US Pharm. 2024;49(9):24-27.

Mediterranean Diet Linked to One-Fifth Lower Risk of Early Death

Investigators from Brigham and Women’s Hospital (the Brigham) identified and assessed underlying mechanisms that may explain the Mediterranean diet’s 23% risk reduction in all-cause mortality risk for American women.

The health benefits of the Mediterranean diet have been reported in multiple studies, but there are limited long-term data of its effects in U.S. women and little understanding about why the diet may reduce risk of death. In a new study that followed more than 25,000 initially healthy U.S. women for up to 25 years, researchers from the Brigham found that participants who had greater Mediterranean diet intake had up to 23% lower risk of all-cause mortality, with benefits for both cancer mortality and cardiovascular mortality. The researchers found evidence of biological changes that may help explain why: They detected changes in biomarkers of metabolism, inflammation, insulin resistance, and more. The results were published in the Journal of the American Medical Association.

“For women who want to live longer, our study says watch your diet! The good news is that following a Mediterranean dietary pattern could result in about one-quarter reduction in risk of death over more than 25 years, with benefit for both cancer and cardiovascular mortality, the top causes of death in women (and men) in the U.S. and globally,” said senior author Samia Mora, MD, a cardiologist and the director of the Center for Lipid Metabolomics at the Brigham.

The Mediterranean diet is a diverse, plant-based diet that is rich in nuts, seeds, fruits, vegetables, whole grains, and legumes. The main fat is olive oil (usually extra virgin), and the diet additionally includes moderate intake of fish, poultry, dairy, eggs, and alcohol, and rare consumption of meats, sweets, and processed foods.

The current study investigated the long-term benefit of adherence to a Mediterranean diet in a U.S. population recruited as part of the Women’s Health Study and explored the biological mechanisms that may explain the diet’s health benefits. The study investigators evaluated a panel of approximately 40 biomarkers representing various biological pathways and clinical risk factors.

Biomarkers of metabolism and inflammation made the largest contribution, followed by triglyceride-rich lipoproteins, adiposity, and insulin resistance. Other biological pathways related to branched-chain amino acids, high-density lipoproteins, low-density lipoproteins, glycemic measures, and hypertension had a smaller contribution.

“Our research provides significant public health insight: Even modest changes in established risk factors for metabolic diseases—particularly those linked to small molecule metabolites, inflammation, triglyceride-rich lipoproteins, obesity, and insulin resistance—can yield substantial long-term benefits from following a Mediterranean diet. This finding underscores the potential of encouraging healthier dietary habits to reduce the overall risk of mortality,” said lead author Shafqat Ahmad, PhD, an associate professor of epidemiology at Uppsala University in Sweden and a researcher in the Center for Lipid Metabolomics and the Division of Preventive Medicine at the Brigham.

The current study identifies important biological pathways that may help explain all-cause mortality risk. The authors noted some key limitations, however, including that the study was limited to middle-aged and older, well-educated female health professionals who were predominantly non-Hispanic and white. The study relied on food-frequency questionnaires and other self-reported measures, such as height, weight, and blood pressure. But the study’s strengths include its large scale and long follow-up period. The authors also noted that as the concept of the Mediterranean diet has gained popularity, the diet has been adapted in different countries and cultures.

“The health benefits of the Mediterranean diet are recognized by medical professionals, and our study offers insights into why the diet may be so beneficial. Public health policies should promote the healthful dietary attributes of the Mediterranean diet and should discourage unhealthy adaptations,” said Dr. Mora.


Perinatal Depression Heightens Later CVD Risk

Women who are diagnosed with perinatal depression are more likely to develop cardiovascular disease (CVD) in the following 20 years compared with women who have given birth without experiencing perinatal depression, according to research published in the European Heart Journal.

Perinatal depression, meaning depression during pregnancy or after birth, is believed to affect one in five women giving birth worldwide.

The study is the first of its kind to look at cardiovascular health after perinatal depression and included data on around 600,000 women. It found the strongest links with risks of high blood pressure, ischemic heart disease, and heart failure.

The research was by Emma Bränn, Donghao Lu, and colleagues from the Karolinska Institutet, Stockholm, Sweden. Dr. Lu said, “Our research group has already found that perinatal depression is linked to an increased risk of several other health issues, including premenstrual disorders, autoimmune disorders, and suicidal behavior, as well as premature death.

“Cardiovascular disease is one of the leading causes of death globally, and there has been an ongoing discussion about including reproductive health when assessing the risk among women. We wanted to know if a history of perinatal depression could help predict cardiovascular disease risk,” added Dr. Lu.

