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Supplemental Digital Content is available in the text., Background: The common intronic deletion, MYBPC3Δ25, detected in 4% to 8% of South Asian populations, is reported to be associated with cardiomyopathy, with ≈7-fold increased risk of disease in variant carriers. Here, we examine the contribution of MYBPC3Δ25 to hypertrophic cardiomyopathy (HCM) in a large patient cohort. Methods: Sequence data from 2 HCM cohorts (n=5393) was analyzed to determine MYBPC3Δ25 frequency and co-occurrence of pathogenic variants in HCM genes. Case-control and haplotype analyses were performed to compare variant frequencies and assess disease association. Analyses were also undertaken to investigate the pathogenicity of a candidate variant MYBPC3 c.1224-52G>A. Results: Our data suggest that the risk of HCM, previously attributed to MYBPC3Δ25, can be explained by enrichment of a derived haplotype, MYBPC3Δ25/−52, whereby a small subset of individuals bear both MYBPC3Δ25 and a rare pathogenic variant, MYBPC3 c.1224-52G>A. The intronic MYBPC3 c.1224-52G>A variant, which is not routinely evaluated by gene panel or exome sequencing, was detected in ≈1% of our HCM cohort. Conclusions: The MYBPC3 c.1224-52G>A variant explains the disease risk previously associated with MYBPC3Δ25 in the South Asian population and is one of the most frequent pathogenic variants in HCM in all populations; genotyping services should ensure coverage of this deep intronic mutation. Individuals carrying MYBPC3Δ25 alone are not at increased risk of HCM, and this variant should not be tested in isolation; this is important for the large majority of the 100 million individuals of South Asian ancestry who carry MYBPC3Δ25 and would previously have been declared at increased risk of HCM.

ObjectivesThis study sought to assess the impact of body mass index (BMI) on cardiac phenotypic and clinical course in a multicenter hypertrophic cardiomyopathy (HCM) cohort.BackgroundIt is unresolved whether clinical variables promoting left ventricular (LV) hypertrophy in the general population, such as obesity, may influence cardiac phenotypic and clinical course in patients with HCM.MethodsIn 275 adult HCM patients (age 48 ± 14 years; 70% male), we assessed the relation of BMI to LV mass, determined by cardiovascular magnetic resonance (CMR) and heart failure progression.ResultsAt multivariate analysis, BMI proved independently associated with the magnitude of hypertrophy: pre-obese and obese HCM patients (BMI 25 to 30 kg/m2 and >30 kg/m2, respectively) showed a 65% and 310% increased likelihood of an LV mass in the highest quartile (>120 g/m2), compared with normal weight patients (BMI 120 g/m2 were LV outflow obstruction (HR: 4.9; 95% CI: 2.4 to 9.8; p < 0.001), systemic hypertension (HR: 2.2; 95% CI: 1.1 to 4.5; p = 0.026), and male sex (HR: 2.1; 95% CI: 0.9 to 4.7; p = 0.083). During a median follow-up of 3.7 years (interquartile range: 2.5 to 5.3), obese patients showed an HR of 3.6 (95% CI: 1.2 to 10.7, p = 0.02) for developing New York Heart Association (NYHA) functional class III to IV symptoms compared to nonobese patients, independent of outflow obstruction. Noticeably, the proportion of patients in NYHA functional class III at the end of follow-up was 13% among obese patients, compared with 6% among those of normal weight (p = 0.03).ConclusionsIn HCM patients, extrinsic factors such as obesity are independently associated with increase in LV mass and may dictate progression of heart failure symptoms.

Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease with a frequency as high as 1 in 200. In many cases, HCM is caused by mutations in genes encoding the different components of the sarcomere apparatus. Hypertrophic cardiomyopathy is characterized by unexplained left ventricular hypertrophy, myofibrillar disarray, and myocardial fibrosis. The phenotypic expression is quite variable. Although most patients with HCM are asymptomatic, serious consequences are experienced in a subset of affected individuals who present initially with sudden cardiac death or progress to refractory heart failure. The Hypertrophic Cardiomyopathy Registry study is a National Heart, Lung, and Blood Institute-sponsored 2,750-patient, 44-site, international registry and natural history study designed to address limitations in extant evidence to improve prognostication in HCM (NCT01915615). In addition to the collection of standard demographic, clinical, and echocardiographic variables, patients will undergo state-of-the-art cardiac magnetic resonance for assessment of left ventricular mass and volumes as well as replacement scarring and interstitial fibrosis. In addition, genetic and biomarker analyses will be performed. The Hypertrophic Cardiomyopathy Registry has the potential to change the paradigm of risk stratification in HCM, using novel markers to identify those at higher risk.

