Closed-chest transapical valve implantations (aortic, mitral, and tricuspid) and cardiac structural procedures requiring large-sized introducer sheaths cannot be safely performed with the available technology. We tested a self-expanding apical closure device in a closed-chest animal model, using large-sized introducer sheaths and human-sized animals to establish the technique for future tests in humans. Six human-sized pigs (mean weight: 89.7 ± 3.7 kg) received general anesthesia, intubation, and full heparinization (15,000 IU/animal; expected activated clotting time >200 s). Under fluoroscopy and multimodality imaging guidance with next-generation fusion imaging prototypes, a 15-cm long needle and a standard guidewire were percutaneously inserted under the xiphoidal aponeurosis and into the ventricular apex. After the exchange with a stiff guidewire, a 21-Fr introducer sheath for transapical procedures (outer diameter: 25-Fr) was placed in the left ventricle through the apex. The self-expanding closure device was inserted and deployed under fluoroscopic guidance while the 21-Fr sheath was gently removed. Hemodynamic conditions were monitored for 30 min and then the chest was opened to inspect the closure device and quantify the blood loss in the pericardium. Animals were killed and the hearts were removed and inspected. All six apical closure devices were successfully deployed without adverse events. No death, hemodynamic collapse, or cardiac tamponade occurred during the 30-minobservational period (mean systolic and diastolic pressures: 88 ± 11 and 58 ± 13 mmHg, respectively; mean heart rate: 60 ± 11 beats per minutes). Pre- and postdeployment (after protamine administration) mean activated clotting time was 541 ± 263 and 217 ± 62 s, respectively. The plugs provided good sealing with a mean of 27.2 ± 13.86 ml of blood lost in the pericardium. Postmortem inspection showed good plug fixation without myocardial damage. This self-expanding apical closure device successfully sealed the percutaneous access sites made with large-sized introducer sheaths in human-sized animals. This preclinical study suggests that transapical valve and structural procedures requiring large-sized introducer sheaths can be performed percutaneously.