High Protein Diet for Atherosclerosis

(HPA Trial)

Recruiting at 2 trial locations

Overseen By Babak Razani, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Missouri-Columbia

Must not be taking: Medications, supplements confounding outcomes

Disqualifiers: Organ dysfunction, Alcohol use disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day per meal type

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how different high-protein diets affect atherosclerosis, a condition that can lead to heart attacks and strokes. Researchers are testing meals with high animal protein, high plant protein, and plant protein with added leucine (an amino acid) to determine their influence on plaque buildup in arteries. Individuals who struggle with maintaining a healthy weight and have a BMI between 25.0 and 39.9 kg/m² might be a good fit for this trial.

As an unphased trial, this study offers a unique opportunity to contribute to understanding dietary impacts on heart health.

Will I have to stop taking my current medications?

The trial excludes participants who use medications or dietary supplements that could affect the study outcomes, so you may need to stop taking certain medications. It's best to discuss your specific medications with the trial coordinators.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that most people can handle a high-protein diet without problems. Studies have found that consuming more protein, whether from animals or plants, does not increase the risk of stroke or heart-related deaths. Some research even suggests that plant proteins might help lower blood pressure and reduce heart disease risks.

However, early animal studies suggested that a high-protein diet, especially with added leucine, might lead to plaque buildup in arteries, potentially raising the risk of heart issues. These effects have not been proven in humans.

In general, while a high-protein diet is usually safe, the type of protein consumed can affect heart health differently. Eating more plant-based proteins might benefit heart health more than animal proteins. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about these high-protein diet treatments for atherosclerosis because they offer a potential new way to combat this condition beyond standard medications like statins. Unlike typical treatments that focus on managing cholesterol levels through drugs, these diets emphasize increasing protein intake, specifically from plant and animal sources, which may influence heart health differently. The addition of leucine to one of the plant-based meal options could enhance muscle synthesis and overall cardiovascular benefits, setting these diets apart from conventional approaches. By exploring the impact of dietary protein on atherosclerosis, researchers hope to uncover alternative strategies that may complement or even reduce the need for medication.

What evidence suggests that this trial's treatments could be effective for atherosclerosis?

This trial will compare different dietary interventions: high plant protein meals, high animal protein meals, and standard meals. Research has shown that plant protein benefits heart health. Studies have found that replacing animal protein with plant protein can lower bad cholesterol levels. Plant protein is also linked to a reduced risk of heart disease and improved blood pressure. In contrast, animal protein might increase the risk of atherosclerosis, where plaque builds up in the arteries. Consuming large amounts of animal protein has been associated with a higher risk of heart problems. Another arm of this trial will test high plant protein meals with added leucine, an amino acid found in animal protein, which might reduce some heart health benefits of plant protein by contributing to plaque buildup. ^{3 5 6 7 8}

Who Is on the Research Team?

Bettina Mittendorfer

Principal Investigator

University of Missouri-Columbia

Are You a Good Fit for This Trial?

This trial is for adults aged 45-75 with a BMI of 25.0 to less than 40.0 kg/m2, who do not smoke and have no significant organ dysfunction or allergies to meal ingredients. It excludes those on certain medications or supplements, highly active individuals, alcohol users with disorders, premenopausal women, prisoners, and anyone unable to consent.

Inclusion Criteria

Your body mass index is between 25 and 40.

I am between 45 and 75 years old.

Exclusion Criteria

Your blood triglyceride level is less than 125 mg/dl.

prisoners

You exercise regularly for more than 150 minutes each week.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive different dietary protein meals to study the impact on macrophage mTOR signaling and atherosclerosis

1 day per meal type

1 visit per meal type (in-person)

Follow-up

Participants are monitored for changes in monocyte p-S6 content and other cardiovascular markers

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• High Protein Diet

Trial Overview The study tests the effects of different diets on atherosclerosis: high plant protein meals (with and without extra leucine), standard meals, and high animal protein meals. The focus is on how these diets might influence heart disease by affecting plaque in arteries.

How Is the Trial Designed?

Group I: High plant protein meal with additional leucine Experimental Treatment 1 Intervention

Group II: High plant protein meal Experimental Treatment 1 Intervention

Group III: High animal protein meal Experimental Treatment 1 Intervention

Group IV: Standard meal Active Control 1 Intervention

Who Is Running the Clinical Trial?

University of Missouri-Columbia

Lead Sponsor

Trials

387

Recruited

629,000+

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Published Research Related to This Trial

Recent studies indicate that higher protein intake, especially from plant sources, may lower blood pressure and reduce the risk of cardiovascular diseases, contrasting previous assumptions about protein's negative effects.

