Twenty - years History of the Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine

Cardiovascular disease is the leading cause of death and has been the major health care issue worldwide 1)-3) . Tremendous effort has been continuously made against cardiovascular disease from the bench, bed side and population science. In the clinical cardiology field, new development of technology continuously improved the patient outcome resulting marked improvement of prognosis during recent several decades 4) . In this period, the Department of Cardiovascular Medicine (Department of Cardiology), Juntendo University has been actively working in the clinical practice, research and education especially in the field of coronary artery disease and atherosclerosis. In this article, I will review the twenty-years progress of this department especially in the field of catheter intervention, clinical trials and porcine model research as well as cardiac rehabilitation.

Cardiovascular disease is the leading cause of death and has been the major health care issue worldwide 1)- 3) . Tremendous effort has been continuously made against cardiovascular disease from the bench, bed side and population science. In the clinical cardiology field, from the development of open-heart surgery to genome wide analysis for the onset of myocardial infarction, new development of technology continuously improved the patient outcome resulting marked improvement of prognosis ( Figure-1) 4) . For example, the mortality of ST elevation myocardial infarction reduced by one fifth over 50 years. During this era, one of the most rapidly advanced area in cardiology field is the area of coronary artery disease in which invention of coronary angiogram, coronary bypass surgery, percutaneous catheter intervention and new drug such as statin were developed. Advance of cardiac rehabilitation is also important from the stand point of preventive cardiology. The Department of Cardiovascular Medicine (Department of Cardiology), Juntendo University has been a leading institution of the coronary artery disease practice in Japan. In this article, I will review the twenty-years progress of cardiology especially in the field of atherosclerosis and coronary artery disease in the Juntendo University Graduate School of Medicine.

Trend of PCI in Juntendo University Hospital (JUH)(Figure-2)
With regard to percutaneous coronary intervention (PCI), the first percutaneous transluminal coronary angioplasty was performed in Juntendo University in February 1, 1984. Since then, number of catheter intervention gradually increased with advance of technology and expansion of indication. In early 1990, several new catheter technologies so called new devices had introduced including rotational ablation catheter, directional coronary atherectomy catheter and bare metal stent. In 1994, the first case of coronary stent was performed in July 18. Between the era of PTCA (Percutaneous Balloon Angioplasty) and Stent, the issue of restenosis after balloon injury was one of the major research interest of cardiology community. In the Juntendo University, two multicenter trials were conducted targeting the prevention of restenosis after PTCA. The LDL Angioplasty Restenosis Trial (LART) was designed to test the hypothesis that ) levels are associated with an increase incidence of restenosis after angioplasty. Using low-density lipoprotein (LDL) apheresis with a dextran sulfate cellulose column as an Lp (a) absorbent, this study indicated that reducing Lp (a) levels could prevent restenosis after angioplasty in high Lp (a) patients, particularly when combined with lipid-lowering drugs 5) . The Probucol Angioplasty Restenosis Trial (PART) was a prospective, randomized, controlled study that investigated the effectiveness of probucol in reducing the rate of restenosis after PTCA 6) 7) . Probucol administered beginning 4 weeks before PTCA appears to reduce restenosis rates. After the introduction of stent, restenosis was halved and ten years later, drug eluting stent was developed with the advance of drug eluting system which almost eliminate the concern of restenosis. Meanwhile in the catheter laboratory, the technical advance stimulated the indication and increased the number of peripheral artery intervention in 2000-2010. In 2016, first TAVI (Transcatheter Aortic Valve Implantation) was performed in JUH which rapidly increased and structural heart intervention became one major area of practice in the Department of Cardiovascular Medicine. In 2018, the first Mitra Clip was performed which is still a challenge of structural heart disease field ( Figure-2). Regarding to the clinical research activity, the Juntendo Catheterization Registry which was initiated to investigate the long-term outcome after PCI, established in the Catheterization Laboratory, publishing more than 100 papers between 2000 and 2019.

