Effect of "Natural Polypill", Xuezhikang on Serum Cholesterol Metabolism Markers in Early Menopausal Women with Hypercholesterolemia.

OBJECTIVE: To analyze the effect of Xuezhikang on the markers of the serum lipid levels of cholesterol synthesis and absorption in early menopausal women with hypercholesterolemia, and preliminarily explore its lipid-lowering mechanism. METHODS: A total of 90 early menopausal women with hypercholesterolemia were enrolled from December, 2014 to May, 2016 from Beijing Anzhen Hospital, Capital Medical University, who were randomly allocated to receive Xuezhikang (1200 mg/d, orally) or atorvastatin (10 mg/d, orally) according to a random number table. Serum levels of some related biomarkers, including cholesterol synthesis markers (squalene, dihydrocholesterol, dehydrocholesterol, and lathosterol), and absorption markers (campesterol, stigmasterol, and sitosterol) as well as safety indices were obtained at baseline and after 8 weeks of the intervention. RESULTS: Eight weeks after treatment, both Xuezhikang and atorvastatin significantly reduced the levels of total cholesterol, triglycerides, low density cholesterol compared to baseline (all P<0.01). Xuezhikang significantly reduced the levels of squalene, dehydrocholesterol and lathosterol compared to baseline (all P<0.01), but atorvastatin only significantly reduced the level of squalene (P<0.01), compared to baseline. All cholesterol absorption markers showed no significant differences before and after treatment (P>0.05), however, a more obvious downward trend was shown in the Xuezhikang group. In addition, all the safety indices showed no significant differences between the two groups. Although the creatinekinase level in the Xuezhikang group was significantly higher, it remained within the safe range. CONCLUSIONS: Xuezhikang may have more comprehensive effects on the markers of cholesterol synthesis and metabolism in early menopausal women with hypercholesterolemia through ergosterol and flavonoids in its "natural polypill."

Assessing the genomic relatedness and evolutionary rates of persistent verotoxigenic Escherichia coli serotypes within a closed beef herd in Canada.

Verotoxigenic Escherichia coli (VTEC) are food- and water-borne pathogens associated with both sporadic illness and outbreaks of enteric disease. While it is known that cattle are reservoirs of VTEC, little is known about the genomic variation of VTEC in cattle, and whether the variation in genomes reported for human outbreak strains is consistent with individual animal or group/herd sources of infection. A previous study of VTEC prevalence identified serotypes carried persistently by three consecutive cohorts of heifers within a closed herd of cattle. This present study aimed to: (i) determine whether the genomic relatedness of bovine isolates is similar to that reported for human strains associated with single source outbreaks, (ii) estimate the rates of genome change among dominant serotypes over time within a cattle herd, and (iii) identify genomic features of serotypes associated with persistence in cattle. Illumina MiSeq genome sequencing and genotyping based on allelic and single nucleotide variations were completed, while genome change over time was measured using Bayesian evolutionary analysis sampling trees. The accessory genome, including the non-protein-encoding intergenic regions (IGRs), virulence factors, antimicrobial-resistance genes and plasmid gene content of representative persistent and sporadic cattle strains were compared using Fisher's exact test corrected for multiple comparisons. Herd strains from serotypes O6:H34 (n=22), O22:H8 (n=30), O108:H8 (n=39), O139:H19 (n=44) and O157:H7 (n=106) were readily distinguishable from epidemiologically unrelated strains of the same serotype using a similarity threshold of 10 or fewer allele differences between adjacent nodes. Temporal-cohort clustering within each serotype was supported by date randomization analysis. Substitutions per site per year were consistent with previously reported values for E. coli; however, there was low branch support for these values. Acquisition of the phage-encoded Shiga toxin 2 gene in serotype O22:H8 was observed. Pan-genome analyses identified accessory regions that were more prevalent in persistent serotypes (P≤0.05) than in sporadic serotypes. These results suggest that VTEC serotypes from a specific cattle population are highly clonal with a similar level of relatedness as human single-source outbreak-associated strains, but changes in the genome occur gradually over time. Additionally, elements in the accessory genomes may provide a selective advantage for persistence of VTEC within cattle herds.

Multi-Year Persistence of Verotoxigenic Escherichia coli (VTEC) in a Closed Canadian Beef Herd: A Cohort Study.