Epidemiological evidence suggests that increased protein consumption is linked to lower blood pressure over time and a reduced risk of ischemic heart disease, although more compelling data is needed before making dietary recommendations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of protein intake on blood pressure and cardiovascular disease. Appel, LJ.[2019]

A study suggests that diet may be linked to the prevalence of atherosclerosis, particularly in wealthier countries, highlighting the need for systematic comparisons between high-risk and low-risk areas.

The research focuses on five Central European countries, where Austria, Czechoslovakia, and Hungary have high ischemic heart disease mortality rates, while Poland and Romania have lower rates, indicating that dietary differences could help identify potential causes of atherosclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diet and atherogenesis. Seely, S.[2019]

A study on rats showed that a low protein diet (10% casein) led to increased plasma triglycerides and higher platelet aggregability, which are risk factors for atherosclerosis and thrombosis, compared to moderate (20% casein) and high protein (60% casein) diets.

The low protein group produced more thromboxane A2 (which promotes clotting) and less prostaglandin I2 (which prevents clotting), suggesting that higher protein intake may help reduce the risk of arterial thrombosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of dietary protein level on platelet aggregation in rat. Morita, I., Takahashi, R., Ebisawa, H., et al.[2019]

Higher-protein diets (1.2 to 1.6 g protein per kg of body weight per day) have been shown to lead to greater weight loss, fat mass loss, and preservation of lean mass compared to lower-protein diets, based on several meta-analyses of short-term studies.

While short-term studies consistently show benefits of higher protein intake, longer-term studies yield mixed results, primarily due to dietary compliance; those who adhered to higher-protein diets experienced significant improvements in body weight and cardiometabolic risk factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of protein in weight loss and maintenance. Leidy, HJ., Clifton, PM., Astrup, A., et al.[2023]

In a study analyzing data from the Cholesterol Lowering Atherosclerosis Study, increased consumption of total fat and polyunsaturated fat was linked to a higher risk of developing new atherosclerotic lesions over two years.

When participants reduced their fat intake, they compensated by increasing dietary protein and carbohydrates, suggesting that these substitutes may be more beneficial than replacing fats with other types of fats in preventing new lesions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The influence of diet on the appearance of new lesions in human coronary arteries. Blankenhorn, DH., Johnson, RL., Mack, WJ., et al.[2016]

In a study of 215 obese adults over 12 weeks, a high protein (HP) diet led to greater reductions in triglycerides and total cholesterol compared to a standard protein (SP) diet, indicating improved lipid profiles for cardiovascular disease (CVD) risk.

While overall weight loss was similar between the HP and SP diets, individuals with higher baseline triglyceride levels experienced significantly greater weight loss and fat loss on the HP diet, suggesting it may be particularly beneficial for those at increased risk of CVD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High protein diets decrease total and abdominal fat and improve CVD risk profile in overweight and obese men and women with elevated triacylglycerol. Clifton, PM., Bastiaans, K., Keogh, JB.[2015]

High-protein diets (25%-35% of energy) are effective for weight loss and are more satiating than diets high in carbohydrates or fats, leading to lower serum triglyceride levels.

The impact of high-protein diets on cholesterol levels varies based on carbohydrate restriction and saturated fat intake, with some individuals experiencing an increase in low-density lipoprotein cholesterol despite weight loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic effects of high-protein diets. Clifton, PM., Keogh, J.[2022]

In a study of 26 individuals over one year, those who followed a prescribed treatment and dietary guidelines showed significant regression of coronary artery disease (CAD) and recovery of viable heart tissue, with 43.75% of myocardial segments improving.

Conversely, individuals on a high-protein diet experienced worsening of key risk factors and a 39.7% progression in CAD, suggesting that such diets may negatively impact heart health by increasing inflammation and lipid deposition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of high-protein diets on coronary blood flow. Fleming, RM.[2017]

A high protein diet was found to reduce the incidence of stroke, with high fish protein specifically helping to lower severe hypertension, while high soybean protein did not have the same effect.

Certain amino acids, particularly lysine, threonine, isoleucine, leucine, and methionine, were linked to the reduced risk of stroke and the antihypertensive effects of high protein diets, suggesting that these amino acids may play a key role in the protective benefits of such diets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prophylactic trials for stroke in stroke-prone SHR. (3) Amino acid analysis of various diets and their prophylactic effect. Yamori, Y., Horie, R., Ohtaka, M., et al.[2023]

The study found that a high-fat plus high-cholesterol diet in Göttingen Miniature Swine led to significant atherosclerosis development, with lesions observed as early as one month and worsening by nine months, indicating the diet's strong impact on cardiovascular health.

The lesions observed in the swine were similar to those found in humans, suggesting that these swine can serve as a valuable model for studying atherosclerosis and its relationship with hypercholesterolemia and hyper-beta-lipoproteinemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Göttingen miniature swine as a model for diet-induced atherosclerosis]. Tanigawa, M., Akaike, I., Adachi, J., et al.[2019]

In a study involving 32 male Wistar rats over 8 weeks, dietary supplementation with the nonpolar amino acids valine and leucine significantly reduced serum cholesterol levels in a high-fat diet context.

The reduction in cholesterol levels also helped mitigate the prooxidant status induced by hypercholesterolemia, suggesting that these amino acids may be beneficial in reducing the risk of atherosclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The effects of some nonpolar aminoacids--valine, leucine--administration on the arterial wall already exposed to a hypercholesterolemic diet]. Cojocaru, E., Zamfir, CL., Lupuşoru, CE., et al.[2015]

In a study of 29,017 postmenopausal women followed for 15 years, substituting vegetable protein for carbohydrates was linked to a 30% reduction in coronary heart disease (CHD) mortality, suggesting that plant-based proteins may be healthier than carbohydrates.

Conversely, higher intake of red meats and dairy products was associated with increased CHD mortality, indicating that not all protein sources are equally beneficial and that long-term high-protein diets could have negative health effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Associations of dietary protein with disease and mortality in a prospective study of postmenopausal women. Kelemen, LE., Kushi, LH., Jacobs, DR., et al.[2023]

In a study of dietary habits from 253 deceased New Orleans men, higher intakes of plant-based proteins, carbohydrates, starch, and fiber were linked to less severe atherosclerotic lesions in coronary arteries, suggesting a protective effect against heart disease.

Conversely, diets high in animal protein and fat were associated with greater atherosclerotic involvement, indicating that a diet rich in plant-based foods may contribute to better cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary-atherosclerosis study on deceased persons. Relation of selected dietary components to raised coronary lesions. Moore, MC., Guzmán, MA., Schilling, PE., et al.[2022]

High protein diets, exceeding the recommended dietary allowance of 0.8 g protein/kg body weight/day, are associated with several potential health risks, including bone disorders, renal dysfunction, increased cancer risk, liver issues, and progression of coronary artery disease, based on a review of 32 studies involving healthy adults.

The review suggests that there is insufficient scientific evidence to support the recommendation of high protein intake for healthy adults, highlighting the need for further research, particularly large randomized controlled trials, to better understand the long-term effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Effects Associated with Protein Intake above the Recommended Dietary Allowance for Adults. Delimaris, I.[2021]

A diet plays a crucial role in preventing atherosclerosis, a condition characterized by the buildup of fats and cholesterol in arteries.

New functional meat foods have been developed that contain significantly lower cholesterol levels compared to traditional meat, making them a promising option for atherosclerosis prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Functional meat food in atherosclerosis prevention]. Chernobel'skiĭ, GN., Davletbaev, RM., Sazonova, EN., et al.[2006]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10058321/

The Impact of High Protein Diets on Cardiovascular ... We conducted a meta-analysis to assess the impact of high protein diets compared to normal protein consumption on cardiovascular outcomes in adults.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7053091/

High-protein diets increase cardiovascular risk by ... We show that dietary protein drives atherosclerosis and lesion complexity. Protein ingestion acutely elevates amino acid levels in blood and atherosclerotic ...

3. observatoireprevention.org observatoireprevention.org/en/2024/05/30/high-protein-intake-could-increase-the-risk-of-cardiovascular-events/

High protein intake could increase the risk of cardiovascular ... A very high intake of animal protein, about twice the recommended intake, could therefore promote the development of atherosclerosis and ...

4. peterattiamd.com peterattiamd.com/protein-and-ascvd/

Silencing the alarm over a recent paper on dietary protein ... 4) Atherosclerosis-prone mice demonstrate a greater atherosclerotic plaque burden after eight weeks on a high-protein (or high-leucine) western ...

5. academic.oup.com academic.oup.com/nutritionreviews/article/83/3/e814/7715016

Impact of Quantity and Type of Dietary Protein on ... Higher protein diets (HPDs) have shown favorable outcomes on weight maintenance and body-composition management; however, their protective ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05235464

NCT05235464 | High Protein Diet and Atherosclerosis The investigators' extensive preliminary data in animal models show that dietary protein increases atherosclerotic plaque formation and size and promotes ...

7. pubs.rsc.org pubs.rsc.org/en/content/articlehtml/2025/ra/d4ra08221d

Adhering to recommended dietary protein intake for optimizing ... They reported that while intake of total protein and animal protein is not associated with the risk of cancer and CVD, an additional 3% daily ...

8. bmj.com bmj.com/content/370/bmj.m2412

Dietary intake of total, animal, and plant proteins and risk ... Conclusions Higher intake of total protein was associated with a lower risk of all cause mortality, and intake of plant protein was associated ...