Lorenzo Bonetti

Association between Atrial Septal Aneurysm and Patent Foramen ovale in Young Patients with Recent Stroke and Normal Carotid Arteries

Background: Atrial septal aneurysm (ASA) has been considered a potential source of cardiogenic embolism for many years. The ASA Multicenter Italian (ASA-MI) Study evaluated the prevalence and characteristics of ASA in patients with stroke and normal carotid arteries compared with control patients without stroke. The purpose of the present study was to evaluate the frequency of ASA and the association with patent foramen ovale (PFO) in the subgroup of younger patients (aged less than 55 years) included in the ASA-MI Study. Methods: The ASA-MI Study included 606 patients, enrolled between November 1990 and December 1996: 245 patients with a previous cerebral embolic attack and normal carotid study and a control group of 316 patients. They all underwent transthoracic and transesophageal echocardiography. The subgroup of younger patients aged less than 55 years included 90 patients (61 men and 29 women of mean age 49 ± 5 years) (group AY). This group was evaluated and compared with an age- and sex-matched control population (61 men; of mean age 48 ± 6 years) (group BY). Results: The prevalence of ASA was 48.8% (95% confidence interval 40–61) in group AY and 22.2% in the group BY (95% confidence interval 18–33) (χ2 = 5.968; p = 0.01). Morphological features were similar in the 2 groups of patients. ASA involved the entire septum in 52% of patients of group AY, and in 47.2% of group BY. The prevalence of PFO was 58.8% (95% confidence interval 43–62) in group AY and 28.8% in group BY (95% confidence interval 17–35) (χ2 = 5.811; p = 0.01). A strong association was found between ASA and PFO. Of the 90 younger patients with stroke, 39 of 44 (88.6%) with ASA also had PFO, compared with 14 of 46 (30.4%) without ASA (χ2 = 7.370; p = 0.007). Conclusion: We found that ASA and PFO were independent predictive factors for stroke in younger patients with stroke and normal carotid arteries and that the association between ASA and PFO bore an increased odds risk.

Heparin/PF4 antibodies formation after heparin treatment : Temporal aspects and long-term follow-up

BACKGROUND Heparin-induced thrombocytopenia is characterized by the presence of heparin-induced antibodies against heparin/platelet factor-4 (PF4) complex and paradoxical thrombosis. Little is known on the persistence of antiheparin antibodies in blood. The aim of this study was to evaluate the time course of heparin/PF4 antibodies in patients exposed to heparin. METHODS We initially enrolled 500 patients treated with unfractionated heparin as part of perioperative management of coronary artery bypass graft; those who developed serologically confirmed heparin/PF4 antibodies were selected for further follow-up. Over 3 years, we repeatedly assessed serum concentration of antibodies (by enzyme-linked immunosorbent assay) and occurrence of thrombotic events. RESULTS One hundred thirty-one patients (26.2%) developed anti-PF4/heparin antibodies, which persisted for a median time of 90 days (Quartile 1-Quartile 3, 31-186). At 30 days, patients with antibodies had higher incidence of thrombotic events (28.2% vs 14.9%, P < .01) and death/myocardial infarction (14.5% vs 7.8%, P < .001). Of the 131 patients with antiheparin/PF4 antibodies, 78 had already developed antibodies before cardiac surgery; such patients became serologically negative more slowly than patients who developed antibodies after surgery. Over 3 years of follow-up, patients with anti-PF4/heparin antibodies developed 65 thrombotic events, 25 patients developed deep vein thrombosis and/or pulmonary embolism, and 20 patients myocardial infarction. CONCLUSIONS Patients with heparin-induced antibodies are more likely to develop thrombosis after cardiac surgery. Patients in whom antibodies are present before surgery show longer persistence of antibodies and increased incidence of thrombotic events over time. Persistence of antibodies suggests that these patients may be at risk for developing thrombosis; and therefore, further exposure to heparin should be limited.

