Publications by authors named "Raymond H Chan"

61 Publications

Improved Quantification of Myocardium Scar in Late Gadolinium Enhancement Images: Deep Learning Based Image Fusion Approach.

J Magn Reson Imaging 2021 Feb 17. Epub 2021 Feb 17.

Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.

Background: Quantification of myocardium scarring in late gadolinium enhanced (LGE) cardiac magnetic resonance imaging can be challenging due to low scar-to-background contrast and low image quality. To resolve ambiguous LGE regions, experienced readers often use conventional cine sequences to accurately identify the myocardium borders.

Purpose: To develop a deep learning model for combining LGE and cine images to improve the robustness and accuracy of LGE scar quantification.

Study Type: Retrospective.

Population: A total of 191 hypertrophic cardiomyopathy patients: 1) 162 patients from two sites randomly split into training (50%; 81 patients), validation (25%, 40 patients), and testing (25%; 41 patients); and 2) an external testing dataset (29 patients) from a third site.

Field Strength/sequence: 1.5T, inversion-recovery segmented gradient-echo LGE and balanced steady-state free-precession cine sequences ASSESSMENT: Two convolutional neural networks (CNN) were trained for myocardium and scar segmentation, one with and one without LGE-Cine fusion. For CNN with fusion, the input was two aligned LGE and cine images at matched cardiac phase and anatomical location. For CNN without fusion, only LGE images were used as input. Manual segmentation of the datasets was used as reference standard.

Statistical Tests: Manual and CNN-based quantifications of LGE scar burden and of myocardial volume were assessed using Pearson linear correlation coefficients (r) and Bland-Altman analysis.

Results: Both CNN models showed strong agreement with manual quantification of LGE scar burden and myocardium volume. CNN with LGE-Cine fusion was more robust than CNN without LGE-Cine fusion, allowing for successful segmentation of significantly more slices (603 [95%] vs. 562 (89%) of 635 slices; P < 0.001). Also, CNN with LGE-Cine fusion showed better agreement with manual quantification of LGE scar burden than CNN without LGE-Cine fusion (%Scar = 0.82 × %Scar , r = 0.84 vs. %Scar  = 0.47 × %Scar , r = 0.81) and myocardium volume (Volume = 1.03 × Volume , r = 0.96 vs. Volume  = 0.91 × Volume , r = 0.91).

Data Conclusion: CNN based LGE-Cine fusion can improve the robustness and accuracy of automated scar quantification.

Level Of Evidence: 3 TECHNICAL EFFICACY: 1.
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http://dx.doi.org/10.1002/jmri.27555DOI Listing
February 2021

Progression of Myocardial Fibrosis in Hypertrophic Cardiomyopathy: A Cardiac Magnetic Resonance Study.

JACC Cardiovasc Imaging 2020 Nov 25. Epub 2020 Nov 25.

Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada. Electronic address:

Objectives: This study examined fibrosis progression in hypertrophic cardiomyopathy (HCM) patients, as well as its relationship to patient characteristics, clinical outcomes, and its effect on clinical decision making.

Background: Myocardial fibrosis, as quantified by late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR), provides valuable prognostic information in patients with HCM.

Methods: A total of 157 patients with HCM were enrolled in this study, with 2 sequential CMR scans separated by an interval of 4.7 ± 1.9 years.

Results: At the first CMR session (CMR-1), 70% of patients had LGE compared with 85% at CMR-2 (p = 0.001). The extent of LGE extent increased between the 2 CMR procedures, from 4 ± 5.6% to 6.3 ± 7.4% (p < 0.0001), with an average LGE progression rate of 0.5% ± 1.0%/year. LGE mass progression was correlated with higher LGE mass and extent on CMR-1 (p = 0.0017 and 0.007, respectively), greater indexed left ventricular (LV) mass (p < 0.0001), greater LV maximal wall thickness (p < 0.0001), apical aneurysm at CMR-1 (p < 0.0001), and lower LV ejection fraction (EF) (p = 0.029). Patients who were more likely to have a higher rate of LGE progression presented with more severe disease at baseline, characterized by LGE extent >8% of LV mass, indexed LV mass >100 g/m, maximal wall thickness ≥20 mm, LVEF ≤60%, and apical aneurysm. There was a significant correlation between the magnitude of LGE progression and future implantation of insertable cardioverter-defibrillators (p = 0.004), EF deterioration to ≤50% (p < 0.0001), and admission for heart failure (p = 0.0006).

Conclusions: Myocardial fibrosis in patients with HCM is a slowly progressive process. Progression of LGE is significantly correlated with a number of clinical outcomes such as progression to EF ≤50% and heart failure admission. Judicious use of serial CMR with LGE can provide valuable information to help patient management.
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http://dx.doi.org/10.1016/j.jcmg.2020.09.037DOI Listing
November 2020

Arrhythmogenic risk of late gadolinium enhancement in patients with hypertrophic cardiomyopathy: Burden and location?

Rev Port Cardiol 2020 11 6;39(11):623-624. Epub 2020 Nov 6.

University Health Network, University of Toronto, Toronto, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.repc.2020.10.002DOI Listing
November 2020

Genetic Testing for Diagnosis of Hypertrophic Cardiomyopathy Mimics: Yield and Clinical Significance.

Circ Genom Precis Med 2020 04 9;13(2):e002748. Epub 2020 Mar 9.

Division of Cardiology, Peter Munk Cardiac Centre (S.H., M.H., R.H.C., M.H.G., H.R., A.A.), Toronto General Hospital, Canada.

Background Genetic testing is helpful for diagnosis of hypertrophic cardiomyopathy (HCM) mimics. Little data are available regarding the yield of such testing and its clinical impact. Methods The HCM genetic database at our center was used for identification of patients who underwent HCM-directed genetic testing including at least 1 gene associated with an HCM mimic (, , , , , , and ). Charts were retrospectively reviewed and genetic and clinical data extracted. Results There were 1731 unrelated HCM patients who underwent genetic testing for at least 1 gene related to an HCM mimic. In 1.45% of cases, a pathogenic or likely pathogenic variant in one of these genes was identified. This included a yield of 1% for Fabry disease, 0.3% for familial amyloidosis, 0.15% for -related cardiomyopathy, and 1 patient with Noonan syndrome. In the majority of patients, diagnosis of the HCM mimic based on clinical findings alone would have been challenging. Accurate diagnosis of an HCM mimic led to change in management (eg, enzyme replacement therapy) or family screening in all cases. Conclusions Genetic testing is helpful in the diagnosis of HCM mimics in patients with no or few extracardiac manifestations. Adding these genes to all HCM genetic panels should be considered.
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http://dx.doi.org/10.1161/CIRCGEN.119.002748DOI Listing
April 2020

The Effect of Continuous Positive Airway Pressure on Vascular Function and Cardiac Structure in Diabetes and Sleep Apnea. A Randomized Controlled Trial.

Ann Am Thorac Soc 2020 04;17(4):474-483

The Rongxiang Xu MD Center for Regenerative Therapeutics.

