05 October 2020

This week in PVD

New virtual tool may allow fast, accurate PH diagnosis during COVID-19

A new virtual tool, called VEST, is aiding clinicians in remotely diagnosing people with Group 1 pulmonary hypertension (PH) per the World Health Organization (WHO) classification, a new study reports.

VEST, short for virtual echocardiography screening tool, uses images from routine echocardiography exams of a person’s heart to diagnose PH. Researchers say this represents an advance for virtual care during the current COVID-19 pandemic, since clinical resources may be more limited and PH patients are considered a high-risk group.

The study, “Virtual echocardiography screening tool to differentiate hemodynamic profiles in pulmonary hypertension,” was published in the journal Pulmonary Circulation.

 Since the COVID-19 pandemic started, it became evident that people with PH are among those at risk for worse outcomes, if infected. Changes in clinical practice have been implemented to minimize patients’ exposure, with only urgent cases of hospitalization or clinical assessment being evaluated in person.

Right heart catheterization (RHC), which measures blood properties on the heart’s right chamber, is the gold standard method to diagnose people with different subtypes of PH. But it is an invasive exam that must be done in a medical centre.



With PH patients being managed virtually and remotely during the pandemic, evaluations by RHC have been greatly reduced. However, this could have serious implications for those with PH, “where delays in accurate diagnosis and subsequent initiation of PH-specific therapies pose a significant risk on morbidity and mortality,” the investigators wrote.

Thus, a team led by researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) developed a new tool that allows the remote diagnosis of different subtypes of PH. The tool, called VEST, is based on echocardiography, a traditional and routine exam that captures images and important parameters — including the size and shape of the heart chambers — of blood circulation in the heart.

“VEST enables physicians to quickly evaluate patients for pulmonary hypertension by simply searching for routine key measures indicated in echocardiogram reports,” Anjali Vaidya, MD, the study’s lead author, said in a press release.

Vaidya is the co-director of the Pulmonary Hypertension, Right Heart Failure & CTEPH Program at Temple University Hospital, in Philadelphia, and an associate professor of Medicine at LKSOM.

VEST uses data from several parameters measured in echocardiograms to predict blood flow in PH and diagnose PH due to pulmonary vascular disease. The diagnostic tool gives a score ranging from -3 to +3, in which higher scores indicate a higher probability of PH due to pulmonary vascular disease.

First, the researchers tested VEST in a group of 96 patients (mean age 62.4 years, 68.7% women) diagnosed with PH with available echocardiography and RHC data. The median period between RHC and echocardiographic assessment was 27.5 days.

In total, 42 patients (43.8%) were diagnosed with WHO Group 1 pulmonary hypertension and 32 (33.3%) with WHO Group 2. An additional 12 patients (12.5%) were evaluated as belonging to WHO Group 3, while six (6.3%) were identified as WHO Group 4 and four (4.2%) as WHO Group 5.

Researchers found that a VEST score above zero had an 80.0% sensitivity and a 75.6% specificity for diagnosing PH due to pulmonary vascular disease (WHO Group 1). Of note, a test’s sensitivity is its ability to correctly identify those with a given disease, while specificity refers to correctly identifying those without it.

Meanwhile, a VEST score of +3 was 92.7% specific, with a predictive value of 88.0%. Negative vest scores were predictive of WHO Group 2 PH.

Overall, a positive VEST score was 83.7% sensitive and 66.0% specific for the diagnosis of WHO Group 1 PH.

“We demonstrated that this novel VEST using three routine parameters that can be easily extracted from standard echocardiographic reports can successfully capture PH patients with a high likelihood of PHPVD [PH due to pulmonary vascular disease],” the researchers wrote.

Then, the team tested a simpler echocardiography parameter, known as e-velocity, in replacement for one of the three initial parameters that was harder to assess. Results showed that this simplified VEST score had similar outcomes to the original VEST, with a 81.4% sensitivity and a 69.4% specificity.

Moreover, it also allowed the team to discriminate PH due to pulmonary vascular disease (WHO Group 1) from other WHO PH groups.

Next, the results were validated in a second group of 30 patients, including 10 with PH due to pulmonary vascular disease and 20 with PH not linked with vascular disease.

