Caitlin Harrigan

Occurrence and Frequency of Arrhythmias in Hypertrophic Cardiomyopathy in Relation to Delayed Enhancement on Cardiovascular Magnetic Resonance

OBJECTIVES Our aim was to determine whether myocardial fibrosis, detected by cardiovascular magnetic resonance (CMR), represents an arrhythmogenic substrate in hypertrophic cardiomyopathy (HCM). BACKGROUND Myocardial fibrosis is identified frequently in HCM; however, the clinical significance of this finding is uncertain. METHODS We studied prevalence and frequency of tachyarrhythmias on 24-h ambulatory Holter electrocardiogram (ECG) with regard to delayed enhancement (DE) on contrast-enhanced CMR in 177 HCM patients (age 41 +/- 16 yrs; 95% asymptomatic or mildly symptomatic). RESULTS Premature ventricular contractions (PVCs), couplets, and nonsustained ventricular tachycardia (NSVT) were more common in patients with DE than those without DE (PVCs: 89% vs. 72%; couplets: 40% vs. 17%; NSVT: 28% vs. 4%; p < 0.0001 to 0.007). Patients with DE also had greater numbers of PVCs (202 +/- 655 vs. 116 +/- 435), couplets (1.9 +/- 5 vs. 1.2 +/- 10), and NSVT runs (0.4 +/- 0.8 vs. 0.06 +/- 0.4) than non-DE patients (all p < 0.0001); DE was an independent predictor of NSVT (relative risk 7.3, 95% confidence interval 2.6 to 20.4; p < 0.0001). However, extent (%) of DE was similar in patients with and without PVCs (8.2% vs. 9.1%; p = 0.93), couplets (8.5% vs. 8.4%; p = 0.99), or NSVT (8.3% vs. 8.5%; p = 0.35). CONCLUSIONS In this large HCM cohort with no or only mild symptoms, myocardial fibrosis detected by CMR was associated with greater likelihood and increased frequency of ventricular tachyarrhythmias (including NSVT) on ambulatory Holter ECG. Therefore, contrast-enhanced CMR identifies HCM patients with increased susceptibility to ventricular tachyarrhythmias.

Hypertrophic Cardiomyopathy Phenotype Revisited After 50 Years With Cardiovascular Magnetic Resonance

OBJECTIVES Our purpose was to characterize the pattern and distribution of left ventricular (LV) hypertrophy by cardiovascular magnetic resonance (CMR) to more precisely define phenotypic expression and its clinical implications in hypertrophic cardiomyopathy (HCM). BACKGROUND Based on prior pathologic and 2-dimensional echocardiographic studies, HCM has been regarded as a disease characterized by substantial LV wall thickening. METHODS Cine and late gadolinium enhancement CMR were performed in 333 consecutive HCM patients (age 43 +/- 17 years). RESULTS Basal anterior LV free wall and the contiguous anterior ventricular septum were the most commonly hypertrophied segments (n = 256; 77%). LV hypertrophy was focal (involving < or = 2 segments [< or = 12% of LV]) in 41 patients (12%), intermediate (3 to 7 segments [13% to 49% of LV]) in 112 patients (34%), and diffuse (> or = 8 segments [> or = 50% of LV]) in 180 patients (54%); 42 patients (13%) showed hypertrophied segments separated by regions of normal thickness. The number of hypertrophied segments was greater in patients with LV outflow tract obstruction (> or = 30 mm Hg) than without (10 +/- 4 vs. 8 +/- 4 per patient; p = 0.0001) and was associated with an advanced New York Heart Association functional class (p = 0.007). LV wall thickness was greater in segments with late gadolinium enhancement than without (20 +/- 6 mm vs. 16 +/- 6 mm; p < 0.001). We also identified 40 (12%) of HCM patients with segmental LV hypertrophy largely confined to the anterolateral free wall, posterior septum, or apex, which was underestimated or undetected by echocardiography. CONCLUSIONS Although diverse, patterns of LV hypertrophy are usually not extensive in HCM, involving < or = 50% of the chamber in about one-half the patients, and are particularly limited in extent in an important minority. Contiguous portions of anterior free wall and septum constituted the predominant region of wall thickening, with implications for clinical diagnosis. These observations support an emerging role for CMR in the contemporary evaluation of patients with HCM.