Although both type 2 diabetes mellitus (T2DM) and obstructive sleep apnea (OSA) are independently recognized as risk factors for cardiovascular disease, little is known about their interaction. We hypothesized that T2DM and OSA act synergistically to increase vascular risk, and that treatment of OSA would improve vascular reactivity in patients with T2DM plus OSA. Cross-sectional study of 141 adults with T2DM, OSA, T2DM plus OSA, and control subjects, followed by a 3-month, parallel-arm, randomized, placebo-controlled trial comparing active and sham continuous positive airway pressure (CPAP) in 53 adults with T2DM plus OSA. Endothelium-dependent macro- and microvascular reactivity (flow-mediated dilation [FMD] of the brachial artery and acetylcholine-induced dilation of forearm microvasculature, respectively) and cardiovascular magnetic resonance to assess left- and right-ventricular mass/volume. Mean (±SD) FMD was 6.1 (±4.0)%, 7.3 (±3.6)%, 6.8 (±4.5)%, and 4.8 (±2.9)% in control subjects, T2DM only, OSA only, and T2DM plus OSA, respectively. We observed a significant T2DM × OSA interaction on FMD, such that the mean effect of OSA in those with T2DM was 3.1% (95% confidence interval [CI], 0.6 to 5.6) greater than the effect of OSA in those without T2DM. A total of 3 months of CPAP resulted in a mean absolute increase in FMD of 0.3% (95% CI, -1.9 to 2.5; primary endpoint), with a net improvement of 1.1% (95% CI, -1.4 to 3.6) among those with adherence of 4 h/night or greater. A significant T2DM × OSA interaction was found for both left ventricular (LV) and right ventricular end-diastolic volume, such that OSA was associated with a 22.4 ml (95% CI, 3.2 to 41.6) greater LV end-diastolic volume and 23.2 ml (95% CI, 2.6 to 43.8) greater right ventricular end-diastolic volume in those with T2DM compared with the impact of OSA in those without T2DM. We observed a net improvement in LV end-diastolic volume of 8.7 ml (95% CI, -7.0 to 24.4). The combination of T2DM plus OSA is associated with macrovascular endothelial dysfunction beyond that observed with either disease alone. CPAP for 3 months did not significantly improve macrovascular endothelial function in the intent-to-treat analysis; however, cardiovascular magnetic resonance results suggest that there may be a beneficial effect of CPAP on LV diastolic volume.Clinical trial registered with www.clinicaltrials.gov (NCT01629862).
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http://dx.doi.org/10.1513/AnnalsATS.201905-378OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175977PMC
April 2020

Three-dimensional Deep Convolutional Neural Networks for Automated Myocardial Scar Quantification in Hypertrophic Cardiomyopathy: A Multicenter Multivendor Study.

Radiology 2020 01 12;294(1):52-60. Epub 2019 Nov 12.

From the Departments of Medicine (Cardiovascular Division) (A.S.F., U.N., W.J.M., R.N.) and Radiology (W.J.M.), Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave, Boston, MA 02215; Toronto General Hospital, University Health Network, Toronto, Ontario, Canada (R.H.C.); and Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, Mass (E.J.R., M.S.M.).

Background Cardiac MRI late gadolinium enhancement (LGE) scar volume is an important marker for outcome prediction in patients with hypertrophic cardiomyopathy (HCM); however, its clinical application is hindered by a lack of measurement standardization. Purpose To develop and evaluate a three-dimensional (3D) convolutional neural network (CNN)-based method for automated LGE scar quantification in patients with HCM. Materials and Methods We retrospectively identified LGE MRI data in a multicenter ( = 7) and multivendor ( = 3) HCM study obtained between November 2001 and November 2011. A deep 3D CNN based on U-Net architecture was used for LGE scar quantification. Independent CNN training and testing data sets were maintained with a 4:1 ratio. Stacks of short-axis MRI slices were split into overlapping substacks that were segmented and then merged into one volume. The 3D CNN per-site and per-vendor performances were evaluated with respect to manual scar quantification performed in a core laboratory setting using Dice similarity coefficient (DSC), Pearson correlation, and Bland-Altman analyses. Furthermore, the performance of 3D CNN was compared with that of two-dimensional (2D) CNN. Results This study included 1073 patients with HCM (733 men; mean age, 49 years ± 17 [standard deviation]). The 3D CNN-based quantification was fast (0.15 second per image) and demonstrated excellent correlation with manual scar volume quantification ( = 0.88, < .001) and ratio of scar volume to total left ventricle myocardial volume (%LGE) ( = 0.91, < .001). The 3D CNN-based quantification strongly correlated with manual quantification of scar volume ( = 0.82-0.99, < .001) and %LGE ( = 0.90-0.97, < .001) for all sites and vendors. The 3D CNN identified patients with a large scar burden (>15%) with 98% accuracy (202 of 207) (95% confidence interval [CI]: 95%, 99%). When compared with 3D CNN, 2D CNN underestimated scar volume ( = 0.85, < .001) and %LGE ( = 0.83, < .001). The DSC of 3D CNN segmentation was comparable among different vendors ( = .07) and higher than that of 2D CNN (DSC, 0.54 ± 0.26 vs 0.48 ± 0.29; = .02). Conclusion In the hypertrophic cardiomyopathy population, a three-dimensional convolutional neural network enables fast and accurate quantification of myocardial scar volume, outperforms a two-dimensional convolutional neural network, and demonstrates comparable performance across different vendors. © RSNA, 2019
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http://dx.doi.org/10.1148/radiol.2019190737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939743PMC
January 2020

Markers of responsiveness to disopyramide in patients with hypertrophic cardiomyopathy.

Int J Cardiol 2019 12 9;297:75-82. Epub 2019 Oct 9.

Department of Cardiology, Toronto General Hospital, Toronto, Canada. Electronic address:

Background: Significant left-ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) may result in symptoms and is associated with adverse outcomes. Although disopyramide can reduce resting gradients, nearly 30% of HCM patients do not respond. We sought to study the clinical and echocardiographic variables associated with disopyramide-induced LVOT-gradient reduction.

Methods: Forty-one disopyramide-treated HCM patients (average daily-dose 305 mg) were subdivided into two groups: (1) nineteen responders, with a reduction of LVOT-gradients of at least 30% from baseline, and (2) twenty-two non-responders, in whom LVOT-gradients did not change or increased following treatment. All patients had a thorough clinical and echocardiographic assessment pre- and post-treatment initiation.

Results: Patients who responded to disopyramide had better pretreatment left ventricular (LV) systolic function (LV ejection fraction of 67.9 ± 5.6% vs. 59.7 ± 5.8%, p = 0.0001), better LV global longitudinal strain (-17.9 ± 2.3% vs. -16.1 ± 2.5%, p = 0.048), less mitral regurgitation, smaller LV size (indexed LV end-systolic volume of 16.2 ± 5.1 ml/m vs. 23.2 ± 6.8 ml/m, p = 0.001), and lower LV maximal wall thickness (17.2±3 mm vs.19.2 ± 3.4 mm, p = 0.046). Baseline left atrial (LA) volumes were significantly lower in the responders, with higher indices of LA ejection fraction (62 ± 11.2% vs. 50.5 ± 12.2%, p = 0.005), systolic LA strain (34 ± 12.4% vs. 25.8 ± 10.6%, p = 0.04), and LA strain-rate (1.34 ± 0.49%/sec vs. 0.99 ± 0.24%/sec, p = 0.012). In multivariable analysis, the presence of reduced LV systolic function and systolic LA strain-rate remained independently associated with poor response to disopyramide.

Conclusions: Obstructive HCM patients with more severe disease at baseline tend to respond less to disopyramide treatment. In those patients, early referral for alcohol septal ablation or myectomy surgery should be considered.
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http://dx.doi.org/10.1016/j.ijcard.2019.09.066DOI Listing
December 2019

The relationship between the quantitative extent of late gadolinium enhancement and burden of nonsustained ventricular tachycardia in hypertrophic cardiomyopathy: A delayed contrast-enhanced magnetic resonance study.

