The 86th Annual Scientific Meeting of the Japanese Circulation Society

Program

Presidential Lecture

Chairperson: Masunori Matsuzaki
The Professer Emeritus of Yamaguchi University
Speaker: Hiroshi Ito
Department of Cardiovascular Medicine, Okayama University

Mikamo Lecture (Sponsored by Japan Heart Foundation)

Chairperson: Ryozo Nagai
Jichi Medical University
Speaker: Valentin Fuster
Physician-in-Chief, Mount Sinai Hospital, New York, USA
Director, Mount Sinai Heart, New York, USA
General Director, National Center for Cardiovascular Research, Madrid, Spain

Mashimo Memorial Lecture

Chairperson: Masatsugu Hori
Osaka International Cancer Institute
Speaker: Shimon Sakaguchi
Immunology Frontier Research Center, Osaka University

Special Lecture

Chairperson: Hiroshi Ito
Department of Cardiovascular Medicine, Okayama University
Speaker: Michifumi Isoda
International Research center for Japanese Studies

Plenary Session

English

Novel approaches targeting immune system in atherosclerosis

Chairperson: Ken-ichi Hirata
Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine
Chairpersons' Message

Atherosclerotic cardiovascular disease (ASCVD) such as myocardial infarction or stroke have been increasing and become a leading cause of death or loss of healthy life in an aging society. Although the importance of management of traditional risk factors such as LDL-cholesterol, diabetes or hypertension has been established, we cannot fully suppress the incidence of ASCVD until now. Novel strategies in managing and preventing atherosclerosis are desired.
Next generation sequencing based technologies for genomics, transcriptomics, and epigenomics are now increasingly focused on the characterization of individual cells
These single-cell analyses allow researchers to uncover new and potentially unexpected biological discoveries relative to traditional profiling methods that assess bulk populations. Single-cell RNA sequencing (scRNA-seq), for example, can reveal complex and rare cell populations and track the trajectories of distinct cell lineages in development.
These novel technologies enable us to assess complex immune systems leading the formation of atherosclerosis. For example, the heterogeneous component of immune cells in atherosclerosis has been revealed by scRNA-seq. Clonal hematopoiesis in bone marrow was reported to affect the formation of atherosclerosis. A new antigen for atherosclerosis ‘ALDH4A1’ was discovered by a single cell repertoire analysis. We would like to discuss novel progresses targeting immune systems in a research field of atherosclerosis in this symposium.

English

Overview & Future Perspective of MINOCA

Chairperson: Kenichi Tsujita
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
  Gaku Nakazawa
Kindai University Faculty of Medicine
Chairpersons' Message

Although several years have passed since the concept of myocardial infarction with nonobstructive coronary arteries (MINOCA), it remains a puzzling clinical entity. Whereas the prevalence of MINOCA has been globally reported to be approximately 6% of MI patients with relatively better prognosis, a Japanese nationwide administrative database in the super-aging society demonstrated their higher prevalence of MINOCA up to 10% and higher in-hospital mortality in patients with MINOCA, indicating that the in-hospital mortality depends on the pathogenesis of MINOCA. Moreover, compared to patients with MI with obstructive coronary artery disease, MINOCA is a group of heterogeneous diseases arising from a variety of potential causes. Therefore, MINOCA was considered a “working diagnosis” analogous to heart failure, prompting further evaluation regarding its underlying mechanisms.

In this fascinating plenary session, we would like to summarize the previous global and domestic evidences about the MINOCA, and discuss on the current status of MINOCA practice and future perspective.

Japanese

Medical system and interhospital communication for acute aortic emergency: Current status and problems to be solved

Chairperson: Nobuyoshi Azuma
Department of Vascular Surgery, Asahikawa Medical University
  Koji Maemura
Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences 
Chairpersons' Message

Although survival rate of acute aortic emergency including acute aortic dissection and ruptured aneurysm has been gradually improved by establishment of treatment techniques, advancement of perioperative care, and applying endovascular devices, there is still wide room to improve the survival rate and quality of patient care.
The Japanese National Plan for Promotion of Measures Against Cerebrovascular and Cardiovascular Disease was published in 2020, which intensively mentions about medical service system for acute aortic emergency. JCS has immediately responded to the law and announced the second five-year plan “Stop CVD” that describes the importance of emergency medical service renovation by proposing network formation to select adequate hospital and shorten the door to intervention time. Interhospital communication as well as communication between cardiovascular surgeons and cardiologists through the network may be important especially in the countryside.

Meaningful discussion with reporting specific issues and ingenuities by speakers in this session hopefully contributes to improve medical system for the acute aortic emergency in each area.

English

COVID-19 and Cardiovascular Disease

Chairperson: Koichi Node
Department of Cardiovascular Medicine Saga University
Chairpersons' Message

COVID-19 is rampant all over the world, and as of February 2021, the cumulative number of SARS-CoV-2 positives is about 420,000 and the cumulative number of deaths is about 7,500. With COVID-19, it has been reported that the aggravation rate and mortality rate increase with aging, and the majority of COVID-19 deaths in Japan are elderly people in their 60s or older. Coexistence of cardiovascular disease in COVID-19 has been reported to be associated with increased mortality from COVID-19. Especially in the elderly, there are few complications of cardiovascular disease, and there is concern that the prognosis may worsen due to the overlapping risk of aggravation. On the other hand, regarding the relationship between cardiovascular disease and COVID-19, not only the coexistence of cardiovascular disease is a poor prognosis factor, but also SARS-CoV-2 infection directly or indirectly damages the cardiovascular system. It has been reported to cause coronavirus-related cardiovascular disease. In this session, we will discuss the existence of new coronavirus-related cardiovascular diseases, the existence of cardiovascular diseases as aggravating factors in COVID-19, and the effects of COVID-19 epidemics and lockdown on cardiovascular diseases.