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.

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.

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 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.

Current guidelines recommend an implantable cardioverter-defibrillator (ICD) according to the left ventricular ejection fraction (LVEF). However, they do not mandate volumetric LVEF assessment. We sought to determine whether volumetric LVEF measurement using cardiovascular magnetic resonance imaging (CMR-LVEF) is superior to conventional LVEF measurement using 2-dimensional transthoracic echocardiography (Echo-LVEF) for risk stratifying patients referred for primary prevention ICD. Patients who underwent primary prevention ICD implantation at our institution and had undergone preimplantation CMR-LVEF from November 2001 to February 2011 were identified. Volumetric CMR-LVEF was determined from cine short-axis data sets. CMR-LVEF and Echo-LVEF were extracted from the clinical reports. The end point was appropriate ICD discharge (shock and/or antitachycardia pacing). Of 48 patients, appropriate ICD discharge occurred in 9 (19%) within 29 – 25 months (range 1 to 99, median 20). All patients met the Echo-LVEF criteria for ICD implantation; however 25% (95% confidence interval 13% to 37%) did not meet the CMR-LVEF criteria. None (0%) of these latter patients had received an appropriate ICD discharge. Using CMR-LVEF ≤30% as a threshold for ICD eligibility, 19 patients (40%) with a qualifying Echo-LVEF would not have been referred for ICD, and none (0%) received an ICD discharge. For primary prevention ICD implantation, volumetric CMR-LVEF might be superior to clinical Echo-LVEF for risk stratification and can identify a large minority of subjects in whom ICD implantation can be safely avoided. In conclusion, if confirmed by larger prospective series, volumetric methods such as CMR should be considered a superior “gatekeeper” for the identification of patients likely to benefit from primary prevention ICD implantation.

Hypothesis/Introduction : We investigated whether diabetes modified the effectiveness of renin–angiotensin–aldosterone system (RAAS) inhibition on left ventricular hypertrophy (LVH) regression in hypertensive patients in the Aliskiren in Left Ventricular Hypertrophy (ALLAY) trial. Materials and methods : Participants ( n =465) with LVH and a BMI > 25 kg/m 2 were randomized to aliskiren 300mg, losartan 100mg or both daily for 36 weeks, and LVH regression was assessed by cardiac magnetic resonance imaging. Renin concentration, plasma renin activity and aldosterone were assessed in a subset of patients. Results : Patients with diabetes mellitus (DM) ( n =111, 24%) were older (61±9 vs. 58±11 years, p =0.03), had higher BMI (32.2±4.2 vs. 30.7 ± 4 kg/m 2 , p =0.004), higher systolic blood pressure (148±14 vs. 145±14mmHg, p =0.03) and lower eGFR (79±16 vs. 84±16ml/min, p =0.03) at baseline. Combination therapy with aliskiren plus losartan was associated with greater LVH reduction than losartan alone in patients with DM ( p =0.01), but not in patients without DM ( p =0.91; unadjusted interaction p =0.06; adjusted p = 0.038). In a subset of 138 participants, plasma aldosterone was reduced to a greater extent in patients with DM ( p -interaction = 0.004). Conclusions : Patients with DM and LVH may derive differential benefit with dual RAAS inhibition with a combination of aliskiren and losartan compared with losartan alone with respect to LVH reduction. Whether these findings will result in improved outcomes will be further explored in larger studies.

Background: High circulating aldosterone levels stimulate myocardial fibrosis and left ventricular hypertrophy (LVH). However, it is not clear whether suppression of aldosterone directly contributes to LVH regression in hypertensive patients. Methods: The Aliskiren in Left Ventricular Hypertrophy (ALLAY) trial randomised 465 hypertensive overweight subjects with LVH to the direct renin inhibitor aliskiren 300 mg, losartan 100 mg or the combination and followed patients for 9 months. All patients were treated to standard blood pressure targets. Left ventricular (LV) mass index (LVMI) and LV wall thickness (LVWT) were assessed by cardiac magnetic resonance. A subset of 136 patients who had plasma aldosterone concentration (ALDO) measured at baseline and study end was analysed. Results: At baseline, plasma ALDO was modestly related to systolic blood pressure, LVMI, and wall thickness (all, p < 0.05). Aliskiren, either alone or in combination, was associated with a significantly greater reduction from baseline to 9 months in plasma aldosterone than losartan alone ( p < 0.02). Reduction in ALDO was related to reduction in LVMI even after adjustment for baseline ALDO, BP reduction and treatment group ( p for trend = 0.042). Conclusion: In hypertensive patients with increased LVWT, aliskiren alone or in combination with the angiotensin receptor blocker losartan provides greater reduction in aldosterone compared to losartan alone. Moreover, suppression of aldosterone was associated with reduction of LVH, independently of the change in SBP, suggesting that suppression of aldosterone, a known mediator of LVH, may be particularly important for LVH regression and as a target for therapy.

