Development of an Interleukin-1ß Vaccine in Patients with Type 2 Diabetes.

Interleukin-1ß (IL-1ß) is a key cytokine involved in inflammatory illnesses including rare hereditary diseases and common chronic inflammatory conditions as gout, rheumatoid arthritis, and type 2 diabetes mellitus, suggesting reduction of IL-1ß activity as new treatment strategy. The objective of our study was to assess safety, antibody response, and preliminary efficacy of a novel vaccine against IL-1ß. The vaccine hIL1bQb consisting of full-length, recombinant IL-1ß coupled to virus-like particles was tested in a preclinical and clinical, randomized, placebo-controlled, double-blind study in patients with type 2 diabetes. The preclinical simian study showed prompt induction of IL-1ß-specific antibodies upon vaccination, while neutralizing antibodies appeared with delay. In the clinical study with 48 type 2 diabetic patients, neutralizing IL-1ß-specific antibody responses were detectable after six injections with doses of 900 µg. The development of neutralizing antibodies was associated with higher number of study drug injections, lower baseline body mass index, improvement of glycemia, and C-reactive protein (CRP). The vaccine hIL1bQb was safe and well-tolerated with no differences regarding adverse events between patients receiving hIL1bQb compared to placebo. This is the first description of a vaccine against IL-1ß and represents a new treatment option for IL-1ß-dependent diseases such as type 2 diabetes mellitus (ClinicalTrials.gov NCT00924105).

Real-time left ventricular pressure-volume loops during percutaneous mitral valve repair with the MitraClip system.

BACKGROUND: Percutaneous mitral valve repair with the MitraClip device has emerged as an alternative to surgery for treating severe mitral regurgitation. However, its effects on left ventricular loading conditions and contractility have not been investigated yet. METHODS AND RESULTS: Pressure-volume loops were recorded throughout the MitraClip procedure using conductance catheter in 33 patients (mean age, 78±10 years) with functional (45%), degenerative (48%), or mixed (6%) mitral regurgitation. Percutaneous mitral valve repair increased end-systolic wall stress (WSES; from [median] 184 mm Hg [interquartile range (IQR), 140-200 mm Hg] to 209 mm Hg [IQR, 176-232 mm Hg]; P=0.001) and decreased end-diastolic WS (WSED; from 48 mm Hg [IQR, 28-58 mm Hg] to 34 mm Hg [IQR, 21-46 mm Hg]; P=0.005), whereas the end-systolic pressure-volume relationship was not significantly affected. Conversely, cardiac index increased (from 2.6 L·min(-1)·m(-2) [IQR, 2.2-3.0 L·min(-1)·m(-2)] to 3.2 L·min(-1)·m(-2) [IQR, 2.6-3.8 L·min(-1)·m(-2)]; P<0.001) and mean pulmonary capillary wedge pressure decreased (from 15 mm Hg [IQR, 12-20 mm Hg] to 12 mm Hg [IQR, 10-13 mm Hg]; P<0.001). Although changes in WSES were not correlated with changes in cardiac index, changes in WSED correlated significantly with changes in mean pulmonary capillary wedge pressure (r=0.63, P<0.001). Total mechanical energy assessed by the pressure-volume area remained unchanged, resulting in a more favorable index of forward output (cardiac index) to mechanical energy (pressure-volume area) after mitral valve repair. On follow-up (153±94 days), New York Heart Association functional class was reduced from 2.9±0.6 to 1.9±0.5 (P<0.001) at 3 months, and echocardiographic follow-up documented a stepwise reduction in end-diastolic volume (from 147 mL [IQR, 95-191 mL] to 127 mL [IQR, 82-202 mL]; P=0.036). CONCLUSIONS: Percutaneous mitral valve repair improves hemodynamic profiles and induces reverse left ventricular remodeling by reducing left ventricular preload while preserving contractility. In nonsurgical candidates with compromised left ventricular function, MitraClip therapy could be considered an alternative to surgical mitral valve repair.

The impact of modern noninvasive cardiac imaging on coronary intervention rates.

