Prospective study of matrix metalloproteinase-9 and risk of myocardial infarction and stroke in older men and women

ObjectivesThe endopeptidase matrix metalloproteinase-9 (MMP-9) is implicated in atherosclerotic plaque rupture. We investigate prospective associations between MMP-9 and MI or stroke in an older general population cohort, accounting for established and novel cardiovascular risk factors.MethodsBaseline serum MMP-9 was measured in incident MI (n = 368) and stroke (n = 299) cases and two controls per case, ‘nested’ in prospective studies of 4252 men and 4286 women aged 60–79 years, sampled from General Practices in Britain in 1998–2000, with 7-year follow-up for fatal and non-fatal MI and stroke.ResultsGeometric mean MMP-9 was 528 ng/mL (IQR 397, 743) in MI cases compared to 501 ng/mL (IQR 370, 743) in controls, p = 0.10. Participants in the top compared to bottom third of MMP-9 levels had an age-adjusted odds ratio for MI of 1.53 (95% CI 1.09, 2.13), which attenuated to 1.18 (95% CI 0.81, 1.70) after adjustment for established and novel cardiovascular risk factors. There was weak evidence that OR differed according to pre-existing CVD; the OR for MI in 187 participants with pre-existing CVD was 2.20 (1.04, 4.64) and 1.24 (0.84, 1.82) in 715 participants without (LR test for interaction p = 0.06). Geometric mean MMP-9 levels were higher in stroke cases than controls; 522 ng/mL (IQR 363, 673) vs 487 (IQR 393, 704), p = 0.045; however adjustments similarly attenuated the associations.ConclusionsWhile serum MMP-9 is univariately associated with risk of MI and stroke, it is not a strong independent risk marker for either.     

Prolongation of the heart rate-corrected QT interval is associated with cardiovascular diseases: Systematic review and meta-analysis

BackgroundConflicting findings have described the association between prolonged heart rate-corrected QT interval (QTc) and cardiovascular disease.AimsTo identify articles investigating the association between QTc and cardiovascular disease morbidity and mortality, and to summarize the available evidence for the general and type 2 diabetes populations.MethodsA systematic search was performed in PubMed and Embase in May 2022 to identify studies that investigated the association between QTc prolongation and cardiovascular disease in both the general and type 2 diabetes populations. Screening, full-text assessment, data extraction and risk of bias assessment were performed independently by two reviewers. Effect estimates were pooled across studies using random-effect models.ResultsOf the 59 studies included, 36 qualified for meta-analysis. Meta-analysis of the general population studies showed a significant association for: overall cardiovascular disease (fatal and non-fatal) (hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.33–2.12; I² = 69%); coronary heart disease (fatal and non-fatal) in women (HR 1.27, 95% CI 1.08–1.50; I² = 38%; coronary heart disease (fatal and non-fatal) in men (HR 2.07, 95% CI 1.26–3.39; I² = 78%); stroke (HR 1.59, 95% CI 1.29–1.96; I² = 45%); sudden cardiac death (HR 1.60, 95% CI 1.14–2.25; I² = 68%); and atrial fibrillation (HR 1.55, 95% CI 1.31–1.83; I² = 0.0%). No significant association was found for cardiovascular disease in the type 2 diabetes population.ConclusionQTc prolongation was associated with risk of cardiovascular disease in the general population, but not in the type 2 diabetes population.     

Risk factors for foot ulcers—A cross sectional survey from a primary care setting in Brazil

