ABSTRACT Coronary chronic total occlusions (CTOs) are atherosclerotic plaques comprised of hard fibro-calcific material that restrict luminal cross-section by 100% resulting in complete stoppage of blood flow in the affected artery for at least three months. CTO symptoms include shortness of breath with chronic fatigue and chest pain. The three primary CTO treatment regimens are medical therapy (MT), coronary artery bypass graft (CABG) and percutaneous coronary interventions (PCI). MT can reduce symptoms such as chest pain but fail to address the underlying disease mechanisms. CABG does provide marked improvements in both patient morbidity and mortality, however, this open-heart surgical intervention is highly invasive, traumatic, expensive and has a limited lifetime. Because most CABG grafts utilize re-purposed veins, 50% become occluded within ten years after bypass surgery. PCI procedures are provided over a 24-hour hospital stay, have one-two days of recovery time and cost approximately one-fourth of CABG yet are currently administered to only 10% of CTO patients. In the most common PCI procedure, subintimal crossing, a mechanical wire is advanced past the CTO inside the vessel wall. Few interventionalists practice subintimal crossing because the procedure is difficult, risky and associated with higher MACE, restenosis, acute MI and death. Although many intravascular devices have been introduced to perform PCI true-lumen CTO crossing, all have failed in the coronary arteries. Failure of these previous devices is due to at least one of three causes: 1) large-diameter catheters that are too rigid with poor steerability; 2) non-specific injury to the vessel wall resulting from CTO cutting; and 3) absence of a navigational guidance system based on real-time imaging of the catheter tip relative to the arterial wall. An optoacoustic (OA) and ultrasound (US) image-guided cold laser wire (CLW) is proposed that provides controlled cutting that will allow any interventional cardiologist to provide patients safe and efficacious PCI true-lumen CTO crossing. Development of the transvenous OA/US image-guided CLW will be accomplished by completing three specific aims: Aim 1: Develop an Optoacoustic (OA)/Ultrasound (US) Transvenous Image-Guided Cold Laser Wire; Aim 2: Test CLW True-Lumen PCI CTO Crossing in ex vivo Human CABG Hearts; Aim 3: Test CLW True-Lumen PCI Crossing of Calcified CTOs in in vivo Animal Models. Successful completion of the proposed research and development program will introduce a true-lumen PCI CTO crossing procedure that when followed by stenting can establish a superior and new treatment paradigm for interventional cardiology and can impact other surgical disciplines.