Aim: Hypertriglyceridemia is a type of dyslipidemia that contributes to atherosclerosis and coronary heart disease. Variants in lipoprotein lipase (LPL), apolipoprotein CII (APOC2), apolipoprotein AV (APOA5), glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation factor 1 (LMF1), and glucokinase regulator (GCKR) are responsible for hypertriglyceridemia. We investigated the molecular basis of severe hypertriglyceridemia in adult patients referred to the Clinical Laboratory at Fukuoka University Hospital.

Methods: Twenty-three adult patients with severe hypertriglyceridemia (＞1,000 mg/dL, 11.29 mmol/L) were selected. The coding regions of candidate genes were sequenced by next-generation sequencing. Forty-nine genes reportedly associated with hypertriglyceridemia were analyzed.

Results: In the 23 patients, we detected 70 variants: 28 rare and 42 common ones. Among the 28 rare variants with ＜1% allele frequency, p.I4533L in APOB, p.M490I in MLXIPL, p.L152M in NCAN, and p.S264T in TIMD4 were novel. We did not observe single gene homozygous or compound heterozygous disease-causing rare variants in any of the 23 hypertriglyceridemia cases. However, in silico algorithms and previous reports indicated that five rare variants, APOA5 (p.T184S), GCKR (c.354＋1G＞A), LMF1 (p.G410R), and LRP1 (p.G813R; p.R2173Q), and seven common variants, APOA5 (pG185C), APOE (p.C130R; p.E262K/p.E263K), GCKR (p.V103M), GPIHBP1 (p.C14F), LRP1 (p.Y4054F), and MLXIPL (p.Q241H), can cause hypertriglyceridemia. However, all five disease-causing rare variants detected in this study were heterozygous.

Conclusions: The prevalence of disease-causing rare variants in candidate genes in severe hypertriglyceridemia patients was low. The major causes of severe hypertriglyceridemia were not single gene abnormalities, but involved multiple gene variations and environmental factors.

Aim: The importance of sarcopenia in cardiovascular diseases has been recently demonstrated. This study aims to examine whether skeletal muscle mass (SMM), an important component of sarcopenia, is associated with an increased risk of poor outcome in patients after ST-segment elevation myocardial infarction (STEMI).

Methods: We measured SMM in 387 patients with STEMI using dual-energy X-ray absorptiometry. Patients were divided into low- and high-appendicular skeletal mass index (ASMI: appendicular SMM divided by height squared (kg/m²)) groups using the first quartile of ASMI (≤ 6.64 kg/m² for men and ≤ 5.06 kg/m² for women). All patients were followed up for the primary composite outcome of all-cause death, nonfatal myocardial infarction, nonfatal ischemic stroke, hospitalization for congestive heart failure, and unplanned revascularization.

Results: Low-ASMI group was older and had a more complex coronary lesion, a lower left ventricular ejection fraction, and a higher prevalence of Killip classification ≥ 2 than high-ASMI group. During a median follow-up of 33 months, the event rate was significantly higher in low-ASMI group than in high-ASMI group (24.7% vs 13.4%, log-rank p=0.001). Even after adjustment for patients' background, low ASMI was independently associated with the high risk of primary composite events (adjusted hazard ratio 2.06, 95% confidence interval 1.01– 4.19, p=0.04). In the subgroup analyses of male patients (n=315), the optimal cutoff point of ASMI for predicting primary composite outcome was 6.75 kg/m², which was close to its first quartile value.

Conclusions: Low ASMI is independently associated with poor outcome in patients with STEMI.

Aim: Familial hypercholesterolemia (FH) is the most commonly encountered genetic condition that predisposes individuals to severe autosomal dominant lipid metabolism dysfunction. Although more than 75% of the European population has been scrutinized for FH-causing mutations, the genetic diagnosis proportion among Chinese people remains very low (less than 0.5%). The aim of this study was to identify genetic mutations and help make a precise diagnosis in Chinese FH patients.

Methods: We designed a gene panel containing 20 genes responsible for FH and tested 208 unrelated Chinese possible/probable or definite FH probands. In addition, we called LDLR copy number variation (CNVs) with the panel data by panelcn.MOPS, and multiple ligation-dependent probe amplification (MLPA) was used to search for CNVs in LDLR, APOB, and PCSK9.

Results: A total of 79 probands (38.0%) tested positive for a (likely) pathogenic mutation, most of which were LDLR mutations, and three LDLR CNVs called from the panel data were all successfully confirmed by MLPA analysis. In total, 48 different mutations were identified, including 45 LDLR mutations, 1 APOB mutation, 1 ABCG5 mutation, and 1 APOE mutation. Among them, the five most frequent mutations (LDLR c.1879G＞A, c.1747C＞T, c.313＋1G＞A, c.400T＞C, and APOB c.10579C＞T) were detected. Moreover, we also found that patients with LDLR variants of CNVs and splicing and nonsense had increased low-density lipoprotein cholesterol levels when compared with those who carried missense variants.