OBJECTIVES: It remains still unclear whether the use of modern noninvasive diagnostic modalities for evaluation of coronary artery disease (computed tomography coronary angiography (CTCA), nuclear myocardial perfusion imaging (MPI)) were able to change the "diagnostic yield" of invasive coronary angiography (ICA). METHODS: The total number of ICA in the years 2000-2009 was related to the number of percutaneous interventions (PCIs) and we assessed whether there was a significant trend over time using time series analyses. We compared these data with the number of patients undergoing CTCA and nuclear MPI in the same time period. RESULTS: During the 10-year observational period, 23,397 ICA were performed. The proportion of purely diagnostic ICA (without PCI) remained stable over the whole study period (tau = -0.111, P = 0.721). A CTCA program was initiated in 2005 and 1,407 examinations were performed until 2009. Similarly, the number of nuclear MPI increased from 2,284 in the years 2000-2004 to 5,260 in the years 2005-2009 (P = 0.009). CONCLUSION: Despite increasing availability, noninvasive testing modalities did not significantly alter the rate of purely diagnostic ICA, and still are underused as gatekeeper to ICA. Further effort is needed to optimize the use of noninvasive imaging modalities in the work-up process for coronary artery disease.

Haemodynamically irrelevant pericardial effusion is associated with increased mortality in patients with chronic heart failure.

AIMS: Pericardial effusion (PE) is a common finding in cardiac patients with chronic heart failure. The prognostic relevance of a small, haemodynamically non-compromising PE in such patients, however, remains to be determined. METHODS AND RESULTS: All patients referred to our heart failure clinic and having a baseline echocardiography and follow-up clinical visits were included. Patients with a haemodynamically relevant PE, acute myo-/pericarditis, systemic sclerosis, rheumatoid arthritis, heart transplantation, heart surgery within the last 6 months or malignancies within the last 3 years were excluded. Patients with or without a haemodynamically irrelevant PE were compared regarding all-cause mortality as the primary and cardiovascular death or need for heart transplantation as secondary outcomes. A total of 897 patients (824 patients in the control vs. 73 patients in the PE group) were included. In the PE group, left ventricular ejection fraction (LVEF) was lower [31%, interquartile range (IQR): 18.0-45.0] than in controls (34%, IQR: 25.0-47.0; P = 0.04), while the end-systolic diameters of the left ventricle and the left atrium were larger (P = 0.01 and P = 0.001, respectively). Similarly, in patients with PE, the right ventricle (RV) systolic function was lower (P < 0.005 for both the fractional area change and the tricuspid annulus movement), the dimensions of RV and right atrium (RA) were larger (P < 0.05 for RV and P < 0.01 for RA), and the degree of tricuspid regurgitation was higher (P < 0.0001). Furthermore, in the PE group, the heart rate was higher (P < 0.001) and the leukocyte count as well as CRP values were increased (P = 0.004 and P < 0.0001, respectively); beta-blocker use was less frequent (P = 0.04), while spironolactone use was more frequent (P = 0.03). The overall survival was reduced in the PE group compared with controls (P = 0.02). Patients with PE were more likely to suffer cardiovascular death (1-year estimated event-free survival: 86 ± 5 vs. 95 ± 1%; P = 0.01) and to require heart transplantation (1-year estimated event-free survival: 88 ± 4 vs. 95 ± 1%; P = 0.009). A multivariate Cox proportional hazard model revealed the following independent predictors of mortality: (a) PE (P = 0.04, hazard ratio (HR): 1.95, 95% confidence interval (CI): 1.0-3.7), (b) age (P = 0.04, HR: 1.02, 95% CI: 1.0-1.04) and (c) LVEF <35% (P = 0.03, HR: 1.7, 95% CI: 1.1-2.8). CONCLUSION: In chronic heart failure, even minor PEs are associated with an increased risk of all-cause mortality, cardiac death, and need for transplantation.

[Pregnancy Management in a Patient with Long QT Syndrome Type 2 (LQT2) carrier of the variant KCNH2: Trp100X].

INTRODUCTION: Long QT syndrome (LQTS) is a congenital ion channel disorder causing prolonged ventricular repolarization and presents on surface ECG with a prolonged QTc interval. This condition predisposes to ventricular arrhythmias and also sudden cardiac death. LQTS without appropriate therapy during pregnancy and the postnatal phase poses an additionally increased risk of sudden cardiac death due to physiological changes associated with gestation. We present a case report of a 30-year-old pregnant woman with known long QT syndrome Type 2 (LQT2) and discuss the management in cardiological practice.

Marked respiratory-related fluctuations in left ventricular outflow tract gradients in hypertrophic obstructive cardiomyopathy: an observational study.

