Cardiovascular diseases are still among the top causes of death worldwide, and especially prevalent in developed countries. Myocardial infarctions, commonly known as “heart attacks,” are on the rise, resulting in a significant number of deaths each year.

Heart attacks typically kill millions of cardiac muscle cells, leaving the heart in a weakened state. Since mammals cannot regenerate cardiac muscle cells on their own, heart transplants are currently the only clinically viable option for patients suffering (or likely to suffer) heart failure. Given that full heart transplants are expensive and donors difficult to come by, it is no surprise that alternative therapies are highly sought after by the medical community.

One promising strategy that has been steadily gaining traction is using human induced pluripotent stem cells (HiPSCs) for regenerative heart therapy. Simply put, HiPSCs are cells derived from mature cells that can be effectively ‘reprogrammed’ into a completely different cell type, such as cardiac muscle cells (cardiomyocytes). By transplanting or injecting cardiomyocytes derived from HiPSCs into damaged areas of the heart, it is possible to recover some lost functionality. Unfortunately, studies have reported that this approach can increase the risk of arrythmias, posing a major hurdle to clinical trials.

In a recent study, a Japanese research team from Shinshu University and Keio University School of Medicine, tested a new strategy for regenerative heart therapy that involves injecting ‘cardiac spheroids’ derived from HiPSCs into monkeys with myocardial infarction. This study, published on April 26, 2024, in the journal Circulation, was led by Professor Yuji Shiba from the Department of Regenerative Science and Medicine, Shinshu University.

The team included Hideki Kobayashi, the first author, and Koichiro Kuwahara from the Department of Cardiovascular Medicine, Shinshu University School of Medicine, as well as Shugo Tohyama, and Keiichi Fukuda from the Department of Cardiology, Keio University School of Medicine, among others.

In their novel approach, the researchers cultivated HiPSCs in a medium that led to their differentiation into cardiomyocytes. After carefully extracting and purifying cardiac spheroids (three-dimensional clusters of cardiac cells) from the cultures, they injected approximately 6 × 10⁷ cells into the damaged hearts of crab-eating macaques (Macaca fascicularis). They monitored the condition of the animals for twelve weeks, taking regular measurements of cardiac function. Following this, they analyzed the monkeys’ hearts at the tissue level to assess whether cardiac spheroids could regenerate the damaged heart muscles.

First, the team verified the correct reprogramming of HiPSCs into cardiomyocytes. They observed, via cellular-level electrical measurements, that the cultured cells exhibited potential patterns typical of ventricular cells. The cells also responded as expected to various known drugs. Most importantly, they found that the cells abundantly expressed adhesive proteins such as connexin 43 and N-cadherin, which would promote their vascular integration into an existing heart.

Afterwards, the cells were transported from the production facility at Keio University to Shinshu University, located 230 km away. The cardiac spheroids, which were preserved at 4 °C in standard containers, withstood the four-hour journey without problem. This means that no extreme cryogenic measures would be needed when transporting the cells to clinics, which would make the proposed approach less expensive and easier to adopt.

Finally, the monkeys received injections of either cardiac spheroids or a placebo directly into the damaged heart ventricle. During the observation period, the researchers noted that arrythmias were very uncommon, with only two individuals experiencing transient tachycardia (fast pulse) in the first two weeks among the treatment group. Through echocardiography and computed tomography exams, the team confirmed that the hearts of monkeys that received treatment had better left ventricular ejection after four weeks compared to the control group, indicating a superior blood pumping capability.

Histological analysis ultimately revealed that the cardiac grafts were mature and properly connected to pre-existing existing tissue, cementing the results of previous observations. “HiPSC-derived cardiac spheroids could potentially serve as an optimal form of cardiomyocyte products for heart regeneration, given their straightforward generation process and effectiveness,” remarks Assistant Professor Kobayashi. “We believe that the results of this research will help solve the major issue of ventricular arrhythmia that occurs after cell transplantation and will greatly accelerate the realization of cardiac regenerative therapy,” he further adds.

Although tested in monkeys, it is worth noting that the cardiac spheroid production protocol used in this study was designed for clinical application in humans. “The favorable results obtained thus far are sufficient to provide a green light for our clinical trial, called the LAPiS trial. We are already employing the same cardiac spheroids on patients with ischemic cardiomyopathy,” comments Asst. Prof. Kobayashi.

Let us all hope for a resounding success in the LAPiS trial, paving the way for expanded and effective treatment avenues for people suffering from heart problems.

