doi: 10.1161/hc4601.097997
(Circulation. 2001;104:2517.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Impact of Atrial Fibrillation on the Clinical Course of Hypertrophic Cardiomyopathy
From Cardiologia S. Luca, Azienda Ospedaliera Careggi, Florence, Italy (I.O., F.C., A.D.), and the Minneapolis Heart Institute Foundation, Minneapolis, Minn (S.A.C., J.H.T., B.J.M.).
Correspondence to Dr Iacopo Olivotto, Via Jacopo Nardi 30, Florence, 50132, Italy. E-mail jacoli{at}flownet.it
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Abstract |
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Background Clinical impact of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) is largely unresolved. Thus, we analyzed the prognostic implications of AF in a large, community-based HCM population assembled from Italian and US cohorts.
Methods and Results Occurrence of AF and outcome were assessed in 480 consecutive HCM patients (age at diagnosis, 45±20 years; 61% male) who were followed up for 9.1±6.4 years. AF occurred in 107 patients (22%; incidence, 2%/y) and was independently predicted by advancing age, congestive symptoms, and increased LA size at diagnosis. Patients with AF had increased risk for HCM-related death (OR, 3.7; P<0.002) because of excess heart failure–related mortality but not sudden, unexpected death. This risk associated with AF was substantially greater in patients with outflow obstruction or with earlier development of AF (
50 years of age). AF patients were also at increased risk for stroke (OR, 17.7; P=0.0001) and severe functional limitation (OR for NYHA class III or IV, 2.8; P<0.0001). Compared with those with exclusively paroxysmal AF, patients developing chronic AF showed higher combined probability of HCM-related death, functional impairment, and stroke (P<0.0001). In a subgroup of 37 patients with AF (35%), the clinical course was largely benign in the absence of stroke and severe symptoms.
Conclusions In a community-based HCM population, AF (1) was common, with 22% prevalence over 9 years; (2) was associated with substantial risk for heart failure–related mortality, stroke, and severe functional disability, particularly in patients with outflow obstruction, those 50 years of age, or those developing chronic AF; and (3) was nevertheless compatible with benign outcome in 35% of patients.
Key Words: cardiomyopathy • fibrillation • prognosis
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Introduction |
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Atrial fibrillation (AF) is a commonly reported complication of hypertrophic cardiomyopathy (HCM).1–14 However, studies regarding long-term prognosis of AF in HCM patients have been sparse and often conflicting, with some reports suggesting a generally unfavorable prognosis associated with this arrhythmia5–9 and others indicating a relatively benign course.10,11 Thus, many crucial issues regarding the determinants and clinical impact of AF on HCM patients remain unresolved; therefore, the present investigation was undertaken in our community-based population, including the largest series of HCM patients with AF assembled to date.
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Methods |
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Patient Selection
Two HCM patient cohorts were combined for this analysis; both represent regional populations consecutively enrolled and prospectively followed up at their respective institutions, ie, Azienda Ospedaliera Careggi; Florence, Italy (n=202 patients), and Minneapolis (Minn) Heart Institute (n=278 patients). Therefore, the final study group comprised 480 patients. Selected data from these populations have been previously reported.4,5
Follow-up was 9.1±6.4 years. Mean age at diagnosis was 45±20 years (range, 1 to 87 years); 292 patients (61%) were male; and 125 (26%) had basal left ventricular (LV) outflow obstruction 
30 mm Hg. Maximal LV thickness was 22±5 mm.
Management Strategies
Over the extended period of clinical practice encompassed by the present study (>20 years), treatment of AF in the 2 participating centers was not designed to follow a systematic protocol, involved a number of treating clinicians, and thereby reflected changes in standard practice guidelines.4,5 In general terms, in patients presenting with recent-onset AF, restoration of sinus rhythm was attempted by pharmacological treatment (class IA, IC, or III agents such as quinidine, propafenone, and amiodarone) or DC cardioversion after optimal anticoagulation with warfarin. Conversely, patients with chronic AF were usually treated aggressively to achieve optimal ventricular rate control with verapamil (29%), ß-adrenergic blocking agents (37%), or both (22%). Moreover, amiodarone was often administered in combination with either of these drugs (37%). Warfarin was often used to prevent embolic complications in patients with both paroxysmal and chronic AF.15
Definitions
Hypertrophic Cardiomyopathy
Diagnosis of HCM was based on echocardiographic identification of a hypertrophied, nondilated LV in the absence of another cardiac or systemic disease capable of producing the magnitude of hypertrophy evident.1
Atrial Fibrillation
Documentation of AF was based on ECG recordings obtained either after acute onset of symptoms or fortuitously during routine medical examination in asymptomatic patients. AF was defined as paroxysmal when it was either self-terminating or successfully cardioverted to sinus rhythm; AF was considered chronic when it became established.
