Novel blood test helps evaluate severity in pulmonary arterial hypertension, a rare lung disease

Researchers at the National Institutes of Health have found that a novel blood test can be used to easily evaluate disease severity in patients with pulmonary arterial hypertension (PAH) and predict survivability. PAH is a rare, life-threatening condition that causes unexplained high blood pressure in the lungs. In early clinical studies, the researchers showed the test to significantly improve upon conventional tests, some of which use invasive tools.

Computed tomography 3D surface rendering of the lungs and heart from a patient with pulmonary arterial hypertension demonstrating trachea and major airways (yellow), an enlarged heart (red), enlarged main pulmonary artery (large blue vessel on top of heart) and thinning of the peripheral pulmonary vessels (blue). Marcus Y. Chen, M.D., NHLBI

The new blood test measures DNA fragments shed by damaged cells. Researchers found that these fragments, called cell-free DNA, were elevated in the blood of patients with PAH and increase with disease severity. If future studies confirm the findings, this first-of-its-kind blood test for PAH patients could allow doctors to intervene faster to prevent or delay progression of the disease and possibly save lives. Cell-free DNA is a relatively new analytical technique that is growing in its potential medical uses, which include the early detection of heart- and lung-transplant rejection as well as early detection of cancer.  

The study was funded by the National Heart, Lung, and Blood Institute (NHLBI) and the NIH Clinical Center, both part of NIH. The findings will appear online in the journal Circulation, a publication of the American Heart Association.

PAH is a rare form of pulmonary hypertension that can cause difficulty breathing, chest pain, and fatigue. The disease, whose exact cause is unknown, is estimated to affect less than 50,000 people in the United States, according to the NIH’s Genetic and Rare Diseases Information Center. It is characterized by progressive narrowing and blockage of the small pulmonary arteries of the lungs, strain on the right side of the heart, and eventual death from heart failure. The damage to the lung in severe cases can require lung transplantation. Patients with PAH have a high death rate, and the condition mostly affects women. Despite treatment advances, it currently has no cure.

Current tests used to monitor PAH severity rely on established risk prediction scores based on clinical symptoms and on the use of an invasive catheter to measure pressure in the lungs. Doctors sometimes use echocardiography, or heart imaging, to measure pressures in the heart as an indirect measurement of lung pressure, but these tests tend to lack reliability and sensitivity.

“Researchers have been actively searching for novel, less-invasive approaches to evaluate PAH severity, disease progression, and response to therapy for more than a decade. These cell-free DNA analyses represent progress toward that goal,” said study co-author Michael A. Solomon, M.D., M.B.A., who is part of the NHLBI Cardiovascular Branch and co-director of the NIH Clinical Center Pulmonary Arterial Hypertension Section.

Sean Agbor-Enoh, M.D., Ph.D., study co-author and chief of the NHLBI’s Laboratory of Applied Precision Omics, agreed. “Here we’re proposing a one-time test where you collect a vial of blood from a patient and use that to predict survival. We’re very encouraged by the early results.”

 In the current study, the research team analyzed cell-free DNA from blood samples taken from 209 adult patients, predominately women, diagnosed with PAH at two large U.S. medical centers. The researchers compared the results to cell-free DNA measured from a control group of 48 healthy volunteers without PAH at the NIH Clinical Center. 

They found that cell-free DNA was elevated in patients with PAH, and also found that cell-free DNA concentrations increased in proportion to the severity of the disease. Patients with the highest level of cell-free DNA had a 3.8 times greater risk of either death or a need for lung transplantation compared to those with the lowest level of cell-free DNA, the researchers said.

Further analyses of cell-free DNA samples revealed that multiple tissue types – including the heart, blood vessels, fat tissue, and inflammatory cells circulating in the blood – were affected by PAH. The new blood test will allow researchers to better pinpoint the specific tissues involved in the PAH disease process. This knowledge may lead to new drug interventions for PAH, whose current treatment options may slow but not halt or reverse disease progression.

In addition to funding from the Intramural Research Program of the NHLBI, this research is supported by the NIH Clinical Center Research Award for Staff Clinicians Program, the NIH Distinguished Scholar Award, the Lasker Clinical Research Scholars Program, and the Intramural Research Programs of the NIH Clinical Center. 