English

Autonomic nerves in arrhythmia / heart failure; pathophysiology and treatment

Chairperson: Hiroshi Morita
Cardiovascular Therapeutics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
  Peng-Sheng Chen
Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, USA
Chairpersons' Message

Recently, the significances of autonomic nervous system [ANS] on various heart disease have been well recognized. ANS is important as an arrhythmic trigger and an aggravating factor of heart failure [HF]. In arrhythmic diseases, activities of sympathetic and parasympathetic nerves trigger atrial and ventricular tachyarrhythmias and arrhythmic storm. Then, autonomic nerve modulation is useful for therapy of various arrhythmias in addition to antiarrhythmic agents and a radiofrequency catheter ablation those directly modulate arrhythmic foci or circuits. 𝛽-blocker is a basic ANS modulation therapy in arrhythmias. From the 1990’s, cardiac sympathetic nerve denervation has been used for the therapy of congenital long QT syndrome. Recently, usefulness of GP ablation in atrial fibrillation and denervation of cardiac and renal sympathetic nerve systems in malignant ventricular tachyarrhythmias with organic heart diseases have been reported. In HF, sympathetic activation aggravates myocardial injury and results in worsening of HF. 𝛽-blocker is established as an essential ANS modulation in HF. Since parasympathetic inactivation is also an aggravating factor of HF, various devices that stimulate spinal cord, auricle or neck carotid body to activate parasympathetic nerve have been investigated. Expertise of molecular and genetic factors, evaluation methods and modulative therapies in cardiac ANS are now developing. We expect to know new findings and have useful discussions on cardiac ANS.

Japanese

Comprehensive Treatment Strategy for Atrial Fibrillation to Extend Healthy Life Expectancy

Chairperson: Kazuo Minematsu
Medical Corporation ISEIKAI
  Wataru Shimizu
Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School
Chairpersons' Message

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and its prevalence increases with age. AF is associated with the risk of developing stroke 5 times higher, cognitive impairment 3 times higher, and heart failure (HF) 2 times higher than sinus rhythm. Since these 3 all cause long-term care in elderly patients, it is extremely important to develop a comprehensive treatment strategy for the extension of healthy life expectancy. In the cardiovascular area, catheter ablation (CA) has become popular as a rhythm control therapy. CA is reported to be associated with better prognosis and less HF hospitalization in patients with HF, and is indicated to be associated with less stroke than medical therapy (rate or rhythm control). However, the effectiveness by CA is limited in patients with persistent or chronic AF, thus comprehensive treatment for comorbidities and underlying cardiovascular diseases in addition to pharmacological therapy is strongly recommended. On the other hand, in cerebrovascular area, appearance of thrombectomy has dramatically changed the acute therapy for cardiogenic cerebral embolism. Moreover, the Basic Plan to Promote Stroke and Cardiovascular Disease Control Programs published by the Japanese Government has included the building of seamless medical system from rehabilitation to home medical care. In this plenary session, expert cardiologists and cranial neurologists are welcome to discuss a comprehensive treatment strategy for AF management.

English

What is an ideal long-term management of continuous-flow ventricular assist device in the era of destination therapy?

Chairperson: Minoru Ono
Department of Cardiovascular Surgery, Graduate School of Medicine, The University of Tokyo
Chairpersons' Message
Destination therapy (DT) using continuous-flow ventricular assist device (cf-VAD) was approved for health insurance coverage in May, 2021. DT Committee of The Council for Clinical Use of Ventricular Assist Device Related Academic Societies worked up a consensus document for smooth introduction of DT. HeartMate3 is an approved device for DT, and seven hospitals which had participated in DT trial were designated as initial implanting centers. Requirements for caregivers which are strict for BTT were decided to be mitigated for DT, however, evaluation methods of cognitive function were newly mandated to secure a patient understanding ability to a certain level. There was no age limit for DT, but an evaluation of general condition including organ function reserve and 5-year expected survival is required. Bridge to bridge surgery in which a paracorporeal VAD is converted to cf-VAD is approved for DT, though it is thought be more invasive than a primary implant, conditional by a careful patient selection. The J-MACS report revealed that a long-term survival in patients older than 50 years is inferior to that of the younger counterpart. This means that a careful patient selection and post-implantation management is mandatory particularly for those aged over 65, who are deemed to be good candidates for DT. Safety and efficacy have to be demonstrated in the post-market surveillance in order that DT will be recognized as a routine treatment. In this session, reasonable strategies to enable a safe and secure long-term DT treatment will be discussed based on clinical experiences to treat BTT patients and heart-team discussion for future DT therapy in each center.

English

Utilization of AI in cardiovascular imaging

Chairperson: Masataka Sata
Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
Chairpersons' Message

Artificial intelligence (AI) refers to technology that allows computers to mimic human cognitive functions, learn from collected data, and solve problems. In the field of cardiovascular imaging, the aim of AI is to diagnosis, predict outcomes, and select optimal treatments. AI for cardiovascular imaging can provide new clinical insights by combining big data sources with clinical information from electronic medical records and mobile health devices. AI has the potential to advance cardiovascular imaging, because of its ability to handle large amounts of input data.

In this symposium, we would like to describe the role of AI in cardiovascular imaging, including echocardiography, nuclear medicine imaging, computed tomography, and cardiac magnetic resonance, and discuss current applications of AI in automation, disease recognition, and prediction.

English

Latest CMR diagnostic strategy for myocardial hypertrophy

Chairperson: Hajime Sakuma
Department of Radiology, Mie Univeristy Hospital
Chairpersons' Message

Cine MRI and late gadolinium-enhanced MRI have been widely used for the evaluation of patients with myocardial diseases by cardiac magnetic resonance (CMR). Recently, CMR parametric mapping, which can quantitatively evaluate myocardial T1 relaxation time, extracellular volume (ECV), and myocardial T2 relaxation time, has emerged, increasing the importance of CMR in the diagnosis and prognosis of patients with myocardial diseases. Parametric mapping is particularly useful in the diagnosis of cardiac amyloidosis (T1 prolongation) and Fabry disease (T1 shortening), where there is little overlap compared to the measurements in normal myocardium. On the other hand, the magnitude of T1 change in cardiomyopathy is relatively limited, and the T1 relaxation time may vary depending on the pulse sequences and imaging parameters. In this session, we will discuss what kind of tissue changes parametric mapping reflects, the accuracy and reproducibility of T1 and T2 measurements, and the usefulness of parametric mapping in myocardial diseases showing myocardial hypertrophy, aiming to expand the use of CMR parametric mapping in Japan.

