Category: 8. Health

A multi-center study has identified critical risk factors that increase the likelihood of death in children with a heart defect who are awaiting or have recently undergone heart transplantation, according to findings published in Circulation.

Fontan circulatory failure (FCF) is a long-term complication in children born with single-ventricle heart defects who have undergone a series of surgeries that culminates with the Fontan procedure. While this surgery helps reroute blood flow and extend life expectancy, it can lead to chronic health problems, including heart failure and damage to other organs. Many of these patients eventually require a heart transplant.

The new study, conducted across 20 U.S. medical centers, offers new insights into how specific health complications affect survival in children with the condition, said Anna Joong, MD, associate professor of Pediatrics in the Division of Cardiology, who was a co-author of the study.

“We have a strong interest in understanding patients with Fontan circulatory failure: how we can better manage their heart failure, when the ideal time is to list them for a heart transplant, and what the risk factors are while waiting for a transplant,” Joong said.

In the study, investigators analyzed data from 409 patients who had undergone a Fontan procedure and were listed for heart transplant between 2008 and 2022. They tracked outcomes from the time of waitlisting through one year after transplant. They found that 5.9 percent died awaiting a transplant, and among those transplanted, 8.5 percent died within the first year.

The investigators also found that certain pre-existing conditions significantly increased the risk of death, including:

• Repeated hospitalizations in the year before being listed for transplant doubled the risk of death.
• Clinical cyanosis — a condition in which oxygen levels in the blood are dangerously low — was associated with a fivefold increase in mortality risk.
• Sleep apnea, mental health conditions requiring treatment, and anatomical complications like Fontan pathway obstruction were all linked with a higher risk of death.

“Overall, survival has improved for patients who have single ventricle physiology and who had a Fontan,” Joong said. “A really novel finding of this study was that patients with low oxygen levels were associated with poor outcomes. That’s an important thing for clinicians and families to know about, as an additional risk factor and when to refer to advanced heart failure therapies.”

The findings should guide clinicians in identifying high-risk patients earlier and considering more aggressive interventions, including earlier heart failure team and transplant referral, Joong said. Overall, the study lays the groundwork for improving transplant outcomes and tailoring care to the specific needs of children born with single-ventricle heart defects.

Moving forward, Joong and her collaborators will continue to study children post-heart transplant to understand their quality of life and address any functional limitations, she said.

Kurt Schumacher, MD, clinical professor of pediatric cardiology at the University of Michigan, was first author of the study.

The study was supported by a grant from the Additional Ventures and Enduring Hearts organizations and a gift from the Van Hooser family.

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Chronic fatigue syndrome or myalgic encephalomyelitis (ME/CFS) is a debilitating and long-neglected disease that experts typically dismissed as psychosomatic for decades.

To this day, some physicians still believe the illness is all in a patient’s head, but the largest genetic analysis of its kind suggests there are real biological origins.

A UK research project, called DecodeME, has investigated the genome-wide associations and uncovered eight possible signals associated with ME/CFS.

The preprint findings, which have not yet been published or peer-reviewed, suggest that an individual’s genes at least partly contribute to their chances of developing ME/CFS.

Related: Long COVID Fatigue Shows Up as Distinct Changes in Brain Scans

One of the eight genetic variants “nicely overlays” a signal that was previously linked to chronic pain, a common symptom of ME/CFS explains the project leader of DecodeME, bioinformaticist Chris Ponting from the University of Edinburgh.

In addition, three of the eight signals are known to act as first responders to viral or bacterial infections. The findings could help explain why ME/CFS patients often report an infection before their first symptoms, and why numbers have surged since the pandemic.

“DecodeME’s results, grounded in the principles of statistical genetics, now place ME/CFS research on a firm biological foundation,” concludes the DecodeME team of more than 50 researchers. This “should help to reduce the stigma of the illness,” they add.

Neuropsychiatrist Alan Carson from the University of Edinburgh, who was not involved in the study, says it is “by someway the largest study ever conducted on genetics of CFS/ME.”

DecodeME’s analysis brought together more than 16,000 patients, most of whom are female and of European descent. The criteria for diagnosis was stringent so that only the most clear-cut cases were included.

Patients must have had an official diagnosis of ME/CFS as well as a key symptom, called post-exertional malaise, which essentially translates to undue fatigue following exercise or other energy-consuming activities, including concentrating or socializing.

