*1.3. Abnormalities in Titin Contribute to Systolic and Diastolic Heart Failure*

The essential function of titin in the sarcomere and cardiac function is illustrated by the significant cardiac phenotypes in patients who have *TTN* mutations. In addition, patients who develop heart failure related to other causes have significant changes to titin at the transcriptional and post translational level. Cardiomyopathy and heart failure are categorized clinically into systolic dysfunction and diastolic dysfunction. In systolic dysfunction, there is decreased contraction of the heart leading to decreased stroke volume and elevated cardiac pressures. Systolic dysfunction is categorized into dilated cardiomyopathy and hypertrophic cardiomyopathy. In dilated cardiomyopathy, dysfunction of the cardiomyocytes during contraction leads to remodeling of the myocardium in an eccentric pattern which causes dilation of the ventricle. In hypertrophic cardiomyopathy, changes in myocardial function result in concentric hypertrophy and thickening of the ventricle. Restrictive cardiomyopathy is caused by progression of diastolic dysfunction where the contractile force of the heart is preserved; however, due to abnormal relaxation of the heart during diastole, the ventricle cannot fill appropriately resulting in decreased cardiac function. In both systolic and diastolic dysfunction, there are elevated cardiac

filling pressures leading to the clinical presentation of heart failure with development of peripheral and pulmonary edema, dyspnea, and fatigue.

We will review how mutations in *TTN* contribute to cardiomyopathy. We will discuss how transcriptional changes and regulation of titin affect cardiac physiology. We will describe post-translational modifications of titin that occur with heart failure. In covering these topics, there will be a translational focus on associating molecular pathways with clinical phenotypes and how these pathways may lead to novel therapeutic targets for treatment of cardiomyopathy.
