Cardiovascular DiseaseNCT01606410
The Impact of Age and Fitness on Reperfusion Injury and Ischemic Preconditioning to Prevent This Injury
An observational study of Cardiovascular Disease, run by Radboud University Medical Center at 1 site in Netherlands.
Trial summary
Rationale: Ischaemic preconditioning (IP) refers to the reduction of ischemia-reperfusion injury induced by a brief preceding period of ischemia. Also the arterial endothelium can be protected by IP. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Cardiovascular Disease
- What is being tested?
- IPC
- How many people
- 30 participants
- Where
- 1 siteNetherlands
- Study dates
- Apr 2011to Nov 2013
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: Study population: Young sedentary volunteers (n=23, age 18-30), young active volunteers (n=23, age 18-30), older sedentary subjects (n=23, >55 years) and older physically active subjects (n=23, >55 years).
Who may be able to join
- Healthy young volunteers : age 18-30
- Healthy older volunteers: age >55 years
- Sedentary: <1 h exercise per week
- Trained: >5 h exercise per week
- All subjects: written informed consent
Who cannot join
- Smoking
- History of any cardiovascular disease
- Hypertension (in supine position: systole >140 mmHg, diastole >90 mmHg)
- Diabetes Mellitus (fasting glucose >7.0 mmol/L or random glucose >11.0 mmol/L)
- Hyperlipidaemia (fasting total cholesterol >6.5 mmol/L)
- Chronic use of medication known to interfere with the cardiovascular system
- Professional athletes
- BMI >30 kg/m2
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Impact of Age and Fitness on Endothelial Reperfusion Injury and the Ability of Ischemic Preconditioning to Prevent This Injury
Rationale: Ischaemic preconditioning (IP) refers to the reduction of ischemia-reperfusion injury induced by a brief preceding period of ischemia. Also the arterial endothelium can be protected by IP. Several studies performed in animals and humans have demonstrated that the protective effects of IP are attenuated with aging. However, no previous study directly examined the underlying mechanisms of this observation. Possibly, the reduced protective effect of IP with aging relates to a direct effect on the endothelium, consequently leading to an attenuated ability of IP to prevent endothelial dysfunction after ischaemia reperfusion injury.
Several previous studies failed to demonstrate the ability of pharmacological stimuli to mimic the beneficial effects of IP in aged vessels. Restoration of the age-related reduction in effectiveness of IP may be possible through exercise training. In aged animals, physical training restores the efficacy of ischemic preconditioning. Indirect evidence indicates that physical activity, independent of other cardiovascular risk factors, protects against a occurrence as well as the severity of a myocardial infarction in humans. Although this suggests that physical activity may beneficially influence the age-related reduction in IP, no previous study provided direct evidence for this hypothesis.
Objective: To examine the impact of age and physical fitness on the ability of ischaemic preconditioning to protect endothelial damage in response to ischaemia reperfusion injury in healthy humans. A secondary objective is to explore the role of Toll-like receptor (TLR) signalling in the induction of IP in young and old subjects.
Read the detailed description
Cardiovascular disease has become a worldwide burden. In the Netherlands over 40.000 persons die annually due to coronary artery disease, either acute myocardial infarction or heart failure.1 Through plaque formation and negative vascular remodelling, significant stenotic lesions develop in the coronary arteries that subsequently limit coronary blood flow and ultimately can cause ischemic events. Reperfusion therapy (either pharmacologic, endovascular or surgical) is mandatory for salvage of ischemic tissue. However, during reperfusion several deleterious events take place causing further damage. Murry found that ischemia and reperfusion injury (IR-injury) could be reduced by a phenomenon called ischemic preconditioning.2 Short lasting repetitive episodes of ischemia prior to an ischemic event can induce tissue tolerance against IR-injury.
After discovery of this phenomenon, ample research has been devoted to elucidation of the underling protective mechanism, but also factors that improve or impair the ability of this phenomenon to protect arteries against ischaemia reperfusion injury. Several studies performed in animals and humans have demonstrated that the protective effects of IP are attenuated with aging. Much of this work has been performed in animal models or in human in vitro studies. Interestingly, no previous study directly examined the underlying mechanisms of this observation in humans using in vivo techniques. One potential explanation for an age-related reduction of the protective effect of IP relates to a direct effect on the endothelium.
Much scientific effort has been devoted to develop a human in vivo model to study ischemia and reperfusion injury. Recently, publications emerged using the flow mediated dilation (FMD) of the brachial or radial artery before and after a sustained ischaemic stimulus (20 minutes) to establish the presence of a blunted endothelial function after ischaemia reperfusion injury.3, 4 This effect of reperfusion injury on the endothelial function can be abrogated by ischemic preconditioning.3 Endothelial dysfunction is acknowledged to be the first (subclinical) manifestation of atherosclerosis and cardiovascular disease.5, 6 It is significantly correlated to occurrence of myocardial infarction and stroke.6 Assessment of the flow mediated dilation of the brachial artery as measure of endothelial (dys)function, is a validated model to research effects of possible protective strategies3, 4 and perform mechanistic experiments4, 7, 8 on IR-injury in humans in vivo.
