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.

Clinical Impact of Carotid Plaque Score rather than Carotid Intima-Media Thickness on Recurrence of Atherosclerotic Cardiovascular Disease Events.

AIM: Carotid plaque score (cPS) reflecting throughout the carotid artery plaque burden may be a better marker than carotid intima-media thickness (cIMT) is. We aimed to compare the prognostic utility of these measurements in patients with atherosclerotic cardiovascular disease (ASCVD). METHODS: We retrospectively examined 2,035 Japanese patients with ASCVD who underwent carotid ultrasonography between January 2008 and December 2015 at Kanazawa University Hospital. Median follow-up period was 4 years. We used Cox models that adjusted for established risk factors of ASCVD, including age, gender, hypertension, diabetes, smoking, and serum lipids to assess the association of cIMT as well as cPS with major adverse cardiac events (MACE). MACE was defined as all-cause mortality or rehospitalization for a cardiovascular-related illness. RESULTS: During follow-up, 243 participants experienced MACE. After adjustment for established risk factors, cPS was associated with MACE (hazard ratio [HR]=3.38 for top quintile vs. bottom quintile of cPS; 95% confidence interval [CI] 1.82-6.27; P trend ＜0.001), while cIMT was not (HR=0.88, P=0.57). Addition of the cPS to established risk factors significantly improved risk discrimination (C-index 0.726 vs. 0.746; P=0.017). CONCLUSION: These results suggest that cPS, rather than cIMT may be a better marker to identify increased risk for recurrence of MACE among patients with secondary prevention setting.

Antegrade Balloon Aortic Valvuloplasty for the Highly Frail Patient of Severe Aortic Stenosis Complicated with Transthyretin-type Cardiac Amyloidosis.

Transcatheter aortic valve implantation (TAVI) is widely accepted as the treatment for patient with severe aortic stenosis (AS) whose prognosis may be over one year; however, there is no consensus concerning extremely high-risk patients whose prognosis may not exceed one year. We herein report a highly frail patient with severe AS complicated with transthyretin-type cardiac amyloidosis who had a very poor prognosis. Given his condition, we treated him by percutaneous antegrade balloon aortic valvuloplasty (A-BAV) instead of TAVI. A-BAV may be a beneficial option for treating extremely high-risk severe AS patients, including those with cardiac amyloidosis.

Prevalence and outcome of patients with cancer and acute coronary syndrome undergoing percutaneous coronary intervention: a BleeMACS substudy.

BACKGROUND: The prevalence and outcome of patients with cancer that experience acute coronary syndrome (ACS) have to be determined. METHODS AND RESULTS: The BleeMACS project is a multicentre observational registry enrolling patients with acute coronary syndrome undergoing percutaneous coronary intervention worldwide in 15 hospitals. The primary endpoint was a composite event of death and re-infarction after one year of follow-up. Bleedings were the secondary endpoint. 15,401 patients were enrolled, 926 (6.4%) in the cancer group and 14,475 (93.6%) in the group of patients without cancer. Patients with cancer were older (70.8±10.3 vs. 62.8±12.1 years, P<0.001) with more severe comorbidities and presented more frequently with non-ST-segment elevation myocardial infarction compared with patients without cancer. After one year, patients with cancer more often experienced the composite endpoint (15.2% vs. 5.3%, P<0.001) and bleedings (6.5% vs. 3%, P<0.001). At multiple regression analysis the presence of cancer was the strongest independent predictor for the primary endpoint (hazard ratio (HR) 2.1, 1.8-2.5, P<0.001) and bleedings (HR 1.5, 1.1-2.1, P=0.015). Despite patients with cancer generally being undertreated, beta-blockers (relative risk (RR) 0.6, 0.4-0.9, P=0.05), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (RR 0.5, 0.3-0.8, P=0.02), statins (RR 0.3, 0.2-0.5, P<0.001) and dual antiplatelet therapy (RR 0.5, 0.3-0.9, P=0.05) were shown to be protective factors, while proton pump inhibitors (RR 1, 0.6-1.5, P=0.9) were neutral. CONCLUSION: Cancer has a non-negligible prevalence in patients with acute coronary syndrome undergoing percutaneous coronary intervention, with a major risk of cardiovascular events and bleedings. Moreover, these patients are often undertreated from clinical despite medical therapy seems to be protective. Registration:The BleeMACS project (NCT02466854).

Assessments of Carotid Artery Plaque Burden in Patients With Familial Hypercholesterolemia.