The findings revealed over a dozen genetic signals linked to ME/CFS, but only eight could be replicated in a second dataset, including more than 13,000 cases.

A third dataset of more than 14,000 cases failed to reproduce the results. This may have been due to differences in how ME/CFS was defined and diagnosed.

While these eight genome-wide associations are not exclusive to those with ME/CFS, the findings suggest that they are more likely to occur in those with the disease.

Many of the eight gene signals were expressed in brain tissue, including the ones associated with pain and the immune system.

“Drugs targeting these genes’ proteins might help protect against the consequences of microbial infection and therefore could reduce the risk of acquiring ME/CFS,” the authors suggest.

The signals are modest, and we don’t yet know what they mean. While there are limitations to the research, University of Hertfordshire geneticist Alena Pance, who was also not involved in the study, says the study is a “great advance towards understanding the illness better.”

But while Carson agrees the research is important, he sees a long road ahead. Carson points out that in disorders like depression, finding a few associated genes has not advanced our understanding of the disease or improved treatments just yet.

Still, important strides are being made with the help of patients. Ponting and his team argue that their recent findings help explain the heritable component of ME/CFS, improve the likelihood of finding effective drugs, and place the disease on more equal terms with other common genetic conditions.

“We’ve gone from knowing almost nothing about the causes of ME to having specific genetic information to delve much deeper into,” says study contributor Sonya Chowdhury, the CEO of UK health charity, Action for ME.

“For decades people with ME have asked to be heard, and now science is catching up.”

The research is available via preprint here.

Lupus is a chronic autoimmune disease which disproportionately impacts women of childbearing age, particularly women of color.¹ It is two to three times more prevalent among African American, Hispanic/Latina, Asian American, Native American, Alaska Native, Native Hawaiian and other Pacific Islander women than among White women.² In the U.S, about 90% of people living with lupus are women, and most people experience initial symptoms between ages 15 and 44.¹ Despite its prevalence, treatment options for lupus have long been limited.

The epidemiology of those living with lupus underscores why representative participation in clinical trials is so vital: New therapies should include the patient populations that are affected by the disease to ensure the therapies are effective. Shanelle also recognizes it’s not just about clinical trial enrollment, but about the entire experience.  

“One of the challenges in the clinical trial process is the lack of diversity in staffing and accessibility within the communities that need it most. For a lot of people, it means something to have somebody that culturally relates to them,” Shanelle explained. Today, she is a vocal advocate who works to raise awareness of lupus and its effects, particularly on women of color. 

For patients with gastrointestinal (GI) cancers, chemotherapy can sometimes cause severe, even life-threatening side effects in those who carry certain genetic variants that may impact how their bodies process the drugs used to treat their disease. Testing for variants in two genes before starting chemotherapy may significantly improve patient safety by providing physicians with information to help tailor doses, according to new research from the Perelman School of Medicine at the University of Pennsylvania, published by Tuteja et al in JCO Precision Oncology. The study showed that dose adjustments based on preemptive genetic testing cut chemotherapy side effects in half, as compared with patients who have the genetic variants and received standard doses without prior testing.

“For too long, the [United States] lagged behind Europe in adopting genetic testing for chemotherapy dosing, but our study shows it’s not only feasible but also critical for patient safety,” said the study’s lead author Sony Tuteja, PharmD, MS, Director of Pharmacogenomics in the Penn Medicine Center for Genomic Medine and Research Assistant Professor of Translational Medicine and Human Genetics. “With up to 1,300 deaths in the U.S. each year due to side effects from one of the most common forms of chemotherapy drugs, we’ve worked to make testing fast and actionable, getting results in about a week to help doctors make safer treatment decisions.”

Nearly 290,000 Americans are diagnosed with GI cancers each year—including colorectal cancer, the third most common cancer diagnosis in the nation. Current chemotherapy protocols use standard dosing standards that do not account for genetic differences in how patients process these drugs.

Genetic Variants Guide Safer Chemotherapy

The study focused on variants in two genes: DPYD and UGT1A1. The DPYD gene produces an enzyme that helps the liver break down drugs like fluoropyrimidines, which are commonly used in GI cancer treatment. About 5% to 8% of people carry DPYD variants that hinder the body’s ability to process fluoropyrimidine, causing it to build up to harmful levels, which can lead to serious side effects like reduced blood cell production, mouth sores, or hand-foot syndrome. Similarly, the UGT1A1 gene affects how the body processes irinotecan, another key chemotherapy drug often used to treat GI cancers. Variants in UGT1A1 can lead to the body processing the drug too slowly, increasing the risk of severe diarrhea or low white blood cell counts. By identifying these variants, physicians can lower chemotherapy doses to prevent harmful side effects without compromising treatment effectiveness.

