Genetic Association of Lipid-Lowering Drugs with Aortic Aneurysms: A Mendelian Randomization Study.

AIMS: The lack of effective pharmacotherapies for aortic aneurysms (AA) is a persistent clinical challenge. Lipid metabolism plays an essential role in AA. However, the impact of lipid-lowering drugs on AA remains controversial. The study aimed to investigate the genetic association between lipid-lowering drugs and AA. METHODS: Our research used publicly available data on genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) studies. Genetic instruments, specifically eQTLs related to drug-target genes and SNPs (single nucleotide polymorphisms) located near or within the drug-target loci associated with low-density lipoprotein cholesterol (LDL-C), have been served as proxies for lipid-lowering medications. Drug-Target Mendelian Randomization (MR) study is used to determine the causal association between lipid-lowering drugs and different types of AA. RESULTS: The MR analysis revealed that higher expression of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) was associated with increased risk of AA (OR = 1.58, 95% CI = 1.20-2.09, p = 1.20 × 10-03) and larger lumen size (aortic maximum area: OR = 1.28, 95% CI = 1.13-1.46, p = 1.48 × 10-04; aortic minimum area: OR = 1.26, 95% CI = 1.21-1.42, p = 1.78 × 10-04). PCSK9 (Proprotein convertase subtilisin/kexin type 9) and CETP (Cholesteryl ester transfer protein) show a suggestive relationship with AA (PCSK9: OR = 1.34, 95% CI = 1.10-1.63, p = 3.07 × 10-03; CETP: OR = 1.38, 95% CI = 1.06-1.80, p = 1.47 × 10-02). No evidence to support genetically mediated NPC1L1 (Niemann-Pick C1-Like 1) and LDLR (low-density lipoprotein cholesterol receptor) are associated with AA. CONCLUSIONS: This study provides causal evidence for the genetic association between lipid-lowering drugs and aortic aneurysms. Higher gene expression of HMGCR, PCSK9, and CETP increases AA risk. Furthermore, HMGCR inhibitors may link with smaller aortic lumen size.

This Mendelian Randomization study used publicly available data involving over 1 million individuals to demonstrate the causal relationship between five target genes of LDL-C-lowering medicines and the risk of aortic aneurysms, and implied one lipid-lowering drug may link with the lumen size of aortic aneurysms. Key findings High expression of HMGCR, PCSK9, and CETP was positively correlated with the risk of aortic aneurysms, highlighting that the corresponding lipid-lowering drugs may be preferred for preventing arterial aneurysms in high-risk individuals with dyslipidemia. We found that genetically predicted HMGCR inhibitors were positively associated with smaller aortic lumen size, which is the first time to support the causal association of gene HMGCR on the lumen size of aortic aneurysms.

[Ebstein's anomaly with refractory right-sided heart failure and leg ulcers: a case report].

Ebstein malformation is a congenital heart disease characterized pathologically by displacement of the septal leaflet of the tricuspid valve towards the apex of the right ventricle of the heart. Hypoplasia, dysfunction of the right ventricle and tricuspid regurgitation cause an increased volume load of the right heart and result in the clinical manifestations of chest tightness, shortness of breath and fatigue after activities, palpitation, cyanosis and heart failure. We report a case of Ebstein's anomaly with refractory right heart failure and leg ulcers.

Nicorandil in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: a systematic review and meta-analysis.

BACKGROUND: Nicorandil, as an adjunctive therapy with primary percutaneous coronary intervention (PCI), had controversial benefits in cardioprotection in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: We performed a systematic review of randomized controlled trials (RCTs) comparing treatment with nicorandil prior to reperfusion therapy with control (placebo or no nicorandil) in patients who suffered from AMI and performed primary PCI. PubMed, EMBASE and CENTRAL databases and other sources were searched without language and publication restriction. 14 trials involving 1680 patients were included into this meta-analysis. Nicorandil significantly reduced the incidence of thrombolysis in myocardial infarction (TIMI) flow grade ≤ 2 (risk ratio [RR], 0.57; 95% confidence interval [CI]: 0.42 to 0.79), the Timi frame count (TFC) (mean difference [MD], -5.19; 95% CI: -7.13 to -3.26), increased left ventricular ejection fraction (LVEF) (%) (MD, 3.08; 95% CI: 0.79 to 5.36), and reduced the incidence of ventricular arrhythmia (RR, 0.53; 95% CI: 0.37 to 0.76) and congestive heart failure (CHF) (RR, 0.41; 95% CI: 0.22 to 0.75). No difference in the pear creatine kinase (CK) value (MD, -290.19; 95% CI: -793.75 to 213.36) or cardiac death (RR, 0.39; 95% CI: 0.09 to 1.67) was observed. CONCLUSIONS: Nicorandil prior to reperfusion is associated with improvement of coronary reflow as well as suppression of ventricular arrhythmia, and further improves left ventricular function in patients who suffered from AMI and underwent primary PCI. But the definite clinical benefits of nicorandil were not found, which may be due to the small sample size of the selected studies.

