Inflammatory gene haplotype-interaction networks involved in coronary collateral formation.

OBJECTIVES: Formation of collateral circulation is an endogenous response to atherosclerosis, and is a natural escape mechanism by re-routing blood. Inflammatory response- related genes underlie the formation of coronary collaterals. We explored the genetic basis of collateral formation in man postulating interaction networks between functional Single Nucleotide Polymorphisms (SNPs) in these inflammatory gene candidates. METHODS: The contribution of 41 genes as well as the interactions among them was examined in a cohort of 226 coronary artery disease patients, genotyped for 54 candidate SNPs. Patients were classified to the extent of collateral circulation. Stepwise logistic regression analysis and a haplotype entropy procedure were applied to search for haplotype interactions among all 54 polymorphisms. Multiple testing was addressed by using the false discovery rate (FDR) method. RESULTS: The population comprised 84 patients with and 142 without visible collaterals. Among the 41 genes, 16 pairs of SNPs were implicated in the development of collaterals with the FDR of 0.19. Nine SNPs were found to potentially have main effects on collateral formation. Two sets of coupling haplotypes that predispose to collateral formation were suggested. CONCLUSIONS: These findings suggest that collateral formation may arise from the interactions between several SNPs in inflammatory response related genes, which may represent targets in future studies of collateral formation. This may enhance developing strategies for risk stratification and therapeutic stimulation of arteriogenesis.

Effect of persistent use of antihypertensives on blood pressure goal attainment.

OBJECTIVE: Discontinuation rates with antihypertensive drugs in real life are high. The present study investigates the relationship between persistence with antihypertensive drugs (AHT) and blood pressure (BP) goal attainment in daily clinical practice. METHODS: In the PHARMO Record Linkage System, which includes drug dispensing and hospital records for > 2 million inhabitants in the Netherlands, new users of AHT > or = 18 years were identified for the period 1999-2004. Patients with elevated blood pressure (systolic BP > or = 140 and/or diastolic BP > or = 90 mmHg) within 6 months prior to onset of AHT treatment and a BP measurement within 6-12 months of treatment onset were included in the study cohort. Persistent AHT use was determined by summing the number of days of continuous treatment (gap between dispensings < 30 days) from start of treatment onwards. Patients with a BP below 140/90 mmHg at the first BP measurement within 6-12 months of treatment onset were defined as having attained goal. RESULTS: The study included 1271 patients with a mean systolic BP of 174 +/- 22 mmHg and a mean diastolic BP of 100 +/- 12 mmHg. Persistent AHT use was associated with a 40% increased chance of BP goal attainment (RR(adj) = 1.41; 95% CI: 1.08-1.85) after adjustment for gender, age, systolic blood pressure at start, and time to the BP measurement. CONCLUSION: Persistent use of AHT leads to increased blood pressure goal attainment in daily clinical practice.

Treatment with inhaled corticosteroids in asthma is too often discontinued.

PURPOSE: To study persistence with inhaled corticosteroids (ICS) and its determinants in asthma-patients. METHODS: From the PHARMO database, asthma-patients (age < 35 years) with a first dispensing for ICS in 1999-2002 and > or = 2 dispensings in the first year were included. Persistence during the first year was defined as the number of days from start to time of first failure to continue renewal of the initial ICS. Potential determinants of persistence were assessed at ICS-start and 1 year before. RESULTS: The study-cohort included 5563 new users of single ICS and 297 of fixed-combined ICS. Less than 10% of patients using single ICS and 15% of patients using fixed-combined ICS were persistent at 1 year. Similar persistence-rates were observed when stratified for age (children/adolescents: 0-18 years and adults: 19-34 years). Increased persistence with single ICS was observed with the type of ICS (budesonide), prescriber (specialist), prior use of long-acting beta-agonists, previous hospitalization for asthma, metered-dose inhaler, low starting-dose and once-daily dosing regimen at start. Persistence with fixed combined ICS-treatment increased with younger age and was decreased in patients having high starting-dose of ICS and prior use of antibiotics. CONCLUSION: New users of both single and fixed combined ICS have alarming low persistence rates with ICS-treatment in the first year of follow-up. Persistence was mainly related to patient factors, such as severity of disease, and to treatment-related factors, such as once-daily dosing frequency.