J Cardiovasc Electrophysiol 2019 05 2;30(5):651-657. Epub 2019 Feb 2.

Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Objectives: To examine the relationship between late gadolinium enhancement (LGE) extent and nonsustained ventricular tachycardia (NSVT) characteristics in patients with hypertrophic cardiomyopathy (HCM).

Background: NSVT has been shown to be independently associated with sudden cardiac death (SCD) in HCM. Previous studies have found LGE on cardiac magnetic resonance (CMR) to be independently associated with NSVT.

Methods: Seventy-three patients who had 14-day Holter monitoring for either risk stratification for SCD (n = 62) or evaluation of atrial fibrillation (n = 11) on a CMR study were included. Areas of LGE in left ventricle (LV) were visually identified and analyzed quantitatively for both high (≥6 SD above the mean signal intensity of normal myocardium) and intermediate (≥4 but <6 SD) LGE signal intensity.

Results: Patients with more extensive LGE had longer (P = 0.0028) and more frequent (P = 0.02) episodes of NSVT. In univariate analyses, frequency of NSVT was associated with LGE extent (r  = 0.43, P = 0.001), LV ejection fraction (r  = -0.38, P < 0.001), LV mass (r  = 0.32, P = 0.005), LV maximal wall thickness (r  = 0.28, P = 0.016), and left atrium diameter (r  = 0.29, P = 0.001); maximal length of NSVT was associated with LGE extent (r  = 0.52, P < 0.001), LV ejection fraction (r  = -0.44, P < 0.001), LV mass (r  = 0.37, P = 0.001), and left atrium diameter (r  = 0.3, P < 0.001). In multivariable analyses, LGE extent remained the sole variable independently associated with frequency (P = 0.001) and maximal length of episodes of NSVT (P = 0.001). No significant association was found between the rate of NSVT and LGE extent.

Conclusions: LGE extent is independently associated with a greater burden and longer episodes of NSVT in HCM. These findings support the association between myocardial fibrosis as represented by LGE and ventricular tachyarrhythmias in HCM.
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http://dx.doi.org/10.1111/jce.13855DOI Listing
May 2019

Effect of Spironolactone on Myocardial Fibrosis and Other Clinical Variables in Patients with Hypertrophic Cardiomyopathy.

Am J Med 2018 07 28;131(7):837-841. Epub 2018 Mar 28.

Hypertrophic Cardiomyopathy Institute, Division of Cardiology, Tufts Medical Center, Boston, Mass.

Background: Myocardial fibrosis has proved to be an important marker and determinant in the pathogenesis of hypertrophic cardiomyopathy. In particular, scar formation, if substantial, can promote ventricular tachyarrhythmias or progressive heart failure in the absence of left ventricular outflow obstruction. Therefore, an intervention to mitigate myocardial fibrosis would be potentially advantageous to hypertrophic cardiomyopathy patients.

Methods: Eligible hypertrophic cardiomyopathy patients were randomized 1:1 in a prospective double-blind fashion to spironolactone 50 mg or placebo to be taken over a 12-month period. The primary endpoint was the effect of mineralocorticoid receptor blockade on serum markers of collagen synthesis and degradation. A number of other functional and morphologic variables and biomarkers comprised secondary exploratory measures.

Results: Fifty-three hypertrophic cardiomyopathypatients (41 ± 13 years old; 72% men) were randomized; demographic and clinical variable were well matched at baseline. Absolute change between baseline and 12 months did not differ between hypertrophic cardiomyopathy patients treated with spironolactone and those receiving placebo with respect to serum markers of collagen synthesis or degradation, fibrosis by late gadolinium enhancement on cardiac magnetic resonance imaging, or other clinical variables, including objective measure of functional capacity (peak VO), New York Heart Association functional class, left ventricular wall thickness, mass and volume, and left atrial size, as well as assessment of diastolic function (P = .4-1.0).

Conclusions: These findings do not support the use of spironolactone in hypertrophic cardiomyopathy to improve left ventricular remodeling by mitigating myocardial fibrosis or altering clinical course.
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http://dx.doi.org/10.1016/j.amjmed.2018.02.025DOI Listing
July 2018

Interaction of Adverse Disease Related Pathways in Hypertrophic Cardiomyopathy.

Am J Cardiol 2017 Dec 20;120(12):2256-2264. Epub 2017 Sep 20.

Hypertrophic Cardiomyopathy Institute, Division of Cardiology, Tufts Medical Center, Boston, Massachusetts.

Hypertrophic cardiomyopathy (HC) has been characterized as a generally progressive genetic heart disease, creating an ominous perspective for patients and managing cardiologists. We explored the HC disease burden and interaction of adverse clinical pathways to clarify patient expectations over long time periods in the contemporary therapeutic era. We studied 1,000 consecutive HC patients (52 ± 17 years) at Tufts Medical Center, followed 9.3 ± 8 years from diagnosis, employing a novel disease pathway model: 46% experienced a benign course free of adverse pathways, but 42% of patients progressed along 1 major pathway, most commonly refractory heart failure to New York Heart Association class III or IV requiring surgical myectomy (or alcohol ablation) or heart transplant; repetitive or permanent atrial fibrillation; and least commonly arrhythmic sudden death events. Eleven percent experienced 2 of these therapeutic end points at different times in their clinical course, most frequently the combination of advanced heart failure and atrial fibrillation, whereas only 1% incurred all 3 pathways. Freedom of progression from 1 to 2 disease pathways, or from 2 to 3 was 80% and 93% at 5 years, respectively. Annual HC-related mortality did not differ according to the number of pathways: 1 (0.8%), 2 (0.8%), or 3 (2.4%) (p = 0.56), and 93% of patients were in New York Heart Association classes I or II at follow-up. In conclusion, it is uncommon for HC patients to experience multiple adverse (but treatable) disease pathways, underscoring the principle that HC is not a uniformly progressive disease. These observations provide a measure of clarity and/or reassurance to patients regarding the true long-term disease burden of HC.
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http://dx.doi.org/10.1016/j.amjcard.2017.08.048DOI Listing
December 2017

Discrepant Measurements of Maximal Left Ventricular Wall Thickness Between Cardiac Magnetic Resonance Imaging and Echocardiography in Patients With Hypertrophic Cardiomyopathy.

Circ Cardiovasc Imaging 2017 Aug;10(8)

From the Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Ontario, Canada.

Background: We sought to compare maximal left ventricular (LV) wall thickness (WT) measurements as obtained by routine clinical practice between echocardiography and cardiac magnetic resonance (CMR) and document causes of discrepancy.

