Intensive Combination LDL-Lowering Therapy in a Patient With Homozygous Familial Hypercholesterolemia.

We present a young boy with a diagnosis of homozygous familial hypercholesterolemia who presented with statin and ezetimibe resistance. The patient received lipoprotein apheresis at 6 years of age. His low-density lipoprotein cholesterol levels significantly were reduced by adding lomitapide and evinacumab, and his carotid plaque started to regress.

Preclose Versus Postclose Using Suture-Mediated Vascular Closure System for Catheter Ablation With Femoral Vein Access.

BACKGROUND: Differences in the efficacy and safety between the preclose and postclose suture-mediated vascular closure systems for femoral vein access have not been adequately studied. OBJECTIVES: This study aimed to evaluate the efficacy and safety of these 2 suturing techniques in femoral vein access. METHODS: Patients subjected to elective catheter ablation via the femoral vein using a sheath of 8- to 13-F inner diameter (n = 282) were randomized to the preclose or postclose groups for the single-suture technique using ProGlide/ProStyle (Abbott Vascular). Duplex ultrasound was performed on days 1 and 90 after the procedure to evaluate vascular complications. The primary efficacy endpoint was rebleeding requiring recompression, and the primary safety endpoint was any major complication occurring within 90 days. The secondary efficacy endpoints included time to hemostasis and time to ambulation, and the secondary safety endpoint was any minor complication occurring within 90 days. RESULTS: The preclose group demonstrated a significantly lower rebleeding rate (5 of 141 [3.5%] vs 15 of 141 [10.6%]; P = 0.03) and shorter time to hemostasis (254.0 ± 120.4 seconds vs 299.8 ± 208.2 seconds; P = 0.02) compared with the postclose group. Five patients in each group were lost to follow-up at 90 days. Incidence of major complications were similar in both groups (1 of 136 [0.7%]; P = 1.00), whereas minor complications were observed in 18 of 136 (13.2%) and 21 of 136 (15.4%) patients in the preclose and postclose groups, respectively, without a significant difference (P = 0.73). CONCLUSIONS: In femoral vein access using the single-suture technique with ProGlide/ProStyle, the preclose technique presented a higher hemostasis rate than the postclose technique, without compromising safety.

The first Japanese case with familial combined hypolipidemia without any complications caused by loss-of function variants in ANGPTL3: Case report.

Familial combined hypolipidemia, previously known as Familial hypobetalipoproteinemia 2 (FHBL2) is considered as an extremely rare recessive disease. Here, we present the case of familial combined hypolipidemia with homozygous loss-of function (LOF) variants in angiopoietin-like protein 3 (ANGPTL3) ((NM_014495.4) c.439_442del (p.Thr146_Asn147insTer)) using panel sequencing (46 yr male whose LDL cholesterol = 34 mg/dL). The serum level of ANGPTL3 was quite low (undetectable). Despite of extreme decreasing LDL cholesterol, this case did not have any complications as hypobetalipidemia (HBL), such as steatorrhea vomiting, hematological, neuromuscular, or ophthalmological symptoms. In addition, we did not find any systemic atherosclerosis in his carotid arteries and in coronary arteries. Based on the findings suggest that inhibition of ANGPTL3 effectively reduce LDL cholesterol without any apparent side effects, although it is still unclear if he will suffer any disadvantages because of this situation in the future.

Impact of changes in Achilles tendon thickening on cardiovascular events in patients with familial hypercholesterolemia.

Background: Achilles tendon thickening (ATT) can be ameliorated by lowering low-density lipoprotein (LDL) levels in patients with familial hypercholesterolemia (FH). The Japan Atherosclerosis Society (JAS) defines ATT as ≥8.0 mm in males and ≥7.5 mm in females. We aimed to determine the clinical impact of changes in ATT on the development of major adverse cardiovascular events (MACE). Methods: Patients with clinically diagnosed heterozygous FH (HeFH) (N = 1273; 614 males, 659 females) with ATT data from X-ray were assessed. Patients were divided into four groups: patients without ATT from baseline until follow-up (group 1), patients without ATT at baseline but developed ATT at follow-up (group 2), patients with ATT at baseline but regressed at follow-up (group 3), and patients with ATT from baseline until follow-up (group 4). Cox proportional hazard models were used to assess the factors associated with MACE, including cardiovascular death and any coronary events. Results: On follow-up (median: 10.9 years), 142 MACEs were observed, and the median ATT regressed from 7.8 to 7.6 mm. Changes in ATT were significantly associated with the occurrence of MACE in all groups, when compared to group 1 (hazard ratio [HR]: 2.73; 95 % confidence interval [CI]: 1.33-4.13 [p < 0.001], HR: 2.18, 95 % CI: 1.08-3.28, [p < 0.001], HR: 6.34, 95 % CI: 3.10-9.58, [p < 0.001], in groups 2, 3, and 4, respectively). Conclusions: Assessing ATT has diagnostic value and allows for risk stratification among patients with HeFH.

