Pyruvate Imaging for High Blood Pressure

Recruiting at 1 trial location

Overseen By Nadia Bragagnolo, MSc

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Sunnybrook Health Sciences Centre

Disqualifiers: Claustrophobia, Low hemoglobin, Low GFR, others

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

Compensation: Varies

Number of Visits: 2

112 Participants Needed

Trial Summary

What is the purpose of this trial?

The prevalence of congestive heart failure (CHF) in Canada is high, representing one of the health care system's most expensive diagnoses. Despite major advances in medicine, the mortality and morbidity from CHF remains great. Currently, magnetic resonance imaging (MRI) is used for non-invasive imaging of the cardiovascular system to enable the structure and anatomy of the organ to be visualized. However, current MRI methods have limitations when assessing and aiding in the management of CHF. A new imaging method has recently been developed that is showing great promise as a tool in the management of patients with CHF. Rapid imaging of biochemical reactions within myocytes using MRI has recently become possible through the use of the Dynamic Nuclear Polarization (DNP) and dissolution method. DNP-dissolution results in an intravenous contrast agent that is "hyperpolarized", producing a magnetic signal that is enhanced by up to 100,000 fold. The particular agent is carbon-13 labelled pyruvate. In this study, we demonstrate the first 13C-metabolic images of the human heart, along with the required hardware and data acquisition methods.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are taking investigational drugs, you must not have received them within 1 month before or after joining the study.

What data supports the effectiveness of the treatment Hyperpolarized Carbon-13 Pyruvate Injection for high blood pressure?

Research shows that Hyperpolarized Carbon-13 Pyruvate Injection is effective in rapidly and non-invasively investigating metabolic processes in diseases like cancer and cardiovascular conditions. This suggests potential for understanding and possibly managing high blood pressure by providing insights into metabolic changes. ^{1 2 3 4 5}

Is hyperpolarized pyruvate safe for use in humans?

Research shows that hyperpolarized pyruvate has been used safely in human studies, such as those investigating brain metabolism, with no reported safety issues. It has been tested in both animals and humans, demonstrating a safety profile comparable to other established techniques. ^{1 6 7 8 9}

What makes Hyperpolarized 13C Pyruvate Injection unique for treating high blood pressure?

Hyperpolarized 13C Pyruvate Injection is unique because it uses a special form of pyruvate that is enhanced to allow real-time imaging of metabolic processes in the body, which can help in understanding and potentially treating conditions like high blood pressure by providing insights into cardiac metabolism. ^{1 2 10 11 12}

Research Team

Charles Cunningham, PhD

Principal Investigator

Sunnybrook Research Institute

Eligibility Criteria

This trial is for adults with heart enlargement or high blood pressure. Participants aged 19-50 and 30-75 are needed, depending on the group they fall into. They must have specific heart conditions like left-ventricular hypertrophy, diagnosed cardiomyopathy, stable heart failure with elevated LV mass, or type 2 diabetes with controlled HcA1c levels.

Inclusion Criteria

Written consent

Age: 19 to 50 in Arm 1, 30 to 75 in Arm 2

Group 2A and 2E participants have left-ventricular hypertrophy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Imaging Procedure

Participants undergo metabolic imaging of the heart using Hyperpolarized Pyruvate 13C Injection and standard cardiovascular MRI workup

Single visit, approximately 3 hours

1 visit (in-person)

Follow-up

Participants receive a follow-up telephone call to ascertain any study-related adverse events

1 week

1 call (virtual)

Long-term Follow-up

The entire study is expected to take about 3 years, with results known approximately six months after study completion

3 years

Treatment Details

Interventions

• Gadolinium
• Hyperpolarized (13C) Pyruvate Injection

Trial Overview The study tests a new MRI method using Hyperpolarized (13C) Pyruvate Injection to improve imaging of the cardiovascular system in patients with congestive heart failure. This could help doctors better manage CHF by visualizing biochemical reactions in heart cells more clearly.

Participant Groups

Group I: Hypertension Hypertrophy Volunteers Experimental Treatment 2 Interventions

Arm 2 * Group 2A: patients aged 30 to 75 with hypertension and hypertrophy * Group 2B: patients aged 30 to 75 with non-obstructive hypertrophic cardiomyopathy (HCM). * Group 2C: stable outpatients with NYHA class 1-3 heart failure who have evidence of elevated LV mass (LVH), irrespective of LVEF. * Group 2D: stable patients with type 2 DM who have a HcA1c between 6.5-9% on oral hypoglycemic agents. * Group 2E: patients aged 30 to 75 with hypertrophy * Group 2F: patients aged 30 to 75 with hypertrophic cardiomyopathy (HCM). * Group 2G: stable outpatients with NYHA class 1-3 heart failure who have evidence of elevated LV mass (LVH), irrespective of LVEF. * Group 2H: stable patients with type 2 DM who have a HcA1c between 6.5-9% on oral hypoglycemic agents.

