Status In Pulmonary Arterial Hypertension Research Articles

Abstract 13128: IGFBP8 as a Novel Biomarker for Hemodynamics and Functional Status in Pulmonary Arterial Hypertension

Background: Previous studies have shown that insulin-like growth factor binding proteins (IGFBPs) are correlated with pulmonary artery hypertension (PAH) disease severity. IGFBP8 has been shown in- vitro to be associated with pulmonary vessel remodeling and PAH in gene deletion experiments. However, no studies have evaluated IGFBP8 levels in adults with PAH. Research Question: This study sought to assess if IGFBP8 concentrations are elevated in patients with PAH and if levels are associated with survival, hemodynamic, and clinical PAH measurements. Methods: Serum IGFBP8 was measured in 2,763 adults with PAH and 92 adult controls. Two PAH cohorts and two control cohorts were used for analysis. A Mann-Whitney U test was used to compare IGFBP8 levels in PAH and controls. Samples were adjusted for age and sex using linear and logistic regression for continuous and categorical variables, respectively. IGFBP8 levels in the PAH cohort were compared to mean right atrial (mRAP), mean pulmonary artery pressures (mPAP), pulmonary vascular resistance (PVR) and functional measures such as six-minute walk distance (6-MWD), and New York Heart Association Functional Class (NYHA FC). Analysis of composite outcome (death or transplant) was conducted using a Cox proportional hazard model. Results: IGFBP8 levels were higher in PAH vs controls patients (Figure 1B, p<0.0001). Among PAH patients, for every natural log unit higher, IGFBP8 was associated with death or transplant with Cox proportional hazard ratio of 1.313 (95% CI 1.034-1.666; p=0.025). Higher IGFBP8 levels were associated with lower 6-MWD (p=0.035) and increased NYHA FC (p=0.026). Hemodynamically, increased IGFBP8 levels were associated with lower cardiac index (p=0.014), increased mRAP (p=0.012) and lower stroke volume (p=0.002) but not mPAP or PVR (Figure 1A). Conclusions: IGFBP8 is a novel biomarker in PAH. Higher levels are associated with worse survival, worse hemodynamics, and poor functional status.

Wearable Devices in Pulmonary Arterial Hypertension: What Are We Trying to Learn?

Background Wearable technologies (accelerometers) are currently being evaluated as an alternative to the 6-minute walk test as an objective measure of functional status in pulmonary arterial hypertension (PAH). Multiple observational studies incorporating accelerometers have shown patients with PAH have low physical activity (PA) time. Implications for clinicians Despite widespread use of accelerometers, PA has not been shown to increase after adding vasodilator therapy, which suggests a behavioral component influencing activity. A decrease in PA from baseline may identify clinical worsening and someone at risk for future hospitalization. Cardiac Effort, the number of heart beats used during the 6-minute walk test/6-minute walk distance (beats per meter), has less variability than 6-minute walk distance and provides a comparable clinic measurement in the home setting. Cardiac Effort may provide a better remote measurement than changes in total daily activity when evaluating for clinical improvement. Conclusions The amount and duration of PA achieved in patients with PAH is likely related to a combination of right ventricular (RV) function, deconditioning, and environmental factors. Strategies to target all aspects are needed to improve PA. Further studies are needed to determine the optimal remote measure and monitoring period.

Nutritional status in pulmonary arterial hypertension.

