Feature 1 // Distinct plasma gradients of microRNA-204 in the pulmonary circulation of patients suffering from WHO Groups I and II pulmonary hypertension
Pulmonary hypertension (PH), a heterogeneous vascular disease, consists of subtypes with overlapping clinical phenotypes. MicroRNAs, small non-coding RNAs that negatively regulate gene expression, have emerged as regulators of PH pathogenesis. The muscle-specific micro RNA (miR)-204 is known to be depleted in diseased pulmonary artery smooth muscle cells (PASMCs), furthering proliferation and promoting PH. Alterations of circulating plasma miR-204 across the trans-pulmonary vascular bed might provide mechanistic insights into the observed intracellular depletion and may help distinguish PH subtypes. MiR-204 levels were quantified at sequential pulmonary vasculature sites in 91 patients with World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) (n ¼ 47), Group II PH (n ¼ 22), or no PH (n ¼ 22). Blood from the right atrium/superior vena cava, pulmonary artery, and pulmonary capillary wedge was collected. Peripheral blood mononuclear cells (PBMCs) were isolated (n ¼ 5/group). Excretion of miR-204 by PAH-PASMCs was also quantified in vitro. In Group I patients only, miR-204 concentration increased sequentially along the pulmonary vasculature (log fold-change slope ¼ 0.22 [95% CI ¼ 0.06–0.37], P ¼ 0.008). PBMCs revealed insignificant miR-204 variations among PH groups (P ¼ 0.12). Cultured PAH-PAMSCs displayed a decrease of intracellular miR-204 (P ¼ 0.0004), and a converse increase of extracellular miR-204 (P ¼ 0.0018) versus control. The stepwise elevation of circulating miR-204 across the pulmonary vasculature in Group I, but not Group II, PH indicates differences in muscle-specific pathobiology between subtypes. Considering the known importance of miR-204 in PH, these findings may suggest pathologic excretion of miR-204 in Group I PAH by PASMCs, thereby accounting for decreased intracellular miR-204 concentration.
Feature 2 // Switching to riociguat: A potential treatment strategy for the management of CTEPH and PAH
Currently, five classes of drug are approved for the treatment of pulmonary arterial hypertension (PAH): phosphodiesterase 5 inhibitors (PDE5i), endothelin receptor antagonists, prostacyclin analogs, the IP receptor agonist selexipag, and the soluble guanylate cyclase (sGC) stimulator riociguat. For patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), riociguat is currently the only approved pharmacotherapy. Despite the development of evidence-based guidelines on appropriate use of specific drugs, in clinical practice patients are often prescribed PAH-targeted therapies off label or at inadequate doses.
PDE5i are the most often prescribed class of drugs as initial therapy, either alone or in combination with other drug classes. However, a proportion of patients receiving PAH therapies do not reach or maintain treatment goals. As PDE5i and riociguat target different molecules in the nitric oxide-sGC-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway, for patients with PAH without an initial or sustained response to PDE5i, there is a biological rationale for switching to riociguat. However, robust data from randomized controlled trials on the safety and efficacy of switching are lacking, as is formal guidance for clinicians. Here we review studies of sequential combination therapy, and trial data and case studies that have investigated switching between PAH-approved therapies, particularly from PDE5i to riociguat in patients with PAH with an insufficient response PDE5i, and in patients with CTEPH who were receiving off-label treatment. These studies summarize the current evidence and practical reallife experience on the concept of switching treatments.
Preserving right ventricular function in patients with pulmonary arterial hypertension: single centre experience with a cardiac magnetic resonance imaging-guided treatment strategy
The feasibility and usefulness of routine cardiac magnetic resonance imaging (CMR) in the management of idiopathic pulmonary arterial hypertension (IPAH) is unknown. Aims: To study whether 1) a decrease in CMR-derived right ventricular ejection fraction (RVEF) coincides with clinical deterioration; 2) to determine whether RVEF is responsive to early escalation of PAHspecific therapy.
This was a prospective study including 30 incident IPAH patients. Patients underwent right heart catheterization (RHC) and CMR at regular follow-up visits (baseline, 4, 8, 12, 24 months, no RHC at 8 months). NYHA II patients started with monotherapy (endothelin receptor antagonist (ERA) or phosphodiesterase-5-inhibitor (PDE5I)) and NYHA III patients with combination therapy (ERA plus PDE5I). In case of a deterioration in RVEF more than 3% compared to the previous measurement, PAH-specific therapy was added (i.e. treatment escalation).
