News from AHA Scientific Sessions 2011

The American Heart Association conducted its annual scientific sessions 2011 in Orlando Florida November 13 -16. The Hypertrophic Cardiomyopathy Association participating in its 14th AHA scientific sessions with an exhibit booth and attendance at sessions related to HCM, sudden cardiac arrest in the young and surveillance systems for identifying those at risk for cardiac disease.

American Heart Association Scientific Sessions Review of HCM Highlights

By: Lisa Salberg

The purpose of this section is to briefly discuss some highlights of the latest in our appreciation of HCM and related issues. This information should not be used by patients to alter treatment and as always consultation with hypertrophic cardiomyopathy expert is suggested to evaluate each individual case of hypertrophic cardiomyopathy appropriately.  The sessions in the area of hypertrophic cardiomyopathy in this scientific session are best described as helping to better identify risk stratification tools with the use of CMR/MRI, a better appreciation for the anatomy of HCM and her need to appreciate areas of the heart previously not well visualized including papillary muscles and mitral valve apparatus and the ongoing dilemma of how to identify those at risk for adverse outcomes from HCM to be identified.  The highlight of AHA for HCM was the release of HCM guidelines which are now available.  The overwhelming response to the Guidelines at the HCMA booth could best be summed up a being viewed as a welcome addition to the body of data to treat this population – yet long.

Bernard Gersh of the Mayo Clinic and co-chair of the HCM guidelines committee presented the guidelines in a large session that addressed all new guidelines.   There were two areas he highlighted in his talk – 1. High volume HCM programs are important to patient care and 2 – myectomy remains the gold standard yet alcohol septal ablation in the right patients can have good outcomes but the BOTH procedures should only be preformed by high volume operators in high volume HCM programs.  There is no abstract available on this talk but a complete copy is available on the HCMA website.

Does the 12-lead ECG Have Limitations in Detecting Hypertrophic Cardiomyopathy in the Pre-Participation Screening of Athletes?

Ethan J Rowin¹; Evan Appelbaum²; Thomas H Hauser³; Caitlin Harrigan¹; C. Michael Gibson⁴; John R Lesser⁵; Tammy S Haas⁵; James E Udelson¹; Warren J Manning⁶; Barry J Maron⁵; Martin S Maron¹

¹ Hypertrophic Cardiomyopathy Cntr, Div of Cardiology, Tufts Med Cntr, Boston, MA,
² PERFUSE Core Laboratory and Data Coordinating Cntr, Harvard Med Sch, Dept of Medicine (Cardiovascular Div), Beth Israel Deaconess Med Cntr, Boston, MA,
³ Dept of Medicine (Cardiovascular Div), Beth Israel Deaconess Med Cntr, Boston, MA,
⁴ PERFUSE Core Laboratory and Data Coordinating Cntr, Harvard Med Sch, Dept of Medicine (Cardiovascular Div), Beth Israel Deaconess Med Cntr, Boston, MA,
⁵ The Hypertrophic Cardiomyopathy Cntr, Minneapolis Heart Institute Foundation, Minneapolis, MN,
⁶ PERFUSE Core Laboratory and Data Coordinating Cntr, Harvard Med Sch, Dept of Medicine (Cardiovascular Div) and Radiology, Beth Israel Deaconess Med Cntr, Boston, MA

Background. Pre-participation screening of athletes with 12-lead electrocardiograms (ECGs) has been recommended for detection of asymptomatic cardiovascular disease, particularly hypertrophic cardiomyopathy (HCM). However, while false positive rates of 10-20% have been recognized for HCM, the false negative rates are unkown.

Objective: We assessed the accuracy of recommended ECG screening criteria for suspected heart disease in trained athletes (based on recent European Society of Cardiology [ESC] recommendations), in a large cohort of patients with HCM studied by cardiovascular magnetic resonance (CMR), an imaging technique that allows for precise assessment of left ventricular hypertrophy (LVH).

Design and Setting. CMR and 12-lead ECGs were obtained in 343 HCM patients (41±17 years; 71% male). ECGs were analyzed according to recent ESC recommendations for distinguishing normal from pathologic ECG patterns in athletes. Non-pathologic ECGs were either within normal limits or demonstrated changes regarded consistent with physiologic alterations of athletic training.

