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Introduction: Drug induced cardiotoxicity is a major cause of market withdrawal. The limited availability of human heart tissue has led to inaccurate interpretations of cardiac related drug effects. Our group had developed a culture system for pig/human heart slices that is functionally and structurally viable 6 days under electric stimulation and enriched media and could reliably demonstrate the subacute toxic effect of anti-cancer therapeutics. However, by day 10, the slices underwent cardiomyocyte dedifferentiation and fibrotic remodeling, making them inadequate for long-term cardiotoxicity testing. Aims: Including physiological mechanical and humoral cues within the culture system can prolong the viability of the human heart tissue in culture. Methods and Results: Following small molecule screening, we found that incorporation of 100 nM Tri-iodo-thyronine (T3) and 1 μM Dexamethasone (Dex) into our culture media preserved microscopic structure for 12 days in pig and human slices. However, RNA sequencing revealed a significant down regulation in cardiac contractile genes as early as day 8 in culture. To address this, we developed a novel bioengineered Cardiac Tissue Culture Model (CTCM) that can electro-mechanically stimulate heart slices with physiological preload and afterload during each cardiac cycle (Figure 1). Transcriptionally, combining CTCM with T3/Dex treatment, CTCM system was able to maintain the cardiac contractile gene expression at the same levels as the fresh hear tissue. Functionally, heart slices cultured in our CTCM with T3/Dex treatment, completely preserved structural viability and metabolic activity for 12 days. Conclusion: This study demonstrates a new physiological culture system for human heart slices that provides physiological mechanical and humoral cues for maintaining viability and functionality of the heart slices. CTCM may be an ideal platform for chronic cardiotoxicity testing.