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.

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.

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.

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.

Increased vascular endothelial growth factor 165 binding to kinase insert domain-containing receptor after infection of human endothelial cells by recombinant adenovirus encoding the Vegf(165) gene.

BACKGROUND: The angiogenic effect of vascular endothelial growth factor (VEGF(165)) is mediated mainly through the high-affinity tyrosine kinase receptor VEGF-R2 (KDR/flk-1). This study examined the effects of VEGF overexpression by primary human endothelial cells (ECs), which do not express VEGF under physiological conditions, on cell proliferation, VEGF binding to the kinase insert domain-containing receptor (KDR), and KDR expression. METHODS AND RESULTS: Human primary ECs and SMCs were infected by recombinant adenoviral vector encoding VEGF(165) (rAdVEGF). Proliferation rate, bromodeoxyuridine incorporation, (125)I-labeled VEGF(165) binding to the KDR receptor, and KDR expression were tested in the infected cells and in cells supplemented with VEGF protein. Enhanced proliferation and a significant increase in (125)I-VEGF(165) binding to the KDR receptor were induced by rAdVEGF infection of ECs (autocrine effect) as well as by addition of recombinant VEGF(165) to noninfected cells. Infection of ECs by rAdVEGF led to posttranscriptional upregulation of the KDR receptor, whereas KDR mRNA expression levels remained unchanged. Similar effects were observed with supplemented recombinant VEGF(165) to noninfected ECs; nevertheless, this phenomenon occurred only with high VEGF(165) concentrations (10 ng/mL). CONCLUSIONS: The effect of VEGF(165) on proliferation and upregulation of KDR receptor expression demonstrated an autocrine phenomenon of EC sensitization. The fact that high concentrations of VEGF may be achieved in vivo by local continuous overexpression of VEGF(165) by gene transfer emphasizes the potential advantage of gene transfer over protein supplementation for therapeutic angiogenesis.

Predicting late restenosis after coronary angioplasty by very early (12 to 24 h) thallium-201 scintigraphy: implications with regard to mechanisms of late coronary restenosis.

To examine whether late coronary restenosis may be predicted by abnormalities of myocardial perfusion in the early hours after successful percutaneous transluminal coronary angioplasty and to study in greater detail the mechanisms involved in the development of late coronary restenosis after angioplasty, a prospective study was undertaken in 90 consecutive patients. Thallium-201 scintigrams were recorded at rest and during the stress of atrial pacing, 12 to 24 h after angioplasty, and the results were related to the findings at angiography in 70 patients undergoing late cardiac catheterization. A reversible thallium-201 perfusion defect was found in 39 (38%) of 104 myocardial regions supplied by the dilated coronary vessel and identified a subset of patients at high risk of late (6 to 12 months) angiographic restenosis (sensitivity 77%, specificity 67%). In contrast, late coronary restenosis developed in only 7 (11%) of 65 vessels and in 5 (14%) of 37 patients with a nonischemic thallium-201 scintigram on day 1 (p less than 0.005). Multivariate logistic regression analysis of 14 possible preangioplasty and periangioplasty clinical and angiographic variables selected reversible perfusion defect on the thallium-201 scintigram on day 1 (p = 0.016) and immediate postangioplasty residual coronary narrowing (p = 0.004) as significant independent predictors of late restenosis, with younger patient age as an additional less powerful predictor (p less than 0.05). The findings have important implications regarding the pathogenesis of late coronary restenosis in patients undergoing successful angioplasty and they imply that in the majority of these patients pathophysiologic events in the early minutes and hours after angioplasty may determine the development of late restenosis.

Long-term (10-year) outcome in patients with unstable angina pectoris treated by coronary balloon angioplasty.