The study enrolled 517 patients with GI cancer at three cancer care sites in the University of Pennsylvania Health System who were scheduled to begin treatment with fluoropyrimidine or irinotecan. A group of 288 received blood tests to check for DPYD and UGT1A1 variants.

Among 16 patients who were found to have genetic variants and received tailored dose reductions based on test results, 38% experienced severe treatment-related adverse events. In comparison, 65% of 17 patients with the genetic variants from a biobank group who received standard doses without prior testing experienced the serious side effects. The tested group also saw a significantly lower need to change treatment dosage and frequency (38% vs 76%) and fewer treatment discontinuations (31% vs 47%).

Disclosure: The research was funded in part by grants from the Penn Center for Precision Medicine and the National Institute of Health’s National Center for Advancing Translational Sciences. For full disclosures of the study authors, visit ascopubs.org.

Cholesterol plays a vital role in the body, providing structural support to cells and serving as a building block for hormone synthesis. However, when cholesterol accumulates or is improperly distributed, it can contribute to the development and progression of disease. In a new study, published in Proceedings of the National Academy of Sciences, Yale School of Medicine (YSM) researchers showed that excess cholesterol stored in the liver can directly drive fibrosis in the context of metabolic disease.

Led by Gerald I. Shulman, MD, PhD, the study aimed to identify key molecular triggers of metabolic dysfunction–associated steatohepatitis (MASH), a progressive liver disease marked by fat accumulation, inflammation, and fibrosis. According to Shulman, George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology at YSM, understanding the drivers of fibrosis is critical to improving outcomes for patients with MASH.

“Once fibrosis develops, it becomes very difficult to reverse and may ultimately progress to end-stage liver disease,” he says.

Interestingly, says Shulman, it wasn’t the total amount of cholesterol in the liver that mattered most, but rather where it was stored. Specifically, cholesterol accumulated within liver fat droplets emerged as a key driver of liver inflammation and fibrosis.

“It’s not just how much cholesterol is present, it’s about where it ends up,” says Shulman. “In this case, it was the cholesterol in the lipid droplets that triggers the damage. When it comes to lipids and liver disease, it’s all about location.”

The researchers first identified this link using preclinical models and then validated their findings in human liver tissue. They hypothesize that when cholesterol accumulates within liver fat droplets, it may protrude through the droplet coating and trigger an inflammatory response.

“We think that exposed cholesterol triggers intracellular stress pathways, particularly involving lysosomes, that in turn activate hepatic stellate cells and set off a chain reaction that leads to liver inflammation and fibrosis,” says Shulman.

This mechanistic insight offers a possible explanation for how cholesterol drives liver injury and points to new potential therapeutic targets. Shulman and his team are now investigating whether inhibiting the cholesterol synthesis pathway, possibly in combination with other agents, can improve not only liver inflammation and fibrosis but also insulin resistance and fat accumulation in the liver.

“This work gives us new insight into the pathophysiology of MASH,” he says. “We now have the tools and drugs to test this hypothesis, and within the next few years, we hope to design studies that can evaluate these potential therapies more effectively.”

Other Yale authors of the study include Ikki Sakuma, Rafael Gaspar, Ali Nasiri, Sylvie Dufour, Mario Kahn, Jie Zheng, Traci LaMoia, Mateus Guerra, Dean Yimlamai, Daniel Vatner, Kitt Falk Petersen, and Varman Samuel.

The research reported in this news article was supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (awards F31DK126362, T32GM007324, P30DK34989, R01DK119968, R01DK113984, P30DK045735, and R01DK133143) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the Manpei Suzuki Diabetes Foundation, Mishima Kaiun Memorial Foundation, Kowa Life Science Foundation, Japan Foundation for Applied Enzymology, Takeda Science Foundation, Ono Medical Research Foundation, and Japan’s Ministry of Education, Culture, Sports, Science, and Technology.

Endocrinology and Metabolism, one of 10 sections in the Yale Department of Internal Medicine, improves the health of individuals with endocrine and metabolic diseases by advancing scientific knowledge, applying new information to patient care, and training the next generation of physicians and scientists to become leaders in the field. To learn more, visit Endocrinology and Metabolism.