Methods And Results: One-hundred and ninety-five patients with hypertrophic cardiomyopathy (median age, 52.8±15.1 years) who underwent echocardiography and CMR imaging within 6 months (median, 41 days; interquartile range, 16-97 days) were included. LVWT was assessed in parasternal long and short axis by 2-dimensional echocardiography and in short axis by CMR. By Bland-Altman plot, mean maximal LVWT difference between echocardiography and CMR was 0.5 mm (95% confidence interval, -6.9, 7.8) with equal distribution of discrepancy along the full range of LVWT. Ninety-seven patients (49.7%) were identified to have intermodal measurement discrepancies ≥10%. In 7 patients (7.2%), reported measurement by CMR was inaccurate because of interpretation error. In 90 patients (92.8%), echocardiography underestimated (n=32; 33.0%) or overestimated (n=58; 59.8%) maximal LVWT. Underestimation was because of focal LV hypertrophy (n=10; 10.3%) or poor acoustic windows (n=22; 22.7%) while overestimation resulted from inclusion of right ventricular myocardium (n=37; 38.1%), LV trabeculations (n=5; 5.2%), papillary muscle (n=3; 3.1%), and apical-septal bundle (n=1; 1.0%), as well as imaging plane obliquity (n=7; 12.5%). In 31 (15.9%) patients, measurement discrepancy occurred at diagnostic or prognostic cut-offs.

Conclusions: Although maximal LVWT by echocardiography in general measured similar to CMR, discordance because of limitations in echocardiography technique was present in a significant subset of patients. As measurement of LVWT impacts diagnosis and sudden death management, CMR should be considered as part of routine evaluation of all patients with hypertrophic cardiomyopathy.
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http://dx.doi.org/10.1161/CIRCIMAGING.117.006309DOI Listing
August 2017

Safety of Outpatient Initiation of Disopyramide for Obstructive Hypertrophic Cardiomyopathy Patients.

J Am Heart Assoc 2017 May 26;6(6). Epub 2017 May 26.

Division of Cardiology, Toronto General Hospital and University of Toronto, Toronto, Ontario, Canada

Background: Disopyramide is effective in ameliorating symptoms in patients with hypertrophic cardiomyopathy; however, its potential for proarrhythmic effect has raised concerns about its use in the ambulatory setting. The risk of initiating disopyramide in this manner has never been evaluated.

Methods And Results: All charts of patients seen in the outpatient hypertrophic cardiomyopathy clinic between 2010 and 2014 were screened for initiation of disopyramide and data were extracted. Disopyramide in our clinic is usually initiated at a dose of 300 mg daily and titrated during follow-up. A total of 2015 patients were seen in the clinic, including 168 who were started on disopyramide. There were no cardiac events within 3 months of disopyramide initiation. During long-term follow-up (255 patient-years; mean, 447 days; interquartile range, 201-779), only 2 patients developed cardiac events (syncope of unknown cause in both). Thirty-eight patients (23%) developed side effects of disopyramide and 18 (11%) stopped the drug because of these side effects. Of the patients continuing disopyramide long term, 63% remained free of septal reduction interventions at end of follow-up. Disopyramide at a dose of 300 mg prolonged the mean QTc interval by 19±23 ms; however, increasing the dose to 600 mg had no further significant effect.

Conclusions: Initiation of disopyramide in the outpatient setting is safe and the risk of subsequent sudden cardiac death is low. Because of its QT-prolonging effect, precautions may be necessary in patients at higher risk of torsades de pointes.
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http://dx.doi.org/10.1161/JAHA.116.005152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669159PMC
May 2017

Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy: Revisiting the Gene-Dose Effect.

Circ Cardiovasc Genet 2017 Apr;10(2)

From the Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada (D.F., A.W.-S., W.H., R.H.C., M.H.G., H.R., A.A.); Fred A. Litwin & Family Center in Genetic Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada (M.C., K.A.S.).

Background: Available data suggests that double mutations in patients with hypertrophic cardiomyopathy are not rare and are associated with a more severe phenotype. Most of this data, however, is based on noncontemporary variant classification.

Methods And Results: Clinical data of all hypertrophic cardiomyopathy patients with 2 rare genetic variants were retrospectively reviewed and compared with a group of patients with a single disease-causing variant. Furthermore, a literature search was performed for all studies with information on prevalence and outcome of patients with double mutations. Classification of genetic variants was reanalyzed according to current guidelines. In our cohort (n=1411), 9% of gene-positive patients had 2 rare variants in sarcomeric genes but only in 1 case (0.4%) were both variants classified as pathogenic. Patients with 2 rare variants had a trend toward younger age at presentation when compared with patients with a single mutation. All other clinical variables were similar. In data pooled from cohort studies in the literature, 8% of gene-positive patients were published to have double mutations. However, after reanalysis of reported variants, this prevalence diminished to 0.4%. All patients with 2 radical mutations in in the literature had severe disease with death or heart transplant during the first year of life. Data on other specific genotype-phenotype correlations were scarce.

Conclusions: Double mutations in patients with hypertrophic cardiomyopathy are much less common than previously estimated. With the exception of double radical mutations, there is little data to guide clinical decision making in cases with double mutations.
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http://dx.doi.org/10.1161/CIRCGENETICS.116.001685DOI Listing
April 2017

Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (β-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy.

Circ Cardiovasc Imaging 2017 Feb;10(2)

From the Division of Cardiology (A.W.-S., W.H., C.G., D.F., M.C., A.M.C., H.R., R.H.C.) and Joint Department of Medical Imaging (A.M.C.), University Health Network, Toronto, Ontario, Canada; Division of Cardiology, Cardiovascular Center, University Hospital Zurich, Switzerland (C.G.); Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (E.A., W.J.M., R.H.C.); Hypertrophic Cardiomyopathy Center, Tufts Medical Center, Boston, MA (E.R., J.E.U., B.J.M., M.S.M.); The Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, MN (J.R.L., T.S.H.); and Referral Center for Cardiomyopathies, Careggi University Hospital, Florence, Italy (I.O., B.T.).

Background: The 2 most commonly affected genes in hypertrophic cardiomyopathy (HCM) are MYH7 (β-myosin heavy chain) and MYBPC3 (β-myosin-binding protein C). Phenotypic differences between patients with mutations in these 2 genes have been inconsistent. Scarce data exist on the genotype-phenotype association as assessed by tomographic imaging using cardiac magnetic resonance imaging.

Methods And Results: Cardiac magnetic resonance imaging was performed on 358 consecutive genotyped hypertrophic cardiomyopathy probands at 5 tertiary hypertrophic cardiomyopathy centers. Genetic testing revealed a pathogenic mutation in 159 patients (44.4%). The most common genes identified were MYH7 (n=53) and MYBPC3 (n=75); 33.1% and 47% of genopositive patients, respectively. Phenotypic characteristics by cardiac magnetic resonance imaging of these 2 groups were similar, including left ventricular volumes, mass, maximal wall thickness, morphology, left atrial volume, and mitral valve leaflet lengths (all =non-significant). The presence of late gadolinium enhancement (65% versus 64%; =0.99) and the proportion of total left ventricular mass (%late gadolinium enhancement; 10.4±13.2% versus 8.5±8.5%; =0.44) were also similar.

Conclusions: This multicenter multinational study shows lack of phenotypic differences between MYH7- and MYBPC3-associated hypertrophic cardiomyopathy when assessed by cardiac magnetic resonance imaging. Postmutational mechanisms appear more relevant to thick-filament disease expression and outcome than the disease-causing variant per se.
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http://dx.doi.org/10.1161/CIRCIMAGING.116.005311DOI Listing
February 2017

Usefulness of 14-Day Holter for Detection of Nonsustained Ventricular Tachycardia in Patients With Hypertrophic Cardiomyopathy.

Am J Cardiol 2016 Oct 29;118(8):1258-1263. Epub 2016 Jul 29.