The drug, dapagliflozin, was initially approved for the treatment of Type 2 diabetes, but it since has been shown to reduce the risk of hospitalization for heart failure and death in patients with serious health problems that include heart and chronic kidney disease and heightened cardiovascular risk.

Reporting this month in the Journal of the American College of Cardiology, the researchers found that dapagliflozin also benefits patients after admission to the hospital for acute heart failure. The drug improves diuresis, the elimination of excess fluid from the lungs, thereby relieving congestion, and it can reduce hospital stays.

“We demonstrated safety and efficacy of initiating dapagliflozin within the first day of hospitalization for acute heart failure,” said the paper’s first author, Zachary Cox, PharmD, professor of Pharmacy Practice at Lipscomb University. This “will have international impact on the treatment of acute heart failure.”

Each year 800,000 patients with acute heart failure are admitted to U.S. hospitals from emergency rooms. These patients are at high risk for prolonged hospital stays and death. The annual cost of treating acute heart failure in the United States is estimated to exceed $34 billion.

Diuretics are administered to most patients with acute heart failure to improve symptoms and lung congestion caused by fluid buildup. However, the optimal approach to diuretic therapy in patients hospitalized for acute heart failure remains poorly defined and contributes to prolonged inpatient stays and high death and readmission rates.

Furthermore, many patients do not respond to diuretics, and about half of patients are discharged with persistent congestion. This can result in patients returning to the hospital soon after discharge and being readmitted for further heart failure therapy.

Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that acts on the kidneys to increase the removal of sodium and glucose from the body. In April 2020, VUMC began a randomized, clinical trial of the drug in patients hospitalized with acute heart failure.

The study was designed by VUMC’s JoAnn Lindenfeld, MD, and Sean Collins, MD, MSc, and by Cox, a member of VUMC’s heart failure research team.

Lindenfeld, professor of Medicine in the Division of Cardiology, is nationally known for her innovative contributions to the field of heart failure.

Collins, professor of Emergency Medicine, directs the Center for Emergency Care Research and Innovation (CERI), a national leader in emergency care research, co-directs the Vanderbilt Coordinating Center, which supports VUMC-led clinical research, and is associate director for clinical trials research in the Vanderbilt Institute for Medicine and Public Health.

Cox is a fellow of the Heart Failure Society of America who has published extensively in the field.

Despite the COVID-19 pandemic, which reached its crescendo in the middle of the study, the researchers were able to enroll 240 patients and complete the trial, “thanks to the diligent effort and collaboration between the CERI research team, and … the departments of emergency medicine and cardiology,” Cox said.

“This unique partnership allows VUMC to conduct trials in acute heart failure that are only possible in a small number of medical centers across the world,” he said.

The trial “really highlights the novelty of our Emergency Medicine infrastructure, and why we are a leader in designing and conducting highly impactful clinical trials such as this one,” Collins added.

Patients were enrolled at five sites in addition to VUMC: TriStar Centennial Medical Center and Ascension St. Thomas Hospital West in Nashville, the University of North Carolina at Chapel Hill, the University of Mississippi Medical Center in Jackson, and INTEGRIS Health Baptist Medical Center in Oklahoma City.

Within 24 hours of admission for acute heart failure, patients were randomized to receive either dapagliflozin or conventional diuretic treatment.

While early administration of dapagliflozin did not improve weight-based diuretic efficiency compared to conventional treatment, patients who received the drug experienced no increase in adverse events, required shorter periods of IV diuresis, and were discharged faster during the five-day study period.

The trial demonstrated the safety and efficacy of starting a drug during early hospitalization that will continue to be prescribed upon discharge to help achieve optimal outpatient therapy and reduce the likelihood of readmission.

“It is a way to both improve diuresis AND get a head start on implementing Guideline Directed Medical Therapy in patients with acute heart failure,” Lindenfeld said.

Other VUMC co-authors are Cathy Jenkins, MS, and Frank Harrell Jr., PhD, Department of Biostatistics, and Christina Kampe, MAcc, Karen Miller, RN, MPA, and William Stubblefield, MD, MPH, Department of Emergency Medicine.

The study was an investigator-initiated trial funded by AstraZeneca but independently conducted by VUMC investigators. Dapagliflozin is marketed under the brand name FARXIGA. Acute heart failure research at VUMC is supported in part by the National Heart, Lung and Blood Institute of the National Institutes of Health.

