CRISPLD1: a novel conserved target in the transition to human heart failure

Area of Science:

• Cardiology
• Molecular Biology
• Genetics

Background:

• Heart failure poses a significant global health burden with high morbidity and mortality.
• Limited patient data exists for the compensated stage of heart failure, hindering understanding of disease transition.
• Existing research heavily relies on animal models, necessitating human data for clinical relevance.

Purpose of the Study:

• To investigate molecular changes during the transition from compensated hypertrophy to moderate heart failure in humans.
• To identify conserved genes and pathways regulated by pressure overload in both human and mouse models.
• To elucidate the function of the novel gene CRISPLD1 in cardiac physiology and pathophysiology.

Main Methods:

• Myocardium biopsies from aortic stenosis patients with compensated hypertrophy and moderate heart failure were analyzed.
• Transcriptomic analysis was performed on human samples and compared with mouse models of transverse aortic constriction.
• CRISPR/Cas9 gene editing was used to create CRISPLD1 loss-of-function in human-induced pluripotent stem cell-derived cardiomyocytes.

Main Results:

• Twenty-five candidate genes showed conserved regulation in response to pressure overload in human and mouse models.
• The gene cysteine-rich secretory protein LCCL domain containing 1 (CRISPLD1) was found to be upregulated during the transition to heart failure.
• CRISPLD1 loss-of-function resulted in dysregulated calcium handling and altered signaling pathways in cardiomyocytes.

Conclusions:

• CRISPLD1 plays a role in calcium handling and may contribute to adverse cardiac remodeling in heart failure.
• The study identifies novel candidate genes, including CRISPLD1, with potential for therapeutic intervention in heart failure.
• Findings provide new insights into calcium regulation and molecular mechanisms underlying heart failure progression.