In this second group, a positive VEST score (greater than zero) was 100.0% sensitive and 75.0% specific for a diagnosis of PH due to pulmonary vascular disease. A VEST score of +3 was 90.0% specific for the same diagnosis.

“This is the first time that routine interpretation of echocardiogram reports, without direct advanced review of imaging, has proven to be effective,” Vaidya said. “By using parameters routinely reported in echocardiograms to assess hemodynamic profiles, VEST truly facilitates the diagnosis of pulmonary hypertension.”

Vaidya said this will be useful during the continuing pandemic as clinicians try to diagnose PH.

“VEST makes early recognition of the condition possible, allowing patients to receive more timely referral for appropriate evaluation. The fact that this can be done remotely during virtual telemedicine visits is especially relevant in the COVID-19 era,” Vaidya added.

In the future, the researchers aim to assess VEST’s long-term impact on PH patient outcomes.

“Now that we have a tool for assisting virtual diagnosis of pulmonary hypertension that any physician could use, we have a real opportunity to examine long-term outcomes in patients referred for treatment based on VEST findings,” Vaidya concluded.

Rare variants of ABCC8 gene identified in Spanish PAH patients

Rare variants of the ABCC8 gene were found among pulmonary arterial hypertension (PAH) patients in Spain, a study reports.

The variants, or mutations, are predicted to alter the SUR1 protein that the ABCC8 gene provides instructions to make, but exactly how these variants might affect PAH remains unknown.

The study, “Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients,” was published in Nature Scientific Reports.

ABCC8 previously was reported to be associated with PAH through loss-of-function mutations. This kind of mutation inactivates proteins or prevents their production.

SUR1 protein forms one component of the K-ATP potassium ion channel. Ion channels allow specific charged ions to cross the cell membrane. Mutations in several ion channels have been associated with PAH and potential therapies targeting them have been proposed.

Now, a team of Spanish researchers sought more information on loss-of-function mutations in ABCC8 by looking for patients carrying mutations in that specific gene in the Spanish PAH Registry (REHAP), and then characterizing those mutations in the lab.


The team analysed records of 579 adult and 45 paediatric PAH patients, and 120 first-degree relatives (parents, offspring, or siblings). From this group, 11 patients had ABCC8 mutations (1.76% of the patients analysed).

The mean age of these 11 patients was 34 years, six were female, and five were diagnosed with idiopathic PAH — meaning the cause of their condition was unknown.

Each of these patients carried a different variant of the gene. Five variants had been described in diabetes or congenital hyperinsulinism, while the rest had no known association with disease. None of the patients carrying the mutation related to congenital hyperinsulinism showed signs of that disorder.

The investigators estimated each variant’s disease-causing potential, or pathogenicity, based on criteria from the American College of Medical Genetics and Genomics (ACMG).

Based on this analysis, two variants were classified as pathogenic, six as likely pathogenic, and three were of uncertain significance.

The team then examined nine variants in greater detail, looking for evidence of alternative gene splicing. Alternative splicing enables a single gene to make different proteins depending on the exons — portions of a gene that instruct making amino acids, the building blocks of proteins — included in the final protein-making instructions. Mutations that alter gene splicing can generate unstable proteins or no protein at all.

Researchers found that four ABCC8 variants did not alter splicing, while one variant caused an exon to be skipped. The investigators could not determine whether the remaining five variants cause alternative splicing.

Further analysis of the altered proteins’ predicted structures suggested that two of them likely would be unstable.

A patient carrying one of the likely pathogenic variants also had a mutation in the SMAD1 gene. Since some evidence links mutations in SMAD1 to PAH, the investigators hypothesized that both mutations could drive PAH in this patient.

Although the experiments carried out in this study, which used cultured cells, showed an association between mutations in ABCC8 and the likely loss of SUR1 protein function, studies in animals will be needed to confirm the link between ABCC8 loss of function and PAH.

SUR1 is found mainly in the pancreas, but it also is detectable in the lungs, pulmonary arteries, and the atrium of the heart.

“Therefore, the only way to link the loss of function in ABCC8 with PAH is if it induces a vasoconstrictor effect,” the researchers wrote.