Japanese

Desicion making an appropriate candidate of invasive treatment in elderly patients with severe aortic stenosis

Chairperson: Akira Shiose
Department of Cardiovascular Surgery, Kyushu University
  Masanori Yamamoto
Toyohashi heart center
Chairpersons' Message

It is global agreement that the invasive therapy should be considered for patients with severe aortic stenosis (AS) regardless of the patient's age such as octogenarians because of their poor prognosis. A less invasive transcatheter aortic valve implantation (TAVI) has emerged as a therapeutic option for elderly patients with AS, and the indications for TAVI are rapidly expanding based on the clinical data. Similarly, surgical aortic valve replacement (SAVR) is classical established therapy for elderly patients with AS. With the development of device technology and improvement the early safety of the procedure, the indication of both SAVR and TAVI is expanding in this decade. However, an adequate pre-screening or risk stratification should be required before the procedure. In addition, the decision making for appropriate invasive therapy candidates should be clinically determined by balancing the risk and benefit. In this session, we would share the current status of SAVR and TAVI therapy in Japan and discuss the possible advantages of invasive therapy for AS patients.

English

T2DM as cardiovascular disaease:
Pathophysiology and new treatment strategy

Chairperson: Hiroshi Ito
Department of Cardiovascular Medicine, Okayama University, Graduate School of Medicine
  E. Dale Abel
University of Iowa, Carver College of Medicine, USA
Chairpersons' Message

Until now, type 2 diabetes (T2DM) has been classified as a metabolic disease, although it is a risk factor for cardiovascular disease, and has been treated by diabetologists to control blood glucose. This trend was changed by the results of cardiovascular outcome trials (CVOTs), which were conducted as safety trials for new diabetes drugs.  By reducing the hard endpoints of cardiovascular death, myocardial infarction, and stroke, it was clarified that GLP-1RA and SGLT2 inhibitors have a preventive effect on cardiovascular events beyond glycemic control. Based on the results of CVOTs, the guidelines for diabetes treatment were rewritten in Europe and the United States, and it was clarified that the selection of diabetes drugs is important for improving the prognosis of high-risk T2DM patients. SGLT2 inhibitors have been shown to be able to improve the prognosis of HFrEF patients and have been added to the essential treatment of heart failure. In addition, results of CVOTs provide a new perspective on the pathogenic mechanism of T2DM-induced arteriosclerosis, heart failure, and atrial fibrillation. The pathogenic mechanisms include endothelial dysfunction due to hyperglycemia, dyslipidemia as well as AGE / RAGE accumulation, complications of hypertension, persistent microinflammation, abnormal energy metabolism at mitochondrial level, sympathetic nerve hyperactivity, RAA system enhancement and hyperinsulinemia, which enhances cell proliferation and Na retention. And elucidation of the pathology leads to new therapeutic targets. This plenary session discusses the latest pathological mechanism why T2DM causes cardiovascular disease and provides common treatment strategies for diabetologists and cardiologists to prevent cardiovascular events and improve prognosis of T2DM patients.

English

Unsolved issues and future perspective in ACHD: Beyond the Guidelines

Chairperson: Teiji Akagi
Department of Cardiovascular Medicine, Okayama University
  Michael Gatzoulis
Royal Brompton Hospital London, UK
Chairpersons' Message

Adult congenital heart disease has become an unavoidable reality for adult cardiologists. As has been speculated in the past, the proportion of congenital heart disease requiring management by cardiologists is increasing in moderate to severe heart disease. Postoperative cases of complex heart disease, mainly cyanotic heart disease, have become an avoidable problem in adulthood, including arrhythmia, heart failure, and pulmonary hypertension. These are the issues that cardiologists face in their daily practice, however, in the field of adult congenital heart disease, the cardiac problems of individual patients are different. In addition, each patient often undergoes different surgical treatment options, further contributing to the diversity of postoperative conditions. The diversity of cardiac diseases complicates the treatment strategy and requires personalized therapy for each patient. In addition, the number of cases of each cardiac disease is limited, making homogeneous evaluation in large numbers of patients difficult. Adult congenital heart disease is a new group of diseases that have not been encountered in the field of cardiology, and surgical approaches have changed over time, such as the Fontan procedure. Although Japanese Circulation Society or International guidelines have established a standard of the management of adult congenital heart disease, there are various areas in which evidence is low, and the establishment of appropriate treatment guidelines is expected to change in the future. In this session, we would like to clarify the clinical issues that have not been clarified yet due to limited evidence in adult congenital heart disease and discuss the future prospects of these issues and new therapeutic modalities based on the latest findings.

English

Progress of genome medicine in cardiovascular diseases

Chairperson: Issei Komuro
The University of Tokyo
Chairpersons' Message

Progress of cancer research has enabled us to understand the underlying mechanisms of cancer development. Cancer is induced by the mutations of genes which are usually involved in cell growth and these genes are called as driver genes. Many molecular targeted drugs have been developed and prognosis of cancer has been remarkably improved. Nowadays, molecular targeted drugs are selected after identifying the driver genes.   Although various environmental factors play important roles in the development of cardiovascular diseases, genetic factors are also critically involved in cardiovascular diseases. In the near future, genomic medicine will be done for cardiovascular diseases; genetic factors will be determined and then treatment will be decided based on the genetic factors.  Advances in genomic medicine of cardiovascular diseases will be discussed in this plenary session.

English

Artificial Intelligence in Cardiovascular Medicine.: New perspectives and challenges

Chairperson: Satoshi Yasuda
Tohoku University Graduate School of Medicine
Chairpersons' Message

Artificial intelligence (AI) and machine learning are poised to influence the cardiovascular medicine. nearly every aspect of the human condition, and cardiology is not an exception to this trend. AI is bringing a paradigm shift, powered by increasing availability of data and rapid progress of analytics techniques, in the three major areas of early detection and diagnosis, treatment, as well as outcome prediction and prognosis evaluation. This session will review selected applications of these methods in cardiovascular filed to date and identify how cardiovascular medicine could incorporate artificial intelligence in the future.