Clinical Profile and Significance of Delayed Enhancement in Hypertrophic Cardiomyopathy

Background—Contrast-enhanced cardiovascular magnetic resonance with delayed enhancement (DE) can provide in vivo assessment of myocardial fibrosis. However, the clinical significance of DE in hypertrophic cardiomyopathy (HCM) remains unresolved. Methods and Results—Cine and cardiovascular magnetic resonance with DE were performed in 202 HCM patients (mean age, 42±17 years; 71% male), DE was compared with clinical and demographic variables, and patients were followed up for 681±249 days for adverse disease events. DE was identified in 111 (55%) HCM patients, occupying 9%±11% of left ventricular myocardial volume, including >25% DE in 10% of patients. The presence of DE was related to occurrence of heart failure symptoms (P=0.05) and left ventricular systolic dysfunction (P=0.001). DE was present in all patients with ejection fraction ≤50% but also in 53% (102/192) of patients with preserved ejection fraction (P<0.001); %DE was both inversely related to (r=−0.3; P<0.001) and an independent predictor of ejection fraction (r=−0.4; P<0.001). DE (7%±7% of left ventricle) was present in 54 patients who were asymptomatic (and with normal ejection fraction). Over the follow-up period, the annualized adverse cardiovascular event rate in patients with DE exceeded that in patients without DE but did not achieve statistical significance (5.5% versus 3.3%; P=0.5). Conclusions—In a large HCM cohort, DE was an independent predictor of systolic dysfunction but with only a modest relationship to heart failure symptoms. These data suggest an important role for myocardial fibrosis in the clinical course of HCM patients but are not sufficient at this time to consider DE as an independent risk factor for adverse prognosis.

Mitral Valve Abnormalities Identified by Cardiovascular Magnetic Resonance Represent a Primary Phenotypic Expression of Hypertrophic Cardiomyopathy

Background— Whether morphological abnormalities of the mitral valve represent part of the hypertrophic cardiomyopathy (HCM) disease process is unresolved. Therefore, we applied cardiovascular magnetic resonance to characterize mitral valve morphology in a large HCM cohort. Methods and Results— Cine cardiac magnetic resonance images were obtained in 172 HCM patients (age, 42±18 years; 62% men) and 172 control subjects. In addition, 15 HCM gene-positive/phenotype-negative relatives were studied. Anterior mitral leaflet (AML) and posterior mitral leaflet lengths were greater in HCM patients than in control subjects (26±5 versus 19±5 mm, P<0.001; and 14±4 versus 10±3 mm, P<0.001, respectively), including 59 patients (34%) in whom AML length alone, posterior mitral leaflet length alone, or both were particularly substantial (>2 SDs above controls). Leaflet length was increased compared with controls in virtually all HCM age groups, including young patients 15 to 20 years of age (AML, 26±5 versus 21±4 mm; P=0.0002) and those ≥60 years of age (AML, 26±4 versus 19±2 mm; P<0.001). No relation was evident between mitral leaflet length and LV thickness or mass index (P=0.09 and P=0.16, respectively). A ratio of AML length to LV outflow tract diameter of >2.0 was associated with subaortic obstruction (P=0.001). In addition, AML length in 15 genotype-positive relatives without LV hypertrophy exceeded that of matched control subjects (21±3 versus 18±3 mm; P<0.01). Conclusions— In HCM, mitral valve leaflets are elongated independently of other disease variables, likely constituting a primary phenotypic expression of this heterogeneous disease, and are an important morphological abnormality responsible for LV outflow obstruction in combination with small outflow tract dimension. These findings suggest a novel role for cardiac magnetic resonance in the assessment of HCM.

Diagnostic and Prognostic Utility of Cardiovascular Magnetic Resonance Imaging in Light-Chain Cardiac Amyloidosis

Although the presence of abnormal late gadolinium enhancement (LGE) in cardiac amyloidosis has been well established, its prognostic implication and utility to identify cardiac involvement in patients with systemic amyloidosis is unknown. The aim of this study was to assess the diagnostic and prognostic significance of cardiovascular magnetic resonance imaging in patients with amyloid light-chain amyloidosis but unknown cardiac involvement. Cardiovascular magnetic resonance imaging with LGE was performed in 28 patients with systemic amyloidosis. The presence of cardiac amyloidosis was determined by separate clinical evaluation. The performance of LGE for the prediction of cardiac amyloidosis and prognostic implications of LGE were determined. LGE was observed in 19 patients (68%). The sensitivity, specificity, positive predictive value, and negative predictive value of LGE for the identification of clinical cardiac involvement were 86%, 86%, 95%, and 67%, respectively. During a median follow-up period of 29 months, there were 5 deaths (82% survival). LGE itself did not predict survival (p = 0.62). LGE volume was positively correlated with serum level of B-type natriuretic peptide (BNP; R = 0.64, p < or =0.001), and in multivariate analysis, LGE volume proved the strongest independent predictor of BNP. BNP was correlated with New York Heart Association class (p = 0.03). Reduced right ventricular end-diastolic volume (p <0.01) and stroke volume (p = 0.02) were associated with mortality. In conclusion, in patients with systemic amyloidosis, LGE is highly sensitive and specific for the identification of cardiac involvement but does not predict survival. LGE is strongly correlated with heart failure severity as assessed by BNP.