“In conclusion, we report eleven novel changes in ABCC8 gene found in PAH patients. Thanks to in vitro biochemical analyses and [computational] tools we were able to classify them according to ACMG: two as pathogenic, six as likely pathogenic and three as [variants of uncertain significance],” the team wrote.

Letairis shows efficacy and safety in children with PAH in phase 2b trial

Letairis (ambrisentan), an approved therapy for pulmonary arterial hypertension (PAH) in adults, appears to also be effective and safe in children ages 8 and older, a study based on clinical trial data reports.

All doses tested were well tolerated by children with PAH, and Letairis’ benefit-risk profile was similar to that seen in adults.

The study, “A Randomized Study of Safety and Efficacy of Two Doses of Ambrisentan to Treat Pulmonary Arterial Hypertension in Pediatric Patients,” was published in The Journal of Pediatrics: X and was conducted by an international team of researchers.

The treatment of PAH in children is challenging, and most targeted PAH therapies are used off-label in this patient population — meaning a drug is used to treat a condition for which it has not been officially approved.

Because Letairis “is not associated with liver safety concerns and has a low risk of drug interactions” it is seen as “a promising candidate in children with PAH,” the researchers wrote.

An open-label, Phase 2b study (NCT01332331) was conduced to assess the safety and efficacy of Letairis in pediatric patients with PAH (ages 8 to 18). Of note, Letairis is marketed in the U.S. by Gilead, and in Europe by GlaxoSmithKline under the brand name Volibris.

In total, 41 enrolled children were included in this analysis. Each had been randomized to a high (5, 7.5, or 10 mg) or low (2.5 or 5 mg) dose of oral Letairis, once daily for 24 weeks. Most patients were receiving other PAH medication that could not be changed during the trial.

The study’s primary goal was to evaluate the safety, measured by the occurrence of treatment-emergent adverse events (TEAEs).

Efficacy endpoints served as secondary goal, and included changes in: exercise capacity over 24 weeks, assessed by 6-minute walk distance test (6MWD), the distance walked in six minutes; WHO functional classifications (WHO FC); and in the blood levels of a PAH biomarker called n-terminal pro-b-type natriuretic peptide (NT-proBNP).

Results showed that one or more TEAEs were experienced by most patients (80%). In terms of severity, 22% were mild and 49% were moderate, with no differences observed between dose groups.


Most common TEAEs observed were headache (24%), nausea (17%),  abdominal pain (12%), and nasopharyngitis (a cold, 12%). Eight patients had serious TEAEs, and two children died. Neither death was considered by investigators to be related to the treatment.

“Treatment with low or high doses was well tolerated and no new adverse safety findings were identified beyond those previously reported in the adult PAH population,” the researchers wrote.

Contrary to previous studies in adults using Letairis, no relevant changes in blood tests or measures of liver health were observed, supporting the potential safety of the therapy in children.

Improvements were seen on all efficacy measures analysed at both doses.

An improvement in the 6MWD was observed across the 24 weeks of the study in both dose groups, with patients walking a mean of 40.69 meters more compared to the study’s start.

After 24 weeks, the WHO functional class was maintained in 70% of the patients, and improved in 27% of them.

In both dose groups, a general decrease in NT-proBNP levels was also seen after 12 weeks (minus 14.29 nanogram/L) and at the end of the study (minus 29.63 nanogram/L).

“In children, change in NT-proBNP serum level is predictive of Functional Class, some echocardiogram parameters and survival,” the researchers noted.

An additional efficacy endpoint analysed was the change in cardiorespiratory hemodynamics — how well the blood flows in the heart and lung vessels — as assessed by right heart catheterization and echocardiogram.

Improvements were observed in the 21 patients given the low dose, as their mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were reduced. No valid hemodynamic assessment was available from the 20 children in the high dose group.

“Overall, efficacy findings were in line with those previously reported in studies evaluating ambrisentan in the adult PAH population, and compared well with those reported for other PAH treatments studied and licensed for use in children,” the researchers wrote.

