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.
Numerous randomized clinical trials have established statins as the major standard therapy for atherosclerotic diseases because these molecules decrease the plasma level of low-density lipoprotein ...(LDL) cholesterol and moderately increase that of plasma high-density lipoprotein (HDL) cholesterol. The reverse cholesterol transport pathway, mediated by HDL particles, has a relevant antiatherogenic potential. An important approach to HDL-targeted therapy is optimization of the HDL-cholesterol level and enhanced removal of plasma cholesterol, together with the prevention and mitigation of inflammation related to atherosclerosis. Small-molecule inhibitors of cholesteryl ester transfer protein (CETP) increase the HDL-cholesterol level in subjects with normal or low HDL-cholesterol. However, CETP inhibitors do not seem to reduce the risk of atherosclerotic diseases. HDL therapies using reconstituted HDL, including apolipoprotein (Apo) A-I Milano, ApoA-I mimetics, or full-length ApoA-I, are dramatically effective in animal models. Of those, the ApoA-I-mimetic peptide called FAMP effectively removes cholesterol via the ABCA1 transporter and acts as an antiatherosclerotic agent by enhancing the biological functions of HDL without elevating the HDL-cholesterol level. Our review of the literature leads us to conclude that HDL-targeted therapies have significant atheroprotective potential and thus may effectively treat patients with cardiovascular diseases. (Circ J 2015; 79: 2523–2528)
During out-of-hospital cardiac arrest, it is unclear how long prehospital resuscitation efforts should be continued to maximize lives saved.
Between 2005 and 2012, we enrolled 282 183 adult patients ...with bystander-witnessed out-of-hospital cardiac arrest from the All-Japan Utstein Registry. Prehospital resuscitation duration was calculated as the time interval from call receipt to return of spontaneous circulation in cases achieving prehospital return of spontaneous circulation or from call receipt to hospital arrival in cases not achieving prehospital return of spontaneous circulation. In each of 4 groups stratified by initial cardiac arrest rhythm (shockable versus nonshockable) and bystander resuscitation (presence versus absence), we calculated minimum prehospital resuscitation duration, defined as the length of resuscitation efforts in minutes required to achieve ≥99% sensitivity for the primary end point, favorable 30-day neurological outcome after out-of-hospital cardiac arrest. Prehospital resuscitation duration to achieve prehospital return of spontaneous circulation ranged from 1 to 60 minutes. Longer prehospital resuscitation duration reduced the likelihood of favorable neurological outcome (adjusted odds ratio, 0.84; 95% confidence interval, 0.838-0.844). Although the frequency of favorable neurological outcome was significantly different among the 4 groups, ranging from 20.0% (shockable/bystander resuscitation group) to 0.9% (nonshockable/bystander resuscitation group; P<0.001), minimum prehospital resuscitation duration did not differ widely among the 4 groups (40 minutes in the shockable/bystander resuscitation group and the shockable/no bystander resuscitation group, 44 minutes in the nonshockable/bystander resuscitation group, and 45 minutes in the nonshockable/no bystander resuscitation group).
On the basis of time intervals from the shockable arrest groups, prehospital resuscitation efforts should be continued for at least 40 minutes in all adults with bystander-witnessed out-of-hospital cardiac arrest.
URL: http://www.umin.ac.jp/ctr/. Unique identifier: 000009918.
Aim: The purpose of this study was to compare two homogeneous assays of low-density lipoprotein-cholesterol (LDL-C) with a modified beta quantification reference measurement for LDL-C (BQ-LDL), ...fractions of chylomicron (CM), very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) by quantitative ultracentrifugation in patients with hypertriglyceridemia.Methods: Two homogeneous LDL-C assays (LDL-C(K), Kyowa Medex and LDL-C(S), Sekisui Medical) were used to measure 198 samples of fresh anonymized leftover sera with hypertriglyceridemia (≥ 150 mg/dL). Of these, 32 samples with discrepant LDL-C levels or hypertriglyceridemia (≥ 400 mg/dL) were used for further analysis. Quantitative ultracentrifugation was used to separate samples.Results: The two homogeneous LDL-C assays had a strong correlation with each other for the samples from 198 patients with hypertriglyceridemia. LDL-C(K) and LDL-C(S) in 32 selected samples were strongly correlated with BQ-LDL. In both homogeneous assays, cholesterol in the CM and VLDL fractions was measured as part of the LDL-C. A weak correlation was found between cholesterol in the VLDL fraction and LDL-C using the two homogeneous assays, but no correlation was found with cholesterol in the CM fraction. Cholesterol in the IDL fraction was also measured as part of the LDL-C in both assays.Conclusion: Both homogeneous assays partially detected cholesterol in the chylomicron and VLDL fractions, but LDL-C measured by both homogeneous assays correlated with BQ-LDL.
