Title: A prototype tool to calculate 'virtual' myocardial fractional flow reserve (vFFR) non-invasively (VIRTU-3)
Funder: Department of Health and Social Care

Abstract: We have developed a method (VIRTUheart&trade;) of reconstructing 3D coronary arteries from 2D coronary angiograms (CAGs) in a computer and then using engineering software to calculate blood flow. These methods were developed in our pilot study (VIRTU-1) (13) and made more accurate, accelerated and personalised in VIRTU-2. We propose translating this tool into a reliable, robust, user-friendly and intuitive Mk 3 prototype for clinicians and industry suitable for use in a clinical trial. Work Package 1: In silico implementation ['Content'] (Lead: Professor Hose) The workflow incorporates several computational steps (Fig 1). The methods have been developed and validated, and they now require refinement and full implementation. The code will be practical and applicable to any standard CAG as a bolt-on software step in the cardiac cath lab. Incorporated into the workflow will be personalisation of the distal boundary conditions. This will optimise accuracy using simple clinical parameters, analysed with a non-linear, auto-regressive, mathematical model with moving averages (NARMAX)(17). Work Package 2: Software development ['Presentation'] (Lead: Professor Hose) A software developer will ensure the code is de-bugged, robust, reliable and intuitive for a non-expert to use. Regular developer-clinician workshops will provide formal feedback and ensure that the Mk3 prototype is fit for purpose. It will have an installer, installation guide, help function and automatic update facility. Two versions will be produced: clinical, containing only the functions essential to compute vFFR rapidly; and research, containing extra features allowing parameter setting, manipulation and data exchange for fine tuning. Work Package 3: Clinical revalidation [ Revalidation ] (Lead: Professor Gunn) Our tool is already validated, but we must maintain standards as software development occurs. So, at three stages throughout the development of the vFFR tool, it will be validated against clinically measured FFR (mFFR) values obtained from Sheffield patients who have had FFR measured for clinical reasons. Before completion, we will present 12 cases with mFFR and vFFR to an expert clinical panel to ensure that it performs to clinical expectations. Work Package 4: Commercialisation and Regulatory progress ['Application'] (Lead: Professor Lawford) Our medical device consultants (D4D, Sheffield) outline a potential path to commercialisation and regulatory approval: &ldquo;The route to achieving a CE Mark would be eased and the rate accelerated if it included a manufacturer accredited to ISO 13485 (quality management system specific to medical devices) and applying all relevant parts of the medical device risk management standard (ISO 14971) plus software lifecycle requirements of IEC 62304&rdquo;. Data will be generated by the system designers in WP1 and software developers in WP2 to fulfil the requirements of a Class III medical device. Dr Smith (Business Manager) will liaise with developers and regulatory consultants to ensure progress is towards an MHRA Class III device. Preliminary testing and quality assurance will be performed via our expert panel internally and via clinical colleagues externally. The advanced prototype will be demonstrated to manufacturers with a view to securing licence(s) and embedding the workflow (or key aspects thereof) into their medical grade systems and/or generate a bolt-on upgrade. Milestones M1 (Month 3) Appoint personnel, collate current toolchain, conduct first workshop. M2 (Month 6) Streamline coding, engage MHRA consultant, seek industrial partner, develop commercialisation plan, consult patent lawyer. M3 (Month 12) Finalise coding, start software development, develop commercialisation plans, develop patent plans, conduct second workshop. M4 (Month 18) Finalise software, start clinical validation, finalise industrial partnership. M5 (Month 24) Complete clinical validation, conduct final workshop, obtain QA, complete commercialisation plan, plan clinical trial, plan MHRA submission.

Lay abstract: Coronary artery disease is the disease with the greatest impact of all upon human health. Its diagnosis rests upon a characteristic history and the results of tests, including a coronary angiogram in many cases. Its treatment involves medication, coronary angioplasty (stenting) or open heart surgery. The angiogram is key to decision making. Dye is injected down the arteries and X-ray pictures are taken. The heart specialist examines the images and estimates whether the blood flow through narrowed segments is sufficiently reduced to account for the patient s symptoms and to guide treatment. A more scientific way to do this is to measure the pressure gradient across each narrowing with a probe. This measurement (fractional flow reserve, FFR) is superior to the traditional eyeball method, with savings in lives, procedures and costs. But passing a wire can only be performed if an angioplasty can be done. Therefore only about 5% of angioplasties and less than 1% of diagnostic angiograms incorporate FFR. We have developed a method of reconstructing coronary arteries in 3D in a computer, and then using engineering software to calculate the blood flow and FFR for each narrowing seen. We have made it accurate by making some simple assumptions and incorporating a few individual patient variables. We have developed a workflow (series of computer tools) to do this. It works well, but requires some time to train staff. If we are to use the technique in a clinical trial, we have to make it slicker, simple to use, fool-proof, robust enough to satisfy the regulatory authorities and configured to be attractive to commercialise. We plan to use this grant to do that, by working with the imaging industry and software developers to generate an advanced, demonstrable, 'virtual' FFR prototype.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR