Angiotensin-(1-7) for Cardiovascular Health in Aging

Overseen By Amy Arnold, PhD

Age: 65+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Milton S. Hershey Medical Center

Must not be taking: Anticoagulants, Glucocorticoids, Stimulants, others

Disqualifiers: Diabetes, Hypertension, Cardiovascular disease, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 2 visits, each lasting approximately 4 hours

26 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether angiotensin-(1-7), a hormone in the body, can lower blood pressure and improve blood vessel function in older adults. The researchers aim to understand how this treatment might reduce heart-related risks with age. Participants will receive either the hormone or a saline solution through an IV, and the effects will be compared. The trial seeks healthy individuals aged 65 to 80 who do not have high blood pressure or serious heart conditions. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to contribute to groundbreaking medical knowledge.

Will I have to stop taking my current medications?

The trial requires that you do not take medications that influence sympathetic activity, anticoagulants, chronic systemic glucocorticoids, or investigational drugs within a month before the study. If you are on these medications, you may need to stop them to participate.

Is there any evidence suggesting that angiotensin-(1-7) is likely to be safe for humans?

Research has shown that angiotensin-(1-7) is a hormone that might protect the heart and blood vessels. Studies suggest it could slow aging in blood vessels by preventing cell damage and other harmful changes. However, limited information exists about its effects on humans. Most research has examined its effects when administered directly into the arteries, often finding potential benefits for heart health.

In past animal studies, angiotensin-(1-7) improved heart and metabolic health, especially in cases of high blood pressure and other heart issues. These results are promising, but more information is needed about its safety in humans. Since this trial is in an early stage, it primarily focuses on assessing the treatment's safety and how well the body tolerates it. While some evidence indicates potential benefits, the full safety profile in humans is still under investigation. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Angiotensin-(1-7) is unique because it targets the renin-angiotensin system differently than traditional cardiovascular treatments like ACE inhibitors or beta-blockers. Unlike these standard treatments that often focus on blocking harmful effects, Angiotensin-(1-7) works by promoting beneficial cardiovascular effects, such as vasodilation and anti-inflammatory actions. Researchers are excited about this treatment because it has the potential to improve cardiovascular health in aging populations by enhancing protective pathways rather than merely inhibiting damaging ones.

What evidence suggests that angiotensin-(1-7) might be an effective treatment for cardiovascular health in aging?

This trial will compare Angiotensin-(1-7) with a saline placebo to evaluate its effects on cardiovascular health in aging. Research has shown that Angiotensin-(1-7), a hormone in the body, might help lower blood pressure. Animal studies found that it directly lowers blood pressure by counteracting another hormone that raises it. Angiotensin-(1-7) also seems to prevent blood vessels from aging, helping them remain flexible and healthy. This hormone may reduce the activity of the body's stress response, lessening strain on the heart and blood vessels. While more research is needed in humans, these early findings suggest it could be promising for older adults at risk of heart problems. ^{1 2 3 6 7}

Who Is on the Research Team?

Amy Arnold, PhD

Principal Investigator

Pennsylvania State University College of Medicine

Are You a Good Fit for This Trial?

This trial is for healthy older adults aged 65-80 with normal blood pressure and BMI between 18.5 and 30 kg/m2. Participants must be fluent in English, able to consent, not on certain medications or have conditions like impaired liver/renal function, anemia, diabetes, serious cardiovascular or cerebrovascular disease.

Inclusion Criteria

Fluent in written and spoken English

I am between 65 and 80 years old.

My gender or ethnicity does not limit my participation.

Exclusion Criteria

Prisoners

I have difficulty making decisions due to a mental condition.

Highly trained athletes

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Treatment

Participants receive intravenous angiotensin-(1-7) or saline infusion to assess cardiovascular effects

2 visits, each lasting approximately 4 hours

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Angiotensin-(1-7)
• Saline

Trial Overview The study investigates if angiotensin-(1-7), a hormone that could help the heart and blood vessels work better, can lower sympathetic nervous system activity and improve blood vessel function in aging individuals compared to saline (a placebo).

How Is the Trial Designed?