AimsTo identify the prevalence of higher risk of foot ulceration and associated factors among patients with diabetes mellitus (DM) at primary health care services.MethodsIndividuals with DM, registered at primary health care services in a municipality in southern Brazil, were interviewed and underwent foot examinations. Their risk of ulceration was classified in accordance with the recommendations of the International Working Group on the Diabetic Foot. Poisson bivariate and multivariate analyses were performed and adjusted prevalence ratios (PR) and 95% confidence intervals (CI) were calculated.ResultsThe prevalence of higher risk of foot ulceration among the 337 interviewees was 27.9% (95% CI 23.1–32.9). The following factors were associated with this risk: having been diagnosed with DM for more than 10 years (Adjusted-PR 1.669; 95% CI 1.175–2.373; p = 0.004); having had previous diagnoses of acute myocardial infarction (Adjusted-PR 1.873; 95% CI 1.330–2.638; p < 0.001) and stroke (Adjusted-PR 1.684; 95% CI 1.089–2.604; p = 0.019); presenting interdigital mycosis (Adjusted-PR 1.539; 95% CI 1.030–2.300; p = 0.035) and calluses (Adjusted-PR 1.654; 95% CI 1.117–2.451; p = 0.012).ConclusionsThe prevalence of higher risk of ulceration was high, which reinforces the importance of continued education for health care professionals in order to prevent complications in the feet of these patients.     

The addition of pioglitazone in type 2 diabetics poorly controlled on insulin therapy: A meta-analysis

AimTo quantify the effect of a pioglitazone on glycemic control and lipid parameters, as well as the risk of adverse events when incorporated into the treatment regimen of patients with type 2 diabetes inadequately controlled on insulin.MethodsThe electronic databases PubMed, Embase and The Cochrance Library were searched systematically to identify randomized controlled trials (RCTs) of pioglitazone therapy in patients with type 2 diabetes mellitus (DM) inadequately controlled after treatment with insulin. Data on change of haemoglobin A1C (HbA1c), fasting plasma glucose (FPG), lipid parameters and risk of hypoglycemic, edema events were extracted from each study and pooled according to fixed effect model or random effect model in meta-analyses.ResultsFour RCTs including 1767 patients were included. The pooled estimate of change in HbA1c from baseline was 1.22% (95% CI 1.01–1.44, p < 0.001 vs. baseline) and of change in FPG from baseline was 1.63 mmol/l (95% CI 0.75–2.50, p < 0.001 vs. baseline). Pioglitazone significantly increased high-density lipoprotein cholesterol (HDL-c) level (0.2 mmol/L, 95%CI: 0.13–0.28) and low-density lipoprotein cholesterol (LDL-c) level (0.10 mol/L, 95%CI: 0.09–0.17), and lowered triglyceride (TG) level (0.05 mmol/L, 95%CI: 0.01–0.09). The odds of experiencing a hypoglycemic event in pioglitazone-treated arms was significantly higher than comparator treatments (RR = 1.57, 95% CI 1.12–2.20, p < 0.001). The case was the same with edema (RR = 2.42, 95% CI 1.67–3.50, p < 0.001).ConclusionsOur study implied that in patients with type 2 DM whose control is inadequate on insulin therapy, the additional pioglitazone could significantly improve glucose metabolism and might have a positive effect on important components of the lipid profile, which may have important implications in reducing the risk of cardiovascular disease, a major long-term complication in type 2 diabetes mellitus. Besides, the adverse events (AEs) were well tolerated.     

Aspirin in the primary prevention of cardiovascular disease on diabetic patients: Systematic review and meta-analysis

AimsThe publication of new trials brought additional data to the controversial topic of aspirin use in diabetic patients for primary prevention. Therefore, we aimed to systematically review all randomized controlled trials evaluating the clinical impact of aspirin in this setting.MethodsWe searched for randomized controlled trials (RCTs) evaluating the impact of aspirin in patients with diabetes in primary prevention, in MEDLINE, EMBASE, CENTRAL (November/2018). The primary outcomes were all-cause mortality and the composite outcome of major adverse cardiovascular events (MACE). A meta-analysis was performed deriving risk ratios (RR) and 95% confidence intervals (CI).ResultsAll-cause mortality was not significantly reduced with RR 0.96 (95% CI 0.90–1.03; 7RCT; 27,595 patients). Regarding MACE, there was an 8% risk reduction (RR 0.92, 95% CI 0.84-0.999; I² = 0%; 8RCT; 29,814 patients). The risks of major bleeding (RR 1.30, 95% CI 1.10–1.53; 2RCTs, 18,019 patients), and major GI bleeding (RR 1.39, 95% CI 1.08–1.80; 2RCTs, 18,019 patients) were significantly increased.The risks of cardiovascular mortality, myocardial infarction, stroke and amputation were not significantly different from control arm.ConclusionsAspirin use among diabetic patients in primary prevention appears was associated with increased risk of major bleeding, a modest decrease of MACE and lack of mortality benefit.     