Frigid winters, food scarcity, intense competition for territories and the threat of becoming prey to large predators like the Canada lynx are just some of the trials they face.

Early-life struggles and trauma can literally get under their skin, affecting long-term survival, said Lauren Petrullo, a University of Arizona assistant professor in the Department of Ecology and Evolutionary Biology. Scientists want to know what factors, if any, can buffer young squirrels against these threats.

Petrullo is part of the Kluane Red Squirrel Project, a multi-university long-term field project involving the University of Alberta, University of Michigan, University of Colorado Boulder and University of Saskatchewan. The project has tracked and studied thousands of wild North American red squirrels in the southwestern part of Canada’s Yukon territory for over 30 years.

A new study — which Petrullo led with David Delaney, a postdoctoral fellow at the University of Colorado Boulder — finds that the more challenges young squirrels face in the year they are born, the shorter their adult lifespan.

Red squirrels who make it past their first year of life live about 3 1/2 years, on average, but early life adversity can cut life expectancy by at least 14%.

But there’s a big caveat.

“The ecosystem red squirrels inhabit in this region is unique,” Petrullo said. “Every three to seven years, their favorite food — seed from cones of white spruce trees — is produced in superabundance during what we call a food boom. We found that these booms, even though rare, can interrupt the biological embedding of early-life adversity. If a squirrel had a harsh first year of life, if they were lucky enough to experience a food boom in their second year of life, they lived just as long — if not longer — in spite of early-life adversity.”

The team replicated a food boom by offering wild squirrels in the Yukon peanut butter as a supplemental food source. The peanut butter didn’t have the same effect as the naturally occurring food boom did.

“This suggests that the buffering effect we see is not really just about an increase in available calories,” Petrullo said. “It’s probably about shifts in larger population-level dynamics, like competition.”

What squirrels can teach us about humans

Petrullo and her colleagues are eager to tease out the mechanisms that link squirrels’ early developmental conditions with later-life survival. What they learn could inform scientific understanding of human resilience, too.

“Our findings in red squirrels echo what we know about how early-life adversity can shorten adult lifespan in humans and other primates,” Petrullo said. “Humans vary widely in how vulnerable or resilient they are to challenges faced during early development. Our study demonstrates that future environmental quality might be an important factor that can explain why some individuals appear to be more, or less, susceptible to the consequences of early-life adversity.”

While it might be surprising that scientists can glean insights about human resilience from wild red squirrels, Petrullo pointed out that squirrels are rodents, and rodents are commonly used as models for humans in laboratory settings.

“Many lab experiments have limited relevance for broader dynamics between ecology and evolution, because it can be hard to really replicate the ecological challenges that animals have evolved to cope with in a lab setting,” she said.

Wild red squirrels, on the other hand, allow for such investigations and are an especially useful study group for questions regarding the early-life environment, Petrullo said. Although growing up as a young squirrel in the Yukon can be difficult, with lots of things making early development challenging, there are also things that can go right.

“Some red squirrels have the luck of being born into gentler early environments, akin to being born with a silver spoon,” Petrullo said. “Because of this, we’ve got this really nice individual variation in early-life environmental quality across a natural ecological environment.”

This environment, however, is expected to experience a great deal of change as global temperatures continue to rise.

“As food boom patterns begin to change,” Petrullo said, “the pathways that connect early-life experiences and lifespan may change as well, potentially offering important insight into how animals may adapt to increasingly challenging environments.”

The analysis was led by the German Centre for Integrative Biodiversity Research (iDiv) and the Martin Luther University Halle-Wittenberg (MLU) and is the largest modelling study of its kind to date. The researchers compared thirteen models for assessing the impact of land-use change and climate change on four distinct biodiversity metrics, as well as on nine ecosystem services.

GLOBAL BIODIVERSITY MAY HAVE DECLINED BY 2% TO 11% DUE TO LAND-USE CHANGE ALONE

Land-use change is considered the largest driver of biodiversity change, according to the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES). However, scientists are divided over how much biodiversity has changed in past decades. To better answer this question, the researchers modelled the impacts of land-use change on biodiversity over the 20th century. They found global biodiversity may have declined by 2% to 11% due to land-use change alone. This span covers a range of four biodiversity metrics¹ calculated by seven different models.

“By including all world regions in our model, we were able to fill many blind spots and address criticism of other approaches working with fragmented and potentially biased data,” says first author Prof Henrique Pereira, research group head at iDiv and MLU. “Every approach has its ups and downsides. We believe our modelling approach provides the most comprehensive estimate of biodiversity trends worldwide.”

