification) in both scales were analyzed in 19 patients with PAH confirmed in RHC. WHO-FC, Panama-FC scales, and questionnaire-based on Panama-FC were conducted independently by three different physicians. Results of assessments were compared with each other and with 6MWD, NTproBNP level, and echo parameters (TAPSE, RV/LV ratio). The Panama-FC scale results obtained using the medical interview method and questionnaire did not differ. Both WHO-FC and Panama-FC classes well-reflected disease advancement confirmed by non-invasive parameters (NTproBNP, 6MWD, TAPSE, RV/LV ratio). Differences between grading the class in both scales were observed: 5pts were classified to II (Panama-FC) vs I (WHO-FC), 2pts were in lower risk group in WHO-FC (II) vs Panama (IIIa). Worsening or improvement after treatment intensification in functional status in both scales was connected with the significant change of NTproBNP level. The 6-min walking distance did not change. TAPSE, RV/LV ratio changed significantly in 3pts with IPAH, accordingly to change in WHO-FC and Panama-FC. WHO-FC and Panama-FC well reflect the disease advancement. The questionnaire method simplified the use of the Panama-FC scale. The Panama-FC scale appears to be better for assessing functional status during long-term follow-up, while the WHO-FC scale was more useful in short-term treatment monitoring.

Focused Update on Pulmonary Hypertension in Children-Selected Topics of Interest for the Adult Cardiologist.

Pulmonary hypertensive vascular disease (PHVD), and pulmonary hypertension (PH), which is a broader term, are severe conditions associated with high morbidity and mortality at all ages. Treatment guidelines in childhood are widely adopted from adult data and experience, though big differences may exist regarding aetiology, concomitant conditions and presentation. Over the past few years, paediatric aspects have been incorporated into the common guidelines, which currently address both children and adults with pulmonary hypertension (PH). There are multiple facets of PH in the context of cardiac conditions in childhood. Apart from Eisenmenger syndrome (ES), the broad spectrum of congenital heart disease (CHD) comprises PH in failing Fontan physiology, as well as segmental PH. In this review we provide current data and novel aspects on the pathophysiological background and individual management concepts of these conditions. Moreover, we focus on paediatric left heart failure with PH and its challenging issues, including end stage treatment options, such as mechanical support and paediatric transplantation. PH in the context of rare congenital disorders, such as Scimitar Syndrome and sickle cell disease is discussed. Based on current data, we provide an overview on multiple underlying mechanisms of PH involved in these conditions, and different management strategies in children and adulthood. In addition, we summarize the paediatric aspects and the pros and cons of the recently updated definitions of PH. This review provides deeper insights into some challenging conditions of paediatric PH in order to improve current knowledge and care for children and young adults.

DLNO/DLCO ratio evolution under targeted therapy in patients with pulmonary hypertension.

The ratio of the diffusing capacity of the lung for carbon monoxide (DLCO) and for nitric oxide (DLNO) measured simultaneously is modified in patients with precapillary pulmonary hypertension (PH). The potential impact of targeted therapy on the DLCO/DLNO ratio is unknown. Simultaneous measurements of DLNO and DLCO were performed at baseline, 3-4 month follow-up (first evaluation) and 12-month follow-up (second evaluation) after initiation of targeted PH therapies in incident cases of precapillary PH. The main outcome was the change in DLNO/DLCO ratio under treatment between baseline and the first evaluation. Twenty-nine patients were included (mean age: 66.8 years, 62.1% female). No significant change in the DLNO/DLCO ratio was found between baseline and the first evaluation. Similarly, no significant differences were noted with regard to changes in Dm or Vc, the DLNO/DLCO ratio in different patient subgroups, or in the 20 patients evaluated at the second follow-up. Within the limitations of this study, the DLNO/DLCO ratio is not useful in monitoring the response to treatment in PH.

Clinical update on pulmonary hypertension.

