Plasma remnant-like lipoprotein particles or LDL-C as major pathologic factors in sudden cardiac death cases

We have previously reported that the majority of sudden cardiac death (SCD) events were associated with postprandial hyperlipidemia in Japanese subjects. In this investigation, we have compared LDL-cholesterol (LDL-C) and remnant-like lipoprotein particles (RLP) as cardiovascular risk factors in SCD cases, especially in Pokkuri death syndrome (PDS) cases who had nearly normal coronary arteries. To predict the risk of plasma RLP-cholesterol, triglyceride (RLP-C, RLP-TG) and LDL-C in fatal clinical events associated with SCD cases with or without atherosclerosis (PDS), we calculated the cut-off values and likelihood ratio of these lipoproteins from ROC analysis. Sixty-eight percent of SCD cases were above cut-off value of RLP-C (>12.8 mg/dL) versus 32% for control death cases (P < 0.0001) and the likelihood ratio of RLP-C was 2.12. Significantly higher incidence of RLP-C above cut-off value (>10.1 mg/dL) was seen in PDS compared to controls (P < 0.0001) and the likelihood ratio was 3.13. Similarly, significantly higher incidence of RLP-TG above cut-off values, SCD > 53 mg/dL and PDS > 67 mg/dL, was seen compared to controls (P < 0.0001) and the likelihood ratio was 1.86 and 2.73, respectively. Further, significantly higher incidence of LDL-C above cut-off value (>93 mg/dL) was seen in SCD compared to controls (P < 0.0001) and the likelihood ratio was 1.68. However, the incidence of LDL-C above cut-off value (LDL-C > 106 mg/dL) was not significantly different between PDS and controls and the likelihood ratio was 1.52.

In conclusion, this study has shown high levels of plasma remnant lipoproteins in PDS and that PDS cases did not present with atherosclerotic lesions or elevated LDL-C. In contrast, SCD cases showed high levels of plasma remnant lipoproteins together with elevated plasma LDL-C. Accordingly, we believe that plasma remnant lipoproteins level rather than plasma LDL-C is a major pathologic factor in cardiovascular events.     

Association of plasma triglyceride-rich lipoprotein remnants with coronary atherosclerosis in cases of sudden cardiac death

Among the risk factors for coronary atherosclerosis, elevated LDL-C level is best known. The action of lipoprotein lipase on triglyceride-rich lipoproteins produces remnant lipoprotein particles enriched in cholesterol and apolipoprotein E (apo E). Apo E serves as the ligand for uptake of remnant lipoproteins via the LDL-receptor or the remnant receptor. In this study, postmortem plasma total cholesterol, triglycerides (TG), VLDL-C, HDL-C, lipoprotein (a) [Lp(a)] and remnant-like lipoprotein particles (RLP)-cholesterol, RLP-TG, apolipoproteins B, C III and E were measured, together with LDL-C to assess their potential contribution to the severity of coronary and aortic atherosclerosis of the 197 cases of sudden death (132 cardiac death and 65 non-cardiac death). In all cases, the severity of coronary atherosclerosis was determined at postmortem pathological examination. RLP-cholesterol (RLP-C) and LDL-C concentrations were significantly higher in cases with advanced coronary atherosclerosis compared with those without coronary atherosclerosis; respective median values were 13.5 vs 8.4 mg/dl (P < 0.001) and 140 vs 115 mg/dl (P < 0.05). RLP-C levels were more strongly correlated with the severity score of coronary atherosclerosis than LDL-C.     

Myocardial bridging does not predict sudden death in children with hypertrophic cardiomyopathy but is associated with more severe cardiac disease

OBJECTIVES

We sought to examine the association between systolic compression of sections of epicardial coronary vessels (myocardial bridging) with myocardial perfusion abnormalities and clinical outcome in children with hypertrophic cardiomyopathy (HCM).

BACKGROUND

It has recently been suggested that myocardial bridging is an important cause of myocardial ischemia and sudden death in children with HCM.

METHODS

Angiograms from 57 children with HCM were reviewed for the presence of bridging (50% or more maximum systolic arterial compression). QT interval indices, echocardiographic and cardiac catheterization findings, treadmill exercise tests, exercise thallium scintigraphy, Holter monitoring and electrophysiologic study findings were compared in children with and without bridging. The findings were also related to the presence or absence of compression of septal branches of the left anterior descending artery (LAD).