“There is a persistent need for robust clinical evidence to support treatment selection in children with PAH; our findings support a potentially similar benefit-risk profile in paediatric (8 to <18 years) and adult patients with PAH,” the team concluded.

Effect of normobaric hypoxia on exercise performance in pulmonary hypertension

Patients with pulmonary hypertension (PH) exhibited a reduced exercise capacity under hypoxic conditions, although with high inter-individual variability, according to the results of a clinical trial published in CHEST.

Investigators conducted a randomized controlled, single-blinded, crossover trial (ClinicalTrials.gov Identifier: NCT03592927) between August 2018 and April 2019 at the University Hospital Zürich in Zürich, Switzerland. They sought to explore the effect of hypoxia compared to normoxia on constant-work-rate-exercise-test (CWRET) time in patients with PH and to evaluate the physiologic mechanisms that are involved in the process. Adult patients who had been diagnosed with pulmonary arterial hypertension (PAH)/chronic thromboembolic pulmonary hypertension (CTEPH) — both summarized as PH herein — were recruited from outpatients of the PH-center Zürich.

All of the participants were randomly assigned to breathe ambient air (normoxia, fraction of inspired oxygen [FiO2]: 21%) initially, followed by normobaric hypoxia (FiO2: 15%), or vice versa, using a sealed facemask with a non-rebreathing 2-way valve during 20 or more minutes of rest. This was followed by use of a symptom-limited cycle-ergometer CWRET until exhaustion.

The primary study outcome was the difference in CWRET time under conditions of normobaric hypoxia compared to ambient air. Arterial blood gases, Borg-dyspnea, tricuspid regurgitation pressure gradient, and mean pulmonary artery pressure (mPAP)/cardiac output ratio by echocardiography were evaluated before and after CWRET.


A total of 28 participants were included in the study. The median patient age was 66 years; 13 of the participants were women. The mean PAP was 41 mm Hg; pulmonary vascular resistance (PVR) was 5.4 Wood Units. CWRET times were 16.9 minutes and 6.7 minutes under normoxia and hypoxia, respectively (P =.006).

At the end of exercise under conditions of normoxia and hypoxia, the median values were as follows: partial pressure of oxygen (PaO2): 8.0 kPa vs 6.4 kPa, respectively; arterial oxygen content: 19.2 mL/dL vs 17.2 mL/dL, respectively; partial pressure of carbon dioxide (PaCO2): 4.7 kPa vs 4.3 kPa, respectively; and lactate: 3.7 mmol/L vs

3.7 mmol/L, respectively (P <.05 for all). The following measurements remained unchanged: Borg scale: 7 vs 6, respectively; tricuspid pressure gradient: 89 mm Hg vs 77 mm Hg, respectively; and mPAP/cardiac output: 4.5 Wood Units vs 3.3 Wood Units, respectively. Per multivariable regression, baseline PVR was the sole factor that predicted hypoxia-induced change in CWRET time.

The investigators concluded that additional studies at real altitude are warranted to explore longer-term changes and adaptive mechanisms to hypoxia in patients with PH, the potential adverse effects, and their risk factors.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Schneider SR, Mayer LC, Lichtblau M, et al. Effect of normobaric hypoxia on exercise performance in pulmonary hypertension – randomized trial. CHEST. Published online September 8, 2020. doi:10.1016/j.chest.2020.09.004

In Memoriam: Professor Ingram Schulze-Neick, MD, PhD (1960–2020)

Department of Pediatric Cardiology and Pediatric Intensive Care, Medical Hospital of the University of Munich, Ludwig Maximilians University Munich, Munich, Germany; 2 Department of Pediatric Cardiology and Congenital Heart Defects, German Heart Centre Berlin and Charité – University Medicine Berlin, Berlin, Germany and 3 Klinik für Angeborene Herzfehler / Kinderkardiologie Deutsches Herzzentrum Berlin und Charité – Universitätsmedizin Berlin, Berlin, Germany


Ingram Schulze-Neick, died suddenly and unexpected on April 3rd, 2020. He was born on October 17th, 1960 in Bonn, Germany, which was at that time the capital of the Federal Republic of Germany. His father was a High School teacher, and his mother was a teacher at an Elementary School. Together with his younger sister, he spent his entire school time in Bonn from 1966 until June, 1977. Like every young man at that time, he had to enter his military service after school, but after three months of military service, he decided to refuse further military service and continued his community service at the University of Bonn instead, as a research assistant in epilepsy research and General Surgery at the faculty of medicine. Ingram started his medical studies at the University of Bonn in 1980 and spent his time for the preclinical years there. After passing his Physikum, he moved to Hamburg, Germany, where he graduated from his medical studies in July, 1987.

