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Dr. Pawan Singal
Principal Investigator, Cell Pathophysiology
Director, Institute of Cardiovascular Sciences
Research Focus
There have been significant developments in cardiac care and treatment, and yet many patients who survive a heart attack will subsequently go into heart failure. Is the mishandling of oxygen in the body a contributing factor? When life-sustaining oxygen is improperly handled within a cell, free radicals are created – a new, toxic species that tends to be removed in the normal scheme of things. However, if the body’s natural defenses are lowered, they can wreak havoc.
Dr. Singal’s pioneering studies have led the way in understanding how various antioxidants have the potential to prevent or treat the damage associated with free radical induced oxidative stress. Different animals models of heart failure (chronic, subchronic) are utilized to examine cell, sub-cell and molecular changes to understand the pathogenesis of heart failure due to a variety of causes.
Our working hypothesis is that “free-radical based oxidative stress contributes to the pathogenesis of heart failure”.
Why is this work important?
Moving from artificial models of heart failure to animal models, Dr. Singal’s laboratory has determined that following a heart attack, the production of free radicals in the myocardial cells is increased and natural defense mechanisms (antioxidants) become weak. In animals, treatment with various substances that increase antioxidant capacity, can delay the process of heart failure and can fortify defense mechanisms in the myocardium of the heart.
Clearly, the potential for lives saved and quality of lives enhanced in heart patients is enormous. The challenge is to determine the battery of agents that will do the job. No single antioxidant agent will provide a “magic bullet” for combating all free radicals. Different agents will be needed according to whether the radicals lurk on the cell membrane or in any number of compartments within the cell. Currently, various substances are being tested in the lab to determine identify new molecular targets for better management of these patients.
To date, only heart failure following myocardial infarction and drug-induced heart failure have been studied, and there are many different types of heart failures which remain to be investigated. However, it is possible that the various entry points into heart failure may ultimately merge in some common pathway, and free radicals may be involved at that point.
What techniques and equipment are used in this laboratory?
We create different animal models of heart failure. We have the techniques as well as necessary tools to induce heart failure in rats due to pressure overload (i.e. uncontrolled hypertension), myocardial infarction (i.e. loss of heart muscle due to a heart attack) and drug-induced heart failure (e.g. anti-cancer drug, adriamycin). Cardiovascular function of these animals is assessed invasively (cardiac catheterization) or non-invasively (echocardiography).
Heart function is also studied in isolated hearts. Isolated myocytes are used in primary cultures for the study of oxidative stress, antioxidants, subcellular and molecular functions. Different agents are used to mitigate or prevent the progression of heart failure.
About Dr. Pawan K. Singal
Dr. Singal is recognized as the world leader in this field. He has published more than 250 papers, 25 books and has given over 200 talks all around the world. Dr. Singal has been recognized more than 40 times with honors and awards by the local, national and international organizations/agencies.
For more information, please contact:
Dr. Pawan K. Singal
Director, Institute of Cardiovascular Sciences
St. Boniface General Hospital Research Centre
R3021, 351 Tache Avenue
Winnipeg, MB R2H 2A6 Canada
Tel: 204-235-3631
Fax: 204-233-6723
Email:
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In Detail
WHEN GOOD OXYGEN GOES BAD
There have been significant developments in cardiac care and treatment, and yet many patients who survive a heart attack will subsequently go into heart failure. Is the mishandling of oxygen in the body a contributing factor? When life-sustaining oxygen is improperly handled within a cell, free radicals are created – a new, toxic species that tends to be removed in the normal scheme of things. However, if the body’s natural defenses are lowered, they can wreak havoc. Not only are free radicals nasty, they’re tricky as well. Dr. Singal describes radicals as “hiding, like rats, in different parts of the cells.” Different agents are needed to attack them in different places.
Dr. Singal’s pioneering studies have led the way in understanding how various antioxidants have the potential to prevent or treat the damage associated with free radical induced oxidative stress.
THE THERAPEUTIC POTENTIAL OF ANTIOXIDANTS
After almost 20 years of study, Dr. Singal probably understands free radicals better than anyone in the world does. His hypothesis: free-radical based oxidative stress contributes to the pathogenesis of heart failure.
Moving from artificial models of heart failure to animal models, his laboratory has determined that following a heart attack, the production of free radicals in the myocardial cells is increased and natural defense mechanisms (antioxidants) become weak. In animals, treatment with various substances that increase antioxidant capacity, such as vitamin E and various drugs, can delay the process of heart failure and can fortify defense mechanisms in the myocardium of the heart.
Clearly, the potential for lives saved and quality of lives enhanced in heart patients is enormous. The challenge is to determine the battery of agents that will do the job. No single antioxidant agent will provide a “magic bullet” for combating all free radicals. Different agents will be needed according to whether the radicals lurk on the cell membrane or in any number of compartments within the cell. Currently, various substances are being tested in the lab to determine their effectiveness.
IMPLICATIONS FOR CANCER TREATMENT
Among the treatments available for cancer patients is an anti-tumor drug called adriamycin. Some 80% of cancers respond to this drug, making it perhaps the most effective treatment available. But soon after its introduction, a deadly side effect became apparent, and that was congestive heart failure. Finding a solution was a challenge Dr. Singal couldn’t resist.
Working with animal models of adriamycin-induced heart failure, his laboratory worked to understand what happens pathologically and histologically to the cell structure during this process. The finding was that the drug increases the production of free radicals and reduces the defense mechanisms against free radicals – a fatal combination leading to heart failure.
The next step was to study the effects of different antioxidants in combating the negative effects of the adriamycin. Eventually, an existing drug, probucol, was discovered to reverse the negative effects leading to heart failure without diluting the anti-cancer properties of the treatment.
This research is now ready to proceed to clinical trials. If human patients respond in the same way as the animal models have, it will have dramatic implications for the successful treatment of a wide range of cancers.
FINDING THE COMMON PATHWAY
To date, only heart failure following myocardial infarction and drug-induced heart failure have been studied, and there are many different instigators which remain to be investigated. However, it is possible that the various entry points into heart failure may ultimately merge in some common pathway, and free radicals may be involved at that point.
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