Symposium

Japanese

Current status and challenges for reduction of in-hospital and out-hospital mortality from acute myocardial infarction

Chairperson: Tetsuya Amano
Aichi Medical University
  Yoshihiro Morino
Iwate Medical University
Chairpersons' Message

There is no doubt about improvements of life prognosis by emergent revascularization (i.e. primary percutaneous coronary intervention) as an initial treatment of acute myocardial infarction (AMI). However, actual in-hospital mortality has not been improved for the past several years, which requires additional measures for regional disparities of rates of emergent revascularization, out-of-hospital triage, and medical service systems during recovery as well as chronic periods in order to further reduce the mortality. Moreover, “The Basic Act on extension of healthy life expectancy for strokes and cardiac diseases (No. 105, Dec. 14th, Heisei 30)”, established in last year, requires discussion of actions on prevention, diagnosis, treatment, and rehabilitation for reduction of mortality of cardiovascular diseases with adequate temporal perspectives. Furthermore, any effects of coronavirus crisis on AMI treatment must be considered at the timing of “with Corona”. In this session, re-evaluating current status of AMI with real-world data, we would like to discuss on the issues of any potential challenges for reduction of mortality of AMI considering entire time courses including at prevention, acute, recovery, and chronic phases.

Japanese

Diagnostic and therapeutic strategy for CCS following ISCHEMIA TRIAL

Chairperson: Yuji Ikari
Tokai University
  Genichi Sakaguchi
Department of Cardiovascular Surgery, Kindai University Hospital
Chairpersons' Message

ISCHEMIA Trial is the randomized trial comparing the two groups: initially conservative treatment group vs immediate revascularization group.  There was no significant difference in 2-year survival. Notably, a fourth of the patients in the conservative group had received PCI or CABG for within 4 years.  The immediate revascularization group had more angina relief and reduced the risk of MI.  The sub-analysis suggested that the immediate revascularization group improved the prognosis of the patients with the history of heart failure.  
Currently, revascularization is justified when ischemia is proved. On the other hand, it should be deferred for non-ischemic vessels. The trial showed that the medical treatment can be prior to the immediate revascularization even if ischemia is proven. However, one-fourth of the patients in the conservative group needed revascularization within 4 years.

Given these evidences, we need to rethink the strategy of diagnosis and therapy for CCS. We expect this session to organize the evidences and to show the future direction to go.

English

Takayasu arteritis: Pathogenesis, current diagnosis and treatment

Chairperson: Mitsuaki Isobe
Sakakibara  Heart Institute
Chairpersons' Message

Takayasu arteritis is a refractory arteritis affecting aorta and other systemic organs mainly in young females. The etiology is still unknown but recent investigation reveals some molecular aspects associated with the pathogenesis. The primary point of diagnosis of Takayasu arteritis is to suspect the existence of this disease, since the symptoms are quite nonspecific and specific clinical test is not present to date. Definite diagnosis is usually made from the pattern of arterial imaging such as FDG-PET/CT, CT angiography and MR angiography. Prednisolone is the first line immunosuppressant for this disease, however, two thirds of patients experience relapse of inflammation during the tapering. New immunosuppressive agents including infliximab and tocilizumab have been increasingly applied. Still these agents are not effective in some patients and diagnosis of flare up during tocilizumab treatment is an emerging serious issue. Vascular repair is required in about 25% of patients. The utility of intravascular treatment for occlusive arterial lesion has not been established because of very high rate of restenosis. In this symposium we expect to introduce and discuss current knowledge on this disease from the aspects of basic research, epidemiology, diagnosis, medical and surgical treatment.

English

The strategic distinction for CLTI among BSX, EVT and medications

Chairperson: Katsuyuki Hoshina
Department of Vascular Surgery, The University of Tokyo
  Yoshimitsu Soga
Department of Cardiology, Kokura Memorial Hospital
Chairpersons' Message

It is not easy for patients with CLTI (chronic threatening limb ischemia) to consider which is the optimal practice among surgical revascularization, endovascular therapy and medication (including primary amputation). The goal of CLTI is not successful revascularization, but wound healing as well as the improvement of its mortality. The current guideline from western countries were revised to indicate that life expectancy of >2 years is an important factor for the initial revascularization in CLTI patients. However, this concept is extremely limited because there is no obvious definition of 2-year life expectancy. Furthermore, the evidence regarding Japanese CLTI patients including many dialysis patients is insufficient to apply in a clinical setting. Recently, the effectiveness of EVT for infra-popliteal lesion in CLTI has been published. However, high restenosis and high reintervention rate is still big issue.

Through this CLTI symposium, to achieve effective complete wound healing and for better life prognosis, we would like to discuss what approaches should we adopt to improve wound healing, the border of strategic appropriate revascularization and multidisciplinary approach, the perspective and risk stratification in CLTI, and the role of adjuvant therapy (lumbar sympathectomy, hyperbaric oxygen therapy、carbon dioxide bath、blood apheresis…)

English

Genomic medicine for arrhythmic diseases

Chairperson: Tetsushi Furukawa
Medical Research Institute, Tokyo Medical and Dental University
Chairpersons' Message

Genome research on arrhythmic diseases began in the 1990s when ion channel genes were identified as causative genes for long QT syndrome and Brugada syndrome by linkage analysis. Since the phenotype of ion channel gene mutations can be analyzed with high precision using the patch clamp method, genomic research has advanced ahead of other diseases. Since then, the spread of next-generation sequencing technology has dramatically advanced the understanding of familial arrhythmia diseases, and the existence of modifier-gene polymorphisms as well as causative gene mutations is becoming clear. In addition, many disease-sensitive gene polymorphisms for common arrhythmia diseases such as atrial fibrillation have been identified by the development of whole genome-related analysis (GWAS). Genomic medicine, in which the information obtained from these genomic studies is applied in clinical practice, is also being carried out. Long QT syndrome is treated differently depending on the causative gene. For atrial fibrillation, high-risk patients are identified from genomic risk scores calculated from multiple atrial fibrillation susceptibility gene polymorphisms, and early detection of atrial fibrillation onset can be detected with long-term Holter ECG monitoring, and wearable devices such as Apple Watch, etc. This symposium will cover the state-of-the-art precision medicines for arrhythmic diseases based on these genomic research information.

