Multiomics Analysis Provides Novel Pathways Related to Progression of Heart Failure

Ouwerkerk, Wouter; Belo Pereira, Joao P.; Maasland, Troy; Emmens, Johanna E.; Figarska, Sylwia M.; Tromp, Jasper; Koekemoer, Andrea L.; Nelson, Christopher P.; Nath, Mintu; Romaine, Simon P.R.; Cleland, John G.F.; Zannad, Faiez; van Veldhuisen, Dirk J.; Lang, Chim C.; Ponikowski, Piotr; Filippatos, Gerasimos; Anker, Stefan; Metra, Marco; Dickstein, Kenneth; Ng, Leong L.; de Boer, Rudolf A.; van Riel, Natal; Nieuwdorp, Max; Groen, Albert K.; Stroes, Erik; Zwinderman, Aeilko H.; Samani, Nilesh J.; Lam, Carolyn S.P.; Levin, Evgeni; Voors, Adriaan A.

doi:10.1016/j.jacc.2023.08.053

Cited by 16 publications

(3 citation statements)

References 52 publications

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“…'Multi-omics' technology is necessary to adequately understand the complex molecular milieu of human diseases. Molecular profiling can classify diseases like HF by analysing the molecular signatures associated with the disease at various omics levels 30,31 (Table 1).…”

Section: Molecular Approachmentioning

confidence: 99%

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404‐error “Disease not found”: Unleashing the translational potential of ‐omics approaches beyond traditional disease classification in heart failure research

Esquivel Gaytan,

Bomer,

Grote Beverborg

et al. 2024

European J of Heart Fail

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The emergence of personalized medicine, facilitated by the progress in ‐omics technologies, has initiated a new era in medical diagnostics and treatment. This review examines the potential of ‐omics approaches in heart failure, a condition that has not yet fully capitalized on personalized strategies compared to other medical fields like cancer therapy. Here, we argue that integrating multi‐omics technology with systems medicine approaches could fundamentally transform heart failure management, moving away from the traditional paradigm of ‘one size fits all’. Our review examines how omics can enhance understanding of heart failure's molecular foundations and contribute to a more comprehensive disease classification. We draw attention to the current state of medical practice that only relies on clinical evidence and a number of standard laboratory tests. At the same time, we propose a shift towards a universal approach that uses quantitative data from multi‐omics to unravel complex molecular interactions. The discussion centres around the potential of the transition as a means to enhance individual risk assessment and emphasizes management within clinical settings. While the use of omics in cardiovascular research is not recent, many past studies have focused only on a single omics approach. In order to achieve a better understanding of disease mechanisms, we explore more holistic approaches using genomics, transcriptomics, epigenomics, and proteomics. This review concludes with a call to action to adopt multi‐omics in clinical trials and practice to pave the way for more personalized disease management and more effective heart failure interventions.

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Section: Molecular Approachmentioning

confidence: 99%

“…These findings were corroborated in a separate cohort of 1738 patients, showcasing the efficacy and potential of artificial intelligence in integrating clinical and molecular data for HF research. 31…”

Section: Challenges and Advances In Personalized Medicine And Evidenc...mentioning

confidence: 99%

404‐error “Disease not found”: Unleashing the translational potential of ‐omics approaches beyond traditional disease classification in heart failure research

Esquivel Gaytan,

Bomer,

Grote Beverborg

et al. 2024

European J of Heart Fail

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“…In the physiologic situation, 70% to 85% of the total cellular volume of the heart consists of cardiomyocytes, ensuring adequate cardiac contractility and pulsatile perfusion of all organs Zhou & Pu, 2016). The lack of understanding about true regeneration of the human heart is reflected in the current medical therapies for heart failure, that do not aim to cure the underlying deficit of functional cardiomyocytes (Galdos et al, 2017;Lazar, Sadek, & Bergmann, 2017;Ouwerkerk et al, 2023). A growing number of studies describe the reactivation of embryonic signalling pathways in the failing left ventricle.…”