Aims: Left ventricular outflow (LVOT) obstruction in patients with hypertrophic cardiomyopathy (HCM) is dynamic and sensitive to many variables that affect left ventricular preload, afterload, and contractility. The haemodynamic effect of normal respiration on LVOT obstruction has not been described. Methods and results: We examined 20 patients with HCM who were noted to have phasic respiratory variation of LVOT obstruction on initial transthoracic 2D echocardiogram and Doppler examination. LVOT gradients were re-examined with simultaneous recording of a respirometer. LVOT gradients varied widely during the respiratory cycle; peak gradients were uniformly lowest during inspiration (50.8 mmHg + 25.6) and highest during expiration (90.1 mmHg + 41.8). On average, there was 82.4% ± 39.1 (P ≤ 0.0001) incremental change from inspiration to expiration, in the severity of LVOT obstruction. In 11 patients with mitral annulus inflow, LV inflow (preload) was decreased during inspiration. In 16 patients with isovolumic relaxation time and ejection time measurements, decreased left atrial filling pressure was noted during inspiration, consistent with decreased LVOT obstruction. When compared with a control group of 20 HCM patients who did not have respiratory variation, the study group patients were more overweight (mean body mass index cases 35.1 ± 7.3 vs. control group 29.1 ± 5.1, P = 0.0045) and more likely to have sleep-disordered breathing (n = 15 study group, n = 5 control group). Conclusions: Counterintuitive respiratory-related fluctuations in LVOT gradients were observed in this case series of 20 HCM patients. These findings challenge traditional haemodynamic teaching and demonstrate the contribution of LV transmural pressure to LVOT obstruction in certain HCM patients.

Diastolic function assessment in clinical practice: the value of 2-dimensional echocardiography.

BACKGROUND: The aim of this study was to test the hypothesis that diastolic dysfunction associated with increased filling pressures is unlikely in a structurally normal heart and to assess whether 2-dimensional echocardiography can facilitate diastolic function grading in a clinical setting. METHODS: Consecutive patients referred for transthoracic echocardiography received a comprehensive Doppler echocardiographic evaluation of diastolic function and measurements of left ventricular ejection fraction (EF) by biplane Simpson's method, left atrial volume index (LAVI) by area-length method, and interventricular septal thickness (IVS) from 2-dimensional images. Patients with atrial fibrillation, cardiac pacemaker, severe mitral regurgitation, or mitral prosthesis were excluded. RESULTS: Of 187 patients, 38 had normal diastolic function and 77 had grade I; 54, grade II; and 18, grade III diastolic dysfunction. The presence of any 2-dimensional abnormality (EF < 55%, IVS > or = 14 mm, LAVI > or = 40 mL/m2) identified any diastolic dysfunction (grade I-III) with 92.6% sensitivity and 92.1% specificity. In a receiver operating characteristic analysis to predict any diastolic dysfunction, the areas under the receiver operating characteristic curve for EF, IVS, and LAVI and the sum of all 3 abnormalities were 0.69, 0.81, 0.87, and 0.95 (all P < .0001), respectively. Among all patients with at least one abnormality, the probability of diastolic dysfunction was 97.9% (138/141). Interpretation of 2-dimensional abnormalities together with the mitral inflow pattern resulted in correct diastolic function grading in 98.4% (184/187). CONCLUSIONS: Structural abnormalities on 2-dimensional echocardiography are not only statistically associated with diastolic dysfunction, but the combination of LAVI, EF, and IVS is of practical value for diastolic function grading. The presence of any such 2-dimensional abnormality should be considered indicative of diastolic dysfunction.

Hand-carried ultrasound-guided pericardiocentesis and thoracentesis.

To date, ultrasound-guided centeses have required the use of large, diagnostic ultrasound equipment that can be cumbersome and not readily available. In this study, we sought to evaluate the use of portable, hand-carried ultrasound devices in guidance of pericardiocentesis and thoracentesis. Hand-carried ultrasound was used to define location of the maximal extent of the effusion and its proximity to the skin surface, confirm needle entry and site, and to evaluate postprocedural result. A total of 12 patients who were stable and hospitalized were prospectively enrolled, 9 for pericardiocentesis and 3 for thoracentesis. We concluded that under the direction of a suitably trained physician, hand-carried ultrasound provided images suitable for guidance of a pericardiocentesis or thoracentesis preprocedurally, intraprocedurally, and postprocedurally.

Adventitial response to intravascular brachytherapy in a rabbit model of restenosis.