Detection of Epicardial Connection Through Intercaval Bundle Involving Right Pulmonary Veins After Ipsilateral Circumferential Ablation by Intra-Atrial Activation Sequence Pacing From the Right Pulmonary Vein.

BACKGROUND: An epicardial connection (EC) through the intercaval bundle (EC-ICB) between the right pulmonary vein (RPV) and right atrium (RA) is one of the reasons for the need for carina ablation for PV isolation and may reduce the acute and chronic success of PV isolation. We evaluated the intra-atrial activation sequence during RPV pacing after failure of ipsilateral RPV isolation and sought to identify specific conduction patterns in the presence of EC-ICB. METHODS AND RESULTS: This study included 223 consecutive patients who underwent initial catheter ablation of atrial fibrillation. If the RPV was not isolated using circumferential ablation or reconnected during the waiting period, an exit map was created during mid-RPV carina pacing. If the earliest site on the exit map was the RA, the patient was classified into the EC-ICB group. The exit map, intra-atrial activation sequence, and RPV-high RA time were evaluated. First-pass isolation of the RPV was not achieved in 36 patients (16.1%), and 22 patients (9.9%) showed reconnection. Twelve and 28 patients were classified into the EC-ICB and non-EC-ICB groups, respectively, after excluding those with multiple ablation lesion sets or incomplete mapping. The intra-atrial activation sequence showed different patterns between the 2 groups. The RPV-high RA time was significantly shorter in the EC-ICB than in the non-EC-ICB group (69.2±15.2 versus 148.6±51.2 ms; P<0.001), and RPV-high RA time<89.0 ms was highly predictive of the existence of an EC-ICB (sensitivity, 91.7%; specificity, 89.3%). CONCLUSIONS: An EC-ICB can be effectively detected by intra-atrial sequencing during RPV pacing, and an RPV-high RA time of <89.0 ms was highly predictive.

Genetic Counseling and Genetic Testing for Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is one of the most common autosomal codominant Mendelian diseases. The major complications of FH include tendon and cutaneous xanthomas and coronary artery disease (CAD) associated with a substantial elevation of serum low-density lipoprotein levels (LDL). Genetic counseling and genetic testing for FH is useful for its diagnosis, risk stratification, and motivation for further LDL-lowering treatments. In this study, we summarize the epidemiology of FH based on numerous genetic studies, including its pathogenic variants, genotype-phenotype correlation, prognostic factors, screening, and usefulness of genetic counseling and genetic testing. Due to the variety of treatments available for this common Mendelian disease, genetic counseling and genetic testing for FH should be implemented in daily clinical practice.

Improved Efficiency of the Clinical Diagnostic Criteria for Familial Hypercholesterolemia in Children: A Comparison of the Japan Atherosclerosis Society Guidelines of 2017 and 2022.

AIMS: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels, which increases the risk of premature coronary artery disease. Early detection and treatment are vital, especially in children. To improve FH diagnosis in children, the Japan Atherosclerosis Society (JAS) released new guidelines in July 2022. This study assessed and compared the sensitivity and specificity of the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022. METHODS: From September 2020 to March 2023, 69 children with elevated plasma LDL-C levels (≥ 140 mg/dL) were included in a pediatric FH screening project in Kagawa. The children were evaluated using genetic testing alongside the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022. RESULTS: Using the JAS pediatric FH 2017 criteria, eight children were diagnosed as FH-positive and 61 children as FH-negative. The JAS pediatric FH 2022 criteria identified 15 children with definite FH, 31 with probable FH, and 23 with possible FH. Genetic testing detected FH pathogenic variants in 24 children. The sensitivity and specificity for the JAS pediatric FH 2017 criteria were 0.292 and 0.978, respectively. For the JAS pediatric FH 2022 criteria, the sensitivity was 0.542 for definite FH with a specificity of 0.956, and 0.917 for probable FH with a specificity of 0.467. CONCLUSION: The clinical diagnostic criteria of the JAS pediatric FH 2022 guidelines demonstrated improved diagnostic efficiency compared with those of 2017, as evidenced by the increased sensitivity while preserving specificity.