OBJECTIVES: We sought to examine completed 10-year survival and event-free survival in patients with stable and unstable angina pectoris treated by coronary balloon angioplasty. BACKGROUND: Patients with unstable angina are at increased risk for recurrent acute coronary events. METHODS: The study included 208 consecutive patients (133 with stable and 75 with unstable angina pectoris) undergoing angioplasty from 1984 to 1986. The balloon crossed the lesion in 185 patients (121 with stable and 64 with unstable angina pectoris). Angioplasty was performed in patients with unstable angina pectoris 12+/-15 days (median 8) after symptom onset. Patients with unstable angina pectoris were classified retrospectively into Braunwald class I (n=3), class II (n=20), class III (n=28), class B (n=52) and class C (n=12). Follow-up data were obtained from hospital charts, telephone interview and official death certificates where applicable. The study had >80% power to detect a clinically significant 20% difference in survival and a 20% difference in event-free survival between the stable and unstable patient groups. RESULTS: Despite similar baseline characteristics, early (40-day) mortality was slightly higher in patients with unstable angina (4.7% [3 of 64 patients] vs. 0.8% [1 of 121 patients], p=NS). Long-term outcome was not different, because survival curves were parallel thereafter (10-year survival was 83% for those with stable and 77% for those with unstable angina, p=NS). Survival free of myocardial infarction or coronary artery bypass graft surgery at 10 years was 53% in patients with stable and 47% in patients with unstable angina (p=NS), and survival free of infarction, bypass surgery or repeat angioplasty was 32% for both groups at 10 years. In patients with Braunwald class III unstable angina, 10-year survival was 80%, as compared with 85% in other patients with unstable angina, due to the early hazard (p=NS). Survival and event-free survival were similar in patients who had had a recent myocardial infarction (Braunwald class C) and in patients with acute electrocardiographic changes. Repeat hospital admissions were not more frequent in patients with unstable angina (3.1+/-3.5 vs. 3.0+/-2.6, p=NS). CONCLUSIONS: Ten-year survival and event-free survival were similar in patients with stable and unstable angina pectoris treated by coronary balloon angioplasty, with no evidence of an increased rate of recurrent cardiovascular events in the unstable group.

Patient comprehension and reaction to participating in a double-blind randomized clinical trial (ISIS-4) in acute myocardial infarction.

BACKGROUND: Although randomized clinical trials are currently the standard for the evaluation of new therapeutic strategies, little attention has been paid to the viewpoint of the patients recruited to these trials. OBJECTIVES: To examine the perspective of the Israeli patient cohort who participated in the Fourth International Study of Infarct Survival, a randomized trial in acute myocardial infarction. METHODS: A patient questionnaire was mailed to 360 Israeli patients who participated in the Fourth International Study of Infarct Survival and was returned by 150 of them. Main outcome measures included patient perception of consent procedures, comprehension of the study, subjective reaction to participating in the trial, and interest in present and future trials. RESULTS: Forty (31%) of 129 patients perceived that they had full comprehension of the trial, while 64 (50%) claimed partial understanding and 25 (19%), no understanding at all. Comprehension was related to a recollected explanation of 5 minutes or more (P<.001) and to an opportunity for discussion at the time of consent (P<.001). Most patients recollected the oral explanation; fewer, the written material. Patient consent was given by 64 (43%) of 150 patients in the hope of better treatment. In 36 cases (25%), the patients felt they received better treatment because of participation in the trial. CONCLUSIONS: Despite proper attention to accepted ethical and legal standards, perceived patient comprehension in this trial in acute myocardial infarction was incomplete or lacking in a considerable number of subjects. Much progress must be made toward the goal of true informed consent in clinical trials.

Selection of saphenous vein bypass gradt diameter to support patency of the stenosed coronary artery.

Injudicious selection of a saphenous vein graft can adversely affect the the late postoperative patency of the proximal coronary artery which it bypasses. The purpose of this investigation was to deduce an upper bound for graft diameter, at small angle of distal anastomosis, below which the stenosed artery will remain patent, from a mathematical model of aortocoronary bypass haemodynamics.

Angiogenesis by gene therapy: a new horizon for myocardial revascularization?

The concept of therapeutic angiogenesis is based on the premise that the potential for vascular growth inherent in vascular tissue can be utilized to promote the development of new blood vessels under the influence of the appropriate growth factors. Direct application of growth factors of the fibroblast (acidic, basic fibroblast growth factor, FGF-5), endothelial (vascular endothelial growth factor) and other series has been effective in preliminary studies. Angiogenesis by gene transfer provides an attractive alternative, with the advantage that the protein may continue to be secreted for a longer period of time and that the gene may be targeted to specific tissues to enhance efficacy and reduce systemic side effects. Angiogenesis by gene transfer is currently under investigation using a variety of growth factors and a wide array of potential delivery systems. These include application of the gene as naked DNA or by viral vector in the proximal vessel by direct intravascular injection, interventional cardiologic techniques (hydrogel coating on balloon, double balloon system, stent implantation) or by direct application to adventitia, pericardium or ischemic tissue distal to the site of arterial obstruction. As our understanding of the molecular and genetic processes underlying angiogenesis increases, and as we examine the results of preliminary animal and human protocols, we hope to develop the potential of angiogenesis by gene transfer for therapeutic use.