Division of Cardiology, Department of Medicine, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada. Electronic address:

Nonsustained ventricular tachycardia (NSVT), defined as ≥3 consecutive ventricular beats at ≥120 beats/min lasting <30 seconds, is an independent predictor of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HC). Current guidelines recommend 24- to 48-hour Holter monitoring as part of SCD risk stratification. We sought to assess the difference in diagnostic yield of 14-day Holter monitoring compared to 24-48 hours for the detection of NSVT and to assess the prevalence and characteristics of NSVT in patients with HC with prolonged monitoring. We retrospectively analyzed the 14-day Holter monitors of 77 patients with HC from May 2014 to March 2016. Number of episodes and maximal length and rate on each day were recorded. NSVT was detected in 75.3% of patients during 14-day Holter monitoring. The median number of runs was 2 (range 0 to 26 runs). The median number of beats of the longest run was 10.5 (range 3 to 68 beats) with a mean maximum rate of 159.5 ± 20.8.4 beats/min (range 102 to 203 beats/min). First episodes of NSVT were detected throughout the 14 days, with only 22.5% and 44.8% of the episodes captured within the first 24 and 48 hours of monitoring, respectively. In conclusion, prolonged Holter monitoring revealed ≥1 episode of NSVT in 75% of patients with HC of which <50% were detected within the first 48 hours. Hence, prolonged Holter monitoring may be superior for SCD risk stratification in HC. However, the high prevalence of NSVT in this population may limit its utility in evaluating the risk for SCD of the individual patient.
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http://dx.doi.org/10.1016/j.amjcard.2016.07.043DOI Listing
October 2016

Prognostic Value of LGE-CMR in HCM: A Meta-Analysis.

JACC Cardiovasc Imaging 2016 12 20;9(12):1392-1402. Epub 2016 Jul 20.

Cyrus Tang Hematology Center and Ministry of Education Engineering Center of Hematological Disease, the First Affiliated Hospital, and the Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China. Electronic address:

Objectives: The aims of this study included performing a meta-analysis of the predictive value of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) for adverse events and death in hypertrophic cardiomyopathy (HCM).

Background: CMR with LGE can identify areas of myocardial fibrosis; however, controversies remain regarding the independent prognostic importance of LGE-CMR in HCM.

Methods: We searched PubMed and Web of Science for studies that investigated the prognostic value of LGE in patients with HCM. Pooled odds ratios (ORs), hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated to assess the role of LGE CMR in the risk stratification of HCM.

Results: Seven studies were retrieved from 393 citations for the analysis, of which 2 were eliminated because of overlapping data. In total, 2,993 patients (mean age 54.6 years; median follow-up 36.8 months) were included in the analysis. Meta-analysis showed the presence of LGE was associated with an increased risk for sudden cardiac death (SCD) (OR: 3.41; 95% CI:1.97 to 5.94; p < 0.001), all-cause mortality (OR: 1.80, 95% CI: 1.21 to 2.69; p = 0.004), cardiovascular mortality (OR: 2.93, 95% CI: 1.53 to 5.61; p = 0.001), and a trend for heart failure death (OR: 2.21, 95% CI: 0.84 to 5.80; p = 0.107). Extent of LGE was associated with an increased risk of SCD (HR: 1.56/10% LGE; 95% CI: 1.33 to 1.82; p < 0.0001), heart failure death (HR: 1.61/10% LGE; 95% CI: 1.21 to 2.13; p = 0.001), all-cause mortality (HR: 1.29/10% LGE; 95% CI: 1.09 to 1.51; p = 0.002), and cardiovascular mortality (HR: 1.57/10% LGE; 95% CI: 1.30 to 1.89; p < 0.001). After adjusting for baseline characteristics, the extent of LGE remained strongly associated with the risk of SCD (HR: 1.36/10% LGE; 95% CI: 1.10 to 1.69; p = 0.005).

Conclusions: Quantitative LGE by CMR exhibited a substantial prognostic value in SCD events prediction, independent of baseline characteristics. Assessment of LGE can be used as an effective tool for risk stratifying patients with HCM.
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http://dx.doi.org/10.1016/j.jcmg.2016.02.031DOI Listing
December 2016

Contemporary Natural History and Management of Nonobstructive Hypertrophic Cardiomyopathy.

J Am Coll Cardiol 2016 Mar;67(12):1399-1409

The Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota.

Background: Left ventricular outflow tract gradients are absent in an important proportion of patients with hypertrophic cardiomyopathy (HCM). However, the natural course of this important patient subgroup remains largely unresolved.

Objectives: The authors systematically employed exercise (stress) echocardiography to define those patients without obstruction to left ventricular outflow at rest and/or under physiological exercise and to examine their natural history and clinical course to create a more robust understanding of this complex disease.

Methods: We prospectively studied 573 consecutive HCM patients in 3 centers (44 ± 17 years; 66% male) with New York Heart Association functional class I/II symptoms at study entry, including 249 in whom left ventricular outflow tract obstruction was absent both at rest and following physiological exercise (<30 mm Hg; nonobstructive HCM) and retrospectively assembled clinical follow-up data.

Results: Over a median follow-up of 6.5 years, 225 of 249 nonobstructive patients (90%) remained in classes I/II, whereas 24 (10%) developed progressive heart failure to New York Heart Association functional classes III/IV. Nonobstructive HCM patients were less likely to experience advanced limiting class III/IV symptoms than the 324 patients with outflow obstruction (1.6%/year vs. 7.4%/year rest obstruction vs. 3.2%/year provocable obstruction; p < 0.001). However, 7 nonobstructive patients (2.8%) did require heart transplantation for progression to end stage versus none of the obstructive patients. HCM-related mortality among nonobstructive patients was low (n = 8; 0.5%/year), with 5- and 10-year survival rates of 99% and 97%, respectively, which is not different from expected all-cause mortality in an age- and sex-matched U.S. population (p = 0.15).

Conclusions: HCM patients with nonobstructive disease appear to experience a relatively benign clinical course, associated with a low risk for advanced heart failure symptoms, other disease complications, and HCM-related mortality, and largely without the requirement for major treatment interventions. A small minority of nonobstructive HCM patients progress to heart transplant.
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http://dx.doi.org/10.1016/j.jacc.2016.01.023DOI Listing
March 2016

Effect of Left Ventricular Outflow Tract Obstruction on Left Atrial Mechanics in Hypertrophic Cardiomyopathy.

Biomed Res Int 2015 16;2015:481245. Epub 2015 Dec 16.

Division of Cardiology, Toronto General Hospital, Toronto, ON, Canada M5G 2C4.

Left atrial (LA) volumes are known to be increased in hypertrophic cardiomyopathy (HCM) and are a predictor of adverse outcome. In addition, LA function is impaired and is presumed to be due to left ventricular (LV) diastolic dysfunction as a result of hypertrophy and myocardial fibrosis. In the current study, we assess the incremental effect of outflow tract obstruction (and concomitant mitral regurgitation) on LA function as assessed by LA strain. Patients with HCM (50 obstructive, 50 nonobstructive) were compared to 50 normal controls. A subset of obstructive patients who had undergone septal myectomy was also studied. Utilising feature-tracking software applied to cardiovascular magnetic resonance images, LA volumes and functional parameters were calculated. LA volumes were significantly elevated and LA ejection fraction and strain were significantly reduced in patients with HCM compared with controls and were significantly more affected in patients with obstruction. LA volumes and function were significantly improved after septal myectomy. LVOT obstruction and mitral regurgitation appear to further impair LA mechanics. Septal myectomy results in a significant reduction in LA volumes, paralleled by an improvement in function.
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http://dx.doi.org/10.1155/2015/481245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695661PMC
October 2016

Independent Assessment of the European Society of Cardiology Sudden Death Risk Model for Hypertrophic Cardiomyopathy.

