Research news tip sheet: Story ideas from Johns Hopkins Medicine

OBESITY WEAKENS HEART MUSCLE IN PATIENTS WITH A COMMON TYPE OF HEART FAILURE

Media Contact: Vanessa McMains, Ph.D., vmcmain1@jhmi.edu

For decades, physicians have known that about half of all patients with heart failure appear to have hearts that contract normally -- a syndrome now known as heart failure with a preserved ejection fraction (or HFpEF, pronounced hef-pef). This type of heart failure was first seen primarily in slim, elderly women with high blood pressures and thicker heart muscle. But as the incidence of obesity and diabetes has increased, many patients with HFpEF are now found to be severely obese with blood pressures not as high and heart muscle not as thick as seen in previous patients.

New research from Johns Hopkins Medicine has uncovered that greater obesity seems to make muscle contraction much weaker in this very common form of heart failure. In their study, published Dec. 2, 2020, in Circulation, the researchers say "the surprising findings upends the field," as it challenges the view that the disease is all about having a stiff heart that cannot relax.

"Obesity would seem to have changed the heart muscle," says senior study author David Kass, M.D., the Abraham and Virginia Weiss Professor of Cardiology at the Johns Hopkins University School of Medicine. "The "p" in HFpEF stands for preserved, and that's what contraction was supposed to be, and what HFpEF used to be. But, as more patients are obese and our results show this reduces contraction strength, we will need to rethink our concepts and along with it, our treatments."

Traditionally, this form of heart failure has been treated with medicines that often reduce contraction strength while improving the heart's relaxation. Further research, Kass says, will need to determine if this approach needs to be modified.

Johns Hopkins Medicine has one of the few dedicated HFpEF clinics in the country, run by study co-author Kavita Sharma, M.D., associate professor of medicine and director of the heart failure transplant program at the Johns Hopkins University School of Medicine.

As part of the evaluation of patients with HFpEF, a tiny piece of heart muscle is collected using a standard heart biopsy procedure. The biopsy samples taken from patients who were less obese (a body mass index, or BMI, averaging 30) but had high blood pressure and thick heart muscle were compared with those with severe obesity (BMI averaging 40) but lower blood pressure and less thick heart muscle. The investigators teased out single muscle cells from these samples and studied their function. When the researchers added calcium to stimulate the cells to contract, those from the less-obese group responded normally.

However, the force response to high calcium was reduced by 40% in cells from patients with obesity. In a third group of patients who had both high blood pressure and thicker hearts, as well as severe obesity, the force response in the cells given calcium was similarly reduced as in the mostly obese group. Kass and his colleagues believe this points to obesity as the key factor.

HFpEF was previously called diastolic heart failure, emphasizing the idea that although the heart could contract normally, it didn't properly fill with blood when the heart relaxed in preparation for the next beat (called diastole). While preserved contraction appears still true for less obese patients with high blood pressure and thick heart muscle, it doesn't appear to hold true when they also have severe obesity.

Severe obesity alters underlying human biology -- most recently brought in focus with the COVID-19 pandemic as obesity has been shown to be an independent risk factor for more severe disease and worse outcome. Many of COVID-19's effects on artery function, the immune system and inflammation, and metabolism and heart stress may also be relevant to HFpEF, the researchers say.

"We do not yet know why this reduced force happens," says Kass. "But, we are trying to figure it out with the goal of testing new and different drugs to improve contraction and personalize treatment for our patients with HFpEF and obesity."

Kass is available for interviews.

ARTIFICIAL ENZYME MAY BE FIRST STEP TOWARD TREATMENT FOR PARKINSON'S DISEASE

Media Contact: Ayanna Tucker, atucke25@jhmi.edu

A growing body of research has shown that misshapen and misfolded alpha-synuclein, the protein culprit behind Parkinson's disease and its characteristics, travels from the gut to the brain, where it spreads and sticks together in lethal clumps known as Lewy bodies. As these clumps accumulate, they cause brain cell death.

Now, Johns Hopkins Medicine researchers have created an artificial enzyme that stops misfolded alpha-synuclein from spreading and could become the basis for a new treatment for Parkinson's disease.

The results were announced in a study published online Nov. 20, 2020, in the journal Nano Today.

The artificial enzymes, nanosized (a nanometer is a billionth of a meter) combinations of platinum and copper called PtCu bimetallic nanoalloys, were created by the research team for their strong antioxidant properties. The antioxidant capability is dependent largely on the alloy composition.

"Oxidative stress caused by reactive oxygen species is inescapable, and increases with age due to mechanistic slowdowns in processes such as protein degradation," says senior study researcher Xiaobo Mao, Ph.D., assistant professor of neurology at the Johns Hopkins University School of Medicine. "This indicates the importance of antioxidants, because in Parkinson's disease, roaming reactive oxygen species promote the spread of misfolded alpha-synuclein, leading to worse symptoms."

When injected into the brain, the nanozymes scavenge for reactive oxygen species, gobbling them up and preventing them from causing damage to neurons in the brain. The nanozymes mimic catalase and superoxide dismutase, two enzymes found in our bodies that break down reactive oxygen species. Adding the nanozymes strengthens our body's response to them.

The study used a research method known as the alpha-synuclein preformed fibril model, which replicates the pathology, spreading and neurodegeneration resulting from Lewy bodies. The nanozyme was found to decrease alpha-synuclein induced pathology and inhibit neurotoxicity, in addition to decreasing reactive oxygen species. The nanozyme also prevented alpha-synuclein from passing from cell to cell, and from the substantia nigra to the dorsal striatum, two areas in the midbrain that influence movement and cognition.

Mao has long collaborated with fellow Parkinson's disease expert Ted Dawson, M.D., Ph.D., professor of neurology and director of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. Dawson recently added to evidence that misfolded alpha-synuclein travels along the vagus nerve from the gut to the brain. Mao hopes that further research can connect the two findings and lead to a Parkinson's disease treatment that targets the gut.

"We know that the nanoenzymes work when injected directly into the brain," says Mao. "Now, we'd like to see if the nanoenzymes can block the disease progression induced by pathogenic alpha-synuclein traveling from the gut, across the blood-brain barrier and into the brain."

Mao is available for interviews.

GENETIC MARKER FOR PROSTATE CANCER FOUND TO BE COMMON AMONG BLACK MALES

Media Contact: Brian Waters, bwaters3@jhmi.edu

Johns Hopkins Medicine and University of Southern California researchers have announced that a genetic marker tied to prostate cancer -- previously seen in a significant number of Ugandan men with the disease -- also could be found in larger populations of Black males with prostate cancer, including African Americans.

The finding was reported in the Sept. 2020 issue of the journal European Urology. The collaborative study was led by Christopher Haiman, Sc.D., professor of preventive medicine at the Keck School of Medicine of USC.

The biological marker that the researchers studied is a single variation in the DNA of chromosome 8 of the human genome. Known as a single nucleotide polymorphism (SNP), such variants can help scientists identify the connections between genes and specific diseases. Carrying the chromosome 8 SNP marker has been linked to a twofold increase in a man's risk for prostate cancer, going to threefold or higher in men with a family history of the disease.

The research team examined the DNA of prostate cancer patients of African descent across the United States and found results similar to those observed in previous studies in Ugandan men. As this SNP is not found in Americans of European descent, the researchers say this finding may partly explain why African American men are significantly more likely to be diagnosed with prostate cancer and die from the disease.

This information opens an important door for future genetic testing. Study co-author William Isaacs, Ph.D., professor of urology and oncology at the Johns Hopkins University School of Medicine, says that a set of these SNP markers is being developed as a diagnostic tool for determining an individual's prostate cancer risk level.

"We have to get these tests into the general practitioner's office," he says.

Having an SNP diagnostic test for prostate cancer, Isaacs explains, would enable clinicians to screen patients who they believe may be at highest risk for developing the disease, so they can be monitored for it and treated at an early stage if diagnosed.

Isaacs is available for interviews.

SCIENTISTS FIND HINTS FOR HOW A FATTY COMPOUND FUNCTIONS IN THE CELL'S POWERHOUSE

Media Contact: Rachel Butch, rbutch1@jhmi.edu

In a study of yeast, Johns Hopkins Medicine researchers say they have found how a fatty compound called cardiolipin helps create cellular energy. The researchers say their findings will help shed light on conditions that impact human metabolism, such as heart disease, diabetes and Barth syndrome, a rare genetic disorder that weakens the heart.

Cardiolipin is found in almost every one of the body's cells and resides within the labyrinth of membranes that make up mitochondria. It's thought to help mitochondria create adenosine triphosphate (ATP), the molecule that fuels cell metabolism. Cardiolipin has been implicated in a number of metabolic and immune diseases, including blood clotting disorders caused by an abnormal immune reaction to the fatty molecule.

In its study published Aug. 28, 2020, in Science Advances, the Johns Hopkins Medicine team found how cardiolipin helps stabilize other structures within mitochondrial membranes.

"Mitochondrial membranes are some of the busiest structures in the body, packed with fats and proteins that give our cells the energy they need to keep us alive," says Steven Claypool, Ph.D., professor of physiology at the Johns Hopkins University School of Medicine.

Within this membrane matrix is an important transport protein called Aac2 that ships the building blocks of ATP into the mitochondria and then moves activated ATP out into the cell. Previous studies hinted that cardiolipin was important in helping Aac2 transport proteins do their job. However, not much was known about this process.