The study was based on the Swedish Medical Birth Register, which records all births in the country. The researchers compared 55,539 Swedish women who were diagnosed with perinatal depression between 2001 and 2014 with another group of 545,567 Swedish women who had also given birth during that time but were not diagnosed with perinatal depression. All the women were followed up to 2020 to assess if they developed any CVD.

Among the women with perinatal depression, 6.4% developed CVD compared with 3.7% of women who had not suffered perinatal depression. This equates to a 36% higher risk of developing CVD. Their risk of high blood pressure was around 50% higher, the risk of ischemic heart disease was around 37% higher, and the risk of heart failure was around 36% higher.

Dr. Bränn, senior author, said, “Our findings may help identify people who are at a higher risk of cardiovascular disease so that steps can be taken to reduce this risk. This study also adds to the established health risks of perinatal depression. We know that perinatal depression is both preventable and treatable, and for many people it’s the first episode of depression they’ve ever experienced. Our findings provide more reason for ensuring maternal care is holistic, with equal attention on both physical and mental health.

“It remains unclear how and through what pathways perinatal depression leads to cardiovascular disease. We need to do more research to understand this so that we can find the best ways to prevent depression and lower the risk of cardiovascular disease.”

Researchers also compared the women who suffered perinatal depression with their sisters and found that they had a 20% higher risk of CVD.

“The slightly lower difference in risk between sisters suggest that there could be genetic or familial factors partly involved,” Dr. Bränn said. “There could also be other factors involved, as is the case for the link between other forms of depression and cardiovascular disease. These include alterations in the immune system, oxidative stress, and lifestyle changes implicated in major depression.”


Alcohol Raises Heart Disease Risk, Particularly Among Women

Young to middle-aged women who reported drinking eight or more alcoholic beverages per week—more than one per day, on average—were significantly more likely to develop coronary heart disease compared with those who drank less, a study presented at the American College of Cardiology’s Annual Scientific Session found. The risk was highest among both men and women who reported heavy episodic drinking, or binge drinking, and the link between alcohol and heart disease appears to be especially strong among women, according to the findings.

The study focused on 18- to 65-year-old adults and is among the largest and most diverse studies to date examining the links between alcohol and heart disease. Heart attacks and other forms of heart disease are on the rise in younger populations in the U.S., fueling concern about worsening health outcomes. At the same time, alcohol use and binge drinking have become more common among women than in previous decades.

“When it comes to binge drinking, both men and women with excess alcohol consumption had a higher risk of heart disease,” said Jamal Rana, MD, PhD, FACC, a cardiologist with the Permanente Medical Group, adjunct investigator in the Division of Research at Kaiser Permanente Northern California, and the study’s lead author. “For women, we find consistently higher risk even without binge drinking. I wasn’t expecting these results among women in this lower age group because we usually see increased risk for heart disease among older women. It was definitely surprising.”

The researchers used data from more than 430,000 patients who received care in the Kaiser Permanente Northern California integrated health organization, including nearly 243,000 men and 189,000 women. Participants on average were aged 44 years and did not have heart disease at the start of the study. Information on participants’ alcohol intake was collected during primary care visits using the health organization’s standard Alcohol as a Vital Sign screening initiative, which includes visual reference posters to help patients estimate alcohol quantities according to standard measurements.

Researchers analyzed the relationship between the level of alcohol intake that participants reported in routine assessments from 2014 to 2015 and coronary heart disease diagnoses during the 4-year period that followed. Based on self-report assessments, the scientists categorized participants’ overall alcohol intake as low (one to two drinks per week for both men and women); moderate (three to 14 drinks per week for men and three to seven drinks per week for women); or high (15 or more drinks per week for men and eight or more drinks per week for women). They separately categorized each participant as either engaging in binge drinking or not. Binge drinking was defined as more than four drinks for men or more than three drinks for women in a single day in the past 3 months. People who reported no alcohol use were not included in the study. The researchers adjusted the data to account for age, physical activity, smoking, and other known cardiovascular risk factors.

Overall, 3,108 study participants were diagnosed with coronary heart disease during the 4-year follow-up period, and the incidence of coronary heart disease increased with higher levels of alcohol consumption. Among women, those who reported high alcohol intake had a 45% higher risk of heart disease compared with those reporting low intake and had a 29% higher risk compared with those reporting moderate intake. The difference was greatest among individuals in the binge-drinking category; women in this category were 68% more likely to develop heart disease compared with women reporting moderate intake. Men with high overall intake were 33% more likely to develop heart disease compared with men who had moderate intake.