Results. Among 343 HCM patients, 308 (90%) demonstrated  1 pathologic ECG abnormality, including Romhilt-Estes criteria for LVH in 197 (57%), ST-T wave changes in 181 (53%), and abnormal Q waves in 129 (38%). The remaining 35 patients (10%) had normal ECGs or non-pathologic variants and therefore defined a subgroup of HCM patients in whom screening ECGs would have failed to raise suspicion of heart disease (i.e., false negatives). Of those HCM patients with false negative ECGs, maximal LV wall thickness was 19 ± 3 mm (range, 13 to 26) and LV outflow tract obstruction ( 30 mmHg) was present in 7 (20%); 15 (43%) were <40 years of age. Patients with or without pathologic ECGs did not differ with respect to age, gender, or presence of obstruction, however, maximal LV wall thickness was lower in HCM patients without pathologic ECG abnormalities (19 ± 3 mm vs 22 ± 5mm; p<0.01).

Conclusions. We identified an important proportion of patients with HCM (10%) in whom suspicion of disease would not likely have been raised by screening ECG testing. This high false negative rate represents a limitation with respect to 12-lead ECG screening in large athletic populations.

HCMA Comment:

The data already published on false positives indicates between 12 and 19% and this study now reporting a 10% false negative therefore the combined false readings (positive or negative) now appear to be in the 22 to 29% range.  This means that 1/3 of all screening ECG’s not able to clear or diagnosis cardiac disease in the young.    The labor, logistics, cost, and low predictive value remain challenges in this concept to “screen all youth” with ECG’s.  

Sudden Cardiac Death Screening in the High School Athlete: A Statewide Evaluation of Compliance with the American Heart Association Guidelines

Nicolas L Madsen¹; Jonathan A Drezner²; Jack C Salerno¹

¹ Pediatrics, Univ of Washington, Seattle, WA
² Sports Medicine, Univ of Washington, Seattle, WA

Background: The preparticipation physical evaluation (PPE) is the standard of care for annually screening 6-7 million high school athletes for their risk of sudden cardiac death (SCD) at an estimated cost of $250 million/year.

Purpose: Our aim was to evaluate primary care provider compliance with the American Heart Association (AHA) consensus statement on SCD screening.

Methods: The Washington Chapter of the American Academy of Pediatrics (AAP) and the Washington Association of Family Physicians (WAFP) were provided a 36 question survey. Responses were evaluated for compliance with individual elements of the AHA guidelines, as well as by a score of overall compliance. In addition, every Washington State high school athletic director was surveyed to determine their school's compliance with the AHA guidelines.

Results: We received an excellent response rate (72% (559/776) from the AAP, 56% (554/990) from the WAFP, and 75% (317/424) from the athletic directors). Only 5.7% of all providers and 0% of schools were in complete compliance with the AHA guidelines. Less than half (47%) of the providers and 6% of athletic directors were aware of the AHA guidelines. Notably, 28% of providers don’t always ask about exertional chest pain, 22% don’t always ask about syncope, and 26% don’t always ask about family history of premature death. There was no difference in overall compliance between provider types (p-value 0.20). Provider location, years of experience, and exposure to SCD were not significantly associated with overall compliance. Provider knowledge of the guidelines, level of satisfaction with the PPE, number of PPE/month, and number of referrals to cardiology were all positively associated with improved overall compliance (p-value <0.05).

Conclusion: Less than 6% of primary care providers are in full compliance with national PPE guidelines, which have remained unchanged for 15 years. This lack of compliance does not reflect clinical experience, practice location, or provider type, but rather a lack of knowledge of the guidelines themselves. New directions for provider education and policy requirements are needed to improve this implementation gap.

HCMA comment:

This was an intriguing poster and the dialogue that took place in front of it is testament to the fact that many in the cardiology arena feel frustrated at the lack of appreciation of sudden cardiac arrest risk by general practitioners and pediatricians.  The sudden cardiac arrest risk assessment tool provided by the Hypertrophic Cardiomyopathy Association and distributed to any and all peoples interested will be an excellent tool to help parents communicate better with healthcare providers if there is an area of risk. We do not believe there's one answer to this complicated problem of identifying those at risk for sudden cardiac death however there is much to be said for thoughtful methods to improve surveillance in the multidisciplinary fashion.

Hypertrophic Cardiomyopathy with Longevity into the Tenth Decade of Life

 Barry J Maron; Sue A Casey; Tammy S Haas; Carrie Kitner; Ross Garberich 

Background. Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in the young, but survival to particularly advanced age is less well appreciated.

Methods. We report the prevalence, clinical features and demographics of HCM patients surviving to the age of 90 years or older, identified by interrogation of the HCM Center database (Minneapolis Heart Institute Foundation).

