Pulmonary Hypertension, Common in TAVR Patients, Linked to Lower Survival - TCTMD
Pulmonary Hypertension, Common in TAVR Patients, Linked to Lower Survival - TCTMD |
- Pulmonary Hypertension, Common in TAVR Patients, Linked to Lower Survival - TCTMD
- Liminal Biosciences's PBI-4050 Reduces Pulmonary Hypertension, Preclinical Data Show - Pulmonary Hypertension News
- Pulmonary arterial hypertension targeted for new treatment by Sheffield scientists - EurekAlert
- MitraClip Cases Often Involve Risky Pulmonary HTN - MedPage Today
- Actelion Pulls Requests to Treat Inoperable CTEPH with Opsumit, Will Gather More Data - Pulmonary Hypertension News
| 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.  |
| 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:  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. × 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. Latest Posts  |
| Pulmonary arterial hypertension targeted for new treatment by Sheffield scientists - EurekAlert Posted: 15 Nov 2019 12:00 AM PST 
Scientists at the University of Sheffield, working in collaboration with drug and vaccine developer Kymab Ltd, Cambridge, have identified a novel antibody that has the potential to become a new treatment for pulmonary arterial hypertension (PAH). Research published today in Nature Communications (Friday 15 November 2019) from the University's Department of Infection, Immunity and Cardiovascular Disease shows that treatment with a specific antibody can reverse the process behind the development of PAH, and will now be considered for clinical development. Pulmonary arterial hypertension or PAH is a rare but fatal disease with the only cure being lung transplantation. It results in high blood within the lungs due to the constriction and overgrowth of the cells within the arteries that supply blood to the lungs. Over time this growth restricts blood flow through these vessels, putting strain on the heart and eventually causing heart failure. The study found osteoprotegerin (OPG) - which has primarily been thought to just regulate bone density - drives the process behind the growth of the cells within the blood vessel walls affected in PAH. A therapeutic human anti-OPG antibody was found to stop the progress of the disease in experimental lab rodent and cell models, and reverse the proliferation of cells which cause the arteries to thicken. Allan Lawrie, Professor of Translational Cardiopulmonary Science at the University of Sheffield, said: "Current treatments for PAH ease the symptoms by relaxing and dilating the affected blood vessels which can help extend the life expectancy for those living with PAH, but they do not stop the underlying drivers of the disease. "The great benefit of this research is the potential for this new drug to be used in conjunction with current treatments, to ease symptoms and further halt or reverse the progression of the disease." PAH is a rare disease, affecting less than 1 in 2000 people and has 'orphan disease' designation, meaning that despite smaller numbers of patients affected there is a recognised need for effective treatments to be developed. Sheffield Teaching Hospitals NHS Foundation Trust and the University of Sheffield are one of the largest specialist centres in the world for diagnosis, treatment and leading research into PAH, with this study being the first time that this particular mechanism of the disease has been targeted with a therapeutic human antibody. "The support from the Medical Research Council in collaboration with Kymab Ltd - which generated the antibody - and the British Heart Foundation to fund this research through the recently formed Donald Heath Research Programme in Sheffield is a hugely significant recognition of the importance of research in this field of medicine which aims to improve the outcome for patients suffering from PAH," added Professor Lawrie. ### The University of Sheffield With almost 29,000 of the brightest students from over 140 countries, learning alongside over 1,200 of the best academics from across the globe, the University of Sheffield is one of the world's leading universities. A member of the UK's prestigious Russell Group of leading research-led institutions, Sheffield offers world-class teaching and research excellence across a wide range of disciplines. Unified by the power of discovery and understanding, staff and students at the university are committed to finding new ways to transform the world we live in. Sheffield is the only university to feature in The Sunday Times 100 Best Not-For-Profit Organisations to Work For 2018 and for the last eight years has been ranked in the top five UK universities for Student Satisfaction by Times Higher Education. Sheffield has six Nobel Prize winners among former staff and students and its alumni go on to hold positions of great responsibility and influence all over the world, making significant contributions in their chosen fields. Global research partners and clients include Boeing, Rolls-Royce, Unilever, AstraZeneca, GlaxoSmithKline, Siemens and Airbus, as well as many UK and overseas government agencies and charitable foundations. Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.  |
| MitraClip Cases Often Involve Risky Pulmonary HTN - MedPage Today Posted: 20 Nov 2019 03:30 PM PST  As in the case of mitral valve surgery, there is a graded association between pulmonary hypertension and increased mortality following the MitraClip procedure, a registry study showed. Higher invasive mean pulmonary arterial pressure (mPAP) at baseline was associated with greater likelihood of death and heart failure readmission 1 year after transcatheter mitral valve repair (P<0.001):
