Heart transplantation (HTx) is the effective way to improve quality of life as well as survival in terminal heart failure (HF) patients. Since the first heart transplant in 1968 in Japan and in earnest in 1987 at Taiwan, HTx has been continuously increasing in Asia. Although the current percentage of heart transplants from Asia comprises only 5.7% of cases in the International Society of Heart and Lung Transplantation (ISHLT) registry, the values were under-reported and soon will be greatly increased. HTx in Asia shows comparable with or even better results compared with ISHLT registry data. Several endemic infections, including type B hepatitis, tuberculosis, and cytomegalovirus, are unique aspects of HTx in Asia, and need special attention in transplant care. Although cardiac allograft vasculopathy (CAV) is considered as a leading cause of death after HTx globally, multiple observations suggest less prevalence and benign nature of CAV among Asian populations. Although there are many obstacles such as religion, social taboo or legal process, Asian countries will keep overcoming obstacles and broaden the field of HTx.

In most patients with chronic heart failure (HF), levels of circulating cytokines are elevated and the elevated cytokine levels correlate with the severity of HF and prognosis. Various stresses induce subcellular component abnormalities, such as mitochondrial damage. Damaged mitochondria induce accumulation of reactive oxygen species and apoptogenic proteins, and subcellular inflammation. The vicious cycle of subcellular component abnormalities, inflammatory cell infiltration and neurohumoral activation induces cardiomyocyte injury and death, and cardiac fibrosis, resulting in cardiac dysfunction and HF. Quality control mechanisms at both the protein and organelle levels, such as elimination of apoptogenic proteins and damaged mitochondria, maintain cellular homeostasis. An imbalance between protein synthesis and degradation is likely to result in cellular dysfunction and disease. Three major protein degradation systems have been identified, namely the cysteine protease system, autophagy, and the ubiquitin proteasome system. Autophagy was initially believed to be a non-selective process. However, recent studies have described the process of selective mitochondrial autophagy, known as mitophagy. Elimination of damaged mitochondria by autophagy is important for maintenance of cellular homeostasis. DNA and RNA degradation systems also play a critical role in regulating inflammation and maintaining cellular homeostasis mediated by damaged DNA clearance and post-transcriptional regulation, respectively. This review discusses some recent advances in understanding the role of sterile inflammation and degradation systems in HF.

Twenty years ago, chromosomal abnormalities were the only identifiable genetic causes of a small fraction of congenital heart defects (CHD). Today, a de novo or inherited genetic abnormality can be identified as pathogenic in one-third of cases. We refer to them here as monogenic causes, insofar as the genetic abnormality has a readily detectable, large effect. What explains the other two-thirds? This review considers a complex genetic basis. That is, a combination of genetic mutations or variants that individually may have little or no detectable effect contribute to the pathogenesis of a heart defect. Genes in the embryo that act directly in cardiac developmental pathways have received the most attention, but genes in the mother that establish the gestational milieu via pathways related to metabolism and aging also have an effect. A growing body of evidence highlights the pathogenic significance of genetic interactions in the embryo and maternal effects that have a genetic basis. The investigation of CHD as guided by a complex genetic model could help estimate risk more precisely and logically lead to a means of prevention.

Background:Atrial fibrillation (AF) is a common cardiac arrhythmia, associated with increased cardiovascular morbidity and mortality including thromboembolic events. The aims of this study were to assess the prevalence of left atrial appendage (LAA) thrombi in Japanese non-valvular atrial fibrillation (NVAF) patients undergoing preprocedural transesophageal echocardiography (TEE) during anticoagulation therapy, and to compare the efficacy of warfarin and direct oral anticoagulants (DOAC).

Methods and Results:This retrospective study reviewed records of 559 consecutive NVAF patients (445 men; age, 62±11 years) undergoing preprocedural TEE following at least 3 weeks of anticoagulation therapy. Of these, 275 patients had non-paroxysmal AF (49%). LAA thrombus was observed in 15 patients (2.7%). The prevalence of LAA thrombi was similar between the DOAC group (2.6%) and the warfarin group (2.8%, P=0.86). No patients with CHA₂DS₂-VASc score=0, or paroxysmal AF without prior stroke or transient ischemic attack, had LAA thrombi. On univariate analysis, non-paroxysmal AF, structural heart disease, antiplatelet therapy, larger left atrium, higher brain natriuretic peptide (BNP), reduced LAA flow, and higher CHA₂DS₂-VASc score were all associated with LAA thrombi. On multivariate analysis, BNP ≥173 pg/mL remained the only independent predictor of LAA thrombi.