Japanese

Recent Advances of Nonpharmacological Therapy for Persistent Atrial Fibrillation-Topics for Left Atrial Appendage Occlusion Device, Catheter Ablation and Surgical Therapy

Chairperson: Kengo Kusano
Dept. of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
  Hiroshi Tada
Department of Cardiovascular Medicin, Faculty of Medical Sciences, University of Fukui
Chairpersons' Message

Atrial fibrillation (AF) is associated with the cerebral/systemic embolism as well as heart failure development. Recently, nonpharmacological therapy of catheter ablation for AF has been demonstrated a great advantage for reducing the cerebral embolism or the heart failure development, and the number of catheter ablation has dramatically increased in Japan. Catheter ablation strategy for paroxysmal AF is nearly established, but AF is a progressive disease and atrial remodeling causes AF persisted, leading the mitral regurgitation deteriorated or easy to create the clot formation in the atrium. Accordingly, effective and safety strategy for advanced persistent AF is needed in the clinical setting. In this session, the topics of nonpharmacological therapy for persistent AF, regarding the recent advances of catheter ablation, left atrial appendage occlusion and surgical approaches will be demonstrated by experts, and we will make a discussion about the effective and safety strategy for persistent AF.

English

Position statement on endomyocardial biopsy

Chairperson: Kazufumi Nakamura
Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
  Petar M. Seferovic
Serbian Academy of Sciences and Arts, University of Belgrade Faculty of Medicine, Serbia 
Chairpersons' Message

The endomyocardial biopsy method using a catheter, which was developed by Dr. Konno and Dr. Sakakibara in Japan in 1962, has become popular worldwide as a useful test method.  It is now an indispensable test method for the diagnosis of heart transplant rejection and the diagnosis of myocarditis and cardiomyopathy.  In recent years, new treatments have been developed for cardiomyopathy-related diseases and diagnostic methods using multimodality imaging have advanced, and it is time to renew our views on endomyocardial biopsy.  In 2021, the Heart Failure Association of the ESC, Heart Failure Society of America and Japanese Heart Failure Society also released a new “Position statement on endomyocardial biopsy”.  In this symposium, we would like to discuss the views on indications, procedures, interpretation and utilization of the results of endomyocardial biopsy while adding topics such as new disease concepts, treatment methods, and multimodality imaging.

English

Breakthroughs in the pathophysiology and treatment of HFpEF

Chairperson: Kazuhiro Yamamoto
Department of Cardiovascular Medicine, and Endocrinology and Metabolism, Tottori University
  Barry A Borlaug
Mayo Clinic, USA
Chairpersons' Message

No treatment strategy has been found to improve the life expectancy of HFpEF patients in contrast to HFrEF. One of the main reasons for this is that investigations about pathophysiology and effective therapeutic approach in HFpEF have been conducted in terms of one-size-fits-all, despite the fact that the pathophysiology of HFpEF is diverse partly because HFpEF is common in the elderly. Recently, in order to solve this problem, HFpEF has been divided into several clusters by phenomapping and other methods, and attempts have been made to investigate the pathophysiology of each cluster. Some studies have shown that racial differences should be taken into account for clustering, and thus, studies with Japanese patients are awaited. In terms of treatment, the efficacy of some drug therapies and non-drug therapies such as interatrial shunt device is being investigated. Targeting comorbidities that affect the severity of HFpEF has also received attention. Interventions for atrial fibrillation, atrial functional mitral regurgitation caused by atrial fibrillation, skeletal muscle dysfunction, and nutritional disorders, and other approaches from various angles are being tried. In this session, we would like to discuss how far we have progressed in elucidating the pathophysiology of HFpEF using new approaches, and what methods of therapeutic intervention are being explored, based on the latest findings.

English

Challenge for treatment of heart failure based on new molecular pathogenesis

Chairperson: Masafumi Yano
Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine
  Koichiro Kuwahara
Shinshu University School of Medicine
Chairpersons' Message

Recently, the effectiveness of new therapeutic agents for heart failure such as ARNI and SGLT2 inhibitors has been proved by large-scale RCTs, and these agents are already clinically available in Japan, and it is expected that the prognosis of heart failure patients will be improved. However, the prognosis of patients with heart failure is still poor, and a fundamental treatment for heart failure has not been developed yet. Recent detailed studies at the cellular and molecular levels have revealed that a wide range of factors are involved in the pathophysiology of heart failure, such as activation of neurological and humoral factors associated with inflammation and oxidative stress, metabolic disorders, intracellular Ca2+ handling disorders, cell proliferation / cell death, etc. Molecules and systems that link the heart to other organs and tissues can also be therapeutic targets. In this session, we would like to explore new treatments for heart failure based on the latest research on the molecular mechanism of heart failure.

Japanese

Front line of pharmacological therapy for heart failure

Chairperson: Yoshihiko Saito
Department of Cardiovascular Medicine, Nara Medical University
  Hiroyuki Tsutsui
Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University
Chairpersons' Message

Based on the elucidation of the pathophysiology of heart failure through basic research and evidence based on large-scale clinical trials, the pharmacological treatment for heart failure has been shifted from conventional therapy with diuretics and positive inotropes to the inhibition of neurohumoral activation. In addition to ACE inhibitor, angiotensin receptor blocker (ARB), mineralocorticoid receptor antagonist (MRA), and β-blockers for heart failure with reduced ejection fraction (HFrEF), newer drugs have been approved such as the If channel inhibitor ivabradine, the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril valsartan, and the SGLT-2 inhibitors dapagliflozin and empagliflozin. Furthermore, the efficacy of the soluble guanylate cyclase (sGC) stimulator, vericiguat, and the cardiac myosin activator, omecamtiv mecarbil, was also demonstrated in HFrEF. The efficacy and safety of these drugs are now being evaluated based on the experience in the daily clinical practice. Despite advances in the drug treatment for heart failure, its prognosis remains still poor, and basic research aimed to develop more effective therapeutic agents is being actively conducted. In this symposium, we would aim to present the recent findings on heart failure drug treatment from both clinical and basic research and to overview the present and future of heart failure treatment.