Nutrient in plant-based foods may help lower heart disease risk

A type of molecule called a lignan, found in plant-based foods, may help lower heart disease risk, according to a new study by Harvard T.H. Chan School of Public Health researchers. The molecule, which is found in whole grains, fruits and vegetables, nuts and seeds, red wine, and coffee, was found to have antioxidant and anti-inflammatory effects.

The study was published online in the August 2021 issue of the Journal of the American College of Cardiology.

First author Yang Hu, a research fellow in the Department of Nutrition at Harvard Chan School, and colleagues studied data on the eating patterns of more than 200,000 people. They found that those whose diets included higher amounts of foods rich in lignans had a significantly reduced risk of coronary heart disease compared to those who ate low amounts of lignans. The protective effect appeared to increase among those who had higher amounts of fiber in their diet.

“This opens another avenue of research because we can take further steps to see how the gut microbiota and fiber interact with the production of lignans and how these might affect disease risk for other conditions, such as diabetes,” Hu said in an August 9 article in WebMD.

Cardiac arrest treatment that uses life support machine boosts survival

Using a life support machine to replicate the functions of the heart and lungs significantly improved the survival of people who suffered from out-of-hospital cardiac arrest, according to a new study published today in The Lancet(link is external).

The treatment program involving the life support machine called extracorporeal membrane oxygenation (ECMO) proved so much more effective than the standard treatment for this usually fatal condition that the trial was stopped early after enrolling just 30 of the expected 165 patients.

The study, known as the Advanced Reperfusion Strategies for Refractory Cardiac Arrest (ARREST) trial, was funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

“This is the first trial to show a significant difference in outcomes after hospital admission among patients treated for out-of-hospital cardiac arrest with a team-based ECMO strategy,” said George Sopko, M.D., M.P.H., program director in the NHLBI’s Division of Cardiovascular Sciences. “We can improve outcomes for this common health condition, and we believe this study is a significant step in that direction.”

Approximately 340,000 people die of cardiac arrest each year in the United States. The condition occurs when the heart suddenly stops beating. There is no blood flow to the body, including the heart and brain. Immediate emergency treatment is essential to prevent death, but standard treatments are only marginally effective. Less than 10% of people who suffer a cardiac arrest survive. Some cardiac arrest patients do not respond to any standard cardiac arrest treatments. The ARREST investigators, led by Demetris Yannopoulos, M.D., a cardiologist and professor of medicine at the Center for Resuscitation Medicine at the University of Minnesota Medical School in Minneapolis, hypothesized that this was because these patients had severe and extensive blockages in the arteries to their heart. To find out what approach might help cardiac arrest patients, the ARREST trial compared standard treatment with treatment with ECMO as soon as possible in 30 people who suffered a cardiac arrest. The average age was 61, and 25 of the 30 patients were men.

The ECMO machine connects to a patient by tubes inserted in an artery and vein in the groin. The machine pulls blood out of the patient’s body, pumps it through a part of the machine that acts as an artificial lung, and then returns it back to the body. This gives doctors time to stabilize the patient and, if suitable, clear any blockages in the arteries of the heart

Substance use disorders linked to COVID-19 susceptibility

A National Institutes of Health-funded study found that people with substance use disorders (SUDs) are more susceptible to COVID-19 and its complications.

Colorized scanning electron micrograph of an apoptotic cell (blue) heavily infected with SARS-COV-2 virus particles (yellow), isolated from a patient sample. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland.NIAID

The research, published Monday in Molecular Psychiatry, was co-authored by Nora D. Volkow, M.D., director of the National Institute on Drug Abuse (NIDA). The findings suggest that health care providers should closely monitor patients with SUDs and develop action plans to help shield them from infection and severe outcomes.

By analyzing the non-identifiable electronic health records (EHR) of millions of patients in the United States, the team of investigators revealed that while individuals with an SUD constituted 10.3% of the total study population, they represented 15.6% of the COVID-19 cases. The analysis revealed that those with a recent SUD diagnosis on record were more likely than those without to develop COVID-19, an effect that was strongest for opioid use disorder, followed by tobacco use disorder. Individuals with an SUD diagnosis were also more likely to experience worse COVID-19 outcomes (hospitalization, death), than people without an SUD.

