Ischemic Preconditioning Clinical Trial
Official title:
Conditioning Based Intervention Strategies - ConBIS. A Research Study on the Potential of Remote Conditioning for Activation of Endogenous Organ Protection and the Underlying Molecular Mechanisms
The overall objective of this study is to uncover and utilize the mechanisms behind the activation of endogenous organ protection by remote ischemic conditioning (RIC), high intensity traditional resistance training (TRT) and low intensity blood flow restricted resistance exercise (BFRE) with the perspective of defining their applicability for immediate organ protection in ischemia-reperfusion injury (acute conditioning) and subsequent tissue repair (chronic conditioning) during a prolonged recovery period. This objective will be achieved by studying which and how molecular pathways underlying these protective mechanisms are shared and can be transferred to treat medical conditions. A specific focus is the roles of EVs and miRNAs. Another objective is to explore how exercise training with and without ischemia can counteract muscle wasting.
Background
Clinical background - ischemia related and inflammatory conditions The pandemic of
cardiovascular disease has immense negative effects on global population health and life
expectancy. The most detrimental acute ischemic events are myocardial infarction and stroke.
Organ failure caused by ischemia-reperfusion syndromes such as stroke and myocardial
infarction constitutes the leading cause of death globally and carry a vast socio-economical
burden. Overall, 17 million people worldwide are estimated to die from cardiovascular
diseases (7.4 million from ischemic heart disease and 6.7 million from stroke). Attempts to
modify risk factor and life style related growth in cardiovascular disease are important and
have been successful in some parts of the world, but improved treatment of acute and chronic
cardiovascular disease is crucial to alleviate the disease burden.
In acute ischemic conditions such as myocardial infarction and stroke, early and successful
restoration of tissue perfusion following an ischemic event is the most effective strategy to
reduce tissue injury and improve clinical outcome, but reperfusion may induce further tissue
damage itself, so-called reperfusion injury. Although reperfusion strategies continue to
progress with improved logistics and medical treatment, even optimal acute reperfusion
treatment may leave patients with chronic ischemic disease. Actually, as initial survival has
improved due to improvements in acute reperfusion therapy, the number of patients with
chronic ischemic heart disease is growing globally (more than 35 million people worldwide
suffering from heart failure). Collectively, patients with heart failure have a poorer 5-year
survival rate than patients with most types of cancer. However, the development of effective
drugs to target the detrimental effects of reperfusion injury itself has proven to be a
challenge. Several pharmacologic strategies showing convincing effects in animal models of
ischemia-reperfusion injury have failed to translate into clinical benefit.
A key feature of heart failure caused by chronic ischemic heart disease is inflammation,
which shares mechanisms with other inflammatory conditions such as inflammatory bowel disease
and ankylosing spondylitis. Further debilitating, heart failure also exerts a negative effect
on habitual physical activity and skeletal muscle tissue health, producing multiple
detrimental effects on whole-body metabolism and mobility. A common underlying mechanistic
trait of these processes could be regulation by circulating small non-coding RNAs (micro RNAs
or miRNAs/miRs).
Scientific background Remote ischemic conditioning The main prognostic determinant of outcome
in acute myocardial infarction is the extent of tissue damage (infarct size), which is
determined not only by the duration of ischemia but also by injury caused by reperfusion
injury. Remote Ischemic Conditioning (RIC) is a new treatment modality to attenuate
reperfusion injury. Organ protection by RIC can be achieved simply by inducing 3 or 4
five-minute cycles of limb ischemia and reperfusion using a tourniquet or simple blood
pressure cuff. With few exceptions, RIC has consistently been shown to exert powerful
protection against ischemia-reperfusion injury in the heart, brain, kidneys, lungs, and liver
in animal models, and RIC has successfully been translated into clinical use. A specific
advantage of RIC is its easy applicability during ongoing ischemia of the target organ, which
has been exploited in animal models and humans to show that RIC reduces injury during
evolving myocardial infarction and stroke.
While the mediators and mechanisms of RIC remain to be identified, RIC has been shown to 1)
induce cytoprotection, 2) improve endothelial function and microcirculation, and 3) modify
inflammation - all three key players in the pathology behind heart failure - suggesting a
potentially powerful tool to simultaneously counteract detrimental biological processes
involved in the development of heart failure. RIC may have further potential because
continued RIC after myocardial infarction seems to induce sustained benefits during the
following adverse remodeling of the heart. The anti-inflammatory effects may be of importance
in other conditions involving acute or chronic inflammation.