Results. Of the 1297 HCM patients, 26 (2.0%) had achieved the age of at least 90 years; 18 (69%) were women. Age at HCM diagnosis was 61 to 92 years ( 75 years in 21), with disease recognition under fortuitous circumstances by detection of a heart murmur or during family screening (n = 6), or after onset of new symptoms (n = 20). At most recent evaluation (or death) patients were 90.0 to 96.7 years of age (mean 92.2 ± 2), with 6 presently alive at 90 to 96 years of age; HCM did not appear to be the primary cause of demise in any patient. Maximum LV wall thicknesses were 15-31 mm (mean 20 ± 3 mm); 8 patients (31%) had obstruction to LV outflow at rest (gradients, 38-135 mmHg). HCM-related complications occurred in18 patients (69%), including heart failure symptoms, atrial fibrillation, and non-fatal embolic stroke. Although no patient died suddenly, 13 (50 %) nevertheless carried conventional HCM markers of risk. A greater proportion of patients in this cohort reached  90 years of age (2.0%) than expected in the general population (0.8%; p < 0.001).

Conclusions. HCM is consistent with survival to normal life expectancy, including particularly advanced age into the tenth decade of life, with demise ultimately largely unrelated to this disease. This principle regarding the natural history of HCM can afford a measure of reassurance to many patients.

HCMA Comment:

Patients, families and physicians should take this information to heart when thinking of what a diagnosis of HCM really means to ones life span – as the HCMA has long suspected and now it is proven many with HCM can and do live far past the average age of mortality.     A diagnosis of HCM is NOT a diagnosis of early death.

Double or Compound Sarcomere Mutations Associated with Sudden Death Risk in Hypertrophic Cardiomyopathy in the Absence of Conventional Risk Factors

Christopher Semsarian¹; Martin Maron²; Barry J Maron³

¹ Molecular Cardiology, Univ of Sydney, Newtown 2042, Australia
² Molecular Cardiology, Tufts Med Cntr, Boston, MA,
³ HCM Cntr, Minneapolis Heart Institute Foundation, Minneapolis, MN

Background: Risk stratification strategies employing sarcomere gene mutational analysis have proved imprecise in hypertrophic cardiomyopathy (HCM). Additional genetic risk markers that reliably identify patients predisposed to sudden death are needed. Whether multiple disease- causing sarcomere mutations can be regarded as markers for sudden death in the absence of other conventional risk factors is unresolved.

Methods: The databases of 3 HCM centers were assessed in Minneapolis, Boston and Sydney. From 2000-2010, HCM patients were identified who had undergone sudden death risk factor evaluation and in whom genetic testing had been performed for the 8 most common sarcomere genes.

Results: Of 330 HCM probands, 18 (5.5%) had 2 disease-causing mutations in genes encoding proteins of the cardiac sarcomere. Severe disease progression or adverse cardiovascular events occurred in 7 of these 18 patients (39%), including 3 patients (ages 31, 37, 57 years) who experienced sudden cardiac arrest, but also were without evidence of conventional HCM risk factors; 2 survived with timely defibrillation and therapeutic hypothermia and one died. These 3 probands carried distinct and heterozygous disease-causing sarcomere mutations (including a man who inherited one mutation independently from each of his parents with HCM) - i.e., double MYBPC3 and TNNI3 mutations and compound MYBPC3 mutations, as the only predisposing clinical markers evident to potentially explain their unexpected cardiac event.

Conclusions: These observations support the emerging hypothesis that double (or compound) sarcomere mutations appear to confer a gene dosage effect in HCM, predisposing patients to adverse disease progression. Multiple mutations were also associated with a risk of sudden death, even in the absence of conventional risk factors. These data suggest that genetic testing may contribute to the assessment of clinical course and prognosis among select HCM patients.

HCMA Comment:

The presents of multiple mutations has long been a concern to the HCMA – we have seen too many poor outcomes in these patients.  This research supports our observations that multiple mutations are to be taken seriously and yet again further support for the use of genetic testing to help better manage patients with HCM.

