<Emphasis Type="Italic">PON1</Emphasis> Q192R genetic variant and response to clopidogrel and prasugrel: pharmacokinetics,pharmacodynamics, and a meta-analysis of clinical outcomes

Clopidogrel and prasugrel are antiplatelet therapies commonly used to treat patients with cardiovascular disease. They are both pro-drugs requiring biotransformation into active metabolites. It has been proposed that a genetic variant Q192R (rs662 A>G) in PON1 significantly alters the biotransformation of clopidogrel and affects clinical outcomes; however, this assertion has limited support. The relationship between this variant and clinical outcomes with prasugrel has not been studied. We genotyped PON1 Q192R in 275 healthy subjects treated with clopidogrel or prasugrel and 2922 patients with an ACS undergoing PCI randomized to treatment with clopidogrel or prasugrel in the TRITON-TIMI 38 trial. A meta-analysis was performed including 13 studies and 16,760 clopidogrel-treated patients. Among clopidogrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.62) or change in platelet aggregation (P = 0.51). Consistent with these results, in clopidogrel-treated patients in TRITON-TIMI 38, there was no association between Q192R and the rates of CV death, myocardial infarction, or stroke (RR 11.2 %, QR 8.6 %, and QQ 9.3 %; P = 0.66) or stent thrombosis (RR 2.4 %, QR 0.7 %, and QQ 1.6 %, P = 0.30), with patients with the putative at-risk Q variant having numerically lower event rates. Likewise, among prasugrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.88), change in platelet aggregation (P = 0.97), or clinical outcomes (P = 0.72). In a meta-analysis, the Q variant was not significantly associated with MACE (QQ vs. RR 1.22, 95 % CI 0.84–1.76) or stent thrombosis (QQ vs. RR OR 1.36, 95 % CI 0.77–2.38). Furthermore, when restricted to the validation studies, the OR (95 % CI) for MACE and stent thrombosis were 0.99 (0.77–1.27) and 1.23 (0.74–2.03), respectively. In the present study, the Q192R genetic variant in PON1 was not associated with the pharmacologic or clinical response to clopidogrel, nor was it associated with the response to prasugrel. The meta-analysis reinforced a lack of a significant association between Q192R and cardiovascular outcomes in clopidogrel-treated patients.     

Ruxolitinib reduces <Emphasis Type="Italic">JAK2</Emphasis> p.V617F allele burden in patients with polycythemia vera enrolled in the RESPONSE study

In patients with polycythemia vera (PV), an elevated JAK2 p.V617F allele burden is associated with indicators of more severe disease (e.g., leukocytosis, splenomegaly, and increased thrombosis risk); however, correlations between allele burden reductions and clinical benefit in patients with PV have not been extensively evaluated in a randomized trial. This exploratory analysis from the multicenter, open-label, phase 3 Randomized Study of Efficacy and Safety in Polycythemia Vera With JAK Inhibitor INCB018424 Versus Best Supportive Care trial evaluated the long-term effect of ruxolitinib treatment on JAK2 p.V617F allele burden in patients with PV. Evaluable JAK2 p.V617F-positive patients randomized to ruxolitinib (n = 107) or best available therapy (BAT) who crossed over to ruxolitinib at week 32 (n = 97) had consistent JAK2 p.V617F allele burden reductions throughout the study. At all time points measured (up to weeks 208 [ruxolitinib-randomized] and 176 [ruxolitinib crossover]), mean changes from baseline over time in JAK2 p.V617F allele burden ranged from ?12.2 to ?40.0% (ruxolitinib-randomized) and ?6.3 to ?17.8% (ruxolitinib crossover). Complete or partial molecular response was observed in 3 patients (ruxolitinib-randomized, n = 2; ruxolitinib crossover, n = 1) and 54 patients (ruxolitinib-randomized, n = 33; ruxolitinib crossover, n = 20; BAT, n = 1), respectively. Among patients treated with interferon as BAT (n = 13), the mean maximal reduction in allele burden from baseline was 25.6% after crossover to ruxolitinib versus 6.6% before crossover. Collectively, the data from this exploratory analysis suggest that ruxolitinib treatment for up to 4 years provides progressive reductions in JAK2 p.V617F allele burden in patients with PV who are resistant to or intolerant of hydroxyurea. The relationship between allele burden changes and clinical outcomes in patients with PV remains unclear.     

