Gender differences in the effects of cardiovascular drugs.

Although sex-specific differences in cardiovascular medicine are well known, the exact influences of sex on the effect of cardiovascular drugs remain unclear. Women and men differ in body composition and physiology (hormonal influences during the menstrual cycle, menopause, and pregnancy) and they present differences in drug pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics, so that is not rare that they may respond differently to cardiovascular drugs. Furthermore, women are also less often treated with evidence-based drugs thereby preventing optimization of therapeutics for women of all ages, experience more relevant adverse drug reactions than men, and remain underrepresented in most clinical trials. Thus, current guidelines for prevention, diagnosis, and medical treatment for cardiovascular diseases are based on trials conducted predominantly in middle-aged men. A better understanding of these sex-related differences is fundamental to improve the safety and efficacy of cardiovascular drugs and for developing proper individualized cardiovascular therapeutic strategies both in men and women. This review briefly summarizes gender differences in the pharmacokinetics and pharmacodynamics of cardiovascular drugs and provides recommendations to close the gaps in our understanding of sex-specific differences in drug efficacy and safety.

Co-expression of fibulin-5 and VEGF165 increases long-term patency of synthetic vascular grafts seeded with autologous endothelial cells.

Small caliber synthetic vascular grafts are commonly used for bypass surgery and dialysis access sites but have high failure rates because of neointima formation and thrombosis. Seeding synthetic grafts with endothelial cells (ECs) provides a biocompatible surface that may prevent graft failure. However, EC detachment following exposure to blood flow still remains a major obstacle in the development of biosynthetic grafts. We tested the hypothesis that induced expression by the seeded EC, of vascular endothelial growth factor165 (VEGF165) and of fibulin-5, an extracellular matrix glycoprotein that has a crucial role in elastin fiber organization and increase EC adherence to surfaces, may improve long-term graft patency. Autologous ECs were isolated from venous segments, and were transduced with retroviral vectors expressing fibulin-5 and VEGF165. The modified cells were seeded on expanded polytetrafluoroethylene (ePTFE) grafts and implanted in a large animal model. Three months after transplantation, all grafts seeded with modified EC were patent on a selective angiography, whereas only a third of the control grafts were patent. Similar results were shown at 6 months. Thus, seeding ePTFE vascular grafts with genetically modified EC improved long-term small caliber graft patency. The biosynthetic grafts may provide a novel therapeutic modality for patients with peripheral vascular disease and patients requiring vascular access for hemodialysis.

Post placement positional atrial fibrillation and peripherally inserted central catheters.

Arrhythmias are common in hospitalized patients and during surgery. We present a case of positional atrial arrhythmia related to a peripherally inserted central catheter (PICC). There are other documented case reports of ventricular tachycardia precipitated by body position changes with a PICC. The immediate correction of the arrhythmia with repositioning of the PICC strongly points to the PICC as the cause. This highlights the potential seriousness of cardiac arrhythmias precipitated by PICCs as well as the need for careful catheter placement and perioperative maintenance. Practitioners should consider PICC line tip position as a rare cause of positional atrial arrhythmias.

Development of a capsule endoscopy scoring index for small bowel mucosal inflammatory change.

BACKGROUND: Capsule endoscopy can identify small bowel mucosal inflammatory change. However, there has been no validated index for capsule endoscopy findings. This manuscript documents the development of such an index. AIM: To develop a capsule endoscopy scoring index for small bowel mucosal inflammatory change. METHODS: The index was created in four separate steps. First, parameters and descriptors of inflammatory change were identified. Secondly, blinded readers prospectively graded the presence or absence of each parameter on de-identified videos and graded a perceived global assessment of overall severity. Thirdly, the individual parameters and descriptors were ranked in order of severity. Fourthly, values for each parameter were created using the descent gradient methodology. The premise was to assure that the final numerical score reflected the global assessment and that the global assessment agreed with the ranking of finding severity. Results were compiled for the three categories: no or clinically insignificant change, mild change, and moderate or severe change. Thresholds were determined. RESULTS: The final index includes three parameters: villous oedema, ulcer and stenosis. A score <135 is designated normal or clinically insignificant mucosal inflammatory change, a score between 135 and 790 is mild, and a score > or = 790 is moderate to severe. CONCLUSION: This capsule endoscopy score provides a common language to quantify small bowel inflammatory changes.

High frequency of vitamin B12 deficiency in asymptomatic individuals homozygous to MTHFR C677T mutation is associated with endothelial dysfunction and homocysteinemia.

