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.

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.

First-In-Man application of a miniature self-contained intracoronary magnetic resonance probe. A multi-centre safety and feasibility trial.

AIMS: To assess safety and feasibility of intracoronary Magnetic Resonance (MR) Spectroscopy in living patients, using a self-contained MR catheter. METHODS AND RESULTS: Prospective, multi-centre study in patients with stable or unstable angina that were scheduled for percutaneous coronary diagnostic or therapeutic catheterization. We assessed the feasibility of an intravascular MR catheter, capable of analysing the arterial wall without external magnets or coils, by differentiating lipid rich, intermediate and fibrotic areas of the atherosclerotic plaque on the basis of differential water diffusion.Twenty-nine patients were included at 4 centres. The intracoronary MR-spectroscopy procedure was well tolerated; no MACE and no device related serious adverse event was observed. The MR catheter was successfully advanced into the lesion in 28 patients. Introduction of the MR catheter was not possible in one patient with a tortuous proximal right coronary artery. MR data were obtained in 22 patients. According to the predominant MR pattern, lesions were classified as fibrous plaque in 4 patients, as intermediate plaque in 4 patients and as lipid-rich plaque in 8 patients. Six patients were excluded from analysis because artifacts impeded the quality of the MR signal. Plaque type did not show a correlation with angina status (p=0.552; all groups) or angiographic parameters, such as minimal lumen diameter and diameter stenosis. CONCLUSIONS: This prospective, multi-centre study demonstrates for the first time that coronary artery assessment of potentially vulnerable, non-flow limiting lesions using a dedicated intravascular MR catheter, free of external magnets or coils, is feasible in clinical practice. Assessment of the coronary wall may provide important data regarding the composition of the atherosclerotic lesion, which then could contribute to predicting the likelihood of eventual rupture and clinical instability.

Perceived benefit after participating in positive or negative/neutral heart failure trials: the patients' perspective.

BACKGROUND: Clinical trials, the gold standard for the evaluation of new therapeutic strategies, may prove a drug to be beneficial, harmful or neutral according to its effect on the end-point(s) under study. AIMS: To study the reaction and perspective of the patients participating in a clinical heart failure trial, particularly in relation to whether the trial subsequently proved to be positive, negative or neutral. METHODS: Anonymous self-completed questionnaire was sent to 78 and returned by 70 consecutive patients 1--6 months after participating in six clinical heart failure trials. The trial was neutral or negative regarding the primary end-point in four (47 patients) of the six studies (MACH-1 trial of mibefradil, REACH trial of bosentan, CASCO trial of calcium sensitizer, ecadotril trial of neutral endopeptidase inhibitor) and positive in two (23 patients) (ICARUS Israel carvedilol study, exercise study of candesartan cilexetil). RESULTS: Most patients reported subjective global clinical benefit (78% for positive, 74% for negative or neutral trial, NS) after participating in a clinical trial. After adjustment for age, sex, level of education, previous research, perceived comprehension, and treatment allocation (active drug/placebo) in a stepwise regression model, perceived global improvement was greater in older patients (P=0.02), after participation in a positive trial (P=0.05) and in females (P=0.07). The major reason given by the patient for perceived clinical improvement was better follow-up, some believed it was due to change in medication, particularly those who had participated in a positive trial. CONCLUSIONS: More than 70% of patients participating in clinical trials of new drugs for heart failure reported perceived global improvement. Clinical improvement was greater in, but not limited to, patients who participated in positive trials. These salutary findings support the continued recruitment of patients to clinical heart failure trials.

Similar late revascularization rates 10 to 12 years after angioplasty or bypass surgery for multivessel coronary artery disease: a report from the Lady Davis Carmel Medical Center (LDCMC) Registry.

We compared completed long-term outcome and late repeat revascularization rates in 272 consecutive patients with multivessel coronary disease who underwent revascularization (95 angioplasty cohort, 177 surgical cohort) between 1984 and 1986. Long-term survival was similar at 12 years in the angioplasty (70%) and surgical (74%) cohorts (p = NS), and repeat revascularization, although more frequent in the angioplasty patients during the first 5 years of follow-up, was performed equally in the 2 patient cohorts after 10 to 12 years of follow-up.

Late-onset heart failure as a mechanism for adverse long-term outcome in diabetic patients undergoing revascularization (a 13-year report from the Lady Davis Carmel Medical Center registry).