Associations of <Emphasis Type="Italic">methylenetetrahydrofolate reductase</Emphasis> (<Emphasis Type="Italic">MTHFR</Emphasis>) C677T and A1298C polymorphisms with genetic susceptibility to rheumatoid arthritis: a meta-analysis

The aim of our study was to conduct a meta-analysis to assess whether combined evidence shows associations between C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and genetic susceptibility to rheumatoid arthritis (RA). A total of 11 articles involving 20 comparisons were included, containing 12 comparisons for the MTHFR C677T polymorphism and 8 comparisons for the MTHFR A1298C polymorphism. Significant evidence was detected for the association of RA susceptibility with the MTHFR C677T polymorphism T allele under allelic contrast and dominant model in Asians (T versus C, OR = 1.300, 95 % CI = 1.104–1.531, p = 0.002; TT + CT versus CC, OR = 1.495, 95 % CI = 1.187–1.882, p = 0.001). Significant association between RA susceptibility and the MTHFR A1298C polymorphism A allele under recessive model was found in the overall meta-analysis (AA versus AC + CC, OR = 1.281, 95 % CI = 1.048–1.565, p = 0.016). Our meta-analysis results demonstrate that the MTHFR C677T polymorphism is involved in the genetic susceptibility of RA in Asians, and the MTHFR A1298C polymorphism is associated with genetic susceptibility to RA in the overall population. Given the paucity of studies, especially in non-Asian populations, further studies with larger sample sizes are required to elucidate the role of MTHFR polymorphisms in the genetic basis of RA in different ethnic populations.     

<Emphasis Type="Italic">C-reactive protein</Emphasis> +1444CT (rs1130864) genetic polymorphism is associated with the susceptibility to systemic lupus erythematosus and C-reactive protein levels

The T rare allele of +1444CT (rs1130864) polymorphism of C-reactive protein (CRP) has been associated with increased CRP levels in some inflammatory conditions, but its role on systemic lupus erythematosus (SLE) susceptibility and on CRP levels in SLE patients remains uncertain. The objective of the study was to evaluate the association between the rs1130864 CRP polymorphism with SLE susceptibility, disease activity, and CRP levels in SLE Brazilian patients. The study enrolled 176 SLE patients and 137 controls. SLE disease activity was assessed using the SLE Disease Activity Index (SLEDAI). The rs1130864 CRP polymorphism was determined using polymerase chain reaction and restriction fragment length polymorphism. SLE patients presented higher body mass index (p = 0.046) and CRP levels (p = 0.017) than controls. The genotype and allele frequencies of patients differed from controls [CC vs. CT = odds ratio (OR) 1.730, 95% confidence interval (CI) 1.068–2.803, p = 0.035; CC vs. TT = OR 3.667, 95% CI 1.410–9.533, p = 0.009; C vs. T = OR 1.883, 95% CI 1.299–2.728, p = 0.001)]. Patients carrying the T allele presented higher CRP levels (p = 0.009), were more frequent Caucasians (p = 0.018), and with no use of immunosuppressive treatment (p = 0.004) than those carrying the C allele. However, the SLEDAI and anti-double-stranded DNA positivity did not differ from those carrying T vs. C allele (p = 0.595 and p = 0.243, respectively). The rs1130864 CRP polymorphism was associated with SLE susceptibility and CRP levels, but not with disease activity, suggesting that this polymorphism may play a role in the pathophysiology of SLE through increasing the CRP that, probably, plays an inflammatory role in SLE pathophysiology.     

Associations between PTPRC rs10919563 A/G and FCGR2A R131H polymorphisms and responsiveness to TNF blockers in rheumatoid arthritis: a meta-analysis

We aimed to investigate whether the PTPRC rs10919563 A/G and Fc gamma receptor 2A (FCGR2A) R131H polymorphisms can predict the response to anti-TNF therapy in rheumatoid arthritis (RA) patients. We conducted a meta-analysis of studies on the association between the PTPRC rs10919563 A/G or the FCGR2A R131H polymorphism and responsiveness to anti-TNF therapy in RA patients. Eighteen studies (twelve on PTPRC and six on FCGR2A) from eight articles involving 3058 patients were considered in this meta-analysis. The meta-analysis showed a significant association between the PTPRC rs10919563 A allele and response to TNF-α blockers in RA. The OR of the PTPRC A allele was significantly lower in responders (OR = 0.584, 95 % CI = 0.409–0.835, P = 0.003). Meta-analysis revealed no association between the FCGR2A HH + HR genotype and responsiveness to TNF blockers in all study subjects (OR = 0.762, 95 % CI = 0.543–1.068, P = 0.115). However, stratification by TNF inhibitor type showed that the FCGR2A HH + HR genotype was associated with responsiveness to adalimumab (OR = 0.591, 95 % CI = 0.369–0.947, P = 0.029), but not infliximab and etanercept (OR = 0.929, 95 % CI = 0.354–2.440, P = 0.881; OR = 0.804, 95 % CI = 0.293–2.207, P = 0.673). The PTPRC rs10919563 A allele shows a poor response to anti-TNF therapy, and the FCGR2A HH + HR genotype shows a poor response to adalimumab for RA. Genotyping for these polymorphisms may be useful for predicting the response to TNF-α blockers with respect to personalized medicine.     