Apolipoprotein E genotype predicts cardiovascular endpoints in dialysis patients with type 2 diabetes mellitus

ObjectiveCardiovascular disease (CVD) is the leading cause of death in patients with type 2 diabetes (T2DM) and end-stage renal disease (ESRD). Lipid metabolism is influenced by environmental and genetic factors. Among the latter, the apolipoprotein E (apoE) genotype is known to be associated with CVD risk and thus may affect cardiovascular outcome.Methods and resultsBased on the German Diabetes and Dialysis Study evaluating 1255 T2DM patients on haemodialysis (HD) (median follow-up 4 years), the impact of the apoE genotype (available for 1177 patients) on pre-specified, centrally adjudicated endpoints was investigated: all-cause mortality (n = 558), combined cardiovascular events (CVE: cardiac death, MI, stroke; n = 442), and cardiac death (n = 218). Patients with at least one ?4 allele (?4+) showed a 30% increased risk for CVE (HR 1.299, 95%CI 1.045–1.615, p = 0.018) and a 36% increased risk for cardiac death (HR 1.362, 95%CI 1.002–1.852, p = 0.048) compared to patients with no ?4 allele. Consistently, addition of ?4+ to a multivariate ROC model for risk prediction of CVE including atorvastatin treatment, history of cardiovascular disease, dialysis and lipoprotein parameters, hsCRP, and NT-pro-BNP increased the area under the curve from 0.666 (95%CI 0.634–0.698) to 0.671 (95%CI 0.639–0.702), p = 0.013.ConclusionsThe presence of the ?4 allele increases the risk for CVE and cardiac death in patients with T2DM and ESRD. Whether treatment strategies guided by apoE genotype will improve outcome needs to be evaluated in the future.     

Polymorphism in microRNA-196a2 contributes to the risk of cardiovascular disease in type 2 diabetes patients

AimsTo investigate the effect of the microRNA-196a2 gene polymorphism (rs11614913) on risk of cardiovascular disease in type 2 diabetes patients.MethodsWe examined 920 patients with diabetes and 834 healthy controls. All subjects were genotyped for the miRNA-196a2 SNP by polymerase chain reaction (PCR) and restriction analysis.ResultsThe genotype distribution among controls and patients was in Hardy–Weinberg equilibrium (p = 0.227 and 0.308, respectively). The frequency of the T allele was lower in patients than in controls (p = 0.044). The odds ratio 0.66 (95% CI 0.54–0.79) suggests an association of the T allele with decreased risk of T2DM. For the main purpose of the study, T2DM patients were stratified into patients with CVD and those without it. The T allele and TT genotype were significantly more frequent in patients with CVD compared to those without CVD (p = 0.013, p < 0.001, respectively). The odds ratio for the T allele in the CVD + subgroup vs. CVD − was 1.76 (1.35–2.30), p < 0.0001, mostly due to the overrepresentation of TT homozygotes. The highest risk of development of CVD was observed in the additive model for TT homozygotes (OR 3.33, 95% CI 2.05–5.42, p < 0.0001).ConclusionOur findings suggest that miRNA-196a2 T/C polymorphism (rs11614913) is associated with an increased risk of CVD in type 2 diabetes patients. This provides further insights on pathogenesis of cardiovascular disease in type 2 diabetes patients.     