RESULTS

Bridging was present in 23 (40%) of the children. Multiple coronary arteries were involved in four children. Bridging involved the LAD in 16 of 28 (57%) affected vessels. Myocardial perfusion abnormalities were present in 14 of 30 (47%) children without bridging and in 17 of 22 (94%) children with bridging, P = 0.002. However, bridging was associated with more severe septal hypertrophy (19 ± 8 mm vs. 28 ± 8 mm, p < 0.001), a higher septum:posterior wall thickness ratio (2.7 ± 1.2 vs. 1.8 ± 0.9, p < 0.001), and higher left ventricle (LV) outflow gradient (45 ± 37 mm Hg vs. 16 ± 28 mm Hg, P = 0.002). Compression of septal LAD branches was present in 37 (65%) of the children and was significantly associated with bridging, severity of LV hypertrophy and outflow obstruction. Multivariate analysis demonstrated that LV septal thickness and septal branch compression, and not bridging, were independent predictors of thallium perfusion abnormalities. There was a 90% power at 5% significance to detect an effect of bridging on thallium abnormalities at an odds ratio of 3. Bridging was also not associated with significantly greater symptoms, increased QT and QTc intervals and QTc dispersion, ventricular tachycardia on Holter or induced at EP study, or a worse prognosis.

CONCLUSIONS

Bridging and compression of septal branches of the LAD are common in HCM children and are related to magnitude of LV hypertrophy. Left ventricular hypertrophy and compression of intramyocardial branches of the epicardial coronary arteries may contribute to myocardial perfusion abnormalities. Our findings suggest that bridging does not result in myocardial ischemia and may not cause arrhythmias or sudden death in HCM children.     

Lessons learnt from the autopsies of 445 cases of sudden cardiac death in adults

AIM: To determine the cause of sudden cardiac death in adults who underwent autopsy. METHODS: Four hundred and forty-five sudden cardiac deaths occurred within 1 h of the symptoms onset, and all other cardiac and noncardiac causes having been excluded from autopsy and toxicology screening, were retrospectively identified from among 902 autopsies performed in a 2-year period on the island of Crete. The presence of acute coronary thrombi and myocardial infarction was documented macroscopically and by light microscopy and histology. RESULTS: In all 445 cases, at least one coronary artery had evidence of moderate to advanced atherosclerosis. About two thirds were between 50 and 70 years. Men had a higher incidence than women, but with advancing age (>60 years) this difference was reduced. Myocardial infarction was found in 17 cases (11 acute; 6 acute and healed). Fifty-eight cases (13.0%) had coronary thrombi, mostly involving the left anterior descending and the right coronary arteries (81%); only six of these were associated with acute myocardial infarction. CONCLUSION: In our population, arrhythmia was the most common cause of sudden cardiac death, while acute coronary thrombi and acute myocardial infarction were detected only in some cases. Because of the heterogeneity in the cause of sudden cardiac deaths in adults, a detailed forensic investigation may provide important information on the cause of death and help in the development of primary and secondary prevention.     

Effects of atorvastatin therapy on the low-density lipoprotein subfraction, remnant-like particles cholesterol, and oxidized low-density lipoprotein within 2 weeks in hypercholesterolemic patients.

The short- and intermediate-term pleiotropic effects of atorvastatin were investigated in 18 hypercholesterolemic patients, as well as the temporal differences in these pleiotropic effects. Atorvastatin was given for 3 months and fasting lipid concentrations, thiobarbituric acid reactive substances (TBARS), fibrinolytic parameters, and flow-mediated dilation of the brachial artery (FMD) were measured at baseline and after 2 weeks and 3 months of therapy. Atorvastatin reduced the total cholesterol (273+/-34 vs 188+/-31 mg/dl, p<0.0001), low-density lipoprotein-cholesterol (LDL-C: 174+/-28 vs 111+/-23 mg/dl, p<0.0001), small, dense LDL-C (34+/-22 vs 18+/-20%, p<0.01), remnant-like particles cholesterol (RLP-C: 8.8+/-6.0 vs 5.1+/-2.6 mg/ml, p<0.01), and TBARS (3.3+/-1.0 vs 3.1+/-0.9 nmol/ml, p<0.05) after 2 weeks. Atorvastatin decreased the concentration of small, dense LDL-C again after 3 months (8+/-13%, p<0.0001). The plasma concentrations of the fibrinolytic parameters did not change significantly after 3 months of atorvastatin therapy. FMD increased significantly after 2 weeks (5.6+/-2.1 vs 6.3+/-2.0%, p<0.01) and additionally increased after 3 months of therapy (8.3+/-1.9%, p<0.0001). There were no correlations between the pleiotropic effects and the improvement in the lipid profile. The results indicate some short-term pleiotropic effects of atorvastatin therapy within 2 weeks, which may be important with respect to the early benefits of statin therapy.     

