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June 12, 2026Journal of Clinical InvestigationOpen Access

AAV-mediated long-term TBX18 expression causes cardiac fibrosis and fails to induce pacemaker activity in rodents

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Why the study?

Does AAV-mediated long-term TBX18 expression induce pacemaker activity in rodent models?

Population

Rodent models including adult mice, a complete AV-block rat model, and neonatal rat ventricular myocytes.

Comparison

Adeno-associated virus-mediated long-term… vs AAV-mediated Hcn2 expression, AAV-GFP, AdV-GFP…

Design

Preclinical

Follow-up

up to 8 weeks post injection

Authors

JWJianan WangMRMathilde R. RivaudMKMischa Klerk

Discussion

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Overview

TBX18 AAV fails to induce durable pacing and causes fibrosis in rodents; leaves long-term biological pacemaker viability open and cautions against clinical translation.

Key Points

  • This research aims to determine the long-term effects of AAV-mediated TBX18 expression on cardiac function and fibrosis in rodent models.
  • AAV-mediated expression of TBX18 and Hcn2 was compared in mouse hearts.
  • Electrophysiological studies assessed pacemaker activity and automaticity in TBX18-expressing cells.
  • Cardiac fibrosis levels and gene expression were analyzed post-gene therapy.
  • TBX18 expression resulted in severe cardiac fibrosis with suppressed working myocardial gene expression.
  • No pacemaker activity or hyperpolarization-activated funny current was detected in TBX18-expressing cells.
  • Hcn2 expression successfully induced ectopic pacemaker activity, contrasting TBX18 outcomes.

Structured PICO

Does AAV-mediated long-term TBX18 expression induce pacemaker activity in rodent models?

P
Population
Rodent models including adult mice, a complete AV-block rat model, and neonatal rat ventricular myocytes (NRVMs).
I
Intervention
Adeno-associated virus (AAV)-mediated long-term expression of TBX18 (including optimized AAV-cTnT-uORF-TBX18 vector).
C
Comparator
AAV-mediated Hcn2 expression, AAV-GFP, AdV-GFP, and saline controls.
O
Outcome
Ectopic pacemaker activity and cardiac fibrosis.surrogate

AAV-mediated TBX18 expression fails to generate a viable biological pacemaker due to fibrosis and lack of pacemaker induction, whereas Hcn2 expression successfully induces pacing.

Cite This Study

Wang et al. (2026) studied this question.

synapsesocial.com/papers/6a2bd1386550ea4541ffe94dhttps://doi.org/10.1172/jci190632
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