BACKGROUND: The incidence of late major adverse cardiac events (MACE) after coronary brachytherapy is higher than in controls. Because expansive remodeling has been shown to correlate with poor clinical outcome after vascular interventions, we studied adventitial changes after intravascular irradiation in a rabbit model. METHODS: Twenty normolipidemic rabbits underwent balloon injury in both external iliac arteries. One artery was assigned for subsequent irradiation with a 90Y source (15 Gy or 30 Gy at 0.5 mm in the vessel wall). After four weeks morphometric measurements were made and cell density and collagen amount determined. Staining for Ki67 identified proliferating cells; apoptotic cells were identified by TUNEL staining. Proliferative and apoptotic indices were calculated as the number of respective positive cells/total cell count x100. RESULTS: The neointimal area decreased to 0.27 +/- 0.3 mm2 after irradiation compared with 0.55 +/- 0.2 mm2 in controls (p=0.007), whereas adventitial area increased from 0.62 +/- 0.3 mm2 to 0.87 +/- 0.3 mm2 (p=0.02). Irradiation reduced both the proliferative (0.95 +/- 2.6 vs. 3.73 +/- 4.7, p=0.026) and apoptotic (0.006 +/- 0.02 vs. 0.107 +/- 0.2, p=0.03) indices in the neointima, but not in the other arterial-wall layers. Collagen amount and arterial remodeling did not differ between the groups. There was no difference between 15 and 30 Gy in any of the parameters, although adventitial thickening was more pronounced in the high-dose group. CONCLUSIONS: In normolipidemic rabbits, intravascular beta-irradiation after balloon angioplasty is associated with an increase in neoadventitia and a reduction of neointima. It is conceivable that this phenomenon may contribute to the increased incidence of late MACE after vascular brachytherapy.

Osteoporosis treatment and progression of aortic stenosis.

A decrease in bone mineral density has been reported to be associated with increased progression of aortic stenosis (AS). We hypothesized that osteoporosis treatment (OT) is associated with decreased progression of AS. We performed an observational study of patients with AS from our echocardiographic database comparing 18 patients on OT (bisphosphonates, calcitonin, or estrogen receptor modulators) with 37 patients not on OT. All patients had serial echocardiograms. Patients with mitral stenosis, aortic valve replacement, renal failure, calcium disorders, or left ventricular ejection fraction <40% were excluded. Aortic valve area (AVA) was calculated using the continuity equation. There was no significant difference in age, gender, renal function, hypertension, statin use, diabetes, or calcium level between the 2 groups. Mean baseline AVA was 1.33 cm(2) and not significantly different between groups. After a mean of 2.4 +/- 1.0 years, mean annual changes in AVA were -0.22 +/- 0.22 cm(2) in those not on OT and -0.10 +/- 0.18 cm(2) in patients receiving OT (p = 0.025). There was a graded association between AS progression rate and OT. In a multivariable analysis including age, gender, and statin use, only OT was associated with a change in AVA. In conclusion, OT is strongly and independently associated with decreased progression of AS. This association warrants investigation in a larger, prospective study.

Amounts of aortic atherosclerosis in patients with aortic stenosis as determined by transesophageal echocardiography.

We quantified the graded amounts of aortic atherosclerosis (AA) in patients with aortic stenosis (AS) to better delineate the need for preprocedural risk stratification. Complex AA is strongly related to embolic events, especially during open heart surgery and catheterization. Despite the frequency of these procedures in patients with AS and the increased prevalence of atherosclerosis, current guidelines do not recommend screening for AA. Patients with concomitant transesophageal and transthoracic echocardiograms were retrospectively identified. AS and AA were graded by expert reviewers as mild, moderate, and severe according to established guidelines. Three hundred sixty patients (212 men, mean age 69 +/- 14 years) were identified, 186 (52%) without AS, 82 (23%) with mild AS, 55 (15%) with moderate AS, and 37 (10%) with severe AS. There was a strong graded positive association between AA and AS (p <0.00001). The prevalence of severe AA increased across grades of AS. Of all patients with severe AS, 54% had severe AA. Of patients with severe AS not referred for an embolic event, 57% had severe AA. The odds ratio for severe AA was 4.9 (95% confidence interval 2.3 to 10.3) in patients with severe AS compared with without AS. In conclusion, AS and AA are closely correlated. The majority of patients with severe AS have severe AA, even without previous thromboembolic events. This significant atherosclerotic burden may warrant preprocedural risk assessment with transesophageal echocardiography.

