Mutant LRP6 Impairs Endothelial Cell Functions Associated with Familial Normolipidemic Coronary Artery Disease.

Mutations in the genes low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) and myocyte enhancer factor 2A (MEF2A) were reported in families with coronary artery disease (CAD). We intend to determine the mutational spectrum of these genes among hyperlipidemic and normolipidemic CAD families. Forty probands with early-onset CAD were recruited from 19 hyperlipidemic and 21 normolipidemic Chinese families. We sequenced all exons and intron-exon boundaries of LRP6 and MEF2A, and found a novel heterozygous variant in LRP6 from a proband with normolipidemic CAD. This variant led to a substitution of histidine to tyrosine (Y418H) in an evolutionarily conserved domain YWTD in exon 6 and was not found in 1025 unrelated healthy individuals. Co-segregated with CAD in the affected family, LRP6Y418H significantly debilitated the Wnt3a-associated signaling pathway, suppressed endothelial cell proliferation and migration, and decreased anti-apoptotic ability. However, it exhibited no influences on low-density lipoprotein cholesterol uptake. Thus, mutation Y418H in LRP6 likely contributes to normolipidemic familial CAD via impairing endothelial cell functions and weakening the Wnt3a signaling pathway.

[An analysis of factors affecting the prognosis of patients with cardiac amyloidosis].

OBJECTIVE: To analyze the clinical characteristics, diagnosis, treatment and outcome of patients with cardiac amyloidosis (CA). METHODS: Clinical data from 18 patients diagnosed as CA by endomyocardial biopsy (EMB) from 1995 to 2005 were retrospectively analyzed. RESULTS: Among the 18 patients with CA, all patients had reduced diastolic dysfunction; 12 had mitral valve early diastolic blood flow peak velocity/late diastolic blood flow peak velocity (E/A) > 2.0 and ventricular diastolic early filling deceleration time (DT) < 150 ms; 12 had left ventricular ejection fraction (LVEF) < 50%; and 13 had New York Heart Association (NYHA) classification III or IV. The 1-year, 3-year and 5-year survival rates of 18 patients with CA were 67%, 44% and 17%, respectively. Kaplan-Meier analysis showed, NYHA functional class > II, E/A > 2.0 and DT < 150 ms were associated with increased mortality (log-rank statistic P = 0.026 and 0.001, respectively). CA patients with chemotherapy before heart failure were associated with decreased mortality and extend survival. CONCLUSIONS: The mortality rate goes up and survival rate gradually descends as prolonged onset time. NYHA functional class >IIand E/A > 2.0 (DT< 150 ms) are associated with mortality.

[Ex vivo assessment of coronary lesions by optical coherence tomography and intravascular ultrasound in comparison with histology results].

OBJECTIVE: To explore the diagnostic accuracy of optical coherence tomography (OCT) and intravascular ultrasound (IVUS) in the detection of ex vivo coronary plaques with different compositions compared with histology results. METHODS: OCT and IVUS were performed in 15 autopsied heart specimens and the isolated coronary artery was assessed by routine histological processing thereafter. Coronary plaques were classified into 3 types (lipid-rich plaque, calcified plaque and fibrous plaque) according to standard criteria respectively. Sensitivity and specificity for detection of different types of plaque by OCT and IVUS were calculated according histology results. RESULTS: Seventy seven coronary plaques were analyzed. OCT demonstrated a sensitivity and specificity of 69% and 88% for lipid-rich plaque, 93% and 92% for calcified plaque, 88% and 98% for fibrous plaque. IVUS demonstrated a sensitivity and specificity of 61% and 92%, 98% and 97%, 68% and 90% respectively. The agreement between OCT and IVUS in assessment of coronary plaque was 0.831 (Kappa = 0.72, P < 0.01). CONCLUSIONS: Both OCT and IVUS correctly detected ex vivo coronary plaques and there was a good agreement in assessment of coronary plaques between OCT and IVUS. OCT is superior to IVUS in assessment of fibrous plaque and is similar as IVUS in assessment of calcified plaque.

Antiplatelet Effect of Different Loading Doses of Ticagrelor in Patients With Non-ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: The APELOT Trial.