Conclusions:LAA thrombi were found in 2.7% of Japanese NVAF patients scheduled for procedures despite ongoing oral anticoagulation therapy. Incidence of thrombi was similar for patients on DOAC and on warfarin.

Background:The appropriate duration of prehospital cardiopulmonary resuscitation (CPR)administered by emergency medical service (EMS) providers for patients with out-of-hospital cardiac arrest (OHCA) necessary to achieve 1-month survival with favorable neurological outcome (Cerebral Performance Category 1 or 2, CPC 1–2) is unclear and could differ by age.

Methods and Results:We analyzed the records of 35,709 adult OHCA patients with return of spontaneous circulation (ROSC) before hospital arrival in a prospectively recorded Japanese registry between 2011 and 2014. The CPR duration was defined as the time from CPR initiation by EMS providers to prehospital ROSC. The rate of 1-month CPC 1–2 was 21.4% (7,650/35,709). The CPR duration was independently and inversely associated with 1-month CPC 1–2 (adjusted odds ratio, 0.93 per 1-min increment; 95% confidence interval, 0.93–0.94). The CPR duration increased with age (P<0.001). However, the CPR duration beyond which the proportion of OHCA patients with 1-month CPC 1–2 decreased to <1% declined with age: 28 min for patients aged 18–64 years, 25 min for 65–74 years, 23 min for 75–84 years, 20 min for 85–94 years, and 18 min for ≥95 years.

Conclusions:In patients who achieved prehospital ROSC after OHCA, the duration of CPR administered by EMS providers necessary to achieve 1-month CPC 1–2 varied by age.

Background:Atrial arrhythmias (AAs) are frequent after lung transplantation (LT) and late postoperatively. Several predictive factors of early postoperative AAs after LT have been identified but those of late AAs remain unknown. Whether AA after LT affects mortality is still being debated. This study assessed in a large cohort of LT patients the incidence of AAs early and late after surgery, their predictive factors and their effect on mortality.

Methods and Results:We studied 271 consecutive LT patients over 9 years. Mean follow-up was 2.9±2.4 years. 33% patients developed postoperative AAs. Age (odds ratio (OR) 2.35; confidence interval (CI) [1.31–4.24]; P=0.004) and chronic obstructive pulmonary disease (OR 2.13; CI [1.12–4.03]; P=0.02) were independent predictive factors of early AAs. Late AAs occurred 2.2±2.7 years after transplant in 8.8% of the patients. Pretransplant systolic pulmonary arterial pressure (PTsPAP) was the only independent predictive factor of late AA (OR 1.028; CI [1.001–1.056]; P=0.04). Double LT was associated with long-term freedom from atrial fibrillation (AF) but not from atrial flutter (AFL). Early and late AAs after surgery had no effect on mortality. Double LT was associated with better survival.

Conclusions:Early AA following LT is common in contrast with the low occurrence of late, often organized, AA. Early and late AAs do not affect mortality. PTsPAP is an independent predictor of late AA. Double LT protects against late AF but not AFL.

Background:The CRYO-Japan PMS study indicated that cryoballoon ablation (Cryo-Abl) has a lower acute success rate of pulmonary vein isolation (PVI) for the right and left inferior PVs (RIPV and LIPV, respectively) than for the superior PVs. This study aimed to determine if the orientation and position of the inferior PVs are related to the difficulty of acute success of PVI.