Mode of Death
For survival analysis, 3 modes of HCM-related death were defined16: (1) sudden and unexpected death, in which the collapse occurred in the absence or <1 hour from the onset of symptoms in patients who previously experienced a relatively stable or uneventful course (including resuscitated cardiac arrest and appropriate implantable defibrillator interventions); (2) heart failure–related death, which was in the context of progressive cardiac decompensation 1 year before death, particularly if complicated by pulmonary edema or evolution to the end-stage phase (including patients with heart transplantation); and (3) stroke-related death, which occurred in patients who died as a result of ischemic stroke.
Echocardiography
Echocardiographic studies were performed with Hewlett Packard and Toshiba instruments. M-mode left atrial end-systolic dimension (LA) was measured from the parasternal long-axis view. The extent and magnitude of LV hypertrophy were assessed as previously described.17 Peak instantaneous LV outflow tract basal gradient was estimated with continuous-wave Doppler.17
Statistical Analysis
Student’s t test was used for the comparison of normally distributed data. The 
2 test was used to compare noncontinuous variables expressed as proportions. ORs and 95% CIs were calculated by use of univariate and multivariate Cox proportional-hazard regression models.
Because AF was more common in older and more symptomatic patients, direct comparison of AF patients (n=107) with the overall group of HCM patients in sinus rhythm would have exaggerated the impact of AF on HCM prognosis. Therefore, to make our observations regarding the consequences of AF in HCM more accurate, in each of our survival analyses, the 107 HCM patients with AF were matched to HCM control patients in sinus rhythm with similar baseline features—ie, the same sex, age (±2 years), and NYHA functional class at HCM diagnosis. Thus, 86 patients with AF could be matched to a single sinus rhythm control patient. However, for 21 AF patients, 2 or 3 potential sinus rhythm patients were identified as equally deserving control subjects. To avoid selection bias, each of these potential control subjects was included in the matched control group. Therefore, the final number of control patients in sinus rhythm was 133 for the 107 AF patients.
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Results |
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Clinical Manifestations of AF
Occurrence
Of the 480 patients, 25 (5%) developed AF before the initial HCM diagnosis, including 18 in whom AF constituted the initial manifestation of HCM and led to the diagnosis. Of the remaining 455 patients, 82 (17%) developed AF 2 months to 29 years after initial HCM diagnosis, with an annual rate of 9 new cases over a 9-year follow-up (incidence, 2%/y). Overall, AF was documented in 107 patients, with a prevalence of 22%.
Clinical Profile
AF presented as paroxysmal in 77 patients (with subsequent progression to chronic AF in 32) and as chronic AF in 30 other patients (Table 1). Patients with paroxysmal AF had 4±3 documented episodes, 3 in 35 patients (45%) and 10 in 8 (10%). The average progression time from paroxysmal to chronic AF was 5.1±3.5 years (range, 4 months to 14 years).
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Age
Development of AF occurred over a wide age range, from 19 to 82 years (average, 55±15 years). Although occurrence increased progressively with age and was predominant in patients >60 years of age, AF was frequently documented at relatively early ages; ie, 39 patients (36%) developed AF at 50 years of age (Figure 1).
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Determinants of AF
The strongest predictor of AF was increased LA size, independent of age and NYHA functional class (Table 2 and Figures 2 and 3). LA dimension was 49±9 mm in patients who developed AF compared with 41±8 mm in those remaining in sinus rhythm (P<0.001). LA size 45 mm appeared to represent the threshold value associated with substantial risk of subsequent AF development, which was evident even in asymptomatic patients (NYHA class I; Figure 2, bottom), although it doubled when associated with congestive symptoms (NYHA classes II through IV).