Am J Cardiol 2015 Sep 4;116(5):757-64. Epub 2015 Jun 4.

Division of Cardiology, Hypertrophic Cardiomyopathy Center, Tufts Medical Center, Boston, Massachusetts.

Risk stratification for sudden death (SD) is an essential component of hypertrophic cardiomyopathy (HC) management, given the proven effectiveness of implantable cardioverter-defibrillators (ICD) for preventing SD. Although highly effective in identifying high-risk patients, current stratification algorithms remain incomplete and novel strategies are encouraged. In this regard, reliability of the statistical model to predict SD risk in HC, as recommended by the recent European Society of Cardiology (ESC) guidelines, was retrospectively tested in an independent cohort of 1,629 consecutive patients with HC aged ≥16 years. Of the 1,629 patients, 35 incurred SD events, but only 4 of these (11%) had high predictive risk scores >6%/5 years consistent with an ICD recommendation, and most (60%; n = 21) had scores <4%/5 years that would not justify ICDs. Of 46 high-risk patients with appropriate ICD interventions for ventricular fibrillation/tachycardia, 27 (59%) had low SD risk scores of <4%/5 years, regarded by ESC as insufficient to recommend ICDs, and only 12 (26%) had scores >6%/5 years, considered an ICD indication; 11 of these 12 had already met conventional criteria warranting implantation with 2 to 3 risk markers. Of 414 patients with ICDs but without appropriate interventions, 258 (62%) had low risk scores (<4%/5 years) that would argue against implant. In conclusion, primary risk stratification using the ESC prognostic score applied retrospectively to a large independent HC cohort proved unreliable for prediction of future SD events. Most patients with HC with SD or appropriate ICD interventions were misclassified with low risk scores and therefore would have remained unprotected from arrhythmic SD without ICDs.
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http://dx.doi.org/10.1016/j.amjcard.2015.05.047DOI Listing
September 2015

Significance of Late Gadolinium Enhancement at Right Ventricular Attachment to Ventricular Septum in Patients With Hypertrophic Cardiomyopathy.

Am J Cardiol 2015 Aug 8;116(3):436-41. Epub 2015 May 8.

Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, Massachusetts.

Cardiovascular magnetic resonance (CMR) with extensive late gadolinium enhancement (LGE) is a novel marker for increased risk for sudden death (SD) in patients with hypertrophic cardiomyopathy (HC). Small focal areas of LGE confined to the region of right ventricular (RV) insertion to ventricular septum (VS) have emerged as a frequent and highly visible CMR imaging pattern of uncertain significance. The aim of this study was to evaluate the prognostic significance of LGE confined to the RV insertion area in patients with HC. CMR was performed in 1,293 consecutive patients with HC from 7 HC centers, followed for 3.4 ± 1.7 years. Of 1,293 patients (47 ± 14 years), 134 (10%) had LGE present only in the anterior and/or inferior areas of the RV insertion to VS, occupying 3.7 ± 2.9% of left ventricular myocardium. Neither the presence nor extent of LGE in these isolated areas was a predictor of adverse HC-related risk, including SD (adjusted hazard ratio 0.82, 95% confidence interval 0.45 to 1.50, p = 0.53; adjusted hazard ratio 1.16/10% increase in LGE, 95% confidence interval 0.29 to 4.65, p = 0.83, respectively). Histopathology in 20 HC hearts show the insertion areas of RV attachment to be composed of a greatly expanded extracellular space characterized predominantly by interstitial-type fibrosis and interspersed disorganized myocyte patterns and architecture. In conclusion, LGE confined to the insertion areas of RV to VS was associated with low risk of adverse events (including SD). Gadolinium pooling in this region of the left ventricle does not reflect myocyte death and repair with replacement fibrosis or scarring.
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http://dx.doi.org/10.1016/j.amjcard.2015.04.060DOI Listing
August 2015

Hypertrophic Cardiomyopathy in Adulthood Associated With Low Cardiovascular Mortality With Contemporary Management Strategies.

J Am Coll Cardiol 2015 May;65(18):1915-28

Hypertrophic Cardiomyopathy Center, Tufts Medical Center, Boston, Massachusetts.

Background: Hypertrophic cardiomyopathy (HCM) has been prominently associated with adverse disease complications, including sudden death or heart failure death and a generally adverse prognosis, with annual mortality rates of up to 6%.

Objectives: This study determined whether recent advances in management strategy, including implantable cardioverter-defibrillators (ICDs), heart transplantation, or other therapeutic measures have significantly improved survival and the clinical course of adult HCM patients.

Methods: We addressed long-term outcomes in 1,000 consecutive adult HCM patients presenting at 30 to 59 years of age (mean 45±8 years) over 7.2±5.2 years of follow-up.

Results: Of 1,000 patients, 918 (92%) survived to 53±9.2 years of age (range 32 to 80 years) with 91% experiencing no or only mild symptoms at last evaluation. HCM-related death occurred in 40 patients (4% [0.53%/year]) at 50±10 years from the following events: progressive heart failure (n=17); arrhythmic sudden death (SD) (n=17); and embolic stroke (n=2). In contrast, 56 other high-risk patients (5.6%) survived life-threatening events, most commonly with ICD interventions for ventricular tachyarrhythmias (n=33) or heart transplantation for advanced heart failure (n=18 [0.79%/year]). SD occurred in patients who declined ICD recommendations, had evaluations before application of prophylactic ICDs to HCM, or were without conventional risk factors. The 5- and 10-year survival rates (confined to HCM deaths) were 98% and 94%, respectively, not different from the expected all-cause mortality in the general U.S. population (p=0.25). Multivariate independent predictors of adverse outcome were younger age at diagnosis, female sex, and increased left atrial dimension.

Conclusions: In a large longitudinally assessed adult HCM cohort, we have demonstrated that contemporary management strategies and treatment interventions, including ICDs for SD prevention, have significantly altered the clinical course, now resulting in a low disease-related mortality rate of 0.5%/year and an opportunity for extended longevity.
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http://dx.doi.org/10.1016/j.jacc.2015.02.061DOI Listing
May 2015

Guideline Adherence for Echocardiographic Follow-Up in Outpatients with at Least Moderate Valvular Disease.

J Am Soc Echocardiogr 2015 Jul 3;28(7):795-801. Epub 2015 Apr 3.

Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Attention to resource utilization has led to increased scrutiny of the appropriateness of initial diagnostic imaging studies on the basis of current guidelines. Far less attention has been paid to examining the lack of appropriate follow-up studies.

Methods: A retrospective cross-sectional analysis was performed of 3,781 consecutive outpatients referred for transthoracic echocardiography (TTE) from July to December 2008. Data from the electronic medical records were extracted to see if patients with at least moderate left-sided valvular stenosis or regurgitation underwent subsequent echocardiographic studies within 60 days of the period recommended by the 2006 American College of Cardiology and American Heart Association valve guidelines document.

