S2 Heart Sound Detects Aortic Valve Calcification Independent of Hemodynamic Changes in Mice

Dargam, Valentina; Ng, Hooi Hooi; Nasim, Sana; Chaparro, Daniel; Irion, Camila Iansen; Seshadri, Suhas R; Barreto, Armando; Danziger, Zachary C.; Hutcheson, Joshua D.

doi:10.3389/fcvm.2022.809301

Cited by 7 publications

(5 citation statements)

References 64 publications

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“…Additionally, we presented that adenine+high Pi diet induced hydroxyapatite accumulation in the heart valves ( Figure 1F-G ), showing that this model is suitable to study Pi-induced VC. In agreement with our results using the same mice model Dargam et al recently detected VC by S2 heart sound 34 . The synthetic bisphosphonate fluorescence dye OsteoSense™ that binds specifically to hydroxyapatite, is getting more recognition in the detection of vascular calcification 27,35 .…”

Section: Discussionsupporting

confidence: 94%

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Hypoxia-inducible factor (HIF) activation promotes osteogenic transition of valve interstitial cells and accelerates heart valve calcification in chronic kidney disease (CKD)

Csiki

Ababneh

Tóth

et al. 2023

Preprint

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Objective: Valve calcification (VC) is a widespread complication in chronic kidney disease (CKD) patients on hemodialysis. VC is an active process with the involvement of in situ osteogenic transition of valve interstitial cells (VICs). VC is accompanied by the activation of hypoxia inducible factor (HIF) pathway, but the role of HIF activation in the calcification process remains undiscovered. Approach and Results: Using in vitro and in vivo approaches we addressed the role of HIF activation in osteogenic transition of VICs and CKD-associated VC. Elevation of osteogenic (Runx2, Sox9) and HIF activation markers (HIF-1α and HIF-2α) and VC occurred in adenine-induced CKD mice. High phosphate (Pi) induced upregulation of osteogenic (Runx2, alkaline-phosphatase, Sox9, osteocalcin) and hypoxia markers (HIF-1α, HIF-2α, Glut-1), and calcification in VICs. Down-regulation of HIF-1α and HIF-2α inhibited, whereas further activation of HIF pathway by hypoxic exposure (1% O2) or hypoxia mimetics (desferrioxamine, CoCl2, Daprodustat (DPD)) promoted Pi-induced calcification of VICs. Pi augmented the formation of reactive oxygen species (ROS) and decreased viability of VICs, whose effects were further exacerbated by hypoxia. N-acetyl cysteine inhibited Pi-induced ROS production, cell death and calcification under both normoxic and hypoxic conditions. DPD treatment corrected anemia but promoted VC in the CKD mice model. Conclusion: HIF activation plays a fundamental role in Pi-induced osteogenic transition of VICs and CKD-induced VC. The cellular mechanism involves stabilization of HIF-1α and HIF-2α, increased ROS production and cell death. Targeting the HIF pathways may thus be investigated as a therapeutic approach to attenuate VC. Translational perspective: One in four hemodialysis-dependent CKD patients on DPD treatment experience a major cardiovascular event during a 2.5-year follow-up period. This work provides a possible explanation for this phenomenon and should initiate further studies to address whether DPD-mediated acceleration of valve calcification triggers the unbeneficial effect of DPD.

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Section: Discussionsupporting

confidence: 94%

“…using the same mice model Dargam et al recently detected VC by S2 heart sound 34 . The synthetic bisphosphonate fluorescence dye OsteoSense™ that binds specifically to hydroxyapatite, is getting more recognition in the detection of vascular calcification 27,35 .…”

Section: Discussionmentioning

confidence: 94%

Hypoxia-inducible factor (HIF) activation promotes osteogenic transition of valve interstitial cells and accelerates heart valve calcification in chronic kidney disease (CKD)

Csiki

Ababneh

Tóth

et al. 2023

Preprint

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“…In a noteworthy animal experiment, Dargam et al . [ 54 ] developed an ensemble-learning-based algorithm that uses S2 sounds extracted from PCGs to predict aortic valve calcification. This has major clinical significance due to the poor prognosis of patients with calcified AS [ 55 ].…”

Section: Artificial Intelligence In the Clinical Pathway Workflow For...mentioning

confidence: 99%

“…Morphological assessments, often used for pre-TAVR evaluation, leverage neural networks to analyze the volume and Agatston score of aortic root calcifications based on segmentations [ 77 ]. These assessments are viable even in low-dose CT for lung screening [ 68 ] and auscultation [ 54 ]. supervised AI models can also predict the aortic valve area that supports prosthesis sizing, thereby minimizing inter-observer variability [ 16 ].…”

Section: Artificial Intelligence In the Clinical Pathway Workflow For...mentioning

confidence: 99%

Artificial Intelligence in the Screening, Diagnosis, and Management of Aortic Stenosis

Zhang,

Wang,

Zhang

et al. 2024

Rev. Cardiovasc. Med.

