Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design.

INTRODUCTION: Familial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data-and in particular multicentre data-exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds. METHODS AND ANALYSIS: The Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies. ETHICS AND DISSEMINATION: This study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000038210.

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases.

AIMS: The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. METHODS AND RESULTS: We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analysed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as 'pathogenic' by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that two variants in KCNH2 and SCN5A, four variants in SCN10A, and one variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from 'Uncertain significance' to 'Likely pathogenic' in six probands. CONCLUSION: Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD.

The impact of prehospital assessment and EMS transport of acute aortic syndrome patients.

BACKGROUND: The quality of acute aortic syndrome (AAS) assessment by emergency medical service (EMS) and the incidence and prehospital factors associated with 1-month survival remain unclear. METHODS: We retrospectively analyzed the data collected for 94,468 patients with non-traumatic medical emergency excluding out-of-hospital cardiac arrest during the period of 2011-2014. RESULTS: Of these transported by EMS, 22,075 had any of the AAS-related symptoms, and 330 had an EMS-assessed risk for AAS; of these, 195 received an in-hospital AAS diagnosis. Of the remaining 21,745 patients without EMS-assessed risk, 166 were diagnosed with AAS. Therefore, the sensitivity and specificity of our EMS-risk assessment for AAS was 54.0% (195/361) and 99.4% (21,579/21,714), respectively. EMS assessed the risk less frequently when patients were elderly and presented with dyspnea and syncope/faintness. Sign of upper extremity ischemia was rarely detected (6.9%) and absence of this sign was associated with lack of EMS-assessed risk. The calculation of modified aortic dissection detection risk score revealed that rigorous assessment based on this score may increase the EMS sensitivity for AAS. The 1-month survival rate was significantly higher in patients admitted to core hospitals with surgical teams for AAS than in those admitted to all other hospitals [87.5% (210/240) vs 69.4% (84/121); P<0.01]. Multiple logistic regression analysis demonstrated that Stanford type A, Glasgow coma scale ≤14, and admission to core hospitals providing emergency cardiovascular surgery were associated with 1-month survival. CONCLUSIONS: Improvement of AAS survival is likely to be affected by rapid admission to appropriate hospitals providing cardiovascular surgery.

Heterogeneity of clinical manifestation of hypertrophic cardiomyopathy caused by deletion of lysine 183 in cardiac troponin I gene.

Hypertrophic cardiomyopathy (HCM) is associated with gene mutations that encode sarcomeric proteins. However, the relationship between genotype and histopathologic findings is unclear. We report on two autopsy cases with advanced HCM associated with deletion of lysine 183 mutation in the cardiac troponin I gene. One case, a 74-year-old female exhibited dilated cardiomyopathy-like features. Transmural scarring was diffuse and circumferential, involving the whole left ventricle, especially the ventricular septum which was replaced with extensive fibrosis and showed marked wall thinning. The other case, a 92-year-old male revealed typical HCM findings. Patchy scars which corresponded to replacement fibrosis were found extending from the septum to the anterior wall. These two autopsy cases indicate the clinical heterogeneity of HCM even within the same disease-causing mutation and suggest that the degree and extent of fibrosis determine differences in the clinical manifestations of HCM. This is the first autopsy report that demonstrates identical sarcomeric gene mutations causing different clinical manifestations and histologic findings. The findings suggest that additional genetic or environmental factors influence the phenotypic expressions and clinical courses of HCM caused by genetic mutation of sarcomeric proteins.

Impact of severe earthquake on the occurrence of acute coronary syndrome and stroke in a rural area of Japan.

BACKGROUND: Although acute coronary syndrome (ACS) and stroke are known to increase after earthquake, few data exist regarding the effect of earthquake on these cardiovascular events in rural areas. METHODS AND RESULTS: The Noto Peninsula earthquake with a magnitude of 6.9 occurred at 9:45 a.m. on 25 March 2007. The first case of ACS occurred approximately 15 min later, whereas cerebral hemorrhage (CH) occurred 72 h after the onset of earthquake. During the 35 days after earthquake, among 49 patients who were attended by local ambulance, 5 patients with ACS (10.2%) and 8 with CH (16.3%) were documented and 4 died. The total number of both ACS and CH cases was greater than the averages for the same period of the past 3 years in this area (2.0 vs 5 and 2.3 vs 8, P<0.01). Interestingly, the most cases of ACS had occurred within 7 days after earthquake and for CH not until 35 days later. CONCLUSIONS: Even in rural areas a severe earthquake results in increased incidence of ACS and CH, which can occur at different times after the event, although the effects of other environmental factors should be further investigated.