In a large randomized clinical trial, researchers found that managing patients' vitamin D levels through a "target-to-treat" approach -- where blood levels were monitored and dosages were adjusted to reach an optimal range -- cut the likelihood of a second heart attack by 50%.

The findings were presented on Nov. 9 at the 2025 American Heart Association Scientific Sessions in New Orleans.

Encouraging Early Results from Intermountain Researchers

These results are very encouraging, said Heidi May, PhD, cardiovascular epidemiologist at Intermountain Health and the study's principal investigator. "We observed no adverse outcomes when giving patients higher doses of vitamin D₃ supplementation, and to significantly reduce the risk of another heart attack, which are exciting results," said Dr. May. "We're excited with these results but know we have further work to do to validate these findings."

According to researchers, the results carry global importance, as between one-half and two-thirds of people worldwide have low levels of vitamin D.

In the past, most individuals received sufficient vitamin D through sunlight exposure. Today, with lifestyle changes and medical advice aimed at reducing skin cancer risk, people spend less time in the sun and must rely more on dietary supplements such as vitamin D₃ to maintain healthy levels.

From Observation to Precision Treatment

Low vitamin D levels have long been linked to poor cardiovascular outcomes in observational studies. However, earlier clinical trials that provided standard supplementation doses failed to show measurable reductions in heart disease risk. Intermountain scientists wanted to test a different idea: rather than giving everyone the same dose, what if supplementation was adjusted to reach a specific, healthy vitamin D level?

"Previous studies just gave patients supplementation without regularly checking blood levels of vitamin D to determine what supplementation achieved," said Dr. May. "With more targeted treatment, when we checked exactly how supplementation was working and made adjustments, we found that patients had their risk of another heart attack cut in half."

Inside the TARGET-D Clinical Trial

The Intermountain study, called the TARGET-D trial, ran from April 2017 to May 2023 and included 630 patients who had suffered a heart attack within a month of enrolling. Participants were followed until March 2025 to monitor cardiovascular outcomes.

Patients were randomly assigned to one of two groups: one received no vitamin D management, and the other underwent active, targeted vitamin D₃ treatment.

The goal for the treatment group was to raise blood vitamin D levels to above 40 nanograms per milliliter (ng/mL). At the start, 85% of participants had vitamin D₃ levels below that threshold (<40 ng/mL).

Dosing, Monitoring, and Results

More than half of the patients receiving targeted therapy required an initial dose of 5,000 international units (IU) of vitamin D₃, compared to typical supplement recommendations of 600-800 IU.

Vitamin D blood levels were checked annually for those maintaining healthy levels. Patients with lower levels were tested every three months and had their dosage adjusted until reaching the 40 ng/mL target. Afterward, their levels were monitored once a year.

Researchers tracked major cardiac events (MACE), including heart attacks, strokes, heart failure hospitalizations, or deaths. Out of 630 participants, 107 experienced such events. While there was no significant difference in the overall risk of MACE between the two groups, the chance of having a second heart attack was cut in half among those receiving targeted vitamin D treatment.

Next Steps for Heart and Vitamin D Research

Researchers plan to expand their work with a larger clinical trial to confirm and build upon these findings.

A larger study group will allow us to more fully evaluate whether targeted vitamin D management can reduce not only repeat heart attacks but also other forms of cardiovascular disease, said Dr. May.

"Nearly half of our chronic fatigue subjects had some disorder of breathing -- a totally unappreciated issue, probably involved in making symptoms worse," said Dr. Benjamin Natelson of the Icahn School of Medicine, senior author of the study published in Frontiers in Medicine. "Identifying these abnormalities will lead researchers to new strategies to treat them, with the ultimate goal of reducing symptoms."

Breathe easy

The study included 57 people diagnosed with chronic fatigue syndrome and 25 healthy individuals of similar age and activity level. All participants completed two days of cardiopulmonary exercise tests. During these sessions, the researchers monitored heart rate, blood pressure, oxygen uptake efficiency, blood oxygen saturation, and how much effort participants used to breathe. They also analyzed breathing rate and patterns to detect signs of hyperventilation and dysfunctional breathing.

Dysfunctional breathing is often seen in asthma patients, but it can develop for many different reasons. Typical features include frequent deep sighs, rapid breathing, forceful exhalation from the abdomen, or chest breathing without proper diaphragm use, which prevents the lungs from fully expanding. It can also involve a lack of coordination between chest and abdominal movements, meaning the muscles that support breathing are no longer working smoothly together.

"While we know the symptoms generated by hyperventilation, we remain unsure what symptoms may be worse with dysfunctional breathing," said Dr. Donna Mancini of the Icahn School of Medicine, first author of the study. "But we are sure patients can have dysfunctional breathing without being aware of it. Dysfunctional breathing can occur in a resting state."

Catching your breath

Results showed that people with chronic fatigue syndrome took in roughly the same amount of oxygen as the control group -- their peak VO2 max was similar. However, 71% of the chronic fatigue group showed breathing abnormalities, such as hyperventilation, dysfunctional breathing, or both.

Almost half of the chronic fatigue participants breathed irregularly during the tests, compared to only four people in the control group. About one-third of the fatigue patients hyperventilated, while just one person in the control group did. Nine patients had both hyperventilation and dysfunctional breathing, a combination not seen in any of the controls.

Both of these breathing disorders can produce symptoms similar to those of chronic fatigue, including dizziness, difficulty concentrating, shortness of breath, and exhaustion. When both occur together, they can also cause chest pain, palpitations, fatigue, and (unsurprisingly) anxiety. The researchers believe that these breathing problems may worsen the effects of chronic fatigue or even play a direct role in post-exertional malaise.

"Possibly dysautonomia could trigger more rapid and irregular breathing," said Mancini. "It is well known that chronic fatigue syndrome patients often have dysautonomia in the form of orthostatic intolerance, which means you feel worse when upright and not moving. This raises the heart rate and leads to hyperventilation."

Pulmonary physiotherapy?

These findings suggest that addressing dysfunctional breathing could help relieve some symptoms of chronic fatigue. The researchers plan to continue investigating how dysfunctional breathing and hyperventilation interact. Although more studies are needed before any official treatments are recommended, they already have several promising ideas.

"Breathing exercises via yoga could potentially help, or gentle physical conditioning where breath control is important, as with swimming," suggested Natelson. "Or biofeedback, with assessment of breathing while encouraging gentle continuous breath use. If a patient is hyperventilating, this can be seen by a device that measures exhaled CO2. If this value is low, then the patient can try to reduce the depth of breathing to raise it to more normal values."