How Low is Low Risk in Hypertrophic Cardiomyopathy? Sudden Death in Patients Without Conventional Risk Factors

Paolo Spirito¹; Camillo Autore²; Francesco Formisano¹; Gabriele Egidy Assenza²; Elena Biagini³; Tammy S Haas⁴; Sergio Bongioanni⁵; Chris Semsarian⁶; Emmanuela Devoto¹; Carrie Kitner⁴; Beatrice Musumeci²; Guido Rocchi³; Laura Yeates⁷; Claudio Rapezzi³; Maria Rosa Conte⁵; Barry J Maron⁴

¹ Cardiologia, Ente Ospedaliero Ospedali Galliera, Genova, Italy
² Cardiologia, Università La Sapienza, Rome, Italy
³ Cardiologia, Università di Bologna, Bologna, Italy
⁴ Cardiology, Minneapolis Heart Institute Foundation, Minneapolis, MN
⁵ Cardiologia, Azienda Ospedaliera Ordine Mauriziano, Torino, Italy
⁶ Cardiology, Univ of Sydney, Sidney, Australia
⁷ Molecular Cardiology, Agnes Ginges Cntr for Molecular Cardiology, Centenary Institute, Newtown, Australia

Background: In recent years, research has focused on the identification of patients with hypertrophic cardiomyopathy (HCM) at high risk for sudden death who could be potential candidates for the implantable cardioverter-defibrillator (ICD). While the ICD has been life-saving for many such patients, the outcome of those patients without conventional risk factors who are judged to be at low risk for sudden death, remains unresolved.

Methods: We assessed the risk for sudden death in a consecutive cohort of 721 HCM patients without any of the major conventional risk factors, including family history of sudden death, extreme LV hypertrophy (maximal wall thickness  30 mm), non-sustained ventricular tachycardia on Holter monitoring, and unexplained syncope.

Results: In this study cohort, mean age was 43 years (median 45). Over a median follow-up of 5.1 years, 22 patients (3.1%) died suddenly, for a sudden death incidence of 0.5% per year. Mean age at time of sudden death was 48 years, with 14 patients (64%) < 50 and 7 (32%) < 35. Left ventricular outflow obstruction under basal conditions was present in 6 patients (27%), mean LV wall thickness was 21 mm (range 14 to 27 mm) and left atrial size 45 mm (range 37 to 67 mm).

Conclusions: In this large HCM cohort regarded to be at low risk for sudden death based on generally accepted risk stratification criteria, the absence of conventional risk factors did not guarantee immunity from sudden death, suggesting the need for additional risk markers in this disease.

HCMA Comment:

There is a great number of patients who are at very low risk but to ensure patients are truly in this group annual risk assessment should be preformed by a knowledgeable HCM program.   

Assessing Electrocardiographic Screening in Elite High School Athletes with Comparison to Adolescents with Hypertrophic Cardiomyopathy

Jonathan N Johnson; Justin M Horner; Michael J Ackerman; Bryan C Cannon; Benjamin W Eidem Pediatric Cardiology, Mayo Clinic, Rochester, MN

Background: Electrocardiography (ECG) in athletic screening has been studied widely. In trained athletes, ECG aberrations are common and often prompt evaluation for underlying cardiac pathology. We sought to compare ECG findings in a cohort of elite high school athletes to a cohort of adolescents with hypertrophic cardiomyopathy (HCM).

Methods: We prospectively performed standard 15-lead ECGs followed by echocardiography in 187 high school students (age 15.9 ± 1.5 yrs), including 147 elite nationally-competing high school athletes and 40 healthy non-athlete controls. ECG results were compared to baseline ECGs of a retrospective cohort of 53 adolescents diagnosed with non-syndromic HCM (age 14.1 ± 1.8 yrs). We assessed ECGs for published criteria of left or right ventricular hypertrophy (LVH or RVH) and for ST segment, T wave, or Q wave abnormalities.

Results: Overall, 28/147 (19%) elite athletes satisfied ECG criteria for RVH or LVH (or both), compared to 2/40 (5%) controls (p<0.05) and 33/53 (62%) adolescents with HCM (p<0.0001). Of 20 HCM patients not meeting LVH/RVH criteria, 10 (50%) had other ECG anomalies including Q wave, T wave, and ST segment abnormalities, while the remaining half had normal ECGs. None of the screened student athletes had an abnormal echocardiogram. There was significant overlap in ECG measurements between the three cohorts (Table 1). R and S wave deflections in lead V1 and presence of ST-segment, T wave, and Q wave abnormalities most successfully stratified the HCM cohort from the student cohort independent of athletic activity.

Conclusions: Truly elite athletes have a higher rate of ventricular hypertrophy per ECG criteria than what is reported in standard sports screening literature. There is overlap on ECG between adolescents with HCM and elite high school athletes. A combination of voltages in lead V1 associated with ST segment, T wave, and Q wave abnormalities may be useful as potential markers for HCM.  