Paclitaxel-eluting stents versus sirolimus-eluting stents in patients with diabetes mellitus undergoing percutaneous coronary intervention: a systematic review and meta-analysis of randomized controlled trials

Uncertainties exist with regard to the efficacy of paclitaxel-eluting stents (PES) versus sirolimus-eluting stents (SES) in diabetes patients undergoing percutaneous coronary intervention (PCI). We performed a meta-analysis of randomized controlled trials (RCTs) to investigate the outcome of PES versus SES in diabetes patients undergoing PCI. A literature search was started, and we found all studies conducted from 2005 to 2016. We systematically searched the literature through the MEDLINE, Cochrane library, and EMBASE. Quality assessments were evaluated with the Jadad scale. Data were extracted considering the characteristics of efficacy and the safety of the designs. 12 RCTs satisfy the inclusion criteria. There is a significant decrease of target lesion revascularization (TLR) (MD = 0.65, 95 % CI = 0.42–1.00, P = 0.05) in a year and more than 1 year (MD = 0.54, 95 % CI = 0.37–0.78, P = 0.00010). A significant decrease of target vessel revascularization (TVR) in more than 1 year is (MD = 0.62, 95 % CI = 0.47–0.81, P = 0.0004). A significant decrease of major adverse cardiac events (MACE) in more than 1 year is (MD = 0.73, 95 % CI = 0.60–0.89, P = 0.002). Nevertheless, there is no significant difference in mortality (MD = 0.85, 95 % CI = 0.66–1.11, P = 0.24), stent thrombosis (ST) (MD = 0.65, 95 % CI = 0.35–1.21, P = 0.18), or myocardial infarction (MD = 1.04, 95 % CI = 0.71–1.51, P = 0.84). SES may be more significant in decreasing TLR, TVR, and MACE than PES without significantly increasing mortality, ST and MI in diabetes patients.     

Clinical effectiveness of the systematic use of the GRACE scoring system (in addition to clinical assessment) for ischaemic outcomes and bleeding complications in the management of NSTEMI compared with clinical assessment alone: a prospective study

We assessed the interest of systematically using the GRACE scoring system (in addition to clinical assessment) for in-hospital outcomes and bleeding complications in the management of NSTEMI compared with clinical assessments alone. Multicentre, randomized study that included 572 consecutive NSTEMI patients, randomized 1:1, into group A: clinical stratification alone and group B: clinical+ GRACE score stratification. Main outcome measures: in-hospital outcomes and bleeding complications. There was no significant difference between the two groups for baseline data or for in-hospital MACE. In multivariate analysis, only a GRACE >140 (OR: 3.5, 95 % CI: 1.8–6.6, p < 0.001) and PCI (OR: 0.55, 95 % CI: 0.3–1.0; p = 0.05) were independent predictors of in-hospital MACE. The sub-analysis of group B showed that 56 patients (20 %) were given a compliance score of 0, showing that diagnostic angiography was performed later than as recommended by the guidelines. Interestingly, 91 % had a GRACE score >140, and these patients were significantly older, and were more likely to have a history of diabetes, stroke and renal failure, together with symptoms of heart failure. After multivariate analysis, the independent predictors of a lack of compliance with guideline delays were a GRACE score >140 (OR: 9.2; CI: 4.2–20.3, p < 0.001) and secondary referral from a non-PCI cardiology department (OR: 2.7; CI: 1.4–5.2, p = 0.003). In a real-world setting of patients admitted with NSTEMI, the systematic use of the GRACE scoring system at admission in the PCI centre does not improve in-hospital outcomes and bleeding complications.     