The contribution of clinical and pathological predisposing factors to severe gastro-duodenal lesions in patients with long-term low-dose aspirin and proton pump inhibitor therapy

BackgroundPreventive strategies developed to avoid the complications of antiplatelet therapies recommend the evaluation of risk factors for gastrointestinal events and indicated gastroprotective strategies.AimWe aimed to assess the impact of predisposing factors - histological findings, concomitant drug consumption, comorbidities, symptoms, social habits, Helicobacter pylori infection - on severe gastro-duodenal lesions in patients with low-dose aspirin and concomitant protective therapy with proton pump inhibitors (PPI).MethodWe enrolled 237 patients with LDA and PPI therapy, referred for upper digestive endoscopy, divided into two groups according to the severity of their endoscopic lesions (172 patients with no or mild endoscopic lesions and 65 patients with severe endoscopic lesions).ResultsIn the univariate logistic regression model, the factors associated with severe gastro-duodenal lesions were gender (OR = 1.87, 95% CI: 1.04–3.41), anticoagulants (OR = 2.40, 95% CI: 1.26–4.53), gastric atrophy and/or intestinal metaplasia (OR = 1.85, 95% CI: 1.04–3.32), congestive heart failure (OR = 2.59, 95% CI: 1.16–6.62), anaemia (OR = 3.01, 95% CI: 1.67–5.47) and smoking (OR = 4.29, 95% CI: 1.57–12.32). In the final model, anticoagulants (p = 0.041 < 0.05) and anaemia (p = 0.019 < 0.05) were risk factors for severe lesions via multivariate regression analysis, while for active/inactive chronic gastritis and smoking a positive dependency with a tendency towards statistical significance (p < 0.10) was noticed for severe gastric lesions.ConclusionsIn patients treated with low-dose aspirin and gastroprotective therapy with proton pump inhibitors we have enough evidence to consider co-treatment with anticoagulants and anaemia important predictors for severe endoscopic lesions, while other factors such as inflammation in gastric biopsies, congestive heart failure, co-treatment with clopidogrel and smoking tended to have a positive influence on risk for severe gastro-duodenal lesions.     

Red blood cell distribution width and diabetes-associated complications

AimRed blood cell distribution width (RDW) is a marker of cardiovascular morbidity and mortality. However, there is little data on the relationship between RDW and diabetes-associated complications. The aim was to investigate whether there is any association between RDW, nephropathy, neuropathy and peripheral arterial disease (PAD) in a type 2 diabetic population.MethodsThis study included 196 diabetic patients with proliferative diabetic retinopathy. All subjects were investigated for diabetic nephropathy, diabetic neuropathy and PAD. Participants underwent 24-h blood pressure monitoring and were analysed for markers of the metabolic syndrome, inflammation, and insulin resistance.Results57% of the participants had diabetic nephropathy, 46% had diabetic neuropathy while 26% had PAD. No significant association was found between RDW, diabetic neuropathy and PAD (p = NS). However, RDW was strongly associated with diabetic nephropathy (p = 0.006), even following adjustment for potential confounding variables. Multivariate logistic regression analysis showed RDW (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.15–2.35, p = 0.006), estimated glomerular filtration rate (OR 0.98, 95% CI 0.96–0.99, p < 0.001), night-time diastolic blood pressure (OR 1.07, 95% CI 1.03–1.11, p = 0.001) and erythrocyte sedimentation rate (OR 1.03, 95% CI 1.004–1.05, p = 0.019) to be independently associated with diabetic nephropathy.ConclusionsThis is the first study to report lack of association between RDW, neuropathy and PAD in subjects with type 2 diabetes mellitus. More importantly, RDW was shown to be significantly associated with diabetic nephropathy in a type 2 diabetic population with advanced proliferative retinopathy independent of traditional risk factors, including diabetes duration and glycaemic control.     

Peri-aortic fat,cardiovascular disease risk factors,and aortic calcification: The Framingham Heart Study