Group II: Healthy Volunteers Experimental Treatment 1 Intervention

Arm 1 * Group 1A: control male volunteers between 19 and 50 years of age. * Group 1B: control female volunteers between 19 and 50 years of age. * Group 1C: control male or female volunteers between 19 and 50 years of age, with the MRI scan performed twice * Group 1D: control male volunteers between 19 and 50 years of age. * Group 1E: control female volunteers between 19 and 50 years of age. * Group 1F: control male or female volunteers between 19 and 50 years of age, with the MRI scan performed twice

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Findings from Research

Hyperpolarized (HP) (13)C labeled compounds, particularly HP 1-(13)C pyruvate, are effective MR contrast agents that allow for real-time investigation of metabolic pathways in vivo, with the ability to track pyruvate metabolism for nearly 2 minutes post-injection.

The technique has expanded beyond tumor metabolism to non-invasively assess physiological parameters like pH, highlighting its growing potential in medical research, especially with the increasing availability of dynamic nuclear polarization (DNP) systems for generating hyperpolarized materials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperpolarized 13carbon MR. Rowland, IJ., Peterson, ET., Gordon, JW., et al.[2019]

High-resolution hyperpolarized 13C pyruvate MRI can effectively measure cerebral perfusion in the human brain, showing significant positive correlations with traditional arterial spin labeling (ASL) methods across different brain regions.

This study, involving five healthy volunteers, demonstrates that hyperpolarized pyruvate MRI not only provides detailed spatial imaging of brain structures but also allows for simultaneous assessment of cerebral metabolism and perfusion, enhancing our understanding of brain function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating cerebral perfusion with high resolution hyperpolarized [1-13 C]pyruvate MRI. Hu, JY., Vaziri, S., Bøgh, N., et al.[2023]

A stable hyperpolarized solution of [1-(13)C]-ethyl pyruvate was successfully developed, allowing for its use in metabolic imaging studies.

In a study involving anesthetized rats, hyperpolarized [1-(13)C]-ethyl pyruvate was compared to [1-(13)C]-pyruvate, demonstrating its potential for effective uptake and metabolic imaging in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic imaging in the anesthetized rat brain using hyperpolarized [1-13C] pyruvate and [1-13C] ethyl pyruvate. Hurd, RE., Yen, YF., Mayer, D., et al.[2021]

Hyperpolarized carbon-13 (13C) MRI is a groundbreaking imaging technique that allows for real-time, noninvasive observation of metabolic processes in diseases like cancer and cardiovascular conditions, which were previously difficult to study.

The review highlights the promising clinical applications of HP [1-13C]pyruvate MRI, suggesting it could enhance our understanding of metabolism, improve disease diagnosis, and speed up treatment evaluations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperpolarized 13C MRI: State of the Art and Future Directions. Wang, ZJ., Ohliger, MA., Larson, PEZ., et al.[2020]

Using hyperpolarized [1-(13)C]alanine allows for more accurate measurement of intracellular lactate-to-pyruvate ratios in vivo, showing a ratio of 4.89±0.61 in normal rat tissue, compared to a misleading ratio of 0.41±0.03 when using [1-(13)C]pyruvate.

This study highlights the limitations of using [1-(13)C]pyruvate for metabolic imaging, as it does not accurately reflect intracellular levels due to its extracellular presence, emphasizing the need for alternative agents like [1-(13)C]alanine for better insights into cellular metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo measurement of normal rat intracellular pyruvate and lactate levels after injection of hyperpolarized [1-(13)C]alanine. Hu, S., Zhu, M., Yoshihara, HA., et al.[2021]

A new hyperpolarization technique using parahydrogen-induced polarization by side-arm hydrogenation (PHIP-SAH) can produce highly hyperpolarized [1-13 C]pyruvate solutions quickly and efficiently, achieving concentrations of 70-160 mM in just 85 seconds.

In a study with 48 animals, the safety and image quality of PHIP-SAH were found to be comparable to the established dissolution dynamic nuclear polarization (d-DNP) method, suggesting that PHIP-SAH could be a practical alternative for metabolic MRI applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parahydrogen-Polarized [1-13 C]Pyruvate for Reliable and Fast Preclinical Metabolic Magnetic Resonance Imaging. Nagel, L., Gierse, M., Gottwald, W., et al.[2023]

The study successfully developed methods to prepare hyperpolarized [2-13C]pyruvate for the first human NMR studies, demonstrating its feasibility for investigating brain energy metabolism in four healthy volunteers.

