Destination Therapy by Implantable LVAD: Agenda for Introduction of DT in Japan

S158 Journal of Cardiac Failure Vol. 22 No. 9S September 2016 SY9-1 Destination Therapy by Implantable LVAD: Agenda for Introduction of DT in Japan Shunei Kyo, Takashi Nishimura; Tokyo Metropolitan Geriatric Hospital & Institute Gerontology, Tokyo, Japan Heart transplant (HTx) has been gold standard for end-stage heart failure (HF), however, organ donations is extremely low in Japan. 508 patients are registered as HTx candidates to Japan Organ Transplant Network at the end of May 2016, whereas annual HTx number is still around 40. This led to a growing interest in destination therapy (DT) for increasing patients with end-stage HF. According to AHA Statement on Recommendations for destination therapy (DT) is categorized as class 1 in advanced heart failure failing optimal medical management. DT was dramatically increased after approval in 2010. DT occupies 44% of total LVAD therapy between 2012 and 2015. 5 year survival rate of DT is about 10% inferior to bridge to HTx (BTT) and bridge to candidacy (BTC), however, it is not unreasonable when we take the age difference into account. Japanese HM II DT Clinical Trial will start very soon in Japan. The Japanese Council of VAD relevant academic society has already determined inclusion and exclusion criteria, primary end-point of 12 months survival, evaluation of QOL improvement using SF36. 7 cardiac centers will participate the clinical trial with 9 patients enrollment. As an agenda for DT, we discuss the survival advantage, QOL improvement. economical and mental burden of the family, and cost-effectiveness of DT in Japan.

SY9-2 Pros and Cons in Destination Therapy in Japan Koichiro Kinugawa; The Second Department of Internal Medicine, University of Toyama, Japan Destination therapy, an implantable ventricular assist device therapy without targeting bridge to transplantation, is now a widely accepted concept in United States as well as Europe. In Japan, DT has not been approved yet, but a trial is being started very soon. Long-term VAD therapy is known to associate many considearions including serious adverse events. Therefore, we have to keep in mind if there is a definite benefit over risk among DT candidates. I will summarize several considerations before going into DT, i.e. pros and cons for the thrapy.

SY12-1 Ivabradine: A Selective of Channel Inhibitor Takahiro Okumura, Toyoaki Murohara; Department of Cardiology, Nagoya Univerysity Graduate School of Medicine, Nagoya, Japan Ivabradine acts directly on the sinus node with blocking the cardiac pacemaker funny current (If) and reduces resting heart rate (HR). This agent does not affect atrioventricular or intraventricular conduction times, myocardial contractility or ventricular repolarization. In the BEAUTIFUL study, the HR reduction with ivabradine could not improve cardiac outcomes in all patients with stable coronary artery disease and left ventricular systolic dysfunction. However, in a subgroup with heart rates ≥70 beat per minutes (bpm), the incidence of coronary artery disease were significantly reduced. Subsequently, the SHIFT study reported a 10 bpm HR reduction with ivabradine associated with an 18% relative risk reduction for cardiovascular death and admission for worsening heart failure in patients with left ventricular systolic dysfunction and a HR ≥70 bpm. Based on these results, in the latest AHA or ESC heart failure guidelines, ivabradine is recommended to use in the treatment of adults with NYHA functional class II-IV chronic heart failure with left ventricular ejection fraction ≤35%, in sinus rhythm, with a HR of ≥70 bpm. Although ivabradine for clinical use has not been covered by insurance in Japan, the phase III clinical trials is currently ongoing. It is expected that can be used in clinical practice in the near future.

events in clinical studies of patients with systolic HF, so far. Thus, direct sarcomere modulators could be a novel therapeutic approach for the patients with systolic HF by directly improving cardiac performance without serious adverse effects associated with traditional inotropes. In addition to OM, several direct sarcomere modulators are currently under development. In near future, the development of the new class of inotrope will change the role of inotropes in the treatment of systolic HF.

