Christiane Gruner

Prognostic Value of Quantitative Contrast-Enhanced Cardiovascular Magnetic Resonance for the Evaluation of Sudden Death Risk in Patients With Hypertrophic Cardiomyopathy

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.

Comparison of two different speckle tracking software systems: does the method matter?

Background: Echocardiographic speckle tracking strain has gained clinical importance. However, the comparability of measurements between different software systems is not well defined. Methods: In 47 healthy subjects left ventricular (LV) two‐dimensional (2D) peak strain and time to peak strain (TTP) generated by EchoPAC (2DS) and velocity vector imaging (VVI) were compared. For each type of strain (longitudinal [LS], circumferential [CS], and radial strain [RS]) we compared global, anatomical level and segmental values. Results: When comparing 2DS to VVI, Pearson correlation coefficients (r) of global LS, CS, and RS were 0.68, 0.44, and 0.59, respectively (all P < 0.05). Correlation of global TTP was higher: 0.81(LS), 0.80 (CS), and 0.68 (RS), all P < 0.01. Segmental peak strain differed significantly between 2DS and VVI in 8/18 (LS), 17/18 (CS), and 15/18 (RS) LV segments (P < 0.05). However, segmental TTP significantly differed only in 5/18 (LS), 7/18 (CS), and 4/18 (RS) of LV segments. Similar strain gradients were found for both systems: apical strain was higher than basal and midventricular strain in LS and CS, with a reversed pattern for RS (P < 0.05). Conclusion: TTP strain as well as strain gradients were comparable between VVI and 2DS, but most peak strain values were not. The software‐dependency of peak strain values must be considered in clinical application. Further studies comparing the diagnostic and prognostic accuracy of strain values generated by different software systems are mandatory. (Echocardiography 2011;28:539‐547)

Quantification of Mitral Valve Anatomy by Three-Dimensional Transesophageal Echocardiography in Mitral Valve Prolapse Predicts Surgical Anatomy and the Complexity of Mitral Valve Repair

BACKGROUND Three-dimensional (3D) transesophageal echocardiography (TEE) is more accurate than two-dimensional (2D) TEE in the qualitative assessment of mitral valve (MV) prolapse (MVP). However, the accuracy of 3D TEE in quantifying MV anatomy is less well studied, and its clinical relevance for MV repair is unknown. METHODS The number of prolapsed segments, leaflet heights, and annular dimensions were assessed using 2D and 3D TEE and compared with surgical measurements in 50 patients (mean age, 61 ± 11 years) who underwent MV repair for mainly advanced MVP. RESULTS Three-dimensional TEE was more accurate (92%-100%) than 2D TEE (80%-96%) in identifying prolapsed segments. Three-dimensional TEE and intraoperative measurements of leaflet height did not differ significantly, while 2D TEE significantly overestimated the height of the posterior segment P1 and the anterior segment A2. Three-dimensional TEE quantitative MV measurements were related to surgical technique: patients with more complex MVP (one vs two to four vs five or more prolapsed segments) showed progressive enlargement of annular anteroposterior (31 ± 5 vs 34 ± 4 vs 37 ± 6 mm, respectively, P = .02) and commissural diameters (40 ± 6 vs 44 ± 5 vs 50 ± 10 mm, respectively, P = .04) and needed increasingly complex MV repair with larger annuloplasty bands (60 ± 13 vs 67 ± 9 vs 72 ± 10 mm, P = .02) and more neochordae (7 ± 3 vs 12 ± 5 vs 26 ± 6, P < .01). CONCLUSIONS Measurements of MV anatomy on 3D TEE are accurate compared with surgical measurements. Quantitative MV characteristics, as assessed by 3D TEE, determined the complexity of MV repair.

Toronto Hypertrophic Cardiomyopathy Genotype Score for Prediction of a Positive Genotype in Hypertrophic Cardiomyopathy

Background—Genotyping in hypertrophic cardiomyopathy has gained increasing attention in the past decade. Its major role is for family screening and rarely influences decision-making processes in any individual patient. It is associated with substantial costs, and cost-effectiveness can only be achieved in the presence of high-detection rates for disease-causing sarcomere protein gene mutations. Therefore, our aim was to develop a score based on clinical and echocardiographic variables that allows prediction of the probability of a positive genotype. Methods and Results—Clinical and echocardiographic variables were collected in 471 consecutive patients undergoing genetic testing at a tertiary referral center between July 2005 and November 2010. Logistic regression for a positive genotype was used to construct integer risk weights for each independent predictor variable. These were summed for each patient to create the Toronto hypertrophic cardiomyopathy genotype score. A positive genotype was found in 163 of 471 patients (35%). Independent predictors with associated-risk weights in parentheses were as follows: age at diagnosis 20 to 29 (−1), 30 to 39 (−2), 40 to 49 (−3), 50 to 59 (−4), 60 to 69 (−5), 70 to 79 (−6), ≥80 (−7); female sex (4); arterial hypertension (−4); positive family history for hypertrophic cardiomyopathy (6); morphology category (5); ratio of maximal wall thickness:posterior wall thickness <1.46 (0), 1.47 to 1.70 (1), 1.71 to 1.92 (2), 1.93 to 2.26 (3), ≥2.27 (4). The model had a receiver operator curve of 0.80 and Hosmer–Lemeshow goodness-of-fit P=0.22. Conclusions—The Toronto genotype score is an accurate tool to predict a positive genotype in a hypertrophic cardiomyopathy cohort at a tertiary referral center.