In 11 patients without signs of clinical deterioration, a greater than 3% decrease in RVEF occurred. After treatment escalation, RVEF significantly improved (average improvement of 7%, p=0.009) whereas RV volumes, NTproBNP and six-minute walking distance remained stable. Clinical worsening (CW) did not occur after escalating therapy. Throughout the study, 4 patients presented with CW, despite a stable RVEF. Three of these 4 patients had a baseline RVEF <35%.
In IPAH patients presenting with an early decrease in RVEF but otherwise stable disease, progressive RV failure and subsequent CW did not occur when therapy was escalated. Nevertheless, CW did occur in patients with a low baseline RVEF.
Low-Grade Albuminuria in Pulmonary Arterial Hypertension
Low-grade albuminuria, determined by urinary albumin to creatinine ratio (ACR), has been linked to systemic vascular dysfunction and is associated with cardiovascular mortality. Pulmonary arterial hypertension (PAH) is related to mutations in the bone morphogenetic protein receptor type 2, pulmonary vascular dysfunction and increasingly recognized as a systemic disease. In a total of 283 patients (two independent cohorts) diagnosed with PAH, 18 unaffected BMPR2 mutation carriers and 68 healthy controls, spot urinary ACR and its relationship to demographic, functional, hemodynamic and outcome data were analyzed. PAH patients and unaffected BMPR2 mutation carriers had significantly elevated urinary ACRs compared to healthy controls (p<0.01; p=0.04). In PAH patients, urinary ACR was associated with older age, lower six-minute walking distance, elevated levels of Creactive protein (CRP) and hemoglobin A1c (HbA1c), but there was no correlation between urinary ACR and hemodynamic variables. PAH patients with a urinary ACR above 10µg/mg had significantly higher rates of poor outcome (p<0.001). This study shows that low-grade albuminuria is prevalent in PAH patients and associated with poor outcome. This study shows that albuminuria in PAH is associated with systemic inflammation and insulin resistance.
A Multidisciplinary Pulmonary Embolism Response Team (PERT) – Experience from a national multicenter consortium
We provide the first multicenter analysis of patients cared for by eight Pulmonary Embolism Response Teams (PERTs) in the United States (US); describing the frequency of team activation, patient characteristics, pulmonary embolism (PE) severity, treatments delivered and outcomes.
We enrolled patients from the National PERT ConsortiumTM multicenter registry with a PERT activation between October 18, 2016 to October 17, 2017. Data are presented combined and by PERT institution. Differences between institutions were analyzed using chisquared test or Fisher’s exact test for categorical variables and ANOVA or Kruskal-Wallis test for continuous variables, with a two-sided p value <0.05 considered statistically significant.
There were 475 unique PERT activations across the Consortium with acute PE confirmed in 416 (88%). The number of activations at each institution ranged from 3 to 13 activations/month/1000beds with the majority originating from the emergency department (281/475; 59.3%). The largest percentage of patients were at intermediate-low (141/416, 34%) and intermediate-high (146/416, 35%) risk of early mortality, while fewer were at high-risk (51/416, 12%) and low-risk (78/416, 19%). The distribution of risk groups varied significantly between institutions (p=0.002). Anticoagulation alone was the most common therapy, delivered to 289/416 (70%) patients with confirmed PE. The proportion of patients receiving any advanced therapy varied between institutions (p= 0.0003), ranging from 16% to 46%. 30-day mortality was 16% (53/338) ranging from 9% to 44%.
The frequency of team activation, PE severity, treatments delivered, and 30-day mortality varies between US PERTs. Further research should investigate the sources of this variability.
Interpretation of a new biomarker for the right ventricle introduced to evaluate the severity of pulmonary arterial hypertension
Letter to the editor
Assessment of right ventricular (RV) performance can be a challenge for clinicians and researchers, especially in the diseased heart. In their study on pulmonary arterial hypertension (PAH) in pediatric patients Yang et al. sought to identify a quantitative measure to predict disease progression and to assist treatment planning.
The use of a durable right ventricular assist device for isolated right ventricular failure due to combined pre- and postcapillary pulmonary hypertension
Patients with isolated right ventricular failure have poor outcomes and minimal treatment options. We report a case where a durable RVAD was implanted for end stage right ventricular failure from combined pre- and postcapillary pulmonary hypertension due in part to chronic thromboembolic pulmonary hypertension using a temporary percutaneous RVAD as a bridging strategy. While the patient ultimately died from non-cardiovascular causes, there was significant improvement in markers of cardiogenic shock and hemodynamic RV function parameters without adverse effects from increased pulmonary artery pressures. More research is needed to identify an appropriate long-term mechanical support strategy for this patient population.
