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 “The effect of extracellular vesicles on ischemia reperfusion injury: effects on necrosis with inflammation and its effect on apoptotic cells with program cell death and pardoning of execution ".  

BACKGROUND: Cardiovascular disease is a leading cause of death worldwide.  The United States is no exception.  By cardiovascular disease we mean mostly heart attack and stroke due to atherosclerotic cardiovascular disease as well as heart failure.  Heart attacks are manifested by occlusion of an essential heart artery known as a coronary artery/stroke is occlusion of a brain artery.  Once a vessel is completely or significantly occluded, no blood flow and therefore no oxygen flows distal to that. Consequently, tissue begins to die mostly by lack of oxygen as well as other nutrients.  Most vital organs in our bodies do not regenerate these essential organ primary cells. Therefore, when a person suffers a heart attack, they lose heart muscle cells known as myocytes which do not regenerate or are significantly faulty if they do survive and cause issues like arrhythmias but are replaced by fibrous tissue.  The brain also has no capacity to regenerate those nerve cells and therefore strokes lead to significant motor impairment as well as speech and cognition impairment if an artery is significantly or completely occluded.  

When an artery is occluded and the tissues begin to suffer from lack of oxygen, physiological effects begin to take place. Immediately the cells begin to die within minutes lacking oxygen and this so-called cell death is by a process known as necrosis, which is very inflammatory.  However, certain cells are programmed for cell death by a process known as apoptosis, which is non-inflammatory but does require energy/substrate.  

Apoptotic cells are unique in the sense that since they are either intrinsically or extrinsically programmed for cell death (requiring energy) but also a process-before the cell is committed to program cell death and therefore, these cells are salvageable if they are "Pardoned" from execution order for cell programed death.  However, when reperfusion is established, there is a phenomenon known as Ischemia reperfusion injury (IRI) that occurs.  These cells that die of necrosis produce a lot of information and destruction of the cell. Cells that are programmed for cell death by apoptosis are potentially salvageable and can have a significant impact on Restoration and preservation of tissue function. 

Note however, that these cells that are programmed for cell death by apoptosis, is an energy requiring process.  The apoptotic cells basically take the essential elements apart for recycling.  It's ironic the body has to deal with an acute occlusion of an artery, only to deal with an even bigger problem once the artery is opened up again, causing more death and destruction.

 "The effect of extracellular vesicles on ischemia reperfusion injury: effects on necrosis with inflammation and its effect on apoptotic cells with program cell death and pardoning of execution". 

This study is going to be conducted as a preclinical confirmatory study in diabetic mice. The study design will be to use: 

• A) control mice mimicking acute heart attacks       not receiving the Extracellular vesicles Post reopening of occluded artery 

                          and

• B) treatment mice that will receive the       medications at different intervals of artery occlusion and reopening and subsequent administration of extracellular vesicles intravenously.

Extracellular vesicles administered post reestablishment of blood flow will decrease inflammation/oncosis and therefore the devastating effects of necrosis but also will salvage apoptotic cells by pardoning them from execution order, by supplying the substrate and other messaging signals, rescuing these essential and irreplaceable cells.  Their effect should decrease loss of tissue and therefore consequences like reperfusion arrhythmia to include lethal arrhythmias which are leading causes of death and occlusion of coronary arteries and a decrease in heart failure due to rescuing and salvaging essential non regenerated myocardial cells and preserving left ventricular function.    

Advanced Therapeutics to include biologic agents are the treatments of the future and are currently used in regenerative medicine advanced therapeutics as well as in the field of oncology as immunotherapy.  Its true application is priceless in the cardiovascular space since it has the leading cause of death.  We truly appreciate all your help, and your contribution is paramount.

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