English

Progress in Heart Failure Imaging

Chairperson: Yasushi Sakata
Department of  Cardiovascular Medicine, Osaka University Graduate School of Medicine
  Kaoru Dohi
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine
Chairpersons' Message

Regardless of the underlying etiology, heart failure is a clinical syndrome that causes systemic and/or pulmonary congestion and organ hypoperfusion due to the loss of compensation for reduced cardiac pump function. From this perspective, it should be emphasized that all areas of cardiovascular imaging which can assess clinical conditions and pathophysiology of heart failure are regarded as “heart failure imaging”. The choice of heart failure imaging modality depends on the disease trajectory and treatment strategy for each patient, and therefore proper use of multiple heart failure imaging is required in the assessment of hemodynamic profiles as well as heart failure stages under varying disease conditions during the time course of heart failure. In addition, the development of imaging strategy helps physicians predict patient outcomes and provide optimal palliative care. We would like to discuss current challenges and future directions in heart failure imaging using new technologies such as hybrid imaging, molecular imaging and IoT.

Japanese

Optimal diagnostic method for coronary microcirculation

Chairperson: Naoya Matsumoto
Nihon University Hospital, Department of Cardiology
  Nobuhiro Tanaka
Tokyo Medical University Hachioji Medical Center
Chairpersons' Message

Evidence of myocardial ischemia is a requirement for coronary revascularization. Fractional flow reserve (FFR) examination or stress myocardial perfusion modalities (myocardial scintigraphy, CT, MRI, etc.) are recently used for the detection of coronary artery stenotic lesion causing myocardial ischemia. The positive threshold of the FFR is 0.75 -0.8 with myocardial scintigraphy as the SOT, but the discrepancy between FFR and myocardial scintigraphy is a common phenomenon in daily clinical practice. In recent years, it has also been called Ischemia with no obstructive coronary artery disease (INOCA), which is partly due to the so-called coronary microvascular dysfunction (CMD) in arterioles. The prognosis for patients with CMD is poor and has been associated with reduced left ventricular diastolic function or HFpEF. Epicardial coronary angioplasty in patients with CMD does not always improve CMD, therefore multimodality diagnosis is important. Invasively, CMD evaluation includes Index of Microcirculatory Resistance (IMR) and noninvasive measurement of coronary blood flow at rest and stress using PET/CT (coronary flow reserve: CFR) is common.

In this symposium, we would like to discuss the selection of modalities, methods of stress, and treatments as optimal diagnostic methods for CMD.

Japanese

Transcatheter and Surgical Intervention for Secondary Mitral Regurgitation caused by LV dysfunction; MitraClip/TMVR or Valve repair/replacement

Chairperson: Yoshiro Matsui
Hanaoka Seishu Memorial Hospital
  Nozomi Watanabe
Cardiovascular Physiology, University of Miyazaki Faculty of Medicine
Chairpersons' Message

Management of functional mitral regurgitation (MR) is always challenging based on various basic condition with generally poor prognosis due to reduced LV function. Heterogeneous valve geometry causing functional MR makes the therapeutic assessment more complicated, and it is difficult to make a ‘standard’ in the assessment of the major contributor of refractory heart failure. This session aims to help understanding the mechanisms and pathophysiology of the complex disease and to get up-to-date knowledge from the prognostic insights of functional MR, and then to discuss the indication of surgical intervention and transcatheter surgery including edge-to-edge MV repair and TMVR. Customized treatment considering multiple factors including the unique valve characteristics and each patient’s basic condition is required in the assessment of functional MR, and we hope that we can get an active discussion for this topic from the various clinical insights.

Japanese

Can aortic valve repair be the standard procedure for patients with aortic regurgitation? Current indications

Chairperson: Yutaka Okita
Cardio-Aortic Center, Takatsuki General Hospital
  Satoshi Nakatani
Saiseikai Senri Hospital
Chairpersons' Message

Many techniques of aortic valve repair for patients with aortic regurgitation have been reported since 1960s, however, these procedures have not been popularized because the early or long-term outcome was inferior to mitral valve repair. Since 1990s, techniques of aortic valve sparing root replacement have developed, many clinical experiences of aortic valve sparing method have been accumulated mainly in young patients. Recent development of concise knowledge of aortic root anatomy, trans-esophageal echocardiography, and CT scans were contributed. In this symposium, clinical applications of the aortic valve repair technique, including preoperative morphological or quantitative diagnosis of aortic regurgitation, operative procedures and outcomes, in patients with aortic regurgitation should be discussed.

Japanese

Exploring the possibilities of remote cardiac rehabilitation

Chairperson: Shigeru Makita
Saitama Medical University International Medical Center
  Shin-ichiro Miura
Department of Cardiology, Fukuoka University School of Medicine
Chairpersons' Message

Telemedicine is drawing attention as a result of the spread of the new coronavirus infection. Research has progressed on the application of telemedicine in the field of cardiac rehabilitation. Outpatient cardiac rehabilitation currently has a low rate of patients’ continuing their hospital visits. Furthermore, outpatient cardiac rehabilitation involves group instruction, which contributes to crowding. Thus, it is expected that "remote cardiac rehabilitation" will become increasingly important in the future. Based on reports to date, the efficacy and safety of home-based cardiac rehabilitation are equivalent to those of outpatient cardiac rehabilitation, and it is recommended as class II in the guidelines for rehabilitation in cardiovascular disease revised in 2021. However, from the viewpoint of safety, necessity, and effectiveness, a remote system that patients, families, and medical staff can use with peace of mind is needed. At this symposium, the researchers will report on cardiovascular diseases and exercise programs for which "remote cardiac rehabilitation" is indicated, and their implementation status. Furthermore, we would like to discuss current issues and how to overcome them in terms of two-way communication, exercise equipment, sensors, surveillance systems, and medical costs.

English

Re-intervention for congenital heart disease in adulthood

Chairperson: Isao Shiraishi
National Cerebral and Cardiovascular Center
Chairpersons' Message

Advances in diagnosis and surgical operation have rescued many child patients with congenital heart disease, and now approximately 90% of patients have grown up to adulthood. These patients are able to spend a satisfactory life during the growing childhood. However, after adulthood, they start to suffer from novel symptoms including intractable arrhythmias and progressive heart failure due to complications and residual lesions of the surgical operation. In addition, patients after Fontan procedure often develop multi-organ disorders called failing Fontan. Therefore, accurate detection of these newly emerging lesions and re-intervention at an appropriate timing is essential to improve the prognosis of the patients with adult congenital heart disease. In this symposium, we would like to discuss timing and method of re-intervention for adult congenital heart disease patients from the stand point of surgical operation, catheter intervention, and catheter ablation.