Quantity and quality of potential drug interactions with coumarin anticoagulants in the Netherlands.

OBJECTIVE: Coumarin anticoagulants are prone to potentially life-threatening drug-drug interactions due to a combination of unfavorable properties. However, real life data on the actual occurrence are scarce. The aim of this study was to quantify and qualify potential drug interactions with coumarin anticoagulants in daily practice. METHODS: A cohort study including all users of phenprocoumon or acenocoumarol during the period 1991-2003 in the PHARMO Record Linkage System. All 24 individual drugs and 11 drug groups interacting with coumarins according to central database used in the Dutch pharmacies were considered. MAIN OUTCOME MEASURE: Frequency and type of potential drug interactions during anticoagulant therapy with coumarins. RESULTS: 48,627 out of 76,455 mainly acenocoumarol-users (64%) were dispensed at least one potentially interacting drug (PID) during anticoagulant therapy. About 35% of these cases were dispensed a (very) strongly interacting drug, whereas 3% were dispensed a contraindicated drug. Antibacterial drugs and NSAIDs (39% and 37% of all users, respectively) were the most frequently dispensed PIDs. CONCLUSION: Potential drug interactions with coumarins frequently occur in daily practice, confronting two-thirds of patients with an increased risk of bleeding. To a large part, this is attributable to commonly prescribed medication like antibacterial drugs and NSAIDs. This situation substantiates the need for proper monitoring or new anticoagulants with less drug-drug interactions.

Analysis of case-cohort data: a comparison of different methods.

OBJECTIVE: The case-cohort design combines the advantages of a prospective cohort study and the efficiency of a case-control design. Usually a Cox proportional-hazards model is used for the analyses. However, adaptation of the model is necessary because of the sampling. We compared three methods that were proposed in the literature, which differ in weighting of study subjects: Prentice's, Barlow's, and Self and Prentice's method. STUDY DESIGN AND SETTING: In a cohort of 17,357 women we studied the relationship between body mass index and cardiovascular disease (n=821) with varying subcohort sizes (sampling fraction=0.005, 0.01, 0.05, 0.10, 0.15). RESULTS: Even with a sampling fraction of 0.01, all three methods showed identical estimates and standard errors (SE). With sampling fractions >or=0.10, results of the case-cohort analyses were similar to the full-cohort analyses. With simulations, the three methods provided different results if the full cohort is small (<1,250 subjects, subcohort=10%, 8% failures) or if the subcohort size was smaller than 15% (full cohort of 1,000 observations, 8% failures). The difference between the methods did not change with the number of failures or with different effect sizes. CONCLUSION: In the above-mentioned situations, the effect estimates and SE of Prentice's method most resembled the estimates of the full-cohort estimates.

Enhanced persistence with tiotropium compared with other respiratory drugs in COPD.

BACKGROUND: Tiotropium is a once-daily inhaled anticholinergic maintenance treatment with demonstrated effectiveness in chronic obstructive pulmonary disease (COPD). OBJECTIVE: To compare persistence of tiotropium-use with other inhaled respiratory drugs in COPD in current clinical practice. METHODS: The PHARMO database includes, among others, drug-dispensing and hospital discharge records for 2> or = million subjects in the Netherlands. All probable COPD-patients were identified by new respiratory drug use (age >54 years) or COPD-hospitalisations. New users of tiotropium, ipratropium, long-acting beta-agonists (LABAs), or fixed combination of LABA and inhaled corticosteroids (LABA+ICS), in 1998-2003, were included in the study. Persistence was assessed quarterly during the first year of follow-up. Patients with a proportion of days covered (PDC) > or =80% were considered persistent. Persistence was analysed using generalised estimating equations model. RESULTS: About 37% of new users of tiotropium continued treatment for 1 year, compared with 14% for ipratropium, 13% for LABA, and 17% for LABA+ICS. Multivariate analyses showed that tiotropium-users were 2-3 times more persistent with their therapy than patients using ipratropium (relative risk [RR]: 2.0; 95% confidence interval [CI]: 1.8-2.3), LABA (RR: 2.9; 95% CI: 2.4-3.6), or LABA+ICS (RR: 2.4; 95% CI: 2.1-2.8), respectively. Sub-analyses in patients with a prior hospitalisation for COPD showed that 1-year persistence rates were increased for all treatments (varying from 33% for patients using LABA+ICS to 61% for patients using tiotropium), while persistence with tiotropium was again 2-3 times higher compared with other treatments. CONCLUSION: Persistence with tiotropium was higher compared to other inhaled respiratory drugs in COPD in clinical practice.