Several previous studies failed to demonstrate the ability of pharmacological stimuli to mimic the beneficial effects of IP in aging vessels.9 Restoration of the age-related reduction in effectiveness of IP may be possible through exercise training. Indirect evidence indicates that physical activity, independent of other cardiovascular risk factors, protects against an occurrence as well as the severity of a myocardial infarction in humans.10 Although this suggests that physical activity may beneficially influence the age-related reduction in IP, no previous study provided direct evidence for this hypothesis in humans.
In this cross-sectional observational experiment we will study the impact of aging (young versus older subjects) and physical fitness (sedentary versus trained older subjects) on the protective effects of ischaemic preconditioning on brachial artery endothelial function after ischaemia-reperfusion injury in healthy humans in vivo.
We hypothesize that aging is associated with an attenuated ability of ischaemic preconditioning to prevent the decrease in brachial artery endothelial function observed after ischaemia reperfusion injury. Moreover, we expect that the age-related reduction in effectiveness of ischaemic preconditioning to prevent endothelial dysfunction after reperfusion injury is (at least partly) preserved in trained older subjects.
- Conditions
- Cardiovascular Disease
- Being tested
- IPC
- Medical subject headings
- Cardiovascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IPCOther
repeated cuff inflation (220 mmhg) around an upper limb for 5 minutes, followed by 5 minutes of reperfusion (repeated 4 times)
| Study group | Role | What they receive |
|---|---|---|
| young, sedentary | Not described Receives: Other: IPC | |
| young, active | Not described Receives: Other: IPC | |
| old, sedentary | Not described Receives: Other: IPC | |
| old, active | Not described Receives: Other: IPC |
What is being measured
The primary outcome is the main question the study is designed to answer.
endothelial reperfusion injury
Change in endothelial function (measured with flow mediated dilation) after ischaemia reperfusion injury (induced by 20 minutes ischemia) with and without precedence of ischaemic preconditioning (by 3 cycles of 5-minutes of ischaemia).
Measured: cross-sectional observation (single time point)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 May 2012 (estimated)
- Study startApr 2011
- Primary completionNov 2013
- Study completionNov 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Cardiovascular DiseaseStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Dick Thijssen, PhD, Principal investigator, Radboud University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01606410
- Sponsor's protocol ID
- IRI-IPC-aging
- Status last verified
- Nov 2013
- First submitted
- 23 May 2012
- Last updated
- 20 Nov 2013
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Nov 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Impact of Age and Fitness on Endothelial Reperfusion Injury and the Ability of Ischemic Preconditioning to Prevent This Injury
- ClinicalTrials.gov ID
- NCT01606410
- Acronym / sponsor ID
- IRI-IPC-aging
- Conditions
- Cardiovascular Disease
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- Apr 2011
- Primary completion
- Nov 2013 (actual)
- Study completion
- Nov 2013 (actual)
- First posted
- 25 May 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Rationale: Ischaemic preconditioning (IP) refers to the reduction of ischemia-reperfusion injury induced by a brief preceding period of ischemia. Also the arterial endothelium can be protected by IP. Several studies performed in animals and humans have demonstrated that the protective effects of IP are attenuated with aging. However, no previous study directly examined the underlying mechanisms of this observation. Possibly, the reduced protective effect of IP with aging relates to a direct effect on the endothelium, consequently leading to an attenuated ability of IP to prevent endothelial dysfunction after ischaemia reperfusion injury.
Several previous studies failed to demonstrate the ability of pharmacological stimuli to mimic the beneficial effects of IP in aged vessels. Restoration of the age-related reduction in effectiveness of IP may be possible through exercise training. In aged animals, physical training restores the efficacy of ischemic preconditioning. Indirect evidence indicates that physical activity, independent of other cardiovascular risk factors, protects against a occurrence as well as the severity of a myocardial infarction in humans. Although this suggests that physical activity may beneficially influence the age-related reduction in IP, no previous study provided direct evidence for this hypothesis.
Objective: To examine the impact of age and physical fitness on the ability of ischaemic preconditioning to protect endothelial damage in response to ischaemia reperfusion injury in healthy humans. A secondary objective is to explore the role of Toll-like receptor (TLR) signalling in the induction of IP in young and old subjects.