Methods and Results:We investigated 30 consecutive patients who underwent Cryo-Abl. A “difficult PV” was defined as the requirement for >2 cooling applications and/or touch-up ablation to achieve PVI. We measured the ventral angle between the vertical line and the direction of each PV trunk (PV angle) on the transverse plane of enhanced CT images. PV position was defined as the difference in the levels between the bottom of the RIPVs and the non-coronary cusp of the aorta. PV angle <105° and PV position <1.250 mm were independent factors of difficult RIPV isolation (PV angle: odds ratio (OR)=23.80, confidence interval (CI) −3.15528 to −0.53622, P=0.002; PV position: OR=12.14, CI −2.77301 to −0.23160, P=0.014). PV position <16.875 mm was also related to the difficulty of LIPV isolation (OR=5.78, CI −1.77095 to −0.09474, P=0.027).

Conclusions:RIPV with ventral orientation may require difficult maneuvers to advance an ablation system towards it. Low take-off of the inferior PVs may cause non-coaxial configuration of balloon catheters towards the direction of these veins.

Background:We evaluated whether vessel diameters measured by preprocedural computed tomography angiography (CTA) affects the immediate and late outcomes of endovascular therapy for iliac artery diseases.

Methods and Results:A total of 254 patients who underwent endovascular treatment for iliac artery diseases were retrospectively evaluated. Minimum vessel diameters were measured on preprocedural CTA images at target lesions, common iliac arteries, and external iliac arteries (EIA). Predictors of immediate and late procedural outcomes were analyzed. Procedural failure or vessel-specific complications occurred in 29 patients (11%): wire passage failure (n=10), rupture (n=8), and distal embolization (n=11). Target lesion revascularization (TLR) was required in 6.0% at 2 years. Independent predictors of procedural failure or vessel-specific complications were small minimum vessel diameter of the target lesion (odds ratio [OR]=0.68, P=0.008) or EIA (OR=0.67, P=0.008), and chronic total occlusions (OR=3.78, P=0.036). Small minimum EIA diameter (hazard ratio [HR]=0.66, P=0.017) and chronic total occlusions (HR=4.45, P=0.024) were independent predictors of TLR in patients with technical success.

Conclusions:Small vessel diameter of the target lesion or EIA was an independent predictor of procedural failure or vessel-specific complications. Small vessel diameter, particularly of the EIA, was also associated with increased TLR after successful endovascular therapy for iliac artery lesions.

Background:Understanding that the common iliac arteries (CIA) are shorter in Asian patients, we investigated whether this anatomic difference affects the clinical outcomes of internal iliac artery (IIA) exclusion during endovascular aneurysm repair (EVAR) of aortoiliac aneurysm and thus limits the use of IIA-preserving devices in Japanese patients.

Methods and Results:From 2008 to 2014, 69 Japanese patients underwent EVAR of aortoiliac aneurysms with 53 unilateral and 16 bilateral IIA exclusions. One patient had persistent buttock claudication during follow-up; however, colonic or spinal cord ischemia was not observed. Anatomic suitability was investigated for the iliac branch device (IBD) by Cook Medical and the iliac branch endoprosthesis (IBE) by WL Gore: 87 aortoiliac segments were analyzed, of which 17% met the criteria for the IBD, 25% met the criteria for the IBE and 40% met the criteria for either. Main exclusions for the IBD were IIA diameter >9 mm or <6 mm (47%) and CIA length <50 mm (39%). Main exclusions for the IBE were proximal CIA diameter <17 mm (44%) and aortoiliac length <165 mm (24%).

Conclusions:EVAR with IIA exclusions in Japanese patients showed low incidence of persistent buttock claudication and no major pelvic complications. Aorto-iliac morphology demonstrated smaller proximal CIA diameters and shorter CIA lengths, limiting the use of IIA-preserving devices.

Background:We evaluated the outcomes of totally endoscopic minimally invasive surgery for atrial septal defect (ASD) using a glutaraldehyde-treated autologous pericardial patch in the transcatheter interventional era.

Methods and Results:We retrospectively reviewed 37 consecutive patients who underwent totally endoscopic ASD closure with a glutaraldehyde-treated autologous pericardial patch between June 2011 and April 2015. All patients had been deferred from catheter-based intervention for clinical or anatomical reasons. We analyzed operative outcomes and postoperative echocardiographic data. The mean age was 45.7±16.5 years, and 25 patients (67.6%) were women. The mean ratio of pulmonary to systemic flow was 2.4±0.7. Six patients (16.2%) underwent concomitant tricuspid valve repair, and 3 patients (8.1%) underwent concomitant atrial fibrillation surgery. There were no operative deaths, and the median length of hospital stay was 5 days. Postoperative echocardiography revealed trivial residual shunt in 1 patient. During the follow-up period, there were no re-interventions for ASD or readmission for heart failure. Follow-up echocardiography revealed no recurrent shunt or calcification of the autologous pericardial patch.