Results showed that the conversion of hyperpolarized [2-13C]pyruvate to [2-13C]lactate and [5-13C]glutamate can be measured, with conversion rates comparable to previous studies using [1-13C]pyruvate, indicating the potential for this technique in metabolic research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First hyperpolarized [2-13C]pyruvate MR studies of human brain metabolism. Chung, BT., Chen, HY., Gordon, J., et al.[2022]

This study demonstrates the successful use of hyperpolarized 13C spectroscopy to detect metabolic products in the rat brain, specifically identifying [1-(13)C]lactate and [13C]bicarbonate after injecting [1-(13)C]pyruvate.

The research highlights the potential of using hyperpolarized [2-(13)C]pyruvate to detect [2-(13)C]lactate, although it did not reveal other metabolites, indicating that different pyruvate isotopes can yield varying insights into metabolic processes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo 13C spectroscopy in the rat brain using hyperpolarized [1-(13)C]pyruvate and [2-(13)C]pyruvate. Marjańska, M., Iltis, I., Shestov, AA., et al.[2021]

The study successfully synthesized various hyperpolarized 1-13C-acetates and 1-13C-pyruvates, which can be used as effective contrast agents for molecular imaging, achieving yields of up to 70%.

Using a method called parahydrogen-induced polarization (PHIP), the researchers demonstrated that hyperpolarized 1-13C-pyruvate can be produced with a polarization of approximately 3.2%, enabling enhanced imaging capabilities in 13C magnetic resonance imaging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis of Unsaturated Precursors for Parahydrogen-Induced Polarization and Molecular Imaging of 1-13C-Acetates and 1-13C-Pyruvates via Side Arm Hydrogenation. Chukanov, NV., Salnikov, OG., Shchepin, RV., et al.[2020]

Hyperpolarized [1-13 C]pyruvate imaging is a feasible and reproducible technique for studying cardiac metabolism in large animal models, showing no adverse effects on blood pressure or ejection fraction during the study.

Infusion of glucose-insulin-potassium (GIK) enhances the conversion of pyruvate to metabolic products like lactate, alanine, and bicarbonate, although this process exhibited increased variability, indicating potential challenges in consistent metabolic modulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imaging porcine cardiac substrate selection modulations by glucose, insulin and potassium intervention: A hyperpolarized [1-13 C]pyruvate study. Hansen, ESS., Tougaard, RS., Nørlinger, TS., et al.[2018]

The study successfully measured in vivo cardiac T2∗ values of hyperpolarized [1-13 C]pyruvate and its metabolites in both rodents and humans, demonstrating the effectiveness of a new imaging technique that can capture cardiac metabolism noninvasively.

In humans, T2∗ values for [1-13 C]pyruvate were significantly higher in the ventricles (108.7 ms in the left and 129.4 ms in the right) compared to rodents, indicating differences in cardiac metabolism that could be important for future research and clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

>Cardiac T2∗ measurement of hyperpolarized 13 C metabolites using metabolite-selective multi-echo spiral imaging. Ma, J., Chen, J., Reed, GD., et al.[2022]

This study demonstrates that using (13)C hyperpolarization enhanced MRI is a feasible method for monitoring pyruvate metabolism in the heart during ischemic episodes, allowing for real-time visualization of metabolite concentrations.

In pigs subjected to 15 and 45 minutes of artery occlusion, significant changes in bicarbonate and alanine levels were observed, indicating that this imaging technique can effectively detect metabolic alterations associated with heart ischemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac metabolism measured noninvasively by hyperpolarized 13C MRI. Golman, K., Petersson, JS., Magnusson, P., et al.[2015]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Hyperpolarized 13carbon MR. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Investigating cerebral perfusion with high resolution hyperpolarized [1-13 C]pyruvate MRI. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Metabolic imaging in the anesthetized rat brain using hyperpolarized [1-13C] pyruvate and [1-13C] ethyl pyruvate. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Hyperpolarized 13C MRI: State of the Art and Future Directions. [2020]

5. Netherlands pubmed.ncbi.nlm.nih.gov

In vivo measurement of normal rat intracellular pyruvate and lactate levels after injection of hyperpolarized [1-(13)C]alanine. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

Parahydrogen-Polarized [1-13 C]Pyruvate for Reliable and Fast Preclinical Metabolic Magnetic Resonance Imaging. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

First hyperpolarized [2-13C]pyruvate MR studies of human brain metabolism. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

In vivo 13C spectroscopy in the rat brain using hyperpolarized [1-(13)C]pyruvate and [2-(13)C]pyruvate. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Synthesis of Unsaturated Precursors for Parahydrogen-Induced Polarization and Molecular Imaging of 1-13C-Acetates and 1-13C-Pyruvates via Side Arm Hydrogenation. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Imaging porcine cardiac substrate selection modulations by glucose, insulin and potassium intervention: A hyperpolarized [1-13 C]pyruvate study. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

>Cardiac T2∗ measurement of hyperpolarized 13 C metabolites using metabolite-selective multi-echo spiral imaging. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Cardiac metabolism measured noninvasively by hyperpolarized 13C MRI. [2015]