Titin-Related Dilated Cardiomyopathy: The Clinical Trajectory and the Role of Circulating Biomarkers in the Clinical Assessment
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Definitions
2.3. Biomarker Measurements
2.4. DNA Sequencing and TTN Mutation Analysis
2.5. Statistical Analysis
3. Results
3.1. Molecular Findings in the Study Cohort
3.2. Clinical Characteristics of the Study Population
3.3. Penetrance of Cardiotitinopathy Indicators
3.4. Results of Screening in Carriers of Cardiotitinopathy-Causing Truncating Variants
3.5. Outcome and Risk Stratification in Cardiotitinopathy
4. Discussion
4.1. Penetrance of Cardiotitinopathy Indicators
4.2. Risk Stratification including Biomarkers
4.3. Molecular Findings in the Study Cohort
4.4. Study Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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All Carriers N = 108 | DCM N = 70 (64.8%) | non-DCM N = 38 (35.2%) | p | |
---|---|---|---|---|
Age, years | 39.7 ± 15.5 | 40.5 ± 14.6 | 38.3 ± 17.2 | 0.475 |
Men | 67 (62.0%) | 55 (78.6%) | 12 (31.6%) | <0.001 |
Probands | 43 (39.8%) | 43 (61.4%) | 0 | <0.001 |
Symptoms | ||||
Heart failure | 54 (50.0%) | 54 (77.1%) | 0 | <0.001 |
NYHA class ≥3 | 14 (13.0%) | 14 (20.0%) | 0 | 0.002 |
Family history of SCD <50 years | 28 (25.7%) | 15 (21.4%) | 13 (34.2%) | 0.148 |
Arrhythmias and CCD | ||||
Atrial arrhythmias | 25 (23.1%) | 22 (31.4%) | 3 (7.9%) | 0.006 |
nsVT (n = 106) | 42 (39.6%) | 38 (55.1%) | 4 (10.8%) | <0.001 |
LBBB | 11 (10.2%) | 11 (15.7%) | 0 | 0.007 |
AV block (≥1st degree) | 15 (13.9%) | 13 (18.6%) | 2 (5.3%) | 0.056 |
Echocardiography | ||||
LVEF < 50% | 66 (61.1%) | 62 (88.6%) | 4 (10.5%) | <0.001 |
LVEF, % | 43.5 ± 13.8 | 36.2 ± 11.0 | 56.9 ± 6.6 | <0.001 |
LVEDD, mm | 58.3 ± 9.6 | 63.2 ± 8.0 | 49.4 ± 4.8 | <0.001 |
LAs, mm (n = 103) | 40.6 ± 8.1 | 43.7 ± 8.0 | 35.3 ± 4.9 | <0.001 |
Biomarkers in stable phase | ||||
hs-cTnT, ng/L (n = 90) | 4.4 [<3.0; 8.3] | 6.7 [3.8; 9.3] | <3.0 [<3.0; 4.2] | <0.001 |
hs-cTnT > 14 ng/L | 9 (10.0%) | 7 (12.5%) | 2 (5.9%) | 0.474 |
NT-proBNP, pg/mL (n = 72) | 244 [76; 1225] | 534 [157; 1498] | 72 [23; 94] | <0.001 |
NT-proBNP > 125 pg/mL | 47 (65.3%) | 46 (79.3%) | 1 (7.1%) | <0.001 |
NT-proBNP > 650 pg/mL | 24 (33.3%) | 24 (41.4%) | 0 | 0.003 |
Implantable devices | ||||
PM for bradyarrhythmias | 5 (4.6%) | 5 (7.1%) | 0 | 0.159 |
CRT-D | 2 (1.8%) | 2 (2.9%) | 0 | 0.540 |
ICD/CRT-D | 14 (13.0%) | 14 (20.0%) | 0 | 0.002 |
Events during Follow-Up | Total N = 108 | Men N = 67 (62.0%) | Women N = 41 (38.0%) | p |
---|---|---|---|---|
ICD in secondary prophylaxis | 2 (1.9%) | 1 (1.5%) | 1 (2.4%) | 1.00 |
CRT-D | 7 (6.5%) | 6 (9.0%) | 1 (2.4%) | 0.249 |
ICD/CRT-D implantation | 27 (25.0%) | 21 (31.3%) | 6 (14.6%) | 0.052 |
Malignant ventricular arrhythmia, n = 107 | 13 (12.1%) | 9 (13.4%) | 4 (10.0%) | 0.763 |
Appropriate ICD intervention, n = 27 | 13 (48.1%) | 9 (42.9%) | 4 (66.7%) | 0.384 |
Cardiopulmonary resuscitation, n = 106 | 2 (1.9%) | 2 (3.0%) | 0 | 0.530 |
Sudden cardiac death, n =106 | 1 (0.9%) | 0 | 1 (2.6%) | 0.368 |
End-stage heart failure, n = 107 | 13 (12.1%) | 12 (17.9%) | 1 (2.5%) | 0.024 |