MIXED TRENDS FOR ECOSYSTEM SERVICES

Using another set of five models, the researchers also calculated the simultaneous impact of land-use change on so-called ecosystem services, i.e., the benefits nature provides to humans. In the past century, they found a massive increase in provisioning ecosystem services, like food and timber production. By contrast, regulating ecosystem services, like pollination, nitrogen retention, or carbon sequestration, moderately declined.

CLIMATE AND LAND-USE CHANGE COMBINED MIGHT LEAD TO BIODIVERSITY LOSS IN ALL WORLD REGIONS

The researchers also examined how biodiversity and ecosystem services might evolve in the future. For these projections, they added climate change as a growing driver of biodiversity change to their calculations.

Climate change stands to put additional strain on biodiversity and ecosystem services, according to the findings. While land-use change remains relevant, climate change could become the most important driver of biodiversity loss by mid-century. The researchers assessed three widely-used scenarios — from a sustainable development to a high emissions scenario. For all scenarios, the impacts of land-use change and climate change combined result in biodiversity loss in all world regions.

While the overall downward trend is consistent, there are considerable variations across world regions, models, and scenarios.

PROJECTIONS ARE NOT PREDICTIONS

“The purpose of long-term scenarios is not to predict what will happen,” says co-author Dr Inês Martins from the University of York. “Rather, it is to understand alternatives, and therefore avoid these trajectories, which might be least desirable, and select those that have positive outcomes. Trajectories depend on the policies we choose, and these decisions are made day by day.” Martins co-led the model analyses and is an alumna of iDiv and MLU.

The authors also note that even the most sustainable scenario assessed does not deploy all the policies that could be put in place to protect biodiversity in the coming decades. For instance, bioenergy deployment, one key component of the sustainability scenario, can contribute to mitigating climate change, but can simultaneously reduce species habitats. In contrast, measures to increase the effectiveness and coverage of protected areas or large-scale rewilding were not explored in any of the scenarios

MODELS HELP IDENTIFY EFFECTIVE POLICIES

Assessing the impacts of concrete policies on biodiversity helps identify those policies most effective for safeguarding and promoting biodiversity and ecosystem services, according to the researchers. “There are modelling uncertainties, for sure,” Pereira adds. “Still, our findings clearly show that current policies are insufficient to meet international biodiversity goals. We need renewed efforts to make progress against one of the world’s largest problems, which is human-caused biodiversity change.”

¹global species richness, local species richness, mean species habitat extent, biodiversity intactness

The researchers fed hungry mice that could only see and smell the food without eating it. After just a few minutes, the researchers analysed the mitochondria in the liver and found that processes normally stimulated by food intake were activated.

Mitochondria in the liver get ready

The studies show that it is sufficient for the mice to see and smell food for a few minutes to influence the mitochondria in the liver cells. This is mediated by a previously uncharacterised phosphorylation in a mitochondrial protein. Phosphorylation is an important modification for the regulation of protein activity. The researchers also show that this phosphorylation affects the sensitivity of the liver to insulin. The researchers have thus discovered a new signalling pathway that regulates insulin sensitivity in the body.

Nerve cells in the hypothalamus

The effect on the liver is mediated by a group of nerve cells called POMC neurons. These neurons are activated within seconds by the sight and smell of food, signalling the liver to prepare for the incoming nutrients. The researchers also showed that the activation of POMC neurons alone is sufficient to adapt the mitochondria in the liver, even in the absence of food.

“When our senses detect food, our body prepares for food intake by producing saliva and digestive acid. We knew from previous studies that the liver also prepares for food intake. Now we have taken a closer look at the mitochondria in liver cells, because they are essential cell organelles for metabolism and energy production, and realised how surprisingly fast this adaptation takes place,” explains Sinika Henschke, first author of the study. Jens Brüning, head of the study and director at the Max Planck Institute for Metabolism Research: “Our study shows how closely the sensory perception of food, adaptive processes in the mitochondria and insulin sensitivity are linked. Understanding these mechanisms is also important because insulin sensitivity is impaired in type 2 diabetes mellitus.”

Jens Brüning is also a research group leader at the CECAD Cluster of Excellence in Ageing Research at the University of Cologne and Director of the Department of Endocrinology, Diabetology and Preventive Medicine at Cologne University Hospital.