“Women feel they’re protected against heart disease until they’re older, but this study shows that even when you’re young or middle aged, if you are a heavy alcohol user or binge drink, you are at risk for coronary heart disease,” Dr. Rana said.

The results showed no significant difference in risk between people who reported moderate versus low alcohol intake, regardless of whether they also were categorized as binge drinking.

Alcohol has been shown to raise blood pressure and lead to metabolic changes that are associated with inflammation and obesity. Women also process alcohol differently than men. The researchers said that the study calls attention to the health risks of alcohol consumption and underscores the importance of considering alcohol use in heart disease risk assessment and prevention efforts.

“When it comes to heart disease, the number one thing that comes to mind is smoking, and we do not think about alcohol as one of the vital signs,” Dr. Rana said. “I think a lot more awareness is needed, and alcohol should be part of routine health assessments moving forward.”

One limitation of the study is that people tend to underreport their alcohol intake when asked by a healthcare provider. As a result, the study likely provides conservative estimates of the heart disease risk associated with alcohol consumption. The researchers also said that the manner in which alcohol screening is performed in a health clinic can influence how patients and clinicians discuss the risks of alcohol consumption and that further research could help determine optimal strategies. This study was funded by a grant from the National Institute on Alcohol Abuse and Alcoholism.


Approved Drug Studied for Ovarian Cancer

An iron-binding drug that is already approved for treatment of other diseases could provide a novel way to attack ovarian tumors, according to a new study led by Weill Cornell Medicine researchers. The preclinical study, which combined the analysis of human ovarian tumors and animal models of the disease, was published in Cancer Discovery, a journal of the American Association for Cancer Research.

Iron is essential for multiple cellular processes, so actively multiplying cancer cells often need larger amounts of it than normal cells. That is especially true in ovarian cancers.

“We thought that was a perfect opportunity to try a new approach, because there is an FDA-approved iron-chelating drug called deferiprone that has been successfully used for other diseases with abnormal iron accumulation,” said senior author Juan Cubillos-Ruiz, the William J. Ledger, MD, Distinguished Associate Professor for Infection and Immunology in Obstetrics and Gynecology at Weill Cornell Medicine. Iron-chelating drugs bind tightly to iron, preventing cells from using it.

To confirm the importance of iron in ovarian cancer, Dr. Cubillos-Ruiz’s team first looked at a collection of human tumor samples that they amassed over the past decade and analyzed public genomic datasets from ovarian cancer patients with the help of an international team of collaborators.

“We can isolate different components of tumors from ovarian cancer patients and study their molecular processes,” said Dr. Cubillos-Ruiz, who is also coleader of the Cancer Biology Program in the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

The scientists found that ovarian cancer cells demonstrate increased expression of iron-related genes, which correlated with poor patient prognosis. The investigators also found that fluid surrounding ovarian tumors contains high iron content that is readily available to cancer cells.

The investigators next looked at animal models of the disease. “We have advanced mouse models of metastatic ovarian cancer that are immunocompetent, so this allows us to study the immune system response in the disease, which is a crucial component,” Dr. Cubillos-Ruiz said. Previous iron-related studies used mice with compromised immune systems, precluding the understanding of how different therapies affect immune responses to tumors.

The investigators found that the mice recapitulated the disease features quite well: As ovarian cancer progressed, there was more iron accumulation in the tumor, and the cancer cells selectively overexpressed the iron-related gene signatures.

In the animals, deferiprone treatment worked even better than cisplatin, the current standard for ovarian cancer chemotherapy, and functioned directly inside the cells. “We demonstrated that deferiprone can chelate iron in ovarian cancer cells, in vivo,” said lead author Tito Sandoval, a former postdoctoral fellow in Dr. Cubillos-Ruiz’s laboratory.

“We found that combining cisplatin and deferiprone markedly extended the survival of mice with metastatic ovarian cancer, working synergistically compared with the monotherapies,” said Dr. Sandoval, who is now a senior scientist in radiation oncology at Washington University School of Medicine in St. Louis. “So, we decided to identify the mechanisms behind this effect.”

The team found that by starving cancer cells of iron, deferiprone triggers a cellular stress response, which prompts the immune system to attack them. Cisplatin affects cancer cell DNA replication, so the two drugs appear to be complementary.

Dr. Cubillos-Ruiz is working with clinical collaborators to design human trials of the new approach. Though deferiprone is already approved for treating other conditions, he emphasized that the team still needs to determine the best way to use it against ovarian cancer. “We want to maximize the potential therapeutic effects, so the clinical trial design is critical,” he said.

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