In this study, fecal samples were collected from a closed beef herd in Alberta, Canada from 2012 to 2015. To limit serotype bias, which was observed in enrichment broth cultures, Verotoxigenic Escherichia coli (VTEC) were isolated directly from samples using a hydrophobic grid-membrane filter verotoxin immunoblot assay. Overall VTEC isolation rates were similar for three different cohorts of yearling heifers on both an annual (68.5 to 71.8%) and seasonal basis (67.3 to 76.0%). Across all three cohorts, O139:H19 (37.1% of VTEC-positive samples), O22:H8 (15.8%) and O?(O108):H8 (15.4%) were among the most prevalent serotypes. However, isolation rates for serotypes O139:H19, O130:H38, O6:H34, O91:H21, and O113:H21 differed significantly between cohort-years, as did isolation rates for some serotypes within a single heifer cohort. There was a high level of VTEC serotype diversity with an average of 4.3 serotypes isolated per heifer and 65.8% of the heifers classified as "persistent shedders" of VTEC based on the criteria of >50% of samples positive and ≥4 consecutive samples positive. Only 26.8% (90/336) of the VTEC isolates from yearling heifers belonged to the human disease-associated seropathotypes A (O157:H7), B (O26:H11, O111:NM), and C (O22:H8, O91:H21, O113:H21, O137:H41, O2:H6). Conversely, seropathotypes B (O26:NM, O111:NM) and C (O91:H21, O2:H29) strains were dominant (76.0%, 19/25) among VTEC isolates from month-old calves from this herd. Among VTEC from heifers, carriage rates of vt1, vt2, vt1+vt2, eae, and hlyA were 10.7, 20.8, 68.5, 3.9, and 88.7%, respectively. The adhesin gene saa was present in 82.7% of heifer strains but absent from all of 13 eae+ve strains (from serotypes/intimin types O157:H7/γ1, O26:H11/ß1, O111:NM/θ, O84:H2/ζ, and O182:H25/ζ). Phylogenetic relationships inferred from wgMLST and pan genome-derived core SNP analysis showed that strains clustered by phylotype and serotype. Further, VTEC strains of the same serotype usually shared the same suite of antibiotic resistance and virulence genes, suggesting the circulation of dominant clones within this distinct herd. This study provides insight into the diverse and dynamic nature of VTEC populations within groups of cattle and points to a broad spectrum of human health risks associated with these E. coli strains.

Genetically confirmed familial hypercholesterolemia in outpatients with hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism which can lead to premature coronary heart disease (pCHD). There are about 3.8 million potential FH patients in China, whereas the clinical and genetic data of FH are limited. METHODS: Dutch Lipid Clinic Network (DLCN) criteria was used to diagnose FH in outpatients with hypercholesterolemia. Resequencing chip analysis combined with Sanger sequencing validation were used to identify mutations in the definite FH patients according to DLCN criteria. In silico analysis was conducted in mutations with previously unknown pathogenicity. Then, the novel mutant receptors were transfected into human embryo kidney 293 (HEK-293) cells. The binding and the internalization activities of the mutant receptors were analyzed by flow cytometry. RESULTS: The prevalence of definite FH in outpatients with hypercholesterolemia in this study is 3.2%. Using genetic testing, one homozygous FH (HoFH), one heterozygous FH (HeFH) and three compound heterozygous FH patients were confirmed. Eight mutations in low-density lipoprotein receptor (LDLR) gene were identified, in which c.357delG was a novel mutation and co-segregated with the FH phenotype. Bioinformatic analysis confirmed that c.357delG was a pathogenic mutation. Furthermore, when compared with the wild-type LDLRs by flow cytometry analysis, the binding and internalization activities of c.357delG mutant LDLRs were reduced by 35% and 49%, respectively. CONCLUSIONS: This study identified eight LDLR gene mutations in five patients with definite FH, in which c.357delG is a novel pathogenic mutation. These findings increase our understanding of the genetic spectrum of FH in China.

Novel Approaches for the Treatment of Familial Hypercholesterolemia: Current Status and Future Challenges.