Background— Cell therapy for myocardial infarction (MI) may be limited by poor cell survival and lack of transdifferentiation. We report a novel technique of implanting whole autologous myocardial tissue from preserved myocardial regions into infarcted regions. Methods and Results— Fourteen rats were used to optimize cardiomyotissue size with peritoneal wall implantation (300 μm identified as optimal size). Thirty-nine pigs were used to investigate cardiomyotissue implantation in MI induced by left anterior descending balloon occlusion (10 animals died; male-to-female transplantation for tracking with in situ hybridization for Y chromosome, n=4 [2 donors and 2 MI animals]; acute MI implantation cohort at 1 hour, n=13; and healed MI implantation at 2 weeks, n=12). Assessment included echocardiography, magnetic resonance imaging, hemodynamics, triphenyltetrazolium chloride staining, and histological and molecular analyses. Tracking studies demonstrated viable implants with donor cells interspersed in the adjacent myocardium with gap junctions and desmosomes. In the acute MI cohort, treated animals compared with controls had improved perfusion by magnetic resonance imaging (1.2±0.01 versus 0.86±0.05; P P =0.04; triphenyltetrazolium chloride: anterior wall, 10.3±4.6% versus 28.9±5.8%, P P P P =0.006) than control animals. Infarcts in the treated animals contained more mdr-1 + cells and fewer c-kit + cells with a trend for decreased expression of matrix metalloproteinase-2 and increased expression of tissue inhibitor of metalloproteinase-2. Conclusion— Autologous cardiomyotissue implanted in an MI area remains viable, exhibits electromechanical coupling, decreases infarct size, and improves left ventricular function.

Late gadolinium enhancement score (LGE-Score) for prediction of extensive late gadolinium enhancement in hypertrophic cardiomyopathy Raymond H Chan, Barry J Maron, Iacopo Olivotto, Gabriele Egidy Assenza, Tammy S Haas, John R Lesser, Christiane Gruner, Andrew Crean, Harry Rakowski, James E Udelson, Ethan J Rowin, Massimo Lombardi, Franco Cecchi, Benedetta Tomberli, Paolo Spirito, Francesco Formisano, Elena Biagini, Claudio Rapezzi, Carlo Nicola De Cecco, Camillo Autore, Susie N Hong, Michael C Gibson, Warren J Manning, Evan Appelbaum, Martin Maron

Background Hypertrophic cardiomyopathy (HCM) patients with massive left ventricular hypertrophy (LVH) (hereby defined as maximal LV wall thickness >30mm) are known to have lower rates of survival. Recently, contrast-enhanced cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) has emerged as a potential novel marker of increased cardiovascular risk in HCM. Methods Cine CMR and LGE imaging were performed on HCM patients with massive LV hypertrophy and compared with those with a maximal LV wall thickness

Background Hypertrophic cardiomyopathy (HCM) is most common in patients under 40 years and is associated with early sudden death, but HCM is increasingly recognized in elderly patients. We sought to characterize and identify features unique to elderly HCM patients when compared with youthful patients using CMR. Methods Cine CMR and late gadolinium enhancement (LGE) imaging were performed in 902 HCM patients, including 202 young (15-35 years; mean 24.5 ± 6.3 years), and 143 elderly patients (age > 65 years; mean 70.9 ± 4.8 years). ). Results Elderly HCM patients had a lower proportion of males (53.8% elderly vs 70.3%, p=0.002). They had significantly lower left ventricular (LV) mass (153 ± 64g elderly vs 183 ± 90g, p 30mm) (OR 0.15, 95% C.I. 0.030.64, p=0.01). Elderly HCM patients had a smaller LV cavity size, with lower LV end-diastolic volume (138 ± 41ml elderly vs 165 ± 45ml, p 0.1) and similar rates of depressed ( 0.10) and percentage of LV with LGE (8.6 ± 10.4% elderly vs 6.9 ± 8.3%, p>0.10) were similar. Conclusions

ObjectivesOur aim was to determine whether myocardial fibrosis, detected by cardiovascular magnetic resonance (CMR), represents an arrhythmogenic substrate in hypertrophic cardiomyopathy (HCM).BackgroundMyocardial fibrosis is identified frequently in HCM; however, the clinical significance of this finding is uncertain.MethodsWe 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).ResultsPremature 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).ConclusionsIn 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.