[Mechanism of lumen loss of the left circumflex ostium after main vessel stent implantation: observations by intravascular ultrasound].

OBJECTIVE: To explore the mechanism of lumen loss of the left circumflex ostium after main vessel stent implantation. METHODS: Twenty-eight patients undergoing provisional T technique were enrolled in this study. Intravascular ultrasound (IVUS) examination was performed before and after main vessel stenting and kissing balloon post-dilatation to evaluate the geometrical changes of the vessels. RESULTS: The CSA of LCX ostium lumen decreased significantly from 5.9∓2 mm(2) to 4.9∓1.9 mm(2) (P<0.01) after the procedure, and the CSA of LCX ostium P and M increased from 5.4∓2.9 mmmm(2) to 5.7∓2.9 mm(2) (P=0.21) after the main vessel stenting. The changes in LCX ostium lumen CSA was correlated with the changes of LCX ostium EEM CSA but not the LCX ostium P and M CSA. After kissing balloon post-dilatation, the CSA of LCX ostium lumen increased from 4.9∓1.9 mm(2) to 5.5∓1.9 mm(2) (P<0.01) , and the CSA of LCX ostium P and M showed no obvious changes (5.7∓2.9 mmmm(2) vs 5.7∓2.6 mmmm(2), P=0.89). The changes of LCX ostium lumen CSA were correlated with the those of the LCX ostium EEM CSA (R=0.432, P=0.02). CONCLUSION: After stent implantation from the LMCA to the LAD, most of lumen losses of the LCX are due to carina shift, and in occasional cases, plaque shift occurs from the distal LMCA to the ostium of the LCX. Kissing balloon technique can adjust carina shift but can not improve plaque shift.

A probable novel splicing isoform of human vascular endothelial growth factor.

OBJECTIVE: To characterize a new alternative splicing isoform of human vascular endothelial growth factor (VEGF) gene. METHODS: The total RNA was extracted from the lung tissue of a legally aborted 4-month-old fetus and amplified by RT-PCR. The amplified product was cloned into the plasmid pMD18-T and plasmid pcDNA3.1- for sequence analysis. RESULTS: Electrophoresis of the RT-PCR products displayed one short band for VEGF(121) (487 bp) and a long band. The latter was characterized to contain two fragments: one was normal VEGF(165) (619 bp), and the other (639 bp) had an identical nucleotide sequence to VEGF(165) with a 20 bp fragment inserted between exons 3 and 4. Sequence analysis showed that this 20-bp nucleotide was inserted from the 3' end of the third intron containing a splicing signal, thus causing shift mutation in the reading frame of VEGF gene and early appearance of the stop codon UAG in the middle of exon 4. CONCLUSION: A new alternative splicing isoform of VEGF probably exists in the lung tissue of a legally aborted human fetus, and its biological significance remains to be further investigated.

[Evaluation of two arterial closure devices, Angioseal and Perclose, in coronary catheter interventions].

OBJECTIVE: To assess the efficacy and safety of two arterial closure devices, Angioseal and Perclose, in patients undergoing coronary angiography and invasive interventions. METHODS: From January 2001 to April 2011, 997 inpatients underwent coronary angiography and interventions with arterial closure using Perclose (486 cases) or Angioseal (511 cases). The time to ambulation and hemostasis, major vascular complications and deployment success rate with the two devices were compared. RESULTS: The time to hemostasis was significantly shorter in Angioseal group than in Perclose group (3∓0.9 min vs 10.8∓4.8 min, P<0.001), but the time to ambulation was comparable between the two groups (6.4∓1.2 h vs 6.3∓0.7 h, P>0.05). The incidences of vascular complications showed no significant differences between the two groups (4.5% vs 3.7%, P>0.05), and none of the cases in either group developed femoral artery thrombosis or low limb embolism following the procedures. The deployment success rate was comparable between the two groups (97.8% vss 98.6%, P>0.05), and deployment failure was associated mainly with mishandling and design defect of the devices. CONCLUSIONS: Angioseal and Perclose are both effective and safe for arterial closure with reduced hemostasis and ambulation time and low incidences of vascular complications. Angioseal appears to have better performance than Perclose in shortening the hemostasis time and is easier to handle.