Ischemia and conditioning with blood flow restricted resistance exercise Exercise is
traditionally categorized and practiced as either oxygen-demanding aerobic endurance exercise
with effect on metabolic properties or mechanically stressing resistance exercise with effect
on contractile properties. In addition to local myocellular effects, exercise appears to
promote molecular inter-organ communication. Indeed, recent studies have demonstrated the
ability of traditional exercise regimens to protect against e.g. myocardial
ischemia-reperfusion injury and also to improve cognitive function, hence the conception that
"exercise is medicine". Studies suggest that these remote effects are induced by myocellular
production of circulatory mediators to influence tissues of remote organs. Exercise-induced
muscle-organ cross-talk may, similar to RIC, rely on extracellular vesicle derived miRNA (see
next paragraph). Supporting such a notion, is the finding that high intensity traditional
resistance exercise evokes increased transcription of miR133b, since miR133b has recently
been demonstrated to promote recovery after stroke via transfer of exosome-enriched
extracellular particles. However, high intensity traditional exercise can produce muscle
injury and may therefore not comply with exercise in patients with cardiovascular or other
chronic muscle wasting diseases.
A novel approach may be offered by Ischemic resistance exercise training conducted as
low-intensity blood flow restricted resistance exercise (BFRE), with a low occlusion pressure
stimulus, which only compromises venous but not arterial blood flow. Much like RIC, BFRE is
conducted as 3-5 cycles (sets of exercise) interspaced by short duration of recovery. By this
mechanically very gentle approach, muscle accretion similar to that of high intensity
traditional resistance training (TRT) can be achieved, possibly due to acceleration of
metabolic build-up or activation of muscle stem cells. Interestingly, new results by us,
demonstrate that BFRE can mediate long-lasting preconditioning effects in muscle. Since
low-intensity BFRE mimics events of both traditional high intensity resistance exercise
(occlusion-reperfusion) and traditional aerobe exercise (hypoxia), BFRE can be speculated to
drive health beneficial metabolic as well as anabolic adaptations in the muscle. Based on its
resemblance to RIC, BFRE likely also affect remote tissues and infer remote organ protection.
The extent to which RIC and exercise regimens may share or overlap or differ mechanistically
- and potentially exert additive effects - is unknown, but application of BFRE entails highly
promising clinical perspectives.
Micro RNA signaling Circulating extracellular vesicles (EVs) are small particles released
from plasma membranes from almost all cell types. These EVs seem to act as transport systems
in the body carrying a cargo of signaling substances including miRNAs. miRNAs are also
effector molecules in ischemic events, e.g. myocardial miRNA144 (miR144) levels are reduced
by ischemic reperfusion injury (IR injury), which is attenuated by RIC. RIC also induces
increased circulatory EV levels, while EVs enriched with miR22 and miR451 from anoxic
cultured MSCs and cardiomycyte progenitor cells mitigate cardiac injury. Potentially,
treatment with specific miRNA loaded into EVs may provide protection against acute and
chronic effects of myocardial ischemia-reperfusion injury in patients [19]. EVs are also
believed to contain other substances including anti-inflammatory components acting in synergy
with miRNA to exert the full effect of the signaling cascade.
Objectives The overall objective of this study is to uncover and utilize the mechanisms
behind the activation of endogenous organ protection by remote ischemic conditioning (RIC),
high intensity traditional resistance training (TRT) and low intensity blood flow restricted
resistance exercise (BFRE) with the perspective of defining their applicability for immediate
organ protection in ischemia-reperfusion injury (acute conditioning) and subsequent tissue
repair (chronic conditioning) during a prolonged recovery period. This objective will be
achieved by studying which and how molecular pathways underlying these protective mechanisms
are shared and can be transferred to treat medical conditions. A specific focus is the roles
of EVs and miRNAs. Another objective is to explore how exercise training with and without
ischemia can counteract muscle wasting.
Hypotesis
The overall hypothesis of the proposal is that RIC and exercise potentiated by BFRE and TRT
release circulating protective mediators that exert immediate protective effects against IR
injury as well as promote beneficial repair during subsequent tissue rebuilding and in
chronic inflammatory conditions. Specifically, we will test the following hypotheses:
1. RIC, BFRE and TRT share organ protecting and anti-inflammatory properties induced
through common miRNA signaling pathways
2. Long lasting effect of RIC, BFRE and TRT can be achieved by repeated treatment, and the
chronic effects include anti-inflammatory and anti-ischemic properties of clinical
relevance by:
1. Improving ventricular function and reduce symptoms in patients with heart failure
and chronic ischemic heart disease (individual sub-study, a separate application
has been submitted to and approved by De Videnskabsetiske Komitéer).
2. Counteracting muscle wasting in patients with heart failure.
3. BFRE is a more effective mean to increase muscle mass, muscle power and muscle function
compared to TRT.
4. Non-conditioned EVs can be loaded with RIC, BFRE and specific miRNA, in vitro and exert
immediate protective effects against IR injury upon intravenous injection (future
sub-study)
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