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

Sara Khadjeh,Lukas Cyganek,Gerd Hasenfuss,Setare Torkieh,Frederike Weber,Belal A Mohamed,Dawid Lbik,Malte Tiburcy,Stefan Bonn,Vanessa Hindmarsh,Karl Toischer,Katrin Streckfuss-Bömeke,Ramon O Vidal

doi:10.1007/s00395-020-0784-4

Abstract

Heart failure is a major health problem worldwide with a significant morbidity and mortality rate. Although studied extensively in animal models, data from patients at the compensated disease stage are lacking. We sampled myocardium biopsies from aortic stenosis patients with compensated hypertrophy and moderate heart failure and used transcriptomics to study the transition to failure. Sequencing and comparative analysis of analogous samples of mice with transverse aortic constriction identified 25 candidate genes with similar regulation in response to pressure overload, reflecting highly conserved molecular processes. The gene cysteine-rich secretory protein LCCL domain containing 1 (CRISPLD1) is upregulated in the transition to failure in human and mouse and its function is unknown. Homology to ion channel regulatory toxins suggests a role in Ca2+ cycling. CRISPR/Cas9-mediated loss-of-function leads to dysregulated Ca2+ handling in human-induced pluripotent stem cell-derived cardiomyocytes. The downregulation of prohypertrophic, proapoptotic and Ca2+-signaling pathways upon CRISPLD1-KO and its upregulation in the transition to failure implicates a contribution to adverse remodeling. These findings provide new pathophysiological data on Ca2+ regulation in the transition to failure and novel candidate genes with promising potential for therapeutic interventions.

Highlights

Systolic heart failure (HF) is a leading cause of hospital admission and mortality in industrialized nations
The major difference between the two aortic stenosis (AS) pathology groups is the ejection fraction (EF), which is preserved with values over 55% (58.4% ± 2.9) in the compensated hypertrophy (CH) group and reduced with values of about 33% (33.5% ± 4.1) in the moderate HF (mHF) group
1 week and 8 weeks post-transverse aortic constriction (TAC), we aimed to compare the human data to the TAC mouse model of pressure overload (PO)-induced CH and HF

Summary

Introduction

Systolic heart failure (HF) is a leading cause of hospital admission and mortality in industrialized nations. The first response of the heart upon a cardiac insult (such as hypertension, valvular stenosis or insufficiency) is a compensated hypertrophy (CH) with preserved ejection fraction (EF) and cardiac function. This adaptive response is accompanied by molecular changes that impair contractility over time leading to “decompensated” HF with decreased cardiac function and left ventricular dilation [16, 26, 47, 49]. Primary sources for the analysis of progression steps during disease development are animal models. Despite a common phenotype, results gained from animal models cannot necessarily be transferred to the human situation [8, 11, 23]. Adequate models for understanding the transcriptional basis of HF disease progression are missing

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