Management of subacute myocardial infarction in a patient with left coronary artery originating from the right coronary artery.

OBJECTIVE: Although the majority of coronary artery anomalies are found incidentally and not clinically significant, the interarterial course between the major vessels of the aberrant artery may be responsible for syncope, angina, arrhythmias or sudden death. There are only a few case reports describing the origination of all the coronary arteries from a single ostium. This anomaly occurs in only 0.024%-0.044% of the population. Left coronary artery originating from the right coronary is a rare coronary abnormality. Here we report a case of acute myocardial infarction in a patient with anomalous left coronary artery originating from the right coronary artery, as was confirmed by computerized tomography angiogram, which showed that only one single coronary artery stem originating from the right sinus of Valsalva trifurcated into a right coronary artery, left circumflex artery and a hypoplastic left anterior descending artery. Subsequent percutaneous coronary intervention (PCI) procedures were performed successfully. PCI procedures should be carried out with great caution in such cases, and this condition should be managed as a left main lesion.

[Ultrasound-mediated microbubble cavitation enhances gene transduction in rat pulmonary endothelial cells partially by affecting membrane fluidity and cytoskeleton structure].

OBJECTIVE: To evaluate the effect of therapeutic ultrasound-induced microbubble's cavitation on plasmid gene transduction in rat pulmonary endothelial cells in relation to the changes of membrane fluidity and cytoskeleton structure. METHODS: Rat endothelial cells cultured in vitro were transfected with EGFP plasmid in the presence of protein microbubbles. During the transfection process, the cells were exposed to continuous 2 MHz ultrasonic irradiation for 30, 60, 90, 120 and 180 s (groups A, B, C, D and E, respectively) with the constant mechanical index (MI) of 1.0, or for 60 s with different mechanical index (MI) of 0.5, 0.75, 1.0, 1.5, and 1.8 (groups B1, B2, B3, B4 and B5, respectively). The changes of endothelial cytoskeletal structure and membrane fluidity were evaluated by immunofluorescence staining after the exposure. RESULTS: EGFP gene transduction increase obviously with prolonged echo irradiation and increased MI. The intensity of immunofluorescence staining, which represented endothelial membrane fluidity, was 0.173±0.013, 0.250±0.037, 0.364±0.022, 0.381±0.019, and 0.395±0.009 in groups A-E, as compared with 0.171±0.017, 0.255±0.026, 0.378±0.007, 0.382±0.009 and 0.397±0.008 in groups B1-B5, respectively. The recovery intensity of the immunofluorescence staining representing the changes in microtubulin of the cytoskeleton structure was 159.15±4.79, 188.23±6.20, 205.80±4.48, 208.99±8.34, and 213.70±5.09 in groups A-E, and was 176.84±3.10, 187.57±14.52, 206.41±11.66, 220.12±13.39 and 221.16±12.78 in groups B1-B5, respectively. The endothelial membrane fluidity and microtubule fluorescence recovery intensity increased remarkably compared with the baseline (P<0.01) within the MI range of 0.50-1.0 and the exposure time of 30-90 s, but underwent no further changes in response to prolonged exposure time (180 s) at the MI of 1.5 (P>0.05). No changes in microfilament fluorescence intensity were observed after exposure to different MI or irradiation time. CONCLUSION: Therapeutic ultrasound-mediated albumin microbubble cavitation allows enhances plasmid gene transduction without causing cytoskeleton damages. Increased endothelial membrane fluidity and changes in cytoskeleton structure, especially microtubulin, partially contribute to this enhancement.

[Plasma matrix metalloproteinases-2 and -9 levels are elevated in patients with acute coronary syndrome and coronary chronic total occlusion].