The adverse long-term prognosis following myocardial revascularization in diabetic patients has been ascribed to accelerated coronary disease, a higher incidence of late coronary restenosis after revascularization, and myocardial dysfunction. To examine the development of heart failure and its prognostic implications in diabetic patients, we analyzed the long-term (13-year) follow-up data of 363 patients-193 percutaneous transluminal coronary angioplasties and 170 coronary artery bypass operations-revascularized in a single cardiovascular center from 1984 to 1986. Baseline characteristics (age, previous infarction, baseline ventricular function) were similar in the 80 diabetic and 283 nondiabetic patients; multivessel disease and hypertension were marginally more common in diabetics (p = NS). Cumulative incidence of hospitalization for heart failure was high in the diabetic cohort (25% vs 11%, p = 0.001), with a rapidly increasing incidence after 5 years. Survival after first hospitalization for heart failure was markedly reduced in diabetics (11 of 20 [55%] vs 25 of 31 [81%] at 3 years; p = 0.04), as was survival free of further hospitalization for heart failure (5 of 20 [25%] vs 20 of 30 [63%]; p <0.005). Long-term 13-year survival (43% vs 78%, p <0.0001) and survival free of heart failure (33% vs 71%, p <0.0001) were decreased in diabetics, especially those with reduced ventricular function at baseline (17% vs 42%, p = 0.07). Multivariate analysis showed diabetes to be the strongest independent predictor of decreased survival (odds ratio 3. 6, 95% confidence interval 2.0 to 6.2; p <0.0001) and survival free of heart failure (odds ratio 4.0, 95% confidence interval 2.2 to 7. 1; p <0.0001) in patients undergoing revascularization. In summary, late-onset heart failure was frequent in diabetic patients after percutaneous transluminal coronary angioplasty or coronary artery bypass grafting, and once present heralded an unrelenting progressive downhill clinical course.

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.

Same-day combined coronary angioplasty and minimally invasive coronary surgery.

Integrated myocardial revascularization combines the advantages of angioplasty, stenting, and minimally invasive surgery to revascularize patients with multivessel coronary artery disease without cardiopulmonary bypass. This pilot study showed that a new same-day management strategy, consisting of percutaneous coronary intervention followed immediately by minimally invasive surgery, was feasible and provided complete all-arterial revascularization with minimal surgical trauma, short hospital stay, and excellent early therapeutic result in 14 patients with multivessel coronary disease.

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.

Importance of diabetes mellitus and systemic hypertension rather than completeness of revascularization in determining long-term outcome after coronary balloon angioplasty (the LDCMC registry). Lady Davis Carmel Medical Center.

The study examined the 10-year outcome in a cohort of 227 unselected, consecutive patients (age 58+/-10 years) undergoing coronary balloon angioplasty between 1984 and 1986 and followed in a single cardiac center (Lady Davis Carmel Medical Center registry). In particular, we sought to identify the relative importance of the systemic risk factors diabetes and hypertension and the extent of coronary disease as opposed to procedure-related technical variables, the immediate success of the procedure, or completeness of revascularization. By life-table analysis (99% follow-up), 94% of the patients were alive at 5 years, and 77% at 10 years after angioplasty. Ten-year survival was reduced in patients with diabetes mellitus (59% vs 83%, p = 0.0008), in patients with previous myocardial infarction (68% vs 85%, p = 0.01), in patients with ejection fraction <50% (55% vs 82%, p = 0.005), and in patients with 3-vessel disease (58% vs 84% and 86% for 1- and 2-vessel disease, respectively, p = 0.04). Diabetes mellitus was the major independent predictor of poor survival (adjusted odds ratio 3.1, 95% confidence interval 1.55 to 6.19, p = 0.001). Survival at 10 years was identical in 199 patients in whom angioplasty was complete and in 25 in whom the balloon catheter did not cross the lesion, although bypass surgery was more frequent in the latter group (45% vs 21%, p = 0.001). Incomplete revascularization did not predict poor survival (72% vs 79% with complete angioplasty, p = NS). Event-free survival at 10 years for the whole group was 29%, and 49% of patients survived with no event other than a single repeat angioplasty procedure. Multivessel disease, hypertension, and diabetes mellitus were independent predictors of decreased event-free survival, but incomplete revascularization was not. Thus, long-term outcome after coronary balloon angioplasty was related to diabetes mellitus, systemic hypertension, and extent of coronary disease, but not to the immediate success of the procedure or completeness of revascularization.

Accuracy of exercise-induced left axis QRS deviation as a specific marker of left anterior descending coronary artery disease.

In this prospective study, we examined the diagnostic accuracy of exercise-induced left QRS axis deviation as a marker of LAD coronary artery stenosis. The mean frontal QRS axis of 66 consecutive patients with chest pain and exercise-induced ST segment depression referred for diagnostic coronary angiography was analyzed and related to the angiographic findings. An exercise-induced leftward QRS axis deviation was found in 9/40 patients with and 0/26 patients without obstructive (> or = 70%) LAD disease (sensitivity 23%, specificity 100%, p = 0.025). In 7 of the 9 patients with left axis deviation, the lesion was proximal to and in 2 in the region of the first septal perforator. Inclusion of patients with 0 degrees exercise-induced QRS axis deviation provided a more sensitive but less specific marker of LAD disease [sensitivity 53% (21/40), specificity 81% (21/26), p = 0.015]. The findings were similar in patients with single and with multivessel coronary artery disease. Grouping all patients in the present prospective and two previous retrospective studies (n = 165), the sensitivity was 29% and specificity 100% (p < 0.0001). Exercise-induced left QRS axis deviation was a highly specific marker of LAD coronary artery stenosis.