LVAD | 5 (4.6%) | 5 (7.3%) | 0 | 0.155 |
Heart transplantation | 8 (7.4%) | 8 (11.9%) | 0 | 0.024 |
HF death, n = 106 | 5 (4.6%) | 4 (3.7%) | 1 (2.6%) | 0.650 |
Death | 9 (8.3%) | 6 (9.0%) | 3 (7.3%) | 1.00 |
Cumulate Incidence | p-Value Log-Rank | Univariable | Multivariable | |||
---|---|---|---|---|---|---|
HR [95% CI] | p-Value Wald | HR [95% CI] | p-Value Wald | |||
MVA + esHF | at 6 Years of Follow-Up | |||||
Sex: male vs. female | 32 vs. 14 | 0.033 | 3.08 [1.04; 9.18] | 0.043 | ||
AA: yes vs. no | 50 vs. 18 | 0.001 | 3.77 [1.56; 8.90] | 0.002 | ||
nsVT: yes vs. no | 46 vs. 7 | <0.001 | 5.5 [1.9; 16.5] | 0.002 | ||
LAs: ≥45 vs. <45 mm | 67 vs. 5 | <0.001 | 28.9 [6.7; 124.8] | <0.001 | ||
LVEF: <30 vs. ≥30% | 78 vs. 9 | <0.001 | 14.0 [5.5; 35.7] | <0.001 | ||
LBBB: yes vs. no | 86 vs. 16 | <0.001 | 8.5 [3.6; 20.4] | <0.001 | ||
NT-proBNP ≥650 vs. <650 pg/mL | 68 vs. 8 | <0.001 | 14.4 [3.6; 57.5] | <0.001 | 31.3 [4.0; 246] # | 0.001 # |
hs-cTnT: ≥18 vs. <18 ng/L | 75 vs. 13 | <0.001 | 7.7 [2.1; 28.6] | 0.002 |
Cumulate Incidence | p-Value Log-Rank | Univariable | Multivariable | |||
---|---|---|---|---|---|---|
HR [95% CI] | p-Value Wald | HR [95% CI] | p-Value Wald | |||
MVA | at 6 Years of Follow-Up | |||||
Sex: Male vs. Female | 21 vs. 14 | 0.362 | 1.72 [0.52; 5.59] | 0.368 | ||
SCD <50 in family: yes vs. no | 13 vs. 20 | 0.684 | 0.76 [0.21; 2.78] | 0.685 | ||
AA: yes vs. no | 35 vs. 14 | 0.010 | 3.81 [1.28; 11.36] | 0.016 | ||
nsVT: yes vs. no * | 39 vs. 2 | <0.001 | 12.5 [2.2; 72.7] | 0.005 | ||
LAs: ≥45 vs. <45 mm | 52 vs. 5 | <0.001 | 16.9 [3.7; 77.4] | <0.001 | ||
LVEF: <30% vs. ≥30% | 65 vs. 8 | <0.001 | 9.9 [3.2; 30.2] | <0.001 | ||
LBBB: yes vs. no * | 83 vs. 10 | <0.001 | 14.6 [4.8; 44.3] | <0.001 | ||
NT-proBNP ≥650 vs. <650 pg/mL | 59 vs. 8 | <0.001 | 12.7 [2.8; 58.3] | 0.001 | 11.7 [2.4; 56.6] # | 0.002 # |
hs-cTnT: ≥14 vs. <14 ng/L | 25 vs. 13 | 0.808 | 1.29 [0.16; 10.3] | 0.808 |
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Chmielewski, P.; Truszkowska, G.; Kowalik, I.; Rydzanicz, M.; Michalak, E.; Sobieszczańska-Małek, M.; Franaszczyk, M.; Stawiński, P.; Stępień-Wojno, M.; Oręziak, A.; et al. Titin-Related Dilated Cardiomyopathy: The Clinical Trajectory and the Role of Circulating Biomarkers in the Clinical Assessment. Diagnostics 2022, 12, 13. https://doi.org/10.3390/diagnostics12010013
Chmielewski P, Truszkowska G, Kowalik I, Rydzanicz M, Michalak E, Sobieszczańska-Małek M, Franaszczyk M, Stawiński P, Stępień-Wojno M, Oręziak A, et al. Titin-Related Dilated Cardiomyopathy: The Clinical Trajectory and the Role of Circulating Biomarkers in the Clinical Assessment. Diagnostics. 2022; 12(1):13. https://doi.org/10.3390/diagnostics12010013
Chicago/Turabian StyleChmielewski, Przemysław, Grażyna Truszkowska, Ilona Kowalik, Małgorzata Rydzanicz, Ewa Michalak, Małgorzata Sobieszczańska-Małek, Maria Franaszczyk, Piotr Stawiński, Małgorzata Stępień-Wojno, Artur Oręziak, and et al. 2022. "Titin-Related Dilated Cardiomyopathy: The Clinical Trajectory and the Role of Circulating Biomarkers in the Clinical Assessment" Diagnostics 12, no. 1: 13. https://doi.org/10.3390/diagnostics12010013