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Among the 107 AF patients, a subset of 13 (12%) with normal LA dimension (40 mm) was identified. These patients, compared with AF patients with LA >40 mm, were similar in age, degree of functional limitation, and prevalence of outflow obstruction at diagnosis. Moreover, patients with LA 40 mm and >40 mm were similar with respect to the prevalence of chronic AF (23% versus 29%; P=0.3) and stroke (31% versus 27%, P=0.4).
Maximum LV thickness was greater in patients with AF (23±5 mm) than in patients in sinus rhythm (22±5 mm; P<0.01), but outflow obstruction showed similar frequency (32% versus 25%, respectively; P=0.1) and therefore was not predictive of AF. Moderate to severe mitral regurgitation was present in only a minority of AF patients (n=16; 15%).
Outcome and Functional Status
Mortality
During follow-up, 74 patients died of HCM-related causes, including 38 (35%) among the 107 AF patients (sudden death in 13, heart failure–related death in 17, and stroke-related death in 8; Table 1). When AF patients were compared with 133 matched control subjects in sinus rhythm, AF was associated with markedly increased risk for HCM-related death (Figure 3). Annual HCM-related mortality was 3% in AF patients compared with 1% among control patients in sinus rhythm (P<0.001; Figure 3). This increased risk was explained by an excess stroke- and heart failure–related mortality (P<0.001). Conversely, no association was evident between AF and sudden death (P=0.2). HCM-related mortality was similar among patients with 2 episodes of paroxysmal AF and 3 episodes or chronic AF (37% versus 36%, respectively).
Independent determinants of HCM-related mortality identified with multivariate analysis were AF (OR, 3.7; 95% CI,1.7 to 8.1; P<0.0001); NYHA class III or IV at diagnosis (OR, 2.2; 95% CI,1.2 to 4.1; P=0.01), and older age (>50 years) at diagnosis (OR, 2.0; 95% CI,1.2 to 3.5; P=0.01). Of note, the association of AF and outflow obstruction (30 mm Hg) significantly increased the risk of HCM-related death compared with nonobstructive AF patients (OR, 2.6; 95% CI,1.3 to 5.0; P<0.01; Figure 4).
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Symptomatic Status
AF produced variable consequences in symptomatic status. Over the short term, AF onset produced new or worsening clinical manifestations in most of the 107 patients (n=90; 84%), including dyspnea and/or chest pain (n=54), heart failure, and pulmonary edema (n=16), and impaired consciousness, including syncope (n=20). In a minority of patients (n=17; 16%), new symptoms did not occur after development of AF, which was identified fortuitously during routine outpatient examination. Over the long term, AF was associated with substantial functional deterioration (OR for NYHA class III or IV at the end of follow-up, 2.8; 95% CI,1.8 to 4.5; P<0.0001) compared with 133 control HCM patients in sinus rhythm (Figure 5).
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Stroke
Ischemic strokes were 8 times more frequent among AF patients than among those in sinus rhythm (21% versus 2.6%), occurring after an average of 3.5±3.4 years after AF development and causing death in 8 patients and permanent disability in 11. The prevalence of stroke was independent of whether AF was exclusively paroxysmal or chronic AF (22% versus 27%, respectively; P=0.54) and of the number of AF paroxysms (1 only compared with 2, 23% versus 18%, respectively; P=0.6).
Compared with 133 matched patients in sinus rhythm, the independent OR for stroke in AF patients was 17.7 (95% CI, 4.1 to 75.9; P=0.0001). Of note, patients developing AF 50 years of age were at greater risk (Figure 5); however, fatal strokes occurred only in patients developing AF at >50 years of age (n=8).
Patient Subgroup Analysis
Younger age at AF development was associated with a more unfavorable prognosis. Indeed, patients with early (50 years) compared with later (>50 years) development of AF showed a 1.7-, 3.6-, and 1.5-fold independent increase in HCM-related mortality, stroke prevalence, and progression of symptoms, respectively, at 5 years of follow-up (Figure 5). In addition, compared with patients developing exclusively paroxysmal AF, those developing chronic AF showed a higher combined probability of HCM-related death, functional impairment, and stroke (P<0.0001; Figure 6). However, heart failure–related mortality did not differ between patients with chronic or paroxysmal AF at the end of follow-up (13% versus 18%, respectively; P=0.4).