Left atrial size and function after spontaneous cardioversion of atrial fibrillation and their relation to n-terminal atrial natriuretic peptide

L atrial (LA) stunning after cardioversion of atrial fibrillation (AF) has been reported during spontaneous conversion to sinus rhythm.1 This observation suggest that atrial stunning is a function of underlying arrhythmia and not of the mode of cardioversion. It is known that AF causes atrial dilation, and progressive LA enlargement occurs when AF becomes chronic.2 Recently, it has been shown that multiple factors contribute to LA enlargement, including the presence and persistence of arrhythmia.3 Many reports suggest that if sinus rhythm is restored then dilation may regress.4 The Framingham Study showed a relation between LA size and the risk of stroke in men and the risk of death in both genders.5–7 Previous studies have suggested that N-terminal atrial natriuretic peptide (NANP) levels are elevated in patients with AF.8,9 It is unclear whether AF rather than LA dilation,10 hemodynamic impairment,11 or another hormonal alteration, can result in the elevation of N-ANP levels.8 The present report evaluates the changes in LA size and function after spontaneous cardioversion of AF and their relation to N-ANP. • • • Hemodynamically stable patients referred for cardioversion for nonrheumatic AF between September 1997 and March 2000 were considered for inclusion in this investigation. The initial study group included 202 consecutive patients; 98 patients spontaneously recovered sinus rhythm within 48 hours from the onset of arrhythmia and were selected for the study (Group A). The study population included 57 men and 41 women of mean age 60 16 years; patients were compared with 98 ageand gender-matched control subjects (mean age 61 16 years) who underwent pharmacologic cardioversion within 48 hours from the onset of arrhythmia (Group B). Patients received intravenous propafenone 2 mg/kg of body weight; the drug was dissolved in 100 ml of 5% glucose and infused over 30 minutes. Exclusion criteria were: atrial flutter, valvular stenosis, valvular prosthesis, significant valvular insufficiency, atrial and/or left ventricular thrombosis, spontaneous echo contrast, patent foramen ovale or an atrial septal aneurysm, or decreased LV function (ejection fraction 45%). No patients received long-term therapy with antiarrhythmic drugs. Demographic and clinical characteristics of the patients are listed in Table 1. Clinical records included age, gender, time and circumstances of the onset of symptoms related to AF, and the duration of AF estimated from the initial onset of symptoms until the time of the in-hospital conversion. The protocol was approved by the Ethical Committee of our university and all patients signed an informed consent form. The initial Doppler echocardiographic study was performed during AF and after cardioversion (mean 3 1.5 hours). A complete monoand 2-dimensional color Doppler echocardiogram was performed in each patient using a commercial Hewlett-Packard echocardiograph (Andover, Massachusetts) with a 2.5-MHz probe. LA function was assessed using these parameters: (1) transmitral pulsed Doppler recorded from the apical 4-chamber view with the sample volume positioned between the tips of the mitral leaflets; peak early filling (E) and atrial filling (A) velocities; and From the Departments of Cardiology and Biomedics, University of Modena and Reggio Emilia, Modena, Italy. Dr. Mattioli’s address is: Department of Cardiology, University of Modena, Via del pozzo, 71, 41100 Modena, Italy. E-mail: mattioli.annavittoria@ unimo.it. Manuscript received December 17, 2002; revised manuscript received and accepted March 3, 2003. TABLE 1 Demographics and Clinical Characteristics

Thrombotic events in patients with antiplatelet factor 4/heparin antibodies

Background: Antibodies to the heparin/platelet factor 4 (PF4) complex are linked to the pathogenesis of heparin-induced thrombocytopenia type II, and to the thrombotic complications associated with this syndrome. We investigated the long-term relation between antibody concentration and thrombosis. Methods: 250 patients who had been treated with unfractionated heparin as part of cardiac surgery management were included in the study. The immunoassay ELISA test was used to detect the presence and the plasma concentration of heparin/PF4 antibodies (as optical density value, OD). Follow-up lasted one year and new thrombotic events (myocardial infarction, stroke, pulmonary embolism), and death from any cause, were evaluated. Results: 79 of 250 patients (31.6%) developed anti-PF4/heparin antibodies after cardiac surgery. Nadir platelet count was significantly lower in patients who developed antibody positivity (82 (31)/109 vs 105 (52)/109, p<0.001). At follow-up, patients with anti-PF4/heparin antibodies were more likely to die or develop myocardial infarction (25.3% vs 10.5%, p<0.001), pulmonary embolism (20.2% versus 5.8%, p<0.001) or stroke (12.6% vs 5.8%, p<0.001), than patients who were antibody-negative. Patients were categorised in quintiles of antibody concentration according to the OD. The risk of developing thrombotic events markedly increased with increasing quintile of OD, with the highest group showing an odds ratio of 7.68 (95% CI 4.04 to 9.20) (p<0.001). Conclusions: Patients who develop antibodies to the PF4/heparin complex have a significantly higher rate of thrombotic events during a one-year follow-up than those who lack these antibodies; within this group the risk of developing thrombosis increases with increasing plasma concentration of antibodies.

