Nutritional Ketosis as a Novel Therapeutic Strategy to Stabilize Chronic Aortic Dissection in Marfan Syndrome
Phase: NA
Conditions: Marfan Syndrome, Aortic Dissection
Sponsor: Washington University School of Medicine

NUTRITIONAL KETOSIS AS A NOVEL THERAPEUTIC STRATEGY TO STABILIZE 
CHRONIC AORTIC DISSECTION IN MARFAN SYNDROM 
 
 
Washington University School of Medicine 
Department of Surgery, Division of Vascular Surgery 
 660 South Euclid Avenue, Campus Box 8109 
St. Louis, MO 63110 
Protocol#: 
TBD 
Version Date: 
17 October 2025 
Version Number: 
1.0 
 
 
 
Principal Investigator: 
Mohamed Zayed, MD, PhD, MBA, DFSVS, FAHA, FACS 
Phone: (314) 362-5648 
E-mail: zayedm@wustl.edu 
 
 
 
 
 
 
 
 
Funded by: 
Divisional funds 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure. Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them. 
 

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Initial Approval Version 
Protocol Revision History 
17 Oct 2025 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
1.0 Synopsis .................................................................................................................................................... 3 
2.0 Introduction ............................................................................................................................................... 5 
2.1 Background ........................................................................................................................................... 5 
2.2 Study Rationale ..................................................................................................................................... 6 
2.3 Risks and Benefits ................................................................................................................................. 7 
3.0 Objectives and Endpoints .......................................................................................................................... 8 
4.0 Study Population ....................................................................................................................................... 8 
4.1 Inclusion Criteria ................................................................................................................................... 8 
4.2 Exclusion Criteria .................................................................................................................................. 9 
4.3 Historical Control Cohort ...................................................................................................................... 9 
6.0 Study Interventions.................................................................................................................................... 9 
6.1 Study Procedures ................................................................................................................................... 9 
6.2 Duration of Participation...................................................................................................................... 11 
7.0 Regulatory and Reporting Requirements .................................................................................................. 11 
7.1 Unanticipated Problems and Adverse Event Reporting ......................................................................... 11 
7.2 WU PI Reporting Requirements ........................................................................................................... 11 
8.0 Data Collection and Security ................................................................................................................... 11 
9.0 Data Safety and Monitoring ..................................................................................................................... 12 
10.0 Statistical Considerations ....................................................................................................................... 12 
11.0 References ............................................................................................................................................. 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 Synopsis 
 
Title: 
Nutritional Ketosis as a Novel Therapeutic Strategy to Stabilize 
Chronic Aortic Dissection in Marfan Syndrome 
Study Description: 
Patients with Marfan syndrome who have chronic or residual aortic 
dissection remain at ongoing risk for progressive aortic dilation and 
eventual 
need 
for 
operative 
repair. 
Despite 
advances 
in 
antihypertensive therapy and open/endovascular/hybrid techniques, 
no medical therapy has been shown to slow aortic enlargement once 
chronic dissection is established. But promising results have been 
demonstrated in rodent studies utilizing ketogenic dietary 
interventions. Therefore, this prospective, single-arm, intent-to-treat 
pilot clinical trial will test the feasibility, safety, and potential efficacy 
of inducing and maintaining nutritional ketosis in patients with 
Marfan syndrome and chronic aortic dissection 
Objectives: 
Primary Objective: 
• To test the feasibility, safety, and potential efficacy of 
inducing and maintaining nutritional ketosis in patients with 
Marfan syndrome and chronic aortic dissection (Prior type 
A dissection with residual distal dissection or Stanford Type 
B; and a maximal aortic diameter 4.0-5.0 cm). 
Secondary Objective: 
• Observation of changes related to aortic dissection 
and inflammatory markers 
• Patient 
adherence 
to 
ketogenic 
dietary 
recommendations 
 
Endpoints: 
Primary Endpoint: 
• Freedom from aortic intervention at 12 months compared 
with historical controls.  
Secondary Endpoints: 
• Change in aortic diameter 
• Growth rate 
• Systemic inflammatory markers 
• Dietary adherence metrics 
Study Population: 
15 patients- Prospective Cohort 
15 patients- Historical Control 
Phase: 
N/A 
Description of Sites / 
Facilities Enrolling: 
Washington University School of Medicine / Barnes-Jewish 
Hospital 