Clinical trials and epidemiological studies have revealed a negative correlation between serum high-density lipoprotein (HDL) cholesterol levels and the risk of cardiovascular events. Currently, ...statin treatment is the standard therapy for cardiovascular diseases, reducing plasma low-density lipoprotein (LDL) cholesterol levels. However, more than half of the patients have not been able to receive the beneficial effects of this treatment. The reverse cholesterol transport pathway has several potential anti-atherogenic properties. An important approach to HDL-targeted therapy is the optimization of HDL cholesterol levels and function in the blood to enhance the removal of circulating cholesterol and to prevent or mitigate inflammation that causes atherosclerosis. Cholesteryl ester transfer protein inhibitors increase HDL cholesterol levels in humans, but whether they reduce the risk of atherosclerotic diseases is unknown. HDL therapies using HDL mimetics, including reconstituted HDL, apolipoprotein (Apo) A-IMilano, ApoA-I mimetic peptides, or full-length ApoA-I, are highly effective in animal models. In particular, the Fukuoka University ApoA-I-mimetic peptide (FAMP) effectively removes cholesterol via the ABCA1 transporter and acts as an anti-atherosclerotic agent by enhancing the biological functions of HDL without elevating HDL cholesterol levels. Our literature review suggests that HDL mimetics have significant atheroprotective potential and are a therapeutic tool for atherosclerotic diseases.
Background: Hyogo Prefecture has managed smoking ban legislation with partial restrictions in public places (Hyogo-L) since 2013. Previous studies have reported a significant decrease in admissions ...for acute coronary syndrome (ACS) in Kobe-city, but not in other districts of Hyogo Prefecture in the 2 years after Hyogo-L. The aim of the present study was to define the long-term effect of Hyogo-L.Methods and Results: The JROAD-DPC dataset was used to collect information on the number of hospitalizations for ACS in Hyogo Prefecture, and in Osaka-city without smoking ban legislation, from April 2013 to March 2020. Poisson regression analysis was performed to calculate incident rate ratios (IRRs) and 95% confidence intervals (CIs). ACS records of 3,101 in Kobe-city, 11,375 in areas of Hyogo Prefecture other than Kobe-city and 11,079 in Osaka-city were collected for admissions. The incidence of ACS reduced significantly over time in Kobe-city IRR (95% CI); 0.96 (0.94–0.97), but did not reduce in the others. The decrease in Kobe-city was observed in ACS patients without smoking, hypertension, and hyperlipidemia, but not in those with such risk factors.Conclusions: The long-term ACS reduction or non-reduction under Hyogo-L was determined at the initial period and the same scenario continued, supporting the importance of legislation and compliance with the smoking ban. The lowering effect was remarkable in ACS patients without risk factors such as non-smoking.
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 (>1,000mg/dL, 11.29mmol/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.
We herein report a 79-year-old man with recurrent atrial flutter (AFL) following catheter ablation for pulmonary vein (PV) isolation and block line of the cavotricuspid isthmus. An ...electrophysiological study and three-dimensional mapping results revealed left atrium (LA)-PV macroreentrant flutter caused by a conduction gap, possibly correlated to prior application, which mimicked cavotricuspid isthmus-dependent AFL. This LA-PV flutter was terminated after applying radiofrequency to the gap at the antrum near the bottom left inferior PV in the posterior LA wall. During follow-up, the patient did not present with atrial tachyarrhythmias; antiarrhythmic drugs were therefore not administered.
The associations between the presence or severity of coronary artery disease (CAD) and measurements of various kinds of fat as assessed by multidetector row computed tomography (MDCT) are unclear. We ...enrolled 300 patients who were clinically suspected to have CAD or who had at least one cardiac risk factor and had undergone MDCT. The number of significantly stenosed coronary vessels (VD), and measurements of pericardial fat index, paracardial fat index, epicardial fat index, visceral fat index, and subcutaneous fat index were quantified using MDCT. Plasma levels of adiponectin, pentaxin-3, and high-sensitivity C-reactive protein factors were also measured. Pericardial fat index, paracardial fat index, and visceral fat index in a CAD group were significantly greater than those in a non-CAD group. In addition, the levels of these fat indices tended to increase as the number of VD increased and were positively correlated with the Gensini score. The area-under-the-curve for paracardial fat index was significantly greater than those for the other parameters of fat index measured by a receiver-operating characteristic curve analysis. The cut-off level of paracardial fat index that gave the greatest sensitivity and specificity for the diagnosis of CAD was 54.9 cm3/m2 (sensitivity 0.710, specificity 0.552). The presence of CAD was independently associated with paracardial fat index, in addition to age and diabetes mellitus, by a multiple logistic regression analysis. In conclusion, paracardial fat index may be a marker for evaluating the presence or severity of CAD.
The ability of pro-protein convertase subtilisin/kexin type 9 (PCSK9) levels to predict the presence or severity of coronary artery disease (CAD) remains controversial. The purpose of this study was ...to investigate these associations. We enrolled 393 patients who were clinically suspected to have CAD or who had at least one cardiac risk factor and underwent multidetector-row computed tomography coronary angiography. The presence of CAD (≥50% coronary stenosis), the number of significantly stenosed coronary vessels, and plasma levels of PCSK9 by ELISA were analyzed. Plasma PCSK9 levels (log-transformed data) were significantly associated with the presence of CAD. Next, we divided the patients into two groups (non-statin and statin groups) according to statin treatment. PCSK9 levels in the non-statin group were significantly lower than those in the statin group. There were no significant differences in PCSK9 levels between the absence and presence of CAD in the statin group. However, in the non-statin group, PCSK9 levels in patients with CAD were significantly higher than those in patients without CAD. PCSK9 levels, in addition to age, gender, BMI, DM and HDL-C, were independently associated with the presence of CAD by a multivariable analysis. In conclusion, our results demonstrated that plasma PCSK9 levels may be a marker for evaluating the presence of CAD.
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