SY13-1 Development of Novel Therapeutic Strategy for Heart Failure via Activating Invariant Natural Killer T Cells Naoki Ishimori1, Akimichi Saito2, Shintaro Kinugawa2, Wataru Mizushima2, Ryousuke Shirakawa2, Hiroyuki Tsutsui2; 1Clinical Training Center, Hokkaido University Hospital, Sapporo, Japan; 2Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Japan Previous basic and clinical research has advanced the modern treatment of heart failure (HF), however, its efficacy is still limited. Invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes, play an important role in regulating tissue inflammation. We have demonstrated that the administration of α-galactosylceramide (α-GalCer), which specifically activates iNKT cells, could protect the heart against left ventricular (LV) remodeling and failure after myocardial infarction (MI). Based on these results from basic research, we are now developing α-GalCer-pulsed human dendritic cells (αGalCer/DC) as the novel therapeutic strategy for HF with translational approach, which is supported by AMED. To obtain α-GalCer/DC, peripheral blood mononuclear cells were separated from donors by apheresis, cultured with GM-CSF and IL-2 for 6 days, and pulsed with α-GalCer. Non-clinical studies have demonstrated that, similar to α-GalCer itself, intravenous administration of α-GalCer/DC (3.0 × 106 cells, 1 and 4 days after the creation MI) into the MI mice could also efficiently activate iNKT cells and had a protective effect against LV remodeling and failure. Furthermore, they had no toxicity when administered to nude mice under the GLP standard. According to the face-to-face advices by the PMDA, phase I/II clinical trial of iNKT cell-targeted therapy is planned to determine its clinical safety and efficacy in HF patients on top of the standard pharmacological and non-pharmacological treatments.

SY13-5 Clinical Effects of Extenal Counterpulsation Circulatory Support System “Compact CP” Shunei Kyo1,2, Taskashi Nishimura1, Takuya Ito1, Yuko Takaoka1, Masaaki Ishi1, Tsuyoshi Shimizu2; 1Department of Cardiac Surgery, Tokyo Metropolitan Geriatric Hospital & Institute Gerontology, Tokyo, Japan; 2Department of Cardiaovascular Surgery, Nagano Matsushiro General Hospital, Japan Most popular external counterpulsation (ECP) circulatory support system “Enhanced Extenal CounterPulsation (EECP)” treatment received recommendation of class IIa for drug-resistant angina in 2013 ESC Guidelines. However, 15% of EECP cases lead to cancellation of treatment by pain and the skin damage related to the caph pressure in European and American EECP Registry. We developed ECP device compact CP (CCP) using double caph system (DCS) and have been examining its clinical usefulness. The shock and pain of the lower part of the body was largely relaxed by DCS unlike EECP using single caph system (SLC), and there was no cancellation case for pain during past 10-year clinical study. To avoid the shock to the skin produced by rapid inflation of the inner caphs the outside caphs were always inflated with constant pressure of 60 mmHg before start of the circulatory support. Almost same effects of counterpulsation circulatory support of CCP and EECP were confirmed in 8 patients of CABG during the follow-up period between 11 and 38 months. CCP may be especially useful for preoperative stabilization of unstable circulatory condition, introduction of general anesthesia, and treatment for perioperative moderate to severe circulatory failure in the surgery of ischemic heart diseases including ischemic mitral regurgitation.

SY14-1 SY12-4 Direct Sarcomere Modulators Open a New Era in the Management of Heart Failure With Reduced Systolic Function Osamu Tsukamoto; The Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Japan The use of inotropes in the management of heart failure (HF) still remains controversial because inotropes improves hemodynamic compromise at the expense of an increased risk of sudden cardiac death and mortality, although inotropes are crucial in managing HF patients with reduced cardiac output and poor end-organ perfusion. Recently, several direct sarcomere modulators has been identified and developed. Omecamtiv mecarbil (OM) is a novel cardiac myosin modulator, which directly increases cardiac contractility and prolongs systolic ejection time by increasing the rate of release of inorganic phosphate from cardiac myosin ATPase. Importantly, OM does not have apparent effects on myocardial oxygen consumption and Ca2+ transient in cardiomyocytes, both of which are putative mechanisms of adverse effects of traditional inotropes. Indeed, OM is safe, well tolerated and improves cardiac performance without increasing adverse

Oxidative Stress as a Prognostic Marker in Heart Failure Satoshi Suzuki, Yasuchika Takeishi; Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan It has been widely recognized that oxidative stress plays pivotal roles in progression of heart failure. Therefore, several oxidative stress markers are used in heart failure patients. An 8-hydroxy-2‘-deoxyguanosine (8-OHdG) is one of the oxidative DNA damage markers, and high serum 8-OHdG level group demonstrated severe NYHA functional class and higher incidence of cardiac events, although plasma BNP level was not different between high and normal 8-OHdG groups. Interaction of advanced glycation end products (AGEs) and its receptor (RAGE) induces oxidative stress and cytokine production, therefore AGEs and RAGE are recognized as oxidative stress markers. Serum levels of pentosidine, which is one of the AGEs, and soluble form of RAGE were measured, and higher levels of pentosidine and soluble RAGE predict higher incidence of cardiac event in heart failure patients. In the multivariate Cox proportional hazard analysis, pentosidine and soluble RAGE levels were independent predictors for cardiac events. Neopterin is produced by activated monocytes/macrophages upon stimulation with interferon-γ and associated with reactive oxygen species. Serum neopterin concentra-