Putative Pathogenic Variants of ABCG5 and ABCG8 of Sitosterolemia in Patients With Hyper-Low-Density Lipoprotein Cholesterolemia.

Objective: Sitosterolemia is a rare autosomal recessive disease caused by the deleterious variants of adenosine 5'-triphosphate (ATP)-binding cassette sub-family G member 5 (ABCG5) or ATP-binding cassette sub-family G member 8 (ABCG8). There are only few data on the pathogenicity of ABCG5 and ABCG8. This study aimed to propose a scheme for determining variant pathogenicity and to catalog the putative pathogenic variants in sitosterolemia. Methods: This study enrolled 377 consecutive Japanese patients with hyper-low-density lipoprotein cholesterolemia (mean age: 46.5±19.8 years, with 192 men) who have targeted-sequenced data on ABCG5 or ABCG8 (among 21 Mendelian lipid genes for any dyslipidemias) and serum sitosterol levels at Kanazawa University Hospital from 2016 to 2021. Serum sitosterol levels were divided by 0.79 in patients treated with ezetimibe, accounting for the average reduction with this drug. ABCG5 or ABCG8 variants were defined as putative pathogenic if associated with serum sitosterol levels ≥5 µg/mL or homozygous if associated with serum sitosterol levels ≥10 µg/mL. Results: Twenty-three ABCG5 or ABCG8 variants (16 missense, 2 nonsense, 2 frameshift, 2 deletion, and 1 splice mutation) were identified. Based on our definition, 11 putative pathogenic variants (median sitosterol level: 10.1 [6.5-17.1] µg/mL) were found in 36 individuals and 12 benign variants (median sitosterol: 3.5 [2.5-4.1] µg/mL) in 14 individuals. Conclusion: The scheme proposed for assessing the pathogenicity of genetic variations (ABCG5 and ABCG8) is useful. Using this scheme, 11 putative pathogenic, and 12 benign variants in ABCG5 or ABCG were classified.

A Family with Familial Hypobetalipoproteinemia Caused by a c.1468C>T in APOB.

We herein report the first family of Japanese individuals with familial hypobetalipoproteinemia caused by the c.1468C>T mutation in apolipoprotein B (APOB). A 13-year-old boy with extremely low levels of low-density lipoprotein (LDL) cholesterol (24 mg/dL) was referred to our hospital. The patient had no secondary causes of hypobetalipoproteinemia. His father and grandmother also exhibited low LDL cholesterol levels. A genetic analysis confirmed that they all had this variant in APOB (c.1468C>T). None of the patients exhibited atherosclerotic cardiovascular diseases or any other complications associated with low LDL cholesterol levels, including fatty liver, neurocognitive disorders, and cerebral hemorrhaging.

Performance of Generative Pretrained Transformer on the National Medical Licensing Examination in Japan.

The remarkable performance of ChatGPT, launched in November 2022, has significantly impacted the field of natural language processing, inspiring the application of large language models as supportive tools in clinical practice and research worldwide. Although GPT-3.5 recently scored high on the United States Medical Licensing Examination, its performance on medical licensing examinations of other nations, especially non-English speaking nations, has not been sufficiently evaluated. This study assessed GPT's performance on the National Medical Licensing Examination (NMLE) in Japan and compared it with the actual minimal passing rate for this exam. In particular, the performances of both the GPT-3.5 and GPT-4 models were considered for the comparative analysis. We initially used the GPT models and several prompts for 290 questions without image data from the 116th NMLE (held in February 2022 in Japan) to maximize the performance for delivering correct answers and explanations of the questions. Thereafter, we tested the performance of the best GPT model (GPT-4) with optimized prompts on a dataset of 262 questions without images from the latest 117th NMLE (held in February 2023). The best model with the optimized prompts scored 82.7% for the essential questions and 77.2% for the basic and clinical questions, both of which sufficed the minimum passing scoring rates of 80.0% and 74.6%, respectively. After an exploratory analysis of 56 incorrect answers from the model, we identified the three major factors contributing to the generation of the incorrect answers-insufficient medical knowledge, information on Japan-specific medical system and guidelines, and mathematical errors. In conclusion, GPT-4 with our optimized prompts achieved a minimum passing scoring rate in the latest 117th NMLE in Japan. Beyond its original design of answering examination questions for humans, these artificial intelligence (AI) models can serve as one of the best "sidekicks" for solving problems and addressing the unmet needs in the medical and healthcare fields.

Successful Endovascular Treatment of Calcified Superior Mesenteric Artery Complicated by Intramural Hematoma in Chronic Mesenteric Ischemia.