Seasonality, but not prevalence of sudden infant death syndrome varies by region in mainland Britain.

This study aimed to investigate whether seasonal variation in day length contributed to winter/summer variation in sudden infant death syndrome (SIDS) at different latitudes in mainland Britain. Over 11 yrs 13,973 deaths were studied. Using appropriate analytic techniques a sine curve was fitted to monthly rates with the amplitude indicating magnitude of seasonal change. The rate of SIDS per 1,000 live births was the same (1.73) in the north as in the south. The amplitude was a quarter less in the north (41.3%) than in the south (54.2%) (p<0.001). While annual rates did not differ, the within year distribution did. The findings for seasonality of SIDS births were similar (amplitudes: north 213%, south 32.3%). Correlations were made between SIDS amplitude and individual environmental factors, particularly temperature and day length. These complex issues, while reported briefly, do not allow firm conclusions. In the north the winter day length is shorter, sunshine hours are less and temperature is lower, but the winter increment in SIDS is less. The extent of seasonal variation of sudden infant death syndrome is greater in the south as compared with the colder, darker north but this has no effect on sudden infant death syndrome rates. Changing photoperiod by latitude, amongst other environmental influences, may hold clues to the aetiology of sudden infant death syndrome.     

Serum adiponectin is related to plasma high-density lipoprotein cholesterol but not to plasma insulin-concentration in healthy children: the FLVS II study

Although low levels of plasma adiponectin were associated with an increase in cardiovascular risk in adults, few data investigated that relationship in children. The aim of this study was to investigate the relationship between plasma adiponectin and cardiovascular risk factors in healthy children. This cross-sectional population-based study was conducted in Fleurbaix and Laventie, 2 cities in the north of France. The main outcome measure was the correlations between plasma adiponectin and adiposity variables (the body mass index, the sum of 4 skinfolds, waist circumference [WC], and percent body fat [bioimpedance]), blood pressure, plasma glucose, triglycerides, high-density lipoprotein (HDL) cholesterol and insulin. In 398 children of both sexes, adiponectin was not significantly related to age and pubertal stage. In boys only, adiponectin correlated with WC (r = -0.19; P = .008) and body mass index (r = -0.15; P = .04) but not with other adiposity variables. After taking into account WC, adiponectin was positively correlated with HDL-cholesterol in boys (r = 0.14; P = .05) and girls (r = 0.25; P = .0004), but was not correlated with insulin and homeostasis model assessment index for insulin resistance in both sexes. These results suggest that, in apparently healthy children, adiponectin is related to the level of HDL-cholesterol independently of fat mass. The relationship between adiponectin and insulin resistance previously reported in obese or diabetic children was not apparent in these subjects and may therefore occur only at later age with fat accumulation.     

云南省不明原因心源性猝死病区人群谷胱甘肽过氧化物酶活力与心肌肌钙蛋白I相关性

目的 探讨云南省不明原因心源性猝死病区人群体内谷胱甘肽过氧化物酶(GsH-Px)活力与心肌损伤的特异性标志物心肌肌钙蛋白I(cTnI)的相关性.方法 根据是否采取补硒措施将发病地区分为硒干预病区和未干预病区,并在病区外设立对照组.采用5,5'-二硫双-2-硝基苯甲酸(DTNB)分光光度法检测全血GSH-Px活力:酶联免疫吸附试验(ELISA)测定血浆中的cTnI.结果 硒干预病区人群GSH-Px活力[(117.913±18.355)U/L]明显高于未干预病区[(96.255±17.358)U/L]及对照组[(100.108±10.091)U/L],差异有统计学意义(P＜0.05);未干预病区人群cTnI[(3.236±0.998)μg/L]最高,对照组[(2.814±0.670)μg/L]次之,硒干预病区[(2.147±0.476)μg/L]最低;GSH-Px活力与cTnI呈显著负相关(r=-0.351,P＜0.01).结论 云南省不明原因心源性猝死病区人群体内GSH-Px活力与cTnI呈负相关,提示提高机体GSH-Px活力水平对心肌损伤可能有保护作用.     