Familial hypercholesterolemia (FH) is an autosomal-dominant disorder that is characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and an increased risk of cardiovascular disease. Despite the use of high-dose statins and the recent addition of proprotein convertase subtilisin/kexin type 9 inhibitors as a treatment option, many patients with homozygous FH fail to achieve optimal reductions of LDL-c levels. Gene therapy has become one of the most promising research directions for contemporary life sciences and is a potential treatment option for FH. Recent studies have confirmed the efficacy of a recombinant adeno-associated virus 8 vector expressing the human LDL-c receptor gene in a mouse model, and this vector is currently in phase 2 clinical trials. Much progress has also been achieved in the fields of antisense oligonucleotide- and small interfering RNA-based gene therapies, which are in phase 1-2 clinical trials. In addition, novel approaches, such as the use of minicircle DNA vectors, microRNAs, long non-coding RNAs, and the CRISPR/Cas9 gene-editing system, have shown great potential for FH therapy. However, the delivery system, immunogenicity, accuracy, and specificity of gene therapies limit their clinical applications. In this article, we discuss the current status of gene therapy and recent advances that will likely affect the clinical application of gene therapy for the treatment of FH.

A case of sitosterolemia misdiagnosed as familial hypercholesterolemia: A 4-year follow-up.

Familial hypercholesterolemia (FH) is a common inherited disease that exhibits significantly increased levels of low-density lipoprotein cholesterol (LDL-C), skin or tendon xanthomas, corneal arcus and premature coronary heart disease (CHD). The prevalence of heterozygous FH is nearly 1/300 worldwide, and the prevalence of homozygous FH (HoFH) is 1/160,000 - 1/300,000. The Dutch Lipid Clinic Network diagnostic (DLCN) criteria is the most commonly recommended criteria for diagnosing FH patients. However, another disease with a similar clinical phenotype to FH must be differentiated from FH. This disease is a rare autosomal recessive disorder, sitosterolemia, and its incidence rate is approximately 1/5 million. We report a 16-month-old child with suspected HoFH and LDL-C levels that were reduced from 14.69 mmol/L to 3.24 mmol/L after dietary control without statin therapy. Gas chromatography detection of plant sterol levels and targeted exon sequencing chips for genetic testing were used to reach confirmed the diagnosis of sitosterolemia.

The serum anion gap is associated with disease severity and all-cause mortality in coronary artery disease.

OBJECTIVE: To evaluate the associations between the serum anion gap (AG) with the severity and prognosis of coronary artery disease (CAD). METHODS: We measured serum electrolytes in 18,115 CAD patients indicated by coronary angiography. The serum AG was calculated according to the equation: AG = Na+[(mmol/L) + K+ (mmol/L)] - [Cl- (mmol/L) + HCO3- (mmol/L)]. RESULTS: A total of 4510 (24.9%) participants had their AG levels greater than 16 mmol/L. The serum AG was independently associated with measures of CAD severity, including more severe clinical types of CAD (P < 0.001) and worse cardiac function (P = 0.004). Patients in the 4th quartile of serum AG (≥ 15.92 mmol/L) had a 5.171-fold increased risk of 30 days all-cause death (P < 0.001). This association was robust, even after adjustment for age, sex, evaluated glomerular filtration rate [hazard ratio (HR): 4.861, 95% confidence interval (CI): 2.150-10.993, P < 0.001], clinical diagnosis, severity of coronary artery stenosis, cardiac function grades, and other confounders (HR: 3.318, 95% CI: 1.76-2.27, P = 0.009). CONCLUSION: In this large population-based study, our findings reveal a high percentage of increased serum AG in CAD. Higher AG is associated with more severe clinical types of CAD and worse cardiac function. Furthermore, the increased serum AG is an independent, significant, and strong predictor of all-cause mortality. These findings support a role for the serum AG in the risk-stratification of CAD.

Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an autosomal dominant disease with widespread global prevalence that partially accounts for the high prevalence of premature coronary heart disease. Although the majority of research on FH has focused on single heterozygous LDLR mutations, there have been limited reports of double LDLR mutations on the same chromosome. The aim of this study was to gain insight into the clinical consequences of the presence of multiple mutations in the LDLR gene. METHODS: DNA from two clinical homozygous FH patients and their relatives was analysed using targeted exome sequencing and DNA resequencing. Functional characterization of novel variants was performed by Western blot, flow cytometry and confocal microscopy. RESULTS: Proband 1 carried p.Q12X, NTDA (p.N276T and c.892delA) mutations in LDLR, and Proband 2 carried c.971delG, GSDN (p.G77S + D601N). Results showed that p.Q12X, c.892delA, and c.971delG are non-functional LDLR variants. Conversely, N276T and G77S are non-pathogenic variants. Interestingly, while D601N alone only slightly diminishes LDLR activity, its co-presence with the non pathogenic p.G77S mutation results in a more strongly pathogenic variant with LDLR activity reduced by 40%. One of the double mutants, NTDA, is as non functional as c.892delA alone. The other double mutant, GSDN, is more severe than either of the component single mutants. CONCLUSIONS: An early gene screening and laboratory functional verification of LDLR activity is of vital importance to enable a definite FH diagnosis. Functional verification is also necessary for prenatal and postnatal care in patients with FH.