“The lungs and cardiovascular system are often compromised in people with SUD, which may partially explain their heightened susceptibility to COVID-19,” said Dr. Volkow. “Another contributing factor is the marginalization of people with addiction, which makes it harder for them to access health care services. It is incumbent upon clinicians to meet the unique challenges of caring for this vulnerable population, just as they would any other high-risk group.”

NIDA’s Dr. Volkow and Rong Xu, Ph.D., of Case Western Reserve University in Cleveland, Ohio, analyzed EHR data collected until June 15, 2020, from 360 hospitals nationwide. The EHRs were de-identified to ensure privacy.

The study population consisted of over 73 million patients, of which over 7.5 million had been diagnosed with an SUD at some point in their lives. Slightly more than 12,000 were diagnosed with COVID-19, and about 1,880 had both an SUD and a COVID-19 diagnosis on record. The types of SUDs investigated in the study were tobacco, alcohol, opioid, cannabis, and cocaine.

The complicating effects of SUD were visible in increased adverse consequences of COVID-19. Hospitalizations and death rates of COVID-19 patients were all elevated in people with recorded SUDs compared to those without (41.0% versus 30.1% and 9.6% versus 6.6%, respectively).

Additionally, African Americans with a recent opioid use disorder diagnosis were over four times more likely to develop COVID-19, compared to whites. Results showed that hypertension, diabetes, cardiovascular diseases, and renal diseases, which are risk factors for COVID-19, were more prevalent among African Americans than whites with opioid use disorder.

According to the authors, the study findings underscore the need to screen for, and treat, SUDs as part of the strategy for controlling the pandemic. Additional research needs to be done to better understand how best to treat those with SUDs who are at risk for COVID-19 and counsel on how to avoid the risk of infection.

NIH-developed technique prevents obstruction in heart valve replacement

A novel technique has proven successful in preventing coronary artery obstruction during transcatheter aortic valve replacement (TAVR), a rare but often fatal complication.

Called Bioprosthetic Aortic Scallop Intentional Laceration to prevent Iatrogenic Coronary Artery obstruction (BASILICA), the technique will increase treatment options for high-risk patients who need heart valve procedures. The findings by researchers at the National Institutes of Health will be published in the Journal of the American College of Cardiology: Cardiovascular Interventions on June 12.

TAVR, a procedure used to treat aortic valve stenosis, involves threading a long, thin, flexible tube, called a catheter, through the femoral artery in the leg to the heart. Aortic valve stenosis is a narrowing of the valve controlling blood leaving the heart to the rest of the body. This narrowing reduces blood flow to vital organs, resulting in shortness of breath, chest pain, blackouts, and heart failure.

Illustration of the BASILICA procedure. (A) a catheter directs an electrified guidewire through the base of the left aortic cusp into a snare in the left ventricular outflow tract; (B) after snare retrieval, the mid-shaft of the guidewire is electrified to lacerate the leaflet (C); (D) the leaflet splays after TAVR permitting coronary flow.

For elderly or frail patients, TAVR offers an effective and less invasive alternative to open heart surgery. However, a small subset of these patients may develop coronary artery obstruction during the TAVR procedure. For more than half of these patients, this complication has been fatal.

During TAVR, the surgeon places a catheter inside the heart and uses a balloon to open a new valve inside the aortic valve. However, in some patients whose hearts have uncommon structures, such as unusually large valve leaflets or small aortic roots, the large leaflets block the flow of blood to the coronary arteries as the new valve’s scaffolding opens.

BASILICA was developed at the National, Heart, Lung, and Blood Institute (NHLBI), part of NIH, to offer a solution to the problem of coronary obstruction during TAVR and increase the safety of TAVR for this subset of patients. The interventional cardiologist weaves an electrified wire the size of a sewing thread through a catheter and uses it to split the original leaflet in two so that it cannot block the coronary artery once it has been pushed aside by the transcatheter heart valve.

After animal experiments proved promising, the researchers successfully performed the procedure on seven patients who qualified for compassionate use of the technique — then untested in humans — because no other care options were available.