Exercise testing in patients with chest pain and normal coronary arteries: improving test specificity by use of a simple logistic model.

Despite an exercise electrocardiogram (ECG) positive for ischemia by established criteria, many patients referred for coronary angiography to evaluate chest pain are found to have angiographically normal coronary arteries (NCA). Exercise ECG were analyzed from 27 patients with chest pain and angiographically NCA and 28 patients with chest pain and coronary artery disease (CAD) using univariate and multivariate logistic regression analysis. We derived the following logistic model for the logit probability of CAD: 3 + SEX x 4 - METs x 0.7 + STDV5 x 0.8, where SEX = 0 for female and SEX = 1 for male, METs = maximal estimated work load (metabolic equivalents) and STDV5 = horizontal or downsloping ST depression (mm) in V5. A logit probability > or = 0 identified CAD with a sensitivity of 79% and a specificity of 89%. The model correctly identified 28/36 (78%) patients with CAD, and 7/10 (70%) patients with NCA (correct diagnosis 76%; p < 0.02) in a separate random group of 46 unselected patients with positive exercise tests undergoing diagnostic coronary angiography.

Ventricular remodeling: from bedside to molecule.

The multiple mechanisms that bring about the decompensation of the hypertrophic remodeled myocardium are synergistic and not fully understood. Our current hypothesis is that the increased stress on the ventricle is initially offset by compensatory myocardial hypertrophy. In many instances, however, progressive ventricular dilatation and heart failure occur as a result of maladaptive hypertrophy (abnormal myosin-actin production), programmed cell death (apoptosis) and/or changes in the interstitial vasculature and collagen composition. The molecular and genetic background to these processes includes changes in myocardial gene expression, activation of the local tissue renin-angiotensin and other neurohormonal systems, increased matrix metalloproteinase activity (including collagenase), and expression of certain components of the immune system, such as TNF-alpha. Future research will hopefully provide better methods for limiting the remodeling-ventricular dilatation process by novel pharmacotherapies, gene therapy and, possibly, surgical therapy, and determine the impact of such interventions on survival.

Importance of immediate and very early postprocedural angiographic and thallium-201 single photon emission computed tomographic perfusion measurements in predicting late results after coronary intervention.

We examined prospectively the hypothesis that the adequacy of initial dilatation may be a major determinant of the late result of coronary angioplasty and that a better assessment of initial dilatation can be made from a combined angiographic and perfusion study than from angiography alone. Angiographic and perfusion (thallium-201 single-photon-emission computed tomography) measurements were made very early (18 to 24 hours) after coronary angioplasty in 59 patients (67 lesions) and also immediately (37 +/- 16 minutes) after the procedures in 19 of them (23 lesions). The early measurements, singly, in combination, and as a restenosis index (restenosis index = thallium-201 ischemic score (units) - minimal luminal area (squared millimeters) were examined as predictors of the late angiographic result. At late angiography (5.5 +/- 2.2 months after angioplasty), residual stenosis was related to the immediate and very early postangioplasty minimal luminal dimension, thallium-201 ischemic score, and restenosis index, and also to day-1 loss and lesion length. The combination of a normal result in the immediate or early thallium-201 perfusion study with a large ( > or = 2 mm) angiographic luminal dimension stratified a group of patients with better long-term results after angioplasty and a lower incidence of late restenosis (p = 0.03). The findings emphasize the importance of the initial procedure as a determinant of the late result of angioplasty.

Usefulness of late potentials on the immediate postoperative signal-averaged electrocardiogram in predicting ventricular tachyarrhythmias early after isolated coronary artery bypass grafting.

The present study was undertaken to determine the value of abnormal late ventricular potentials on signal-averaged electrocardiograms (ECG) in identifying patients at risk of developing ventricular tachycardia or ventricular fibrillation in the early postoperative period after coronary artery bypass grafting. Signal-averaged ECGs were recorded immediately after operation in 72 patients. Abnormal late potentials were defined as the presence of 2 or 3 of the following: (1) root-mean-square amplitude of the last 40 ms of the QRS < 20 microV; (2) duration of the terminal QRS potentials (after 40 microV) > or = 39 ms; and (3) high-frequency QRS duration > 120 ms (in patients with conduction defects, only the first 2 criteria were used). Abnormal late ventricular potentials were present on the immediate postoperative signal-averaged ECG in 26 of the 72 patients (36%). Life-threatening ventricular tachyarrhythmias occurred in 6 patients. Late potentials were present in all 6 patients, but only in 20 of 66 (30%) who did not develop ventricular tachyarrhythmias (p < 0.005) (sensitivity 100%, specificity 70%, predictive accuracy 72%). Of 12 pre- and perioperative variables examined by univariate and multivariate regression analysis, the presence of late potentials on the signal-averaged ECG and low cardiac output postoperatively were found to be independent predictors of life-threatening tachyarrhythmias.