BACKGROUND: We hypothesized that a high ticagrelor loading dose (LD) may improve platelet inhibition in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). METHODS: This interventional multicentre open-label trial randomized 278 patients with NSTE-ACS to a high (360 mg) or conventional (180 mg) ticagrelor LD. The primary outcome was the platelet reactivity index (PRI) 1 hour after administration of the LD. Secondary outcomes included PRI at 0.5 hour, 1 hour, 8 hours, and 24 hours; periprocedural myocardial infarction (PMI); major cardiac adverse events; and bleeding events. RESULTS: Two hundred sixty-two patients completed the major end points. PRI was lower in the high-LD group than in the conventional-LD group at any time point (all, P < 0.05), including at 1 hour (12.2% vs 16.7%; P = 0.023). At 0.5 hour, the high-LD group showed a lower high-platelet reactivity rate (49.6% vs 60.2%; P = 0.013) and a higher low-platelet reactivity rate (24.8% vs 12.8%; P = 0.017) than did the conventional LD group. No significant differences in the bleeding rates were found between the 2 groups (14% vs 14.3%). Four cases of PMI and 1 death in each group, as well as 1 acute myocardial infarction in the conventional LD group, occurred. There was no stroke, target lesion revascularization, or target vessel revascularization. CONCLUSIONS: Doubling the ticagrelor LD achieved faster onset and greater platelet inhibition without an increase in adverse events in patients with NSTE-ACS undergoing PCI.

[Chronic effects of spironolactone in conjunction with an angiotensin-converting enzyme inhibitor enalapril on circulating procollagen marker P III NP and vascular resistance in patients with essential hypertension].

OBJECTIVE: Disturbances of the synthesis and breakdown of the extracellular matrix of arterial walls have emerged as key features of the atherosclerotic process. We observed the changes of circulating procollagen marker for type III collagen turnover rate, the N-terminal propeptide P III NP and vascular resistance in hypertensive patients treated with various antihypertensive regimens. METHOD: A total of 130 light to moderate hypertensive patients were randomly assigned to receive enalapril (group B, n = 43), enalapril + spirolactone (20 mg/d, group A, n = 44) and anti-hypertensive drugs not directly affecting RAAS (calcium antagonist, beta-blocker, group C, n = 43) for 1 year. Target blood pressure is < 130/80 mm Hg. RESULTS: Target blood pressure was reached in all treated patients and was similar among various groups. Under the same blood pressure controlling precondition, serum P III NP were similar at baseline among various groups and remained unchanged in group B [(3.4 +/- 0.3) microg/L vs. (3.7 +/- 0.3) microg/L, P > 0.05] and significantly decreased in group A [(2.3 +/- 0.2) microg/L vs. (3.8 +/- 0.2) microg/L, P < 0.05] while significantly increased in group C [(3.9 +/- 2.0) microg/L vs. (3.2 +/- 1.5) microg/L, P < 0.05]. Vascular resistance was similar among groups before therapy and all significantly decreased after 1 year antihypertensive therapy and the decrease was more significant in group A [(1064.3 +/- 158.6) dyn.s(-1).cm(-5)] than that in group B [(1200.8 +/- 298.7) dyn.s(-1).cm(-5)] and group C [(1205.1 +/- 206.4) dyn.s(-1).cm(-5)]. CONCLUSION: Spironolactone in conjunction with enalapril is a more favorable antihypertensive regimen in decreasing P III NP and improving vascular resistance than enalapril alone or antihypertensive drug regimens not directly affecting RAAS.

[Clinical efficacy and safety of emergent percutaneous coronary intervention for vein-grafts in the patients with acute myocardial infarction: comparison between age groups].