The use of targeted exome sequencing in genetic diagnosis of young patients with severe hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder. Although genetic testing is an important tool for detecting FH-causing mutations in patients, diagnostic methods for young patients with severe hypercholesterolemia are understudied. This study compares the target exome sequencing (TES) technique with the DNA resequencing array technique on young patients with severe hypercholesterolemia. A total of 20 unrelated patients (mean age 14.8 years) with total cholesterol > 10 mmol/L were included. 12 patient samples were processed by DNA resequencing array, 14 patient samples were processed by TES, and 6 patient samples were processed by both methods. Functional characterization of novel mutations was performed by flow cytometry. The mutation detection rate (MDR) of DNA resequencing array was 75%, while the MDR of TES was 100%. A total of 27 different mutations in the LDLR were identified, including 3 novel mutations and 8 mutations with previously unknown pathogenicity. Functional characterization of c.673delA, c.1363delC, p.Leu575Phe and p.Leu582Phe variants found that all of them are pathogenic. Additionally, 7 patients were diagnosed with Heterozygous FH (HeFH) in which lipid levels were significantly higher than common HeFH patients. This data indicates that TES is a very efficient tool for genetic diagnosis in young patients with severe hypercholesterolemia.

Characterization of the unique Chinese W483X mutation in the low-density lipoprotein-receptor gene in young patients with homozygous familial hypercholesterolemia.

BACKGROUND: Recent guidelines suggest that more attention should be focused on children with homozygous familial hypercholesterolemia (HoFH). China may have 3.8 million potential FH patients, but there are limited data focused on HoFH children. OBJECTIVE: We systematically analyzed the characteristic phenotype and the relationship between the genotype and the phenotype in HoFH children with the unique Chinese W483X mutation in the low-density lipoprotein (LDL)-receptor gene. METHODS: A systematic retrospective analysis of the lipid and cardiovascular characteristics of HoFH patients in the atherosclerosis clinic of Beijing Anzhen Hospital was performed. The W483X mutation was confirmed using DNA sequencing of the patients and their parents. RESULTS: Two HoFH and 9 compound heterozygous patients (mean age = 14.7 years) with 2 novel mutations, Q254X and c.1363delC, were found. In total, 81.8% of the patients were from southern China. All the patients had xanthoma, and the average TC and LDL-C levels were 16.8 and 14.4 mmol/L, respectively. Echocardiography showed that 63.6% of the patients had aortic calcification, and 54.5% had mild regurgitation of the aortic valve. The coronary flow velocity reserve had a mean value of 2.12, and the cIMT was 0.17 cm. The follow-up period was between 3 months and 8 years. Although all the patients began the lipid-lowering treatment, 2 patients died because of severe cardiovascular disease. The LDL-C levels of 6 patients were slightly decreased by approximately 21% and remained far from the target values, and the other 3 patients' LDL-C levels increased by 13%. CONCLUSIONS: The results suggest that younger HoFH patients with W483X mutations had a severe phenotype and should receive more aggressive treatment.

Can Platforms Affect the Safety and Efficacy of Drug-Eluting Stents in the Era of Biodegradable Polymers?: A Meta-Analysis of 34,850 Randomized Individuals.

