Brief Report: Case Comparison of Therapy With the Histone Deacetylase Inhibitor Vorinostat in a Neonatal Calf Model of Pulmonary Hypertension
Mean Pulmonary Artery Pressure Over Cardiac Output Slope And HFpEF Characteristics
About 1 in 5 patients with unexplained dyspnea have pulmonary hypertension despite a negative diastolic stress test (DST), researchers reported in the Journal of the American Heart Association.
The prospective cohort study assessed the prevalence and clinical significance of pulmonary hypertension during exercise (exPHT), based on the slope of estimated mean pulmonary arterial pressure over cardiac output (mPAP/CO) and its association with DST in patients with suspected heart failure with preserved ejection fraction (HFpEF).
The participants were referred to a dyspnea clinic in Belgium from January 2016 to December 2022 owing to exertional dyspnea or fatigue and had available mPAP/CO slope data.
The patients were stratified into 3 groups:
All participants had a standardized dyspnea clinic workup, as well as laboratory testing for N-terminal pro-B-type natriuretic peptides (NT-proBNP), a spirometry test, a 12-lead ECG, transthoracic echocardiography at rest, and exercise echocardiography combined with a cardiopulmonary exercise test on a semisupine bicycle at a 45-degree angle.
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…an exercise echocardiography showing a high mean pulmonary artery pressure over cardiac output slope…warrants further evaluation with invasive exercise hemodynamics to diagnose HFpEF, even when the DST is negative.
The cohort included 1936 patients (mean age, 64±15 years; 49% women). Among the participants, 38% had exPHT, defined as an mPAP/CO slope of higher than 3 mm Hg/L per min, and 22% had exPHT with a discordant, negative DST. The patients with exPHT and exE/e′ of less than 15 had a peak Vo2 as low as those with exE/e′ of 15 or higher (24%) and significantly lower compared with patients with exE/e′ of less than 15 and no exPHT (54%).
After adjustment for age, sex, and indexed left atrial volume (LAVi), mPAP/CO had a stronger association with exercise capacity than exE/e′. In addition, mPAP/CO was associated (P <.001) with worse exercise capacity regardless of the DST, and the association was greater in participants who had a lower exE/e′ vs those with increased values (P interaction <.001).
The mPAP/CO slope predicted Vo2 (mL/kg per min) independent of sex, age, LAVi, and exE/e′, regardless of whether HFpEF scores were low (18%), intermediate (64%), or high (17%).
The 2-point mPAP/CO slopes that were obtained with only peak and rest or only intermediate and rest mPAP and CO were comparable, which confirmed the linear relationship between mPAP and CO.
The mPAP/CO slope and exE/e′ independently predicted NT-proBNP and the logistic H2FPEF score, including after adjustment for age, sex, and LAVi.
Among participants with a low mPAP/CO slope (≤3 mm Hg/L per min), 22% had an exercise tricuspid regurgitation velocity (exTRV) of higher than 3.4 m/s. An increased exTRV was associated with greater peak Vo2, and the relationship was negative for mPAP/CO slope. NT-proBNP levels were not associated with exTRV.
The estimation of mPAP/CO slope was more clinically relevant compared with single-point exTRV values, according to the investigators.
Among several study limitations, patients with worse than mild pulmonary disease were excluded, and it is unknown whether the average exE/e′ is superior to septal exE/e′ for diagnosis and prognostication.
"In patients with negative HFpEF scores, an exercise echocardiography showing a high mean pulmonary artery pressure over cardiac output slope rather than maximal tricuspid regurgitation velocity during exercise warrants further evaluation with invasive exercise hemodynamics to diagnose HFpEF, even when the DST is negative," the study authors wrote.
New Insights And Potential Treatments For Pulmonary Hypertension
A new study from researchers with UCLA Health and collaborating organizations has found that asporin, a protein encoded by the ASPN gene, plays a protective role in pulmonary arterial hypertension (PAH).
Their findings, published on August 21 in the peer-reviewed journal Circulation, offer new insights into this incurable, often-fatal disease and suggest potential new ways to treat it.
"We were surprised to find that asporin, which previously had not been linked to PAH, gets upregulated to increased levels as a response to counteract this disease process," said Dr. Jason Hong, a pulmonary and critical care physician at UCLA Health and the study's corresponding author. "This novel finding opens up new avenues for understanding PAH pathobiology and developing potential therapies."
Pulmonary hypertension is a serious medical condition characterized by high blood pressure in the arteries that supply the lungs. It causes these arteries to narrow or become blocked, which, in turn, slows blood flow to the heart, requiring it to work harder to pump blood through the lungs. Eventually, the heart muscle becomes weak and begins to fail.
Need for New Therapies
According to recent estimates, PAH affects about 1% of the global population, but that number climbs to 10% in people who are 65 or older.