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Finally, comparison of the 2 HCM cohorts making up the study population showed that the patients from Florence and Minneapolis were similar with regard to most clinical features, including the proportion of patients with severe symptoms (NYHA functional classes III and IV); family history of HCM-related sudden death; or treatment with drugs, dual-chamber pacemakers, implantable defibrillators, or myotomy-myectomy. Moreover, the 2 cohorts showed similar outcome in terms of overall HCM-related mortality, death caused by heart failure or stroke, sudden death, and incidence of stroke. However, Florence patients were somewhat younger (age at diagnosis, 41±17 versus 47±22 years for Minneapolis patients), less often had outflow obstruction (basal gradient 30 mm Hg; 20% versus 34%), showed a higher prevalence of AF (28% versus 18%), and more often received amiodarone (25% versus 17%).
Variability in Prognosis
Of the 107 patients with AF, 37 (35%) had a largely benign outcome; ie, they survived free of stroke with no or only mild symptoms (NYHA class I or II) until the end of follow-up. Conversely, the remaining 70 patients (65%) died of HCM-related causes (n=38), incurred stroke-related disability (n=11), or progressed to NYHA class III or IV (n=21). These patients with adverse prognosis more frequently had chronic AF than those with benign outcome (60% versus 38%; P<0.05) but were otherwise similar with respect to age, initial NYHA class, LA dimension, and follow-up duration (all P>0.6).
Treatment
Prevention of Stroke
After development of AF, 79 of the 107 patients were treated for prevention of thromboembolic complications with warfarin (n=59) or antiplatelet agents (aspirin or ticlopidine; n=20), and 28 did not receive prophylactic treatment. Indeed, stroke was less common among warfarin-treated patients (n=6; 10%) compared with other patients (39% among untreated and 30% among patients on antiplatelet agents; P=0.001 and P<0.05, respectively, versus warfarin).
Pharmacological Maintenance of Sinus Rhythm
Among the 77 patients who experienced paroxysmal AF, 43 received low-dose amiodarone (200 mg/d) for prevention of recurrences (Table 1). However, the duration of sinus rhythm and survival after the first episode of AF were not different in patients with and without amiodarone treatment (P=0.4 and P=0.8, respectively), even after correction for age at AF development, NYHA class, and LA size.
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Discussion |
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Historical Perspective
Studies addressing the prognostic significance of AF in HCM patients are limited and present conflicting conclusions.6–11 Early observational studies (confined largely to patients with obstruction) emphasized the association of AF onset with severe acute clinical deterioration.6,7 Conversely, a more recent study reported no difference in mortality among patients with AF compared with an HCM control group in sinus rhythm.10 However, the latter investigation was based largely on highly selected patients at a tertiary referral center,4,5 and the deleterious impact of AF may have been obscured by the low survival rate in control patients with sinus rhythm.10 Our large, community-based patient cohort with HCM provided a unique opportunity to assess the prognostic impact of AF in a population largely free of such patient selection bias.
AF Prevalence and Age
AF was common in our study population, with a prevalence of 22% and incidence of 2% new cases annually. Thus, HCM patients appear to have a 4- to 6-fold-greater likelihood of developing AF compared with the general population.15,18 AF prevalence increased progressively with age and was predominant in patients >60 years of age. However, it was not rare in younger patients (50 years of age), in whom it was associated with higher risk for clinical deterioration and HCM-related death.
Predictability of AF
AF proved to have a measure of predictability as a HCM complication. We identified several predictors of AF, the most powerful of which, in addition to age and functional class, was LA size. Modest LA enlargement (ie, 40 to 45 mm) is common in HCM, probably the consequence of impaired diastolic function associated with thickened and noncompliant ventricular chambers.19,20 However, the determinants of more marked LA enlargement ultimately predisposing to AF are unresolved. Neither mitral regurgitation nor presence of outflow obstruction reliably predicted the development of AF; indeed, moderate to severe mitral regurgitation was present only in a minority of AF patients (ie, 15%), and outflow obstruction occurred with similar frequency among patients with and without AF.21
It is possible that specific HCM-causing mutations may increase predisposition to AF, eg, by causing an intrinsic atrial myopathy associated with prolonged and fragmented atrial conduction or presently undefined hemodynamic alterations.13 Such a hypothesis could also explain the development of AF in the absence of LA dilatation in a minority of patients (12% with LA 40 mm in our study group).