OBJECTIVE: In the era of bare metal stents (BMSs), alloys have been considered to be better materials for stent design than stainless steel. In the era of biodegradable polymer drug-eluting stents (BP-DESs), the safety and efficacy of BP-DESs with different metal platforms (stainless steel or alloys) have not yet been reported, although their polymers are eventually absorbed, and only the metal platforms remain in the body. This study sought to determine the clinical safety and efficacy of BP-DESs with different platforms compared with other stents (other DESs and BMSs). METHODS: PubMed, Embase and Clinical Trials.gov were searched for randomized controlled trials (RCTs) that compared BP-DESs with other stents. After performing pooled analysis of BP-DESs and other stents, we performed a subgroup analysis using two classification methods: stent platform and follow-up time. The study characteristics, patient characteristics and clinical outcomes were abstracted. RESULTS: Forty RCTs (49 studies) comprising 34,850 patients were included. Biodegradable polymer stainless drug-eluting stents (BP-stainless DESs) were superior to the other stents [mainly stainless drug-eluting stents (DESs)] in terms of pooled definite/probable stent thrombosis (ST) (OR [95% CI] = 0.76[0.61-0.95], p = 0.02), long-term definite/probable ST (OR [95% CI] = 0.73[0.57-0.94], p = 0.01), very late definite/probable ST (OR [95% CI] = 0.56[0.33-0.93], p = 0.03) and long-term definite ST. BP-stainless DESs had lower rates of pooled, mid-term and long-term target vessel revascularization (TVR) and target lesion revascularization (TLR) than the other stainless DESs and BMSs. Furthermore, BP-stainless DESs were associated with lower rates of long-term death than other stainless DESs and lower rates of mid-term myocardial infarction than BMSs. However, only the mid-term and long-term TVR rates were superior in BP-alloy DESs compared with the other stents. CONCLUSION: Our results indirectly suggest that BP-stainless DESs may offer more benefits than BP-alloy DESs in the era of BP-DESs. Further well-designed RCTs comparing BP-stainless with BP-alloy DESs are needed to confirm which platform is better.

Level of Pregnancy-associated Plasma Protein-A Correlates With Coronary Thin-cap Fibroatheroma Burden in Patients With Coronary Artery Disease: Novel Findings From 3-Vessel Virtual Histology Intravascular Ultrasound Assessment.

Pregnancy-associated plasma protein-A (PAPP-A) level is an independent predictor of acute cardiovascular event occurrence. To test the hypothesis that increased PAPP-A levels would be associated with a higher burden of coronary thin-cap fibroatheroma (TCFA) thereby underlying the heightened risk for cardiovascular events in patients with coronary artery disease; 154 patients (462 vessels and 975 plaques) with stable angina or non-ST-segment elevation acute coronary syndrome (NSTE-ACS) referred for percutaneous coronary intervention were assessed using 3-vessel virtual histology (VH)-intravascular ultrasound (IVUS). Thin-cap fibroatheroma virtual histology was defined as focal, necrotic core (NC)-rich (≥10% of cross-sectional area) plaques in contact with the lumen, and plaque burden ≥40%. Pregnancy-associated plasma protein-A levels were determined by sandwich enzyme-linked immunosorbent assay, and patients were divided into 3 groups based on PAPP-A level tertiles. Although the highest PAPP-A level tertile was not associated with 3-vessel plaque number, it was associated with 3-vessel VH-TCFA number and necrotic core volume. Patients with ≥3 VH-TCFAs had a higher PAPP-A level than patients with 1 to 3 VH-TCFAs or without any VH-TCFA (13.3 ±â€Š11.8 versus 7.8 ±â€Š4.7 versus 7.4 ±â€Š4.7 mIU/L, P < 0.001, respectively). Moreover, PAPP-A level was an independent predictor of higher total number of VH-TCFAs (OR 1.18; 95% CI 1.07-1.29, P = 0.001). This VH-IVUS study demonstrated, for the first time to our knowledge, that higher PAPP-A levels are associated with higher 3-vessel TCFA burden in patients with coronary artery disease. Pregnancy-associated plasma protein-A, therefore, might be a useful serum biomarker to predict increased coronary TCFA burden and plaque instability.

Assessment of Retrograde Coronary Venous Infusion of Mesenchymal Stem Cells Combined with Basic Fibroblast Growth Factor in Canine Myocardial Infarction Using Strain Values Derived from Speckle-Tracking Echocardiography.

Speckle-tracking echocardiography was used to assess retrograde coronary venous infusion of mesenchymal stem cells (MSCs) combined with basic fibroblast growth factor (bFGF) in a canine model of acute myocardial infarction (AMI). AMI was induced by ligation of the left anterior descending coronary artery. Coronary venous retroperfusion was performed at 1 wk after AMI. Twenty-eight animals were randomized into four groups: saline, bFGF+saline, saline+MSCs and bFGF+MSCs. Echocardiography was performed before AMI, at 7 d post-AMI and 40 d after retroperfusion. Apoptotic cardiomyocytes in the border zone of the ischemic region were evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling. Vascular endothelial growth factor and factor VIII concentrations were measured by western blotting. The left ventricular end-systolic volume increased significantly, whereas the left ventricular ejection fraction and global and segmental strain values decreased significantly after AMI. After retroperfusion, the strain values of the infarct zone, but not conventional echocardiographic parameters, were significantly different between control and bFGF+MSC groups. Cardiomyocyte apoptosis decreased, whereas vascular endothelial growth factor and factor VIII concentrations were higher in the bFGF+MSC, bFGF and MSC groups. Cardiomyocyte apoptosis was well correlated with the strain values. Although retrograde coronary venous infusion of bFGF and MSCs promoted neo-vascularization of the infarcted myocardium and inhibited apoptosis, there was only a slight strain improvement without a substantial increase in global cardiac functions.