Nutritional deficiencies have been described in patients with pulmonary arterial hypertension (PAH), such as in iron and vitamin D. However, an extensive description of vitamin and mineral status is lacking and until now there is no data on dietary intake in PAH patients. We analyzed blood samples and determined nutritional intake using a food frequency questionnaire (HELIUS) in a cohort of prevalent PAH patients at a single center in Amsterdam, the Netherlands. Quality of life (QoL) was assessed by the SF-36 questionnaire. In total, 37 patients were included (6 males, 31 females; 48 ± 16 years). The dietary intake of sugar was above 25 g in 87% of the patients and fluid intake was above 1500 ml in 78% of the patients. Sodium intake was below 1800 mg in the majority (56%) of the patients. Sugar and fluid intake were linear related. We confirm previously observed deficiencies of iron and vitamin D in our study population. In addition, we observed a functional vitamin B12 deficiency in 29% of patients, which coincided with an increased expression of methylmalonic acid. 60% of patients had a low vitamin K1 status (<0.8 nmol/L). Finally, 40% of patients had selenium levels below <100 μg/L and low selenium levels associated with reduced vitality in these patients. Besides the known deficiencies in iron and vitamin D levels, we observed in a subset of patients signs of vitamin B12, vitamin K1 and selenium deficiencies. There is room for improving dietary intake. Future research aims to demonstrate the clinical importance and reveal the effect of nutritional interventions.

Imaging of Improved Right Ventricular Coupling, Risk Status and Survival in Pulmonary Arterial Hypertension

<h3>Purpose</h3> Right ventricular function adaptation to afterload as assessed by the ratio of tricuspid annular plane excursion (TAPSE) to systolic pulmonary artery pressure (PASP) has been shown to be of prognostic relevance in pulmonary arterial hypertension (PAH).To test the hypothesis that improvement in TAPSE/PASP under targeted therapies is associated with the likelihood to achieve a better prognostic low-risk status in PAH. <h3>Methods</h3> The study retrospectively enrolled 677 PAH patients (55 % idiopathic) with follow-up clinical, right heart catheterization and echocardiographic evaluations within 12 months (IQR 180-344 days) after initiation of targeted therapies from 2005 to 2017 in 11 Italian centers. European guidelines-derived and United States Registry to Evaluate Early and Long-Term PAH Disease Management registry REVEAL 2.0 risk scores were assessed at baseline and follow-up. <h3>Results</h3> The patients improved their functional class and 6-min walk distance, but a minority of them achieved or mainteined the low risk status as assessed either with the European or the REVEAL score (30% and 27%, respectively). The TAPSE/PASP ratio increased curvilinearly in proportion to decreased pulmonary vascular resistance (PVR) by more than 50 %. Patients at low risk were respectively, 4.93 and 3.37 times more likely to have TAPSE/PASP ≥ 0.35 mm/mmHg than those at intermediate or high risk, according to the ESC/ERS (OR 4.93, C.I. 3.40-7.14; p=0.0001) and the REVEAL 2.0 score (OR 3.37, C.I. 2.32-4.90; p=0.0001). <h3>Conclusion</h3> Improvement of TAPSE/PASP under targeted therapies in PAH is associated with a low risk status and marked reduction in PVR.

121 Imaging of improved right ventricular function and risk status in pulmonary arterial hypertension

Abstract Aims Right ventricular function adaptation to afterload as assessed by the ratio of tricuspid annular plane excursion (TAPSE) to systolic pulmonary artery pressure (PASP) has been shown to be of prognostic relevance in pulmonary arterial hypertension (PAH). To test the hypothesis that improvement in TAPSE/PASP under targeted therapies is associated with the likelihood to achieve a better prognostic low-risk status in PAH. Methods and results The study retrospectively enrolled 677 PAH patients (55% idiopathic) with follow-up clinical, right heart catheterization, and echocardiographic evaluations within 12 months [interquartile range (IQR): 180–344 days] after initiation of targeted therapies from 2005 to 2017 in 11 Italian centres. European guidelines-derived and United States Registry to Evaluate Early and Long-Term PAH Disease Management registry REVEAL 2.0 risk scores were assessed at baseline and follow-up. The patients improved their functional class and 6-min walk distance, but a minority of them achieved or maintained the low risk status as assessed either with the European or the REVEAL 2.0 score (30% and 27%, respectively). The TAPSE/PASP ratio increased curvilinearly in proportion to decreased pulmonary vascular resistance (PVR) by more than 50%. Patients at low risk were, respectively, 4.93 and 3.37 times more likely to have TAPSE/PASP ≥0.35 mm/mmHg than those at intermediate or high risk, according to the ESC/ERS [odds ratio: (OR) 4.93, confidence interval (CI): 3.40–7.14; P = 0.0001] and the REVEAL 2.0 score (OR: 3.37, CI: 2.32–4.90; P = 0.0001). Conclusions Improvement of TAPSE/PASP under targeted therapies in PAH is associated with a low risk status, marked reduction in PVR, and improved outcome.

