Cardiovascular diseases have become a leading global health burden, with rising mortality worldwide. WNT and JAK/STAT have been highlighted as emerging biomarkers in cardiovascular disease pathogenesis. This study assessed the Wnt/JAK-STAT signaling pathway in relation to SFRP5 and genetic polymorphisms in cardiac patients. This prospective case–control study included 100 patients with various cardiac diseases (IHD, valvular heart disease, HF, cardiomyopathy, and arrhythmia) and 50 matched healthy controls. Clinical and echocardiographic assessments were performed. Plasma SFRP5, Wnt5a, and JAK levels were measured using ELISA; STAT5A expression by flow cytometry; and SFRP5 (rs780369540) gene polymorphism by TaqMan real-time PCR were also performed in all participants. Cardiac patients showed significantly higher median BMI (33 vs. 28.5 kg/m², p = 0.001) and markedly increased median value of each Wnt5a (16.85 vs. 5.6 pg/mL, p < 0.001), median JAK (9.45 vs. 2.4 pg/mL, p < 0.001), and STAT5A expression (87.55% vs. 33%, p < 0.001), with lower SFRP5 levels (4 vs. 6.7 ng/L, p < 0.001) compared to control. The SFRP5 (rs780369540) T allele was more frequent in patients (51.5% vs. 32%, p = 0.001), and dominant TT + TC genotypes were higher (66% vs. 42%, p = 0.005) compared to the control group. TT carriers showed higher median Wnt5a, lower median SFRP5, and reduced ejection fraction compared to other genotypes (TC, CC) carriers. Multivariate analysis identified elevated Wnt5a, JAK, and decreased SFRP5 as independent predictors of cardiovascular disease (p < 0.05). Cardiac patients …