The aim of this study was to examine the association of homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation and vitamin B12 deficiency in 360 asymptomatic individuals and to investigate forearm endothelial function in C677T homozygotes. MTHFR C677T mutation and levels of vitamin B12, folic acid, and homocysteine were measured in study participants. Frequency of homozygosity for the C677T mutation was 67/360 (18.6%). Homocysteine levels were elevated in homozygous compared with heterozygous subjects or those without the mutation (20.6 +/- 18.8 vs. 9.4 +/- 3.2 mumol/l; P < 0.0001). The number of subjects with vitamin B12 deficiency (<150 pmol/l) was significantly higher among the homozygote than the heterozygote subjects or subjects without mutation [20/67 (29.8%) vs. 27/293 (9.2%); P < 0.0001]. Homozygote subjects had 4.2 times higher probability of having B12 deficiency (95% confidence interval = 2.1-8.3). Forearm endothelial function was assessed in 33 homozygote and 12 control subjects. Abnormal endothelial function was observed in homozygous subjects and was worse in homozygote subjects with vitamin B12 deficiency. Endothelial function was normalized after B12 and folic acid treatment. We found that homozygosity for the C677T mutation is strongly associated with B12 deficiency. Coexistence of homozygosity for the C677T mutation and B12 deficiency is associated with endothelial dysfunction and can be corrected with vitamin B12 and folic acid treatment.

Integration of computed tomographic coronary angiography into the invasive laboratory and into interventional coronary procedures.

Computed tomographic coronary angiography (CTA) has rapidly evolved to a level where it can be used not only for the diagnosis or exclusion of coronary artery disease, but also to a stage at which the value of CTA derived images in the catheterization laboratory during invasive procedures is under examination. This review will examine the possible role of CTA in selection of patients for invasive coronary angiography (ICA), in the planning of diagnostic ICA in patients who have undergone previous revascularization and the role of CTA in planning percutaneous interventional and surgical procedures.

Effects of fibulin-5 on attachment, adhesion, and proliferation of primary human endothelial cells.

BACKGROUND: Fibulin-5 is a novel extracellular protein that is thought to act as a bridging peptide between elastin fibers and cell surface integrins in blood vessel wall. Fibulin-5 binding to endothelial cell (EC) surface integrins may effect cell proliferation and cell attachment to extracellular matrix (ECM) or to artificial surfaces. In this paper, we describe the effects of fibulin-5 on attachment, adhesion, and proliferation of primary human EC. After demonstrating that fibulin-5 over-expression inhibited EC proliferation, we tested the hypothesis that co-expression of fibulin-5 and VEGF165 will lead to unique EC phenotype that will exhibit increased adherence properties and retain its proliferation capacity. METHODS AND RESULTS: Fibulin-5 and VEGF165 gene transfer to primary human saphenous vein endothelial cells was accomplished using retroviral vectors encoding the two genes. Transgene expression was verified using immunohistochemistry, Western blotting, and ELISA. Fibulin 5 over-expression tended to improve immediate EC attachment (30 min after seeding) and improved significantly adhesion (>40%) under shear stress tested 24h after EC seeding. The effects of fibulin-5 and VEGF165 on EC proliferation in the presence or absence of basic FGF were also tested. EC expressing fibulin-5 had reduced proliferation while VEGF165 co-expression ameliorated this effect. CONCLUSION: Fibulin-5 improved EC attachment to artificial surfaces. Dual transfer of fibulin-5 and VEGF165 resulted in EC phenotype with increased adhesion and improved proliferation. This unique EC phenotype can be useful for tissue engineering on endovascular prostheses.

Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events.

BACKGROUND: Atrial fibrillation (AF) is the most frequently occurring cardiac arrhythmia with often serious clinical consequences. Many patients have contraindications to anticoagulation, and it is often underused in clinical practice. The addition of clopidogrel to aspirin (ASA) has been shown to reduce vascular events in a number of high-risk populations. Irbesartan is an angiotensin receptor-blocking agent that reduces blood pressure and has other vascular protective effects. METHODS AND RESULTS: ACTIVE W is a noninferiority trial of clopidogrel plus ASA versus oral anticoagulation in patients with AF and at least 1 risk factor for stroke. ACTIVE A is a double-blind, placebo-controlled trial of clopidogrel in patients with AF and with at least 1 risk factor for stroke who receive ASA because they have a contraindication for oral anticoagulation or because they are unwilling to take an oral anticoagulant. ACTIVE I is a partial factorial, double-blind, placebo-controlled trial of irbesartan in patients participating in ACTIVE A or ACTIVE W. The primary outcomes of these studies are composites of vascular events. A total of 14000 patients will be enrolled in these trials. CONCLUSIONS: ACTIVE is the largest trial yet conducted in AF. Its results will lead to a new understanding of the role of combined antiplatelet therapy and the role of blood pressure lowering with an angiotensin II receptor blocker in patients with AF.