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The integration of artificial intelligence (AI) into clinical management of aortic stenosis (AS) has redefined our approach to the assessment and management of this heterogenous valvular heart disease (VHD). While the large-scale early detection of valvular conditions is limited by socioeconomic constraints, AI offers a cost-effective alternative solution for screening by utilizing conventional tools, including electrocardiograms and community-level auscultations, thereby facilitating early detection, prevention, and treatment of AS. Furthermore, AI sheds light on the varied nature of AS, once considered a uniform condition, allowing for more nuanced, data-driven risk assessments and treatment plans. This presents an opportunity to re-evaluate the complexity of AS and to refine treatment using data-driven risk stratification beyond traditional guidelines. AI can be used to support treatment decisions including device selection, procedural techniques, and follow-up surveillance of transcatheter aortic valve replacement (TAVR) in a reproducible manner. While recognizing notable AI achievements, it is important to remember that AI applications in AS still require collaboration with human expertise due to potential limitations such as its susceptibility to bias, and the critical nature of healthcare. This synergy underpins our optimistic view of AI’s promising role in the AS clinical pathway.

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“…The 5/6 nephrectomy model, however, has several limitations, including variable surgical success rate, inter-laboratory variations, and irreversibility of the procedure (16). On the other hand, several recent vascular calcification studies not concerned with atherosclerosis have been conducted using a non-surgical adenine-induced model of CKD (17)(18)(19)(20). Excessive oral intake of adenine leads to the accumulation of 2,8-dihydroxyadenine crystals in the renal tubules that cause progressive tubulointerstitial nephropathy (21).…”

Section: Introductionmentioning

confidence: 99%

Paradoxical reduction of plasma lipids and atherosclerosis in mice with adenine-induced chronic kidney disease and hypercholesterolemia

Padalkar

Tsivitis²,

Gelfman³

et al. 2023

Front. Cardiovasc. Med.

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BackgroundAtherosclerotic cardiovascular disease is prevalent among patients with chronic kidney disease (CKD). In this study, we initially aimed to test whether vascular calcification associated with CKD can worsen atherosclerosis. However, a paradoxical finding emerged from attempting to test this hypothesis in a mouse model of adenine-induced CKD.MethodsWe combined adenine-induced CKD and diet-induced atherosclerosis in mice with a mutation in the low-density lipoprotein receptor gene. In the first study, mice were co-treated with 0.2% adenine in a western diet for 8 weeks to induce CKD and atherosclerosis simultaneously. In the second study, mice were pre-treated with adenine in a regular diet for 8 weeks, followed by a western diet for another 8 weeks.ResultsCo-treatment with adenine and a western diet resulted in a reduction of plasma triglycerides and cholesterol, liver lipid contents, and atherosclerosis in co-treated mice when compared with the western-only group, despite a fully penetrant CKD phenotype developed in response to adenine. In the two-step model, renal tubulointerstitial damage and polyuria persisted after the discontinuation of adenine in the adenine-pre-treated mice. The mice, however, had similar plasma triglycerides, cholesterol, liver lipid contents, and aortic root atherosclerosis after being fed a western diet, irrespective of adenine pre-treatment. Unexpectedly, adenine pre-treated mice consumed twice the calories from the diet as those not pre-treated without showing an increase in body weight.ConclusionThe adenine-induced CKD model does not recapitulate accelerated atherosclerosis, limiting its use in pre-clinical studies. The results indicate that excessive adenine intake impacts lipid metabolism.

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S2 Heart Sound Detects Aortic Valve Calcification Independent of Hemodynamic Changes in Mice

Cited by 7 publications

References 64 publications

Hypoxia-inducible factor (HIF) activation promotes osteogenic transition of valve interstitial cells and accelerates heart valve calcification in chronic kidney disease (CKD)

Hypoxia-inducible factor (HIF) activation promotes osteogenic transition of valve interstitial cells and accelerates heart valve calcification in chronic kidney disease (CKD)

Artificial Intelligence in the Screening, Diagnosis, and Management of Aortic Stenosis

Paradoxical reduction of plasma lipids and atherosclerosis in mice with adenine-induced chronic kidney disease and hypercholesterolemia

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