OBJECTIVE: To investigate the changes in plasma matrix metalloproteinases-2 and -9 (MMP2 and MMP9, respectively) levels in patients with different types of coronary heart diseases (CHD), and assess the value of MMP2/MMP9 detection in predicting acute coronary syndrome (ACS). METHODS: According to the findings by coronary angiography and the clinical manifestations, 118 patients were divided in ACS group including 30 patients with unstable angina pectoris (UAP) and 19 with acute myocardial infarction (AMI) and non-ACS group including 23 patients with stable angina pectoris (SAP) and 21 with chronic total occlusion (CTO) of the coronary artery. Twenty-five individuals with normal coronary artery (NCA) served as the control group. Plasma levels of MMP9 and MMP2 were determined in these subjects using enzyme-linked immunosorbent assay (ELISA). RESULTS: Both the ACS and non-ACS groups showed significantly higher MMP9 and MMP2 levels than the NCA group (P<0.05), and MMP2 and MMP9 levels were significantly higher in ACS group than in non-ACS group (P<0.05). Compared with the NCA group, the UAP, AMI and CTO subgroups showed obvious increases in plasma MMP2 and MMP9 levels (P<0.01). Significantly increased MMP9, but not MMP2 level was noted in AMI subgroup in comparison with SAP (P<0.01) and UAP subgroups (P<0.05); both MMP2 and MMP9 levels were elevated in CTO subgroup in comparison with those in SAP (P<0.001), UAP (P<0.01), and AMI subgroups (P<0.05). CONCLUSION: Increased MMP2 and MMP9 levels in patients with CHD suggest the instability of the atherosclerotic plaque in correlation to the severity of ACS, and may serve as good indicators for the prediction of ACS and diagnosis of CTO of the coronary artery.

[Correlation between cardiovascular risk factors and the severity of coronary artery lesions in female patients].

OBJECTIVE: To investigate the association of the traditional and newly emerged cardiovascular risk factors with the severity of coronary artery lesion in female patients with coronary artery disease (CAD). METHODS: This study involved 235 female in-patients undergoing coronary angiography, including 156 with confirmed coronary artery disease (CAD) and 76 non-CAD patients. Univariate and multivariate analysis of the cardiovascular risk factors and the severity of coronary artery lesion were carried out in these patients. RESULTS: Univariate analysis showed that in the CAD patients of different severities, increased number of compromised arteries and total Gensini scores for the lesions were associated with increased incidences of the such risk factors including hypertension, type 2 diabetes, high triglycerides, high total cholesterol, low high-density lipoprotein cholesterol (HDL-C) level, high low density lipoprotein cholesterol (LDL-C) level, high uric acid level and high fibrinogen level. Multivariate regression analysis showed that high LDL-C level was the most significant independent risk factor for CAD, followed by diabetes, triglycerides, high uric acid, low HDL-C, high blood pressure and age. CONCLUSIONS: Female CAD patients are exposed to multiple risk factors, among which high LDL-C level is the most significant independent risk factor, but the other risk factors, especially the newly emerged factor uric acid, should be given due attention in the patients.

[Evaluation of left ventricular diastolic function using velocity vector imaging and quantitative tissue velocity imaging].

OBJECTIVE: To validate the efficacy of velocity vector imaging (VVI) and quantitative tissue velocity imaging (QTVI) for evaluating left ventricular diastolic function. METHODS: Fifty-one patients underwent left heart catheterization were included in this study. Mean of peak early diastolic velocity (Em), EF and the ratio of early (E) to late (A) mitral valve flow velocity (E/A) were measured by echocardiography and the ratio of E to Em (E/Em) was calculated. Left ventricular end diastolic pressure (LVEDP) was measured during catheterization examination. RESULTS: E/Em derived from VVI or QTVI was significantly correlated with LVEDP (r = 0.808, P < 0.01 and r = 0.692, P < 0.01, respectively) and the correlation coefficient between VVI and LVEDP was significantly higher than that between QTVI and LVEDP (Z = 2.246, P = 0.025). Em derived from VVI and QTVI also negatively correlated with LVEDP (r = -0.740, P < 0.01 and r = -0.567, P < 0.01) and the correlation coefficient between VVI and LVEDP was significantly higher than that between QTVI and LVEDP (Z = 2.595, P = 0.009). However, there was no correlation between E/A and LVEDP (r = 0.117, P = 0.415). CONCLUSION: E/Em and Em derived from VVI and QTVI are valuable parameters for evaluating LV diastolic function.

[Cloning of expression vector for VEGF121 and VEGF165 genes encoding human vascular endothelial growth factor].