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Description 
of 
Study 
Intervention: 
A study coordinator and dietitian will provide remote counseling and 
compliance support. Ketosis will be quantified by β-hydroxybutyrate 
levels from finger-stick meters (self-reported through a secure cloud-
based portal) and validated with serum assays every 3 months. 
Standard-of-care CT angiography will be obtained at baseline, 6, and 
12 months to assess aortic diameter, false-lumen status, and 
remodeling. All participants will continue optimal antihypertensive 
and impulse-control therapy under cardiovascular supervision. 
Study Duration: 
Estimated time (in months) from when the study opens to enrollment 
until completion of data analyses: 24 

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2.0 Introduction 
2.1 Background  
People with Marfan syndrome are born with a change in a gene that makes the walls of their 
blood vessels weaker than normal. One of the most serious problems caused by Marfan 
syndrome is a tear in the aorta (aortic dissection), the large blood vessel that carries blood from 
the heart to the rest of the body. When a tear occurs in the first part of the aorta (type A 
dissection), emergency surgery is necessary.  When a tear occurs further down in the aorta (type 
B dissection), optimal medical therapy is most often prescribed. When a residual or chronic 
aortic dissection is present after the acute dissection, the aortic wall is weaker than normal. Over 
time, this weakened part of the aorta can slowly stretch and grow larger. If the aorta keeps 
expanding, patients may eventually need a major operation to repair it. 
Currently, the only way to manage the condition of a chronic aortic dissection is with medicines 
that lower blood pressure and heart rate. These treatments reduce stress on the aorta but do not 
stop the aorta from getting bigger. There is no medical therapy known to slow or stop aortic 
growth once a dissection has already happened. 
In recent animal studies, it was found that when the body uses ketones – natural molecules made 
during a ketogenic diet – the blood vessels become less inflamed and more stable. The ketogenic 
diet is a high-fat, very-low-carbohydrate eating plan that has been safely used for many years to 
treat children with epilepsy. In animals, nutritional ketosis reduced vessel wall injury and limited 
the growth of aneurysms. 
In this pilot clinical trial, we will test whether a carefully supervised ketogenic diet can safely 
help people with Marfan syndrome who already have a chronic or residual aortic dissection. 
Fifteen participants will work with a study coordinator and dietitian to learn how to follow the 
diet and will have regular guidance and check-ins. They will measure their blood ketone levels at 
home with a simple finger-stick device and relay their readings to the research team. Every three 
months, blood samples will also be collected to confirm the body’s level of ketosis. 
Participants will continue their usual heart and blood-pressure medicines and regular visits with 
their doctors. CT scans of the aorta will be performed at the start of the study and then again at 6 
and 12 months to see if the aorta changes in size. 
The main goal is to see how many patients can avoid needing aortic surgery within one year, 
compared with what is normally expected from past studies. We will also track how well patients 
follow the diet, how their aorta changes, and whether inflammation in their blood decreases. 
If this approach proves safe and effective, it could become the first medical treatment aimed at 
stabilizing the aorta in Marfan syndrome, reducing the need for major operations and improving 
long-term health for people living with this genetic condition. 

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2.2 Study Rationale 
Chronic aortic dissections in Marfan syndrome represent a particularly challenging form of 
genetically triggered aortopathy.1-3 Despite meticulous impulse-control therapy with beta-
blockers and angiotensin receptor blockers (ARBs), a large proportion of patients experience 
progressive thoracoabdominal aortic dilation and false-lumen expansion.2,4,6 Over time, these 
changes predispose to rupture, malperfusion, or the need for extensive aortic repair, all of which 
carry substantial morbidity.7-9 Current medical therapies target hemodynamic stress as supportive 
therapy but do not address the molecular drivers of wall degeneration such as oxidative injury, 
smooth muscle cell apoptosis, and extracellular matrix breakdown.2,10 
Preclinical data from our group and others demonstrate that nutritional ketosis – a physiologic 
metabolic state induced by carbohydrate restriction or exogenous ketone supplementation – 
attenuates these same degenerative mechanisms (see Figure 1).11,12 In murine aneurysm and 
dissection models, ketogenic interventions significantly reduced macrophage infiltration, matrix 
metalloproteinase activity, and extracellular matrix degradation, while improving vascular 
smooth muscle cell viability and reparative aortic wall collagen content.13 Collectively, these 
effects promote greater structural stability and reduced inflammatory remodeling.14 
This biologic rationale, combined with the extensive clinical safety record of ketogenic therapy 
in epilepsy and metabolic syndrome, provides a strong foundation for translation to aortic 
disease.12,15-18 Importantly, Marfan aortopathy is characterized by heightened transforming 
growth factor-β signaling and impaired extracellular matrix turnover, both of which are 
influenced by cellular redox balance and energy metabolism – pathways we have previously 
shown to be modulated in the aortic wall by ketone bodies such as β-hydroxybutyrate.13,19-21 
Thus, introducing a ketogenic intervention into this population could yield not only clinical 
benefit but also mechanistic insight into how metabolic modulation impacts connective tissue 
integrity in the setting of Marfan syndrome. 