Although both carotid intima-media thickness (cIMT) and carotid plaque score (cPS) determined by carotid ultrasonography reflect the severity of coronary atherosclerosis, there are few reports on direct comparisons of their clinical utilities in patients with familial hypercholesterolemia (FH). We aimed (1) to compare the clinical utilities of these measurements and (2) to estimate the onset and progression of carotid atherosclerosis in patients with FH. We examined 225 patients with FH (126 males; mean age, 51 ± 18 years) who underwent carotid ultrasonography. We assessed baseline characteristics including lipid levels, other traditional risk factors, and the presence of coronary artery disease (CAD) as well as mean cIMT and cPS. Multivariate logistic analysis revealed that cPS was significantly associated with CAD (odds ratio [OR] 1.22, 95% confidence interval (CI) 1.10-1.37, p = 0.00036), whereas cIMT was not (OR 1.26, 95% CI 0.15 to 11.76, p = 0.84). Adding cPS information to other traditional risk factors improved the risk discrimination of CAD (C-index 0.887 vs 0.909, p = 0.030), whereas adding cIMT information did not (C-index 0.887 vs 0.893, p = 0.33). Regression equations were Y = 0.219X - 3.74 (r = 0.65, p < 0.001) in male and Y = 0.215X - 5.47 (r = 0.72, p < 0.001) in female patients with FH. In conclusion, cPS may provide superior risk stratification in patients with FH compared with cIMT. On average, carotid atherosclerosis may develop at 17 and 26 years of age in male and female patients with heterozygous FH, respectively.

Optimal Medical Therapy in Patients with Malignancy Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome: a BleeMACS Sub-Study.

OBJECTIVE: Our objective was to define the most appropriate treatment for acute coronary syndrome (ACS) in patients with malignancy. METHODS AND RESULTS: The BleeMACS project is a worldwide multicenter observational prospective registry in 16 hospitals enrolling patients with ACS undergoing percutaneous coronary intervention. Primary endpoints were death, re-infarction, and major adverse cardiac events (MACE; composite of death and re-infarction) after 1 year of follow-up. The secondary endpoint was bleeding events during follow-up. We performed sub-study analyses according to whether ß-blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), statins, or proton pump inhibitors (PPIs) were prescribed at discharge. We also calculated the propensity score for optimal medical therapy (OMT; combination of BB, ACEI/ARB, and statins). The study included 926 patients. According to the multivariate analysis, ACEIs/ARBs (hazard ratio [HR] 0.58, 95 % confidence interval [CI] 0.36-1.94; p = 0.03) and statins (HR 0.37, 95 % CI 0.23-0.61; p < 0.01) reduced the risk of MACE, while the effects of BBs (HR 0.85, 95 % CI 0.55-1.32; p = 0.48) and PPIs (HR 1.33, 95 % CI 0.83-2.12; p = 0.23) were not significant. OMT was prescribed at discharge in 300 (32.4 %) patients; after propensity score analysis, OMT showed a significant reduction in death (3 % vs. 12.5 %, HR 0.21, 95 % CI 0.1-0.4; log-rank p < 0.001) and MACE (6.7 vs. 15.2 %, log-rank p = 0.01). CONCLUSION: In patients with ACS and malignancy, OMT reduces the risk of adverse events at 1 year; in particular, ACEIs/ARBs and statins were the most protective drugs. (Clinical trials identifier: NCT02466854).

Impact of Baseline Angiographic Complexities Determined by Coronary Artery Bypass Grafting SYNTAX Score on the Prediction of Outcome After Percutaneous Coronary Intervention.

Although Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) score based on angiographic scoring system was developed in patients with previous coronary artery bypass grafting (CABG), few data exist regarding its prognostic utility in patients undergoing percutaneous coronary intervention (PCI). We examined 272 patients with previous CABG (217 men; mean age, 70.4 ± 9.7 years) undergoing PCI. Severity of the coronary anatomy was evaluated using CABG-SYNTAX score. The primary end point of this study was cardiovascular death. The baseline CABG-SYNTAX score ranged from 2 to 53.5, with an average of 26.0 ± 10.2. In the index procedures, PCI for the native coronary accounted for nearly all patients (88%). During follow-up (median 4.1 years), 40 cardiovascular deaths had occurred. In multivariate analysis, age >75 years (hazard ratio [HR] 2.82, 95% CI 1.45 to 5.52), left ventricular ejection fraction <40% (HR 2.99, 95% CI 1.39 to 6.07), end-stage renal disease (HR 2.90, 95% CI 1.15 to 6.75), peripheral artery disease (HR 2.20, 95% CI 1.10 to 4.64), and CABG-SYNTAX score >25 (HR 2.37, 95% CI 1.19 to 5.05) were independent predictors of cardiovascular death. After creating a composite risk score in consideration of identified predictors, the freedom from cardiovascular death at 5 years was 98%, 86%, and 58% in the low (0 to 1), medium (2), and high (3 to 5) scores, respectively (p <0.001). The area under the receiver-operating characteristic curve for cardiovascular death for the CABG-SYNTAX and composite risk scores were 0.66 and 0.77, respectively (p <0.05). In conclusion, the combination of angiographic and clinical characteristics is useful for risk stratification in patients with previous CABG undergoing PCI.

