Demographic Determinants Influencing the Adoption of Genetic Testing for Cardiovascular Diseases in Japan　- Insights From a Large-Scale Online Survey.

Background: Genetic testing for cardiovascular diseases (CVD) is vital, but is underutilized in Japan due to limited insurance coverage, accessibility, and public disinterest. This study explores demographic factors influencing the decision to undergo CVD genetic testing. Methods and Results: We compared the CVD history and baseline demographics of Japanese adults who underwent genetic testing with those who did not, using an Internet survey. The regression model indicated that men, the young, married individuals, parents, and those with CVD, higher score for rationality, and lower quality of life were more inclined to undergo testing. Conclusions: Targeting strategies for CVD genetic testing could focus on these demographics.

Clinical features of quadricuspid aortic valve in middle-aged and elderly patients: Insights from a regional study.

BACKGROUND: Quadricuspid aortic valve (QAV) is a rare congenital disease. The clinical characteristics of this disease remain unclear except for those in relatively young patients reported from tertiary referral hospitals. The aim of this study was to determine the clinical features of QAV in a regional population. METHODS AND RESULTS: We retrospectively investigated 25 340 consecutive patients over middle age (median age, 73 (IQR 65-80) years; range, 45-102 years) who underwent transthoracic echocardiography (TTE) at our institute during the period from April 2008 to December 2023. Eight (0.032%) of the patients (median age, 65 years; range, 47-91 years) were diagnosed with QAV. Six patients suffered from aortic regurgitation (AR), and one patient had mild aortic stenosis at the time of QAV diagnosis. Two patients who had severe AR at referral underwent aortic valve surgery. The severity of AR in the other patients was moderate or less. During a median follow-up period of 27 months (range, 1-171 months), none of the patients other than above two patients had cardiac events. One patient died from a non-cardiac cause at 94 years of age. CONCLUSIONS: Patients diagnosed with QAV after middle age, who do not exhibit severe valve insufficiency at the time of diagnosis, may not experience worse clinical outcomes. However, further research is required for a better understanding of the long-term outcomes.

Prognostic impact of frailty based on a comprehensive frailty assessment in patients with heart failure.

AIMS: This study aimed to evaluate the impact of frailty and living function domains based on the Kihon Checklist (KCL), a questionnaire for a comprehensive frailty assessment, on prognosis in patients with acute heart failure (AHF). METHODS AND RESULTS: The Kochi Registry of Subjects with Acute Decompensated Heart Failure (Kochi YOSACOI) study was a prospective multicentre cohort study enrolling 1061 patients hospitalized for AHF from May 2017 to December 2019 in Japan. We divided patients into three groups according to the severity of frailty using the KCL and compared clinical outcomes after discharge. The primary endpoint was all-cause death, and the secondary outcomes were cardiovascular death, heart failure (HF) rehospitalization, and the composite event of cardiovascular death and HF rehospitalization. Of 936 patients (median age, 81 years; 48.9% women) who could be assessed for frailty, we identified frailty in 501 patients (53.5%), prefrailty in 290 patients (31.0%), and non-frailty in 145 patients (15.5%). Compared with prefrail and non-frail patients, frail patients were older (83 vs. 79 and 72 years, P < 0.001), were more likely to be women (53.9% vs. 43.1% and 43.4%, P = 0.005), and were more likely to have a history of previous HF hospitalization (35.4% vs. 25.3% and 19.6%, P < 0.001) and multimorbidity (90.8% vs. 81.0% and 73.8%, P < 0.001). Frail patients had a lower rate of discharge to home (79.7% vs. 94.8% and 96.5%, P < 0.001). During the 2 year follow-up period, frail patients had a higher incidence rate of all-cause death, cardiovascular death, and HF rehospitalization (log-rank P < 0.001, P < 0.001, and P = 0.003, respectively). After adjusting for other prognostic factors, multivariate analysis showed that frailty was associated with all-cause death [adjusted hazard ratio (HR): 2.917, 95% confidence interval (CI): 1.326-6.417, P = 0.008] and cardiovascular death (adjusted HR: 7.026, 95% CI: 1.700-29.030, P = 0.007). Among all domains of the KCL, the cognitive function domain was associated with a higher risk of all-cause death (P = 0.004) and cardiovascular death (P < 0.001). The depression domain remained associated with a higher risk of HF rehospitalization (P = 0.045). The risk for all-cause death increased with an increase in total KCL score (adjusted HR: 1.819, 95% CI: 1.300-2.547, P < 0.001). CONCLUSIONS: The KCL is a useful tool for risk stratification of adverse outcomes in patients with AHF. Functional declines in psycho-emotional domains including cognitive function and depressed mood contribute to adverse outcomes.