There's no cure for the disease, but medications and lifestyle changes can help slow progression, manage symptoms and prolong life.
The urgent need for new therapies, combined with the potential of multiomics -- an integrated approach to drive discovery across multiple levels of biology -- inspired Hong and research colleagues, including co-first author Lejla Medzikovic and senior author Mansoureh Eghbali to take a deep dive into the disease. Both work at UCLA's Eghbali Laboratory.
Methodology
For the study, the researchers applied novel computational methods, including transcriptomic profiling and deep phenotyping, to lung samples of 96 PAH patients and 52 control subjects without the condition from the largest multicenter PAH lung biobank available to-date. They integrated this data with clinical information, genome-wide association studies, graphic models of probabilities and multiomics analysis.
"Our detailed analysis found higher levels of asporin in the lungs and plasma of PAH patients, which were linked to less severe disease," Hong said.
Additionally, Medzikovic noted that their cell and living-organism experiments found that asporin inhibited pulmonary artery smooth muscle cell proliferation and a key signaling pathway that occurs with PAH.
"We also demonstrated that recombinant asporin treatment reduced PAH severity in preclinical models," said Medzikovic.
Next Steps
Hong and colleagues plan to further investigate the mechanisms by which asporin exerts its protective effects in PAH and explore potential therapeutic applications, focusing on how to translate their findings into clinical trials.
"Asporin represents a promising new target for therapeutic intervention in pulmonary arterial hypertension," he explained. "Enhancing asporin levels in PAH patients could potentially lead to improved clinical outcomes and reduced disease progression."
Authors: Jason Hong, MD, PhD,* Lejla Medzikovic, PhD*, Wasila Sun, BS‡, Brenda Wong, BA‡, Gregoire Ruffenach, PhD, Christopher J. Rhodes, PhD, Adam Brownstein, MD, Lloyd L. Liang, MS, Laila Aryan, PhD, Min Li, PhD, Arjun Vadgama, Zeyneb Kurt, PhD, Tae-Hwi Schwantes- An, PhD, Elizabeth A. Mickler, MS, Stefan Graf, PhD, Melanie Eyries, PhD, Katie A. Lutz, BS, Michael W. Pauciulo, MBA, Richard C. Trembath, MD, Frederic Perros, PhD, David Montani, MD, PhD, Nicholas W. Morrell, MD, Florent Soubrier, MD, PhD, Martin R. Wilkins, MD, William C. Nichols, PhD, Micheala A. Aldred, PhD, Ankit A. Desai, MD, David-Alexandre Tregouet, PhD, Soban Umar, MD, PhD, Rajan Saggar, MD, Richard Channick, MD, Rubin M. Tuder, MD, Mark W. Geraci, MD, Robert S. Stearman, PhD†, Xia Yang, PhD†, and senior author, Mansoureh Eghbali, PhD†. Legend: *Joint first authors; ‡ Joint second authors; †Joint last authors
Funding: This work was supported by American Heart Association grant 23POST1022457 (L.M.), American Thoracic Society Early Career Investigator Award in Pulmonary Vascular Disease (J.H.), and U.S. NIH grants K08HL169982 (J.H.), R01HL147586 (M.E.), R01HL162124 (M.E.), R01HL159865 (M.E.), R01HL147883 (X.Y.), R24HL105333 (W.N. And M.P.), R01HL160941 (W.N., A.D., and M.P.), British Heart Foundation Senior Basic Science Fellowship FS/SBSRF/21/31025 (C.R.), and funding for the PHBI is provided by NHLBI R24HL123767 and by the Cardiovascular Medical Research and Education Fund (MAA).
Division Of Pulmonary, Critical Care And Sleep Medicine
Fiberoptic Bronchoscopy and Interventional Pulmonary Medicine
A modern bronchoscopy suite with fluoroscopy is available for ambulatory and inpatient bronchoscopic procedures.
Fellows have ample opportunities to develop skills in performing bronchoalveolar lavage, endobronchial and transbronchial lung biopsies in addition to endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS) directed procedures using both linear and radial instruments in diagnostic evaluation and staging in patients with suspected intrathoracic malignancy.
Training in procedures such as PleurX catheter placement, talc pleurodesis, tracheal dilation, rigid bronchoscopy, thoracoscopy, endobronchial stenting, balloon bronchoplasty, argon photocoagulation (APC) and cryotherapy are performed when appropriate under the direction of board certified interventional pulmonology faculty. Percutaneous tracheostomies are performed at the bedside on patients with chronic respiratory failure under bronchoscopic guidance at both SSM Health Saint Louis University Hospital and Mercy Hospital St. Louis.
In addition, fellows gain experience in a number of other invasive diagnostic and therapeutic techniques used in pulmonary medicine such as pleuroscopy, pleural biopsy and the placement and management of chest tubes.
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