A minimal clinically important difference measured by the Cambridge Pulmonary Hypertension Outcome Review for patients with idiopathic pulmonary arterial hypertension.

Several patient-reported outcome measures have been developed to assess health status in pulmonary arterial hypertension. The required change in instrument scores needed, to be seen as meaningful to the individual, however remain unknown. We sought to identify minimal clinically important differences in the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) and to validate these against objective markers of functional capacity. Minimal clinically important differences were established from a discovery cohort (n = 129) of consecutive incident cases of idiopathic pulmonary arterial hypertension with CAMPHOR scores recorded at treatment-naïve baseline and 4–12 months following pulmonary arterial hypertension therapy. An independent validation cohort (n = 87) was used to verify minimal clinically important differences. Concurrent measures of functional capacity relative to CAMPHOR scores were collected. Minimal clinically important differences were derived using anchor- and distributional-based approaches. In the discovery cohort, mean (SD) was 54.4 (16.4) years and 64% were female. Most patients (63%) were treated with sequential pulmonary arterial hypertension therapy. Baseline CAMPHOR scores were: Symptoms, 12 (7); Activity, 12 (7) and quality of life, 10 (7). Pulmonary arterial hypertension treatment resulted in significant improvements in CAMPHOR scores (p < 0.05). CAMPHOR minimal clinically important differences averaged across methods for health status improvement were: Symptoms, –4 points; Activity, –4 points and quality of life –3 points. CAMPHOR Activity score change ≥minimal clinically important difference was associated with significantly greater improvement in six-minute walk distance, in both discovery and validation populations. In conclusion, CAMPHOR scores are responsive to pulmonary arterial hypertension treatment. Minimal clinically important differences in pulmonary hypertension-specific scales may provide useful insights into treatment response in future clinical trials.

Longitudinal changes in risk status in pulmonary arterial hypertension.

AimsLow‐risk status in pulmonary arterial hypertension (PAH) predicts better survival. The present study aimed to describe changes in risk status and treatment approaches over multiple clinical assessments in PAH, taking age and comorbidity burden into consideration.Methods and resultsThe study included incident patients from the Swedish PAH registry, diagnosed with PAH in 2008–2019. Group A (n = 340) were ≤75 years old with <3 comorbidities. Group B (n = 163) were >75 years old with ≥3 comorbidities. Assessments occurred at baseline, first‐year (Y1) and third‐year (Y3) follow‐ups. The study used an explorative and descriptive approach. Group A: median age was 65 years, 70% were female, and 46% had no comorbidities at baseline. Baseline risk assessment yielded low (23%), intermediate (66%), and high risk (11%). Among patients at low, intermediate, or high risk at baseline, 51%, 18%, and 13%, respectively, were at low risk at Y3. At baseline, monotherapy was the most common therapy among low (68%) and intermediate groups (60%), while dual therapy was the most common among high risk (69%). In patients assessed as low, intermediate, or high risk at Y1, 66%, 12%, and 0% were at low risk at Y3, respectively. Of patients at intermediate or high risk at Y1, 35% received monotherapy and 13% received triple therapy. In low‐risk patients at Y1, monotherapy (40%) and dual therapy (43%) were evenly distributed. Group B: median age was 77 years, 50% were female, and 44% had ≥3 comorbidities at baseline. At baseline, 8% were at low, 80% at intermediate, and 12% at high risk. Monotherapy was the most common therapy (62%) in Group B at baseline. Few patients maintained or reached low risk at follow‐ups.ConclusionsMost patients with PAH did not meet low‐risk criteria during the 3 year follow‐up. The first year from diagnosis seems important in defining the longitudinal risk status.