Results: Of 342 outpatients with at least moderate valve dysfunction, 38 (11%) were excluded for reasons that precluded the need for a follow-up study (e.g. death, surgery). Of the remaining 304 patients, only 179 (59%) underwent follow-up echocardiography within the recommended period. Rates of timely follow-up TTE were higher when ordering physicians were cardiologists or cardiovascular surgeons (65%) compared with primary care physicians or internal medicine specialists (45%) (P < .01). Follow-up rates were significantly different for aortic stenosis (77%), mitral stenosis (67%), aortic regurgitation (49%), and mitral regurgitation (49%) (P < .01). Patients receiving timely follow-up TTE were younger (66 ± 15 vs 71 ± 15 years, P = .002) and more likely to be male (odds ratio, 1.79; 95% CI, 1.12-2.85; P = .01).

Conclusions: To the authors' knowledge, this is the first study demonstrating low rates of compliance with guideline-recommended monitoring TTE in patients with at least moderate valve dysfunction. Cardiac practitioners have significantly better compliance. Strategies are needed to improve timely follow-up care in this population.
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http://dx.doi.org/10.1016/j.echo.2015.03.001DOI Listing
July 2015

Advanced heart failure with preserved systolic function in nonobstructive hypertrophic cardiomyopathy: under-recognized subset of candidates for heart transplant.

Circ Heart Fail 2014 Nov 19;7(6):967-75. Epub 2014 Sep 19.

From the Department of Medicine, Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, MA (E.J.R., M.S.K., J.E.U., D.D., M.S.M.); Department of Medicine, the Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M., S.A.C., D.S.F., K.M.H., K.M.H.); Departments of Medicine (Cardiovascular Division) and Radiology, Beth Israel Deaconess Medical Center, Boston, MA (R.H.C.); and Department of Pathology and Medicine, Baylor University Medical Center, Dallas, TX (W.C.R.).

Background: In hypertrophic cardiomyopathy (HCM), heart transplant has been predominantly confined to patients with systolic dysfunction. An underappreciated HCM subset comprises patients with preserved left ventricular (LV) systolic function who may also require consideration for transplantation. Therefore, we sought to define the clinical profile and occurrence of advanced heart failure among patients with nonobstructive HCM and preserved systolic function.

Methods And Results: Databases from 2 referral centers comprising 2100 HCM patients were interrogated. Forty-six nonobstructive HCM patients (2.2%) either received or were listed for heart transplant, including 20 with normal systolic function (ejection fraction ≥50%). At transplant listing, these 20 patients were 42±13 years old, each in New York Heart Association functional class III/IV with ejection fraction of 62±7%. LV was hypertrophied with maximum wall thickness of 22±4 mm and nondilated (end-diastolic dimension, 39±7 mm). Cardiovascular magnetic resonance in 10 (of 15) patients showed no or minimal fibrosis (≤5% LV mass). Elevated LV end-diastolic or pulmonary capillary wedge pressure, consistent with diastolic dysfunction, was present in 15 patients (75%). LV filling was impaired by echocardiographic measures in all patients, including a restrictive inflow pattern in 8 (40%). In 2 patients, traditional criteria for transplant were absent, including peak VO2 >14 mL/kg/min. Heart transplantation was performed in 12 patients with each alive and without cardiovascular symptoms, 2.3±1.7 years later.

Conclusions: A previously under-recognized segment of the broad HCM clinical spectrum consists of nonobstructive patients with advanced heart failure, in the presence of preserved systolic function, for whom heart transplant is the sole definitive therapeutic option.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.114.001435DOI Listing
November 2014

Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy.

Circulation 2014 Aug;130(6):484-95

From the PERFUSE Study Group, Harvard Medical School, Boston, MA (R.H.C., S.N.H., C.M.B., W.J.M., E.A.); Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (R.H.C., S.N.H., C.M.B., W.J.M., E.A.); Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, MN (B.J.M., T.H., J.R.L.); Referral Center for Myocardial Diseases, Azienda Ospedaliera Universitaria Careggi, Florence Italy (I.O., F.C., B.T.); Harvard Clinical Research Institute and Boston University Biostatistics, Boston, MA (M.J.P.); Ospedale Sant'Andrea Universita "La Sapienza," Rome, Italy (G.E.A., C.N.D.C., C.A.); Division of Cardiology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada (C.G., A.M.C., H.R.); Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, MA (J.E.U., E.R., M.S.M.); Fondazione C.N.R./Regione Toscana G. Monasterio, Pisa, Italy (M.L.); Ente Ospedaliero Ospedali Galliera, Genoa, Italy (P.S., F.F.); Policlinico S. Orsola-Malpighi, Bologna, Italy (E.B., C.R.); and Department of Epidemiology, Harvard School of Public Health, Boston, MA (E.F.C.).

Background: Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in the young, although not all patients eligible for sudden death prevention with an implantable cardioverter-defibrillator are identified. Contrast-enhanced cardiovascular magnetic resonance with late gadolinium enhancement (LGE) has emerged as an in vivo marker of myocardial fibrosis, although its role in stratifying sudden death risk in subgroups of HCM patients remains incompletely understood.

Methods And Results: We assessed the relation between LGE and cardiovascular outcomes in 1293 HCM patients referred for cardiovascular magnetic resonance and followed up for a median of 3.3 years. Sudden cardiac death (SCD) events (including appropriate defibrillator interventions) occurred in 37 patients (3%). A continuous relationship was evident between LGE by percent left ventricular mass and SCD event risk in HCM patients (P=0.001). Extent of LGE was associated with an increased risk of SCD events (adjusted hazard ratio, 1.46/10% increase in LGE; P=0.002), even after adjustment for other relevant disease variables. LGE of ≥15% of LV mass demonstrated a 2-fold increase in SCD event risk in those patients otherwise considered to be at lower risk, with an estimated likelihood for SCD events of 6% at 5 years. Performance of the SCD event risk model was enhanced by LGE (net reclassification index, 12.9%; 95% confidence interval, 0.3-38.3). Absence of LGE was associated with lower risk for SCD events (adjusted hazard ratio, 0.39; P=0.02). Extent of LGE also predicted the development of end-stage HCM with systolic dysfunction (adjusted hazard ratio, 1.80/10% increase in LGE; P<0.03).

Conclusions: Extensive LGE measured by quantitative contrast enhanced CMR provides additional information for assessing SCD event risk among HCM patients, particularly patients otherwise judged to be at low risk.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.113.007094DOI Listing
August 2014

Genotype-positive status in patients with hypertrophic cardiomyopathy is associated with higher rates of heart failure events.

Circ Cardiovasc Genet 2014 Aug 8;7(4):416-22. Epub 2014 Jun 8.

From the Division of Cardiology, Peter Munk Cardiac Center, Toronto General Hospital, Toronto, Ontario, Canada (Q.L., L.W., A.W., H.R.); Division of Cardiology, University Hospital of Zurich, Zurich, Switzerland (C.G.); Department of Medicine (Cardiovascular Division) and Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (R.H.C.); Fred A. Litwin and Family Center in Genetic Medicine, Mount Sinai Hospital, University Health Network, Toronto, Ontario, Canada (M.C., K.S.); and Department of Medicine, University of Toronto and Samuel Lunenfeld and Toronto General Research Institutes, Toronto, Ontario, Canada (K.S.).

Background: The aim of the study was to clarify the relationship between genotype status and major cardiovascular outcomes in a large cohort of patients with hypertrophic cardiomyopathy.