Coronary collateral circulation: the effects of smoking and alcohol.

OBJECTIVE: The presence or absence of coronary collaterals is of vital importance during acute ischemia. Smoking and alcohol have been suggested to play a role, but data are scarce. We examined the extent to which smoking and alcohol use affect the presence of coronary collateral circulation. METHODS: Cross-sectional study in 242 patients, admitted for elective PTCA. Smoking was defined as past or current. Pack years were calculated and categorized into never-smokers (reference-category): <10, 10-19, 20-29, and >or=30 pack years. Alcohol consumption was defined as past or current, and categorized into never-users (reference-category): <1, 1-10, 11-20, and >or=21 units per week (UPW). Collaterals were graded with Rentrop's classification. Coronary collateral presence was defined as Rentrop-grade >or=1. RESULTS: Current smoking (odds ratio (OR) 4.17; 95% confidence interval (CI) 1.79-9.71) was positively associated, while pack years of smoking was not related. Current alcohol intake showed a J-shaped tendency with coronary collateral presence, while past moderate alcohol consumption was inversely associated (OR 0.19; 95% CI 0.04-0.98). CONCLUSIONS: Smoking and (to some extent) alcohol use are associated with collateral presence. The results support the view that life-style factors may affect the formation of coronary collaterals in patients with ischemic cardiac disease.

Determinants and prognostic significance of collaterals in patients undergoing coronary revascularization.

There is evidence that coronary collaterals improve the prognosis in patients with acute myocardial infarction (MI). However, there is limited clinical information on the protective role of collaterals in patients with stable coronary artery disease. This information may help risk stratification and the development of novel therapies, such as arteriogenesis and angiogenesis. The relation between collaterals and cardiac death or MI at 1 year after coronary revascularization was studied in 561 patients who were enrolled in a randomized study that compared stent implantation with bypass grafting. Collaterals were assessed on an angiogram using Rentrop's classification and considered present with a Rentrop grade >1. Unadjusted and adjusted odds ratios for cardiac death or MI at 1 year were calculated using univariate and multivariate regression analyses. In addition, determinants of collaterals were assessed using univariate and multivariate analyses. Collaterals were present in 176 patients (31%). The adjusted odds ratio of cardiac death or infarction was 0.18 (95% confidence interval 0.04 to 0.78) in the presence of collaterals. Independent determinants of collaterals were age (odds ratio 0.97, 95% confidence interval 0.95 to 0.99), multivessel disease (odds ratio 1.60, 95% confidence interval 1.02 to 2.51), impaired ventricular function (odds ratio 1.85, 95% confidence interval 1.04 to 3.29), type C lesion (odds ratio 3.72, 95% confidence interval 2.33 to 5.95), and stenosis severity >90% (odds ratio 9.08, 95% confidence interval 4.65 to 17.73). In conclusion, in patients with a low risk profile, the presence of collaterals protects against cardiac death and MI at 1 year after coronary revascularization. Variables that reflect the duration and severity of the atherosclerotic and ischemic burden determine their presence.

Cardiac ischemic score determines the presence of coronary collateral circulation.

PURPOSE: The presence of coronary collaterals is of vital importance during acute ischemia, however, marked interindividual variability exists. We examined the extent to which the burden of cardiac ischemia, expressed as a cardiac ischemic score, affects coronary collateral presence. METHODS: Cross-sectional study in 244 patients, admitted for elective coronary angioplasty. Collaterals were graded with Rentrop's classification. Coronary collateral presence was defined as Rentrop-grade > or =1. The cardiac ischemic score (range 0-4) was calculated by adding 1 point for each of the following four clinical factors present: angina pectoris on exertion, angina pectoris during emotions, previous myocardial infarction, and previous coronary intervention. These four clinical factors were chosen because they can be easily assessed in every patient. We used logistic regression with adjustment for gender, age, hypertension, diabetes mellitus, and hyperlipidemia. RESULTS: The extent of the cardiac ischemic score (odds ratio 1.8 per score-point; 95% confidence interval 1.3-2.5) was strongly associated with coronary collateral presence. Additional adjustment for multivessel coronary disease left the relation essentially unchanged. Also, if the definition of collateral presence was limited to Rentrop-grade 2 and 3, results were effectively the same. CONCLUSION: The extent of the cardiac ischemic score determines the presence of coronary collaterals, and may provide a new index for simple assessment of collateral vascular development.

