Pulmonary Hypertension, Common in TAVR Patients, Linked to Lower Survival - TCTMD

Posted: 26 Nov 2019 11:47 AM PST

The analysis lacks the nuance, one expert says, to tease out exactly which patients with pre-interventional PH will fare poorly.

LONDON, England—Patients with pulmonary hypertension (PH) undergoing TAVR for severe symptomatic aortic stenosis fare significantly worse than those without increased pre-interventional pulmonary pressures, a new analysis shows.

After a mean follow-up of 31 months, patients with PH, which was defined as a mean pulmonary arterial pressure (mPAP) > 25 mm Hg, had a 60% increased risk of all-cause mortality compared with those without PH, reported Dionysios Adamopoulos, MD (Geneva University Hospital, Switzerland), last week at PCR London Valves 2019.

"Pulmonary hypertension is very common in patients with aortic stenosis," said Adamopoulos. Pressure overload of the left ventricle leads to pulmonary vascular remodeling, diastolic dysfunction, and increasing filling pressures in the left atrium, which is then translated to the pulmonary circulation, he said. Past studies have shown that PH is associated with poor clinical outcomes in the general population, but the impact of pre-interventional PH in patients undergoing TAVR is not fully known, said Adamopoulos.

The single-center study included 372 patients undergoing TAVR for severe symptomatic aortic stenosis (mean age 83 years), including 298 who were also evaluated with baseline right heart catheterization. Of these, 56% had PH. Patients with PH were more likely to have chronic obstructive pulmonary disease (22.6% vs 11.5%; P = 0.01), have worse heart failure symptoms (77.7% in NYHA class III/IV heart failure vs 69% of those without PH; P = 0.01), and have a lower left ventricular ejection fraction at discharge (60% vs 62%; P < 0.001).

During follow-up, which was as long as 9 years, 31% of patients died. In the survival analysis, PH was a strong predictor of all-cause mortality (HR 1.60; 95% CI 1.03-2.50). After adjusting for COPD and ejection fraction at discharge, PH remained a significant predictor of all-cause death (HR 1.83; 95% CI 1.10-3.10).

Despite the increased risk of mortality among patients with pre-interventional PH, Adamopoulos said the findings have had little impact on their clinical practice.

"For the moment, no, because we can't really treat them any differently," he answered in response to the question from session co-moderator Rashmi Yadav, MBBS, PhD (Royal Brompton & Harefield NHS Foundation Trust, London, England). "Treatment of these patients is to change the pressure overload in the left ventricle and try to decrease the filling pressures, hoping that the normalization of the left ventricle pressure will reverse the diastolic dysfunction."

In their study, Adamopoulos and colleagues have not yet looked at whether the procedure did in fact reverse diastolic dysfunction, but co-moderator Jane Hancock, MD, PhD (St. Thomas' Hospital, London, England), said such an analysis could be important for identifying PH patients with the best response to TAVR and those in whom the procedure might be futile.

What About Severe PH?

To TCTMD, Yadav said the binary definition of PH used in the analysis is one of the study's limitations, noting that while PH is defined as mPAP > 25 mm Hg, that is a relatively low bar. For those with PH, mild, moderate, and severe disease is typically classified as mPAP 25 to 40, 41 to 55, and > 55 mm Hg, respectively, and many TAVR patients would have some degree of increased pulmonary pressure, she said.

"[We'd like to know] what happens to patients with severe pulmonary hypertension because patients with mild PH we would treat anyway," she said. "It's the severe group that we would sometimes say no to because we know that they have poor outcomes. They don't survive; they might die on the table. The real money is knowing what happens specifically to those with severe PH."

Paul T.L. Chiam, MBBS (Mount Elizabeth Medical Center, Singapore), who moderated the session along with Yadav and Hancock, said the analysis is also confounded by the high prevalence of COPD in their population. These patients, whether they undergo TAVR or not, have poor long-term outcomes. For the patient with PH resulting from left-sided valvular disease, such as aortic stenosis, TAVR will also result in a decrease in pulmonary pressure, particularly in those with mild PH. Like Yadav, Chiam told TCTMD the analysis would be improved by studying which patients with PH drove the increase in mortality after TAVR, noting that the elevated risk was most likely skewed by those with moderate-to-severe PH.