Detailed description
Cardiovascular disease has become a worldwide burden. In the Netherlands over 40.000 persons die annually due to coronary artery disease, either acute myocardial infarction or heart failure.1 Through plaque formation and negative vascular remodelling, significant stenotic lesions develop in the coronary arteries that subsequently limit coronary blood flow and ultimately can cause ischemic events. Reperfusion therapy (either pharmacologic, endovascular or surgical) is mandatory for salvage of ischemic tissue. However, during reperfusion several deleterious events take place causing further damage. Murry found that ischemia and reperfusion injury (IR-injury) could be reduced by a phenomenon called ischemic preconditioning.2 Short lasting repetitive episodes of ischemia prior to an ischemic event can induce tissue tolerance against IR-injury.
After discovery of this phenomenon, ample research has been devoted to elucidation of the underling protective mechanism, but also factors that improve or impair the ability of this phenomenon to protect arteries against ischaemia reperfusion injury. Several studies performed in animals and humans have demonstrated that the protective effects of IP are attenuated with aging. Much of this work has been performed in animal models or in human in vitro studies. Interestingly, no previous study directly examined the underlying mechanisms of this observation in humans using in vivo techniques. One potential explanation for an age-related reduction of the protective effect of IP relates to a direct effect on the endothelium.
Much scientific effort has been devoted to develop a human in vivo model to study ischemia and reperfusion injury. Recently, publications emerged using the flow mediated dilation (FMD) of the brachial or radial artery before and after a sustained ischaemic stimulus (20 minutes) to establish the presence of a blunted endothelial function after ischaemia reperfusion injury.3, 4 This effect of reperfusion injury on the endothelial function can be abrogated by ischemic preconditioning.3 Endothelial dysfunction is acknowledged to be the first (subclinical) manifestation of atherosclerosis and cardiovascular disease.5, 6 It is significantly correlated to occurrence of myocardial infarction and stroke.6 Assessment of the flow mediated dilation of the brachial artery as measure of endothelial (dys)function, is a validated model to research effects of possible protective strategies3, 4 and perform mechanistic experiments4, 7, 8 on IR-injury in humans in vivo.
Several previous studies failed to demonstrate the ability of pharmacological stimuli to mimic the beneficial effects of IP in aging vessels.9 Restoration of the age-related reduction in effectiveness of IP may be possible through exercise training. Indirect evidence indicates that physical activity, independent of other cardiovascular risk factors, protects against an occurrence as well as the severity of a myocardial infarction in humans.10 Although this suggests that physical activity may beneficially influence the age-related reduction in IP, no previous study provided direct evidence for this hypothesis in humans.
In this cross-sectional observational experiment we will study the impact of aging (young versus older subjects) and physical fitness (sedentary versus trained older subjects) on the protective effects of ischaemic preconditioning on brachial artery endothelial function after ischaemia-reperfusion injury in healthy humans in vivo.
We hypothesize that aging is associated with an attenuated ability of ischaemic preconditioning to prevent the decrease in brachial artery endothelial function observed after ischaemia reperfusion injury. Moreover, we expect that the age-related reduction in effectiveness of ischaemic preconditioning to prevent endothelial dysfunction after reperfusion injury is (at least partly) preserved in trained older subjects.
Study design
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| young, sedentary | – | Other: IPC |
| young, active | – | Other: IPC |
| old, sedentary | – | Other: IPC |
| old, active | – | Other: IPC |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- Study population: Young sedentary volunteers (n=23, age 18-30), young active volunteers (n=23, age 18-30), older sedentary subjects (n=23, >55 years) and older physically active subjects (n=23, >55 years).
Key inclusion criteria (5 listed)
- Healthy young volunteers : age 18-30
- Healthy older volunteers: age >55 years
- Sedentary: <1 h exercise per week
- Trained: >5 h exercise per week
- All subjects: written informed consent
Key exclusion criteria (8 listed)
- Smoking
- History of any cardiovascular disease
- Hypertension (in supine position: systole >140 mmHg, diastole >90 mmHg)
- Diabetes Mellitus (fasting glucose >7.0 mmol/L or random glucose >11.0 mmol/L)
- Hyperlipidaemia (fasting total cholesterol >6.5 mmol/L)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IPCrepeated cuff inflation (220 mmhg) around an upper limb for 5 minutes, followed by 5 minutes of reperfusion (repeated 4 times) | Other | old, active, old, sedentary, young, active, young, sedentary |
Primary outcome
endothelial reperfusion injury
Time frame: cross-sectional observation (single time point)
Change in endothelial function (measured with flow mediated dilation) after ischaemia reperfusion injury (induced by 20 minutes ischemia) with and without precedence of ischaemic preconditioning (by 3 cycles of 5-minutes of ischaemia).
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Nov 2013.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dick Thijssen, PhD principal investigator
Radboud University Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Cardiovascular Disease, run by Radboud University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Nov 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
endothelial reperfusion injury (time frame: cross-sectional observation (single time point)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Nov 2013.