云南省祥云县不明原因心源性猝死回顾性调查

目的 了解云南省祥云县不明原因心源性猝死的流行特征。方法 对祥云县2004年以前上报的云南不明原因心源性猝死病例和同发病例开展回顾性调查，疑似病例搜索调查，将资料核实整理、讨论归类后，进行统计学分析。结果 共调查到14例云南不明原因心源性猝死病例，3例同发病例，4例野生菌中毒死亡病例和4例未定论病例。不明原因猝死病例村庄、家庭聚集性明显（P〈0．01），时间分布在7、8月份，发病年龄为10—50岁，性别及民族间发病率差异无统计学意义（P〉0．05）。调查中野生菌中毒死亡的流行特征与不明原因心源性猝死极为相似。结论 祥云县不明原因心源性猝死呈现出明显的地区性、季节性、人群选择性、村庄聚集和家庭聚集的流行特点，提示危险因素在特定条件下存在，猝死病例间具有同源暴露史。     

Induced mutant mouse lines that express lipoprotein lipase in cardiac muscle, but not in skeletal muscle and adipose tissue, have normal plasma triglyceride and high-density lipoprotein-cholesterol levels

The tissue-specific expression of lipoprotein lipase (LPL) in adipose tissue (AT), skeletal muscle (SM), and cardiac muscle (CM) is rate-limiting for the uptake of triglyceride (TG)-derived free fatty acids and decisive in the regulation of energy balance and lipoprotein metabolism. To investigate the tissue-specific metabolic effects of LPL, three independent transgenic mouse lines were established that expressed a human LPL (hLPL) minigene predominantly in CM. Through cross-breeding with heterozygous LPL knockout mice, animals were generated that produced hLPL mRNA and enzyme activity in CM but lacked the enzyme in SM and AT because of the absence of the endogenous mouse LPL gene (L0-hLPL). LPL activity in CM and postheparin plasma of L0-hLPL mice was reduced by 34% and 60%, respectively, compared with control mice. This reduced LPL expression was sufficient to rescue LPL knockout mice from neonatal death. L0-hLPL animals developed normally with regard to body weight and body-mass composition. Plasma TG levels in L0-hLPL animals were increased up to 10-fold during the suckling period but normalized after weaning and decreased in adult animals. L0-hLPL mice had normal plasma high-density lipoprotein (HDL)-cholesterol levels, indicating that LPL expression in CM alone was sufficient to allow for normal HDL production. The absence of LPL in SM and AT did not cause detectable morphological or histopathological changes in these tissues. However, the lipid composition in AT and SM exhibited a marked decrease in polyunsaturated fatty acids. From this genetic model of LPL deficiency in SM and AT, it can be concluded that CM-specific LPL expression is a major determinant in the regulation of plasma TG and HDL-cholesterol levels.     

Factor VII coagulant activity is strongly associated with the plasma concentration of large lipoprotein particles in middle-aged men

A community survey of factor VII coagulant activity (VIIc) and the lipoprotein profile in non-fasting plasma of middle-aged men in NW London was undertaken to search for the determinants of VIIc in the general community. The data demonstrates that associations between VIIc and the plasma concentrations of cholesterol and of triglycerides previously shown in the general population can be explained by the strong and positive associations between VIIc and the large lipoprotein particles, chylomicrons, VLDL and IDL. Consistent with the possibility that the concentration of large lipoproteins determines the in vivo reactivity of factor VII, the association between VIIc and the ratio of lipid in the d greater than 1.019 fraction to the total plasma lipid was also highly significant but negative. The observed correlations between VIIc and lipoproteins smaller than VLDL may be the product of the interrelations that exist between the lipoprotein fractions in plasma. However, the associations between VIIc and the chylomicron lipid concentrations are especially strong when allowance is made for the considerable bias towards zero in the observed correlation, due to large within-person variance in chylomicron concentration.     