Japanese

Beyond the clinical practice guidelines: New horizons in pulmonary arterial hypertension therapies

Chairperson: Yoshihiro Fukumoto
Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
  Takeshi Ogo
National Cerebral and Cardiovascular Center
Chairpersons' Message

Treatment of pulmonary arterial hypertension (PAH) has improved dramatically these 20 years, based on the extensive basic, translational, and clinical research. The use of three type pulmonary vasodilators have significantly improved the prognosis of the patients with PAH. The 6th World Symposium on Pulmonary Hypertension proposed PAH treatment strategy of initial combination therapy based on the evidences of better outcome. However, the etiology of PAH is diverse and various factors are involved in the development and progression of the disease. Outcome with PAH specific treatment is still not always sufficient. It is our mission to solve these problems to improve the prognosis and quality of life in PAH such as refractory PAH, the difference in individual response to treatment, unknown mechanisms of PAH development and progression. Personalized medicine on the basis of each pathogenesis of PAH to achieve could lead better outcome on top of current standard treatment. In this symposium, we would like to discuss possible future PAH treatment based on the results of basic, translational, and clinical research for PAH beyond current treatment guidelines.

Japanese

How to clear the hurdles of carrier - Challenge for the sustainable future

Chairperson: Shiro Uemura
Kawasaki Medical School, Cardiovascular Medicine
  Yasuko K Bando
Department of Cardiology, Nagoya University
Chairpersons' Message

In Japan, number of female students enrolled in medical school has exceeded one-third, and the proportion of female doctors is expected to steadily increase. On the other hand, the field of cardiology, where the pandemic of heart failure becomes more intense with the super-aging population, is an area of expertise where the proportion of female doctors is remarkably low. Irrespective of age or gender, how the doctors continue and improve their careers is an indispensable viewpoint in terms of realizing work style reforms. Especially female doctors in Japan have two social hurdles due to the consciousness of gender roles known as "Unconsciousness bias". It is often difficult to balance work and life such as childbirth, childcare, etc., and female doctors are often forced to interrupt their career around 10 years after graduation of medical school, namely, their mid-30s. This is known as a peculiar M-shaped curve phenomenon in which nearly 20% of these young female doctors facing the crisis of their career. Another hurdle is the lack of female leaders in Japanese medical society. Due to another aspect of the “Unconsciousness bias” that is common among women, that is, the subconsciousness and customs of the person whose virtue is humility, there are few opportunities for women, including those in the medical community, to become leaders. In most Western countries, various systems such as the quota system have already been realized, but Japan is too far from the gender quality to escape from the lowest lank of the OECD countries. Improving the working environment in the medical field and developing female leaders are two-wheeled, Unless such improvement is attained, women's participation and career continuation at the level of developed countries cannot be achieved.

At this symposium, we will clarify the current situation and issues with both female and male experts of junior doctors and senior doctors on how to overcome the barriers of career continuation.

English

Basic biology of aging

Chairperson: Tohru Minamino
Department of Cardiovascular Biology and Medicine Juntendo University Graduate School of Medicine
Chairpersons' Message

In the current era of 100-year lifespans, in Japan we are experiencing a superaged society that the world has never seen before. One of the most important issues in this context is that the discrepancy between the healthy lifespan and the average lifespan has continuously increased, even though significant progress has been made in medical treatments. It is well accepted that age-associated increases in cardiovascular disease, such as ischemic heart disease and stroke, contribute to this discrepancy. Because the incidence of cardiovascular disease increases with advancing age and therefore this type of disease per se could be a part of pathological aging phenotypes in older populations, many researchers suggest that a novel therapeutic strategy for cardiovascular disease should target molecular mechanisms of organismal aging. Several countries, including Japan, are currently conducting national projects with the aim to elucidate the molecular mechanisms of aging. For example, age-associated accumulation of senescent cells in tissues has been shown to provoke chronic inflammation and thereby contribute to pathological aging, and researchers are now trying to develop senolytics that specifically eliminate senescent cells from aged tissues and thus improve pathological aging. An age-associated increase of somatic mutations in hematopoietic cells has been reported to lead to clonal hematopoiesis, which promotes chronic inflammation and causes cardiovascular disease. Promoting DNA repair could be another strategy to improve pathological aging. In this symposium, we will discuss recent progress in aging research and future directions towards developing novel treatments for cardiovascular disease.

English

Cutting-edge Science in Stem Cell, Gene Therapy, and Regeneration for Cardiovascular Disease

Chairperson: Masaki Ieda
University of Tsukuba
Chairpersons' Message

The establishment of human iPS cells was announced in 2007, and 2022 will mark the 15th year. During this period, major developments have been made in various fields such as CRISPR-Cas9 genome editing, single-cell analysis technology, and AI. Until now, the elucidation of the pathophysiology of cardiovascular diseases and the development of treatments have been carried out mainly using model animals and human cell lines. It is now expected that these new basic technologies will be combined and used for these purposes near future. In addition, as a vaccine treatment for covid19, new strategies such as mRNA vaccine and adenovirus vector vaccine have been developed, which are changing the real world significantly. New effective gene therapies have been developed for various diseases and some of them have shown dramatic effects. On the other hand, how about cardiac regenerative medicine? Myocardial regeneration using hematopoietic stem cells and cardiac stem cells heated in the 2000s showed moderate effects in clinic, which is mainly due to paracrine effects rather than direct differentiation of these cells into cardiomyocytes, as revealed by many subsequent scientific verifications. In the future, myocardial regeneration using pluripotent stem cells such as iPS cells, direct cardiac reprogramming, and rejuvenation treatment of cardiomyocytes may be warranted. At this symposium, we would like you to present the latest findings from wide range of cardiovascular research fields.