ObjectivesWe sought to determine the prevalence of noncardiac pathology in a large consecutive series of patients referred for clinical cardiac magnetic resonance (CMR) studies.BackgroundThe imaging field for many CMR sequences extends outside of the heart border. As a result, noncardiac pathology may be identified. These noncardiac findings have clinical significance because they often lead to subsequent imaging/testing and intervention. The prevalence of noncardiac findings on clinical CMR studies has not been well described.MethodsThe reports of all 1,534 (62% male, age 50 ± 15 years) clinical CMR studies performed at an academic medical center during calendar years 2002 to 2006 were reviewed. All studies had been interpreted by both a staff cardiologist (level III trained in CMR) and a board-certified radiologist (with fellowship training in CMR). For each study, sex, age, indication for CMR study, and reported noncardiac pathology were extracted. Follow-up for each major noncardiac pathology was evaluated by reviewing the patient's medical center electronic medical record. These noncardiac pathologies were then categorized as significant if an intervention or change in the patient's management ensued.ResultsA total of 116 (7.6%) studies had at least one noncardiac finding. These findings included 55 major findings (e.g., lymphadenopathy, lung abnormalities, mediastinal masses) in 48 distinct reports (prevalence of 3.1%) and 74 minor findings (e.g., small pleural effusions, liver cysts, renal cysts) in 70 distinct reports (prevalence of 4.6%). The majority (62%) of major findings were previously known, with only 8 findings in 6 (0.4%) of 1,534 reports ultimately deemed to be new and clinically important/significant. The age of those with noncardiac pathology was greater (54 ± 16 years vs. 49 ± 16 years, p < 0.001).ConclusionsIn this large series of consecutive clinical CMR studies interpreted by both staff cardiologists and radiologists, noncardiac pathology is uncommonly reported. When reported, the majority of major findings are previously known. New major findings were detected in

ObjectivesOur 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).BackgroundBased on prior pathologic and 2-dimensional echocardiographic studies, HCM has been regarded as a disease characterized by substantial LV wall thickening.MethodsCine and late gadolinium enhancement CMR were performed in 333 consecutive HCM patients (age 43 ± 17 years).ResultsBasal anterior LV free wall and the contiguous anterior ventricular septum were the most commonly hypertrophied segments (n = 256; 77%). LV hypertrophy was focal (involving ≤2 segments [≤12% of LV]) in 41 patients (12%), intermediate (3 to 7 segments [13% to 49% of LV]) in 112 patients (34%), and diffuse (≥8 segments [≥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 (≥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.ConclusionsAlthough diverse, patterns of LV hypertrophy are usually not extensive in HCM, involving ≤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.

Background Left ventricular (LV) and right ventricular (RV) systolic performance, typically measured as the ejection fraction (EF), is strongly correlated with mortality. However, CMR provides multiple measures that may also reflect systolic performance including LV volumes and cardiac outflow. We examined the predictive relationship of multiple potential measures of cardiac systolic performance with mortality in a large CMR clinical database.

Introduction Heart failure (HF) with depressed systolic function is increasingly prevalent in the United States with coronary artery disease (CAD) the most common etiology. Definitive determination of an ischemic vs. non-ischemic etiology of HF often requires invasive x-ray coronary angiography. Both coronary magnetic resonance imaging (cMRI) and late gadolinium enhancement (LGE) have shown promise in the non-invasive detection of CAD in HF patients.

Background Myocardial fibrosis as detected by late gadolinium enhanced cardiovascular MR (LGE-CMR) is common in patients with hypertrophic cardiomyopathy (HCM) although its clinical significance is uncertain. Current standard 2D LGE CMR imaging However, a recent postmortem report demonstrated an isolated foci of papillary muscle scarring which was not detected by conventional 2D LGE-CMR imaging. Three-dimensional high resolution (3D-HR) LGE CMR imaging has the potential for minimizing the partial volume (blood/papillary scar) effect of lower resolution/conventional 2D imaging and may improve our sensitivity for detecting myocardial fibrosis. Therefore, we sought to determine if 3D-HR LGECMR has a diagnostic advantage over conventional 2D LGE CMR for the detection of myocardial fibrosis in HCM patients.