Significance of Papillary Muscle Abnormalities Identified by Cardiovascular Magnetic Resonance in Hypertrophic Cardiomyopathy

Significance of Papillary Muscle Abnormalities Identified by Cardiovascular Magnetic Resonance in Hypertrophic Cardiomyopathy Caitlin J. Harrigan, BAa, Evan Appelbaum, MDa,b, Barry J. Maron, MDd, Jacqueline L. Buros, BAa, C. Michael Gibson, MD, MSa,b, John R. Lesser, MDd, James E. Udelson, MDe, Warren J. Manning, MDa,b,c, and Martin S. Maron, MDe,* Increased thickness of the left ventricular (LV) wall is the predominant feature of the hypertrophic cardiomyopathy (HC) phenotype. The structural characteristics of the LV papillary muscles (PMs) have received little attention. In this study, cardiovascular magnetic resonance (CMR) was used to characterize PM morphology in a large HC population. Cine and delayed enhancement (DE) CMR images were obtained in 201 patients with HC and 43 control subjects. PM number and mass index were greater in patients with HC compared with controls (2.5 vs 2.1, p <0.001, and 6 ⴞ 2 vs 3 ⴞ 2 g/m2, p <0.001, respectively), including 109 (54%) with PM mass >7 g/m2 (>2 SDs above the mean for controls). Greater LV wall mass index was associated with more substantial PM mass (r ⴝ 0.09, p <0.001). Furthermore, 12 patients with HC (19%) had normal LV mass with localized wall thickness but increased PM mass. In patients with HC with LV outflow obstruction at rest, PMs were positioned closer to the ventricular septum (displaced anteriorly: 58% vs 42% for subjects without obstruction, p ⴝ 0.02), with more marked hypertrophy (9 ⴞ 5 vs 6 ⴞ 4 g/m2, p <0.001). Preoperative CMR identified 3 patients with accessory, anteriorly displaced PMs judged to contribute to outflow obstruction, which were resected during septal myectomy. DE of the PMs was identified in 13 patients with HC (6%), including 3 with DE confined to PMs. In conclusion, CMR demonstrates LV PMs to be part of the cardiomyopathic process in HC, with increases in number and mass, and not uncommonly associated with remodeling with DE. The identification of accessory PMs may be useful in planning preoperative strategy. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;101:668 – 673)

Left ventricular (LV) hypertrophy is the predominant phenotypic feature of hypertrophic cardiomyopathy (HC).1–5 Although papillary muscles (PMs) are part of the LV chamber anatomically,6 – 8 the significance and diverse morphology of these structures in HC has not been systematically characterized. Cardiovascular magnetic resonance (CMR), which provides complete tomographic imaging of the heart with high spatial resolution, creates a unique opportunity to assess the PMs in HC with precision.9 –13 Therefore, we applied CMR to a large cohort of patients with HC to assess the morphology and clinical significance of the PMs. Methods Selection of patients: We prospectively evaluated 201 patients with HC who presented to the Tufts-New England a Perfuse Core Laboratory and Data Coordinating Center, Harvard Medical School; Departments of bMedicine (Cardiovascular Division) and c Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; dThe Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota; and e Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts-New England Medical Center, Boston, Massachusetts. Manuscript received July 12, 2007; revised manuscript received and accepted October 2, 2007. *Corresponding author: Tel: 617-636-8066; fax: 617-636-5913. E-mail address: [email protected] (M.S. Maron).

0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.10.032

Medical Center (Boston, Massachusetts) or the Minneapolis Heart Institute Foundation (Minneapolis, Minnesota) from November 2001 to November 2006. The diagnosis of HC was based on 2-dimensional echocardiographic demonstration of a hypertrophied nondilated left ventricle in the absence of another cardiac or systemic disease capable of producing a similar magnitude of hypertrophy.2,3,14 LV outflow tract obstruction was defined as a peak instantaneous outflow gradient ⱖ30 mm Hg assessed by continuous-wave Doppler echocardiography under rest conditions.15 A group of 43 healthy adult subjects (mean age 49 ⫾ 18 years, 38% men) who underwent CMR at the Beth Israel Deaconess Medical Center Cardiac MR Center (Boston, Massachusetts), served as controls. None of these control subjects had evidence of structural heart disease by echocardiography and CMR or clinical histories of cardiac disease or systemic hypertension. All study patients signed a statement previously approved by the investigational review boards of the respective participating institutions agreeing to the use of their medical information for research purposes. CMR: CMR imaging was performed using a Philips Gyroscan ACS-NT (Philips Medical Systems, Best, The Netherlands) or a Siemens Sonata (Siemens Medical Systems, Erlangen, Germany) 1.5-T whole-body CMR scanner www.AJConline.org