Association of methylenetetrahydrofolate reductase (<Emphasis Type="Italic">MTHFR</Emphasis>) gene C677T polymorphism with autism: evidence of genetic susceptibility

Autism (MIM 209850) is a heterogeneous neurodevelopmental disease that manifests within the first 3 years of life. Numerous articles reported that dysfunctional folate-methionine pathway enzymes may play an important role in the pathophysiology of autism. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme of this pathway and MTHFR C677T polymorphism reported as risk factor for autism in several case control studies. However, controversial reports were also published. Hence the present meta-analysis was designed to investigate the relationship of the MTHFR C677T polymorphism with the risk of autism. Electronic databases were searched for case control studies with following search terms - ‘MTHFR’, ‘C677T’, in combination with ‘Autism’. Pooled OR with its corresponding 95 % CI was calculated and used as association measure to investigate the association between MTHFR C677T polymorphism and risk of autism. Total of thirteen studies were found suitable for the inclusion in the present meta-analysis, which comprises 1978 cases and 7257 controls. Meta-analysis using all four genetic models showed significant association between C677T polymorphism and autism (OR_Tvs.C = 1.48; 95 % CI: 1.18–1.86; P = 0.0007; OR_{TT + CT vs. CC} = 1.70, 95 % CI = 0.96–2.9, p = 0.05; OR_{TT vs. CC} = 1.84, 95 % CI = 1.12–3.02, p = 0.02; OR_{CT vs.CC} = 1.60, 95 % CI = 1.2–2.1, p = 0.003; OR_{TT vs.CT+CC} = 1.5, 95 % CI = 1.02–2.2, p = 0.03). In total 13 studies, 9 studies were from Caucasian population and 4 studies were from Asian population. The association between C677T polymorphism and autism was significant in Caucasian (OR_Tvs.C = 1.43; 95 % CI = 1.1–1.87; p = 0.009) and Asian population (OR_Tvs.C = 1.68; 95 % CI = 1.02–2.77; p = 0.04) using allele contrast model. In conclusion, present meta-analysis strongly suggested a significant association of the MTHFR C677T polymorphism with autism.     

Risk factors and outcomes of acute lower gastrointestinal bleeding in intestinal Behçet’s disease

Background

Intestinal Behçet’s disease (BD) can cause acute lower gastrointestinal bleeding, which is sometimes fatal.

Aim

We aimed to identify the risk factors and outcomes of acute lower gastrointestinal bleeding and factors associated with rebleeding in intestinal BD patients.

Methods

Of the total of 588 intestinal BD patients, we retrospectively reviewed the medical records of 66 (11.2%) patients with acute lower gastrointestinal bleeding and compared them with those of 132 matched patients without bleeding.

Results

The baseline characteristics were comparable between the bleeding group (n = 66) and the non-bleeding group (n = 132). On multivariate analysis, the independent factors significantly associated with lower gastrointestinal bleeding were older age (>52 years) (hazard ratio [HR] 2.2, 95% confidence interval [CI] 1.058–4.684, p = 0.035) and a nodular ulcer margin (HR 7.1, 95% CI 2.084–24.189, p = 0.002). Rebleeding occurred in 23 patients (34.8%). Female patients (p = 0.044) and those with previous use of corticosteroids or azathioprine (p = 0.034) were more likely to develop rebleeding. On multivariate analysis, only use of steroids or azathioprine was significantly associated with rebleeding (HR 3.2, 95% CI 1.070–9.462, p = 0.037).

Conclusions

Age >52 years and the presence of a nodular margin of the ulcer were found to be related to increased risk of bleeding in patients with intestinal BD. Rebleeding is not uncommon and not effectively prevented with currently available medications. Further studies are warranted to identify effective measures to decrease rebleeding in intestinal BD.

     

Three-question set from Michigan Neuropathy Screening Instrument adds independent prognostic information on cardiovascular outcomes: analysis of ALTITUDE trial

Aims/hypothesis

The self-administered Michigan Neuropathy Screening Instrument (MNSI) is used to diagnose diabetic peripheral neuropathy. We examined whether the MNSI might also provide information on risk of death and cardiovascular outcomes.

Methods

In this post hoc analysis of the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial, we divided 8463 participants with type 2 diabetes and chronic kidney disease (CKD) and/or cardiovascular disease (CVD) into independent training (n = 3252) and validation (n = 5211) sets. In the training set, we identified specific questions that were independently associated with a cardiovascular composite outcome (cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction/stroke, heart failure hospitalisation). We then evaluated the performance of these questions in the validation set.