Platelet studies in patients with hypertrophic cardiomyopathy.

Because of a shared abnormality of platelet and muscle in some neuromuscular diseases, platelets were investigated in five cases of hypertrophic cardiomyopathy, a disease likely to be primarily myogenic. Morphometric and chemical differences from normal were found consisting of increased cell size, decreased phosphorus concentrations and increased permeability to cations. The findings suggest membrane and energy metabolism aberrations.

Real time two dimensional echocardiography in constrictive pericarditis.

Real time two dimensional echocardiography was performed in five patients with constrictive pericarditis. The echocardiogram showed several typical features: (1) The heart was normal in size or decreased; the ventricles were small and the atria enlarged. (2) The pericardium was seen as a single or double dense rigid shell surrounding both ventricles and the apex; its immobility was striking. (3) The inferior vena cava and hepatic veins were greatly dilated in keeping with the severe clinical venous congestion. (4) Both interventricular and interatrial septa bulged into the left side of the heart on inspiration. (5) The atrioventricular valves were hypermobile. (6) A prominent ventricular diastolic filling half was seen. The two dimensional echocardiogram excluded other causes of severe cardiac failure such as congestive cardiomyopathy and valvular heart disease, while the dense immobile pericardial echo or echoes and the "normal" texture of the myocardial echoes made the diagnosis of restrictive cardiomyopathy unlikely.

Efficacy and safety of nisoldipine coat core in the management of angina pectoris, systemic hypertension, and ischemic ventricular dysfunction.

The effects of the long-acting dihydropyridine calcium antagonist nisoldipine coat core (CC) have been investigated in > 3,500 patients with angina pectoris, hypertension, and ischemic ventricular dysfunction. In patients with angina pectoris, nisoldipine CC improved total treadmill exercise duration (p = 0.027), delayed the onset of angina pectoris (p = 0.009), and increased time to exercise-induced ST-segment depression (p = 0.061). In general, nisoldipine 20-40 mg was effective, and the dose-response curve flattened thereafter. In patients with hypertension, 10-40 mg once daily as monotherapy reduced blood pressure (p < 0.05), with a fall in diastolic pressure of > or = 10 mm Hg or a final diastolic pressure of < 90 mm Hg in 35-63% of patients. In most patients followed for a year, nisoldipine CC was continued as monotherapy. Efficacy was similar in patients < 65 and > 65 years of age. In the Doppler Flow and Echocardiography in Functional Cardiac Insufficiency: Assessment of Nisoldipine Therapy (DEFIANT-I) study of patients recovering from myocardial infarction, nisoldipine CC had a salutary effect on diastolic ventricular function, with a higher transmitral early filling velocity and shorter isovolumic relaxation time than in patients receiving placebo. Bicycle exercise capacity was greater (by 12 W; 95% confidence interval, 0.8-23.3) and exercise-induced ischemia occurred less frequently. The nisoldipine CC data pool (3,679 patients) showed that the drug was well tolerated with a low incidence of side effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Usefulness of echocardiographically determined mitral leaflet motion for diagnosis of mitral valve prolapse in 17- and 18-year-old men.

Mitral leaflet motion during systole was studied by echocardiography in 102 healthy young men. Mean posterior maximal leaflet motion was 2 +/- 1 mm behind the CD line on 2-dimensionally (2-D) directed M-mode examination. On the apical 4-chamber cross-sectional view a mean area of 0.34 +/- 0.24 mm2 was contained by the mitral leaflets above the plane of the mitral anulus. Elevated values on the M-mode view (greater than or equal to 4 mm) compared with the 2-D 4-chamber view (greater than or equal to 0.70 mm2) were discordant, with 90% (18 of 20) of the elevated values found in 1 view only. Thus, there is a wide spectrum of mitral leaflet motion in asymptomatic young men. The value of the echocardiogram in diagnosis of mitral valve prolapse is questionable because any cutoff point between normal and abnormal is arbitrary and the degree of motion has not been shown to correlate with morbidity or mortality.

Localization of lesions in the coronary circulation.

The location of coronary artery narrowings in coronary disease (CAD) is of considerable importance in assessing the mass of myocardium at risk as well as patient prognosis. The detailed distribution of coronary lesions was mapped in 302 patients with CAD who had coronary angiography for chest pain. All identifiable coronary lesions were measured manually and the site and degree of narrowing were stored in a computer-based multisegmental model of the coronary tree. A high prevalence of CAD was found in proximal vessels and especially at, or adjacent to, proximal points of branching. In the left anterior descending coronary artery, the lesions were most prevalent immediately after the first diagonal branch and at the origin of this branch. In the right coronary artery, there was a high prevalence of narrowing between the infundibular and acute marginal branches and specifically around the origin of the right ventricular branch. In the left circumflex coronary artery, there was a predilection for narrowing in and around the origin of the first marginal branch. When a ramus intermedius was present, its origin was frequently the site of narrowing.

