TY - JOUR
T1 - Titin cardiomyopathy leads to altered mitochondrial energetics, increased fibrosis and long-termlife-threatening arrhythmias
AU - Verdonschot, Job A. J.
AU - Hazebroek, Mark R.
AU - Derks, Kasper W. J.
AU - Aizpurua, Arantxa Barandiaran
AU - Merken, Jort J.
AU - Wang, Ping
AU - Bierau, Joergen
AU - van den Wijngaard, Arthur
AU - Schalla, Simon M.
AU - Hamid, Myrurgia A. Abdul
AU - van Bilsen, Marc
AU - van Empel, Vanessa P. M.
AU - Knackstedt, Christian
AU - Brunner-La Rocca, Hans-Peter
AU - Brunner, Han G.
AU - Krapels, Ingrid P. C.
AU - Heymans, Stephane R. B.
PY - 2018/3/7
Y1 - 2018/3/7
N2 - Aims Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy (DCM). We aim to study clinical parameters and long-term outcomes related to the TTNtv genotype and determine the related molecular changes at tissue level in TTNtv DCM patients. Methods and results A total of 303 consecutive and extensively phenotyped DCM patients (including cardiac imaging, Holter monitoring, and endomyocardial biopsy) underwent DNA sequencing of 47 cardiomyopathy-associated genes including TTN, yielding 38 TTNtv positive (13%) patients. At long-term follow-up (median of 45 months, up to 12 years), TTNtv DCM patients had increased ventricular arrhythmias compared to other DCM, but a similar survival. Arrhythmias are especially prominent in TTNtv patients with an additional environmental trigger (i.e. virus infection, cardiac inflammation, systemic disease, toxic exposure). Importantly, cardiac mass is reduced in TTNtv patients, despite similar cardiac function and dimensions at cardiac magnetic resonance. These enhanced life-threatening arrhythmias and decreased cardiac mass in TTNtv DCM patients go along with significant cardiac energetic and matrix alterations. All components of the mitochondrial electron transport chain are significantly upregulated in TTNtv hearts at RNA-sequencing. Also, interstitial fibrosis was augmented in TTNtv patients at histological and transcript level. Conclusion Truncating titin variants lead to pronounced cardiac alterations in mitochondrial function, with increased interstitial fibrosis and reduced hypertrophy. Those structural and metabolic alterations in TTNtv hearts go along with increased ventricular arrhythmias at long-term follow-up, with a similar survival and overall cardiac function.
AB - Aims Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy (DCM). We aim to study clinical parameters and long-term outcomes related to the TTNtv genotype and determine the related molecular changes at tissue level in TTNtv DCM patients. Methods and results A total of 303 consecutive and extensively phenotyped DCM patients (including cardiac imaging, Holter monitoring, and endomyocardial biopsy) underwent DNA sequencing of 47 cardiomyopathy-associated genes including TTN, yielding 38 TTNtv positive (13%) patients. At long-term follow-up (median of 45 months, up to 12 years), TTNtv DCM patients had increased ventricular arrhythmias compared to other DCM, but a similar survival. Arrhythmias are especially prominent in TTNtv patients with an additional environmental trigger (i.e. virus infection, cardiac inflammation, systemic disease, toxic exposure). Importantly, cardiac mass is reduced in TTNtv patients, despite similar cardiac function and dimensions at cardiac magnetic resonance. These enhanced life-threatening arrhythmias and decreased cardiac mass in TTNtv DCM patients go along with significant cardiac energetic and matrix alterations. All components of the mitochondrial electron transport chain are significantly upregulated in TTNtv hearts at RNA-sequencing. Also, interstitial fibrosis was augmented in TTNtv patients at histological and transcript level. Conclusion Truncating titin variants lead to pronounced cardiac alterations in mitochondrial function, with increased interstitial fibrosis and reduced hypertrophy. Those structural and metabolic alterations in TTNtv hearts go along with increased ventricular arrhythmias at long-term follow-up, with a similar survival and overall cardiac function.
KW - Cardiomyopathy
KW - Titin
KW - Genetics
KW - Prognosis
KW - Genotype-phenotype
KW - Mitochondrial
KW - ESC WORKING GROUP
KW - DILATED CARDIOMYOPATHY
KW - PERICARDIAL DISEASES
KW - POSITION STATEMENT
KW - HEART-FAILURE
KW - DIAGNOSIS
KW - MUTATIONS
KW - MORTALITY
KW - RELEVANCE
KW - VARIANTS
U2 - 10.1093/eurheartj/ehx808
DO - 10.1093/eurheartj/ehx808
M3 - Article
C2 - 29377983
SN - 0195-668X
VL - 39
SP - 864
EP - 873
JO - European Heart Journal
JF - European Heart Journal
IS - 10
ER -