Advanced interstitial lung fibrosis with emphysema and pulmonary hypertension with no evidence for interstitial lung disease on high resolution CT
The diagnosis of idiopathic pulmonary arterial hypertension is complex and besides invasive hemodynamic evaluation includes several diagnostic steps to exclude any underlying diseases. The role of a decreased diffusion capacity of the lung for carbon monoxide (DLCO) is a matter of discussion. Here we present a 76-year old man with a smoking history of 30 PY who was diagnosed with idiopathic pulmonary arterial hypertension after chronic thromboembolic PH was excluded based on a negative perfusion scan, an underlying heart disease was excluded based on echocardiography and right heart catheterisation and a significant lung disease was excluded based on lung function test (FVC=101% predicted, FEV1=104% predicted, FEV1/FVC=77, TLC=97% predicted) and thin slice CT scan. Just DLCO was reduced to 40% predicted, suggesting a possible structural lung disease. Postmortem examination demonstrated severe interstitial lung fibrosis combined with microscopic emphysema. This indicates that both CT imaging and pulmonary function test may be insensitive to a diffuse peripheral combined pattern of fibrosis and emphysema, and that DLCO may be the only sensitive marker of this significant lung pathology.
Sildenafil for bronchopulmonary dysplasia and pulmonary hypertension: a meta-analysis
Bronchopulmonary dysplasia (BPD) is the most common complication in preterm infants and often complicated by pulmonary hypertension (PH), leading to substantial morbidity and mortality. Sildenafil is often used to treat PH and improve symptoms in this condition, even though evidence of safety and effectiveness is scarce.
The aim of this study was to perform a systematic review and meta-analysis about the effectiveness and safety of chronic use of sildenafil in preterm infants with BPD-associated PH. Data Sources: PubMed, EMBASE and Medline. Study selection: Studies reporting the effectiveness of sildenafil therapy in BPD-associated PH in newborns and infants were included. Data extraction: All-cause mortality, improvement in PH, improvement in respiratory scores and adverse events were extracted.
Five studies were included, yielding a total of 101 patients with 94.2 patient-years of total follow-up. The pooled mortality rate was 29.7%/year (95% CI 6.8 – 52.7). Estimated pulmonary arterial pressure improved >20% in 69.3% (95% CI 56.8 - 81.8) of patients within 1-6 months. Respiratory scores improved in 15.0% (95% CI 0.0-30.4) of patients within 2-7 days. There were no serious adverse events during sildenafil therapy.
This systematic review shows that in the treatment of BPD-associated PH in preterm infants, sildenafil may be associated with improvement in PAP and respiratory scores. However, there is no clear evidence of its effect on mortality rates. Considering BPD as a complex disease with variable expression patterns, these results support the need for a prospective registry and standardized approach.
Parameters associated with outcome in pediatric patients with congenital heart disease and pulmonary hypertension subjected to combined vasodilator and surgical treatments
Management of pediatric pulmonary hypertension associated with congenital heart disease (PHT-CHD) is challenging. Some patients have persistently elevated pulmonary artery pressure (PAP) after cardiac surgery, an undesired condition that is difficult to predict. We investigated the value of clinical, hemodynamic and histopathological data in predicting the outcome in a prospective cohort. Patients with PHT-CHD received sildenafil orally pre- and postoperatively for 6 months, and then were subjected to a catheter study. Thirty-three patients were enrolled (age 4.6- 37.0 months). Pulmonary vascular resistance (PVR) was 4.9 (3.9-7.2) Wood units x m2 (median with IQR). Twenty-two patients had a ≥20% decrease in PVR and pulmonary-to-systemic vascular resistance ratio (PVR/SVR) in response to inhaled nitric oxide. The response was directly related to the degree of medial hypertrophy of pulmonary arterioles (p<0.05) (morphometric analysis, intraoperative lung biopsy). Subsequently, five of the nonresponders had a ≥30% increase in pulmonary blood flow in response to sildenafil (3.0 [2.0-4.0] mg/kg/day). Six months after surgery, PAP and PVR were significantly lower (p<0.001 vs. baseline), even in 7 patients with Heath-Edwards grade III/IV pulmonary vascular lesions (p=0.018), but still abnormal in 12 subjects (respectively, >25 mmHg and >3.0 U x m2). A preoperative PVR/SVR of ≥24% during nitric oxide inhalation and a wall thickness of arteries accompanying respiratory bronchioli of ≥4.7 (Z score) were identified, respectively, as risk and protection factors for abnormal postoperative hemodynamics (hazard ratio [95% CI], 1.09 [1.01-1.18], p=0.036, and 0.69 [0.49-0.98], p=0.040, respectively). Thus, in PHT-CHD patients receiving oral sildenafil pre and post-surgical repair of cardiac lesions, midterm postoperative outcome is predictable to some extent.