The Toronto HCM Genotype Score for Prediction of a Positive Genotype in Hypertrophic Cardiomyopathy

Background—Genotyping in hypertrophic cardiomyopathy has gained increasing attention in the past decade. Its major role is for family screening and rarely influences decision-making processes in any individual patient. It is associated with substantial costs, and cost-effectiveness can only be achieved in the presence of high-detection rates for disease-causing sarcomere protein gene mutations. Therefore, our aim was to develop a score based on clinical and echocardiographic variables that allows prediction of the probability of a positive genotype. Methods and Results—Clinical and echocardiographic variables were collected in 471 consecutive patients undergoing genetic testing at a tertiary referral center between July 2005 and November 2010. Logistic regression for a positive genotype was used to construct integer risk weights for each independent predictor variable. These were summed for each patient to create the Toronto hypertrophic cardiomyopathy genotype score. A positive genotype was found in 163 of 471 patients (35%). Independent predictors with associated-risk weights in parentheses were as follows: age at diagnosis 20 to 29 (−1), 30 to 39 (−2), 40 to 49 (−3), 50 to 59 (−4), 60 to 69 (−5), 70 to 79 (−6), ≥80 (−7); female sex (4); arterial hypertension (−4); positive family history for hypertrophic cardiomyopathy (6); morphology category (5); ratio of maximal wall thickness:posterior wall thickness <1.46 (0), 1.47 to 1.70 (1), 1.71 to 1.92 (2), 1.93 to 2.26 (3), ≥2.27 (4). The model had a receiver operator curve of 0.80 and Hosmer–Lemeshow goodness-of-fit P=0.22. Conclusions—The Toronto genotype score is an accurate tool to predict a positive genotype in a hypertrophic cardiomyopathy cohort at a tertiary referral center.

Right Heart Assessment by Echocardiography: Gender and Body Size Matters

BACKGROUND Published reference values for echocardiographic measurements of right-heart dimensions and function do not stratify for gender and body size. The aim of this study was therefore to assess the impact of gender and biometric characteristics on right-heart dimensions and function. METHODS From the echocardiography database at a tertiary care center, 1,625 subjects (mean age, 44 ± 14 years; 47% men) with normal echocardiographic findings between 2000 and 2009 were identified. Gender differences and association with body surface area were assessed retrospectively for right atrial long-axis and short-axis dimensions, right ventricular short-axis dimension, end-diastolic and end-systolic right ventricular area, right ventricular fractional area change, and tricuspid annular plane systolic excursion. The impact of normal values stratified for gender and body surface area was tested in 24 patients with moderate-sized to large atrial septal defects. RESULTS All dimensional right-heart measurements were significantly lower in women. Differences became smaller when measurements were indexed for body surface area, but significant differences persisted, particularly for right ventricular end-diastolic area (7.9 ± 1.6 vs 8.7 ± 1.8 cm(2)/m(2), P < .001) and right ventricular end-systolic area (4.0 ± 1.2 vs 4.7 ± 1.4 cm(2)/m(2), P < .001). Fractional area change and tricuspid annular plane systolic excursion indexed to body surface area were significantly higher in women (50 ± 7% vs 46 ± 9% and 14 ± 3 vs 12 ± 2 mm/m(2), respectively, P < .001 for both comparisons). The use of upper reference ranges for end-diastolic right ventricular area stratified for gender and body surface area improved the detection of enlarged right ventricles in patients with moderate-sized to large atrial septal defects (92% vs 54%, P < .007). CONCLUSIONS Gender and body surface area are important determinants of right ventricular dimensions and systolic function as measured on two-dimensional echocardiography. The investigators thus propose the use of measurements indexed to body surface area, with upper and lower reference ranges stratified for gender.

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

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.

Genotype-Positive Status in Patients With Hypertrophic Cardiomyopathy Is Associated With Higher Rates of Heart Failure Events

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.

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

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.

Sarcomere Protein Gene Mutations in Patients with Apical Hypertrophic Cardiomyopathy

Background— Apical hypertrophic cardiomyopathy (HCM) is a unique form of HCM with left ventricular hypertrophy confined to the cardiac apex. The purpose of our study was to report genetic findings in a large series of unrelated patients with apical HCM and compare them with a nonapical HCM cohort. Methods and Results— Overall, 429 patients with HCM underwent genetic testing. The panel included 8 sarcomere protein genes and 3 other genes (GLA, PRKAG2, and LAMP2). Sixty-one patients were diagnosed with apical HCM. A positive genotype was found in 8 patients with apical HCM. The genotype-positive and genotype-negative patients had similar maximal wall thicknesses (17.5±3.5 mm versus 17.6±3.3 mm, P=0.71) and similar frequency of HCM-related events (2/8; 25% versus 13/53; 25%; P=0.98). Thirteen percent with apical HCM and 40% with nonapical HCM had a positive genotype (P<0.001) most often involving the MYBPC3 and MYH7 genes. Conclusions— In apical HCM, a positive genotype was found less frequently than in nonapical HCM, and it was most often involving MYBPC3 and MYH7 genes. Only 13% of patients with apical HCM were found to be genotype positive, indicating that genome-wide association studies and gene expression profiling are needed for better understanding of the genetic background of the disease. There was no significant genotype-phenotype correlation in our cohort with apical HCM.