Conclusions: The spectrum of FH-causing mutations in the Chinese population is refined and expanded. Analyses of FH causal genes have been a great help in clinical diagnosis and have deep implications in disease treatment. These data can serve as a considerable dataset for next-generation sequencing analysis of the Chinese population with FH and contribute to the genetic diagnosis and counseling of FH patients.

Aim: Synthetic vascular grafts are widely used in surgical revascularization, mainly for medium- to large-sized vessels. However, synthetic grafts smaller than 6 mm in diameter are associated with a high incidence of thrombosis. In this study, we evaluated silk fibroin, a major protein of silk, with high biocompatibility and biodegradability, as a useful material for extremely-small-diameter vascular grafts.

Methods: A small-sized (0.9 mm inner diameter) graft was braided from a silk fibroin thread. The right carotid arteries of 8- to 14-week-old male C57BL/6 mice were cut at the midpoint, and fibroin grafts (5- to 7-mm in length) were transplanted using a cuff technique with polyimide cuffs. The grafts were harvested at different time points and analyzed histologically.

Results: CD31＋ endothelial cells had already started to proliferate at 2 weeks after implantation. At 4 weeks, neointima had formed with α-smooth muscle actin+ cells, and the luminal surface was covered with CD31＋endothelial cells. Mac3＋ macrophages were accumulated in the grafts. Graft patency was confirmed at up to 6 months after implantation.

Conclusion: This mouse model of arterial graft implantation enables us to analyze the remodeling process and biocompatibility of extremely-small-diameter vascular grafts. Biodegradable silk fibroin might be applicable for further researches using genetically modified mice.

Aim: To investigate the association of small dense low-density lipoprotein cholesterol (sdLDL-C) and acute ischemic stroke (AIS) in terms of risk, severity, and outcomes. Prediction models were established to screen high-risk patients and predict prognosis of AIS patients.

Methods: We enrolled in this study 355 AIS patients and 171 non-AIS controls. AIS was subtyped according to TOAST criteria, and the severity and outcomes of AIS were measured. Blood glucose and lipid profiles including total cholesterol, triglyceride, and lipoproteins were measured in all patients using automatic measure. Lipoprotein subfractions were detected by the Lipoprint LDL system.

Results: As compared with the non-AIS control group, the AIS group had higher sdLDL-C levels. Pearson correlation analysis revealed that the sdLDL-C level and risk of AIS, especially non-cardioembolic stroke, were positively correlated. The area under the curve of sdLDL-C for AIS risk was 0.665, better than that of other lipids. Additionally, the sdLDL-C level was significantly correlated with AIS severity and bad outcomes. A logistic regression model for assessing the probability of AIS occurrence and a prognostic prediction model were established based on sdLDL-C and other variables.

Conclusions: Elevated levels of sdLDL-C were associated with a higher prevalence of AIS, especially in non-cardioembolic stroke subtypes. After adjustment for other risk factors, sdLDL-C was found to be an independent risk factor for AIS. Also, sdLDL-C level was strongly associated with AIS severity and poor functional outcomes. Logistic regression models for AIS risk and prognosis prediction were established to help clinicians provide better prevention for high-risk subjects and monitor their prognosis.

Aim: There is no randomized controlled trial to compare the effectiveness and safety of mechanical thrombectomy (MT) to intravenous thrombolysis in patients with posterior circulation occlusion (PCO). Hence, we firstly performed a meta-analysis to investigate the outcomes of MT in PCO and then compared these outcomes to anterior circulation occlusion (ACO) to provide fundamental data to further studies.

Methods: We searched the PubMed, EMBASE, and Cochrane Library from dates of inception to June 2019 for relevant studies. Outcomes including functional independence at 90 days, successful recanalization, mortality, symptomatic intracranial hemorrhage (sICH), and futile recanalization were extracted.

Results: Seven studies involving 474 patients with PCO thrombectomy were analyzed. There was a lower rate of functional independence at 90 days and a higher rate of mortality after thrombectomy in PCO versus ACO (odds ratios (OR) 0.72; 95% confidence interval (CI) 0.57–0.90; OR 2.03; 95% CI 1.30–3.18). Recanalization rates were comparable (OR 1.01; 95% CI 0.62–1.65), but a higher futile recanalization rate was found in basilar artery occlusion (BAO) (OR 1.75; 95% CI 1.30–2.37). There was a lower rate of sICH in MT for patients with PCO versus ACO (OR 0.54; 95% CI 0.29–0.99).

Conclusions: We found that the outcomes of MT for patients with PCO were poorer than with ACO. On the other hand, MT appears to have lower rates of sICH and to increase successful recanalization. Given the high recanalization rate, MT may serve as an adjunct to standard treatment. The key point to improve outcomes is recognizing reliable factors associated with futile recanalization and optimizing the results of MT. But in view of the different characteristics of posterior circulation stroke and anterior circulation stroke, the results are far from robust.