HCMA Comment:

Better understanding of normal variants and abnormal readings will help us to better understand how to screen in the general public for HCM – it is however critical to ensure we have an ethnically matched group to compare to – this study is on a very limited number of athletes and controls – more work is needed.

Texas Adolescent Athlete Heart Screening Registry (TAAHSR): a Statewide Screening Study

Silvana M Lawrence¹; Arnold Fenrich²; Harold W Kohl³; Patrick W Austin⁴; Jennifer Y Hutchings⁵; Michelle Garcia⁵; Michael Guerrero⁵; George Rodgers⁵

¹ Pediatrics, Baylor College of Medicine, Houston, TX
² Pediatrics, Children's Cardiology Associates, Austin, TX
³ Sch of Public Health, Univ of Texas Health Science Cntr Houston, Austin, TX
⁴ Sch of Public Health, Univ of Texas Health Science Cntr Houston, Houston, TX
⁵ Science and Rsch, Championship Hearts Foundation, Austin, TX

Background: Sudden cardiac death (SCD) in athletes, though a rare event, continues to claim lives every year. Optimal athlete screening strategies have proved to be elusive.

Hypothesis: Statewide screening of high school student athletes (SA) for hypertrophic cardiomyopathy (HCM) and other conditions associated with SCD is feasible and establishing a registry may lead to reduction in SCD and improved quality of life. Objective: Identify high school SA at risk for SCD due to presence of HCM and/or other conditions associated with SCD through screening events in the state of Texas, and establish a statewide data bank (registry).

Methods: The target population in this observational screening study included high school age SA who voluntarily presented at screening venues in Texas from March 2010-April 2011. Demographic and cardiac history data, 12-lead ECG and limited two-dimensional echocardiogram (L-ECHO) were obtained on all SA. Studies were read either on site or remotely subsequent to data acquisition. Athletes with positive screenings (SCD-related or other abnormal findings) were referred for complete cardiology evaluation. Follow up data were compared to screening results.

Results: Of 1002 SA screened, 840 agreed to participate in TAAHSR (71% male). Most SA were in grades 9 and 10 (63%), mostly White (55%) or Hispanic (34%). Fifty one percent reported positive at least once in the history. A total of 94 SA (11.2%) had positive screening on ECG (9.6%) and/or L-ECHO (2.1%) and referral was made. Of the 94 SA referred, follow up data were obtained in 91 (98%): Data were still pending at the time in 44 (48%) and complete in 47 (52%). Of the 94, 22 were referred for SCD-related findings: 19 ECG (15 HCM, 3 WPW and 1 Brugada) and 3 L-ECHO (1 HCM, 2 aortic root dilation). Of the 47 SA, screening findings were confirmed in 12 (25%), 3 with WPW (2 underwent ablation) and 1 with LVH considered ‘benign’ but not HCM.

Conclusion: Establishing a registry with statewide screenings in SA for SCD-related conditions is feasible and longitudinal data to assess effectiveness is highly needed at the present time. To date, 3 SA (0.36%) were identified with SCD-related condition (WPW). Future work on cost-effectiveness analysis is imperative to determine value of widespread SA screening for SCD.

HCMA Comment:

I spent a great deal of time at this poster and attempted to get more information from the presenter.  The cases claimed to be suspected for HCM were rather high (based on the 1000 participants statistically you would have 2 cases of HCM – they suspected 16 people – and diagnosed none).  The methods employed by this program have never been proven in an HCM population to be diagnostic in the manner in which this screening is being conducted.   This study would have benefited from starting with a known HCM population and evaluate the screening tools in this population with blinded readers to determine if they were able to identify HCM.  There is an emotional cost as well as a financial to 16 families being sent for additional testing.  These factors are not addressed in this abstract.   Based on the cost, impact and false positives this methodology for identifying those at risk for SCA seems of limited diagnostic benefit.

Detection of Interstitial Fibrosis in Hypertrophic Cardiomyopathy by Post-gadolinium Bolus CMR T1 Mapping

Tevfik F Ismail; Niraj Mistry; Andrew Jabbour; Callum Ettles; Taigang He; Ricardo Wage; Ankur Gulati; Susan Clark; Dudley J Pennell; Sanjay K Prasad CMR Unit, Royal Brompton Hosp, London, United Kingdom

Background: Fibrosis is an important pathogenic driver of adverse cardiac events in hypertrophic cardiomyopathy (HCM). Post-gadolinium cardiovascular magnetic resonance (CMR) T1 mapping holds promise as a means of assessing diffuse myocardial fibrosis not detected by late gadolinium enhancement (LGE) imaging. Accurate assessment requires contrast equilibrium; however, there is no consensus about when this occurs. We aimed to determine the time point at which equilibrium occurs after a gadolinium bolus and to assess the utility of T1 mapping for identifying both manifest and latent fibrosis in HCM.