OBJECTIVE: To evaluate the efficacy and the safety of emergent primary percutaneous coronary intervention (PCI) in the saphenous vein bypass graft (SVBG) of acute myocardial infarction (AMI), and compare the results between aged -patients with non-aged patients. METHODS: Three hundred and nine consecutive AMI patients with culprit SVBG vessels, were analysed, including aged patients 213 cases(>or=70 years old), non-aged patients 96 cases(<70 years old), underwent the emergent primary PCI after confirmed below TIMI III perfusion(TIMI 0-TIMI II) in coronary angiographies. The immediate results and in-hospital outcomes were compared between two groups. RESULTS: Procedural successful rate, re-occlusion rate, and emergency re-CABG had no significant differences between two groups. The rate of slow-flow/no-reflow and in-hospital mortality rate were significantly higher in elderly group (19.7% vs 10.4%, 9.4% vs 4.2%, both P<0.05), with no difference in the rate of the using of distal protection devices between two groups. The comparison of the rate of direct stenting in slow-flow/no-reflow subgroup with normal-flow subgroup, had not showed statistic difference (73.5% vs 67.3%, P>0.05). There was no statistic difference of heavy hemorrhage between two different age groups. CONCLUSION: The primary PCI for the elderly AMI patients with infarction-related SVBG vessels, has higher risks in slow-flow/no-reflow and the mortality, even with using the distal protection devises and direct stents implantation.

Antioxidant and lipid-regulating effects of probucol combined with atorvastatin in patients with acute coronary syndrome.

OBJECTIVE: To investigate the effects of probucol combined with atorvastatin on the serum oxidation index and lipid levels in patients diagnosed with acute coronary syndrome (ACS). METHODS: We randomly assigned 126 ACS patients (77 males and 49 females) to the control group (atorvastatin 20 mg/day, n=62) or the treatment group (atorvastatin 20 mg/day and probucol 750 mg/day, n=64). All the patients were followed up for 12 weeks. As oxidization indices, we measured the serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), oxidized LDL (ox-LDL), and paraoxonase-1 (PON1) before and after treatment. We also monitored the adverse effects of the drugs during the treatment. RESULTS: At baseline, there were no obvious differences (P>0.05) between the two groups (including age, gender, etc.). After 12 weeks of treatment, the ox-LDL levels in the treatment group were significantly lower while PON1 levels were significantly higher than those in the control group. There were no statistically significant difference between the two groups with respect to the side effects (P<0.05). CONCLUSIONS: The combined use of atorvastatin and probucol in ACS patients could reduce ox-LDL expression and increase PON1 expression more effectively than use atorvastatin alone.

Prognostic value of high-sensitivity cardiac troponin T in patients with endomyocardial-biopsy proven cardiac amyloidosis.

OBJECTIVE: To investigate prognostic predictors of long-term survival of patients with cardiac amyloidosis (CA), and to determine predictive value of high-sensitivity cardiac troponin T (hs-cTnT) in CA patients. METHODS: We recruited 102 consecutive CA cases and followed these patients for 5 years. We described their clinical characteristics at presentation and used a new, high-sensitivity assay to determine the concentration of cTnT in plasma samples from these patients. RESULTS: The patients with poor prognosis showed older age (56 ± 12 years vs. 50 ± 15 years, P = 0.022), higher incidences of heart failure (36.92% vs. 16.22%, P = 0.041), pericardial effusion (60.00% vs. 35.14%, P = 0.023), greater thickness of interventricular septum (IVS) (15 ± 4 mm vs. 13 ± 4 mm, P = 0.034), higher level of hs-cTnT (0.186 ± 0.249 ng/mL vs. 0.044 ± 0.055 ng/mL, P = 0.001) and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels (11,742 ± 10,464 pg/mL vs. 6,031 ± 7,458 pg/mL, P = 0.006). At multivariate Cox regression analysis, heart failure (HR: 1.78, 95%CI: 1.09-2.92, P = 0.021), greater wall thickness of IVS (HR: 1.44, 95%CI: 1.04-3.01, P = 0.0375) and higher hs-cTnT level (HR: 6.16, 95%CI: 2.20-17.24, P = 0.001) at enrollment emerged as independent predictors of all-cause mortality. CONCLUSIONS: We showed that hs-cTnT is associated with a very ominous prognosis, and it is also the strongest predictor of all-cause mortality in multivariate analysis. Examination of hs-cTnT concentrations provides valuable prognostic information concerning long-term outcomes.