Age-related differences in hemodynamics and functional status in pulmonary arterial hypertension: Baseline results from the Pulmonary Hypertension Association Registry

The age of patients with pulmonary arterial hypertension (PAH) has increased, with registries now reporting mean ages of 50 to 65 years old. Limited data exist on age-related differences in hemodynamic and functional assessments in PAH. Adults with PAH in the Pulmonary Hypertension Association Registry were divided into 3 groups (18-50, 51-65, and >65 years old). Analysis of variance and chi-square testing were used to assess for baseline differences. Linear regression was used to examine the association of age with continuous hemodynamic and functional variables. A total of 769 patients with mean age of 56 ± 16 years were included. Older patients had more connective tissue disease-associated PAH and less drug-associated PAH. In linear regression models, each year of increased age was associated with shorter 6-minute walk distance (-3.37 meters; 95% CI, -3.97 to -2.76), lower mean pulmonary arterial pressure (-0.21 mmHg; 95% CI, -0.27 to -0.15), and lower pulmonary vascular resistance (-0.06 Wood units; 95% CI, -0.09 to -0.04). Pulmonary arterial compliance, cardiac index, right ventricular stroke work index, and percent predicted 6-minute walk distance were unrelated to age; resistance-compliance time was negatively related to age (-3 milliseconds per year; 95% CI, -4 to -2). Relative to their pulmonary vascular resistance, older patients have lower pulmonary artery compliance and worse right ventricular performance. Based on these findings, we suspect that age influences right ventricular loading conditions and the response of the right ventricle to increased afterload.

Current status of pulmonary arterial hypertension in Korea.

Pulmonary arterial hypertension (PAH) is characterized by remodeling of the distal pulmonary arteries resulting in high pulmonary vascular resistance and, eventually, right ventricular heart failure. Although current advances in PAH therapy have improved outcomes, poor survival remains a reality worldwide, including Korea. One of the most important issues in PAH is the late diagnosis, since screening or diagnostic efforts are often overlooked due to the rarity of disease. Data from Korean registries and observational cohorts show that delayed detection leads to increased morbidity. Additionally, low percentages of Korean patients are committed to intensive PAH-targeted therapy. Current Korean health insurance policies’ lack of coverage for new PAH-targeted drugs and upfront combination therapy may also hamper the improvement of treatment outcomes. Understanding individual variability in response to therapeutics through deep phenotyping is a novel strategy that should be considered when treating PAH. Overall, early detection of PAH by proactive screening together with early, intensive, individualized PAH therapy using deep phenotyping is crucial for improving prognoses for PAH patients in Korea.

Pulmonary Hypertension in Children with Congenital Left to Right Cardiac Shunt Anomalies