Arterioventricular coupling and ventricular efficiency after antihypertensive therapy: a noninvasive prospective study.

Patients with hypertension exhibit impaired energetic coupling between the ventricle and the arterial system, leading to reduced cardiac mechanic efficiency and exercise capacity. We tested whether blood pressure normalization with current antihypertensive therapy can improve arterioventricular coupling. Eighteen hypertensive patients without other cardiovascular disease were examined before and after antihypertensive therapy. Transthoracic echocardiography was performed. Central aortic pressure waveforms, including end-systolic pressure, were derived from radial artery applanation tonometry. Afterload was increased with isometric handgrip exercise. Central aortic end-systolic pressure and ventricular volumes at rest and handgrip were used to calculate ventricular elastance, effective arterial elastance, arterioventricular coupling (effective arterial elastance/ventricular elastance), and mechanical efficiency. After 142+/-67 days, systolic blood pressure decreased from 150.9+/-14.6 to 119.8+/-9.2 mm Hg (P<0.00001), diastolic blood pressure from 85.9+/-14.8 to 68.8+/-8.4 mm Hg (P=0.00002), and cardiac output from 5.8+/-1.7 to 4.9+/-1.8 L/min (P=0.03). Resting left ventricular end-systolic volume, ejection fraction, and septal thickness did not change. Ventricular elastance increased from 1.7+/-1.0 to 3.2+/-1.4 mm Hg/mL (P=0.00002), whereas effective arterial elastance decreased from 1.4+/-0.5 to 1.2+/-0.4 mm Hg/mL (P=0.02). Effective arterial elastance/ventricular elastance decreased in all patients, from 1.1+/-0.8 to 0.4+/-0.2 (P=0.0002). Efficiency improved at rest (72.9+/-5.8% versus 83.5+/-5.7%; P<0.00001) and during handgrip (63.5+/-7.8% versus 78.9+/-7.1%; P<0.00001). In hypertensive patients, optimal brachial and central blood pressure reduction shifts arterioventricular coupling from cardiac output maximization to ventricular mechanical efficiency optimization. This occurs before significant changes in ventricular geometry and may be responsible for early clinical improvements.

Increased left atrial volume index: potent biomarker for first-ever ischemic stroke.

OBJECTIVE: To establish the incidence and correlation of increased left atrial volume index (LAVI) in patients with first-ever ischemic stroke. PARTICIPANTS AND METHODS: Using our institution's epidemiological database, we defined a cohort of 432 patients (cases) who underwent transthoracic echocardiography within 60 days of first ischemic stroke between January 1, 1985, and December 31, 1994. Left atrial volume was measured with the biplane area-length method, indexed to body surface area (LAVI, expressed as mL/m(2)). The control group consisted of 416 community residents who underwent transthoracic echocardiography as participants in a stroke risk factor study. Increased LAVI was defined as 28 mL/m(2) or higher. Survival in patients was compared with expected survival among white Minnesotans and was further modeled as a function of age, sex, LAVI, and clinical risk factors. RESULTS: Among the included 306 patients, 230 (75%) had increased LAVI (mean+/-SD, 49+/-21 mL/m(2)). Patients with increased LAVI were older than those with normal LAVI (mean+/-SD age, 76+/-11 vs 71+/-13 years; P=.003) and had more cardiovascular risk factors (mean+/-SD number, 1.8+/-0.07 vs 1.3+/-0.89; P<.001). Mean LAVI was higher in cases than in age- and sex-matched controls (P<.001). At 5-year follow-up, cases showed excess mortality compared with age-matched controls (P=.001). After variables were adjusted for age, sex, and clinical risk factors, LAVI was independently associated with mortality. CONCLUSION: A useful index for prediction of adverse cardiovascular events, LAVI might also predict first ischemic stroke and subsequent mortality.

Predictive value of normal left atrial volume in stress echocardiography.