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For the purposes of this study, we defined the following: PM mass as the mass confined to PMs; LV wall mass as that of the LV wall, excluding PMs and overlying trabeculations; and total LV chamber mass as the combined PM and LV wall mass. LV wall mass was increased if ⱖ2 SDs greater than the mean of published normative values.17 PM mass was increased when ⱖ2 SDs greater than the mean of control subjects and extreme when ⱖ4 SDs greater than the mean of control subjects. The presence of hyperenhancement in the left ventricle and PMs was assessed on contrast-enhanced short-axis images, using a threshold of ⱕ6 SD greater than the mean signal intensity of nulled myocardium.18 –21

Figure 1. Papillary muscles from a patient with HC at the midventricular level in end-diastole. (A) Method assessing PMs by tracing endocardial borders for planimetry. The PMs in this patient showed an extreme increase in mass (11 g/m2). Tracing of endocardial and epicardial left ventricular borders is also shown. (B) Multiple accessory PMs, 4 in number (arrows). (C) Increased PM mass in a patient with normal left ventricular mass. (D) Anteriorly displaced accessory PM that was subsequently resected (arrow) during surgical septal myectomy. LV ⫽ left ventricle; RV ⫽ right ventricle; VS ⫽ ventricular septum.

using a commercial cardiac coil. Electrocardiographically gated, breath-hold cine images were acquired in multiple short axes using steady-state free precession sequences. Full ventricular coverage was achieved with contiguous 10-mmthick slices. Delayed enhancement (DE) CMR imaging was performed 15 minutes after the intravenous administration of gadolinium diethylenetriamine penta-acetic acid 0.2 mmol/kg (Magnevist; Schering AG, Berlin, Germany) with a breath-hold segmented inversion-recovery sequence (inversion time 240 to 300 ms), acquired in the same orientations as the cine images. CMR measurements: LV volume, mass, wall thickness, and ejection fraction were analyzed using a commercial workstation (QMass MR version 6.1.6; Medis Medical Imaging Systems, Leiden, The Netherlands).16 Individual PMs in the left ventricle were defined on the short-axis cine images as structures attached to the LV free wall and contiguous with the mitral valve via the chordae tendineae. Individual PMs were manually planimetered separately on each end-diastolic frame on short-axis images in every slice in which muscle was visualized. PM mass was calculated after the exclusion of LV wall and intertrabecular blood pool (Figure 1). The shortest distance from the ventricular septum to the leading margin of the most anteriorally displaced PM was manually measured on the short-axis slice that traversed the body of the PMs. After identification of the primary anterolateral and posteromedial PMs, other smaller PMs with chordal attachments to the mitral valve apparatus and that inserted into the LV wall were regarded as accessory. Particular care was taken to distinguish trabeculations and the PMs as distinct from the LV wall. Among the patients who underwent surgical septal myectomy, operative reports were reviewed to determine whether accessory PMs had been identified and resected.

Reproducibility: All CMR studies were analyzed at 1 center (Perfuse Core Laboratory and Data Coordinating Center, Harvard Medical School, Boston, Massachusetts) by 1 observer (CJH) and reviewed and confirmed by a second expert reader (EA). To assess intraobserver variability, 30 CMR studies were reanalyzed 6 months apart, blinded to the previous results. To assess interobserver variability, a second observer (EA) independently analyzed a subset of 15 CMR studies. Statistical analysis: Normally distributed variables are expressed as mean ⫾ SD. All continuous variables were tested for normality using the Shapiro-Wilk test. A paired, 2-tailed Student’s t test was implemented to assess significance between continuous variables. Comparisons of nonnormally distributed variables between groups were evaluated using Wilcoxon’s rank-sum test. Correlations between 2 continuous variables were assessed using Spearman’s ranked correlation statistic (r). Comparisons of proportions were made using Pearson’s chi-square test or Fisher’s exact test as appropriate. All analyses were performed using Stata version 9.2 (StataCorp LP, College Station, Texas). A p value ⬍0.05 was considered significant. Results Study group characteristics: The demographics of the patients with HC and control subjects are listed in Table 1. Controls and patients with HC did not differ with respect to body surface area (p ⫽ NS; Table 1). PM morphology: The number of LV PMs in patients with HC was 2.5 ⫾ 0.6 and significantly greater than in controls (2.1 ⫾ 0.4) (p ⬍0.001; Figure 2), with no difference with respect to gender (Table 1). Three or 4 PMs were identified in 97 patients with HC (48%) but in only 6 (14%) of controls (p ⬍0.001; Figure 1). The mean PM mass index in patients with HC was 6 ⫾ 2 g/m2 and was increased twofold compared with controls (3 ⫾ 2 g/m2) (p ⬍0.001), with no difference according to gender (Figure 3). In addition, this difference in PM mass index between patients with HC and controls remained significant even after adjusting for age (p ⬍0.001), gender (p ⬍0.001), and enrolling center (p ⬍0.0001). Of the 201 patients with HC, 109 (54%) had markedly increased PM mass indexes ⱖ7 g/m2 (ⱖ2 SD greater than the mean for controls), including 35 (17%) who exhibited extreme hypertrophy (ⱖ11 g/m2; Figure 1). PM mass was unrelated to age (p ⫽ 0.09) or heart failure symptoms (p ⫽ 0.9).