α-L-iduronidase fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa) for mucopolysaccharidosis type I: A phase 1/2 trial.

Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose dependently and reached its maximum approximately 4 h after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated that its somatic efficacy was comparable to that of laronidase.

Associations between electrocardiographic findings and echocardiographic profiles in patients with hypertrophic cardiomyopathy.

BACKGROUND: The relationships between electrocardiography (ECG) findings and echocardiographic profiles in patients with hypertrophic cardiomyopathy (HCM) are not fully understood. METHODS: One hundred forty patients (mean age: 62.9 ±â€¯15.3 years, 96 men) with HCM were studied. We assessed the associations between ECG findings and echocardiographic findings including maximum left ventricular wall thickness, HCM subtypes and distribution of left ventricular hypertrophy (LVH): the LV was divided into basal, mid, and apical segments by dividing it into thirds along the long axis. RESULTS: In ECG, LVH by voltage criteria, abnormal Q wave, negative T wave, and giant negative T wave (GNT) were observed in 74 (53 %), 30 (21 %), 132 (94 %), and 25 (18 %) of the patients, respectively. In two groups with and without an LVH pattern according to voltage criteria in ECG, there were no significant differences in maximum LV wall thickness, subtype of HCM, and distribution of LVH. Regarding an abnormal Q wave, the proportion of patients with LVH in the basal segment was significantly higher in patients with an abnormal Q wave than in patients without an abnormal Q wave (87 % vs 61 %, p = 0.008). An abnormal Q wave was not observed in patients with LVH confined to the apex. Patients with a GNT included patients with LVH located at only the apex (apical HCM), LVH from the mid segment to apex, and LVH from the base to apex. No GNT was found in patients with hypertrophy located in the upper region from the base to mid segment of the LV. CONCLUSIONS: In patients with HCM, there was no significant correlation between the presence of LVH by voltage criteria in ECG and echocardiographic findings. An abnormal Q wave was associated with disproportionate hypertrophy of the basal wall and a GNT reflected the presence of LVH in the apical segment.

Mitral valve repair with papillary muscle repositioning for functional mitral regurgitation (Type IIIb) with metal allergies: a case report.

Background: Prosthetic heart valves, rings, and clips commonly used in heart surgery may contain metals, such as nickel and cobalt, that can cause severe hypersensitivity reactions in allergic patients. These reactions can cause paravalvular leakage and valve dysfunction. Similarly, stainless steel sternal wires can cause contact dermatitis. We should select rings, valves, and wires that do not contain any metals known to cause allergies in patients undergoing cardiac surgery. Case summary: We report the case of a 79-year-old man with severe functional mitral regurgitation (Type IIIb) and a history of nickel and cobalt allergies. We safely performed mitral valve repair with papillary muscle repositioning with nickel- and cobalt-free rings in this patient. He was discharged from the hospital on the 26th postoperative day without dialysis intervention. Two years after surgery, mitral and tricuspid regurgitation had not worsened. Discussion: According to the 2020 American Heart Association guidelines, surgery for severe functional mitral valve insufficiency (Type IIIb) is considered class IIb. Meanwhile, transcatheter edge-to-edge repair is class IIa. Long-term regurgitation is difficult to control with valve replacement and annuloplasty alone; recurrence has been observed. Therefore, additional techniques were considered. Papillary muscle repositioning has been reported and shown good results. The method used in the present case made intervening in the subvalvular tissue easy and demonstrated technical feasibility, safety, and effectiveness.