A pooled analysis to evaluate results of capsule endoscopy trials.

BACKGROUND AND STUDY AIM: Capsule endoscopy is a new tool in the evaluation of the small intestine. To speed evaluation and acceptance of this technology, the manufacturer (Given Imaging Ltd, Yoqneam, Israel) funded several trials. The data from these trials were collected at a central repository using a standardized reporting tool. Presentation of this data to the US Food and Drug Administration (FDA) in July 2003 led to the removal of the adjunctive term with regard to indication for capsule endoscopy, recognizing that the method is of independent importance for evaluating the small bowel. The aim of the present study was to combine the data from several capsule trials to help determine the yield and miss rate of capsule endoscopy for different diseases, compared with alternative diagnostic modalities. METHODS: Capsule studies were identified from a master database of funded studies. Studies were included in the pooled analysis if they reported a prospective comparison with another modality for evaluation of the small intestine. RESULTS: 32 studies with a total of 691 patients were found in the master database, of which 24 studies, representing 530 patients, met inclusion criteria and were entered into the pooled analysis. Prior to study entry, patients had undergone a mean of 6.77 diagnostic procedures, without findings. Of these 24 studies, 14 (involving 310 patients) were categorized as "bleeding" studies, and 10 studies (220 patients) as "nonbleeding small-bowel disorders" studies. The comparison procedure was push enteroscopy in 300 patients (in 45 for nonbleeding disorders), small-bowel series in 140 patients (in 125 for non-bleeding disorders), and colonoscopy with ileoscopy in 90 patients (50 for nonbleeding disorders). Overall analysis per patient showed new findings from capsule endoscopy in 50 % of patients; 17 % had new findings from the comparison method; in 22 % there were similar findings; and in 11 % there were no findings. A total of 1349 instances of disease were identified in the 530 examinations. Capsule endoscopy solely detected 87 % of the disease instances, while the comparison method solely detected 13 %. The yield for push enteroscopy alone was 14.8 %, for small-bowel series it was 9.9 %, and for colonoscopy it was 13.2 %. Capsule endoscopy missed 146 disease instances for a miss rate of 10 %; 989 were missed by the comparison methods for a miss rate of 73 %; and 214 were detected by both methods. CONCLUSION: Capsule endoscopy is the state of the art method for noninvasive detection of small-bowel disease.

Congenital bronchiolo-alveolar airway malformation in a cynomolgus macaque (Macaca fascicularis).

Pulmonary congenital anomalies in animals are rare. Previously reported malformations include accessory lung formation, pulmonary hypoplasia, pulmonary agenesis, and various forms of hamartoma. Congenital bronchiolo-alveolar airway malformation, a new entity, is described in a 1-day-old male cynomolgus macaque. This neonate experienced breathing difficulties shortly after birth and died while therapy was being administered. Grossly, the right lung was markedly increased in size, firm, and pink. Histopathologically, sections of right lung showed irregular bronchiole-like and alveolus-like structures. There was marked widening of alveolar septae by loosely arranged mesenchymal cells and many centrally located capillaries. Alveoli were lined by cuboidal epithelial cells. There were scattered islands of immature cartilage. A grossly enlarged lung containing bronchiole-like and alveolus-like structures, immature cartilage islands, and many capillaries within alveolar septae on histopathologic examination, is inconsistent with previously described congenital pulmonary anomalies in animals and humans.

Non-invasive computerised detection of acute coronary occlusion.

The goal of this study was to evaluate the role of a computerised, non-invasive ECG method for detecting acute coronary occlusion (ACO). Ninety-five standard ECG leads were recorded, before and during ACO, from 18 patients undergoing balloon angioplasty. ECG amplitude and derivative parameters were calculated for the ORS, ST and T components of the ECG signal, before and during ACO. Results were obtained for each lead. Sensitivity of the standard visual ECG analysis for detecting ACO was 48%, whereas the percentage of conventional ECG changes during baseline was 14%. For the best ECG parameter, the amplitude parameter of the ORS component, sensitivity was 82%, and the percentage of parameter changes during baseline was 20%. The sensitivity for detecting ACO with five of the six ECG parameters studied was greater than that of the standard visual analysis. Ischaemic changes were detected in 4.3 +/- 1.6 leads per patient using the amplitude parameter of the ORS component, whereas, with the standard visual analysis, 2.5 +/- 2.1 leads demonstrated such changes (p<0.001). Results were then summarized per patient. The standard visual ECG analysis detected ACO in 15 of 18 patients (83%), if at least one lead showed ischaemic changes. The computerised analysis detected ACO in all 18 patients using the same criterion. The sensitivity of the computerised method for detecting ACO in the clinical setting of angioplasty was greater than that of the standard visual analysis. It is suggested that the computerised method may be useful for detecting myocardial ischaemia in other clinical settings of acute myocardial ischaemia.

