A human cell atlas of the pressure-induced hypertrophic heart

Nicin, Luka; Schroeter, Sam Michael; Glaser, Simone F.; Schulze-Brüning, Ralf; Pham, Minh-Duc; Hille, Susanne; Yekelchyk, Michail; Kattih, Badder; Abplanalp, Wesley; Tombor, Lukas; Müller, Oliver; Braun, Thomas; Meder, Benjamin; Reich, Christoph; Arsalan, Mani; Holubec, Tomáš; Walther, Thomas; Emrich, Fabian; Krishnan, Jaya; Zeiher, Andreas M.; John, David; Dimmeler, Stefanie

doi:10.1038/s44161-022-00019-7

Cited by 36 publications

(41 citation statements)

References 47 publications

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“…7 D ). As in a recent report of pressure-induced hypertrophy in humans ( 56 ), we assessed expression of a “cardiomyocyte disease” metagene comprised of combined counts for NPPA, NPPB, MYH7, MYH7B, XIRP2, CMYA5, ANKRD1, TNNI3, ACTA1 , and PFKP . Similarly to the report in humans, this metagene was upregulated after banding in both males and females ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Sex-specific responses to slow progressive pressure overload in a large animal model of HFpEF

Eaton

Berretta

Lynch

et al. 2022

American Journal of Physiology-Heart and Circulatory Physiology

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Approximately 50% of all heart failure (HF) diagnoses can be classified as HF with preserved ejection fraction (HFpEF). HFpEF is more prevalent in females compared to males, but the underlying mechanisms are unknown. We previously showed that pressure overload (PO) in male felines induces a cardiopulmonary phenotype with essential features of human HFpEF. The goal of this study was to determine if slow progressive PO induces distinct cardiopulmonary phenotypes in females and males in the absence of other pathological stressors. Female and male felines underwent aortic constriction (banding) or sham surgery after baseline echocardiography, pulmonary function testing, and blood sampling. These assessments were repeated at 2- and 4-months post-surgery to document the effects of slow progressive pressure overload. At 4-months, invasive hemodynamic studies were also performed. Left ventricle (LV) tissue was collected for histology, myofibril mechanics, extracellular matrix (ECM) mass spectrometry, and single nucleus RNA sequencing (snRNAseq). The induced pressure overload (PO) was not different between sexes. PO also induced comparable changes in LV wall thickness and myocyte cross sectional area in both sexes. Both sexes had preserved ejection fraction, but males had a slightly more robust phenotype in hemodynamic and pulmonary parameters. There was no difference in LV fibrosis and ECM composition between banded male and female animals. LV snRNAseq revealed changes in gene programs of individual cell types unique to males and females after PO. Based on these results, both sexes develop cardiopulmonary dysfunction but the phenotype is somewhat less advanced in females.

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Section: Resultsmentioning

confidence: 99%

“…We also assessed cardiomyocyte expression of Eph receptor tyrosine kinases. Members of the EPHA and EPHB families were reported to have decreased gene expression in human cardiac hypertrophy ( 56 ). Interestingly, in the present study, only EPHA7 was highly expressed in all groups (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

Sex-specific responses to slow progressive pressure overload in a large animal model of HFpEF

Eaton

Berretta

Lynch

et al. 2022

American Journal of Physiology-Heart and Circulatory Physiology

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“…Recently, Nicin et al profiled gene expression changes in cardiomyocytes of human hypertrophic heart. 67 They found 527 upregulated and 2,775 downregulated genes in cardiomyocytes of aortic valve stenosis (AS) patients compared to healthy hearts. Nine of the upregulated genes ( ACTA1, ACTN1, CYB5R1, ENO3, MRPL41, NES, TNNC1, TNNI3, TPM2 ) and three of the downregulated genes ( AZIN1-AS1, DLG2, SDK1 ) were common to our hiPSC-CM model.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomics reveal stretched human pluripotent stem cell-derived cardiomyocytes as an advantageous hypertrophy model

Pohjolainen

Ruskoaho

Talman

2021

Preprint

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Left ventricular hypertrophy, characterized by hypertrophy of individual cardiomyocytes, is an adaptive response to an increased cardiac workload that eventually leads to heart failure. Previous studies using neonatal rat ventricular myocytes (NRVMs) and animal models have revealed several hypertrophy- and mechanical load-associated genes and signaling pathways. However, these models are not directly applicable to humans. Here, we studied the effect of cyclic mechanical stretch on gene expression of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using RNA sequencing. HiPSC-CMs showed distinct hypertrophic changes in gene expression at the level of individual genes and in biological processes. We also identified several differentially expressed genes that have not been previously associated with cardiomyocyte hypertrophy and thus serve as attractive targets for future studies. When compared to previously published data attained from stretched NRVMs and human embryonic stem cell-derived cardiomyocytes, hiPSC-CMs displayed a smaller number of changes in gene expression, but the differentially expressed genes revealed more pronounced enrichment of hypertrophy-related biological processes and pathways. Overall, these results establish hiPSC-CMs as a valuable in vitro model for studying human cardiomyocyte hypertrophy.

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“…To assess the cardiac transcriptome on single nuclear level, nuclei isolation from mouse hearts, single-nuclei separation, library preparation and sequencing were performed as previously described 41 .…”

Section: Single-nucleus Rna Sequencingmentioning

confidence: 99%

Ageing impairs the neuro-vascular interface in the heart

Wagner

Tombor

Malacarne

et al. 2022

Preprint

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Aging is a major risk factor for impaired cardiovascular health. The aging myocardium is characterized by electrophysiological dysfunctions such as a reduced heart rate variability. These alterations can be intrinsic within cardiomyocytes, but might be modulated by the cardiac autonomic nervous system, as well1. It is known that nerves align with vessels during development2, but the impact of aging on the cardiac neuro-vascular interface is unknown. Here, we report that aging reduces nerve density specifically in the left ventricle and dysregulates vascular-derived neuro-regulatory genes. Aging leads further to a down-regulation of miR-145 and de-repression of the neuro-repulsive factor Semaphorin-3A. miR-145 deletion increased Sema3a expression and reduced axon density, thus mimicking the observed aged heart phenotype. Removal of senescent cells, which accumulated with chronological age while nerve density declined, rescued from age-induced dennervation, reduced Sema3a expression and preserved heart rate variability. These data suggest that senescence-associated regulation of neuro-regulatory genes contributes to a declined nerve density of the aging heart and thereby to a reduced heart rate variability.

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A human cell atlas of the pressure-induced hypertrophic heart

Cited by 36 publications

References 47 publications

Sex-specific responses to slow progressive pressure overload in a large animal model of HFpEF

Sex-specific responses to slow progressive pressure overload in a large animal model of HFpEF

Transcriptomics reveal stretched human pluripotent stem cell-derived cardiomyocytes as an advantageous hypertrophy model

Ageing impairs the neuro-vascular interface in the heart

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