Transesophageal echocardiography in patients with recent stroke and normal carotid arteries.

E of cardiac origin are the second most frequent cause of stroke. Transesophageal echocardiography (TEE) has been increasingly used to diagnose intracardiac thrombus as well as a number of other cardiac abnormalities. Evaluation of a suspected cardiac source of embolism is currently the most common indication for TEE in many centers because of transesophageal echocardiographic superiority over transthoracic echocardiography. The aim of the present prospective study was to evaluate the clinical significance of transesophageal echocardiographic findings in patients with normal carotid arteries who had suffered cerebral ischemia. • • • The study group consisted of 245 of the 458 patients referred to 3 institutions. Patients ranged in age from 36 to 86 years (mean 65.7 21); 77 were women and 168 were men (Table 1). All patients were selected on the basis of a recent unexplained cerebral ischemia and were included in the study if they had normal carotid arteries (group A). These patients were compared with 245 ageand sex-matched patients (mean age 64.7 23 years, range 29 to 86) who underwent transesophageal echocardiographic examination during the same period for indication other than cerebral ischemia (group B). Exclusion criteria were chronic atrial fibrillation, mitral prosthesis, and mitral stenosis. In group A, we excluded patients with evidence of a mass or hemorrhage on a computer tomographic head scan. In the study population (group A), a trained neurologist established a clinical diagnosis of transient ischemic attack or stroke. A computed tomographic scan (CT) was performed in all patients, and magnetic resonance imaging in 100 of the 245 patients. Cerebral ischemia was defined as: (1) stroke, sudden development of a permanent focal neurologic deficit after which a brain CT scan establishes a cerebrovascular accident as the cause; (2) reversible ischemic attack with complete or almost complete recovery without the need for therapeutic rehabilitation; (3) transient ischemic attack, which is completely resolved within 24 hours; and (4) reversible ischemic neurologic deficit in which there is full clinical recovery within 7 days. A cardioembolic source was suspected on clinical findings, brain imaging, and on normal duplex carotid ultrasound examination. All patients underwent complete transthoracic and transesophageal echocardiographic studies. In group A patients, the examinations were performed 1 to 7 days after the cerebral ischemic event. A Commercial Hewlett-Packard system (Andover, Massachusetts) with 2.5and 3.5-MHz probes and a 5-MHz biplane or multiplane frequency probe with color Doppler and spectral pulsed Doppler was used. Standard views from the gastric and lower esophageal windows were obtained from every patient. All patients who underwent TEE were given diazepam and pharyngeal xilocaine. Each study was assessed for the presence or absence of the following: left atrial enlargment, mass, thrombus, spontaneous echo-contrast, atrial septal defect, atrial septal aneurysm, patent foramen ovale (PFO), mitral annular calcium, mitral valve prolapse, vegetation or strands, left ventricular dilatation and dysfunction, and ascending aortic arch and descending aortic atherosclerotic plaque. Left atrial enlargment was diagnosed if the left atrial cavity was found to be 40 mm. Thrombus in the left atrium or appendage was defined as the presence of a clearly defined intracavitary mass acoustically distinct from underlying endocardium and not caused by the pectinate ridges of the left atrial appendage. Spontaneous echo contrast was defined as dynamic, smoke-like echoes with a characteristic swirling motion, distinct from the echoes caused by excessive gain. Gain controls had been adjusted optimally to minimize artifact by the physician performing the echo examination. Atrial septal aneurysm was defined as a bulge of 15 mm beyond the plane of the atrial septum as measured by TEE. Atrial septal aneurysm was classified according to Hanley’s diagnostic criteria, and modified by PearFrom the Department of Cardiology, Pierantoni Hospital, Forli; Department of Cardiology, University of Modena, Modena; and School of Medicine, University of Ferrara, Ferrara, Italy. Dr. Mattioli’s address is: Department of Cardiology, University of Modena, Via del pozzo 71, 41100 Modena, Italy. E-mail: mattioli.annavittoria@ unimo.it. Manuscript received February 19, 2001; revised manuscript received and accepted May 17, 2001.