Results

In the training set, three questions (‘Are your legs numb?’, ‘Have you ever had an open sore on your foot?’ and ‘Do your legs hurt when you walk?’) were significantly associated with the cardiovascular composite outcome. In the validation set, after multivariable adjustment for key covariates, one or more positive responses (n = 3079, 59.1%) was associated with a higher risk of the cardiovascular composite outcome (HR 1.54 [95% CI 1.28, 1.85], p < 0.001), heart failure hospitalisation (HR 1.74 [95% CI 1.29, 2.35], p < 0.001), myocardial infarction (HR 1.81 [95% CI 1.23, 2.69], p = 0.003), stroke (HR 1.75 [95% CI 1.20, 2.56], p = 0.003) and three-point major adverse cardiovascular events (MACE) (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) (HR 1.49 [95% CI 1.20, 1.85], p < 0.001) relative to no positive responses to all questions. Associations were stronger if participants answered positively to all three questions (n = 552, 11%). The addition of the total number of affirmative responses to existing models significantly improved Harrell’s C statistic for the cardiovascular composite outcome (0.70 vs 0.71, p = 0.010), continuous net reclassification improvement (+22% [+10%, +31%], p = 0.027) and integrated discrimination improvement (+0.9% [+0.4%, +2.1%], p = 0.007).

Conclusions/interpretation

We identified three questions from the MNSI that provide additional prognostic information for individuals with type 2 diabetes and CKD and/or CVD. If externally validated, these questions may be integrated into the clinical history to augment prediction of CV events in high-risk individuals with type 2 diabetes.

     

Clinical outcomes in patients with diffuse large B cell lymphoma with a partial response to first-line R-CHOP chemotherapy: prognostic value of secondary International Prognostic Index scores and Deauville scores

After introducing a rituximab-containing chemoimmunotherapy (R-CHOP) for diffuse large B cell lymphoma (DLBCL), a partial response (PR) which is regarded as treatment failure is still observed. To investigate the prognostic factors for the DLBCL patients with a PR to R-CHOP, we retrospectively evaluated 758 newly diagnosed DLBCL patients. After R-CHOP, 88 (11.6%) achieved a PR. Three-year progression-free and overall survival rates measured from the date of PR achievement (PFS2 and OS2) were 57.4 and 67.8%, respectively. The secondary International Prognostic Index (IPI2) scores after R-CHOP were low (0–1) in 68.2% and high (2–3) in 31.8% of the patients. The Deauville scores from 18-fluorodeoxyglucose positron emission tomography after R-CHOP showed low (2–3) in 58.0% and high (4) in 42.0% of the patients. High IPI2 and high Deauville scores were associated with worse PFS2 (P < 0.001 and P = 0.009) and OS2 (P = 0.013 and P = 0.067). The high-risk group defined by the IPI2 and Deauville scores, whose scores were both high, showed significantly lower 3-year PFS2 (P < 0.001) and OS2 (P = 0.006) rates compared with those of the other groups. In multivariate analyses, the IPI score of ≥?3 at diagnosis and bone marrow involvement at diagnosis were independent prognostic factors. In addition, high IPI2-Deauville score after R-CHOP was significantly associated with poor PFS2 (P = 0.009) and demonstrated a trend toward inferior OS2. In conclusion, DLBCL patients who partially responded to R-CHOP are still a heterogeneous group, for which IPI2 and Deauville scores should be evaluated for prediction of prognosis.     

Influence of hemodialysis duration on mid-term clinical outcomes in hemodialysis patients with coronary artery disease after drug-eluting stent implantation

Accelerated atherosclerosis in prolonged maintenance hemodialysis (HD) has been recognized; however, whether HD duration is associated with poor clinical outcome in HD patients with coronary artery disease (CAD) after drug-eluting stent (DES) implantation is unknown. We evaluated the impact of HD duration on clinical outcomes in HD patients with CAD after DES implantation. Between April 2007 and December 2012, 168 angina pectoris patients (320 de novo lesions) on HD were treated with DES. Major adverse cardiovascular events (MACE) and target lesion revascularization (TLR) were investigated at 3 years according to the HD duration (≤3 years, 83 patients; >3 years, 85 patients). The incidence of MACE was significantly higher in the long HD duration group (25.3 vs. 50.6 %; P = 0.001). Especially, sudden cardiac death (SCD) was significantly higher in the long HD duration group (3.6 vs. 16.5 %; P = 0.006). On the other hand, the rates of TLR were similar between the two groups (12.0 vs. 14.1 %; P = 0.69). Cox’s proportional hazard analysis revealed that HD duration (HR 1.08 per year, 95 % CI 1.03–1.13, P = 0.002), β-blocker use (0.28, 0.17–0.46, P < 0.001), and diabetes mellitus (2.10, 1.23–3.56, P = 0.007) were independent predictors of MACE. Longer HD duration did not affect TLR; however, SCD was significantly higher in the long HD duration group.     