Genetic Testing for Cardiomyopathy in Japan 2022: Current Status and Issues of Precision Medicine.

Although many causative genes for primary cardiomyopathy have been identified, the use of genetic testing in routine practice is limited in Japan presently. Genetic diagnosis has been reported to be useful for early diagnosis through cascade genetic screening in the family, differentiating secondary cardiomyopathies, and predicting prognosis in some patients; nonetheless, the acquisition of genetic information for cardiomyopathy is stagnating in actual clinical practice. There seem to be a number of reasons for this phenomenon, and although the use of next-generation sequencers has resolved some of the past issues, the importance of pathogenicity studies of variants that are identified is growing. To ensure that patients with cardiomyopathy and their relatives can receive precision medicine, the results of genetic analysis linked to clinical information need to be collected, and a database of variants in Japanese people needs to be established.

High-sensitivity Cardiac Troponin T Is a Useful Biomarker for Predicting the Prognosis of Patients with Systemic Sarcoidosis Regardless of Cardiac Involvement.

Objective Cardiac involvement defines the prognosis for patients with systemic sarcoidosis. Despite advancements in techniques for diagnosing cardiac lesions, there remains significant room for improvement in cardiac screening and prognostic prediction. The present study therefore assessed the prognostic factors associated with cardiovascular events in patients with sarcoidosis. Methods We retrospectively studied 132 patients with systemic sarcoidosis and evaluated the clinical data obtained between 2009 and 2022. A Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate the associations between cardiovascular events and prognostic factors. Results The median age of the patients at the diagnosis was 64.0 (55.0-71.0) years old. During a mean follow-up period of 6.3±3.2 years, 28 patients suffered from cardiovascular events. Patients in the event group had more severe heart failure symptoms, more frequent ventricular tachycardia, higher serum high-sensitivity cardiac troponin T (hs-cTnT) values [0.025 (0.017-0.044) vs. 0.011 (0.007-0.019) ng/mL, p<0.001], and lower left ventricular ejection fraction values than those in the non-event group. These trends were observed even if the patients were not diagnosed with cardiac involvement at the time of enrollment. A multivariate analysis revealed that hs-cTnT was an independent biomarker for the prediction of cardiac events (hs-cTnT >0.014 ng/mL: HR: 7.31, 95% confidence interval: 2.20 to 24.28, p<0.001). Conclusion Hs-cTnT is a useful biomarker for predicting cardiovascular events in patients with sarcoidosis, even if cardiac involvement is not detected at the initial evaluation.

Transient decrease in the depth of the negative T wave in apical hypertrophic cardiomyopathy is a sign of left anterior descending artery stenosis: a case series.

Background: In patients with apical hypertrophic cardiomyopathy (HCM), electrocardiography (ECG) often shows left ventricular hypertrophy (LVH) and a negative T wave. A negative T wave often disappears over time due to degeneration of the apical myocardium. However, there are limited reports on the temporary change of a negative T wave in patients with HCM. Case summary: We report three apical HCM patients with LVH and T wave inversion on their previous ECG who showed a temporary decrease in the depth of the negative T wave. All of them had significant stenosis of coronary arteries including the left anterior descending artery (LAD). After revascularization for the LAD lesion, their ECG returned to the previous depth of the negative T wave. Discussion: The cases presented here suggested that a temporary decrease in the depth of the negative T wave in apical HCM patients may be one of the signs of ischaemia in the anterior-apical region caused by severe stenosis of the LAD.

Current state of knowledge and information sharing among home healthcare professionals involved in heart failure management.