Spectrum and Clinical Significance of Systolic Function and Myocardial Fibrosis Assessed by Cardiovascular Magnetic Resonance in Hypertrophic Cardiomyopathy

In hypertrophic cardiomyopathy (HCM), the clinical significance attributable to the broad range of left ventricular (LV) systolic function, assessed as the ejection fraction (EF), is incompletely resolved. We evaluated the EF using cardiovascular magnetic resonance (CMR) imaging in a large cohort of patients with HCM with respect to the clinical status and evidence of left ventricular remodeling with late gadolinium enhancement (LGE). CMR imaging was performed in 310 consecutive patients, aged 42 +/- 17 years. The EF in patients with HCM was 71 +/- 10% (range 28% to 89%), exceeding that of 606 healthy controls without cardiovascular disease (66 +/- 5%, p <0.001). LGE reflecting LV remodeling showed an independent, inverse relation to the EF (B-0.69, 95% confidence interval -0.86 to -0.52; p <0.001) and was greatest in patients with an EF <50%, in whom it constituted a median value of 29% of the LV volume (interquartile range 16% to 40%). However, the substantial subgroup with low-normal EF values of 50% to 65% (n = 45; 15% of the whole cohort), who were mostly asymptomatic or mildly symptomatic (37 or 82% with New York Heart Association functional class I to II), showed substantial LGE (median 5% of LV volume, interquartile range 2% to 10%). This overlapped with the subgroup with systolic dysfunction and significantly exceeded that of patients with an EF of 66% to 75% and >75% (median 2% of the LV volume, interquartile range 1.5% to 4%; p <0.01). In conclusion, in a large cohort of patients with HCM, a subset of patients with low-normal EF values (50% to 65%) was identified by contrast-enhanced CMR imaging as having substantial degrees of LGE, suggesting a transition phase, potentially heralding advanced LV remodeling and systolic dysfunction, with implications for clinical surveillance and management.

Significance of papillary muscle abnormalities identified by cardiovascular magnetic resonance in hypertrophic cardiomyopathy.

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 +/- 2 vs 3 +/- 2 g/m(2), p <0.001, respectively), including 109 (54%) with PM mass > or =7 g/m(2) (> or =2 SDs above the mean for controls). Greater LV wall mass index was associated with more substantial PM mass (r = 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 = 0.02), with more marked hypertrophy (9 +/- 5 vs 6 +/- 4 g/m(2), 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.

Hypertrophic Cardiomyopathy: Quantification of Late Gadolinium Enhancement with Contrast-enhanced Cardiovascular MR Imaging

PURPOSE To determine the most reproducible semiautomated gray-scale thresholding technique for quantifying late gadolinium enhancement (LGE) in a large cohort of patients with hypertrophic cardiomyopathy (HCM). MATERIALS AND METHODS All study patients signed a statement approved by the internal review boards of the participating institutions, agreeing to the use of their medical information for research purposes. LGE cardiovascular magnetic resonance (MR) imaging was performed in 201 patients (71% male) with a mean age of 41.5 years ± 17.6 (standard deviation [SD]) by using standard techniques with administration of 0.2 mmol of gadopentetate dimeglumine per kilogram of body weight. The presence and quantity of LGE were determined first with visual assessment; then with gray-scale thresholds of 2 SDs, 4 SDs, and 6 SDs above the mean signal intensity for the normal remote myocardium; and then with 2 SDs above noise. The LGE quantifications were repeated 4 or more weeks apart to assess reproducibility. Bland-Altman analysis and correlation coefficients were used to compare the visual and various thresholding methods, with normally distributed variables expressed as means ± SDs. RESULTS LGE was identified in 103 (51%) subjects. The mean quantity of LGE at visual analysis was 13 g ± 20 compared with 12 g ± 17 at 6 SDs, 25 g ± 23 at 4 SDs, 55 g ± 31 at 2 SDs, and 64 g ± 69 at 2 SDs above noise. All gray-scale thresholds were significantly correlated with visual assessment. The 6-SD threshold had the strongest correlation (r = 0.913, P < .0001) compared with thresholds of 2 SDs (r = 0.81) and 4 SDs (r = 0.91) above the mean and 2 SDs above noise (r = 0.53) (P < .001 for all comparisons). In addition, compared with visual assessment, the 6-SD threshold yielded less intraobserver variability (difference, 0.6 g ± 8, κ = 0.66 [P < .0001] vs 1.4 g ± 9, κ = 0.49 [P < .0001]) and less interobserver variability (difference, 5.4 g ± 18, κ = 0.20 [P < .0001] vs -18.4 g ± 18, κ = 0.08 [P < .0001]). CONCLUSION Semiautomated LGE cardiovascular MR gray-scale thresholding with 6 or more SDs above the mean signal intensity for the visually normal remote myocardium yields the closest approximation of the extent of LGE identified with visual assessment and is highly reproducible. This objective method should be considered for quantifying LGE in patients with HCM.