Relationship between HRV measurements and demographic and clinical variables in a population of patients with atrial fibrillation

Little is known about the role of HRV in atrial fibrillation (AF) patients. Aim of our study was to assess the relationship between HRV measurements and demographic and clinical variables in a population of 274 AF patients. We selected all consecutive patients with persistent/permanent AF among whom had performed a Holter ECG in our Department from April 2010 to April 2015. Time-domain analysis of HRV was evaluated. Demographic and clinical variables were collected for each patient. At multivariable logistic regression, a higher pNN50 was associated with ACE inhibitors/ARBs (p = 0.016) and a lower pNN50 with obesity (p = 0.037) and higher heart rate (HR) (p < 0.0005). A higher RMSSD was associated with ACE inhibitors/ARBs (p = 0.001), digitalis (p < 0.0005) and beta-blockers (p = 0.002) and a lower RMSSD with a higher HR (p < 0.0005). A higher SDNN_i was associated with ACE inhibitors/ARBs (p < 0.0005), digitalis (p < 0.0005) and beta-blockers (p = 0.002) and a lower SDNN_i with dysthyroidism (p = 0.048) and higher HR (p < 0.0005). A higher SDANN was associated with non-dihydropyiridine calcium-channel-blockers (p = 0.002) and ACE inhibitors/ARBs (p = 0.002) and a lower SDANN with hypertension (p = 0.034), obesity (p = 0.011), stroke (p = 0.031), pneumonia (p = 0.005) and higher HR (p < 0.0005). A higher SDNN was associated with ACE inhibitors/ARBs (p < 0.0005), digitalis (p < 0.0005) and beta-blockers (p = 0.022) and a lower SDNN with obesity (p = 0.012), pneumonia (p = 0.049) and higher HR (p < 0.0005). Our study showed that, in AF patients, there is a direct relationship between some clinical variables and HRV measurements; as for patients with sinus rhythm, even in AF patients this relationship seemed to reflect the autonomic nervous system activity.     

Differential impact of peripheral endothelial dysfunction on subsequent cardiovascular events following percutaneous coronary intervention between chronic kidney disease (CKD) and non-CKD patients

Chronic kidney disease (CKD) status might modify the predictive effect of peripheral endothelial dysfunction on cardiovascular events after percutaneous coronary intervention (PCI). The aim of this study was to examine the differential effect of peripheral endothelial dysfunction on clinical outcome after PCI between CKD and non-CKD patients. We conducted a cohort study of 435 patients following PCI. CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m². Peripheral endothelial dysfunction was examined using reactive hyperemia-peripheral arterial tonometry index (RHI), and we divided patients into low- and high-natural logarithmic RHI (Ln-RHI) group. The endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, ischemic stroke, hospitalization due to unstable angina pectoris, and coronary revascularization. A total of 56 patients had a cardiovascular event. Patients who suffered a cardiovascular event had significantly lower Ln-RHI than other patients in the non-CKD group (0.46 ± 0.18 versus 0.60 ± 0.25; P = 0.002). Kaplan–Meier analysis demonstrated a significantly higher probability of cardiovascular events in low Ln-RHI patients in the non-CKD group (log-rank test: P = 0.003). Multivariate Cox proportional hazards analysis identified Ln-RHI as an independent and significant predictor of future cardiovascular events in the non-CKD group (HR: 0.096; 95 % CI 0.02–0.47; P = 0.004) but not in the CKD group. There was a differential effect of peripheral endothelial dysfunction on clinical outcome after PCI between CKD and non-CKD patients, and peripheral endothelial dysfunction significantly correlates with subsequent cardiovascular events after PCI in non-CKD patients.     

Genetic variant of <Emphasis Type="BoldItalic">IL-10RA</Emphasis> and susceptibility to rheumatoid arthritis in a Chinese population