Novel Early Life Risk Factors for Adult Pulmonary Hypertension
The role of perinatal insults in the development of adult onset pulmonary hypertension (PH) is unclear. We surveyed patients with and without PH for a history of early life risk factors, and identified prematurity, oxygen use, and respiratory illness each as risk-predictors for development of adult PH.
Statement on imaging and pulmonary hypertension from 2 the Pulmonary Vascular Research Institute (PVRI)
Pulmonary hypertension is highly heterogeneous and despite treatment advances it remains a life shortening condition. There have been significant advances in imaging technologies, but despite evidence of their potential clinical utility practice remains variable, dependent in part on imaging availability and expertise. This statement summarises current and emerging imaging modalities and their potential role in the diagnosis and assessment of suspected pulmonary hypertension. It also includes a review of commonly encountered clinical and radiological scenarios, and imaging and modeling-based biomarkers. An expert panel was formed including clinicians, radiologists, imaging scientists and computational modelers. Section editors generated a series of summary statements based on a review of the literature and professional experience and following consensus review, a diagnostic algorithm and fifty five statements were agreed. The diagnostic algorithm and summary statements, emphasise the key role and added value of imaging in the diagnosis and assessment of pulmonary hypertension and highlight areas requiring further research.
Right ventricular outflow tract velocity time integral-topulmonary artery systolic pressure ratio: A noninvasive metric of pulmonary arterial compliance differs across the spectrum of pulmonary hypertension
Pulmonary arterial compliance (PAC), invasively assessed by the ratio of stroke volume to pulmonary arterial (PA) pulse pressure, is a sensitive marker of right ventricular (RV)-PA coupling that differs across the spectrum of pulmonary hypertension (PH) and is predictive of outcomes. We assessed whether the echocardiographically-derived ratio of right ventricular outflow tract velocity time integral to PA systolic pressure (RVOT-VTI/PASP) (a) correlates with invasive PAC, (b) discriminates heart failure with preserved ejection-associated PH (HFpEF-PH) from pulmonary arterial hypertension (PAH), and (c) is associated with functional capacity.
We performed a retrospective cohort study of patients with PAH (n=70) and HFpEF-PH (n=86), which was further dichotomized by diastolic pressure gradient (DPG) into isolated post-capillary PH (DPG < 7mmHg; Ipc-PH, n = 54), and combined post- and pre-capillary PH (DPG ≥ 7 mm Hg; Cpc- DOI: 10.1177_2045894019841978 PH, n = 32). Of the 156 total patients, 146 had measurable RVOT-VTI or PASP and were included in further analysis.
RVOT-VTI/PASP correlated with invasive PAC overall (ρ=0.61, p<0.001) and for the PAH (ρ=0.38, p=0.002) and HFpEF-PH (ρ=0.63, p<0.001) groups individually. RVOT-VTI/PASP differed significantly across PH spectrum (PAH: 0.13 (0.010-0.25) vs. Cpc-PH: 0.20 (0.12-0.25) vs. Ipc-PH: 0.35 (0.22-0.44; p<0.001), distinguished HFpEF-PH from PAH (AUC 0.72, 95% CI [0.63-0.81]) and Cpc-PH from Ipc-PH (AUC 0.78, 95% CI [0.68-0.88]), and remained independently predictive of 6-minute walk distance after multivariate analysis (standardized β-coefficient [95% CI]: 27.7 [ 9.2 to 46.3]; p=0.004). CONCLUSIONS: Echocardiographic RVOT-VTI/PASP is a novel noninvasive metric of PAC that differs across the spectrum of PH. It distinguishes the degree of pre-capillary disease within HFpEF-PH and is predictive of functional capacity.