SH2 domain-mediated targeting, but not localization, of Syk in the plasma membrane is critical for FcepsilonRI signaling

Aggregation of the high-affinity IgE receptor induces the tyrosine phosphorylation of subunits of the receptor and the subsequent association with the receptor of the cytosolic protein tyrosine kinase Syk. The current experiments examined the functional importance of membrane association of Syk and the role of the SH2 domain in receptor-mediated signal transduction. Wild-type Syk and chimeric Syk molecules with the c-Src myristylation sequence at the amino-terminus were expressed in a Syk-negative mast cell line. Chimeric Syk with the myristylation sequence was membrane associated, and a small fraction was constitutively colocalized with FcepsilonRI, Lyn, and LAT (linker for T-cell activation) in the glycolipid-enriched microdomains or rafts. However, even under these conditions, the tyrosine phosphorylation of Syk and the downstream propagation of signals required FcepsilonRI aggregation. This chimeric Syk was less active than wild-type Syk in FcepsilonRI-mediated signal transduction. In contrast, a truncated membrane-associated form of Syk that lacked the SH2 domains was not tyrosine phosphorylated by receptor aggregation and failed to transduce intracellular signals. These findings suggest that SH2 domain-mediated membrane translocation of Syk is essential for the FcepsilonRI-mediated activation of Syk for downstream signaling events leading to histamine release. Furthermore, the localization of Syk in glycolipid-enriched microdomains by itself is not enough to generate or enhance signaling events.     

High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors.

Analysis of untreated fresh blood plasma from healthy, fasting donors revealed that high density lipoprotein (HDL) particles carry most (approximately 85%) of the detectable oxidized core lipoprotein lipids. Low density lipoprotein (LDL) lipids are relatively peroxide-free. In vitro the mild oxidation of gel-filtered plasma from fasting donors with a low, steady flux of aqueous peroxyl radicals initially caused preferential oxidation of HDL rather than LDL lipids until most ubiquinol-10 present in LDL was consumed. Thereafter, LDL core lipids were oxidized more rapidly. Isolated lipoproteins behaved similarly. Preferential accumulation of lipid hydroperoxides in HDL reflects the lack of antioxidants in most HDL particles compared to LDL, which contained 8-12 alpha-tocopherol and 0.5-1.0 ubiquinol-10 molecules per particle. Cholesteryl ester hydroperoxides (CEOOHs) in HDL and LDL were stable when added to fresh plasma at 37 degrees C for up to 20 hr. Transfer of CEOOHs from HDL to LDL was too slow to have influenced the in vitro plasma oxidation data. Incubation of mildly oxidized LDL and HDL with cultured hepatocytes afforded a linear removal of CEOOHs from LDL (40% loss over 1 hr), whereas a fast-then-slow biphasic removal was observed for HDL. Our data show that HDL is the principal vehicle for circulating plasma lipid hydroperoxides and suggest that HDL lipids may be more rapidly oxidized than those in LDL in vivo. The rapid hepatic clearance of CEOOHs in HDL could imply a possible beneficial role of HDL by attenuating the build-up of oxidized lipids in LDL.     

Loss of luminal Ca2+ activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death

Different forms of ventricular arrhythmias have been linked to mutations in the cardiac ryanodine receptor (RyR)2, but the molecular basis for this phenotypic heterogeneity is unknown. We have recently demonstrated that an enhanced sensitivity to luminal Ca(2+) and an increased propensity for spontaneous Ca(2+) release or store-overload-induced Ca(2+) release (SOICR) are common defects of RyR2 mutations associated with catecholaminergic polymorphic or bidirectional ventricular tachycardia. Here, we investigated the properties of a unique RyR2 mutation associated with catecholaminergic idiopathic ventricular fibrillation, A4860G. Single-channel analyses revealed that, unlike all other disease-linked RyR2 mutations characterized previously, the A4860G mutation diminished the response of RyR2 to activation by luminal Ca(2+), but had little effect on the sensitivity of the channel to activation by cytosolic Ca(2+). This specific impact of the A4860G mutation indicates that the luminal Ca(2+) activation of RyR2 is distinct from its cytosolic Ca(2+) activation. Stable, inducible HEK293 cells expressing the A4860G mutant showed caffeine-induced Ca(2+) release but exhibited no SOICR. Importantly, HL-1 cardiac cells transfected with the A4860G mutant displayed attenuated SOICR activity compared with cells transfected with RyR2 WT. These observations provide the first evidence that a loss of luminal Ca(2+) activation and SOICR activity can cause ventricular fibrillation and sudden death. These findings also indicate that although suppressing enhanced SOICR is a promising antiarrhythmic strategy, its oversuppression can also lead to arrhythmias.     