BACKGROUND: The current state of knowledge related to disease management of heart failure (HF) and information coordination practices provided by non-physician healthcare professionals such as nurses and therapists working at home-visit nursing stations in Japan are not well known. METHODS: A questionnaire survey of healthcare professionals working at home-visit nursing stations was conducted in Kochi Prefecture. Data collected from 151 nurses and therapists were analyzed. RESULTS: Regarding the basic characteristics of the respondents, the majority were in their 30s and 40s, and approximately 75 % were nurses. In terms of HF knowledge, 53.7 % of respondents said that they "knew" about the New York Heart Association classification. A total of 40.0 % of respondents said that they were "aware of the existence of the HF handbook", and only 29.3 % of respondents said that they "knew" the classification of HF stages. When they were asked about their level of satisfaction related to all medical information provided by the hospital and hospital wards, no one was "very satisfied", and the most common response (66.2 %) was "not very satisfied". In the essential medical information that respondents wanted to obtain from hospitals and hospitals wards for managing HF patients at home, "medication at discharge", "current medical history", "fluid intake and restrictions", "symptoms, signs, and response to exacerbation", and "ideal body weight" were the top five contents. CONCLUSION: In the cross-sectional study targeted healthcare professionals working at home-visit nursing stations in Kochi Prefecture, the current state of knowledge related to HF and information coordination practices among healthcare professionals were not fully satisfactory in HF management. It is necessary to increase educational opportunities regarding HF for them and further promote information sharing.

External Validation of the Japanese Clinical Score for Mortality Prediction in Patients With Acute Heart Failure.

BACKGROUND: To predict mortality in patients with acute heart failure (AHF), we created and validated an internal clinical risk score, the KICKOFF score, which takes physical and social aspects, in addition to clinical aspects, into account. In this study, we validated the prediction model externally in a different geographic area.Methods and Results: There were 2 prospective multicenter cohorts (1,117 patients in Osaka Prefecture [KICKOFF registry]; 737 patients in Kochi Prefecture [Kochi YOSACOI study]) that had complete datasets for calculation of the KICKOFF score, which was developed by machine learning incorporating physical and social factors. The outcome measure was all-cause death over a 2-year period. Patients were separated into 3 groups: low risk (scores 0-6), moderate risk (scores 7-11), and high risk (scores 12-19). Kaplan-Meier curves clearly showed the score's propensity to predict all-cause death, which rose independently in higher-risk groups (P<0.001) in both cohorts. After 2 years, the cumulative incidence of all-cause death was similar in the KICKOFF registry and Kochi YOSACOI study for the low-risk (4.4% vs. 5.3%, respectively), moderate-risk (25.3% vs. 22.3%, respectively), and high-risk (68.1% vs. 58.5%, respectively) groups. CONCLUSIONS: The unique prediction score may be used in different geographic areas in Japan. The score may help doctors estimate the risk of AHF mortality, and provide information for decisions regarding heart failure treatment.

Frailty interferes with the guideline-directed medical therapy in heart failure patients with reduced ejection fraction.