ObjectivePerivascular fat through the secretion of paracrine and pro-inflammatory mediators may play a role in obesity-mediated vascular disease. We sought to examine associations between adipose tissue depots immediately surrounding the thoracic aorta, metabolic risk factors, and vascular calcification.MethodsIn participants free of cardiovascular disease (CVD) from the Framingham Heart Study Offspring cohort who underwent computed tomography (n = 1067, mean age 59 years, 56.1% women), thoracic peri-aortic fat depots were quantified. Visceral abdominal tissue (VAT) and calcification of the thoracic and abdominal aorta were also measured.ResultsPeri-aortic fat depots were correlated with body mass index, waist circumference (WC), VAT (all p < 0.0001), hypertension (p = 0.007), low HDL (p < 0.0001), serum triglycerides (p < 0.0001), impaired fasting glucose (p = 0.005), and diabetes (p = 0.02). These associations generally remained significant after adjustment for BMI and WC (all p-values < 0.05), but not after VAT adjustment. Thoracic aortic fat was associated with thoracic calcification in models containing VAT (OR 1.31, 95% CI 1.01–1.71, p = 0.04), but was not significant after adjustment for CVD risk factors (OR 1.16, 95% CI 0.88–1.51, p = 0.30). Thoracic aortic fat, however, was associated with abdominal aortic calcification (OR 1.48, 95% CI 1.11–1.98, p = 0.008) and coronary artery calcification (OR 1.47, 95% CI 1.09–1.98, p = 0.001) even in models including CVD risk factors and VAT.ConclusionsThoracic peri-aortic fat is associated with measures of adiposity, metabolic risk factors, and coronary and abdominal aortic calcification.     

Dipeptidyl peptidase-4 inhibitors and protection against stroke: A systematic review and meta-analysis

BackgroundType 2 diabetes mellitus (T2DM) is associated with an increased risk of stroke and an unfavourable outcome following stroke. Apart from pioglitazone, glucose-lowering modalities have not been shown to protect against stroke. Nevertheless, there is evidence from experimental studies of potential neuroprotective effects with dipeptidyl peptidase (DPP)-4 inhibitors, especially if treatment starts before stroke.ObjectiveTo perform a meta-analysis of available evidence regarding the risk of stroke in individuals taking DPP-4 inhibitors.MethodsAll available data from prospective randomized placebo-controlled trials involving DPP-4 inhibitors in T2DM patients published up to December 2015 were considered. The included trials reported data on the incidence of stroke with a recruitment rate of at least 100 diabetes patients and a follow-up of at least 12 weeks.ResultsA total of 19 small randomized clinical trials (RCTs) evaluating the efficacy and safety of gliptins (n = 9278), along with three multicentre prospective double-blind placebo-controlled RCTs assessing cardiovascular outcomes as the primary endpoint and involving 36,395 T2DM patients, were included in the analysis. Pooled analysis of the small RCTs showed a non-significant trend towards benefit with DPP-4 inhibitors against stroke [odds ratio (OR): 0.639, 95% confidence interval (CI): 0.336–1.212; P = 0.170]. In contrast, in the analysis of RCTs reporting on cardiovascular safety, there was no difference in the risk of stroke with gliptin treatment compared with a placebo (OR: 0.996, 95% CI: 0.850–1.166; P = 0.958).ConclusionThe promising data from experimental studies regarding cardioprotective gliptin-associated effects against stroke were not supported by available data from trials specifically looking at cardiovascular safety.     

Different impact of aspirin on renal progression in patients with predialysis advanced chronic kidney disease with or without previous stroke

BackgroundThe benefit of reducing the risk of stroke against increasing the risk of renal progression associated with antiplatelet therapy in patients with advanced chronic kidney disease (CKD) is controversial.MethodsWe enrolled 1301 adult patients with advanced CKD treated with erythropoiesis stimulating agents from January 1, 2002 to June 30, 2009 from the 2005 Longitudinal Health Insurance Database in Taiwan. All of the patients were followed until the development of the primary or secondary endpoints, or the end of the study (December 31, 2011). The primary endpoint was the development of ischemic stroke, and the secondary endpoints included hospitalization for bleeding events, cardiovascular mortality, all-cause mortality, and renal failure. The adjusted cumulative probability of events was calculated using multivariate Cox proportional regression analysis.ResultsAdjusted survival curves showed that the usage of aspirin was not associated with ischemic stroke, hospitalization for bleeding events, cardiovascular mortality or all-cause mortality, however, it was significantly associated with renal failure. In subgroup analysis, aspirin use was associated with renal failure in the patients with no history of stroke (HR, 1.41; 95% CI, 1.14–1.73), and there was a borderline interaction between previous stroke and the use of aspirin on renal failure (interaction p = 0.0565).ConclusionsThere was no significant benefit in preventing ischemic stroke in the patients with advanced CKD who received aspirin therapy. Furthermore, the use of aspirin was associated with the risk of renal failure in the patients with advanced CKD without previous stroke.     