Group I: Angiotensin-(1-7) Experimental Treatment 1 Intervention

Participants will receive intravenous angiotensin-(1-7) at one study visit for 110 minutes. Angiotensin-(1-7) will be given in escalating doses of 2 ng/kg/min, 4 ng/kg/min, and 8 ng/kg/min. Each of these doses will be infused for 10 minutes. Following the dose escalation, angiotensin-(1-7) will be given at 8 ng/kg/min for an additional 80 minutes. Infusion rates will be calculated for each participant based on body mass.

Group II: Saline Placebo Group 1 Intervention

Participants will receive intravenous saline at one study visit for 110 minutes total. The volume of saline will match the volume of angiotensin-(1-7) infused. Infusion rates will be calculated for each participant based on body mass.

Angiotensin-(1-7) is already approved in United States, European Union for the following indications:

Approved in United States as TXA127 for:

• Duchenne muscular dystrophy (DMD)
• Limb-girdle muscular dystrophy (LGMD)
• Congenital muscular dystrophy MDC1A
• Marfan syndrome
• Dystrophic Epidermolysis Bullosa (DEB)
• Pulmonary arterial hypertension
• Myelodysplastic Syndrome (MDS)

Approved in European Union as TXA127 for:

• Duchenne muscular dystrophy (DMD)

Who Is Running the Clinical Trial?

Milton S. Hershey Medical Center

Lead Sponsor

Trials

515

Recruited

2,873,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Angiotensin-(1-7) has shown promising effects in cardiovascular health, including antihypertensive, antihypertrophic, antifibrotic, and antithrombotic properties, based on various animal studies.

Despite its potential benefits, the clinical use of angiotensin-(1-7) is limited due to its unfavorable pharmacokinetic properties, necessitating the development of more stable analogues or specific delivery methods to enhance its therapeutic application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7): pharmacological properties and pharmacotherapeutic perspectives. Iusuf, D., Henning, RH., van Gilst, WH., et al.[2016]

Angiotensin-(1-7) is a promising hormone that counteracts the harmful effects of angiotensin II, showing potential benefits such as lowering blood pressure and reducing cardiovascular risks through its action on specific receptors in key organs like the heart and kidneys.

While animal studies suggest that angiotensin-(1-7) has various protective cardiovascular effects, there is a lack of clinical research in humans, which hinders the development of effective treatments based on this hormone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7): Translational Avenues in Cardiovascular Control. Medina, D., Arnold, AC.[2020]

In both adult and aged normotensive rats, Angiotensin (1-7) effectively reduced blood pressure, indicating its vasodilatory properties are preserved with aging, although the mechanisms involved change.

While Ang (1-7) primarily acted through angiotensin type 2 receptors (AT(2)R) in younger rats, in aged rats, both AT(2)R and Mas receptors (MasR) contributed to its blood pressure-lowering effects, suggesting a shift in receptor involvement with age.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential mechanisms of ang (1-7)-mediated vasodepressor effect in adult and aged candesartan-treated rats. Bosnyak, S., Widdop, RE., Denton, KM., et al.[2021]

A transgenic rat model overexpressing human ACE2 showed protection against age-related kidney decline, with significantly less albuminuria compared to standard rats, indicating a potential therapeutic role for the ACE2/Ang(1-7)/MAS axis.

The study found that while young transgenic rats had normal kidney function, aged standard rats experienced severe kidney damage, suggesting that enhancing ACE2 activity could mitigate kidney disease associated with aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transgenic angiotensin-converting enzyme 2 overexpression in the rat vasculature protects kidneys from ageing-induced injury. Sanad, AM., Qadri, F., Popova, E., et al.[2023]

Angiotensin(Ang)-(1-7) has protective effects against vascular aging, including reducing cell senescence, inflammation, and oxidative stress, which are key factors in the development of vascular diseases.

This heptapeptide also improves endothelial function, reduces fibrosis and calcification, and promotes blood vessel repair, making it a promising candidate for preventing vascular aging and associated frailty.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7), a protective peptide against vascular aging. Valencia, ., Shamoon, L., Romero, A., et al.[2022]

Chronic treatment with Angiotensin (Ang)-(1-7) significantly lowered blood pressure in aged mice, indicating its potential as a therapeutic option for managing age-related hypertension.