Clinical characteristics of Japanese patients with severe hypertriglyceridemia.

BACKGROUND: Although of interest, few data exist on the clinical characteristics of Japanese patients with an extremely high triglyceride level (≥ 1000 mg/dL). OBJECTIVE: We assessed the clinical characteristics of Japanese patients with an extremely high triglyceride level. METHODS: We investigated the presence of coronary artery disease, history of pancreatitis, the presence of fatty liver, and the potential causes of elevated triglyceride in Japanese subjects with an extremely high level of fasting triglyceride (≥ 1000 mg/dL) among 70,368 subjects whose serum triglyceride was measured for any reason at Kanazawa University Hospital from April 2004 to March 2014. RESULTS: We identified 215 (0.31%) subjects (mean age, 46 years; male, 170, mean body mass index, 25 kg/m(2)) with severe hypertriglyceridemia. Among them, 4 (1.9%) subjects were classified as type I, 97 (45.1%) subjects were type IV, and 114 (53.0%) subjects were type V hyperlipidemia, according to Fredrickson's classification. Among 215 subjects, 116 subjects (54.0%) drank alcohol, 58 (27.0%) showed heavy intake (≥ 60 g/d), and 64 (29.8%) subjects had diabetes. In total, 59 (27.4%) subjects had transient severe hypertriglyceridemia caused by corticosteroids (N = 19), antidepressant (N = 18), l-asparaginase and steroids for acute lymphoid leukemia (N = 15), hormone replacement therapy for breast cancer (N = 9), ß-blocker (N = 5), hypothyroidism (N = 4), pregnancy (N = 4), and panhypopituitarism (N = 2). As many as 119 (55.3%) subjects exhibited fatty liver. Moreover, 12 (5.6%) and 17 (7.9%) subjects had a history of pancreatitis and coronary artery disease, respectively. CONCLUSIONS: A variety of situations can cause severe hypertriglyceridemia. We suggest that potential secondary causes should be carefully assessed for such patients.

Impact of clinical and echocardiographic characteristics on occurrence of cardiac events in cardiac amyloidosis as proven by endomyocardial biopsy.

BACKGROUND: Although patients with immunoglobulin light chain (AL) cardiac amyloidosis exhibit worse outcomes than those with transthyretin (TTR) cardiac amyloidosis, few data exist regarding the occurrence of cardiac events and the echocardiographic indices in endomyocardial biopsy (EMBx) proven amyloidosis. METHODS: From November 2007 to October 2012, we identified 33 patients with EMBx-proven amyloidosis. There were 12 patients (8 men; mean age: 66 years) with AL and 21 patients (20 men; mean age: 78 years) with TTR. We performed serial echocardiography and observed the patients during follow-up; defining all-cause mortality as the primary endpoint and hospitalization for heart failure as the secondary endpoint. RESULTS: The survival rates at 12 months were 20.8% and 85.7% in AL and TTR, respectively (p<0.001). The cumulative incidences of the composite of death or readmission for heart failure at 12 months were 91.7% and 51.3% in AL and TTR, respectively (p<0.001). A multivariate analysis showed that the AL type amyloid was the powerful predictor of mortality (hazard ratio: 8.50, 95% confidence interval: 1.79 to 40.57, p<0.05). Under these conditions, the E/e' in AL tended to increase from 23±13 to 28±11 (p=0.06) with marked increases in B-type natriuretic peptide (779±456 pg/ml to 1576±895 pg/ml, p<0.05), although these remained unchanged in TTR, which exhibited significantly increased left ventricular end-diastolic dimensions from 40±4 mm to 42±4 mm (p<0.05). CONCLUSIONS: The survival rate was generally worse in AL cardiac amyloidosis, although the readmission for heart failure remains high in TTR cardiac amyloidosis with the occurrence of left ventricular dilatation.

Liver sarcoidosis that presented with dysphagia.

We report a case of liver sarcoidosis with dysphagia. Although akinesia of the soft palate, disappearance of the palatal reflex, and pyramidal signs indicated brainstem lesions, brain magnetic resonance imaging showed no lesion and the focus was obscure. Iritis, parotiditis, and hilar lymphadenopathy supported the diagnosis of sarcoidosis. However, lung biopsy was normal. Finally, sarcoidosis was diagnosed by liver biopsy. We speculated that microgranulomas in the brainstem that did not exhibit imaging abnormalities causing the neurological symptoms and that liver biopsy can be an effective diagnostic tool even for cases that presented with neurological signs, but no gastrointestinal symptom.