Abstract Body: Background: We previously reported that the adenine-induced chronic kidney disease (CKD) mouse model develops left-sided cardiac dysfunction, including male-predominant left ventricular hypertrophy and systolic/diastolic dysfunction. We also separately showed that second heart sound (S2) characteristics are altered in adenine-fed mice, but the physiological driver of these S2 changes remained unknown. Because S2 reflects semilunar valve closure and can be influenced by downstream hemodynamics, we hypothesized that adenine-induced CKD leads to progressive right-sided cardiac dysfunction and that the observed alterations in S2 features reflect elevated right ventricular (RV) pressure.

Methods: Male and female mice were fed either normal chow (LabDiet 5V75) or the same diet supplemented with adenine and were studied longitudinally at 3, 6, 9, and 12 weeks (Figure 1A). Pulmonary acceleration time (PAT), PAT/pulmonary ejection time (PAT/PET), RV systolic pressure (RVSP), RV end-diastolic pressure (RVEDP), and change in RV pressure (ΔRVP) were measured to assess right-sided cardiac dysfunction. Circulating NT-proBNP levels were also quantified. S2 duration was quantified directly, and principal component analysis with k-nearest neighbors (PCA/KNN) was used to classify elevated ΔRVP.

Results: Adenine-fed mice developed progressive right-sided dysfunction. PAT and PAT/PET were reduced, with significant decreases emerging by weeks 9-12 (Figures 1B-C), while RVSP was elevated as early as week 3 and remained increased through weeks 6-12 (Figures 1D-E). ΔRVP was markedly increased at weeks 6, 9, and 12 (Figure 1F). No sex-dependent differences were observed in markers of right-sided dysfunction. NT-proBNP was elevated by week 6 in males and week 9 in females (Figure 1G). S2 duration shortened in adenine-fed mice, with significant reductions at weeks 6, 9, and 12 (Figure 2A). Supervised S2-duration thresholds identified elevated ΔRVP with strong separation (Figure 2B,C). PCA/KNN classification of individual S2s showed good discrimination of elevated RV pressure, achieving 80.38% accuracy, 83.63% specificity, and 69.58% sensitivity (Figure 3).

Conclusions: The adenine CKD model develops progressive right-sided cardiac dysfunction in addition to previously reported left-sided abnormalities. Changes in S2, measured directly and by machine learning, track with elevated RV pressure, supporting S2 as a low-cost noninvasive marker of RV dysfunction in CKD.