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Titin truncating variants, cardiovascular risk factors and the risk of atrial fibrillation and heart failure

Nature Cardiovascular Research volume 3, pages 899–906 (2024)Cite this article

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Abstract

High-proportion spliced-in (hiPSI) titin truncating variant (TTNtv) carriers have a higher risk of atrial fibrillation and heart failure1. However, the role of cardiovascular risk factors in modifying the risk of atrial fibrillation and heart failure attributed to hiPSI TTNtv carriers is unknown. Here, we investigate the role of cardiovascular risk, quantified using the pooled cohort equations (PCEs), in influencing the hazard of outcomes attributed to hiPSI TTNtvs among UK Biobank participants without baseline cardiovascular disease. The cohort was stratified based on hiPSI TTNtv carrier status and cardiovascular risk (low: <5%, intermediate: 5.0–7.5% and high: >7.5%). The primary outcome was a composite of atrial fibrillation, heart failure or death. TTNtv noncarriers with low cardiovascular risk were used as the reference group for all analyses. Among 179,752 participants (median age: 56 (49, 62) years; 57.5% female), the risk of the primary outcome was lower in hiPSI TTNtv carriers with low cardiovascular risk (adjusted hazard ratio: 2.23 (95% confidence interval: 1.62–3.07)) than those with high cardiovascular risk (adjusted hazard ratio: 8.21 (95% confidence interval: 6.63–10.18)). A favorable cardiovascular risk factor profile may partially offset the risk of clinical outcomes among hiPSI TTNtv carriers.

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Fig. 1: Cumulative incidence of primary outcome stratified by hiPSI TTNtv carrier status and cardiovascular risk.
Fig. 2: Risk of study outcomes according to hiPSI TTNtv carrier status and cardiovascular risk.
Fig. 3: Cumulative incidence of secondary outcomes stratified by hiPSI TTNtv carrier status and cardiovascular risk.

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Data availability

This study utilized data from the UK Biobank. UK Biobank data are available upon application to the UK Biobank (www.ukbiobank.ac.uk/). Source data are provided with this paper.

Code availability

Code utilized in this study has been deposited on GitHub (https://github.com/Arora-Translational-Lab/TTN_NCVR_2024_shetty_et_al/blob/main/Main_code).

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Acknowledgements

This research has been conducted using the UK Biobank Resource under application no. 58838. P.A. is supported by the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) awards (grant nos. R01HL160982, R01HL163852 and R01HL163081). N.P. is supported by the National Institutes of Health grant no. T32HL007457.

Author information

Authors and Affiliations

  1. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA

    Naman S. Shetty

  2. Harvard Medical School, Boston, MA, USA

    Naman S. Shetty

  3. Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA

    Mokshad Gaonkar, Akhil Pampana, Nirav Patel, Garima Arora & Pankaj Arora

  4. School of Nursing, University of Alabama at Birmingham, Birmingham, AL, USA

    Peng Li

  5. Section of Cardiology, Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA

    Pankaj Arora

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Contributions

P.A. conceptualized and designed the study. P.A., N.S.S., M.G., A.P., N.P., P.L. and G.A. acquired, analyzed or interpreted data. P.A., N.S.S., M.G., A.P., N.P., P.L. and G.A. drafted the manuscript. All authors performed critical revisions of the manuscript. M.G. and A.P. did the statistical analysis. P.A. and P.L. supervised and verified the data analysis.

Corresponding author

Correspondence to Pankaj Arora.

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Competing interests

P.A. reports grant support from Merck Sharp & Dohme LLC and Bristol-Myers Squibb and consulting income from Bristol-Myers Squibb, which are all unrelated to this work. The other authors declare no competing interests.

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Nature Cardiovascular Research thanks N. Larson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1

Study Population Flowchart.

Extended Data Fig. 2 Cumulative Incidence of Study Outcomes Stratified by High Proportion Spliced-In Titin Truncating Variant Carrier Status.

This figure depicts the cumulative incidence of the primary outcome (Panel A), atrial fibrillation (Panel B), heart failure (Panel C), and all-cause mortality (Panel D) stratified by high-proportion spliced-in Titin truncating (hiPSI TTNtv) carrier status. hiPSI TTNtv carriers and non-carriers are depicted in red and blue, respectively. The x-axis represents the follow-up duration since enrollment. The at-risk table below each figure depicts the number of participants at a given age who are at risk of the outcome.

Source data

Extended Data Fig. 3 Cumulative Incidence of Study Outcomes Stratified by Cardiovascular Risk.

This figure depicts the cumulative incidence of primary outcome (Panel A), atrial fibrillation (Panel B), heart failure (Panel C), and all-cause mortality (Panel D) stratified by the cardiovascular risk. Low, intermediate, and high cardiovascular risk are presented in green, blue, and red, respectively. The x-axis represents the follow-up duration since enrollment. The at-risk table below each figure depicts the number of participants at a given age who are at risk of the outcome.

Source data

Extended Data Fig. 4 Risk of Study Outcomes According to Cardiovascular Risk Among High-Proportion Spliced-In Titin Truncating Variant Carriers.

This figure depicts the adjusted hazard ratio for study outcomes according to the cardiovascular risk profile among high-proportion spliced-in Titin truncating (hiPSI TTNtv) carriers. The cardiovascular risk was determined using the Pooled Cohort Equations and categorized into 3 groups [low (<5.0%), intermediate (5.0%-7.5%), and high (>7.5%)]. The low cardiovascular risk group was taken as the reference group. Data are presented as hazard ratio and 95% confidence interval. HR (95% CI) in the figure indicates the hazard ratio and 95% confidence interval. Panel A depicts the primary outcome. Panels B, C, and D depict the secondary outcomes of atrial fibrillation, heart failure, and all-cause mortality, respectively.

Source data

Extended Data Table 1 Baseline Characteristics Stratified by Titin Truncating Variant Carrier Status
Full size table
Extended Data Table 2 Baseline Characteristics Stratified by Cardiovascular Risk
Full size table
Extended Data Table 3 Study Outcomes According to High-Proportion Spliced-In Titin Truncating Variant Carrier Status
Full size table
Extended Data Table 4 Risk of Study Outcomes According to Cardiovascular Risk
Full size table

Supplementary information

Source data

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Shetty, N.S., Gaonkar, M., Pampana, A. et al. Titin truncating variants, cardiovascular risk factors and the risk of atrial fibrillation and heart failure. Nat Cardiovasc Res 3, 899–906 (2024). https://doi.org/10.1038/s44161-024-00511-2

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