Thrombosis and morphology of plaque rupture using optical coherence tomography.

BACKGROUND: Thrombosis following plaque rupture is the main cause of acute coronary syndrome, but not all plaque ruptures lead to thrombosis. There are limited in vivo data on the relationship between the morphology of ruptured plaque and thrombosis. METHODS: We used optical coherence tomography (OCT) to investigate the morphology of plaque rupture and its relation to coronary artery thrombosis in patients with coronary heart disease. Forty-two patients with coronary artery plaque rupture detected by OCT were divided into two groups (with or without thrombus) and the morphological characteristics of ruptured plaque, including fibrous cap thickness and broken cap site, were recorded. RESULTS: The fibrous cap of ruptured plaque with thrombus was significantly thinner compared to caps without thrombus ((57.00 ± 17.00) µm vs. (96.00 ± 48.00) µm; P = 0.0076). CONCLUSIONS: Plaque rupture associated with thrombosis occurs primarily in plaque covered by a thin fibrous cap. Thick fibrous caps are associated with greater stability of ruptured plaque.

[Screening for genes associated with cardiac fibrosis induced by aldosterone].

AIM: To investigate differently expressed genes associated with cardiac fibrosis induced independently by aldosterone. METHODS: Fetal cardiac fibroblasts (FCFs)were isolated and cultured. Total RNA was extracted 8 hours after aldosterone administration. Then gene chips were used to screen these RNA samples. Some of candidate genes were confirmed by RT-PCR and Western blot. RESULTS: Differently expressed 1519 genes were screened. Up-regulated genes were 714 while down-regulated genes were 805. The expression of CCL7, MMP-26 and IL31RA was tested by RT-PCR and western blot, the results is identical with those by gene chips. CONCLUSION: Gene chip can efficiently single out differently expressed genes induced dependently by aldosterone in FCFs. CCL7, MMP-26 and IL31RA may be associated with cardiac fibrosis induced by aldosterone.

Optical coherence tomography assessment of edge dissections after drug-eluting stent implantation in coronary artery.

BACKGROUND: Edge dissections after coronary stent implantation are associated with increased short-term risk of major adverse cardiovascular events. The incidence and outcome of edge dissections after coronary stent implantation were reportedly different using different imaging techniques. We used optical coherence tomography (OCT) to assess the incidence, morphological findings and related factors of edge dissections after drug-eluting stent (DES) implantation. METHODS: Totally 42 patients with 43 de novo lesions in 43 native arteries undergoing DES implantation with OCT imaging were enrolled in this study. RESULTS: Nine edge dissections were detected in 43 arteries after DES implantation. There were four morphological patterns of stent edge dissections indentified in this study: (1) superficial intimal tears (n = 3), (2) subintimal dissections (n = 4), (3) split of media (n = 1), (4) disruption of the fibrotic cap of plaque (n = 1). Stent edge expansion and stent expansion were both higher in the group with dissections than those in the group without dissections (1.682 ± 0.425 vs. 1.229 ± 0.285, P = 0.0290; 1.507 ± 0.445 vs. 1.174 ± 0.265, P = 0.0072). CONCLUSIONS: The incidence of stent edge dissections detected by OCT was 21%. Stent edge dissection is related with stent edge expansion and stent expansion.

Methylprednisolone improves microcirculation in streptozotocin-induced diabetic rats after myocardial ischemia/reperfusion.