CYP2C19*2/ABCB1-C3435T polymorphism and risk of cardiovascular events in coronary artery disease patients on clopidogrel: Is clinical testing helpful?

BackgroundStudies evaluating CYP2C19*2 and ABCB1-C3435T polymorphisms have shown conflicting results. We performed this meta-analysis to evaluate role of clinical testing for these polymorphisms in CAD patients on clopidogrel.Methods19,601 patients from 14 trials were analyzed. The endpoints were major adverse cardiovascular events (MACE), cardiovascular (CV) death, stent thrombosis (ST), myocardial infarction (MI), stroke and major bleeding. Combined relative risks (RR) with 95% confidence intervals (CI) were computed for each outcome by using standard methods of meta-analysis and test parameters were computed.ResultsCYP2C19*2 polymorphism was associated with higher risk of MACE [RR: 1.28, CI: 1.06–1.54; p = 0.009], CV death [RR: 3.21, CI: 1.65–6.23; p = 0.001], MI [RR: 1.36, CI: 1.12–1.65; p = 0.002], ST [RR: 2.41, CI: 1.69–3.41; p < 0.001]. No difference was seen in major bleeding events [RR: 1.02, CI: 0.86–1.20; p = 0.83]. Subgroup analysis showed similar results for elective PCI [RR: 1.34, CI: 1.01–1.76; p = 0.03], and PCI with DES [RR: 1.53, CI: 1.029–1.269; p = 0.03]. CYP2C19*2 polymorphism has very low sensitivity (28–58%), specificity (71–73%), positive predictive value (3–10%) but good negative predictive value (92–99%). ABCB1-C3435T polymorphism analysis revealed similar MACE [RR: 1.13, CI: 0.99–1.29; p = 0.06], ST [RR: 0.88, CI: 0.52–1.47; p = 0.63] and major bleeding [RR: 1.04, CI: 0.87–1.25; p = 0.62] in both groups.ConclusionIn CAD patients on clopidogrel therapy, CYP2C19*2 polymorphism is associated with significantly increased adverse cardiovascular events. However, due to the low positive predictive value, routine genetic testing cannot be recommended at present.     

Prevalence and risk factors for wheezing and allergic diseases in preschool children: A perspective from the Mediterranean coast of Turkey

ObjectivesThe aim of the present study was to determine the prevalence and risk factors of allergic diseases in preschool children from one of the biggest cities in the Mediterranean Region of Turkey.MethodsThe study population included 396 preschool children attending to urban daycare centres in Mersin. In the first stage, a comprehensive standardised questionnaire modified from the International Study of Asthma and Allergies in Childhood (ISAAC) was employed. In the second stage, serum food and inhalant specific IgE, and skin tests were performed in 45 children with frequent wheezing and 28 children with no wheezing.ResultsThe prevalence of ever wheezing, current wheezing, physician-diagnosed asthma, allergic rhinitis and eczema were 53% (210), 33.3% (132), 27.3% (108), 13.4% (53) and 8.3% (33), respectively. A family history of atopy (OR = 2.5, 95% CI: 1.3–4.7, p = 0.004), dampness at home (OR = 2.4, 95% CI: 1.2–4.8, p = 0.008), a history of intestinal parasites (OR = 4.3, 95% CI: 1.7–10.9, p = 0.002), previous history of pneumonia (OR = 6.9, 95% CI: 1.9–25.9, p = 0.004), initiation of complementary foods before the age of three months (OR = 6.1, 95%CI: 1.4–26.9, p = 0.02) and presence of food allergy (OR = 3.1, 95% CI: 1.1–9.2, p = 0.03) were found to be significant risk factors for physician-diagnosed asthma. The risk factors for frequent wheezing were maternal smoking during pregnancy (OR = 5.2, 95% CI: 0.9–28.7, p = 0.05) and high serum IgE levels (OR = 2.9, 95% CI: 0.9–9.0, p = 0.05) at borderline significance.ConclusionOur study was the first epidemiological study in preschool children in the Mediterranean region of Turkey and demonstrated a high prevalence of asthma and allergic diseases, probably related to humid climatic properties in addition to other environmental and genetic factors.     

