Titin cardiomyopathy leads to altered mitochondrial energetics, increased fibrosis and long-term life-threatening arrhythmias

Verdonschot, Job A.J.; Hazebroek, Mark; Derks, Kasper; Aizpurua, Arantxa Barandiarán; Merken, Jort J.; Wang, Ping; Bierau, Joergen; Wijngaard, Arthur van den; Schalla, Simon; Hamid, Myrurgia Abdul; Bilsen, Marc van; Empel, Vanessa van; Knackstedt, Christian; Rocca, Hans‐Peter Brunner‐La; Brunner, Han G.; Krapels, Ingrid P.C.; Heymans, Stéphane

doi:10.1093/eurheartj/ehx808

Cited by 143 publications

(107 citation statements)

References 26 publications

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“…Such defects have been proven to diminish contractile performance in rodents and humans, which can eventually result in a higher risk of HF events. Second, common metabolic and signaling perturbations have been seen in rodent and human hearts with TTNtv, including a shift towards glycolytic metabolism and pronounced cardiac alterations in mitochondrial function, which can be maladaptive responses to stress and lead to susceptibility to HF. Third, TTNtv have been associated with ventricular and atrial arrhythmias, which can also contribute to an increased risk of HF events .…”

Section: Discussionmentioning

confidence: 99%

“…Second, common metabolic and signaling perturbations have been seen in rodent and human hearts with TTNtv, including a shift towards glycolytic metabolism and pronounced cardiac alterations in mitochondrial function, which can be maladaptive responses to stress and lead to susceptibility to HF. Third, TTNtv have been associated with ventricular and atrial arrhythmias, which can also contribute to an increased risk of HF events . These adverse effects can be even more prominent in the context of LVNC, in which there was originally supposed to be a higher risk of HF.…”

Section: Discussionmentioning

confidence: 99%

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Titin‐truncating variants are associated with heart failure events in patients with left ventricular non‐compaction cardiomyopathy

Zhang

Liu

et al. 2019

Clinical Cardiology

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Background Titin‐truncating variants (TTNtv) have been recognized as the most prevalent genetic cause of dilated cardiomyopathy. However, their effects on phenotypes of left ventricular non‐compaction cardiomyopathy (LVNC) remain largely unknown. Hypothesis The presence of TTNtv may have an effect on the phenotype of LVNC. Methods TTN was comprehensively screened by targeted sequencing in a cohort of 83 adult patients with LVNC. Baseline and follow‐up data of all participants were collected. The primary endpoint was a composite of death and heart transplantation. The secondary endpoint was heart failure (HF) events, a composite of HF‐related death, heart transplantation, and HF hospitalization. Results Overall, 13 TTNtv were identified in 13 patients, with 9 TTNtv located in the A‐band of titin. There was no significant difference in baseline characteristics between patients with and without TTNtv. During a median follow‐up of 4.4 years, no significant difference in death and heart transplantation between the two groups was observed. However, more HF events occurred in TTNtv carriers than in non‐carriers (P = 0.006). Multivariable analyses showed that TTNtv were associated with an increased risk of HF events independent of sex, age, and baseline cardiac function (hazard ratio: 3.25, 95% confidence interval: 1.50‐7.01, P = 0.003). Sensitivity analysis excluding non‐A‐band TTNtv yielded similar results, but with less strength. Conclusions The presence of TTNtv may be a genetic modifier of LVNC and confer a higher risk of HF events among adult patients. Studies of larger cohorts are needed to confirm our findings.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Titin‐truncating variants are associated with heart failure events in patients with left ventricular non‐compaction cardiomyopathy

Zhang

Liu

et al. 2019

Clinical Cardiology

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“…Only very few studies linked human DCM mutations to mitochondrial abnormalities so far. Truncating mutations in the gene encoding the sarcomeric protein titin (TTN), frequently found in DCM patients [35], were associated with increased risk of ventricular arrhythmias, decreased cardiac mass as well as significant transcriptional upregulation of all components of the mitochondrial oxidative phosphorylation (OXPHOS) system [36]. The increased levels of respiratory chain complexes could reflect an attempt to enhance ATP production to compensate for the sarcomeric defects related to TTN mutation.…”

Section: Human Dcm Mutations Affecting Mitochondriamentioning

confidence: 99%

Metabolic Alterations in Inherited Cardiomyopathies

Sacchetto

Sequeira

Bertero

et al. 2019

JCM

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The normal function of the heart relies on a series of complex metabolic processes orchestrating the proper generation and use of energy. In this context, mitochondria serve a crucial role as a platform for energy transduction by supplying ATP to the varying demand of cardiomyocytes, involving an intricate network of pathways regulating the metabolic flux of substrates. The failure of these processes results in structural and functional deficiencies of the cardiac muscle, including inherited cardiomyopathies. These genetic diseases are characterized by cardiac structural and functional anomalies in the absence of abnormal conditions that can explain the observed myocardial abnormality, and are frequently associated with heart failure. Since their original description, major advances have been achieved in the genetic and phenotype knowledge, highlighting the involvement of metabolic abnormalities in their pathogenesis. This review provides a brief overview of the role of mitochondria in the energy metabolism in the heart and focuses on metabolic abnormalities, mitochondrial dysfunction, and storage diseases associated with inherited cardiomyopathies.

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“…Truncating filamin C (FLNC) mutations have been associated with an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies, complicated by frequent premature SCD [32]. The same arrhythmic tendency has been shown in carriers of TNNT2 [33], phospholamban (PLN) [34], RNA-binding motif protein 20 (RBM20) [35], TTN [36], and desmosomal mutations. Together, these data suggest that, in the future, genotypes other than LMNA could benefit from an early ICD implantation independently from LVEF reduction.…”

Section: The Challenge Of Arrhythmic Stratificationmentioning

confidence: 97%