Prognostic significance of coronary collaterals in patients with coronary heart disease having percutaneous transluminal coronary angioplasty.

We examined the presence and extent of coronary collaterals as a prognostic determinant of cardiovascular outcome in a prospective case-cohort study of 655 patients admitted for elective coronary angioplasty. In patients with ischemic heart disease, the angiographic presence of coronary collaterals may mark an unfavorable prognosis, particularly in relatively high-risk patients.

Presence of the metabolic syndrome does not impair coronary collateral vessel formation in patients with documented coronary artery disease.

OBJECTIVE: The metabolic syndrome confers an increased risk for cardiovascular morbidity and mortality. The presence of coronary collaterals may have beneficial effects during myocardial ischemia and may improve cardiovascular outcome in patients with coronary artery disease. Impaired collateral formation could be one of the reasons for the increased cardiovascular risk in patients with the metabolic syndrome. The aim of the present study was to determine the influence of the metabolic syndrome and insulin resistance on the presence of coronary collaterals. RESEARCH DESIGNS AND METHODS: We conducted a cross-sectional study in 227 patients referred for elective percutaneous transluminal coronary angioplasty to the University Medical Centre Utrecht. The metabolic syndrome was diagnosed according to Adult Treatment Panel III, and homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were used to quantify insulin resistance. Coronary collaterals were graded with Rentrop's classification. Rentrop grade >/=1 indicated the presence of collaterals. Results were adjusted for age, sex, and severity of coronary artery disease. RESULTS: A total of 103 patients (45%) were diagnosed with the metabolic syndrome. There was no association between the metabolic syndrome and the presence of coronary collateral formation (odds ratio [OR] 1.2 [95% CI 0.7-2.0]). Also, the degree of insulin resistance was not related to the presence of coronary collaterals. The OR for HOMA-IR (highest versus lowest tertile) was 0.7 (0.3-1.5) and for QUICKI (lowest versus highest tertile) 0.8 (0.4-1.6). CONCLUSIONS: The metabolic syndrome and insulin resistance are not related to the presence of coronary collaterals in patients with documented coronary artery disease.

Duodenal motility during a run-bike-run protocol: the effect of a sports drink.

OBJECTIVE: To examine the effect of a sports drink during strenuous exercise on duodenal motility and gastrointestinal symptoms. METHODS: In a cross-over design, seven male triathletes performed two 170-min run-bike-run tests at about 70% peak oxygen uptake (O(2peak)), with either a 7% carbohydrate (CHO) sports drink or tap water. Antroduodenal motility (phase III of the migrating motor complex; MMC) was measured with an ambulant manometry system. The effect of the two exercise trials on the first appearance of the MMC was assessed in the postprandial period. RESULTS: Exercise heart rate, percentage O(2peak) and loss of body mass did not differ significantly between the two trials. After the start of the exercise, the expected time before the first phase III occurrence, based on the actual energy intake of the last meal in the morning before exercise (1048 +/- 294 kcal), a fixed gastric emptying rate and a lag phase for solid food, was 183 +/- 113 min (mean +/- standard deviation [SD]). The real time period between the start of the exercise with CHO and the first phase III was 63 +/- 61 min, which was significantly shorter than that observed with tap water (152 +/- 59 min). Both real time periods were shorter than the expected time period of 183 +/- 113 min (P < 0.05). During exercise, the number of subjects with a phase III was higher with CHO than with tap water (n =6 v. n =1; P < 0.05). Also, the median number of phases III per hour with CHO was higher than with tap water (0.4 v. 0.0; P < 0.05). During cycling, significantly more phases III per hour (0.9) were measured than during running (0.2). All subjects reported one or more gastrointestinal symptoms during exercise, however, without a clear association with the mode of exercise or supplementation. CONCLUSIONS: Prolonged exercise results in gastrointestinal symptoms and a significant interruption of postprandial motility. Only the latter phenomenon depends on the mode of exercise and supplementation.