Polymorphism of HL +1075C, but not -480T, is associated with plasma high density lipoprotein cholesterol and apolipoprotein AI in men of a Chinese population

Eight hundred and twenty-three Chinese Han adults aged over 40, including 466 men and 357 women were enrolled in the study to examine the association of +1075C and -480T polymorphisms in hepatic lipase gene with plasma lipoprotein and apolipoprotein levels. In this population the allele frequencies for HL +1075C and minus -480T were 0.053 and 0.362, respectively and the prevalence of HL +1075C/C and -480T/T were 0.006 and 0.132, respectively. Overall, the normal HDL-C (> or = 35 mg/dl) subjects had a higher carrier frequency of HL +1075C than the low HDL-C (<35 mg/dl) subjects (0.108 vs 0.029, P=0.039). However, when tested separately, the carrier frequency of HL +1075C was not significantly different between normal and low HDL-C females (0.101 vs 0.083, P=0.843). In males, the normal HDL-C subjects had a higher carrier frequency of HL +1075C than the low HDL-C subjects (0.113 vs 0.018, P=0.026). No significant difference of frequencies of HL -480T genotypes -480T/T,-480C/T and -480C/C was found between normal and low HDL-C subjects. Among plasma TG, TC, HDL-C, apo AI, apo AII, apo B100, apo CII, Apo CIII and apoE, only HDL-C and apo AI were significantly different among the three genotypes +1075A/A,+1075A/C and +1075C/C in men (P=0.029 and 0.032). No association was found in women. Male subjects with CC had a higher HDL-C than those with AC (P=0.020) and AA (P=0.013), AC higher than AA (P=0.017). Male subjects with CC had a higher apo AI than AC (P=0.013) and AA (P=0.019), AC higher than AA (P=0.021). Although not so significant (P=0.053) as HDL-C and apo AI, male subjects with CC had a higher apo AII than those with AC and AA. No significant difference of lipoprotein and apolipoprotein traits was found among the three -480T genotypes -480C/C,-480C/T and -480T/T, in the sample overall and in men and women separately. These results indicate that HL +1075C, not -480T polymorphism is associated with plasma high density lipoprotein cholesterol and apolipoprotein AI in men in this Chinese population.     

Current smoking, smoking cessation, and the risk of sudden cardiac death in patients with coronary artery disease

BACKGROUND: Cigarette smoking is a known risk factor for sudden cardiac death (SCD). However, the effect of continued cigarette smoking and smoking cessation on SCD risk in patients with established coronary artery disease (CAD) is subject to controversy. We, therefore, evaluated the effect of cigarette smoking on SCD risk in a large cohort of patients with established CAD. METHODS: The study population was composed of 3122 patients with a previous myocardial infarction or stable angina who participated in the Bezafibrate Infarction Prevention Trial. Patients were prospectively followed up for a mean of 8.2 years. The primary end point was the incidence of SCD according to smoking status. RESULTS: Among the 370 patients who were current smokers, 30 (8.1%) experienced SCD; 83 (4.6%) of the 1821 patients who had quit smoking and 43 (4.6%) of the 931 patients who had never smoked experienced SCD (P =.01). In multivariate analyses, current smoking was associated with a significant increase in the risk of SCD (hazard ratio, 2.47; 95% confidence interval, 1.46-4.19). Patients who had stopped smoking had no significant increase in the risk of SCD compared with patients who had never smoked (hazard ratio, 1.06; 95% confidence interval, 0.70-1.62). CONCLUSIONS: Current cigarette smoking is a powerful independent predictor of SCD risk in patients with CAD. Patients who quit smoking experienced a significant reduction in SCD risk. Thus, efforts to reduce mortality from SCD in patients with CAD should include vigorous smoking cessation strategies.