The Normal Pulmonary Artery (PA) systolic pressure of children and adults is &lt; 30 mm Hg and the mean PA pressure is &lt; 25 mm Hg at sea level. Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure &gt; 25 mm Hg at rest or &gt; 30 mm Hg during exercise. An increase in pulmonary flow, vascular resistance, or both can result in pulmonary hypertension. Pulmonary Arterial Hypertension (PAH) commonly arises in patients with Congenital Heart Diseases (CHD) are usually associated with increased pulmonary blood flow. Greater number of patients with Pulmonary Arterial Hypertension (PAH), associated with congenital heart disease, are now surviving into adulthood, many with increasingly complex cardiac defects. Patients with cardiac defects which result in left-to-right shunting tend to develop PAH, owing to the increased shear stress and circumferential stretch induced by pulmonary blood flow, which leads to endothelial dysfunction and progressive vascular remodeling followed by vascular resistance. Pulmonary hypertension in association with congenital heart diseases is seen in large systemicto- pulmonary communications such as Ventricular Septal Defect (VSD), Patent Ductus Arteriosus (PDA) atrioventricular septal defects, aorticopulmonary window defect etc. Pulmonary hypertension associated with large L-R shunt lesions (e.g. VSD, PDA) is called Hyperkinetic Pulmonary Hypertension (PH). It is the result of an increase in pulmonary blood flow, a direct transmission of the systemic pressure to the pulmonary artery, and compensatory pulmonary vasoconstriction. Hyperkinetic PH is usually reversible if the cause is eliminated before permanent changes occur in the pulmonary arterioles. If large L-R shunt lesions are left untreated, irreversible changes take place in the pulmonary vascular bed, with severe pulmonary hypertension and cyanosis due to a reversal of the L-R shunt. This stage is called Eisenmenger syndrome or Pulmonary Vascular Obstructive Disease (PVOD). Surgical correction is not possible at this stage. Due to lack of formal study which of the L-R congenital shunt is more commonly associated with the development of pulmonary hypertension is not known the cross-sectional study therefore intends to find the pattern of congenital L-R heart diseases commonly attributed to the development pulmonary hypertension. The diagnosis of the abovementioned congenital heart disease will be made by echocardiography. In this study, most of the participant [22 (44.0%)] were in the ‘&lt; 1 years’ age group, female were proportionately higher, most patients presented with cough and difficulty in breathing, dyspnoea and tachycardia were the most common clinical findings, murmur mostly systolic were found, Eisenmenger syndrome was not found in any child, ASD was the most common congenital anomaly. About four-fifth of the participants had single congenital anomaly. Two-fifth of the participant was found having severe PAH. Significant correlation were revealed between age group and Pulmonary arterial pressure (R= 0.775), Status of PAH was found significantly different (p&lt; 0.05) in age groups and presence of number of anomalies.Chatt Maa Shi Hosp Med Coll J; Vol.14 (2); Jul 2015; Page 31-37

Heat stress is associated with reduced health status in pulmonary arterial hypertension: a prospective study cohort.

Summer heat waves with temperature extremes are becoming more frequent with growing numbers in morbidity and mortality in patients with respiratory diseases. The aim of this study was to evaluate the ramifications of heat stress (temperature >25 °C) on the health status of patients with pulmonary arterial hypertension (PAH). Fifteen patients with PAH (mean age = 66.7 ± 5.2 years) continuously wore an accelerometer from April 1 to September 30, 2011, and their daily step count was recorded. In addition, patients kept a diary to record data on seven standardized questions regarding their daily symptoms. Echocardiography, 6-minute walk test, NTproBNP, and Modified Medical Research Council Scale (MMRC) were assessed at baseline and at the end of the study after 6 months. On heat-stress days, patients showed significantly more symptoms and lower total steps/day compared to thermal comfort days (3,995 ± 2,013 steps/day vs. 5,567 ± 2,434 steps/day, respectively; P < 0.001). There was a significant negative correlation between total steps/day and Temp(max) (R = -0.47; P < 0.001) and humidity (R = -0.34; P < 0.001). A significant positive correlation was found between daily symptoms and Temp(max) (R = +0.79; P < 0.001) and humidity (R = +0.23; P < 0.001). Heat stress is associated with a compromised clinical status in patients with PAH. Adaptation strategies must be implemented to prevent heart-related morbidity, including therapeutic adjustments and adequate room cooling in the patient's home and at the hospital.

Updating Clinical Endpoint Definitions

The 6-Minute Walk Distance (6-MWD) has been the most utilized endpoint for judging the efficacy of pulmonary arterial hypertension (PAH) therapy in clinical trials conducted over the past two decades. Despite its simplicity, widespread use in recent trials and overall prognostic value, the 6-MWD has often been criticized over the past several years and pleas from several PAH experts have emerged from the literature to find alternative endpoints that would be more reliable in reflecting the pulmonary vascular resistance as well as cardiac status in PAH and their response to therapy. A meeting of PAH experts and representatives from regulatory agencies and pharmaceutical companies was convened in early 2012 to discuss the validity of current as well as emerging valuable endpoints. The current work represents the proceedings of the conference.