BACKGROUND Chronic mesenteric ischemia (CMI) is defined as ischemic symptoms caused by insufficient supply of blood to the gastrointestinal tract. Patients diagnosed with advanced symptomatic CMI should be treated subsequently, as the transition from CMI to acute mesenteric ischemia can be unpredictable. However, there is little information regarding the management of potential procedural complications during endovascular therapy (EVT) for CMI. CASE REPORT A 70-year-old man was admitted to our hospital with recurrent abdominal pain just after hemodialysis. The angiogram showed significant stenosis with heavy calcification in the proximal of the superior mesenteric artery (SMA), leading to the diagnosis of CMI. To alleviate the symptom, EVT for the stenotic lesion of the SMA was indicated. During the procedure, a cutting balloon was inflated to facilitate vessel expansion in the target lesion. As a result, intravascular ultrasound (IVUS) imaging revealed dissection into the media with extension into the medial space without reentry and demonstrated a semilunar intramural hematoma. We were able to contain the intramural hematoma by covering the whole dissection in the SMA with implantation of self-expandable stents. CONCLUSIONS This case highlights the potential of EVT for heavy calcification of the SMA complicated by dissection without reentry. Intramural hematoma was observed with IVUS examination. We were able to contain the hematoma by the implantation of self-expandable stents over the whole length of the SMA dissection under IVUS-guided EVT.

Association between remnant cholesterol and incident atherosclerotic cardiovascular disease, heart failure, and atrial fibrillation.

BACKGROUND: It remains unclear if remnant cholesterol is associated with atherosclerotic cardiovascular disease (ASCVD) (myocardial infarction, angina pectoris and stroke), heart failure (HF), and atrial fibrillation (AF) under primary prevention settings. OBJECTIVE: We aimed to clarify this issue among a general population without a history of ASCVD, HF or AF. METHODS: Analyses were conducted with a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2022 (n = 1,313,722; median age, 42 years; 54.6% men). We assessed the associations between remnant cholesterol calculated as total cholesterol minus HDL cholesterol minus LDL cholesterol and composite CVD outcomes, including, ASCVD, HF, and AF using Cox proportional hazard model, dividing the individuals into tertiles of remnant cholesterol (T1-T3). RESULTS: The mean follow-up duration was 3.0 years. In total, 43,755 events were recorded. Remnant cholesterol was significantly associated with composite CVD outcomes after adjustments (T3 vs T1: hazard ratio [HR]; 1.07, 95% confidence interval [CI]: 1.04-1.10, p-trend<0.001). Remnant cholesterol was associated with myocardial infarction (T3 vs T1:HR: 1.20, 95% CI: 1.06-1.34, p-trend=0.002), angina pectoris (T3 vs T1:HR: 1.09, 95% CI: 1.05-1.14, p-trend<0.001), stroke (T3 vs T1:HR: 1.08, 95% CI: 1.02-1.14, p-trend=0.007), and HF (T3 vs T1:HR: 1.08, 95% CI: 1.04-1.12, p-trend<0.001), while we found a marginal inverse association between remnant cholesterol and AF (T3 vs T1:HR: 0.92, 95% CI: 0.86-1.00, p-trend=0.054). CONCLUSION: Remnant cholesterol was positively associated with ASCVD and HF, while we found a marginal inverse association between remnant cholesterol and AF.

Study Protocol for the Pleiotropic Effects of Sodium-Glucose Cotransporter 2 Inhibitor on Organ-Specific Sympathetic Nerve Activity and Insulin Sensitivity in Participants with Type 2 Diabetes.

INTRODUCTION: Hyperinsulinemia and hyperglycemia are associated with exaggerated systemic sympathetic nerve activity (SNA) in patients with type 2 diabetes. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower insulin levels, whereas sulfonylureas increase insulin levels. We will test whether these two classes of antidiabetic agents have different effects on SNA. METHODS: The present study is an ongoing, 24-week, one-center (only Kanazawa University Hospital), open-label, randomized, parallel trial (jRCTs 041200035). Participants with type 2 diabetes with multiple atherosclerosis risk factors are randomly assigned in a 1:1 manner to receive 2.5 mg luseogliflozin or 0.5 mg glimepiride once daily. The sample size was calculated to be 14 in each group, with a significance level of 0.05 and a power of 0.80. The design required 40 evaluable study participants. Our primary endpoint will be the change in muscle SNA (MSNA). The secondary endpoints included organ-specific insulin sensitivity measured by a hyperinsulinemic-euglycemic clamp study using an artificial pancreas combined with a stable isotope-labeled glucose infusion, bioelectrical impedance analysis, and organ-specific (cardiac, renal, and hepatic) 123I-meta-iodobenzylguanidine (MIBG) innervation imaging. PLANNED OUTCOMES: Study recruitment started in April 2020 and will end in June 2024, with 40 participants randomized into the two groups. The treatment follow-up of the participants is currently ongoing and is due to finish by March 2025. TRIAL REGISTRATION: The study protocol has been approved by the Certified Review Board, Kanazawa University, Ishikawa, Japan, in accordance with the guidelines stipulated in the Declaration of Helsinki (CRB4180005, 2019-001). This trial is registered with the Japan Registry of Clinical Trials, jRCTs 041200035.

