Previously, in human, we have shown the role of a dis-integrin and metalloproteinase (ADAM) in connexin-43 (Cx43) degradation in human heart end stage heart failure (i.e., heart failure with reduced ejection fraction, HFrEF). We also observed Cx43 degradation and blood heart barrier (BHB) leakage during HFrEF in mice. Although Cx43 coordinates mitochondrial fusion-fission with myocyte contraction-relaxation, respectively, the mechanism is unclear. Interestingly, a mitochondrial ATP citrate lyase inhibition (ACYLi, a lipid lowering agent) mitigated HFpEF, its role in HFrEF is unknown. We hypothesize that during HFrEF activation of ADAMTS1 degrades Cx43, causing dyssynchronous endothelial-myocyte-mitochondrial contraction coupling, and myocytes slippage during contraction and HFrEF. Because HFrEF is more prevalent in males than females, we created chronic cardio-pulmonary volume overload by aorta-vena-cava fistula (AVF) below the kidney in male WT (C57BL/6J) mice of 12-wks old. By serial ECHO, we observed HFrEF after 16-wks. The ADAMTS1 inhibitor (epigallocatechin gallate (EG)) or ACYLi (hydroxycitric acid lactone) were administered in drinking water at same time of AVF. Also, to determine the interoceptive inhibition by Piezo channels, we ganglionic de-nervated the heart prior to AVF. By in gel specific substrate zymography, we measured, NGAL, MMP-2, -9, ADAMTS1, ADAMTS14, and TMPRSS2. The results suggest activation of ADAMTS1 during HFrEF. The connexin-43 degradation and mitochondrial mitophagy by increase in Drp1 were increased.