Angiographic and IVUS trials for prevention of atherosclerosis progression
Between 1990-2000, there were numerous angiographic trials conducted around the world using diet modification, exercise and a combination of lipid lowering drugs and later using statins to investigate whether risk modification could reduce the progression of atherosclerosis. In the Department of Cardiovascular Medicine, Juntendo University, several trials were conducted using pravastatin and LDL apheresis in this decade (Table-1). Overall results of these angiographic trials indicated that aggressive modification of lipids could inhibit atherosclerotic plaque progression and induce regression to some extent. Intravascular Ultrasound (IVUS) was developed as an intra-coronary imaging device which enabled to measure the plaque volume with high reproducibility. In the field of atherosclerosis progression research, substantial numbers of trials using IVUS were conducted since then.
The ESTABLISH trial 11) , JAPAN-ACS 12) and COSMOS study 13) are the three early major coronary plaque regression studies conducted in Japan (Table-2). These three studies are designed to clarify the mechanism of the statin efficacy in secondary coronary artery disease (CAD) prevention and to investigate whether early aggressive lipid-lowering therapy could induce a significant reduction in plaque volume (Table-2, 3).
The ESTABLISH study investigated the efficacy of early aggressive statin therapy in acute coronary syndrome. Early LDL-C lowering by 20 mg of atorvastatin for 6 months significantly reduced the plaque volume in patients with ACS.
The JAPAN-ACS study was designed to evaluate  Although the regression of atherosclerotic plaque is a surrogate marker of clinical outcome, these IVUS trials suggested the clinical efficacy of aggressive LDL-C lowering in Japanese patients with coronary artery disease. Whether plaque volume changes could predict the future events has been a matter of discussion. Dohi et al found significant lower incidence of cardiovascular event in the patients with plaque regression than patients with progression in Extended ESTABLISH trial in Juntendo Medical Journal 66 (1), 2020  In the atherosclerosis research, animal experimental model is essential to further understand the mechanism of development of atherosclerosis and to investigate the effectiveness of treatment and/or development of new treatment option. Among the several animal models in the atherosclerosis research, porcine model is the closest animal to human atherosclerosis. The department of Cardiovascular medicine Juntendo University, started the porcine model research in 2000. In this laboratory, protective effect of pharmacological intervention to vascular injury was intensively investigated. Agents investigated were probucol 20) , Pitavastatin 21) , Fenofibrate 22) , Pioglitazone 23) , etc. We also have tried to develop a statin eluting stent 27) and new porcine atherosclerosis model with LDL-R knockout swine recently 28) .

Development of Cardiac Rehabilitation program (Figure-3)
Cardiac rehabilitation program was started in 1993 in JUH which is gradually developed and became one of the leading institutions in Japan now. Currently more than 12,000 sessions were provided annually in the Cardiovascular Fitness and Cardiac Rehabilitation Center in the JUH. We conducted the one of the earliest randomized trial, J-CARP (Juntendo Cardiac Rehabilitation Program) study in 1997 which investigated the efficacy of phase III cardiac rehabilitation in elderly patients with chronic coronary artery disease 29) . Since then, we have studied and reported the efficacy of cardiac rehabilitation in the coronary risk factor profile, exercise capacity, muscle power, QOL and longterm prognosis in elderly patients, and post CABG patients with diabetes mellitus or metabolic syndrome 30)-32) . More recently, we conducted IVUS trial to investigate the efficacy of cardiac rehabilitation on coronary artery plaque volume and characteristics and found significant correlation between plaque volume or fat content and daily physical activity 18) 19) . A new project is now on going regarding to remote cardiac rehabilitation in which  34) . In 2017, Star-ACS was initiated which is a registration for ACS with atrial fibrillation is still on going. In terms of clinical trial, RESPACT EPA, multi-center interventional trial with EPA is ongoing with 120 institutions on Japan supported by Juntendo Clinical Research and Trial Center which will be completed in 2022.

Summary
The 20 years history of the department of Cardiovascular Medicine, Juntendo University was reviewed from the standpoint of research and clinical practice regarding to atherosclerosis and coronary artery disease. During this two decades, significant advance in science and technology were observed in cardiovascular medicine from acute intervention to chronic patients care as well as disease prevention. Cardiovascular Medicine Team in Juntendo is continuously working to provide better practice and research in the past, present and future.