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Figure 1. Ketogenic Diet Reduces Aortic Aneurysm Expansion in Rodent Model. (published in: Sastriques-Dunlop S, et 
al. Sci Rep 2024; 14(1): 1438) Ketosis attenuates AAA formation and MMP9. (A) Rats underwent exposure to PPE for AAA 
creation. The experimental group was given a ketogenic diet that started one-week prior to PPE exposure (KDp; N = 6) 
while the control group was fed a standard chow diet (SD; N = 5). (B) Ketosis (βHB whole blood levels > 0.5 mM/L) was 
verified at week 0, 1 and 2 in SD (0.2±0.1, 0.3±0.1 and 0.4±0.1) and KDp rats (3±1, 3±1 and 3±0.5) respectively (p < 
0.01). (C) Percent body weight difference in SD versus KDp rats at week 1 (13±5 vs. 2±1.3) and at week 2 (23±5 vs. 8±2) 
respectively (p < 0.001). (D) Percent aortic diameter in SD versus KDp rats at week 1 (154±48 vs. 137±42; p = ns) and at 
week 2 (332±129 vs. 140±152; p = 0.008) respectively (aneurysms were defined by a >100% increase in the aortic diameter 
compared with pretreatment measurements). (E) AAA collagen staining quantification for SD and KDp at week 2 (33±4 vs. 
34±2; p = ns) respectively. (F and G) Trichrome staining of abdominal aortas (cross-section of tissue slides) with 5x 
magnification for SD and KDp rats. Areas with blue staining signify areas with higher collagen deposition. (H) Zymogram 
demonstrating total MMP9 and MMP2 levels were measured by integrated optical density (IOD). (I) Total MMP-9 levels 
for SD and KDp at week 2 (4.6±2 x 103 vs. 1.7±0.8 x 103; p = 0.02) respectively. (J) Total MMP-2 levels for SD and KDp 
at week 2 (5.4±3 x 102 vs. 1±0.6 x 103; p = ns) respectively. (K) Representative western blots of collagen 1, α-SMA, TGFβ-
1 and Caveolin 1 in AAA tissue. (L) Collagen I protein content expressed as a ratio to Caveolin 1 content in AAA tissue of 
SD and KDp rats (0.1±0.1 vs. 0.1±0.1 respectively; p = ns). (M) α-SMA protein content expressed as a ratio to Caveolin 1 
content in AAA tissue of SD and KDp rats (2±0.7 vs. 1.7±0.6 respectively; p = ns). (N) TGFβ protein content expressed as 
a ratio to Caveolin 1 content in AAA tissue of SD and KDp rats (1.3±0.3 vs. 1.2±0.3 respectively; p = ns). 
 
2.3 Risks and Benefits 
Risks: Although a well-formulated ketogenic diet is generally safe for most individuals when 
properly supervised, potential risks include dehydration, electrolyte imbalances (particularly 
low sodium, potassium, or magnesium), and transient increases in serum lipids during the 
early adaptation phase. Some participants may experience gastrointestinal discomfort, fatigue, 
or headache - collectively known as “keto flu” - during the first few weeks of dietary 
transition. In rare cases, prolonged ketosis can exacerbate preexisting hepatic or renal 
dysfunction or cause elevations in uric acid. For patients with cardiovascular disease, 
monitoring of lipid profiles and metabolic parameters is needed. To minimize these risks, 
participants in this study will undergo regular laboratory evaluations, receive individualized 
dietary guidance from the research team and dietitian, and remain under medical supervision 

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throughout the intervention period 
 
The research blood draws performed have a minimal risk of pain, bruising or the feeling of 
lightheadedness at the time of the blood draw.  
 
Patient PHI will be recorded, used and stored during the course of this study, thus there is a 
potential risk of participant loss of confidentiality. All data will be recorded, stored, and 
analyzed using hospital computers on the virtual desktop servers in order to minimize the risk 
of a breach. 
 