Pulmonary hypertension (PH) is a chronic, complex and challenging disease. Advances in treatment are for the subset of patients with pulmonary arterial hypertension. Selected review of the literature was conducted incorporating the European Society of Cardiology/European Respiratory Society 2015 guidelines and recommendations from the Sixth World Symposium on Pulmonary Hypertension. PH is classified into five groups based on WHO classification. Echocardiography remains the initial test of choice, and careful assessment of the right system aids in the diagnosis and prognosis of the disease. Right heart catheterization remains the gold standard of diagnosis and key guidance of treatment. Multidisciplinary approach is recommended for the care of patients with PH. Treatment selection is based on individual risk stratification of patients, and early referral to specialized PH centers improves outcomes of patients. Treating PH is complex and is best carried out in PH centers and with multidisciplinary approach. Early diagnosis and referral to those centers are key not to delay treatment.

Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease.

Pulmonary hypertension and pulmonary vascular remodeling (PVR) are common in many lung diseases leading to right ventricular dysfunction and death. Differences in PVR result in significant prognostic divergences in both the pulmonary arterial and venous compartments, as in pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD), respectively. Our goal was to identify compartment-specific molecular hallmarks of PVR, considering the risk of life-threatening pulmonary edema in PVOD, if treated by conventional pulmonary hypertension therapy. Formalin-fixed and paraffin-embedded tissues from fresh explanted human lungs of patients with PVOD (n = 19), PAH (n = 20), idiopathic pulmonary fibrosis (n = 13), and chronic obstructive pulmonary disease (n = 15), were analyzed for inflammation and kinome-related gene regulation. The generated neuronal network differentiated PVOD from PAH samples with a sensitivity of 100% and a specificity of 92% in a randomly chosen validation set, a level far superior to established diagnostic algorithms. Further, various alterations were identified regarding the gene expression of explanted lungs with PVR, compared with controls. Specifically, the dysregulation of microtubule-associated serine/threonine kinase 2 and protein-o-mannose kinase SGK196 in all disease groups suggests a key role in pulmonary vasculopathy for the first time. Our findings promise to help develop novel target-specific interventions and innovative approaches to facilitate clinical diagnostics in an elusive group of diseases.

Pulmonary hypertension in end-stage renal disease.

Pulmonary hypertension associated with end-stage renal disease (ESRD) is an important yet under-recognized condition and can lead to life-threatening complications. The pathogenesis of pulmonary hypertension is peculiar in ESRD, and understanding it is important to recognize such patients at the earliest and commence appropriate treatment. Many studies have discovered the prevalence of pulmonary hypertension to be up to 80% in ESRD and have been associated with increased mortality. WHO has classified pulmonary hypertension in renal failure to be in group 5, a group defined by unclear multifactorial etiologies. Moreover, there is an improvement with renal transplant and closure of AV fistula, thus confirming the contribution from these. The pharmacological management of pulmonary hypertension in this unique population is not very different from other etiologies. However, one should understand that pulmonary hypertension as such, could be multifactorial, and other secondary causes of pulmonary hypertension should also be recognized and treated accordingly. In this article, we will discuss the concept of pulmonary hypertension in ESRD in detail and the options of treatment.

Impact of the New Pulmonary Hypertension Definition on Heart Transplant Outcomes: Expanding the Hemodynamic Risk Profile.

BACKGROUND: At the recent 6th World Symposium on Pulmonary Hypertension (PH), the definition of PH was redefined to include lower pulmonary artery pressures in the setting of elevated pulmonary vascular resistance (PVR). However, the relevance of this change to subjects with PH due to left-heart disease as well as the preoperative assessment of heart transplant (HT) recipients is unknown. METHODS: The United Network for Organ Sharing database was queried to identify adult recipients who underwent primary HT from 1996 to 2015. Recipients were subdivided into those with mean pulmonary artery pressure (mPAP) < 25 mm Hg and ≥ 25 mm Hg. Exploratory univariable analysis was undertaken to identify candidate risk factors associated with 30-day and 1-year survival (conditional on 30-day survival) in recipients with mPAP < 25 mm Hg, and subsequently, parsimonious multivariable Cox proportional hazards models were constructed to assess the independent association with PVR. RESULTS: Over the study period, 32,465 patients underwent HT, including 12,257 (38%) with mPAP < 25 mm Hg. The median age was 55 years (interquartile range, 47-62) and the median PVR was 1.5 Wood units (WU) (interquartile range, 1-2.2) in recipients with mPAP < 25 mm Hg. After controlling for confounders, PVR was independently associated with increased risk for 30-day mortality (hazard ratio, 1.16; 95% CI, 1.05-1.27; P < .01), but not conditional 1-year mortality (hazard ratio, 1.03; 95% CI, 0.94-1.12; P = .55). PVR ≥ 3 WU was associated with an absolute 1.9% increase in 30-day mortality in those with mPAP < 25 mm Hg, a similar risk to recipients with PVR ≥ 3 WU and mPAP ≥ 25 mm Hg. CONCLUSIONS: Elevated PVR remains associated with a significant increase in the hazard for 30-day mortality after cardiac transplantation, even in the setting of lower pulmonary artery pressures. These data support the validity of the new definition of pulmonary hypertension.