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Table 1 Demographics of the hypertrophic cardiomyopathy patients and control subjects Variable

Age (yrs) Men Body surface area (g/m2) LV outflow tract obstruction ⱖ30 mm Hg PM number PM mass (g) PM mass index (g/m2) PM DE Maximal LV wall thickness (mm) Left ventricle end-diastolic dimension (mm) LV mass (g) LV mass index (g/m2) LV DE

Patients With HC (n ⫽ 201)

42 ⫾ 18 143 (71%) 1.96 ⫾ 0.30 24% 2.5 ⫾ 0.6 12 ⫾ 6 6⫾2 13 (6%) 22 ⫾ 5 52 ⫾ 7 223 ⫾ 91 102 ⫾ 39 103 (81%)

Controls (n ⫽ 43)

49 ⫾ 18 21 (48%) 1.93 ⫾ 0.30 0 2.1 ⫾ 0.4 6⫾2 3⫾2 0 12 ⫾ 3 52 ⫾ 6 104 ⫾ 31 56 ⫾ 10 0

p Value

0.01 0.004 0.4 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 0.6 ⬍0.0001 ⬍0.0001 ⬍0.0001

HC by Gender (n ⫽ 201) Men (n ⫽ 143)

Women (n ⫽ 58)

p Value

41 ⫾ 17 N/A 2.03 ⫾ 0.28 20% 2.6 ⫾ 0.6 13 ⫾ 5 6⫾2 9 (6%) 22 ⫾ 5 53 ⫾ 7 228 ⫾ 79 111 ⫾ 34 75 (52%)

43 ⫾ 17 N/A 1.77 ⫾ 0.26 33% 2.5 ⫾ 0.6 10 ⫾ 4 6⫾2 3 (5%) 22 ⫾ 5 49 ⫾ 6 170 ⫾ 64 96 ⫾ 31 28 (48%)

0.5 N/A ⬍0.0001 0.06 0.6 ⬍0.0001 0.1 0.8 0.9 0.001 ⬍0.0001 0.002 0.6

Figure 2. Number of PMs identified by CMR in 201 patients with HC and 43 healthy control subjects.

Figure 3. Comparison of PM mass index in patients with HC and controls and according to gender.

PM mass contributed ⱖ5% of the total LV chamber mass index in 108 patients with HC (54%) and ⱖ10% in 7 patients (3%). In addition, there was a significant correlation between PM mass index and LV wall mass index (r ⫽ 0.09, p ⬍0.001; Figure 4) and maximal LV wall thickness (r ⫽ 0.02, p ⫽ 0.07). Twelve patients with HC with increased LV wall thickness (19%, 11 of 12 male) had normal wall mass indexes (ⱕ2 SD greater than the mean of normal controls) but increased PM mass indexes (ⱖ7 g/m2; Figure 1). This subgroup of patients with HC did not differ from other patients with HC with regard to age (p ⫽ 0.6), heart failure symptoms (p ⫽ 0.2), presence of LV outflow obstruction at rest (p ⫽ 0.6), or DE in the LV wall or the PMs (p ⫽ 0.6 for both). PMs showed DE in 13 patients with HC (6%) but in none of the controls (p ⫽ 0.1). DE was present in the LV wall and the PMs in 10 patients with HC (77%) and confined to PMs in the other 3 (25%) (Figure 5). Patients with HC with PM DE had significantly increased PM mass indexes compared with other patients (16 vs 11 g/m2, p ⬍0.001).

PM mass indexes in patients with HC with LV outflow obstructions (ⱖ30 mm Hg at rest) exceeded those in patients without obstructions (6.5 ⫾ 2 vs 5.9 ⫾ 2 g/m2, p ⫽ 0.001). In patients with obstructive HC (n ⫽ 48), PM mass index was relatively weakly but significantly correlated with the magnitude of outflow gradient (R2 ⫽ 0.03, p ⫽ 0.03). In addition, nonobstructive patients with HC had PM mass indexes greater than those of controls (5.9 ⫾ 2.2 vs 3.2 ⫾ 0.8 g/m2, p ⬍0.001). The minimum distance between the PM and the ventricular septum (anterolateral 42%, posteromedial 58%) was significantly less in patients with obstructions compared with those without obstructions (6.3 ⫾ 4 vs 9.0 ⫾ 5 mm, p ⬍0.001). With CMR, 15 patients with HC with LV outflow obstructions at rest had hypertrophied PMs identified in close proximity to the anterior septum that were judged to be accessory. In 3 of those patients, accessory PMs were resected at the time of septal myectomy (when judged by the surgeon to be contributing to LV outflow obstruction; Figure 1).