Benefits: There is a potential benefit that the ketogenic dietary interventions implemented 
may help delay the need for aortic repair. Patients will continue standard of care CT imaging 
for monitoring, and all clinical decisions will be made in accordance with the current standard 
of care. 
 
3.0 Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Test the feasibility, safety, and potential efficacy 
of inducing and maintaining nutritional ketosis in 
patients with Marfan syndrome and chronic aortic 
dissection  
 
Freedom from aortic intervention at 12 
months compared with historical controls.  
 
Secondary 
Observation of changes related to aortic 
dissection and inflammatory markers 
 
Patient adherence to ketogenic dietary 
recommendations 
 
Explore the mechanistic relationship between 
circulating ketone levels, systemic inflammation, 
and aortic remodeling as measured by imaging and 
biomarker assays 
Change in maximal descending thoracic 
aortic diameter and annualized growth rate 
Degree of false-lumen thrombosis 
Correlation between serum β-
hydroxybutyrate levels and aortic 
remodeling using finite-element imaging 
analysis 
Changes in systemic inflammatory and 
metabolic biomarkers 
Overall diet adherence and safety. 
 
4.0 Study Population 
4.1 Inclusion Criteria 
1. Adults between 18 and 50 years old. 
2. Ability to understand and willingness to sign an IRB approved written informed 
consent document. 
3. Genetically or clinically confirmed Marfan syndrome 

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4. Chronic descending thoracic aortic dissection present for at least three months 
5. Maximal descending thoracic aortic diameter must measure between 4.0 and 5.0 
cm at baseline on contrast-enhanced CT angiography (CTA) 
6. Have been clinically stable and consistent antihypertensive regimen for at least 
four weeks  
4.2 Exclusion Criteria 
1. Acute or rapidly enlarging dissection (>0.5 cm increase over the preceding three months) 
2. Prior descending thoracic aortic repair or endograft placement 
3. Advanced renal or hepatic dysfunction 
4. Poorly controlled diabetes requiring insulin 
5. Active malignancy, pregnancy, or other metabolic or nutritional disorders that would 
contraindicate ketogenic therapy 
6. Body mass index below 18 kg/m²  
7. Inability to comply with dietary restrictions or follow-up imaging 
8. Current enrollment in another interventional study, which in the opinion of the PI, may 
confound study results. 
9. Patients who, in the opinion of the PI, are not suitable candidates for study participation. 
 
4.3 Historical Control Cohort 
Historical control data will be collected from previously published Marfan dissection cohorts, 
where approximately 20-25% of patients progress to intervention during the first year of follow-
up.2,3 
6.0 Study Interventions 
6.1 Study Procedures 
Participants will initiate a supervised ketogenic diet formulated to provide approximately 
70-75% of calories from fat, 20% from protein, and less than 10% from carbohydrates, 
consistent with protocols successfully used in therapeutic epilepsy trials but adapted for adult 
cardiovascular patients.12,16,24,25 Caloric intake will be individualized to maintain stable weight 
and adequate micronutrient balance. Each participant will receive an orientation session with a 
registered dietitian, followed by weekly virtual or phone check-ins for the first month and bi-
weekly thereafter. Educational materials, individualized meal plans, and recipes will be 
provided. 
To ensure safety and adherence, participants will use a handheld ketone meter (Keto-
Mojo) to measure β-hydroxybutyrate levels three times per week via saliva as well as finger-stick 
blood testing.26,27 These readings will be automatically uploaded to a secure, HIPAA-compliant 
cloud platform monitored by the study team. Serum ketone validation and metabolic panels, 
including electrolytes, lipid profiles, and liver function tests, will be obtained at baseline and 
every three months. A study coordinator will review adherence data weekly and contact 
participants who fall below target ketosis thresholds (≥0.5 mmol/L). Blood pressure logs and 
medication compliance will be reviewed at each visit to ensure consistent impulse control (see 

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Table 1). 
Imaging assessments will be performed using standard-of-care CTA at baseline, 6, and 12 
months. All studies will follow an institutional low-radiation surveillance protocol optimized for 
chronic dissection.2-4 Measurements will include maximal descending thoracic diameter, true and 
false lumen cross-sectional areas, and extent of thrombosis.4,23 Each scan will be reviewed by 
two blinded imaging readers to minimize measurement bias. 
Participants will remain under the care of their treating cardiovascular physicians 
throughout the study, ensuring continuation of best-practice medical management. Any 
indication for surgical or endovascular intervention during the trial will be determined by the 
treating team using standard clinical criteria, and the patient will be considered to have reached 
the primary study endpoint. 
 