Impact of AF on HCM-Related Mortality
The present study identifies AF as a key determinant of HCM-related mortality and limiting symptoms. Development of AF may indeed represent a clinical turning point, often dominating the clinical picture and decisively influencing long-term outcome. Over a 9-year follow-up, patients with AF showed an 
4-fold increase in the risk of HCM-related death compared with matched control subjects in sinus rhythm, reflecting significant increases in heart failure and stroke-related mortality. Conversely, we found no relation between clinically evident AF and the occurrence of sudden unexpected death. Therefore, although a causal link between AF and potentially lethal ventricular arrhythmias has been suggested in individual patient reports,7,22 our data do not support AF as a consistent trigger of sudden death in HCM.
HCM-related mortality was not uniformly distributed among our AF cohort but appeared to preferentially affect certain patient subgroups, such as those with early AF development (50 years). Although the more severe consequences associated with development of AF in younger HCM patients have not been explained satisfactorily, AF may represent a marker of generally more aggressive disease.7 In addition, the combination of AF and basal outflow obstruction proved to be particularly adverse,6 suggesting that obstructive patients may rely on LA contraction for LV filling more than nonobstructive patients and thus may be more prone to long-term deterioration after development of AF.19,20
Clinical Heterogeneity
The impact of AF on long-term prognosis shows substantial heterogeneity among individual HCM patients and should not be regarded as invariably unfavorable. Indeed, although AF was strongly associated with HCM-related mortality and clinical deterioration in our overall study population, 35% of AF patients were alive and free of stroke or severe symptoms at the end of follow-up. The likelihood of a benign outcome was significantly higher in patients with exclusively paroxysmal AF compared with those progressing to chronic AF. These observations imply that therapeutic efforts aimed at preventing or delaying the transition from paroxysmal to chronic AF could improve patient outcome.2,15
Given the retrospective nature of the present study, it was not possible to specifically address in precise terms the importance of ventricular rate control in our patients with chronic AF. However, it is unlikely that inadequate rate control represented a major determinant of HCM-related mortality because of the aggressive management with ß-adrenergic blocking agents, calcium channel blockers, and amiodarone at both institutions. Furthermore, heart failure–related mortality did not differ between patients with chronic or paroxysmal AF at the end of follow-up, whereas an excess mortality in the chronic AF group would probably have been expected in the presence of persistently elevated ventricular rates.
The question of whether the clinical importance of AF may be explained primarily by its hemodynamic impact on LV filling or an underlying cardiomyopathic process remains unresolved. The substantial clinical heterogeneity observed in our study cohort, however, suggests that multiple variables may contribute differently to determine the final outcome in the individual patient with AF.1,4,5
AF and Stroke
In the present study, HCM patients with AF showed an 8-fold increase in risk of ischemic stroke (presumably of cardioembolic origin in most patients) compared with control patients in sinus rhythm.6,8,9,16 Of note, the risk of stroke was comparable between patients with chronic and paroxysmal AF and, among the latter, was not related to the number of documented AF episodes. Specifically, patients with a single AF paroxysm had a prevalence of stroke similar to those with multiple episodes. Oral anticoagulation with warfarin in patients with AF provided protection against stroke, which, however, was not absolute even when international normalized ratio values were maintained in the target range.15 Such observations agree with a wide range of clinical studies on AF in patients with heart diseases other than HCM,15 indicating that the threshold for initiation of anticoagulant treatment in HCM should be low.2 Our data suggest that warfarin treatment should be considered for primary prevention of stroke, regardless of the number of documented AF episodes; nevertheless, this clinical decision needs to be tailored in the individual patient with due consideration for risk of hemorrhagic complications, lifestyle modification, and expected compliance.15
Finally, although we could not establish an efficacy for amiodarone in maintaining sinus rhythm after the development of paroxysmal AF in this retrospective study, we do not wish to dismiss the possibility that long-term low-dose amiodarone may be effective in maintaining sinus rhythm in HCM patients, as has been shown prospectively in other cardiac conditions.15,23
Conclusions
AF was a common occurrence in a community-based HCM population, often representing a turning point in the clinical course by virtue of HCM-related mortality, symptomatic deterioration, and risk of stroke. However, the long-term consequences of AF were not uniformly unfavorable, and about one third of the patients experienced an uneventful course, particularly if progression to chronic AF did not ensue. Nevertheless, the powerful independent association of AF with HCM-related mortality and morbidity underlines the necessity for aggressive therapeutic strategies.
