Cigarette smoking elevates the risk for cardiovascular disease. This study investigates the effects of MS [450, 900, and 1350 µg total particulate matter (TPM)/day; 5 days/week; 90 days] on cardiac functional and phenotypic changes, as well as on cardiovascular gene expression. Langendorff analysis of heart function revealed a statistically significant decrease in baseline perfusion pressure for the SHR groups exposed to 900 and 1350 µg TPM/day in comparison to sham (p≤0.05). Exposure of SHR to 900 µg TPM/day resulted in a statistically significant reduction in post-ischemic recovery after 30 minutes of global ischemia compared to sham (p≤0.05). Ratios of both heart weight and left ventricular weight to (1) body weight, (2) brain weight, and (3) tibia weight were statistically significantly increased for the 900 and 1350 µg TPM/day groups compared to sham (p≤0.05). Affymetrix gene chip analysis indicated that MS induced changes in a panel of ventricular genes. This was confirmed by PCR analysis (e.g., increased tissue inhibitor of metallopeptidase 1 in the 1350 µg TPM/day compared to sham animals; p≤0.05). Multi-analyte profiling of 67 serum proteins revealed statistically significant changes in several markers after exposure to 900 µg TPM/day including increases in interleukin 10, macrophage chemoattractant proteins 1 and 3, stem cell factor, and tissue inhibitor of metalloproteinase (p≤0.05 versus sham). A statistically significant increase in the platelet activation marker 2,3 dinor thromboxane B1 was detected in urine of SHR exposed to 1350 µg TPM/day compared to sham (p≤0.05). The data suggest that this model system may be useful in dissecting the mechanisms involved in smoke-induced cardiovascular disease and potentially for screening reduced-risk tobacco products.