Sudden Cardiac Arrest in Hypertrophic Cardiomyopathy in the Absence of Conventional Criteria for High Risk Status

Two patients with hypertrophic cardiomyopathy are reported from the recent experience of the Hypertrophic Cardiomyopathy Center of the Minneapolis Heart Institute Foundation, demonstrating limitations in the risk stratification algorithm currently used for this disease. One patient, an asymptomatic 21-year-old male college student, was prophylactically implanted with a cardioverter-defibrillator. This decision was based largely on the presence of apparent extensive myocardial fibrosis identified by contrast-enhanced cardiovascular magnetic resonance imaging, currently not considered a risk factor in this disease. Fifteen months later, ventricular fibrillation was interrupted by an appropriate defibrillator shock. The other patient, an asymptomatic 15-year-old male subject without any apparent high-risk markers, died suddenly at home. Necropsy examination of the heart identified scarring confined to portions of both left ventricular papillary muscles, possibly representing a substrate for ventricular tachyarrhythmias. In conclusion, these 2 cases demonstrate that present strategies for assessing high-risk status in hypertrophic cardiomyopathy are inadequate to identify all such patients. However, while the anecdotal nature of these observations cannot yet justify altering the general guidelines for implantation of defibrillators for the primary prevention of sudden death related to hypertrophic cardiomyopathy, 1 of our 2 cases suggests a future role for contrast-enhanced cardiovascular magnetic resonance in the risk stratification of this complex disease.

Intermediate-Signal-Intensity Late Gadolinium Enhancement Predicts Ventricular Tachyarrhythmias in Patients With Hypertrophic Cardiomyopathy

Background— In hypertrophic cardiomyopathy (HCM), the arrhythmic potential associated with a variety of left ventricular myocardial signal intensities evident on contrast-enhanced cardiovascular magnetic resonance with late gadolinium enhancement (LGE) is unresolved. Methods and Results— In 145 HCM patients (43±15 years old), visually identified areas of LGE in left ventricle were analyzed quantitatively for intermediate (≥4 but <6 SD) and high (≥6 SD above the mean signal intensity of normal myocardium) LGE signal intensity (LGE-SI). Ambulatory Holter ECGs were obtained within 7.8±8.3 weeks of cardiovascular magnetic resonance. HCM patients with nonsustained ventricular tachycardia, ventricular couplets, and premature ventricular contractions showed greater amounts of intermediate LGE-SI (17±7 versus 10±10 g, 16±10 versus 10±11 g, and 13±8 versus 10±13 g, respectively; P=0.003 to <0.001) and greater amounts of high LGE-SI (15±6 versus 10±8 g, 14±9 versus 10±12 g, and 12±7 versus 10±8 g, respectively; P=0.02–0.003) than patients without these arrhythmias. In HCM patients with either nonsustained ventricular tachycardia, couplets, or premature ventricular contractions, the extent of intermediate LGE-SI exceeded that of high LGE-SI (17±7 versus 15±6 g, 16±10 versus 14±9 g, and 13±8 versus 12±7 g, respectively; P=0.01–0.04). In addition, the receiver operating characteristic area under the curve established intermediate LGE-SI as a better discriminator of patients with nonsustained ventricular tachycardia than was high LGE-SI, with 7 additional patients with this arrhythmia identified. Conclusions— In patients with HCM, intermediate LGE-SI is a better predictor of ventricular tachyarrhythmias (including nonsustained ventricular tachycardia, a risk factor for sudden death) than is high LGE-SI. Longitudinal studies in larger HCM cohorts are justified to define the independent prognostic impact of intermediate LGE-SI.