Mild elevations in pulmonary pressure before TAVR are unlikely to have a large clinical impact, said Chiam.

Liminal Biosciences's PBI-4050 Reduces Pulmonary Hypertension, Preclinical Data Show - Pulmonary Hypertension News

Posted: 27 Nov 2019 08:00 AM PST

New preclinical data supports the positive effects of Liminal Biosciences's lead candidate, PBI-4050, in reducing pulmonary hypertension and the abnormal enlargement of the heart's right ventricle muscle.

The company presented its latest data on two posters at the American Heart Association 2019 conference, held recently in Philadelphia.

The posters are titled "PBI-4050 Reduces Angio-proliferative Pulmonary Arterial Hypertension: Decreased Human Pulmonary Artery Smooth Muscle Cell Proliferation and Microvascular Endothelial Cell Endoplasmic Reticulum Stress," and "Transcriptomics of Lung Molecular Remodeling in Pulmonary Hypertension Due to Left Heart Disease: Benefits of Combined PBI-4050/Valsartan Therapy."

PBI-4050 is an oral therapy originally developed to treat idiopathic pulmonary fibrosis (IPF). The therapy helps regulate both inflammation and scarring, or fibrosis, by reducing the level of pro-fibrotic cytokines — chemical signals that promote scarring.

Apart from IPF, previous data showed that PBI-4050 reduced pulmonary hypertension (PH) and right ventricular hypertrophy, which is the abnormal enlargement of the heart right ventricle muscle, common among PH patients.

In the first study, researchers used a rat model that closely mimics severe pulmonary arterial hypertension (PAH) in humans, called Sugen/chronic hypoxia. The team assessed the effects of PBI-4050 compared with that of sildenafil or a placebo. Sildenafil, marketed by Pfizer as Revatio, is an approved oral medication for PAH that widens the blood vessels of the lungs, lowering blood pressure.

The rats were treated with PBI-4050 (200 mg/kg/day), sildenafil (100 mg/kg/day), or placebo for 4 weeks.

The results showed that PBI-4050 effectively reduced PAH, right ventricular hypertrophy and dysfunction. It also decreased the scarring of blood vessels.

Sildenafil showed comparable effects, but was better at improving certain parameters of right ventricular (RV) function. These parameters include right ventricular systolic pressure, tricuspid annular plane systolic excursion (TAPSE) — a measure of the efficiency of the right ventricle to eject blood — and RV contractility. Contractility is the inherent strength and vigor of the heart's contraction.

Genetic analyses of the rats' lungs showed that PBI-4050 decreased the levels of the genes that promote fibrosis, including α-smooth muscle actin (α-SMA). It also decreased the levels of the genes that promote inflammation, which include IL-6 and MCP-1. The analyses also showed that PBI-4050 markedly reduced a specific stress pathway, called ER stress, in endothelial cells, which are the cells lining the blood vessels.

Overall, the results showed that PBI-4050 reduced the expression of profibrotic and proinflammatory markers.

This supports the therapy's development as a treatment for PAH, the researchers said.

In the second poster, the investigators used an animal model to study how PBI-4050 could modulate fibrosis in the lung after a heart attack (myocardial infarction) causing PH.

Two days after the heart attack, the team administered PBI-4050, valsartan — an angiotensin receptor blocker that lowers blood pressure — or a combination of the two. This treatment was continued for five weeks. The researchers then analyzed gene activity in the lung tissue after treatment.

The results suggested that the combination of PBI-4050 and valsartan improved right ventricular hypertrophy and function. The gene activity seen after treatment mirrored these biological effects.

"We showed that, after large MI [myocardial infarction] causing PH, PBI-4050 therapy provides added benefit to valsartan, by … improving RV function and hypertrophy," the researchers said.

"Although not a current focus of the Company's research program, this new preclinical data adds to our body of knowledge of our lead compound, PBI-4050," Kenneth Galbraith, CEO of Liminal BioSciences, said in a press release:

Author Details

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.

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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.

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