OBJECTIVE: To clone and construct the expression vector for human vascular endothelial growth factor (VEGF) genes. METHODS: Total RNAs were extracted from human lung tissue of a 4-month-old fetus and subjected to reverse transcriptase-polymerase chain reaction (RT-PCR) with the amplified products cloned into pMD18-T vector. Sequence analysis was performed before the amplified products were cloned into the expression plasmid pcDNA3.1-, the recombinant of which was verified by endonuclease digestion. RESULTS: After RT-PCR using a pair of primers (sense -21/7 bp and antisense 554/576 bp), two bands were identified. The band (487 bp) shorter in length was confirmed as VEGF121 (with the full length of VEGF121 being 444 bp) while the longer band (619 bp) was normal VEGF165 (with the full length of VEGF165 being 576 bp). Interestingly, another slightly longer VEGF165 nucleotide sequence was identified by sequencing analysis, which featured an unique 20 bp insertion precisely between exon 3 and exon 4 from the first ATG of human VEGF165 cDNA. The 20 bp insert was identified as the retaining intron 3 terminal nucleotides containing the splicing signal, which caused frame shift mutation in the reading frame and could probably give rise to a short polypeptides consisting of only 97 amino acid residuals due to the early appearance of stop code UAG in the middle of exon 4. CONCLUSION: We have successfully constructed the expression vector for VEGF121 and VEGF165 genes, and a new possible alternative splicing isoform of VEGF is identified in normal fetus whose molecular mechanism and physiological function needs further investigation.

Construction of eukaryotic expression vector of thrombospondin-1 type I repeat sequence.

OBJECTIVE: To construct eukaryotic expression vector of thrombospondin-1 type I repeat sequences. METHODS: Thrombospondin-1 type I repeat sequence gene was amplified from human fetal lung tissue by reverse transcriptase-PCR (RT-PCR) to construct both recombinant clone vector and expression vector through coupling reaction, followed by transforming these vectors into E.coli DH5alpha. The positive clones were selected for verification by double enzyme digestion and sequence analysis. RESULT: The expected amplification product, thrombospondin-1 type I repeat gene sequence, was acquired by RT-PCR, which had a consistency up to 99% with the sequence from the GenBank. CONCLUSION: The eukaryotic expression vector PcDNA3.1(+)/TSP-1 type I repeat sequence was successfully constructed.

[A novel alternative splicing isoform of vascular endothelial growth factor gene in human beings].

OBJECTIVE: To investigate a new alternative splicing isoform of vascular endothelial growth factor (VEGF) gene in human bejings. METHODS: The total RNA of the lung tissue of a legally aborted 4-month-old human fetus was isolated and then amplified by RT-PCR. The amplified product was cloned into the pMD18-T plasmid and pcDNA3.1(-). Then sequence analysis was conducted. RESULTS: The electrophoresis of the RT-PCR product showed one short band of VEGF121 comprising of 487 bp and a long band with two fragments: one normal VEGF165 comprising of 619 bp and one fragment comprising of 639 bp which was the same VEGF165 nucleotide sequence with a 20 bp fragment inserted between exon 3 and exon 4. Sequence analysis showed that this 20 bp long nucleotide was inserted from the 3' end of the third intron that contained splicing signal, thus causing shift mutation in reading frame of VEGF gene and early appearance of the stop code UAG in the middle of exon 4. CONCLUSION: A new alternative splicing isoform of VEGF has been identified in the lung tissue of a legally aborted human fetus. Its biological significance remains to be further investigated.

Evaluation of myocardial viability with myocardial contrast echocardiography: a preliminary clinical study.

OBJECTIVE: To evaluate the efficacy of myocardial contrast echocardiography (MCE) in the assessment of myocardial viability, with positron emission tomography (PET) as the golden standard. METHODS: Eleven patients with anterior wall Q wave myocardial infarction were enrolled in this study, who received successful percutaneous transluminal coronary angioplasty (PTCA) 3 to 19 months prior to the examinations by PET and MCE that were completed within 2 d. RESULTS: MCE score for the segments of necrotic myocardium, viable myocardium and normal myocardium was mostly 0, 0.5 and 1 respectively, and there was a significant difference between the grades of MCE score in identifying myocardial viability. In terms of diagnosing myocardium survival, MCE result was closely correlated with that of PET (with the correlation index rp of 0.78). CONCLUSION: Myocardial perfusion evaluation can be effectively accomplished by MCE, which might serve as a new approach to assess myocardial viability in clinical practice.