The aim of this study was to investigate the relationship between the single-nucleotide polymorphisms (SNPs) of interleukin 10 alpha receptor (IL10RA) gene and rheumatoid arthritis (RA) in a Chinese population. We examined 533 RA patients and 958 subjects as a control group. Three IL-10RA SNPs (rs9610, rs2229113 and rs3135932) were genotyped using TaqMan genotyping assays on Fluidigm 192.24 system. The IL-10RA rs9610 A allele was increased in patient group compared with control subjects (OR = 1.232, 95 % CI = 1.052–1.442, p = 0.030). Significant difference in genotype distribution was found in RA patients and controls (χ2 = 15.32, p < 0.001). We also discovered a statistical significance under the dominant model (GG + AG versus AA: OR = 0.676, 95 % CI = 0.546–0.837, p < 0.001). However, no significant difference was discovered in the recessive model (GG versus AG + AA: OR = 1.013, 95 % CI = 0.754–1.361, p = 0.932). Interestingly, significant differences were detected both in the allele and genotype frequencies of rs9610 between anti-CCP positive patients and anti-CCP negative patients (χ2 = 7.209, p = 0.007; χ2 = 9.061, p = 0.011; respectively). We also found a significant difference in genotype frequency at rs9610 in females compared with males (χ2 = 7.658, p = 0.022). Unfortunately, we failed to find any significant results between two IL-10RA SNPs (rs2229113 and rs3135932) and RA susceptibility. The findings suggest that IL-10RA rs9610 polymorphism might contribute to RA susceptibility.     

Impacts of nicorandil on infarct myocardium in comparison with nitrate: assessed by cardiac magnetic resonance imaging

In this pilot study, we compared the infarct and edema size in acute myocardial infarction (MI) patients treated by nicorandil with those treated by nitrate, using cardiac magnetic resonance (CMR) imaging. Fifty-two acute MI patients who underwent emergency percutaneous coronary intervention (PCI) were enrolled, and were assigned to receive nicorandil or nitrate at random just before reperfusion. For the assessment of infarct and edema areas, short-axis delayed enhancement (DE) and T2-weight (T2w) CMR images were acquired 6.1 ± 2.4 days after the onset of MI. A significant correlation was observed between the peak creatinine kinase (CK) level and the infarct size on DE CMR (r = 0.62, p < 0.05), as well as the edema size on T2w CMR (r = 0.70, p < 0.05) in patients treated by nicorandil (28 patients). A similar correlation was seen between the peak CK level and the infarct size on DE CMR (r = 0.84, p < 0.05), as well as the edema size on T2w CMR (r = 0.84, p < 0.05) in patients treated by nitrate (24 patients). The maximum CK level was significantly lower in patients treated by nicorandil rather than nitrate (1991 ± 1402, 2785 ± 2121 IU/L, respectively, p = 0.03). Both the edema size on T2w CMR and the infarct size on DE CMR were significantly smaller in patients treated by nicorandil rather than nitrate (17.7 ± 9.9, 21.9 ± 13.7 %; p = 0.03, 10.3 ± 6.0, 12.7 ± 6.9 %, p = 0.03, respectively). The presence and amount of microvascular obstruction were significantly smaller in patients treated by nicorandil rather than nitrate (39.2, 64.7 %; p = 0.03; 2.2 ± 1.3, 3.4 ± 1.5 cm²; p = 0.02, respectively). Using CMR imaging, we demonstrated that the complementary use of intravenously and intracoronary administered nicorandil during PCI favorably acts more on the damaged myocardium after MI than nitrate. We need a further powered prospective study on the use of nicorandil.     

Comparison between drug-coated balloon angioplasty and second-generation drug-eluting stent placement for the treatment of in-stent restenosis after drug-eluting stent implantation

Even though drug-coated balloon (DCB) angioplasty has emerged as a treatment option for drug-eluting stent in-stent restenosis (DES–ISR), the most effective treatment strategy for DES–ISR is still under debate. Therefore, we compared long-term clinical outcomes following DCB treatment of DES–ISR with those following 2nd-generation drug-eluting stent (DES) treatment. We identified 248 DES–ISR lesions in 238 patients that were treated with either 2nd-generation DES implantation (n = 56) or DCB angioplasty (n = 192). We compared the incidences of major adverse cardiac events (MACEs) in the two groups during the 2-year period following treatment. MACE was defined as cardiac death, non-fatal myocardial infarction, or target-vessel revascularization. The percentage of patients with diabetes and the mean age of patients in the DCB group were greater than in the DES group. The DCB group also had a smaller reference vessel diameter. The DES group had a larger post-intervention minimal luminal diameter. We found no significant difference in the MACE rate between the two groups during the 2 years following treatment (11.0 % in the DCB group vs. 8.9 % in the DES group, p = 0.660). Reference segment diameter was the only independent predictive factor for MACE in the post-treatment period (hazard ratio 0.35, 95 % confidence interval: 0.15–0.82, p = 0.016). Clinical efficacy of DCB angioplasty for treatment of DES–ISR was comparable to that of 2nd-generation DES implantation as measured by the rate of MACEs in the two groups. Reference segment diameter was the only statistically significant independent predictor for MACE in the 2-year period following treatment.     

