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

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.