From the Guidelines
The management of Titin (TTN) cardiomyopathy should focus on standard heart failure therapies and prevention of complications, as there are no TTN-specific treatments currently available, according to the most recent systematic review of clinical practice guidelines and recommendations 1. The therapeutic approach for TTN cardiomyopathy overlaps with heart failure treatment, sharing primary therapeutic options, from optimal decongestion to appropriate risk stratification for arrhythmias. Patients should receive guideline-directed medical therapy including:
- ACE inhibitors or ARBs (such as lisinopril 10-40 mg daily or valsartan 80-320 mg daily)
- Beta-blockers (such as metoprolol succinate 25-200 mg daily or carvedilol 3.125-25 mg twice daily)
- Mineralocorticoid receptor antagonists (spironolactone 25-50 mg daily)
- SGLT2 inhibitors (empagliflozin 10 mg daily or dapagliflozin 10 mg daily) For patients with reduced ejection fraction, sacubitril/valsartan may replace ACE inhibitors/ARBs. Device therapy with implantable cardioverter-defibrillators should be considered for patients with ejection fraction ≤35% despite optimal medical therapy for 3 months, as TTN mutations carry an arrhythmia risk. Regular cardiac monitoring with echocardiograms every 6-12 months is recommended to track disease progression. Family screening is essential since TTN cardiomyopathy is inherited in an autosomal dominant pattern, with first-degree relatives requiring clinical evaluation and possibly genetic testing, as suggested by the recent review of clinical practice guidelines and recommendations 1. The management approach is based on the pathophysiology of TTN mutations, which affect sarcomere function and lead to impaired cardiac contractility, with dilated cardiomyopathy being the most common phenotype. Key considerations in the management of TTN cardiomyopathy include:
- Early identification of patients at risk of disease progression
- Optimal medical therapy to prevent complications and improve quality of life
- Regular monitoring to track disease progression and adjust treatment as needed
- Family screening to identify affected relatives and provide genetic counseling.
From the Research
Overview of Titin Cardiomyopathy
- Titin cardiomyopathy, also known as TTN cardiomyopathy, is a condition caused by mutations in the titin gene (TTN) [ 2, 3].
- The titin protein is a crucial component of the sarcomere, the structural unit of striated muscle tissue, and plays a key role in regulating myocardial function [ 4, 5].
Management of Titin Cardiomyopathy
- The management of TTN cardiomyopathy is complex and requires a multi-disciplinary approach [ 2].
- Patients with TTN truncation mutations may benefit from innovative approaches such as gene therapy or preemptive treatments with drugs like angiotensin-converting enzyme inhibitors or beta-blockers [ 2].
- Therapeutic strategies targeting titin are being explored, including the use of splicing factors to adjust isoform ratios or engineered heart tissues to study disease mechanisms [ 5].
Role of Titin in Cardiomyopathy
- Titin truncation variants are the most frequent cause of dilated cardiomyopathy, a leading cause of heart failure and heart transplant [ 6, 3].
- The mechanisms causing the disease are complex and still incompletely understood, involving haploinsufficiency, sarcomere disarray, and altered thick filament regulation [ 5].
- Post-translational modifications of titin, such as phosphorylation, play a crucial role in adjusting titin's stiffness and allowing for rapid adaptation to changing hemodynamic demands [ 4, 5].
Future Directions
- Advances in genetic engineering, including CRISPR, offer promise for modifying TTN to treat titin-related cardiomyopathies [ 5].
- Further research is needed to elucidate the contribution of titin to myofibril assembly, stability, and signal transduction, and to develop novel therapeutic approaches that can modulate titin transcriptional and post-translational defects [ 6].