OBJECTIVES: Our objective was to evaluate whether normal left atrial volume index (LAVI) is a predictor of a normal stress echocardiogram and thus a predictor of low ischemic risk. BACKGROUND: Left atrial enlargement is closely related to the chronicity and intensity of the burden of increased ventricular filling pressure. Typically ischemic heart disease (IHD) has a long period of subclinical dysfunction. Increased filling pressure, reflected by enlarged LAVI, is hypothesized to mirror the burden of subclinical and overt IHD. We hypothesized that a normal LAVI might also be useful in predicting low IHD risk. METHODS: One hundred eighty randomly selected patients (mean age, 63 +/- 15 years; 53% men) underwent outpatient exercise or dobutamine stress echocardiography for known or suspected coronary artery disease. Left atrial volume index was measured retrospectively with the biplane area-length method. The stress echocardiogram was interpreted as abnormal if wall motion abnormalities (WMAs) were noted at rest and/or with stress. RESULTS: Left atrial volume index was categorized as < or =28 ml/m2 (normal), 28.1 to 32 ml/m2, 32.1 to 36 ml/m2, and >36 ml/m2. Abnormal stress echocardiography was identified in 57 patients (31.7%). The percentage of abnormal stress echocardiograms in each LAVI category was 5.7%, 21.9%, 38.7%, and 54.7%, respectively. The negative predictive value for LAVI < or =28 ml/m2 was 94.3%. CONCLUSIONS: Normal resting LAVI (< or =28 ml/m2) was strongly predictive of a normal stress echocardiogram. Left atrial volume index might be a simple means of identifying patients with low ischemic risk and should be further evaluated as a complement to the assessment of ischemic risk.

Left atrial volume predicts the risk of atrial fibrillation after cardiac surgery: a prospective study.

OBJECTIVES: This study sought to identify preoperative predictors of postoperative atrial fibrillation (POAF) among patients undergoing cardiac surgery. BACKGROUND: Postoperative atrial fibrillation is frequent after cardiac surgery and is associated with increased morbidity, mortality, prolonged hospital stay, and increased costs. Left atrial volume (LAV), a marker of chronically elevated left ventricular filling pressure, is a predictor of atrial fibrillation (AF) in the nonsurgical setting. METHODS: A total of 205 patients (mean age 62 +/- 16 years; 35% women) undergoing cardiac surgery were prospectively enrolled. Clinical risk factors were obtained by detailed medical record review and patient interview. Preoperative transthoracic echocardiograms were performed for assessment of LAV, left ventricular ejection fraction, and diastolic function. Follow-up was complete. Detection of POAF was based on documentation of AF episodes by continuous telemetry throughout hospitalization. RESULTS: Postoperative atrial fibrillation occurred in 84 patients (41.4%) at a median of 1.8 days after cardiac surgery. The LAV was significantly larger in patients in whom AF developed (49 +/- 14 ml/m2 vs. 39 +/- 16 ml/m2, p = 0.0001). Patients with LAV >32 ml/m2 had an almost five-fold increased risk of POAF, independently of age and clinical risk factors (adjusted hazard ratio 4.84, 95% confidence interval 1.93 to 12.17, p = 0.001). Age and LAV were the only independent predictors of POAF. The area under the receiver-operator characteristics curve to predict POAF was 0.729 for LAV and 0.768 for the combination of LAV and age (both p < 0.0001). CONCLUSIONS: The LAV is a strong and independent predictor of POAF. Risk stratification using LAV and age enables clinicians to identify high-risk patients before cardiac surgery.

Left atrial volume predicts cardiovascular events in patients originally diagnosed with lone atrial fibrillation: three-decade follow-up.

AIMS: The objectives of this study were to determine the long-term outcome and the predictors of adverse events in patients originally diagnosed with lone atrial fibrillation (AF). METHODS AND RESULTS: This population-based historical cohort study comprised 46 residents of Olmsted County, MN, USA, with well-documented, clinically defined lone AF and a complete two-dimensional echocardiographic examination. The original echocardiographic videotape recordings were analysed in a blinded fashion for left atrial volume (LAV) and left ventricular ejection fraction. With 1296 person-years of follow-up, the median duration of AF was 27 (first quartile=24, third quartile=33) years. Twenty-three (50%) patients developed events. Cerebral infarction occurred in seven patients, myocardial infarction in 11, and congestive heart failure in 16. In a multivariable analysis, patients with indexed LAV >or=32 mL/m(2) had a significantly worse event-free survival (adjusted HR, 4.46; 95% CI, 1.56-12.74; P=0.005). All cerebral infarctions occurred in patients with an indexed LAV >32 mL/m(2). CONCLUSION: Patients originally diagnosed with benign lone AF follow divergent courses based on LAV. Those originally diagnosed with lone AF and normal sized atria had a benign clinical course throughout the long-term follow-up. Patients with increased LAV at diagnosis or later during the follow-up experienced adverse events.