AIMS: Guideline-directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction (HFrEF) is recommended in clinical guidelines, but elderly patients have not fully received GDMT in the clinical situation. The aim of this study was to determine the clinical characteristics of patients who have not received GDMT and the association between implementation of GDMT at discharge and physical frailty in patients with HFrEF who were hospitalized for acute decompensated heart failure (ADHF). METHODS AND RESULTS: This study was a cross-sectional study with a retrospective analysis of the Kochi YOSACOI study, a prospective multicentre observational study that enrolled 1061 patients hospitalized for ADHF from May 2017 to December 2019 in Japan. Of 339 patients (32.0%) with HFrEF, 268 patients who were assessed for physical frailty by the Japanese version of the Cardiovascular Health Study criteria were divided into two groups: those with GDMT (135 patients, 50.4%) and those without GDMT (133 patients, 49.6%). GDMT was defined as the prescription of a combination of renin-angiotensin system (RAS) inhibitors (angiotensin-converting inhibitors or angiotensin receptor blockers) and beta-blockers. The median age of patients with HFrEF was 76 years (interquartile range, 67-83 years). Patients without GDMT were older than patients with GDMT (73 years vs. 78 years, P < 0.001). Patients without GDMT tended to have more prior HF admission than did patients with GDMT (P = 0.004), and patients without GDMT had lower levels of estimated glomerular filtration rate (P < 0.001) than those in patients with GDMT. Physical frailty was observed in 54.1% of the patients without GDMT and in 38.5% of the patients with GDMT (P = 0.014). Patients without GDMT had a higher rate of cognitive impairment than that in patients with GDMT (P = 0.009). RAS inhibitors only, beta-blockers only, and both RAS inhibitors and beta-blockers were less frequently prescribed in patients with physical frailty than in patients with physical non-frailty (52.0% vs. 86.7%, P < 0.05; 70.1% vs. 100.0%, P < 0.05; 42.5% vs. 86.7%, P < 0.01, respectively). In logistic regression analysis, compared with physical non-frailty, physical frailty was significantly associated with no implementation of GDMT (odds ratio: 6.900, 95% confidence interval: 1.420-33.600; P = 0.017), independent of older age and severe renal dysfunction. CONCLUSIONS: The results of this study suggest that physical frailty is one of the factors that may withhold GDMT in patients with HFrEF.

Estimating the prevalence, clinical characteristics, and treatment patterns of hypertrophic cardiomyopathy in Japan: A nationwide medical claims database study.

BACKGROUND: Limited data are available regarding therapies for hypertrophic cardiomyopathy (HCM). This study assessed the prevalence, clinical characteristics, and treatment patterns of HCM in Japan. METHODS: This retrospective database study analyzed data from 438 hospitals in the Japan Medical Data Vision database from 2016 to 2020. We identified 3913 patients (15 %) with obstructive HCM (oHCM) and 21,714 patients (85 %) with nonobstructive HCM (nHCM). RESULTS: The estimated total number of patients with oHCM and nHCM in 2020 among Japanese hospitals was 8500 and 43,500, respectively. The prevalence of oHCM and nHCM steadily increased by 27 % and 12 %, respectively, from 2016 to 2020, with a 1:5.2 ratio of oHCM to nHCM in 2020. The mean age of the oHCM and nHCM populations was 72 and 70 years, respectively, and comorbidities included atrial fibrillation (AF) (oHCM, 33.8 %; nHCM, 32.2 %), other arrythmia (30.1 %; 27.6 %), and stroke (16.6 %; 16.4 %). Furthermore, 45.0 % of oHCM and 37.7 % of nHCM patients had undergone at least one hospitalization. A substantial number of HCM patients aged between 20 and 59 years reported AF (oHCM, 17-37 %; nHCM, 4-24 %) and stroke (oHCM, 0-12 %; nHCM, 3-10 %). ß-blockers (oHCM, 64.0 %; nHCM, 42.1 %) were the most frequently prescribed treatment, followed by Na channel blockers (29.5 %; 5.7 %), calcium channel blockers (18.1 %; 8.8 %), direct oral anticoagulants (14.5 %; 15.2 %), and warfarin (11.0 %; 11.4 %). CONCLUSIONS: This study provides important information on the current epidemiological and clinical characteristics of HCM in Japan.

Unilateral Pulmonary Edema in Patients With Acute Mitral Regurgitation Caused by Chordal Rupture.

