A combined bioinformatics, experimental and clinical approach to identify novel cardiac‐specific heart failure biomarkers: is Dickkopf‐3 (DKK3) a possible candidate?

Abstract

Aims Cardiac specificity provides an advantage in correlating heart failure (HF) biomarker plasma levels with indices of cardiac function and remodelling, as shown for natriuretic peptides. Using bioinformatics, we explored the cardiac specificity of secreted proteins and investigated in more detail the relationship of Dickkopf‐3 (DKK3) gene expression and DKK3 plasma concentrations with cardiac function and remodelling in (pre)clinical studies. Methods and results The cardiac specificity of secreted proteins was determined using RNAseq data for a large panel of organs and tissues. This showed that natriuretic peptides (NPPA and NPPB) are highly cardiac‐specific (>99%), whereas other HF biomarkers, including galectin‐3 (Gal‐3, LGALS3) and growth differentiation factor‐15 (GDF‐15), lack cardiac specificity (<4%). DKK3 was cardiac‐enriched (44%), warranting further investigation. In three different HF mouse models, cardiac Dkk3 expression was altered, but DKK3 plasma concentrations were not. In humans, DKK3 plasma concentrations were higher in HF patients (n = 2090) in comparison with age‐ and sex‐matched controls without HF (n = 240) (46.4 ng/mL vs. 36.3 ng/mL; P < 0.001). Multivariate regression analysis revealed that DKK3 was strongly associated with HF risk factors and comorbidities, including age, kidney function and atrial fibrillation. After correction for existing prediction models, DKK3 did not independently predict HF outcome [all‐cause mortality/HF hospitalization, hazard ratio 1.13 (0.79–1.61) per DKK3 doubling; P = 0.503]. Conclusions Of actively secreted HF biomarkers, only natriuretic peptides showed high cardiac specificity. Despite a cardiac specificity of 44%, secreted DKK3 had limited additional diagnostic and prognostic value.

MicroRNA‑138‑5p drives the progression of heart failure via inhibiting sirtuin 1 signaling

“…Specifically, the accumulation of ROS and oxygen radicals occurs during the pathological progression of myocardial ischemia, reperfusion and cardiac remodeling, thereby damaging the tissues and causing cell necrosis and apoptosis ( 25 ). Piek et al ( 15 ) reported that NPPB may be a specific biomarker of HF and Shi et al ( 16 ) used NPPB as a biomarker of HF and proved that the sodium-glucose cotransporter 2 inhibitor empagliflozin may be effective for HF. The present study generated in vitro HF models by H 2 O 2 induction in AC-16 and HCM cells to mimic oxidative stress damage.…”

“…The present study generated in vitro HF models by H 2 O 2 induction in AC-16 and HCM cells to mimic oxidative stress damage. The increase in NPPB transcription and MFI of ROS was considered as success of the generated model ( 15 , 16 ).…”

“…Following culturing for 24 h, DMEM containing 2.5% FBS was replaced for 12-h synchronization treatment. Subsequently, cells were induced in a medium containing or not containing 200 µM hydrogen peroxide (H 2 O 2 ) for 6 h. Successful generation of the in vitro HF models was defined through detecting the relative level of natriuretic peptide precursor B (NPPB) ( 15 , 16 ).…”

The Time Has Come to Explore Plasma Biomarkers in Genetic Cardiomyopathies

“…Moreover, elevated NT-proBNP and BNP levels in patients with structural heart disease are associated with the risk of ventricular tachyarrhythmias and are predictive for sudden cardiac death and ventricular arrhythmias [ 61 , 62 ]. A recent bioinformatics study revealed that BMP-10 appears to be the only actively secreted protein that shows a similar cardiac restrictive expression to that of NPs [ 63 ]. This protein clearly deserves attention, but except for a study showing that circulating BMP10 can identify patients at risk of recurrent atrial fibrillation after ablation [ 64 ], the biomarker potential of this protein has not been explored.…”

The emerging plasma biomarker Dickkopf-3 (DKK3) and its association with renal and cardiovascular disease in the general population

“…Moreover, preoperative DKK3 urine levels in patients undergoing cardiac surgery were predictive for post-operative acute kidney injury (AKI) and increased risk for long-term loss of kidney function 15 . Finally, in a large cohort of heart failure (HF) patients, plasma DKK3 levels were associated with several cardiovascular risk factors, including kidney function, atrial fibrillation, body mass index (BMI) and blood pressure 16 .…”