Methods And Results: Genetic testing was performed in 558 consecutive proband patients with hypertrophic cardiomyopathy. Baseline and follow-up (mean follow-up 6.3 years) clinical and echocardiographic data were obtained. Pathogenic mutations were identified in 198 (35.4%) patients. Genotype-positive patients were more likely to be women (44% versus 30%; P=0.001), younger (39 versus 48 years; P<0.001), and have a family history of hypertrophic cardiomyopathy (53% versus 20%; P<0.001), as well as family history of sudden cardiac death (17% versus 7%; P=0.002). There were no significant differences in the rates of atrial fibrillation, stroke, or septal reduction procedures. Multivariable analysis demonstrated that genotype-positive status was an independent risk factor for the development of combined heart failure end points (decline in left ventricular ejection fraction to <50%, New York Heart Association III or IV in the absence of obstruction, heart failure-related hospital admission, transplantation, and heart failure-related death; hazards ratio, 4.51; confidence interval, 2.09-9.31; P<0.001). No difference was seen in heart failure events between the myosin heavy chain and myosin-binding protein C genotype-positive patients.

Conclusions: The presence of a pathogenic sarcomere mutation in patients with hypertrophic cardiomyopathy was associated with an increase in heart failure events, with no differences in event rates seen between myosin heavy chain and myosin-binding protein C genotype-positive patients. The presence of a disease-causing mutation seems more clinically relevant than the specific mutation itself.
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http://dx.doi.org/10.1161/CIRCGENETICS.113.000331DOI Listing
August 2014

K-mer natural vector and its application to the phylogenetic analysis of genetic sequences.

Gene 2014 Aug 22;546(1):25-34. Epub 2014 May 22.

Department of Mathematical Sciences, Tsinghua University, Beijing 100084, China. Electronic address:

Based on the well-known k-mer model, we propose a k-mer natural vector model for representing a genetic sequence based on the numbers and distributions of k-mers in the sequence. We show that there exists a one-to-one correspondence between a genetic sequence and its associated k-mer natural vector. The k-mer natural vector method can be easily and quickly used to perform phylogenetic analysis of genetic sequences without requiring evolutionary models or human intervention. Whole or partial genomes can be handled more effective with our proposed method. It is applied to the phylogenetic analysis of genetic sequences, and the obtaining results fully demonstrate that the k-mer natural vector method is a very powerful tool for analysing and annotating genetic sequences and determining evolutionary relationships both in terms of accuracy and efficiency.
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http://dx.doi.org/10.1016/j.gene.2014.05.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096558PMC
August 2014

Significance of left ventricular apical-basal muscle bundle identified by cardiovascular magnetic resonance imaging in patients with hypertrophic cardiomyopathy.

Eur Heart J 2014 Oct 8;35(39):2706-13. Epub 2014 May 8.

Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, MA, USA.

Aims: Cardiovascular magnetic resonance (CMR) has improved diagnostic and management strategies in hypertrophic cardiomyopathy (HCM) by expanding our appreciation for the diverse phenotypic expression. We sought to characterize the prevalence and clinical significance of a recently identified accessory left ventricular (LV) muscle bundle extending from the apex to the basal septum or anterior wall (i.e. apical-basal).

Methods And Results: CMR was performed in 230 genotyped HCM patients (48 ± 15 years, 69% male), 30 genotype-positive/phenotype-negative (G+/P-) family members (32 ± 15 years, 30% male), and 126 controls. Left ventricular apical-basal muscle bundle was identified in 145 of 230 (63%) HCM patients, 18 of 30 (60%) G+/P- family members, and 12 of 126 (10%) controls (G+/P- vs. controls; P < 0.01). In HCM patients, the prevalence of an apical-basal muscle bundle was similar among those with disease-causing sarcomere mutations compared with patients without mutation (64 vs. 62%; P = 0.88). The presence of an LV apical-basal muscle bundle was not associated with LV outflow tract obstruction (P = 0.61). In follow-up, 33 patients underwent surgical myectomy of whom 22 (67%) were identified to have an accessory LV apical-basal muscle bundle, which was resected in all patients.

Conclusion: Apical-basal muscle bundles are a unique myocardial structure commonly present in HCM patients as well as in G+/P- family members and may represent an additional morphologic marker for HCM diagnosis in genotype-positive status.
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http://dx.doi.org/10.1093/eurheartj/ehu154DOI Listing
October 2014

Left atrial remodeling in hypertrophic cardiomyopathy and susceptibility markers for atrial fibrillation identified by cardiovascular magnetic resonance.

Am J Cardiol 2014 Apr 31;113(8):1394-400. Epub 2014 Jan 31.

Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota.

In hypertrophic cardiomyopathy (HC), atrial fibrillation (AF) is an important determinant of clinical deterioration due to heart failure or embolic stroke. This study characterizes left atrial (LA) structural and functional parameters to establish markers predictive of AF risk, using cardiovascular magnetic resonance (CMR) imaging. We studied 427 consecutive patients with HC in sinus rhythm with CMR (age 44±18 years), including 41 who developed clinically overt AF after study entry (2.6±2.1 years), 49 patients with AF before CMR, 337 patients with HC but without AF, and 244 normal controls. LA chamber was assessed for absolute and indexed end-diastolic volume (LAEDV), end-systolic volume, and percent ejection fraction (LAEF). In the 41 prospectively studied patients with HC who developed AF during follow-up, LAEDV was significantly greater than in patients without AF (146±48 vs 107±37 ml) or in normal controls (81±24 ml, p<0.001). Percent LAEF was lower in patients developing AF (36±10%) than without AF (46±12%) or controls (55±9%, p<0.001). Multivariate analysis identified LAEF (<38%), LAEDV (≥118 ml), and age (≥40 years) as independently associated with AF occurrence. In conclusion, CMR measures of LA remodeling and dysfunction reliably identified patients with HC at risk for future development of AF. Decrease in LAEF represents a strong novel marker of susceptibility to AF in this disease.
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http://dx.doi.org/10.1016/j.amjcard.2013.12.045DOI Listing
April 2014

Atherosclerotic biomarkers and aortic atherosclerosis by cardiovascular magnetic resonance imaging in the Framingham Heart Study.

J Am Heart Assoc 2013 Nov 15;2(6):e000307. Epub 2013 Nov 15.

Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

Background: The relations between subclinical atherosclerosis and inflammatory biomarkers have generated intense interest but their significance remains unclear. We sought to determine the association between a panel of biomarkers and subclinical aortic atherosclerosis in a community-based cohort.

Methods And Results: We evaluated 1547 participants of the Framingham Heart Study Offspring cohort who attended the 7th examination cycle and underwent both cardiovascular magnetic resonance imaging (CMR) and assays for 10 biomarkers associated with atherosclerosis: high-sensitivity C-reactive protein, fibrinogen, intercellular adhesion molecule-1, interleukin-6, interleukin-18, lipoprotein-associated phospholipase-A2 activity and mass, monocyte chemoattractant protein-1, P-selectin, and tumor necrosis factor receptor-2. In logistic regression analysis, we found no significant association between the biomarker panel and the presence of aortic plaque (global P=0.53). Using Tobit regression with aortic plaque as a continuous variable, we noted a modest association between biomarker panel and aortic plaque volume in age- and sex-adjusted analyses (P=0.003). However, this association was attenuated after further adjustment for clinical covariates (P=0.09).

Conclusions: In our community-based cohort, we found no significant association between our multibiomarker panel and aortic plaque. Our results underscore the strengths and limitations of the use of biomarkers for the identification of subclinical atherosclerosis and the importance of traditional risk factors.
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http://dx.doi.org/10.1161/JAHA.113.000307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886740PMC
November 2013