Hendrikus L. Granzier, PhD, professor of physiology and cellular and molecular medicine at the University of Arizona College of Medicine - Tucson, has been awarded $1.5 million from the National Institutes of Health to study the role of titin, the largest known protein, in diastolic heart function and disease.
Dr. Granzier and members of his lab will study titin to gain understanding in why women are more prone to diastolic heart disease than men. Heart disease is the number one killer of women and the leading cause of disability among women.
Dr. Granzier is the Allan and Alfie Norville Endowed Chair. The chair was established at the UA Sarver Heart Center by the Norville’s matching a challenge gift by an anonymous donor and provide for a comprehensive research focus on the underlying molecular mechanisms relating to gender differences in cardiovascular diseases.
The Granzier team will study the role of titin during the diastolic or filling of the heart during infant development and in adults. Titin works like a molecular sized spring that recoils and causes the cardiac muscle to relax.
In Diastolic heart disease, the heart is stiffer than normal, which interferes with the heart’s ability to provide enough blood to the organs. “This often is the cause of heart failure in women. In cases of an abnormally stiff heart muscle, the heart contracts as it should, but is too stiff to relax normally and requires a higher amount of pressure to fill the major pumping chamber. This higher pressure backs up into the lungs, resulting in symptoms such as shortness of breath, especially with exertion,” said Lori Mackstaller, MD, associate professor of clinical medicine at the UA College of Medicine and the Edwin J. Brach Foundation/Hazel and Bertram Brodie Endowed Lecturer at the UA Sarver Heart Center.
The team’s research will examine the isoform switching and post-translational modification (chemical modifications to regulate cellular activity) of titin, relative to the change in the stiffness of the extracellular matrix which influences tissue function in both the left and right ventricles of the heart.
They will also study the role of titin in the Frank-Starling mechanism - the ability of the heart to change its force of contraction and stroke volume (the volume of blood pumped from the ventricle with each beat) in response to changes in blood flow return. They also will measure hypertrophy or thickening of the muscular wall within heart's pumping chambers. This work will contribute to the understanding of the mechanisms that give rise to diastolic dysfunction and reduced pump function in heart failure.
Dr. Granzier is a member of the UA Sarver Heart Center and the BIO5 Institute.