Background: Cardiogenic unilateral pulmonary edema (UPE) has been reported as an unusual condition and to occur in association with severe mitral regurgitation (MR). However, the prevalence of UPE in patients with severe MR remains unknown. Methods and Results: Among 143 consecutive patients with chordal rupture and significant MR, 38 patients with acute severe MR were studied. The prevalence of UPE was 50% (19 patients); all these patients had right-sided UPE. Eight (21%) patients had bilateral pulmonary edema (BPE). All 8 patients with BPE and 18 of 19 patients with UPE had chordal rupture of the posterior leaflet. All patients with UPE and BPE had severe MR with similar left atrial size. Chest radiographs taken ≤48 h from symptom onset diagnosed UPE in 15 of 19 (79%) patients and BPE in 3 of 8 (38%) patients (P=0.037). Chest radiographs taken >48 h from symptom onset diagnosed UPE in 4 (21%) patients and BPE in 5 (62%) patients (P=0.037). Conclusions: The prevalence of UPE was estimated as 50%; it was most frequently right sided and almost always associated with chordal rupture of the posterior leaflet. UPE is not rare, but common, particularly shortly after the development of acute severe MR caused by chordal rupture.

Acute Left Circumflex Coronary Artery Occlusion　- Diagnostic Problems of Initial Electrocardiographic Changes.

Background: Acute coronary syndrome (ACS) with occlusion of the left circumflex coronary artery (LCX) poses diagnostic problems that may lead to a delay in reperfusion. Methods and Results: From a group of 1,269 consecutive patients with ACS, 138 patients with ACS due to LCX occlusion were analyzed for clinical, electrocardiographic, and angiographic presentations, as well as door-to-balloon (DTB) time. Electrocardiographic changes were classified into 4 patterns: ST-segment elevation in inferior/lateral leads (ST-E); ST-segment depression in V1-V4 (ST-D); no significant ST changes (No-ST); and others. The No-ST group was associated with a longer DTB time (P<0.0001) compared with the ST-E and ST-D groups. Compared with the No-ST and ST-E groups, the ST-D group presented with a more advanced Killip class (P=0.003), greater peak creatine phosphokinase (P=0.007) and peak creatine kinase-MB (P=0.006), more frequent proximal LCX occlusion (P=0.007), and worse 1-year outcomes (P=0.0034). Conclusions: One-third of ACS patients with LCX occlusion showed no ST-segment changes, resulting in significantly longer DTB time. Improving diagnostic accuracy is challenging but critical to avoid delayed reperfusion in these patients without electrocardiographic changes.

A Drifting Dislodged Leadless Pacemaker in the Bilateral Pulmonary Arteries.

We report a rare phenomenon during implantation of a leadless pacemaker. The device was dislodged into the left pulmonary artery (PA) during the implantation procedure and then migrated the next day from the left PA to the right PA. (Level of Difficulty: Advanced.).

Very long-term prognosis in patients with hypertrophic cardiomyopathy: a longitudinal study with a period of 20 years.

AIMS: We aim to clarify the prognosis on patients with hypertrophic cardiomyopathy (HCM) for a follow-up period of more than 10 years. METHODS AND RESULTS: We retrospectively analysed 102 consecutive patients with HCM diagnosed by 31 December 2000. Complete and detailed clinical records were obtained for 93 (91%) of the 102 patients. Sixty-three (68%) of the 93 patients were men, and the mean age of the patients at the initial evaluation was 51.5 ± 13.0 years. During the mean follow-up period of 19.6 ± 8.1 years (median 20.1 years), HCM-related deaths occurred in 20 patients (21% [1.1%/year]). HCM-related adverse events (including HCM-related deaths and nonfatal HCM-related events: hospitalization for heart failure, embolic stroke admission, and sustained ventricular tachycardia with haemodynamic instability or appropriate implantable cardioverter-defibrillator discharge) occurred in 45 patients (48%). The first HCM-related adverse events occurred in approximately 20% of the patients in every decade, the first decade to the third decade, from the initial evaluation. Forty-seven patients (51%) had documentation of atrial fibrillation at the last follow-up. There were seven patients in the end-stage HCM group at the initial evaluation, and 22 patients (24%) had progression to end-stage HCM during the follow-up period. CONCLUSIONS: In our cohort of patients, HCM-related mortality was relatively favourable. However, approximately half of the patients suffered from HCM-related adverse events during the follow-up period of 20 years. It is important for HCM patients to be carefully followed up over the long-term because HCM is a lifelong disease.