Inorganic arsenic (iAs) exposure has been reported to have an impact on cardiovascular diseases (CVD). However, there is not much known about the cardiac tissue injury of CVD patients in relation to iAs exposure and potential role of single nucleotide polymorphisms (SNPs) of genes related to iAs metabolism, oxidative stress, endothelial dysfunction and inflammation which may play important roles in such CVD cases. In this dual center cross-sectional study, based on the exclusion and inclusion criteria, we have recruited 50 patients out of 270, who came from known arsenic-affected and- unaffected areas of mainly Chittagong, Dhaka and Rajshahi divisions of Bangladesh and underwent open-heart surgery at the selected centers during July 2017 to June 2018. We found that the patients from arsenic affected areas contained significantly higher average iAs concentrations in their urine (6.72 ± 0.54 ppb, P = 0.028), nail (529.29 ± 38.76 ppb, P < 0.05) and cardiac tissue (4.83 ± 0.50 ppb, P < 0.05) samples. Patients' age, sex, BMI, hypertension and diabetes status adjusted analysis showed that patients from arsenic-affected areas had significantly higher iAs concentration in cardiac tissue (2.854, 95%CI 1.017-8.012, P = 0.046) reflecting higher cardiac tissue injury among them (1.831, 95%CI 1.032-3.249, P = 0.039), which in turn allowed the analysis to assume that the iAs exposure have played a vital role in patients' disease condition. Adjusted analysis showed significant association between urinary iAs concentration with AA (P = 0.012) and AG (P = 0.034) genotypes and cardiac iAs concentration with AA (P = 0.017) genotype of AS3MT rs10748835. The AG genotype of AS3MT rs10748835 (13.333 95%CI 1.280-138.845, P = 0.013), AA genotype of NOS3 rs3918181 (25.333 95%CI 2.065-310.757, P = 0.002), GG genotype of ICAM1 rs281432 (12.000 95%CI 1.325-108.674, P = 0.010) and AA genotype of SOD2 rs2758331 (13.333 95%CI 1.280-138.845, P = 0.013) were found significantly associated with CVD patients from arsenic-affected areas. Again, adjusted analysis showed significant association of AA genotype of AS3MT rs10748835 with CVD patients from arsenic affected areas. In comparison to the reference genotypes of the selected SNPs, AA of AS3MT 10748835, AG of NOS3 rs3918181 and AC of rs3918188, GG of ICAM1 rs281432, TT of VCAM1 rs3176867, AA of SOD2 rs2758331 and GT of APOE rs405509 significantly increased odds of cardiac tissue injury of CVD patients from arsenic affected areas. The results showed that the selected SNPs played a susceptibility role towards cardiac tissue iAs concentration and injury among CVD patients from iAs affected areas.