Risk of cardiovascular toxicities in patients with solid tumors treated with sunitinib,axitinib, cediranib or regorafenib: An updated systematic review and comparative meta-analysis

BackgroundWe performed a systematic review and comparative meta-analysis of cardiovascular toxicities associated with sunitinib, axitinib, cediranib or regorafenib; oral multi tyrosine kinase inhibitors.Patients and methodsEligible studies included randomized phase II and III trials of patients with solid tumors on sunitinib, axitinib, cediranib or regorafenib describing daily events of hypertension, left ventricular dysfunction, bleeding or thrombosis.ResultsPatients treated with these four agents had a significantly increased risk of all-grade hypertension and bleeding. The RR of all-grade hypertension, bleeding, thrombosis and cardiac dysfunction were 2.78 (95% CI 2.03–3.81; p < 0.00001), 1.93 (95% CI 1.41–2.64; p < 0.00001), 0.85 (95% CI 0.60–1.19; p = 0.50), 2.36 (95% CI 0.95–5.87; p = 0.06), respectively. Exploratory subgroup analysis showed no effect of the agent used (sunitinib vs. axitinib vs. cediranib) in the risk of hypertension; while for bleeding, only the sunitinib subgroup RR was significant compared to axitinib or cediranib.ConclusionsOur meta-analysis has demonstrated that sunitinib, axitinib, cediranib and regorafenib are associated with a higher risk of developing all grade and high grade hypertension compared with control. While for bleeding, only the sunitinib subgroup RR was significant compared to axitinib or cediranib. Clinicians should be aware of these risks and perform regular cardiovascular monitoring.     

Haplotypes and 5A/6A polymorphism of the matrix metalloproteinase-3 gene in coronary disease: Case–control study and a meta-analysis

ObjectiveMatrix metalloproteinase-3 and its gene, MMP3, have been implicated in atherosclerotic diseases of coronary arteries. We conducted a haplotype analysis to examine the role of common variation of MMP3 in myocardial infarction (MI) and a meta-analysis to combine available evidence on the association between the 5A/6A polymorphism (rs3025058) and coronary diseases.Methods and resultsGenotype distributions of haplotype-tagging single nucleotide polymorphisms (rs522616, rs650108, rs569444, rs635746) and rs3025058 were not significantly different between a group with MI (n = 3657) and a control group (n = 1211) (p ≥ 0.24). Five major haplotypes were established, and their frequencies were not substantially different between the case and control groups (p ≥ 0.11). In a meta-analysis of 15 studies (10,061 cases, 8048 controls), the overall risk of coronary disease was not different between the carriers of the 5A allele and 6A6A genotype of rs3025058 (OR, 1.00; 95% CI, 0.85–1.19). Moderate trends of a reduced risk in the 5A allele carriers of European ancestry (OR, 0.87; 95% CI, 0.76–1.00) and an increased risk in the 5A allele carriers from East Asia (OR, 1.33; 95% CI, 0.94–1.90) were observed.ConclusionsIndividual polymorphisms and haplotypes of MMP3 were not associated with MI in a German case–control study. Evidence was obtained to suggest different risk effects of rs3025058 between Europeans and East Asians.     