Aim: Seaweed is a popular traditional foodstuff in Asian countries. To our knowledge, few studies have examined the association of seaweed intake with mortality from cardiovascular disease. We examined the association of frequency of seaweed intake with total and specific cardiovascular disease mortality.

Methods: We examined the association of seaweed intake with mortality from cardiovascular disease among 40,234 men and 55,981 women who participated in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk. Sex-specific hazard ratios for mortality from cardiovascular disease (stroke, stroke subtypes, and coronary heart disease) according to the frequency of seaweed intake were calculated stratified by study area and adjusted for potential cardiovascular risk factors and dietary factors.

Results: During the 1,580,996 person-year follow-up, 6,525 cardiovascular deaths occurred, of which 2,820 were due to stroke, and 1,378, to coronary heart disease. Among men, the multivariable analysis showed that participants who ate seaweed almost every day compared with those who never ate seaweed had hazard ratios (95% confidence interval; P for trend) of 0.79 (0.62–1.01; 0.72) for total cardiovascular disease, 0.70 (0.49–0.99; 0.47) for total stroke, 0.69 (0.41–1.16; 0.11) for cerebral infarction. Among women, the multivariable-adjusted hazard ratios were 0.72 (0.55–0.95; 0.001) for total cardiovascular disease, 0.70 (0.46–1.06; 0.01) for total stroke, and 0.49 (0.27–0.90; 0.22) for cerebral infarction. No associations were observed between seaweed intake and risk of intraparenchymal hemorrhage and coronary heart disease among either men or women.

Conclusions: We found an inverse association between seaweed intake and cardiovascular mortality among Japanese men and women, especially that from cerebral infarction.

Aim: Epicardial adipose tissue (EAT) may be associated with arrhythmogenesis. P-wave indices such as P-wave dispersion and P-wave variation indicated a slowed conduction velocity within the atria. This study investigated the effect of dapagliflozin on EAT volume and P-wave indices.

Methods: In the present ad hoc analysis, 35 patients with type 2 diabetes mellitus and coronary artery disease were classified into dapagliflozin group (n=18) and conventional treatment group (n=17). At baseline, EAT volume, HbA1c and plasma level of tumor necrotic factor-α (TNF-α) levels, echocardiography, and 12-lead electrocardiogram (ECG) were performed. EAT volume was measured using computed tomography. Using 12-lead ECG, P-wave indices were measured.

Results: At baseline, EAT volumes in the dapagliflozin and conventional treatment groups were 113±20 and 110±27 cm³, respectively. Not only HbA1c and plasma level of TNF-α but also echocardiography findings including left atrial dimension and P-wave indices were comparable between the two groups. After 6 months, plasma level of TNF-α as well as EAT volume significantly decreased in the dapagliflozin group only. P-wave dispersion and P-wave variation significantly decreased in the dapagliflozin group only (-9.2±8.7 vs. 5.9±19.9 ms, p=0.01; -3.5±3.5 vs. 1.7±5.9 ms, p=0.01). The change in P-wave dispersion correlated with changes in EAT volume and plasma level of TNF-α. In multivariate analysis, the change in EAT volume was an independent determinant of the change in P-wave dispersion.

Conclusion: Dapagliflozin reduced plasma level of TNF-α, EAT volume, and P-wave indices, such as P-wave dispersion. The changes in P-wave indices were especially associated with changes in EAT volume.

The number and date of registration: UMIN000035660, 24/Jan/2019

Aim: The importance of precisely quantifying low-density lipoprotein cholesterol (LDL-C) has become more pronounced over the years, with the rise of metabolic syndrome in the population and the reduction in LDL-C treatment goals. This study aims to compare two novel equations indirectly estimating LDL-C and assess their compatibility with Friedewald formula, in a population with high cardiovascular risk.

Methods: This study is a retrospective analysis of the lipid profiles of 10,006 patients who underwent coronary angiography. LDL-C was calculated using Friedewald, Martin, and Sampson equations, and the compatibility between estimations was compared using methods of concordance and reclassification.

Results: Our findings show that Martin and Sampson equations displayed high rates of upward LDL-C reclassification (10.8% and 7.5%, respectively) when compared with Friedewald equation. In comparison to the Sampson method, Martin also reclassified 3.8 % of patients to a higher LDL-C category. The magnitude of discordance between LDL-C estimates was more pronounced in hypertriglyceridemic patients, and this increased progressively with the reduction in LDL-C. The proportion of patients with LDL-C ＜70 mg/dL reclassified to a higher LDL-C category reached 44% (Sampson vs. Friedewald), 65% (Martin vs. Friedewald), and 37% (Martin vs.Sampson) in those with triglyceride levels between 200 and 399 mg/dL.

Conclusions: Both Martin and Sampson LDL-C estimates displayed significant proportion of upward discordance with reclassification to higher LDL-C categories compared to Friedewald formula, particularly in patients with elevated triglycerides and low LDL-C, a population in whom more accurate estimation of LDL-C is required. Further studies are warranted to validate the recently developed Sampson equation with comparison to Martin method that tended to more significantly overestimate LDL-C.