# Sarcomeric remodelling in human heart failure unraveled by single molecule long read sequencing

## TL;DR

This study uses long-read sequencing to show that heart failure causes a coordinated shift in gene isoform expression, especially in sarcomere-related genes like tropomyosin.

## Contribution

The study reveals a convergent isoform landscape in heart failure, regardless of disease origin, using nanopore sequencing to identify novel gene isoforms.

## Key findings

- DCM and ICM heart failure patients show similar transcriptome profiles, indicating a shared isoform landscape.
- Ten out of eleven sarcomere genes showed significant isoform shifts in heart failure.
- TPM3 transcripts, usually low in healthy hearts, are markedly increased in heart failure.

## Abstract

Dysregulation of alternative splicing – mediated by factors such as RBM20 or SLM2 – can affect proper gene isoform control, disrupting gene isoform homeostasis and underpins severe cardiomyopathy in both animal models and patients. Although innovative therapies target various sarcomeric components, the impact of isoform switching in cardiac disease remains poorly understood. Here, we applied nanopore long-read sequencing to map the full-length transcriptome of left ventricular tissue from thirteen nonfailing controls, ten patients with dilated cardiomyopathy (DCM), and ten with ischemic cardiomyopathy (ICM). Our analysis identified 78,520 transcripts, 31% of which represent novel isoforms of known genes. Notably, the transcriptomes of DCM and ICM were largely indistinguishable, indicating that end-stage heart failure is characterized by a convergent isoform landscape, irrespective of disease etiology. Among 11 prototypical sarcomere genes, 10 displayed highly significant isoform shifts (p = 5.23 × 10−45–2.89 × 10−200). Focusing on tropomyosin, we observed that while the predominant cardiac gene TPM1 showed moderate up-regulation of its transcript isoforms, transcripts derived from TPM3—typically expressed at lower levels in the healthy heart—were markedly increased in heart failure.

Cardiomyopathy is a disease of the heart muscle involving structural and/or electrical abnormalities. There are four main types, with dilated cardiomyopathy (DCM) being the most common. Dysregulation of alternative splicing is one of the major underlying causes of cardiomyopathies.

The impact of isoform switching remains poorly understood.Using long-read nanopore sequencing, we mapped full-length transcriptome of left ventricular tissue from DCM amd ICM patients.Of the 11 prototypical sarcomere genes examined, 10 displayed significant shifts in isoform expression, including the tropomyosins. TPM1 and TPM3 showed a marked increase in heart failure.These results highlight a coordinated shift in the expression of heart-specific gene isoforms in the context of heart failure.

The impact of isoform switching remains poorly understood.

Using long-read nanopore sequencing, we mapped full-length transcriptome of left ventricular tissue from DCM amd ICM patients.

Of the 11 prototypical sarcomere genes examined, 10 displayed significant shifts in isoform expression, including the tropomyosins. TPM1 and TPM3 showed a marked increase in heart failure.

These results highlight a coordinated shift in the expression of heart-specific gene isoforms in the context of heart failure.

Cardiomyopathy is a disease of the heart muscle involving structural and/or electrical abnormalities. There are four main types, with dilated cardiomyopathy (DCM) being the most common. Dysregulation of alternative splicing is one of the major underlying causes of cardiomyopathies.