The current research builds on the success of the first-in-human trial. From February to July 2018, the BASILICA technique was evaluated in a multicenter early feasibility study, sponsored by NHLBI. It enrolled 30 gravely ill patients who were at high or extreme risk if undergoing surgery. 

According to the researchers, all patients survived the procedure and underwent a successful TAVR. BASILICA was successful in 93% of patients and was feasible in natural as well as prosthetic aortic valves. At the 30 days mark, there were no coronary artery obstructions, nor a need to repeat the procedure due to valve dysfunction. 

Every year, approximately 5 million people in the United States are diagnosed with heart valve disease, and more than 20,000 die, according to the American Heart Association. 

Long periods of sedentary behavior may increase cardiovascular risk in older women

A new study has found that the longer older women sit or lay down during the course of a day—and the longer the individual periods of uninterrupted sitting—the greater their risk of cardiovascular diseases such as heart disease and stroke.

Physically active women have significantly decreased risk of heart disease. Photo credit:
Medical Xpress

The study noted that reducing their sedentary time by just an hour a day appears to lower the risk of cardiovascular diseases by 12 percent—and for heart disease alone, by a dramatic 26 percent, the research found. The study was funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.  

“This study provides further strong evidence of a link between sedentary behavior, like sitting and laying down, which uses very little energy, and cardiovascular disease,” said David Goff, M.D., Ph.D., director of the Division of Cardiovascular Sciences, NHLBI. “Sedentary behaviors and inactivity are major risk factors for heart disease, and this research also shows that it is never too late, or too early, to move more and improve your heart health.”

In this five-year prospective study, researchers looked at more than 5,000 women ages 63 to 97 and measured both the total time they sat or laid down each day and the duration of discrete sedentary periods. The results, published today in the journal Circulation, are significant.   

“Higher amounts of sedentary time and longer sedentary bouts were directly associated with cardiovascular disease,” said John Bellettiere, Ph.D., research fellow of cardiovascular disease epidemiology at the University of California, San Diego, and lead author of the study. “Importantly, the association showed up regardless of a woman’s overall health, physical function, and other cardiovascular risk factors, including whether they also were engaging in moderate to vigorous physical activity.”

Of the estimated 85.6 million American adults having at least one type of cardiovascular disease, which includes heart disease and stroke, 43.7 million of them are 60 or older. In fact, 67.9 percent of women between 60 and 79 years old, have cardiovascular disease; and heart disease is the leading cause of death among women 65 and older.

The findings, Bellettiere said, could have implications for what health officials communicate to older women about staying heart healthy. Getting up and moving, even if for just a few minutes more throughout the day, he noted, might help reduce their already-high rates of heart disease.

“Encouraging less sedentary time and shorter sedentary bouts in older women could have large public health benefits,” Bellettiere said.

The research involved an ethnically diverse group of 5,638 women, nearly half of whom were over age 80, enrolled between 2012 and 2014. None had a history of myocardial infarction or stroke. The women were part of the NHLBI-funded Objective Physical Activity and Cardiovascular Health (OPACH)—a sub cohort of the Women’s Health Initiative. 

At the start of the study, participants wore hip-mounted accelerometers that measured their movement 24 hours a day for seven consecutive days. Previous studies have largely relied on self-reporting questionnaires; the accelerometers, however, provided researchers more accurate measures of sedentary time overall, as well as the duration of individual bouts of sedentary time. The latter was important because it allowed, for the first time, the study of whether sitting for long uninterrupted periods throughout the day was contributing to higher risk of cardiovascular disease.

The researchers then followed the participants for almost five years, tracking cardiovascular disease events such as heart attacks and strokes. They found that on average, an additional hour of total sedentary time was associated with a 12 percent higher risk for cardiovascular diseases, and when that sitting time was made up of long uninterrupted sedentary sessions, the risk was 52 percent higher than when it was accumulated in short, regularly interrupted bouts of sedentary time.

Yet, just as the risk for heart disease can increase with more sitting and longer sedentary bouts, it can be reduced by getting up and moving, even if only a little, and by doing it often throughout the day, the researchers found.

