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.

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.

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.

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.

Importance of fourth heart sound and preserved left atrial function in wild-type transthyretin amyloidosis.

AIMS: A fourth heart sound (S4) was reported to be almost never present in patients with amyloid light-chain cardiomyopathy. There have been no reports on S4 in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). This study aimed to clarify the clinical implications of S4 in patients with ATTRwt-CM. METHODS AND RESULTS: Seventy-six patients with ATTRwt-CM (mean age: 80.4 ± 5.4 years, 68 males) who had undergone phonocardiography (PCG) were retrospectively assessed. We measured S4 amplitude on digitally recorded PCG. S4 was considered to be present when its amplitude was 1.0 mm or greater on the PCG. Distinct S4 was defined as S4 with an amplitude of 2.0 mm or greater, which is usually recognizable by auscultation. According to the rhythm and presence or absence of S4, the patients were divided into three groups, namely, sinus rhythm (SR) with S4, SR without S4, and non-SR. Non-SR consisted of atrial fibrillation, atrial flutter, and atrial tachycardia. Thirty-six patients were in SR and the remaining 40 patients were in non-SR. In the 36 patients in SR, S4 was shown by PCG to be present in 17 patients (47%), and distinct S4 was recognized in 7 patients (19%) by auscultation. In patients who were in SR, those with S4 had higher systolic blood pressure (124 ± 15 vs. 99 ± 8 mmHg, P < 0.001), lower level of plasma B-type natriuretic peptide (308 [interquartile range (IQR): 165, 354] vs. 508 [389, 765] pg/mL, P = 0.034) and lower level of high-sensitivity cardiac troponin T (0.068 [0.046, 0.089] vs. 0.109 [0.063, 0.148] ng/mL, P = 0.042) than those without S4. There was no significant difference in left atrium (LA) volume index or LA reservoir strain between patients with S4 and without S4. Patients with S4 had more preserved LA systolic function than those without S4 (peak atrial filling velocity: 53 ± 25 vs. 34 ± 9 cm/s, P = 0.033; LA contractile strain: 4.1 ± 2.1 vs. 1.6 ± 2.0%, P = 0.012). Patients in SR without S4 had worse short-term prognosis compared with the other two groups (generalized Wilcoxon test, P = 0.033). CONCLUSIONS: S4 was present in 47% of the patients in SR with ATTRwt-CM. Patients in SR without S4 had more impaired LA systolic function than those in SR with S4. The absence of S4 portends a poor short-term prognosis in patients with ATTRwt-CM.

Early Invasive Strategy for Octogenarians and Nonagenarians With Acute Myocardial Infarction.

Background: Older adults with acute myocardial infarction (AMI) are currently a rapidly growing population. However, their clinical presentation and outcomes remain unresolved. Methods and Results: A total of 268 consecutive AMI patients were analyzed for clinical characteristics and outcomes with major adverse cardiovascular events (MACE) and all-cause mortality within 1 year. Patients aged ≥80 years (Over-80; n=100) were compared with those aged ≤79 years (Under-79; n=168). (1) Primary percutaneous coronary intervention (PCI) was frequently and similarly performed in both the Over-80 group and the Under-79 group (86% vs. 89%; P=0.52). (2) Killip class III-IV (P<0.01), in-hospital mortality (P<0.01), MACE (P=0.03) and all-cause mortality (P<0.01) were more prevalent in the Over-80 group than in the Under-79 group. (3) In the Over-80 group, frail patients showed a significantly worse clinical outcome compared with non-frail patients. (4) Multivariate analysis revealed Killip class III-IV was associated with MACE (odds ratio [OR]=3.51; P=0.02) and all-cause mortality (OR=9.49; P<0.01) in the Over-80 group. PCI was inversely associated with all-cause mortality (OR=0.13; P=0.02) in the Over-80 group. Conclusions: The rate of primary PCI did not decline with age. Although octogenarians/nonagenarians showed more severe clinical presentation and worse short-term outcomes compared with younger patients, particularly in those with frailty, the prognosis may be improved by early invasive strategy even in these very old patients.

Takotsubo Syndrome in Older Men　- Clinical Characteristics Differ by Sex and Age.

Background: Takotsubo syndrome (TTS) in male patients is under-studied, particularly in the older population. Methods and Results: From 226 patients with TTS, 44 older male patients (prevalence rate: 19.5%, age: median 77 years) were compared with 182 older female patients (prevalence rate: 80.5%, age: median 80 years). Emotional triggers of TTS were less frequent (2% vs. 19%; P=0.007), whereas physical triggers were more frequent (75% vs. 58%; P=0.040) in older men than in women. Among physical triggers, serious respiratory infection was more common in older men than in women. As initial clues to the diagnosis, ECG T-wave inversion was more frequent (48% vs. 29%; P=0.018) and chest pain and/or dyspnea were less common (23% vs. 38%; P=0.050) in older men than in women. In total, 14 patients (6%) had cardiogenic shock and 41 (18%) had severe heart failure as complications, although there were no significant differences in the frequency of these complications between older men and women. Although cardiac death occurred in 3 female patients (1%) and noncardiac death in 3 male and 5 female patients (4%), there were no significant differences in death rate between older men and women. Conclusions: Emotional triggers of TTS were extremely infrequent whereas physical triggers were common in older men. Although severe heart failure was common, there were no significant differences in the frequency of complications and in-hospital deaths between older men and women.

Effects of renin-angiotensin system inhibitor and beta-blocker use on mortality in older patients with heart failure with reduced ejection fraction in Japan.

Introduction: Guideline-directed medical therapy with renin-angiotensin system (RAS) inhibitors and beta-blockers has improved the survival of patients with heart failure (HF) and reduced left ventricular ejection fraction (HFrEF). However, it is unclear whether RAS inhibitors and beta-blockers can be administered to older patients with HF. Therefore, this study aimed to investigate the effects of beta-blockers and RAS inhibitors on the prognosis of older patients with HFrEF. Methods: Demographic, clinical, and pharmacological data from 1,061 patients with acute decompensated HF, enrolled in the Kochi Registry of Subjects with Acute Decompensated Heart Failure (Kochi YOSACOI study), were analyzed to assess their impact on mortality. Additionally, a machine learning approach was applied to complement the conventional statistical model for analysis. Patients with HFrEF (n = 314) were divided into the all-cause mortality within 2 years group (n = 80) and the survivor group (n = 234). Results: Overall, 41.1% (129/314) of the patients were aged ≥80, and 25.5% (80/314) experienced all-cause mortality within 2 years. Furthermore, 57.6% (181/314) and 79.0% (248/314) were prescribed RAS inhibitors and beta-blockers, respectively. Our analysis showed that RAS inhibitor use was associated with reduced all-cause mortality and cardiac death in patients with HFrEF of all ages (P < 0.001), and beta-blocker use had an interaction with age. Machine learning revealed that the use of beta-blockers altered the risk of mortality, with a threshold of approximately 80 years of age. Beta-blocker use was associated with lower all-cause mortality and cardiac death in patients with HFrEF aged <80 years (P < 0.001) but not in those aged ≥80 years (P = 0.319 and P = 0.246, respectively). These results suggest that beta blockers may differ in their all-cause mortality benefits according to age. Conclusions: RAS inhibitors prevented all-cause mortality and cardiac death at all ages, whereas beta-blockers had different effects depending on the patient's age. This study suggested that the choice of beta-blockers and RAS inhibitors is more important in older patients with HFrEF than in younger patients with the same condition.