Conclusions:Totally endoscopic ASD closure with a glutaraldehyde-treated autologous pericardial patch demonstrated excellent outcomes. It is a useful option for patients with unfavorable anatomy or other reasons excluding transcatheter intervention.

Background:The natural history of left ventricular noncompaction (LVNC) is largely unsolved, so the aim of the present study was to clarify the clinical features and long-term prognosis of children with LVNC until adulthood.

Methods and Results:We conducted a nationwide survey over 20 years and compared the clinical features, anatomical characteristics and long-term prognosis of 205 patients divided into 2 classifications: infantile type (diagnosed at <1 year of age: 108 cases) and juvenile type (diagnosed 1–15 years of age: 97 cases). Most patients diagnosed during infancy had heart failure (HF) at initial presentation (60.19%), while the majority of juvenile cases were asymptomatic (53.61%) but their event-free survival rate decreased gradually, because of later HF, thromboembolism and fatal arrhythmias. The initial LVEF was significantly lower in the infantile type and correlated with the thickness of the compacted layer in the LV posterior wall (LVPWC) and LV end-diastolic dimension (LVDD) Z-score, but not to the noncompacted to compacted layer (N/C) ratio. Survival analysis showed prognosis was similarly poor for both types after 2 decades. The significant risk factors for death, heart transplantation or implantable cardioverter-defibrillator insertion were congestive HF at diagnosis and lower LVPWC Z-score but not age of onset.

Conclusions:LVNC of both types showed poor long-term prognosis, therefore ongoing follow-up is recommended into adulthood. HF at diagnosis and LVPWC hypoplasia are major determinants of poor prognosis.

Background:Use of cocaine is widespread and associated with several cardiovascular diseases. Recent CMR studies indicate frequent myocardial scar/fibrosis in asymptomatic cocaine abusers (CA).

Methods and Results:This study used a combination of advanced CMR tissue characterization techniques, including late gadolinium enhancement (LGE) for focal, and extracellular volume (ECV) imaging for diffuse myocardial injury/fibrosis, with circulating biomarkers for a comprehensive characterization of myocardial injury. We included 20 cardiac asymptomatic CA and a control group of 20 healthy volunteers. The comprehensive assessment included physical examination, resting ECG, exercise ECG, cardiac biomarkers, transthoracic echocardiogram and CMR. We did not find significant differences between CA and controls either in functional CMR parameters such as LVEDVi, LVESVi, LVEF, LV mass index, or in global myocardial ECV. Neither CA nor controls had evidence of myocardial edema on T2-weighted CMR, but 8 CA (40%), and none of the controls had focal myocardial scar (P<0.01). Interestingly, CA with focal myocardial scar on LGE had significantly higher high-sensitivity troponin I (hs-TNI) compared with CA without focal scar (median, 1.7 ng/L; IQR, 1.3–2.5 ng/L vs. 0.6 ng/L; 0.4–1.3 ng/L; P<0.01).

Conclusions:Focal myocardial injury in terms of subtle LGE in 40% of asymptomatic CA was associated with higher hs-TNI. Comprehensive assessment including advanced ECV imaging indicates a focal rather than diffuse pattern of myocardial involvement in asymptomatic CA.

Background:Heart failure (HF) is a disease of neurohumoral dysfunction and current pharmacological therapies for HF have not improved mortality rates, thus requiring additional new strategies. Waon therapy for HF patients may be a complementary strategy with peripheral vasodilation via nitric oxide. We hypothesized that Waon therapy would improve neurohumoral factors, such as natriuretic peptides (NP) and the renin-angiotensin-aldosterone system (RAAS) in HF.