Japanese

Progress in Medical Device Development -From Non-clinical to Clinical Evaluation-

Chairperson: Masato Nakamura
Toho University, Ohashi Medical Center, Division of Cardiovascular Center
  Masanori Nakamura
Nagoya Institute of Technology
Chairpersons' Message

The COVID-19 pandemic is still ongoing although vaccination is progressing gradually. Domestic development of vaccine is yet to catch up (May 2021), and the safety-net of vaccine procurement from abroad has been rendered unstable. Besides vaccine development, Japan is also behind the world in the development of medical devices. Reportedly, in 2015, Japan experienced an excess of imports of about 800 billion yen in the trade balance for medical devices. Medical devices are now indispensable to support medical care along with pharmaceutical products. Medical devices have a wide variety of produces, from inexpensive ones such as syringes and thermometers to expensive ones such as CT and MRI. One says that 500,000 to 600,000 types of medical devices are currently in use in clinical practice, while medical drugs in use are 15,000. Clinical and non-clinical evaluations of medical devices prior to the market release are essential not only to verify the safety and performance including the clinical benefit but also to speed up the regulatory approval process. From the perspective of animal welfare, non-clinical evaluations will gather more attentions than clinical evaluations. The Japanese Circulation Society and the Japan Society of Mechanical Engineers have signed the collaborative agreement, aiming at mutual understanding between clinical practice and engineering. This session is organized under this collaborative agreement. In this session, we would like to discuss issues concerned with medical device development in light of non-clinical and clinical evaluations. We hope that this session will help solve the problems in the development of medical devices for cardiovascular diseases.

English

Collaboration with cardiologists in the intensive care unit: from cardiovascular management to infection control

Chairperson: Naoki Sato
Department of Cardiovascular Medicine, Kawaguchi Cardiovascular and Respiratory Hospital
  Tomonori Itoh
Iwate Medical University
Chairpersons' Message

Multidisciplinary treatment of cardiovascular emergencies is increasingly required due to the increasing number of elderly patients. In addition to cardiovascular diseases, we are increasingly required to deal with infectious diseases, such as pneumonia and sepsis, and multi-organ disorders, such as renal dysfunction. In order to respond more quickly and accurately to these complex conditions, it is extremely important to collaborate with intensivists. Particularly in the COIVD19 pandemic, an approach to cardiovascular complications, including myocarditis and thrombosis, should be necessary. We would like to provide an opportunity to think about more robust cardiovascular intensive care based on our experience of dealing with this problem through cooperation between cardiologists and intensivists.

English

How to start treatment in the intensive care unit from the pre-hospital stage

Chairperson: Yoshio Tahara
National Cerebral and Cardiovascular Center
  Tomoyuki Endo
Tohoku Medical and Pharmaceutical University Hospital
Chairpersons' Message

Patients admitted to the intensive care unit suffer from a wide variety of diseases. In particular, cardiovascular emergencies such as acute coronary syndromes, heart failure, and acute aortic syndrome require detailed systemic management including the effort to reduce the time to initiate the radical treatment for the causative disease and admit to the intensive care unit, complication management, and hemodynamic assessment.
The effectiveness of quality management in the intensive care unit is built upon the centralization of the patients appropriate for intensive care. For this purpose, collaboration among general practitioners, prehospital ambulance crews, emergency room physicians, and cardiologists is important.
In this session, we will discuss (1) regional registries of cardiovascular diseases requiring intensive care, (2) regional cardiovascular emergency medical care systems (hospital selection, medical control, CCU network), (3) triage in the emergency department (in-hospital systems, establishment of heart teams), (4) emergency treatment of critical cardiovascular illnesses (innovations for early initiation of treatment), (5) hemodynamics evaluation (e.g. ultrasound) and indications for assisted circulation devices (IABP, ECMO, IMPELLA), and (6) measures to assess severity and improve outcome (SOFA score, APACHE score, targeted temperature management, etc.).

In order to establish a system that enables faster and more appropriate transport from emergency scenes to the specialized cardiovascular medical institutions, we hope that the presentations in this session will give useful ideas about the prehospital information and the applicable intervention before hospital admission and contribute to the establishment of a medical care delivery system based on the actual conditions of each region.

English

Challenges and Opportunities in Cancer Therapeutics-Related Cardiovascular Disorders (CTRCD)

Chairperson: Hironobu Minami
Medical Oncology/Hematology, Kobe University Graduate School of Medicine
  Kazuhiro Sase
Clinical Pharmacology & Regulatory Science, Juntendo University
Chairpersons' Message

Progress in medical care for cancer has greatly contributed to lower mortality rates in affected patients, resulting in increasing importance for cancer survivorship care in Japan and throughout the world. Results of epidemiological studies indicate that one of the most important causes of death among cancer survivors is cardiovascular disease (CVD). In addition to common risk factors for CVD and cancer, there is also growing awareness of cancer treatment-related cardiovascular disorders (CTRCD) associated with traditional and modern treatment strategies.

Cardio-oncology is a rapidly developing interdisciplinary field. By sharing the goal of improving patient outcomes, cardiologists and oncologists are tackling new challenges, including the prevention, diagnosis, and treatment of CTRCD. Initially, the need for a team-based approach was recognized at the field level in specialized cancer centers and teaching hospitals. However, as it gradually developed into collaboration at the national and academic levels, the lack of evidence as a basis for clinical practice guidelines and the need for basic, clinical, and epidemiological research became apparent.

In this symposium, with the Japanese Society of Clinical Oncology (JSMO) and the Japanese Society of Oncology and Cardiology (JSMO), we would like to share achievements from the up-to-date cancer therapeutics and discuss the current status and future directions of CTRCD to facilitate interdisciplinary collaboration between oncologists and cardiologists further.

English

Current state and challenges of big data analysis

Chairperson: Satoaki Matoba
Department of Cardiovascular Medicine, Graduate School of Medical Science Kyoto Prefectural University of Medicine
  Yoshihiro Miyamoto
National Cerebral and Cardiovascular Center
Chairpersons' Message

The Second Five-Year Plan to Overcome Stroke and Cardiovascular Disease includes the promotion of registration as one of main five projects. Big data, which is characterized by a large number of cases, relatively quick data conversion, and a large variety of data, is expected to be utilized for understanding the actual state of medical care, improving the quality of medical care, and conducting research. DPC data used in the comprehensive medical payment system can also be considered big data, and Japanese Circulation Society has made DPC data collected through the Japanese Registry Of All cardiac and vascular Diseases (JROAD) available for use in many studies. Registries, such as the JCVSD and J-PCI, with a high degree of completeness can also be considered big data, and many research results have been reported from them. However, many issues remain in the current big data, such as the lack of information on the long-term prognosis of patients and the difficulty in linkage of information on the same patient from different medical institutions. In this symposium, we would like to have you introduce the current status of research using big data and propose remaining issues and their solutions.