BACKGROUND: Methylprednisolone has been demonstrated to decrease inflammation, and it may protect organs from ischemia/reperfusion (I/R) injury. This study aimed to investigate the effects of methylprednisolone on diabetic myocardial I/R injury. METHODS: Forty adult male Sprague-Dawley (SD) rats were randomized into five groups (n = 8 in each group) including a sham operation (sham) group, I/R group, diabetic sham operation (DMS) group, diabetic I/R (DM-I/R) group and methylprednisolone intervention (MP + DM-I/R) group. The diabetic model was produced by injection of streptozotocin (STZ). Body weight and blood glucose levels were determined after diabetes was established. Twelve weeks after induction of diabetes, a segmental I/R of the heart was induced by occluding the left anterior descending artery for one hour and then three hours of reperfusion in the I/R, DM-I/R and MP + DM-I/R groups. Blood pressure and electrocardiogram were continuously recorded during the procedure. IL-1ß, IL-6 and TNF-α were measured at certain time points during the surgery. After reperfusion, a microcirculation scan was performed; myocardial biomarkers and tissue structure were utilized to evaluate the reperfusion damage. Intercellular adhesion molecule (ICAM)-1 and NF-κBp65 expression were quantified by immunohistological staining. Total Toll-like receptor 4 (TLR4) and nuclear NF-κBp65 protein were determined by Western blotting. RESULTS: Twelve weeks after diabetes was established, blood glucose levels were elevated and body weights were lower in diabetic rats. After reperfusion, infarction size was increased, myocardial biomarkers and inflammatory cytokines levels were elevated. Microcirculation perfusion was significantly reduced in the DM-I/R group compared with the I/R group, however it was improved in the MP + DM-I/R group. The expression of NF-κBp65 and ICAM-1 were increased in the DM-I/R group and decreased in the MP + DM-I/R group. Compared with the non-diabetic I/R group, TLR4 and NF-κBp65 protein levels were up-regulated in the DM-I/R group, but down-regulated in the MP + DM-I/R group. CONCLUSIONS: Methylprednisolone improves microcirculation in STZ-induced diabetic rats after myocardial ischemia/reperfusion, which may associate with the suppression of TLR4/NF-κB signaling.

[The effect of Aldosterone on the proliferation and collagen production of cardiac fibroblasts].

AIM: To investigate the effect of aldosterone (ALD) on the proliferation of fetal cardiac fibroblasts (FCFS) and the production of collagen I and collagen III in FCFS. METHODS: FCFS were isolated by collagenase II and purified with differential attachment and detachment method. The proliferation of FCFS after ALD administration was assessed by CCK-8. The mRNA expression of COL1A1 and COL3A1 were assessed by reverse transcription polymerase chain reaction (RT-PCR) and the protein production of COL1A1 and COL3A1 were assessed by Western blot. RESULTS: ALD facilitated the proliferation of FCFS concentration-dependently. ALD with lower concentration (10(-9);, 10(-8);, 10(-7); mol/L) significantly improved the expression of COL1A1 and COL3A1, while ALD with higher concentration of had no obvious effect. CONCLUSION: ALD improved the proliferation of FCFS concentration-dependently. And in a certain concentration range, ALD improved the expression of COL1A1 and COL3A1 while higher concentration had opposite effect. There is no linear relationship among the effects of ALD on the proliferation of FCFS, expression and protein production of COL1A1 and COL3A1.

Omeprazole affects clopidogrel efficacy but not ischemic events in patients with acute coronary syndrome undergoing elective percutaneous coronary intervention.

BACKGROUND: Omeprazole, usually used in the antiplatelet therapy during percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS), has been reported to increase ischemic events in retrospective studies. However, other clinical trials gave paradoxical results. The aim of this study was to assess the effects of omeprazole on clopidogrel efficacy and clinical events. METHODS: All patients (n = 172) received aspirin (loading dose 300 mg and maintenance dose 100 mg/d) and clopidogrel (loading dose 600 mg and maintenance dose 75 mg/d) during the therapy. They were randomized to receive omeprazole (20 mg/d) or placebo for 30 days. Residual platelet activities in the adenosine 5'-diphosphate (ADP) pathway were detected on the fifth day after PCI with thrombelastography (TEG)-mapping. The clinical events were recorded after one month. RESULTS: According to the five levels of platelet activities, the frequency distributions of the inhibition rates were significantly different (P = 0.0062). However, no significant change was seen in the distribution among the highest or the lowest inhibiting levels (> 95% and < 30% inhibition rate). And there were no significant differences (P > 0.05) in events incidence, while gastro-intestinal bleeding decreased in co-administration of omeprazole. CONCLUSIONS: Omeprazole significantly blunts clopidogrel efficacy while not exacerbates ischemic events in ACS undergoing PCI. Omeprazole even can decrease gastro-intestinal bleeding in those patients.