Methods and Results:Plasma samples were collected from patients enrolled in the WAON-CHF Study (Waon therapy (n=77) or control (n=73)) before and after the treatment. B-type NP (BNP), C-type NP (CNP), and aldosterone (Aldo) levels were measured by respective specific radioimmunoassays. Although clinical parameters significantly improved in the Waon group compared with the control group, BNP, Aldo, and CNP levels were not statistically different between groups. On subanalysis with patient variables, BNP levels were improved in the Waon group treated with angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker or spironolactone. In addition, Aldo levels were improved in the Waon group patients with diabetes mellitus, hypertension, and inotrope use, and CNP levels were improved in Waon group patients with estimated glomerular filtration rate <60 mL/min/1.73 m². These changes were not observed in the control group.

Conclusions:Waon therapy may accelerate the favorable actions of RAAS modulators in HF. (WAON-CHF Study: UMIN000006705)

Background:As adolescents rarely experience cardiovascular events, surrogate markers of atherosclerosis are useful to justify and monitor effects of primary prevention and therapy of risk factors. Endothelial function assessed by reactive hyperemic peripheral arterial tonometry (RH-PAT) resulting in a reactive hyperemic index (RHI) is a noninvasive method with limited data for use in children and adolescents.

Methods and Results:We performed a total of 931 RHI measurements in 445 high-school students, aged 10–17 years, over a time period of 5 years. Students were randomized by class to 60 min physical exercise (PE) at school daily (intervention group), or 2 units of 45-min PE weekly (control group). To characterize the factors influencing the RHI, anthropometry, cardiopulmonary exercise testing, blood cholesterol and quality of life were assessed and used to build mixed linear models. Main influential factors were age, with an increase of RHI from 1.53±0.42 in the youngest to 1.96±0.59 in the oldest students, sex, with higher values in girls, and physical activity. This increase adjusted by age and sex was estimated as 0.11 [0.08, 0.14] per year. RHI was higher in the intervention group by 0.09 [−0.05, 0.23] in comparison with the control group.

Conclusions:If RH-PAT is used in research or as a clinical tool in adolescents, the shown age- and sex-dependence of RHI have to be taken in account.

Background:There are no definitive diagnostic criteria or follow-up strategies for long QT syndrome (LQTS) in children with a borderline long QT interval (b-LQT).

Methods and Results:We retrospectively evaluated the clinical course, genetic testing results, corrected QT interval (QTc), and LQTS score of 59 school-aged children (5–18 years old) with a b-LQT (400≤QTc<500 ms). Syncope, but neither aborted cardiac arrest nor sudden cardiac death, occurred in 2 patients during the follow-up (6±3.4 years) with LQTS scores ≥4.5 points. The genetic testing results were positive in 92%, 57%, and 67% of patients with high, intermediate, and low probabilities of LQTS, respectively. The maximum and mean QTc during the follow-up significantly differed among the categories with a probability of LQTS, but not the minimum QTc. However, the QTc at rest and at the recovery point after exercise stress testing dramatically changed at the last follow-up. Consequently, the probability of LQTS changed in half of the patients.

Conclusions:The LQTS score is a reasonable indicator for evaluating school-aged children with a b-LQT, and patients with a low LQTS score appear to be at low risk for cardiac events. However, the LQTS score can change during follow-up. Therefore, when there is doubt or concern for patients with a b-LQT, it is preferable to continue following them. Guidelines on follow-up strategies are desired for b-LQT.

Background:Acute kidney injury (AKI) is associated with poor outcome after acute myocardial infarction (AMI), but whether hemodynamic status at presentation influences this prognostic significance is unknown.

Methods and Results:A total of 2,798 AMI patients admitted within 48 h after symptom onset and who underwent urgent coronary angiography were enrolled in the present study. AKI was defined as an increase in serum creatinine ≥0.3 mg/dL or ≥50% within 48 h during hospitalization. Patients were classified into 3 groups according to Killip class on admission: Killip 1, n=2,164; Killip 2–3, n=366; and Killip 4, n=268. AKI occurred more frequently with increasing Killip class (Killip 1, 2–3, and 4: 6.3%, 15.3%, and 31.3%, respectively; P<0.001). AKI was associated with increased in-hospital mortality, regardless of Killip class (non-AKI and AKI patients: 1.1% vs. 6.6% in Killip 1; 5.2% vs. 35.7% in Killip 2–3, and 28.8% vs. 45.2% in Killip 4, P<0.01 for all). On multivariate analysis, the adjusted OR of AKI for in-hospital mortality in Killip 1, Killip 2–3, and Killip 4 were 3.79 (95% CI: 1.54–9.33, P=0.004), 5.35 (95% CI: 2.67–10.7, P<0.001), and 1.48 (95% CI: 0.94–2.35, P=0.093), respectively.