Familial hypercholesterolemia is related to cardiovascular disease, heart failure and atrial fibrillation. Results from a population-based study.

BACKGROUND: Familial hypercholesterolemia (FH) is associated with atherosclerotic cardiovascular disease (ASCVD). However, the prevalence of FH among a general population remains unknown, and it is unclear if FH is associated with other cardiovascular complications, including heart failure (HF) and atrial fibrillation (AF). METHODS: Analyses were conducted on individuals without a prior history of cardiovascular disease using a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2022 (n = 4,126,642; median age, 44 years; 57.5% men). We defined FH as either LDL cholesterol ≥250 mg/dL or LDL cholesterol ≥175 mg/dL under the lipid-lowering medications under the assumption that lipid-lowering medications reduced LDL cholesterol by 30%. We assessed the associations between FH and composite outcomes, including, ASCVD (myocardial infarction, angina pectoris, and stroke), HF, and AF using Cox proportional hazard model. RESULTS: We identified 11,983 (.29%) FH patients. In total, 181,150 events were recorded during the mean follow-up period of 3.5 years. The status FH was significantly associated with composite outcomes after adjustments (hazard ratio [HR]; 1.38, 95% confidence interval [CI]: 1.30-1.47, p < .001). Interestingly, the status FH was significantly associated with HF (HR: 1.48, 95% CI: 1.36-1.61, p < .001) and AF (HR: 1.33, 95% CI: 1.08-1.64, p < .001) in addition to angina pectoris (HR: 1.45, 95% CI: 1.33-1.58, p < .001) and stroke (HR: 1.19, 95% CI: 1.04-1.36, p < .001). CONCLUSION: We found that the prevalence of FH was .29% in a general population. FH was significantly associated with a higher risk of developing cardiovascular disease, HF and AF. LAY SUMMARY: We sought to identify the prevalence of FH among a general population, and to clarify whether FH increases the risk of not only ASCVD but also HF and AF.

Healthy lifestyle, lipoprotein (a) levels and the risk of coronary artery disease.

BACKGROUND: Lipoprotein (a) [Lp(a)] is associated with coronary artery disease (CAD). However, the role of healthy lifestyle against the risk of CAD with consideration of high Lp(a) levels remains unclear. METHODS: This study examined 4512 participants who underwent serum Lp(a) level assessment at Kanazawa University Hospital from 2008 to March 2016. Their lifestyle habits were examined based on four questionnaires regarding dietary pattern, exercise habits, smoking status and body weight. Logistic regression analyses were performed to identify the association between healthy lifestyle and CAD independent of Lp(a) levels. RESULTS: The Lp(a) levels were significantly associated with CAD (odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.08-1.17, p = 1.3 × 10-7 per 10 mg/dL). Under these circumstances, the lifestyle risk score was also significantly associated with CAD (OR: 1.24, 95% CI: 1.12-1.36, p = 2.4 × 10-8 ). Compared with patients with a favourable lifestyle who have Lp(a) levels of <30 mg/dL, those with an intermediate or unfavourable lifestyle were at higher risk for CAD (OR: 1.11, 95% CI: 1.02-1.20, p = 0.003 and OR: 1.40, 95% CI: 1.16-1.54, p = 3.6 × 10-5 , respectively). Further, patients with a favourable, intermediate or unfavourable lifestyle who have Lp(a) levels of ≥30 mg/dL were at high risk for CAD (OR: 1.21, 95% CI: 1.08-1.34, p = 0.0014; OR: 1.31, 95% CI: 1.14-1.48, p = 1.2 × 10-4 ; and OR: 1.81, 95% CI: 1.44-2.18, p = 2.2 × 10-7 , respectively). CONCLUSIONS: Healthy lifestyle was associated with a lower risk of CAD regardless of Lp(a) levels.