Moderate vasomotor response to acetylcholine provocation test as an indicator of long-term prognosis

The acetylcholine (ACh) provocation test (ACh-test) is used for the diagnosis of vasospastic angina (VSA). However, subjects often show a moderate spasm (MS) response for which diagnosis of VSA is not definitive, and the clinical significance of this response is unknown. We assessed moderate coronary vasomotor response to the ACh test as an indicator of long-term prognosis. A total of 298 consecutive patients who underwent the ACh test for suspected VSA were retrospectively investigated. Coronary spasm severity after intracoronary administration of isosorbide dinitrate was evaluated by measuring epicardial coronary artery diameter reduction after ACh injection. Patients were divided into three groups according to the diameter reduction during the ACh test: severe spasm (SS) showing ≥75 % diameter reduction, MS showing ≥50 % diameter reduction, and others (N). In Kaplan–Meier analysis, the major adverse cardiac event (MACE) rates with a median follow-up of 4.6 years were significantly worse in SS (11.1 %) and MS (8.5 %) than N (1.9 %), (SS vs N; P = 0.009, MS vs N; P = 0.029). Significant difference in MACE rates was not observed between SS and MS (P = 0.534). Cox regression analysis revealed that MS remained an independent predictor of MACE after adjustment for other confounders (HR: 7.18, 95 % CI 1.42–36.4, P = 0.017). Patients with MS by ACh test had a cardiac event rate comparable with that of patients with SS and significantly worse than that of patients with normal vasomotor responses.     

Correlation of NLRP3 with severity and prognosis of coronary atherosclerosis in acute coronary syndrome patients

We decided to assess the prognostic value of NLRP3 inflammasome level in acute coronary syndrome (ACS) patients and whether it was related to coronary atherosclerotic severity. Study population included one-hundred and twenty-three (123) subjects. Peripheral blood monocyte NLRP3 protein level was correlated with clinical presentation, angiographic characteristics and its scoring systems as well as GRACE and TIMI risk scores. Follow-up for major adverse cardiac events (MACE) was carried out at 180 days. Peripheral blood monocyte NLRP3 was found to be elevated in ACS patients (P < 0.05) and showed positive correlation with GRACE score (r = 0.619), TIMI score (r = 0.580), SYNTAX score (r = 0.550), Clinical SYNTAX score (r = 0.564) and Gensini score (r = 0.516). NLRP3 was also increased with increasing number of vessels, the number of lesions present and the presence bifurcation lesions (P < 0.05). Multivariate Cox regression analysis showed NLRP3 to be an independent predictor of MACE (P = 0.043). Kaplan–Meier analysis and receiver operating characteristic curves for NLRP3 showed good predictive value for MACE. There is a positive correlation of NLRP3 level with severity of coronary atherosclerosis. NLRP3 level is a promising prognostic utility and is efficient in event prediction for MACE.     

Association between <Emphasis Type="Italic">SLC2A9</Emphasis> (<Emphasis Type="Italic">GLUT9</Emphasis>) gene polymorphisms and gout susceptibility: an updated meta-analysis

The relationship between the SLC2A9 (solute carrier family 2, member 9) gene polymorphisms and gout was still inconsistent among the individual genetic association studies. Therefore, this present research was aimed to systematically evaluate the association between SLC2A9 gene polymorphisms and gout susceptibility. Relevant studies were enrolled by searching databases systematically. The pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the associations. The heterogeneity between each of the studies was calculated by using the Q statistic methods, and Begg’s funnel plot and Egger’s tests were performed to evaluate publication bias. A total of 13 studies investigated four single nucleotide polymorphisms (SNPs) in SLC2A9 were included. In this study, we found that the allele C of rs3733591 was higher in patients than in controls in both all-pooled population [C vs. T: OR (95 % CI) = 1.432 (1.213–1.691)] and Asians-pooled population [C vs. T: OR (95 % CI) = 1.583 (1.365–1.835)]. The allele frequency C of s6449213 was lower in the gout patients than in controls in both all-pooled population and Caucasians-pooled population. Additionally, the allele frequency T of rs16890979 and the allele frequency C of rs1014290 were lower in gout patients than in controls. This study demonstrated that the genetic susceptibility for gout is associated with the SLC2A9 gene polymorphisms. Four of them except for the rs3733591 are protective SNPs in Caucasians, and rs16890979 and rs1014290 are protective SNPs in both Caucasians and Asians, while rs3733591 may be susceptibility SNP in Asians.