Conclusions:In AMI patients undergoing urgent coronary angiography, AKI was significantly associated with increased in-hospital mortality in Killip 1 as well as Killip 2–3 at presentation, but not in Killip 4.

Background:Although the mainstay of treatment for acute decompensated heart failure (ADHF) is decongestion by diuretic therapy, it is often associated with worsening renal function (WRF). The effect of tolvaptan, a selective V2 receptor antagonist, on WRF in ADHF patients with preserved left ventricular ejection fraction (LVEF) is unknown.

Methods and Results:We enrolled 50 consecutive ADHF patients whose LVEF on admission was ≥45%. Patients were randomly assigned to either tolvaptan add-on (n=26) or conventional diuretic therapy (n=24). The primary endpoint was the incidence of WRF, defined as an increase in serum creatinine (Cr) ≥0.3 mg/dL or 50% above baseline within 48 h of randomization. There was no significant difference between the 2 groups in the change in body weight or the total urine volume during 48 h. However, the change in Cr (∆Cr) at 24 and 48 h after randomization and the incidence of WRF (12% vs. 42%, P=0.0236) were significantly lower, and the fractional excretion of urea (FEUN) at 24 and 48 h after randomization was significantly higher in the tolvaptan group. There was an inverse correlation between ∆Cr and FEUN at 48 h after randomization.

Conclusions:Tolvaptan can alleviate congestion with a significantly lower risk of WRF in ADHF patients with preserved LVEF, presumably through maintenance of renal perfusion.

Background:Balloon aortic valvuloplasty (BAV) is resurging as a bridge treatment in patients with severe aortic stenosis (AS) with a dissemination of transcatheter aortic valve implantation. However, the significantly high periprocedural mortality and complication rates still limit the indications of BAV. Further efforts are needed to improve the safety and efficacy of BAV.

Methods and Results:We retrospectively investigated the safety and efficacy of simultaneous biplane mode of 3-dimensional transesophageal echocardiography (biplane-TEE) guided antegrade transseptal multiple-inflation BAV, with gradual upsizing of the balloon, by enrolling 20 consecutive AS patients who underwent BAV. The median age was 83 years, and there were 6 male patients (30.0%). The clinical frailty scale was 4, and the Society of Thoracic Surgeon score was 14.5%. The balloon was inflated at a median of 18 times, which improved the mean aortic valve pressure gradient from 43.0 to 15.2 mmHg (P<0.001). We safely performed BAV in all patients, without periprocedural death or symptomatic stroke, although asymptomatic stroke was detected in 8 patients (42.1%) on diffusion-weighted magnetic resonance imaging. Kaplan-Meier estimates showed that the survival rate was 84.0% and cardiovascular death-free survival was 88.9% at 1-year.

Conclusions:Biplane-TEE guided antegrade multiple-inflation BAV might have the potential to improve periprocedural survival without increasing complications, compared with conventional retrograde BAV in patients with severe AS.

Background:The mechanisms of heart failure with preserved ejection fraction (HFpEF) need to be clarified immediately.

Methods and Results:We examined diastolic function relative to arterial elasticity among hypertensive patients with preserved EF. Diastolic elastance (EdI)/effective arterial elastance (EaI), EdI/EaI=E/e’/(0.9×systolic blood pressure [SBP]) was significantly more impaired in women than in men among patients ≥75 years. The higher EdI/EaI value in elderly women implies they are intermittently exposed to higher left ventricular filling pressure relative to SBP during daily life.

Conclusions:Highly fluctuating impairment of diastolic function relative to arterial elasticity may predispose elderly women to pulmonary edema.