The overall incidence of the composite outcome was 33.6% in a U.S. registry that showed most people going into valve repair with at least mild pulmonary hypertension, according to the report by Sammy Elmariah, MD, MPH, of Massachusetts General Hospital in Boston, and colleagues, published online in JAMA Cardiology. After multivariable adjustment, pulmonary hypertension remained significantly associated with mortality (HR 1.05 per 5-mm Hg increase in mPAP, 95% CI 1.01-1.09) and heart failure hospitalization (HR 1.04 per 5-mm Hg increase in mPAP, 95% CI 1.01-1.07) after MitraClip placement. The findings have implications for patient management, according to Elmariah's team. "Herein, we demonstrate that even mildly elevated PAPs are associated with adverse clinical outcomes after transcatheter mitral valve repair, raising concerns that current PAP thresholds within the clinical guidelines may suggest mitral valve intervention too late in the disease course," the study authors said. Their retrospective cohort study started off with the more than 4,000 people listed as having received the MitraClip for severe mitral regurgitation in 2013-2017 according to the Transcatheter Valve Therapy (TVT) registry. Median age was 81 years, and 46.3% of patients were women. Primary mitral regurgitation was the predominant etiology of disease in the cohort (75%), and nearly three-quarters had at least mild pulmonary hypertension (median mPAP was 31 mm Hg). Ultimately, only 2,381 patients had sufficient PAP measurements and 1-year clinical outcomes (available through the Centers for Medicare & Medicaid Services records) for the analysis by Elmariah and colleagues. "... [T]he preponderance of primary mitral regurgitation within this cohort and the observed higher pulmonary capillary wedge pressure within groups with more severe pHTN [pulmonary hypertension] implicate mitral regurgitation as the causative factor for pHTN, although additional efforts are needed to determine whether earlier intervention for mitral regurgitation may disrupt and improve associated pHTN," according to the investigators. There are no medications proven to help survival in people with severe mitral regurgitation and pulmonary hypertension, they noted. In their study, more severe pulmonary hypertension was noted in people with younger age and comorbidities such as diabetes, hypertension, and lung disease. Those with pulmonary hypertension had higher baseline STS predicted risk of mortality for mitral valve repair and mitral valve replacement. The presence of pulmonary hypertension did not change the number of clips needed nor did it increase conversion to open heart surgery or use of mechanical support. However, it was associated with more patients being left with residual severe mitral regurgitation after valve repair. Nevertheless, Elmariah's group argued that mitral valve repair should not be denied to patients just because of severe pulmonary hypertension. This subgroup saw a sharp decline in New York Heart Association class III and IV symptoms among those who survived the initial 30-day period after the procedure, the authors reported, adding that these patients also had lower observed 30-day mortality than estimated through STS predicted risk. Missing information -- such as cause of death at 1 year -- was a major limitation of the retrospective study, Elmariah and colleagues acknowledged. "Although extensive statistical adjustment was made to mitigate the effects of potential confounders, pHTN may remain a marker of another causal pathology," they noted. That many MitraClip recipients were excluded from the analysis because of missing PAP measurements also raises the possibility of selection bias. However, baseline characteristics and 30-day TVT outcomes were comparable between those who were included and excluded, according to the investigators. The study was supported by the American College of Cardiology's National Cardiovascular Data Registry. Elmariah reported receiving grants from Edwards Lifesciences and personal fees from Medtronic and AstraZeneca. 2019-11-20T18:30:00-0500  |
| Posted: 25 Nov 2019 05:00 AM PST Actelion Pharmaceuticals has withdrawn all ongoing worldwide requests for expanded approval of Opsumit (macitentan), a pulmonary arterial hypertension (PAH) medicine, to treat adults with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). The decision was not driven by any safety concerns, Actelion, one of Janssen Pharmaceutical companies of Johnson & Johnson, said a press release. Rather, it wants to obtain more clinical data to make a stronger case for Opsumit's filings in Europe, the U.S., and elsewhere. "We remain committed to addressing the high unmet needs that persist in this severe, life-limiting disease, and will continue to study macitentan in this patient population," said Martin Fitchet, MD, global head of Actelion's Research & Development. Actelion's withdrawal followed a response letter by the U.S. Food and Drug Administration (FDA), issued earlier this year, rejecting Opsumit's use for CTEPH. The agency specified that the company needed to conduct more studies to accurately evaluate the medicine's efficacy and safety. Actelion said it is working closely with the FDA to decide on the next steps. European health authorities and study site inspections more recently also indicated that additional clinical data would be needed to extend Opsumit's label. Opsumit is an oral endothelin receptor antagonist (ERA) approved for the treatment of PAH to help ease disease symptoms and slow progression. It works by reducing the blood levels of endothelin, a small protein that constricts blood vessels to raise blood pressure. CTEPH is a rare form of pulmonary hypertension (PH) caused by the formation of blood clots that block pulmonary arteries, leading to abnormally high blood pressure in the lungs. A surgical procedure called pulmonary thromboendarterectomy (PTE) can be used to remove these clots, as well as the scar tissue that forms in the arteries, and restore normal circulation through the lungs. However, surgery is not an option for all patients. For instance, PTE cannot be performed if clots are not easily accessible or are caused by other conditions, such as severe lung disease of left heart disease. Actelion's filings to extend Opsumit's use for inoperable CTEPH relied on data from the Phase 2 clinical trial MERIT-1 (NCT02021292), which evaluated the therapy's efficacy, safety, and tolerance in adults with the condition. The trial included 80 patients given either 10 mg tablets of Opsumit, or a placebo, once a day for up to 24 weeks. Results showed that treatment with Opsumit significantly lowered patients' pulmonary vascular resistance, making it easier for blood to flow through the lungs, and improved their ability to exercise, while being well-tolerated. The MERIT-1 trial was followed by a long-term Phase 2 study, called MERIT-2 (NCT02060721), evaluating if Opsumit's prolonged effects are safe, tolerable, and efficient enough to be used to treat inoperable CTEPH. The study is taking place mostly in Europe and Asia, and is expected to conclude in 2020.  Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases. × Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases. Latest Posts  |
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