The distribution and characteristics of LDL receptor mutations in China: A systematic review.

Familial hypercholesterolemia (FH) is a common and serious dominant genetic disease, and its main pathogenic gene is the low-density lipoprotein receptor (LDLR) gene. This study aimed to perform a systematic review of LDLR mutations in China. Using PubMed, Embase, Wanfang (Chinese), the Chinese National Knowledge Infrastructure (Chinese), and the Chinese Biological and Medical database (Chinese), public data were limited to December 2014. The Medical Subject Headings terms and the following key words were used: "familial hypercholesterolemia", "Chinese", "China", "Hong Kong", and "Taiwan". A total of 74 studies including 295 probands with 131 LDLR mutations were identified. Most of the mutations were located in exon 4 of LDLR and approximately 60% of the mutations were missense mutations. Thirty new mutations that were not recorded in the LDLR databases were found. In silico analysis revealed that most of the mutations were pathogenic. The primary LDLR mutations were C308Y, H562Y, and A606T, and all of the mutations had functional significance. Prevalence data suggest that there are nearly 3.8 million FH patients in China, although reported numbers are much smaller, suggesting that FH is widely misunderstood. This systematic review provides information that is specific to China for inclusion in the international FH database.

Identification of the gene defect responsible for severe hypercholesterolaemia using whole-exome sequencing.

Familial hypercholesterolaemia (FH) is a serious genetic metabolic disease. We identified a specific family in which the proband had typical homozygous phenotype of FH, but couldn't detect any mutations in usual pathogenic genes using traditional sequencing. This study is the first attempt to use whole exome sequencing (WES) to identify the pathogenic genes in Chinese FH. The routine examinations were performed on all parentage members, and WES on 5 members. We used bioinformatics methods to splice and filter out the pathogenic gene. Finally, Sanger sequencing and cDNA sequencing were used to verify the candidate genes. Half of parentage members had got hypercholesterolaemia. WES identified LDLR IVS8[-10] as a candidate mutation from 222,267 variations. The Sanger sequencing showed proband had a homozygous mutation inherited from his parents, and this loci were cosegregated with FH phenotype. The cDNA sequencing revealed that this mutations caused abnormal shearing. This mutation was first identified in Chinese patients, and this homozygous mutation is a new genetic type of FH. This is the first time that WES was used in Chinese FH patients. We detected a novel genetic type of LDLR homozygous mutation. WES is powerful tools to identify specific FH families with potentially pathogenic gene mutations.

Pregnancy-associated plasma protein-A as a marker of culprit lesion instability in unstable angina patients: an intravascular ultrasound study.

BACKGROUND: We evaluated the relationship between pregnancy-associated plasma protein-A (PAPP-A) and coronary plaque instability as assessed by intravascular ultrasound (IVUS). METHODS: We performed greyscale IVUS analysis in culprit lesions of 93 patients with unstable angina (UA) and 72 with stable angina (SA). A sandwich enzyme-linked immunosorbent assay technique was used to assay circulating PAPP-A. RESULTS: Patients with UA had higher PAPP-A levels than those with SA 10.8 mIU/l [interquartile range (IQR) 8.3-14.4] vs. 5.4 (IQR 2.9-9.8) mIU/l, p < 0.001]. Lesions in patients with higher PAPP-A levels were associated with larger plaque burden than lesions in patients with lower PAPP-A levels. IVUS attenuated plaque, positive remodeling and plaque rupture. Thrombus and angiographic Ambrose type-II eccentric lesions or multiple irregularities were more common in patients with higher PAPP-A levels than in those with lower PAPP-A levels. They were also more common in patients with UA and higher PAPP-A levels than in patients with (1) SA and higher PAPP-A levels, (2) UA and lower PAPP-A levels or (3) SA and lower PAPP-A levels. CONCLUSIONS: Higher PAPP-A levels were associated with coronary plaque instability in vivo and unstable symptoms in patients with coronary artery disease.