“Reductions of sedentary time do not need to happen all at once,” said Andrea LaCroix, Ph.D., Chair of the Division of Epidemiology and Director of the Women’s Health Center of Excellence at the University of California, San Diego, who led the OPACH study. “I recommend to all women who, like me, are over 60, to make a conscious effort to interrupt our sitting by getting up and moving around as often as we can.”

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The National Institutes of Health (NIH): the United States medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. 

Blood test shows promise for early detection of severe lung-transplant rejection

This illustration depicts a new blood test that can identify early signs of lung transplant rejection using DNA markers from the organ donor.NHLBI

Researchers have developed a simple blood test that can detect when a newly transplanted lung is being rejected by a patient, even when no outward signs of the rejection are evident.

The test could make it possible for doctors to intervene faster to prevent or slow down so-called chronic rejection—which is severe, irreversible, and often deadly—in those first critical months after lung transplantation. Researchers believe this same test might also be useful for monitoring rejection in other types of organ transplants. The work was funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

The study’s findings were published Jan. 22 in EBioMedicine, a publication of The Lancet.

“This test solves a long-standing problem in lung transplants: detection of hidden signs of rejection,” said Hannah Valantine, M.D., co-leader of the study and lead investigator of the Laboratory of Organ Transplant Genomics in the Cardiovascular Branch at NHLBI. “We’re very excited about its potential to save lives, especially in the wake of a critical shortage of donor organs.”

The test relies on DNA sequencing, Valantine explained, and as such, represents a great example of personalized medicine, as it will allow doctors to tailor transplant treatments to those individuals who are at highest risk for rejection.

Lung transplant recipients have the shortest survival rates among patients who get solid organ transplantation of any kind—only about half live past five years. Lung transplant recipients face a high incidence of chronic rejection, which occurs when the body’s immune system attacks the transplanted organ. Existing tools for detecting signs of rejection, such as biopsy, either require the removal of small amounts of lung tissue or are not sensitive enough to discern the severity of the rejection. The new test appears to overcome those challenges.

Called the donor-derived cell-free DNA test, the experimental test begins with obtaining a few blood droplets taken from the arm of the transplant recipient. A special set of machines then sorts the DNA fragments in the blood sample, and in combination with computer analysis, determines whether the fragments are from the recipient or the donor and how many of each type are present.  Because injured or dying cells from the donor release lots of donor DNA fragments into the bloodstream compared to normal donor cells, higher amounts of donor DNA indicate a higher risk for transplant rejection in the recipient.

In the study, 106 lung transplant recipients were enrolled and monitored. Blood samples collected in the first three months after transplantation underwent the testing procedure. The results showed that those with higher levels of the donor-derived DNA fragments in the first three months of transplantation were six times more likely to subsequently develop transplant organ failure or die during the study follow-up period than those with lower donor-derived DNA levels. Importantly, researchers found that more than half of the high-risk subjects showed no outward signs of clinical complications during this period.

“We showed for the first time that donor-derived DNA is a predictive marker for chronic lung rejection and death, and could provide critical time-points to intervene, perhaps preventing these outcomes,” Valantine said. “Once rejection is detected early via this test, doctors would then have the option to increase the dosages of anti-rejection drugs, add new agents that reduce tissue inflammation, or take other measures to prevent or slow the progression.”

In 2010, Valantine was part of a research team that pioneered the first blood test to diagnose organ rejection. The now-widely used test, called the AlloMap, analyzes the expression of 20 genes in a transplant recipient’s blood sample to determine whether the patient’s immune system is launching an attack. The following year, Valantine and her colleagues showed for the first time that a cell-free DNA blood test could be useful for monitoring early signs of rejection. However, those early studies of the cell-free DNA test only identified signs of “acute” transplant rejection, which is easily reversed. The current study shows that high cell-free DNA levels during the first three months after transplant predicts chronic rejection. If validated, this blood test could become a routine tool used to monitor transplant patients at very early stages of rejection, the researchers said.

This research is supported by The Genomic Research Alliance for Transplantation Study (NCT02423070), which is funded by the Division of Intramural Research of NHLBI. The research is also supported by The Genome Transplant Dynamics Study (NCT01985412), which is funded by the National Institute of Allergy and Infectious Diseases through Grant RC4AI092673.  

About the National Heart, Lung, and Blood Institute (NHLBI): NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.