Protein Kinase G-I Deficiency Induces Pulmonary Hypertension through Rho A/Rho Kinase Activation

Protein kinase G (PKG) plays an important role in the regulation of vascular smooth cell contractility and is a critical mediator of nitric oxide signaling, which regulates cardiovascular homeostasis. PKG-I-knockout (Prkg1(-/-)) mice exhibit impaired nitric oxide/cGMP-dependent vasorelaxation and systemic hypertension. However, it remains unknown whether PKG-I deficiency induces pulmonary hypertension. In this study, we characterized the hypertensive pulmonary phenotypes in Prkg1(-/-) mice and delineated the underlying molecular basis. We observed a significant increase in right ventricular systolic pressure in Prkg1(-/-) mice in the absence of systemic hypertension and left-sided heart dysfunction. In addition, we observed marked muscularization of distal pulmonary vessels in Prkg1(-/-) mice. Microangiography revealed impaired integrity of the pulmonary vasculature in Prkg1(-/-) mice. Mechanistically, PKG-I-mediated phosphorylation of Rho A Ser188 was markedly decreased, and the resultant Rho A activation was significantly increased in Prkg1(-/-) lung tissues, which resulted in Rho kinase activation. The i.t. administration of fasudil, a Rho kinase inhibitor, reversed the hypertensive pulmonary phenotype in Prkg1(-/-) mice. Taken together, these data show that PKG-I deficiency induces pulmonary hypertension through Rho A/Rho kinase activation-mediated vasoconstriction and pulmonary vascular remodeling.

The Status of Pulmonary Arterial Hypertension in 2008

Pulmonary Arterial Hypertension (PAH) is a devastating disease that, until recently, had no effective medical therapy. In 1996, a prostacyclin, epoprostenol, was approved; since then, several therapies, including prostacyclin analogues and agents that modulate other vasoactive pathways – endothelin receptor antagonists and phosphodiesterase inhibitors – have received approval. In this issue of Circulation , Galie et al report the results of the 2 pivotal trials of the endothelin receptor antagonist, ambrisentan, that lead the US Food and Drug Administration to approve this agent in June 2007.1 Article p 3010 With the approval of ambrisentan, 6 different pulmonary-specific vasodilators delivered by various routes have now been approved in the United States for treatment of PAH; moreover, numerous other therapies have either been submitted for approval or are in development. Most physicians who treat PAH are aware of the data that lead to approval of ambrisentan; for this reason, it would seem more logically an opportune time to examine critically the current status of treatment for PAH. With that in mind; I will focus on several issues: (1) Where are we in the treatment of PAH? (2) Are we happy with where we are? (3) If not, why not? and (4) What do we need to do to get there? Although we “pulmonary hypertensionologists” think we have made a significant impact on this disease, is this really true? We believe that we have improved the clinical status of our patients and their survival, but do we have data to support our “gestalt” or has the recognition of the disease and its background treatment changed to such a degree that the pulmonary-specific medications have not really had much of an impact? A recent meta-analysis of randomized clinical trials in PAH suggests that we may have overestimated our success.2 This meta-analysis reviewed …

Oral sildenafil therapy improves health-related quality of life and functional status in pulmonary arterial hypertension

Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase-5 inhibitor, has shown promising results as a novel oral monotherapy in the treatment of pulmonary arterial hypertension (PAH). We conducted a cross-sectional survey of 19 consecutive PAH patients, aged 16–75 years, with WHO functional class II or worse over 3 months of oral sildenafil. Improvement in exercise capacity was achieved in 15/19 (79%) patients. 6-minute walk test distance increased from 299 ± 118 m to 360 ± 127 m, p = 0.016, and WHO functional class decreased significantly. Both PASP and CI showed a non-significant trend toward improvement. Patients also reported significant improvement in physical ( p = 0.002) and social ( p < 0.001) functioning, and general health ( p = 0.01) of Rand SF-36 questionnaire. There was improvement in domains of role limitation due to physical health ( p = 0.16), emotion ( p = 0.14), and energy level ( p = 0.4). Our study suggests that oral sildenafil monotherapy is effective in improving exercise capacity and health-related quality of life amongst PAH patients.