Ang-(1-7) improved insulin sensitivity in aged mice to levels comparable to young mice, suggesting it may help mitigate metabolic issues associated with aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) Improves Integrated Cardiometabolic Function in Aged Mice. Miller, AJ., Bingaman, SS., Mehay, D., et al.[2021]

Angiotensin (Ang)-(1-7) has been linked to blood pressure regulation, primarily through indirect mechanisms involving bradykinin and nitric oxide signaling, based on various studies in humans and animal models.

In addition to its role in blood pressure, Ang-(1-7) exhibits direct cardioprotective effects, such as reducing heart muscle hypertrophy and fibrosis, suggesting its potential as a therapeutic target for cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) as an antihypertensive, antifibrotic target. Katovich, MJ., Grobe, JL., Raizada, MK.[2021]

Angiotensin-(1-7) (Ang-[1-7]) protects heart cells from high glucose-induced damage by inhibiting the reactive oxygen species-leptin-p38 MAPK/ERK1/2 pathways, which are activated during diabetic conditions.

In laboratory tests on H9c2 heart cells, Ang-(1-7) treatment led to increased cell viability, reduced apoptosis, and lower reactive oxygen species production, demonstrating its potential as a therapeutic agent in diabetic cardiovascular diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) protects cardiomyocytes against high glucose-induced injuries through inhibiting reactive oxygen species-activated leptin-p38 mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2 pathways, but not the leptin-c-Jun N-terminal kinase pathway in vitro. Lei, Y., Xu, Q., Zeng, B., et al.[2022]

Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide that has shown beneficial effects against various cardiovascular issues, including heart failure, hypertension, and cardiac arrhythmia.

Research indicates that Ang-(1-7) may also have therapeutic potential beyond cardiovascular diseases, potentially impacting conditions like renal disease, preeclampsia, and cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7): pharmacology and new perspectives in cardiovascular treatments. Trask, AJ., Ferrario, CM.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05301192

Angiotensin-(1-7) Cardiovascular Effects in Aging This study will test the hypothesis that angiotensin-(1-7), a protective hormone of the renin-angiotensin system, can reduce cardiovascular sympathetic outflow ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6856625/

Angiotensin-(1-7): Translational Avenues in Cardiovascular ... Ang-(1–7) is a biologically active RAS component, which antagonizes Ang II actions as well as promotes direct blood pressure lowering effects in animal models.

3. sciencedirect.com sciencedirect.com/science/article/pii/S0196978122000419

Angiotensin-(1−7), a protective peptide against vascular ... Angiotensin-(1−7) has recently emerged as an agent capable to delay vascular aging. This heptapeptide counteracts hallmarks of aging such as cell senescence ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02245230?term=AREA%5BConditionSearch%5D(%22Hypertension%22)%20AND%20AREA%5BInterventionSearch%5D(%22Angiotensin%20I%20(1-7)%22)&rank=1

Cardiovascular Effects of Angiotensin (1-7) in Essential ... The primary outcome will be the decrease in systolic blood pressure produced by Angiotensin (1-7) infusion, with comparisons made between intact and blocked ...

5. ahajournals.org ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.120.006939

Elevated Angiotensin 1–7/Angiotensin II Ratio Predicts ... Importantly, individual Ang 1–7 and Ang II peptide levels failed to predict all-cause mortality or hospitalization duration in our patient ...

6. ahajournals.org ahajournals.org/doi/10.1161/HYPERTENSIONAHA.117.10406

Angiotensin-(1–7) and Vascular Function | Hypertension Hyperactivation of the ACE–Ang II–AT1R axis generally causes deleterious effects, such as vasoconstriction, endothelial dysfunction, ...

7. mdpi.com mdpi.com/1422-0067/25/24/13320

Angiotensin-(1-7) and Central Control of Cardiometabolic ... Overall, central Ang-(1-7) infusion has been shown to improve cardiovascular and metabolic outcomes in animal models of hypertension, fetal programming, and ...