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Figure 4. Scatter plot comparing PM mass index and LV mass index in patients with HC by gender.

Figure 5. Short-axis DE images in patients with HC at the midventricular level in end-diastole. (A) DE confined to anterolateral (thick arrow) and posteromedial PMs (thin arrow), but not evident in the left ventricle. (B) DE involving the anterolateral PM (thick arrow) and ventricular septum (VS) (thin arrow). (C) Extensive subendocardial and transmural DE throughout the LV free wall (thick arrows), with sparing of the PMs (thin arrows). RV ⫽ right ventricle.

Reproducibility: There was good interobserver and intraobserver reproducibility of PM mass and number. Interobserver and intraobserver differences were 2.8 ⫾ 2.9 g (82% agreement) and ⫺1.1 ⫾ 4.0 g (91% agreement) for PM mass and 0.07 ⫾ 0.59 (60% agreement) and ⫺0.06 ⫾ 0.59 (67% agreement) for PM number, respectively. Discussion The present CMR data demonstrate that the LV PMs are commonly involved in HC disease expression. PM hypertrophy was seen in ⬎50% of patients, with twofold greater muscle mass than controls, including about 20% with marked hypertrophy. These differences persisted after cor-

rection for body surface area and were unrelated to gender. In addition, the absolute number of PMs identified in patients with HC significantly exceeded that in controls, with about half of the study group having multiple PMs (i.e., 3 or 4). Furthermore, we identified a novel subgroup of patients with HC with normal LV mass (but with localized increase in wall thickness), who nevertheless showed substantially hypertrophied PMs with increased mass. In such patients, the cardiomyopathic process either disproportionally involved PMs compared with the LV wall or preferentially affected the PMs. Hypertrophy of LV PMs paralleled that of the LV wall. In this regard, the magnitude of PM mass was significantly correlated with maximal LV wall thickness

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and myocardial mass. In addition, about 5% of patients in this study had postcontrast DE (i.e., indicative of myocardial fibrosis) of the PMs. Although DE was much more common within the LV wall, its presence confined to the PMs in 3 patients underscores the premise that the PMs may be part of the adverse remodeling process occurring in HC. Furthermore, it is possible that isolated PM DE could have important clinical consequences in some patients with HC. In this regard, we recently evaluated a young patient with HC who died suddenly22 but did not demonstrate any of the traditional risk markers for sudden death.23 He was subsequently found only to have scarring of the anterolateral PM apex in the absence of myocyte disarray or replacement fibrosis elsewhere in the left ventricle. This finding suggested a possible role for PM remodeling in the assessment of risk in HC. A recent American Heart Association classification of cardiomyopathies characterized HC as a disease morphologically limited to the LV wall.24 However, additional data, including a recent report showing extension of the hypertrophic process into the right ventricular wall in some patients with HC,25 as well as the data presented here for PMs, argue for expansion of that definition to portray a more extensive morphologic process. We found PM mass index to be significantly greater in patients with HC with LV outflow obstruction compared with those without obstruction. Also, PM mass index was significantly greater in nonobstructive patients with HC compared with controls. The totality of these findings suggest that PM hypertrophy in HC may be not only a manifestation of the primary genetic substrate but also a secondary consequence of LV pressure overload from outflow obstruction. Indeed, these findings are consistent with the recent observation that LV mass index is greatest in obstructive patients,26 thereby adding support to the construct that obstruction can lead to secondary hypertrophy in this genetic cardiomyopathy. In 1 large operative series, submitral structures, including accessory PMs that were judged to contribute substantially to LV outflow tract obstruction, were resected as part of an extended septal myectomy.27 The present observations show that CMR imaging of PM morphology has potentially important implications for the surgical management of patients with obstructive HC. Indeed, 3 patients in the present series who underwent extended septal myectomy in fact had resections of anteriorly displaced accessory PMs, which had been identified on preoperative CMR. These findings suggest that CMR imaging applied preoperatively to myectomy patients will be helpful to surgeons in planning their intraoperative strategies. In conclusion, morphologic abnormalities of the PMs are common in HC, including increased number and mass and myocardial fibrosis. These data demonstrate that the PMs are part of the disease process in HC, contributing significantly to overall LV chamber mass and even representing the predominant morphologic abnormality in a subset of patients. In addition, LV outflow obstruction was associated with greater PM mass, consistent with the construct that mechanical obstruction can lead to secondary myocardial hypertrophy in this genetic cardiomyopathy. Finally, CMR can reliably characterize abnormali-

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