Received July 9, 2001; revision received August 16, 2001; accepted August 20, 2001.
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V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society Circulation, August 15, 2006; 114(7): e257 - e354. [Full Text] [PDF]
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I. Olivotto, F. Cecchi, R. Gistri, R. Lorenzoni, G. Chiriatti, F. Girolami, F. Torricelli, and P. G. Camici Relevance of Coronary Microvascular Flow Impairment to Long-Term Remodeling and Systolic Dysfunction in Hypertrophic Cardiomyopathy J. Am. Coll. Cardiol., March 7, 2006; 47(5): 1043 - 1048. [Abstract] [Full Text] [PDF]
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A. Pelliccia, B. J. Maron, F. M. Di Paolo, A. Biffi, F. M. Quattrini, C. Pisicchio, A. Roselli, S. Caselli, and F. Culasso Prevalence and Clinical Significance of Left Atrial Remodeling in Competitive Athletes J. Am. Coll. Cardiol., August 16, 2005; 46(4): 690 - 696. [Abstract] [Full Text] [PDF]
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I. Olivotto, M. S. Maron, A. S. Adabag, S. A. Casey, D. Vargiu, M. S. Link, J. E. Udelson, F. Cecchi, and B. J. Maron Gender-Related Differences in the Clinical Presentation and Outcome of Hypertrophic Cardiomyopathy J. Am. Coll. Cardiol., August 2, 2005; 46(3): 480 - 487. [Abstract] [Full Text] [PDF]
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P. Zimetbaum An Argument for Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation Circulation, June 14, 2005; 111(23): 3150 - 3156. [Full Text] [PDF]
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B. J. Maron Surgery for Hypertrophic Obstructive Cardiomyopathy: Alive and Quite Well Circulation, April 26, 2005; 111(16): 2016 - 2018. [Full Text] [PDF]
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A. Woo, W. G. Williams, R. Choi, E. D. Wigle, E. Rozenblyum, K. Fedwick, S. Siu, A. Ralph-Edwards, and H. Rakowski Clinical and Echocardiographic Determinants of Long-Term Survival After Surgical Myectomy in Obstructive Hypertrophic Cardiomyopathy Circulation, April 26, 2005; 111(16): 2033 - 2041. [Abstract] [Full Text] [PDF]
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C. Autore, P. Bernabo, C. S. Barilla, P. Bruzzi, and P. Spirito The prognostic importance of left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in relation to the severity of symptoms J. Am. Coll. Cardiol., April 5, 2005; 45(7): 1076 - 1080. [Abstract] [Full Text] [PDF]
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X. Liu, F. Ouyang, H. Mavrakis, C. Ma, J. Dong, S. Ernst, D. Bänsch, M. Antz, and K.-H. Kuck Complete pulmonary vein isolation guided by three-dimensional electroanatomical mapping for the treatment of paroxysmal atrial fibrillation in patients with hypertrophic obstructive cardiomyopathy Europace, January 1, 2005; 7(5): 421 - 427. [Abstract] [Full Text] [PDF]
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G. Boriani, B. J. Maron, W.-K. Shen, and P. Spirito Prevention of Sudden Death in Hypertrophic Cardiomyopathy: But Which Defibrillator for Which Patient? Circulation, October 12, 2004; 110(15): e438 - e442. [Full Text] [PDF]
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 R. A. Nishimura and D. R. Holmes Jr. |