Chronic kidney disease (CKD) and cardiovascular disease (CVD) often co-exist, with notable sex-dependent differences in manifestation and progression despite both sexes sharing similar risk factors. Identifying sex-specific diagnostic markers in CKD-induced CVD could elucidate why the development and progression of these diseases differ by sex. Adult, C57BL/6J male and female mice were fed a high-adenine diet for 12 weeks to induce CKD, while control mice were given a normal diet. Adenine-treated males showed more severe CKD than females. Cardiac physiology was evaluated using electrocardiogram (ECG) and echocardiogram markers. Only adenine-treated male mice showed markers of left ventricular (LV) hypertrophy. Adenine males showed markers of LV systolic and diastolic dysfunction throughout regimen duration, worsening as the disease progressed. Adenine males had prolonged QTc interval compared to adenine females and control males. We identified a new ECG marker, S_peak-J duration, which increased with disease progression and appeared earlier in adenine-treated males than in females. We identified sex-dependent differences in cardiac structure, function, and electrophysiology in a CKD-induced CVD mouse model, with adenine-treated males displaying markers of LV hypertrophy, dysfunction, and electrophysiological changes. This study demonstrates the feasibility of using this model to investigate sex-dependent cardiac differences resulting from CKD.

We identified that the type of phosphate salt used to increase dietary phosphate in the adenine-induced CKD mouse model of VC influences calcification severity, survival, renal function, and circulating phosphate levels in a sex- and time-specific manner, with males exhibiting more severe outcomes. These findings highlight the importance of selecting and reporting phosphate salts used to supplement custom-made diets to prevent animal mortality and effectively model CKD-induced VC.

BACKGROUND Chronic kidney disease (CKD) and cardiovascular disease (CVD) often co-exist and interact; however, notable sex-dependent differences are observed in how these conditions manifest and progress in parallel, despite men and women sharing similar risk factors. Identifying sex-specific diagnostic markers of cardiac structure and function throughout CKD progression could elucidate why the development and progression of these diseases differ by sex. METHODS AND RESULTS Adult, C57BL/6J male and female mice were subjected to a high-adenine (0.2%) diet throughout 12-weeks to induce CKD. Control mice were fed a normal chow diet. Every three weeks, electrocardiogram (ECG) and echocardiogram-based markers of cardiac physiology were evaluated. Adenine-induced CKD showed markers of left ventricular (LV) hypertrophy in male mice only. CKD males had markers indicative of LV systolic and diastolic dysfunction throughout regimen duration, worsening as disease progressed. Adenine males had a prolonged QTc and STc intervals when compared to Adenine females and Control males. Sex-dependent differences in the duration of the Speak-J marker, measured via ECG, was identified, with Adenine males showing increases in duration earlier than Adenine females compared to their Control counterparts. CONCLUSIONS In this study, we identified sex-dependent differences in cardiac structure, function, and electrophysiology in a mouse model of CKD-induced CVD throughout disease progression. We found that male mice are more prone to developing LV hypertrophy, systolic dysfunction, and diastolic dysfunction, with significant increases in ECG markers indicative of ventricular dysfunction observed in adenine-treated males at late stages of the disease. Additionally, we identified a new ECG parameter, Speak-J duration, that highlights sex-specific cardiac electrophysiological changes, demonstrating the model’s utility in studying sex-dependent cardiac differences.

Vascular calcification (VC) is a major contributor to cardiovascular diseases (CVD) and progresses rapidly in patients with chronic kidney disease (CKD). Recently, we developed a low-cost, near-infrared spectroscopy (NIRS)-based imaging device (near-infrared optical scanner–NIROS) and used it to detect VC in the aortae via peripheral vascular imaging of the tail in mouse models. Our initial studies indicated distinct hemodynamic changes in the murine tail with and without the presence of VC. This study aims to assess the overall changes in peripheral hemodynamic flow patterns in mice with and without VC using NIROS. The tails of CKD mice with and without VC were imaged using NIROS to obtain the diffuse reflected signals, which were in turn used to calculate the spatiotemporal hemodynamic maps. Pearson’s correlation analysis was performed to obtain the flow correlation maps based on hemodynamic parameters and the NIR diffuse reflectance signals. Results demonstrated a significant decrease ( p -value < 0.05) in hemodynamic flow correlation in the VC group as compared to those without VC. In addition, the flow correlations obtained from both NIRS wavelengths, 682 nm and 826 nm, showed a distinct decrease in correlation ( p -value < 0.05), suggesting a disruption in the flow pattern once the mice developed VC. These results demonstrate the potential of peripheral flow correlation patterns using hemodynamic or NIRS diffuse reflectance signals as an indicator for aortic calcification detection. Future work will focus on correlating these peripheral hemodynamic changes, both peripheral and aortic VC, in a larger cohort of mice.