During the following months, he also completed his Doctoral Thesis in December, 1987 at the Institute for Pathology, with the topic of: “Adenoid cystic carcinoma of the salivary glands: an immunohistological study”, which was granted the second highest grading: “Magna Cum Laude”. During his studies in Hamburg, he took the chance to spend some time outside Germany for several 4-week to 6-week electives. First, he was in Edinburgh, United Kingdom doing Obstetrics and Gynecology, then he visited Harvard University at the Children´s Hospital in Boston, Massachusetts, United States of America for training in Paediatric Cardiology. Following this, he visited the Radcliff Hospital in Oxford, United Kingdom for Neurology, and finally he spent some time in Paediatric and Neonatal Intensive Care at Johns Hopkins University in Baltimore, Maryland, United States of America. These electives clearly had paved the way for his further professional career in Paediatric Cardiology and Intensive Care. After graduation, and in preparation for his planned research time, he passed the relevant United States of America Exams (ECFMG) in January 1988, and he was granted a post-graduate stipendium by the German Research Society for a Research Fellowship.

He had the chance to work as a Post-doctorate Research Assistant from April 1988 until August 1989 at the cardiopulmonary exercise laboratories with the team of Professor Hans U. Wessel at the Department for Paediatric Cardiology, Children’s Memorial Hospital, Northwestern University, Chicago, United States of America. During this time, his deep interest in cardiopulmonary interactions and the pulmonary circulation was born, which never lost its grip on him during the rest of his professional career. In August 1988, he left the United States of America to start his training as a General Paediatrician at the Medical School of Hannover (MHH), where he spent 2 years until August, 1991, and where he was involved in establishing a laboratory research unit. From September, 1991 until July 1996 he moved to the German Heart Center in Berlin (Deutsches Herzzentrum Berlin, DHZB) and the Charité – Universitätsmedizin Berlin from 1996 until April 1997, where he completed his training in Paediatrics.

His professor and mentor, https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1047951120001171 Downloaded from https://www.cambridge.org/core. IP address:, on 06 Oct 2020 at 12:35:50, subject to the Cambridge Core terms of use, available at Professor Peter E. Lange, supported him and his scientific work. Despite a huge clinical workload, Ingram always found the time to do fundamental research work in clinical topics as well as in the animal laboratory. In these days, nitric oxide first became available for the management of pulmonary hypertension. Ingram Schulze Neick was the first to develop a catheter protocol for testing pulmonary vasoreactivity, and thereby made it possible to assess the severity of pulmonary hypertension in these particular patients. He published innovative case reports in the Lancet, and wrote comments in the New England Journal of Medicine, on the first examples of inhaled or intratracheal prostaglandin administration, techniques that all are standard treatment nowadays. During these fruitful days, he became a very good friend and colleague of many paediatric cardiologists, not only in Germany but also in Europe and worldwide, many of whom are now highly qualified specialists and Professors of Paediatric Cardiology in Germany and elsewhere.

From May 1997 until December 2000, Ingram moved to London, United Kingdom, as a Research Fellow, and was simultaneously involved in clinical work as a Clinical Registrar at the Royal Brompton & Harefield Hospitals and The Great Ormond Street Hospital for Sick Children. He joined the team of Professor Andrew Redington and intensified his profound research in pulmonary hypertension and cardiopulmonary cross-talk, and the impact of pulmonary hypertension on the right ventricular function.