Section: Introductionmentioning

confidence: 99%

Unlocking the Molecular Cues for Cardiomyocyte Proliferation

Yuan

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Human induced pluripotent stem cells (hiPSCs) have demonstrated potential for molecular studies and the generation of human heart models, thereby reducing reliance on animal studies. In contrast, the adult heart, lacking the ability to self-repair after a heart attack, hiPSC-derived cardiomyocytes (hiPSC-CMs) present a promising and potentially limitless source of human embryonic-like CMs. To fully harness this potential, it is essential to delve into the developmental molecular cues governing CM proliferation during embryonic development. Moreover, to achieve the objective of precision medicine, understanding the relevant molecular process on CM maturation during cardiac differentiation becomes vital for improving the practical applications of hiPSC-CMs in drug screening and disease remodeling. In this thesis, we initially utilized hiPSC-CMs to investigate the signaling cues that guide cell fate decisions between proliferation and terminal differentiation. A combinatory screen for CHIR99021/Wnt and Insulin/Akt pathways was conducted on spontaneously beating hiPSC-CMs, revealing the synergistic effects of CHIR99021/Wnt and Insulin/Akt pathways on proliferation and the regulation of sarcomere homeostasis. Moreover, we identified a novel temporal interplay between CHIR99021/Wnt via TCF/LEF and Insulin/Akt via FOXO as regulators of cell-fate decisions in immature hiPSC-CMs. The study contributed to the understanding of the effects of targeting embryonic growth pathways for acute and chronic heart failure treatment. Additionally, we explored sarcomere architecture in high proliferative hiPSC-CMs, we observed sarcomere disassembly during mitosis in proliferating hiPSC-CMs treated with CHIR99021, with an emphasis on Wnt/β-catenin signaling. The presence of these signals is higher in highly proliferative hiPSC-CMs compared to non-proliferative hiPSC-CMs. Furthermore, the study demonstrated that CHIR99021 enhances non-viral vector incorporation in highly proliferative hiPSC-CMs, providing a tool for gene manipulation studies. We further continue to investigate the effect of cell-cell contact on the canonical Wnt/β-catenin pathway in response to hiPSC-CM proliferation. Our results indicate that cell-cell contact negatively influences the canonical Wnt/β-catenin signaling pathway, inhibiting proliferation in immature hiPSC-CMs. The involvement of N-cadherin in cell-contact inhibition was found, resulting in the release of more proliferative hiPSC-CMs due to disrupted N-cadherin. Furthermore, reactivation of Wnt/β-catenin signaling in late-stage hiPSC-CMs led to impaired sarcomere function, providing insights into the role of embryonic signaling pathways in failing/injured heart conditions. We finally explored the impact of specific TNNT2 mutations associated with hypertrophic cardiomyopathy and dilated cardiomyopathy on cardiac function using hiPSC-CMs. We assessed contractile parameters and Ca2+ transients, mitochondrial function, and molecular changes under baseline and isoproterenol stimulation conditions using a well-established High-Throughput Analysis System. These findings offer insights into mutation-specific responses and disease pathways relevant to cardiomyopathies.

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Clinical and proteomic profiles of chronic kidney disease in heart failure with reduced and preserved ejection fraction

Voordes,

Voors,

Hoegl

et al. 2024

International Journal of Cardiology

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Multiomics Analysis Provides Novel Pathways Related to Progression of Heart Failure

Cited by 16 publications

References 52 publications

404‐error “Disease not found”: Unleashing the translational potential of ‐omics approaches beyond traditional disease classification in heart failure research

404‐error “Disease not found”: Unleashing the translational potential of ‐omics approaches beyond traditional disease classification in heart failure research

Unlocking the Molecular Cues for Cardiomyocyte Proliferation

Clinical and proteomic profiles of chronic kidney disease in heart failure with reduced and preserved ejection fraction

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