Table 1: Schedule of Activities 
Assessment / 
Measurement 
Baseline 
Month 3 
Month 6 
Month 9 
Month 12 
Clinical Evaluation 
✓ 
✓ 
✓ 
✓ 
✓ 
Dietitian / 
Coordinator Visit 
Weekly 
(Month 0–1), 
then bi-
weekly 
✓ 
✓ 
✓ 
✓ 
Home β-
Hydroxybutyrate 
(Finger-Stick Meter) 
Ongoing, ≥3× 
per week 
Continuous 
Continuous 
Continuous 
Continuous 
Serum β-
Hydroxybutyrate & 
Metabolic Panel 
✓ 
✓ 
✓ 
✓ 
✓ 
Inflammatory 
Biomarkers (hs-
CRP, IL-6, etc.) 
✓ 
– 
✓ 
– 
✓ 
Fasting Lipids, 
HbA1c, Glucose 
✓ 
– 
✓ 
– 
✓ 
Body Weight / BMI 
✓ 
✓ 
✓ 
✓ 
✓ 
Blood Pressure & 
Pulse Logs 
Continuous 
(weekly) 
Continuous 
Continuous 
Continuous 
Continuous 
CT Angiography of 
Thoracic Aorta 
✓ 
– 
✓ 
– 
✓ 
Adverse Event 
Review & Safety 
Labs 
✓ 
✓ 
✓ 
✓ 
✓ 
Diet Adherence 
Assessment 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Notes: 
• ✓ indicates a scheduled assessment 
• Continuous activities (home ketone testing, BP logs) are ongoing throughout the study. 
• All CTAs follow low-radiation, contrast-enhanced dissection surveillance protocols. 
• Data from serum assays, imaging, and clinical monitoring will be integrated for correlation analyses between ketosis level, 
inflammation, and aortic remodeling. 
 

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6.2 Duration of Participation 
The duration of active research participation is 12 months. Participants will remain under the 
care of their treating cardiovascular physicians throughout the study, ensuring continuation of 
best-practice medical management. Any indication for surgical or endovascular intervention 
during the trial will be determined by the treating team using standard clinical criteria, and the 
patient will be considered to have reached the primary study endpoint. 
 
7.0 Regulatory and Reporting Requirements 
The entities providing oversight of safety and compliance with the protocol require reporting 
as outlined below. 
 
7.1 Unanticipated Problems and Adverse Event Reporting 
Adverse events will be tracked from the time of the baseline visit until the 12 Month visit. 
Only events that are considered at least possibly related to participation in this study will be 
recorded on the AE case report form.  
 
7.2 WU PI Reporting Requirements 
The study principal investigator and study coordinator will monitor for breaches of 
confidentiality and other adverse events on an ongoing basis. Once the PI or study coordinator 
becomes aware of a reportable adverse event, the event will be reported to HRPO according to 
institutional guidelines. 
 
Protocol and/or consent revisions will be submitted to HRPO and approved prior to being 
implemented. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the change. 
8.0 Data Collection and Security 
The names of patients enrolled in the study will be recorded on an enrollment log that will 
include the participant’s name and an assigned study ID. Additional data from the patient’s 
medical record will be collected, such as age, sex, comorbidities, etc. 
 
The handheld ketone meter (Keto-Mojo) readings will be automatically uploaded to a secure, 
HIPAA-compliant cloud platform monitored by the study team. 
 
Study data will be stored and analyzed on a password protected, encrypted device. Only approved 
study personnel will have access to subject information. No subject PHI will be shared outside of 
the approved study personnel 

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9.0 Data Safety and Monitoring 
The study Principal Investigator and Research Patient Coordinator will monitor for any safety 
concerns on an ongoing basis. Any symptomatic hypotension, electrolyte disturbance, or 
weight loss exceeding 10% of baseline will prompt protocol review and dietary adjustment 
by the study team.24,25  Should the principal investigator or designee become aware of any 
breach of confidentiality, or adverse event, the event will be reported according to institutional 
guidelines as outlined above, in Section 7.0 
 
10.0 Statistical Considerations 
All analyses will follow an intent-to-treat principle. Continuous variables will be summarized 
as mean ± standard deviation, with within-subject changes analyzed using repeated-measures 
mixed-effects models. Dichotomous outcomes will be reported as proportions with 95% 
confidence intervals. The feasibility benchmark for success will be defined as at least 80% 
participant retention and 70% adherence to target ketosis levels across the study period 
 
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