Pulmonary Hypertension Subtypes and Mortality in CKD.

RATIONALE & OBJECTIVE: Pulmonary hypertension (PH) contributes to cardiovascular disease and mortality in patients with chronic kidney disease (CKD), but the pathophysiology is mostly unknown. This study sought to estimate the prevalence and consequences of PH subtypes in the setting of CKD. STUDY DESIGN: Observational retrospective cohort study. SETTING & PARTICIPANTS: We examined 12,618 patients with a right heart catheterization in the Duke Databank for Cardiovascular Disease from January 1, 2000, to December 31, 2014. EXPOSURES: Baseline kidney function stratified by CKD glomerular filtration rate category and PH subtype. OUTCOMES: All-cause mortality. ANALYTICAL APPROACH: Multivariable Cox proportional hazards analysis. RESULTS: In this cohort, 73.4% of patients with CKD had PH, compared with 56.9% of patients without CKD. Isolated postcapillary PH (39.0%) and combined pre- and postcapillary PH (38.3%) were the most common PH subtypes in CKD. Conversely, precapillary PH was the most common subtype in the non-CKD cohort (35.9%). The relationships between mean pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrial pressure with mortality were similar in both the CKD and non-CKD cohorts. Compared with those without PH, precapillary PH conferred the highest mortality risk among patients without CKD (HR, 2.27; 95% CI, 2.00-2.57). By contrast, in those with CKD, combined pre- and postcapillary PH was associated with the highest risk for mortality in CKD in adjusted analyses (compared with no PH, HRs of 1.89 [95% CI, 1.57-2.28], 1.87 [95% CI, 1.52-2.31], 2.13 [95% CI, 1.52-2.97], and 1.63 [95% CI, 1.12-2.36] for glomerular filtration rate categories G3a, G3b, G4, and G5/G5D). LIMITATIONS: The cohort referred for right heart catheterization may not be generalizable to the general population. Serum creatinine data in the 6 months preceding catheterization may not reflect true baseline CKD. Observational design precludes assumptions of causality. CONCLUSIONS: In patients with CKD referred for right heart catheterization, PH is common and associated with poor survival. Combined pre- and postcapillary PH was common and portended the worst survival for patients with CKD.

Precision medicine: The future of diagnostic approach to pulmonary hypertension?

Pulmonary hypertension (PH) is a common finding that can result from many different pathological conditions. Depending on the etiology, treatment may be quite different, but early diagnosis and correct classification of PH is difficult. With an aging population and recently suggested decreased pulmonary arterial pressure threshold defining PH, we are facing even more diagnostic uncertainties. A new approach to patients' phenotyping is needed. Here we present available data and future perspectives on employing an in-depth analysis of the omics cascade to allow an earlier and more reliable diagnosis and classification of PH. Indeed, with the help of super-fast computing, it became possible to simultaneously consider the levels of thousands of potential biomarkers to find patterns specific for clinically suspected disease. The omics cascade is an invaluable source of information. However, while the genome can be perceived as providing possibilities, transcriptome-as carving them this is metabolome that may tell us 'what is really going on' in an individual living organism. Metabolomics research requires blinded search for characteristic patterns of discreet changes in the levels of detectable metabolites. Since as many as 40,000 various substances are produced as a 'side effect of staying alive', metabolite profiling can be compared to fishing up for organized signals in a universe of chaos. Although difficult, such search for metabolic patterns that might lead to replacing the term biomarker by metabolic fingerprinting in the area of pulmonary circulation has already begun.