After formally completing his training in Paediatric Cardiology in 2000, Ingram Schulze-Neick again joined the team at the DHZB in 2001, as full time Consultant for Paediatric Cardiology, where he shared with the other consultants the responsibilities in the Catheterization Laboratory, the Intensive Care Unit, the Intermediate Care Unit, the transplant service and the outpatient department. During this time, he intensified his research and published numerous papers on the related topics of pulmonary hypertension, cardiopulmonary interactions, congenital heart defects, and intensive care management, mainly in high rated peer reviewed international journals. In addition, he completed his PhD thesis based on his research work: “Postoperative Pulmonary Hypertension after Congenital Heart Surgery: Treatment, Pathophysiology and Vasculo-bronchial Interactions”. Besides his clinical activities, Ingram Schulze-Neick was a driving member of the German Kompetenznetz, a Germanwide research network leading a clinical task force for the research and management of patients with pulmonary hypertension and congenital heart defects.

In March 2007, Ingram Schulze-Neick was appointed as Clinical Director for the Nationwide Service for Children with Pulmonary Hypertension in the United Kingdom, and lead physician at The Great Ormond Street Hospital for Children, London, United Kingdom, where he stayed until 2014. From 2015, Ingram Schulze-Neick joined our team at the Ludwig Maximilians University (LMU) in Munich, Germany, where he established a well-recognized and publicly-accepted Specialist Service for Pulmonary Hypertension at the Department for Paediatric Cardiology and Paediatric Intensive Care at the Klinikum of the University of Munich (KUM). He was appointed an Associate Professorship and awarded the title of full Professor in 2018. In addition, Ingram had another hobby that guided and accompanied his career – the love for music and playing the cello. He started early at school time and played in his school orchestra, later on he joined numerous orchestras of local medical associations, universities, as well as the Orchestra of the German paediatricians. Ingram loved many aspects of music, combining classical music as well as modern jazz. Not to forget, he was one of the co-founders of the Baby Blue Sound Collective, a group of paediatric cardiologists, heart surgeons, nurses, and much more, creating music to support children and adults with congenital heart disease. He joined the last meeting of this famous group in

February 2020, one month ahead of his unforeseeable death. A tribute to Ingram from his bandmates can be found here: https://youtu.be/6AHXZHOwYZE The long and fruitful career and ingenious mind of Ingram Schulze Neick will be continued in the work of his colleagues and friends. Many of them became leaders in their own fields and founders in their own scientific areas, but Ingram’s discussions and thoughts continue to serve as a source of fruitful ideas for many of them. Despite his enormous scientific and clinical research activities, Ingram always remained an excellent physician with all the warmth of a sensible caring doctor. His focus was always the optimal management of the patients and their families, and he always was highly respected for this unique social competence and personal engagement.

He used his scientific background to improve the outcome and quality of life of many patients (both children and adults) with congenital heart defects, right ventricular dysfunction, and pulmonary hypertension of all causes. This desire for comprehensive knowledge was characteristic. His broad culture made him one of the most interesting and respected of colleagues and friends. He was dedicated to his family and his patients, and he was always a loyal friend. Whoever had the chance to meet him, or ever had the privilege to work with him, knows what a warm, wonderful, intelligent physician Ingram was. He was a deep thinker and produced pioneering ideas until his last days. His death leaves an unfillable void. We will miss Ingram, and his inspiration and wisdom. We can commemorate his memory in the only way he would approve, by continuing his work. We will never forget him.

UK Government adds pulmonary vascular disease to guidance on COVID-19: long-term health effects

The UK government has updated its advice on the long term health effects of COVID-19 and listed pulmonary vascular disease as one of many continuing symptoms following discharge. The full list of symptoms includes:

  • respiratory symptoms and conditions such as chronic cough, shortness of breath, lung inflammation and fibrosis, and pulmonary vascular disease
  • cardiovascular symptoms and disease such as chest tightness, acute myocarditis and heart failure
  • protracted loss or change of smell and taste
  • mental health problems including depression, anxiety and cognitive difficulties
  • inflammatory disorders such as myalgia, multisystem inflammatory syndrome, Guillain-Barre syndrome, or neuralgic amyotrophy
  • gastrointestinal disturbance with diarrhoea
  • continuing headaches
  • fatigue, weakness and sleeplessness
  • liver and kidney dysfunction
  • clotting disorders and thrombosis
  • lymphadenopathy
  • skin rashes

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