Claypool and his colleagues found that three areas on Aac2 where cardiolipin binds help Aac2 stay in the right shape to transport ATP. They found that yeast cells engineered to lack cardiolipin did not produce cellular energy as efficiently as yeast cells with abundant cardiolipin levels.

In further experiments analyzing how proteins interacted in the membrane, the researchers found that links between Aac2 and the rest of the ATP production line -- known as respiratory supercomplexes -- also are dependent on the presence of cardiolipin.

The researchers speculate that cardiolipin-protein interactions in mitochondrial membranes evolved as a way to streamline energy production. They believe this occurs by connecting Aac2 with the respiratory supercomplexes that supply ATP materials or by using cardiolipin to protect the membrane proteins from being jostled out of place.

Overall, these results suggest that changes in cardiolipin structure or production could be linked with diseases, say the researchers.

"We may need to look closer at cardiolipin structure or production in diseases or conditions in which cardiolipin metabolism has been implicated," says Claypool.

Claypool and his colleagues are developing new tools to analyze the fats in mitochondrial membranes to study protein-cardiolipin interactions.

Claypool is available for interviews.

MINOR STROKES LEAD TO GLOBAL DISRUPTIONS IN BRAIN SIGNALING AND COGNITIVE DYSFUNCTION

Media Contact: Vanessa McMains, Ph.D.; vmcmain1@jhmi.edu

When most people think about stroke, they picture someone who can't move an entire side of their body or speak. Minor strokes on the surface appear far less disabling, and often people are able to walk and talk normally. However, people who've had minor strokes anecdotally report difficulty in thinking, focusing their attention on more than one task or following conversations.

Now, Johns Hopkins Medicine researchers and colleagues at the University of Maryland have found what is believed to be the first measurable physical evidence of diminished brain processing after a minor stroke.

Minor strokes occur when a small blood clot lodges in one of the tiny blood vessels deep in the brain. They are typically less devastating than a major stroke that blocks a major artery, but still damage tissue needed for the brain to properly function.

In their study published in the Dec. 29, 2020, issue of the Proceedings of the National Academy of Sciences of the United States of America (PNAS), the researchers say that their findings are not only the first step toward better understanding the cause of post-stroke cognitive dysfunction, but they will ultimately enable clinicians to design more effective treatments. Additionally, they say, these therapies may be useful for other neurologic conditions that result in small regions of damaged brain tissue with similar symptoms, such as multiple sclerosis.

"We tend to think that certain parts of the brain are responsible for specific functions but in reality, you need your entire brain to think clearly and complete tasks," says Elisabeth Marsh, M.D., associate professor of neurology at the Johns Hopkins University School of Medicine. "In this study, we show how minor damage anywhere in the brain can disrupt the entire cognitive network and result in a global dysfunction."

As the medical director of the Comprehensive Stroke Center at Johns Hopkins Bayview Medical Center, Marsh implemented the Bayview Stroke Intervention Clinic, a program designed to promote patient follow-up, reduce hospital readmission rates and enhance post-stroke recovery.

For their recent study, the researchers used magnetoencephalography (MEG) to compare the brain function of nine patients who had experienced minor strokes with the mental processing of age-matched healthy controls. MEG is a noninvasive neuroimaging technique that, like an electroencephalogram (EEG), measures electrical activity within the brain in real time.

Once inside the scanner, the study participants had their brain function recorded as they completed word- and picture-matching tasks.

Brain signal strength for the patients with minor stroke was noticeably smaller than the controls, appearing more like rolling hills than the normal sharp mountain peaks. The researchers say this indicates that information isn't effectively traveling through the network and the brain is processing information less efficiently. Stroke patients took nearly twice as long (about a second) as the control group (about half a second) to complete the tasks, which the researchers say leads to a noticeable difference when trying to participate in a three-way conversation or follow complicated instructions.

After six months, six patients who had experienced minor strokes returned for reevaluation. They not only performed better on each task, but also anecdotally reported that their symptoms of impairment were much improved. However, their MEG scans showed only minimal improvement.

"Right now, we don't know the neural mechanisms that allowed the patients to improve," says study co-author Jonathan Simon, Ph.D., professor of electrical and computer engineering at University of Maryland, College Park. "It could be that new neural communication routes have formed to bypass the sluggish pathways. Or it could be that older, less used communication pathways have been repurposed."

He adds, "We hope by looking at the details of which neural connections are disrupted -- and how -- that it will not only be a next step in understanding this particular effect of a minor stroke, but also give us a new window into understanding how information is processed across the brain."

The team plans to bring participants back in early 2021 for further analysis and to begin treatment trials aimed at improving recovery from these minor strokes.

Marsh and Simon are available for interviews.

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