Outcomes and Excess Costs among Patients with Cardiovascular Disease

ObjectiveTo report on two-year cardiovascular (CV) event rates and quantify the cost of cardiovascular disease using the Australian Reduction of Atherothrombosis for Continued Health (REACH) registry.MethodsProspective registry of 2873 patients with multiple risk factors (MRF), coronary artery disease (CAD), cerebrovascular disease (CerVD) and peripheral artery disease (PAD), recruited through 273 Australian general practitioners. Government reimbursement data from 2011 was used to calculate direct health care costs (pharmaceuticals, outpatient and hospitalisation costs). The main outcome of interest was two-year rates and associated excess costs of cardiovascular death, myocardial infarction, stroke, and hospitalisation for cardiovascular procedures.ResultsThe two year follow-up data were available for 2856 (99.4%) patients. Incidence of any hospitalisation and cardiovascular death was highest among those with previous history of PAD at baseline 49% (n = 126), and 5.1% (n = 13). Non-fatal cardiovascular events were highest among the PAD and CAD groups (21.8% (n = 56) and 14.1% (n = 297) respectively). Those with previous history of PAD and CerVD at baseline had the highest likelihood of CV death (OR = 2.53 (95% CI: 1.58–4.08) and OR = 1.61 (1.05–2.46) respectively) in comparison to other groups. Patients with PAD had the highest likelihood of vascular interventions OR = 3.11 (95% CI: 2.09–4.63) at two years. Overall, the mean (SD) direct expenditure over two years of follow-up per person was A$7544 (A$10,758). In the adjusted model, patients with CAD and PAD incurred A$1093 (95% CI A$24 – A$2072) and A$4890 (95% CI A$3105 – A$6869) more in mean total costs compared to patients with MRF.ConclusionsPatients with PAD had the highest likelihood of vascular interventions and CV death, and incurred high excess costs in comparison to other groups.     

Morphofunctional characteristics of the foot in patients with diabetes mellitus and diabetic neuropathy

AimsTo determine the structural and biomechanical characteristics associated with the conditions diabetes mellitus and diabetic neuropathy.MethodsObservational study of 788 patients conducted between February 2007 and February 2009, which included subjects with and without diabetes mellitus who had no active ulcer at enrollment. Demographic variables and the general and specific history of diabetes mellitus were recorded. The patient's foot type according to the Foot Posture Index, joint mobility and deformity were recorded.ResultsNo associations were found between the different foot types (neutral, pronated and supinated) and the structural and demographic variables at a general level, except for the pronated foot that was associated with a higher body mass index, longer suffering from diabetes and the presence of neuropathy [p < 0.001, OR (95% CI): 6.017 (4.198–8.624); p < 0.001, OR (95% CI): 1.710 (1.266–2.309); p = 0.010, OR (95% CI): 0.759 (0.615–0.937), respectively].ConclusionsThe confluence of risk factors such as neuropathy, body mass index, duration of diabetes and limited joint mobility in patients with diabetes mellitus and pronated foot may be a high-risk anthropometric pattern for developing associated complications such as Charcot foot. A prospective analysis of these patients is required to define the risk for developing Charcot neuroarthropathy.     

Metabolic syndrome and cardiovascular risk prediction in peripheral arterial disease

Background and aimsMetabolic syndrome (MetS) was reported to be associated with increased cardiovascular risk in various settings, however its prognostic impact in peripheral arterial disease (PAD) is scanty.Methods and resultsWe prospectively studied 173 patients with intermittent claudication and ankle/brachial index (ABI) <0.90, in whom MetS was defined using the criteria of both the revised version of the Adults Treatment Panel III (rATP III) and the International Diabetes Federation (IDF). Of these patients, 52.6% met the rATP III and 54.9% the IDF criteria for MetS. During a median follow-up of 31 months, 54 cardiovascular events occurred. Kaplan–Meier curves showed a greater incidence of ischemic events in patients with MetS than in those without. However, adjusted Cox analyses revealed that only IDF-MetS was independently associated with increased cardiovascular risk (HR = 1.91, 95% CI 1.03–3.51, p = 0.038). Kaplan–Meier curves for the four groups of patients delineated according to the bootstrapped ABI cut-off value (0.73) and the presence or absence of IDF-MetS revealed that the syndrome improved the predictive power of ABI alone. Actually, among patients with an ABI ≤ 0.73, those with IDF-MetS had a higher cardiovascular risk than those without the syndrome (HR = 2.55, 95% CI 1.22–5.12, p = 0.012). This was confirmed by c-statistic, which was 0.56 for ABI alone and increased to 0.65 (p = 0.046) when IDF-Mets was added to the pressure index.ConclusionIn PAD, IDF-MetS, but not rATP III-MetS, is associated with an increased risk of cardiovascular events. Furthermore, IDF-MetS adds to the prognostic value of ABI, currently the most powerful prognostic indicator in PAD.