Chronotropic effect of hydralazine and its mechanism of symptomatic sinus bradycardia.

The positive chronotropic effect of hydralazine was studied in 9 patients with symptomatic sinus bradycardia. Hydralazine was given in an intravenous dose of 0.15 mg/kg and heart rate, blood pressure, sinoatrial conduction time (Narula method) and corrected sinus node recovery time were measured. The effect of hydralazine was also studied after total autonomic nervous system blockade using 0.04 mg/kg of atropine and 0.2 mg/kg of propranolol intravenously. In the control state hydralazine produced an increase of 28 +/- 15% (mean +/- standard deviation) in heart rate, and this was essentially due to a decrease in sinoatrial conduction time (by 32 +/- 32%, p less than 0.05). Corrected sinus node recovery time also tended to shorten (decrease of 21 +/- 34%, difference not significant). After total autonomic blockade intrinsic heart rate did not change or increased very little (9 +/- 14%) after administration of hydralazine and there was no consistent change in sinoatrial conduction and corrected sinus node recovery times. The small residual effect of hydralazine on heart rate was related to incomplete autonomic blockade, since the effect of postural change (standing) on heart rate was also not totally abolished. The study showed that the positive chronotropic effect of hydralazine was mainly due to a change in sinoatrial conduction with a smaller change in corrected sinus node recovery time, and the major chronotropic effect of the drug was mediated by the autonomic nervous system.

Identifying patients at high risk for restenosis after percutaneous transluminal coronary angioplasty for unstable angina pectoris.

To study the determinants of late restenosis after percutaneous transluminal coronary angioplasty (PTCA) performed in patients with unstable angina pectoris, a prospective study was undertaken in 90 patients. Primary PTCA success was achieved in 84 (93%) patients, dilating 116 of 118 coronary narrowings (1.4/patient), while major complications during PTCA occurred in only 1 patient (1 death). Eighty-two patients (114 dilated arteries) were followed for 25 +/- 11 months: 68 (83%) were in New York Heart Association functional class I or II, 11 (13%) in class III, and there were 3 deaths. Late restenosis was found in 16 (25%) of 65 lesions (29% of 49 patients) studied by angiography 9 +/- 7 months after PTCA. Restenosis was more frequent in left anterior descending coronary artery lesions (p = 0.07) and in those which at the time of PTCA had multiple irregularities (67 vs 14%, odds ratio 12.5, p = 0.002), decreased coronary perfusion (Thrombolysis in Myocardial Infarction grade less than 3) (50 vs 15%, odds ratio 5.7, p = 0.02) or intraluminal thrombus (67 vs 19%, odds ratio 8.7, difference not significant). Multiple irregularities (p = 0.003) and decreased flow (p = 0.02) remained independent predictors of restenosis (goodness of fit 0.88) after adjustment for 12 pre- and peri-PTCA clinical and angiographic variables by logistic regression analysis. These data underline the feasibility of early revascularization by PTCA in patients with unstable angina pectoris. Careful follow-up should be instituted in patients with multiple irregular lesions, decreased coronary perfusion or intraluminal thrombus at the time of PTCA. In such patients, late restenosis may be the rule rather than the exception.

Effects of high gravity on cardiac dimensions in trained air crew.

We conclude that there is no difference in LV wall thickness, dimensions, or functional parameters between air crew members who fly high + Gz aircraft and those who fly other types of aircraft. No differences were detected between high +Gz air crew personnel and others in development of structural and functional changes over the short-term course of a flying career.

An unusual case of mitral valve aneurysm: two dimensional echocardiographic and cineangiocardiographic features.

A patient is described in whom an aneurysm of the posterior mitral leaflet caused severe mitral incompetence and cardiac failure. The aneurysm was seen as an additional echo-free space within the left atrium in the real time two dimensional echocardiogram. Both echocardiographic and cineangiocardiographic appearances were misinterpreted initially because the aneurysmal leaflet did not more into the left ventricle during diastole. This feature was explained during the successful surgical repair of the valve by the observation that the aneurysm was adherent to the left atrial wall.