Efficacy of hirudin in reducing cardiovascular events in patients with acute coronary syndrome undergoing early percutaneous coronary intervention.

AIMS: Although hirudin is superior to unfractionated heparin for prevention of death, myocardial infarction, or refractory ischaemia in patients with non-ST-elevation acute coronary syndrome, it is not clear whether hirudin is also of benefit in acute coronary syndrome patients undergoing early percutaneous coronary intervention. METHODS AND RESULTS: In the OASIS 2 trial, 10 141 patients with non-ST-elevation acute coronary syndrome were randomized to 72 h of intravenous hirudin or unfractionated heparin. Percutaneous coronary intervention was performed at the discretion of the investigator. One hundred and seventeen patients underwent percutaneous coronary intervention within the first 72 h ("early percutaneous coronary intervention"). In patients undergoing early percutaneous coronary intervention, hirudin compared with unfractionated heparin was associated with a significantly lower incidence of death or myocardial infarction at 96 h (6.4% vs 21.4%, OR 0.30; 95% CI: 0.10-0.88) and 35 days (6.4% vs 22.9%, OR 0.25; 95% CI: 0.07-0.86). In the unfractionated heparin group, death or myocardial infarction was significantly higher at 35 days in patients undergoing early percutaneous coronary intervention compared with those managed conservatively (22.9% vs 7.3%, OR 3.14, P<0.001) but this early percutaneous coronary intervention-related hazard was not observed in hirudin-treated patients (6.4% vs 6.8%, OR 0.94 P=1.0). A time-dependent covariate for percutaneous coronary intervention was not significant in a Cox regression model, suggesting a similar treatment benefit with hirudin before and after percutaneous coronary intervention. After adjustment for percutaneous coronary intervention propensity, the benefits of hirudin remained significant. There were three major bleeds in patients undergoing early percutaneous coronary intervention, all in patients randomized to hirudin. CONCLUSION: In patients with non-ST-elevation acute coronary syndrome undergoing early percutaneous coronary intervention, a direct thrombin inhibitor such as hirudin may be more effective than heparin in reducing the incidence of ischaemic complications.

Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.

BACKGROUND: Despite the use of aspirin, there is still a risk of ischaemic events after percutaneous coronary intervention (PCI). We aimed to find out whether, in addition to aspirin, pretreatment with clopidogrel followed by long-term therapy after PCI is superior to a strategy of no pretreatment and short-term therapy for only 4 weeks after PCI. METHODS: 2658 patients with non-ST-elevation acute coronary syndrome undergoing PCI in the CURE study had been randomly assigned double-blind treatment with clopidogrel (n=1313) or placebo (n=1345). Patients were pretreated with aspirin and study drug for a median of 6 days before PCI during the initial hospital admission, and for a median of 10 days overall. After PCI, most patients (>80%) in both groups received open-label thienopyridine for about 4 weeks, after which study drug was restarted for a mean of 8 months. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or urgent target-vessel revascularisation within 30 days of PCI. The main analysis was by intention to treat. FINDINGS: There were no drop-outs. 59 (4.5%) patients in the clopidogrel group had the primary endpoint, compared with 86 (6.4%) in the placebo group (relative risk 0.70 [95% CI 0.50-0.97], p=0.03). Long-term administration of clopidogrel after PCI was associated with a lower rate of cardiovascular death, myocardial infarction, or any revascularisation (p=0.03), and of cardiovascular death or myocardial infarction (p=0.047). Overall (including events before and after PCI) there was a 31% reduction cardiovascular death or myocardial infarction (p=0.002). There was less use of glycoprotein IIb/IIIa inhibitor in the clopidogrel group (p=0.001). At follow-up, there was no significant difference in major bleeding between the groups (p=0.64). INTERPRETATION: In patients with acute coronary syndrome receiving aspirin, a strategy of clopidogrel pretreatment followed by long-term therapy is beneficial in reducing major cardiovascular events, compared with placebo.