Methods: Eight HCM patients free of significant comorbidity and 22 controls were studied. Short-axis T1 maps were acquired using the Modified Look Locker Inversion Recovery sequence at the base,mid-ventricle and apex for HCM patients and at the mid-ventricle for controls pre-gadolinium bolus and then at 2, 5, 7, 9, 11, 15, 20 and 25 minutes. Signal intensity-time curves for myocardial and blood pool regions of interest were used to determine T1 relaxation times through a non-linear curve-fit (CMR42, Circle Cardiovascular Imaging, Calgary, Canada). Plots of T1 times for the myocardium and blood pool against time were used to determine the point of equilibrium. The gadolinium partition coefficient ( ) at equilibrium, an index of fibrosis, was determined by plotting the reciprocal of myocardial T1 times against that of T1 times for the blood pool at various time points once contrast equilibrium was reached, and calculating the slope of the resultant linear regression line.

Results: Contrast equilibrium occurred within 5 minutes of gadolinium injection in both groups. The  was significantly elevated in HCM(mean±SD: 0.42±0.13 versus 0.24±0.03; p=0.006). This remained true even for slices not exhibiting LGE (0.38±0.10 versus 0.24±0.03; p=0.02) suggesting the presence of interstitial fibrosis.

Conclusion: Contrast equilibrium occurs quickly after a gadolinium bolus making early post-contrast T1 mapping a clinically feasible protocol. We found  to be significantly raised in HCM both in regions with and without LGE. It may therefore provide a novel means of non-invasively detecting diffuse myocardial fibrosis which is not currently visualised by LGE CMR.

Clinical and CMR Predictors of Myocardial Fibrosis in Hypertrophic Cardiomyopathy: Role of LV Wall Thickness

Tevfik F Ismail¹; Andrew Jabbour¹; Bibek Das¹; Thomas Cowling¹; Niraj Mistry¹; Ankur Gulati¹; Ricardo Wage¹; Susan Clark¹; Carl Shakespeare¹; Amanda Varnava²; Dudley J Pennell¹; Sanjay K Prasad¹

¹ CMR Unit, Royal Brompton Hosp, London, United Kingdom
² Inherited Cardiac Conditions Service, St Mary's Hosp, London, United Kingdom

Background: Current risk stratification of patients with hypertrophic cardiomyopathy (HCM) relies upon the identification of risk markers which indirectly reflect disease severity. Individually however, these markers have poor positive predictive valve. There is growing recognition that fibrosis as assessed by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) may more accurately reflect the state of the underlying substrate. Its presence has been promulgated as a novel risk factor for adverse cardiac events and is potentially of independent prognostic significance. We sought to determine the clinical and CMR predictors of LGE in a large cohort of patients with HCM.

Methods: We enrolled 695 consecutive patients with HCM referred for CMR (486 male, age 55.6±14.6 years). Their diagnosis was made using current clinical guidelines. All patients underwent a standard volumes and LGE-CMR study with full myocardial coverage. Established clinical and CMR predictors were evaluated with binary logistic regression analysis.

Results: LV ejection fraction and wall thickness were the only significant predictors of LGE status. However, the combination of these factors did not significantly improve the ability to predict LGE over wall thickness alone (Harrell's c-statistic [±SE] 0.796±0.018 versus 0.776±0.019 respectively, Figure 1). Receiver operator characteristic analysis revealed a wall thickness of  18 mm as the optimum predictor of the presence of LGE with a sensitivity of 67.1%, specificity of 77.5%, positive predictive value of 86.7%, and negative predictive value of 51.8%.

Conclusions: LV wall thickness is a strong predictor of the presence of LGE. Future models assessing the significance of the presence of LGE must adequately control for the strong association between fibrosis and maximum wall thickness. Further work is required to delineate the temporal relationship between the amount of LGE and wall thickness.

A Systematic Review for Sudden Cardiac Death in Hypertrophic Cardiomyopathy Patients With Myocardial Fibrosis: A CMR LGE Study

Nackle J Silva; Antonio Tito Paladino F.; Mark Doyle; Sahadev T Reddy; Diane Vido; Geetha Rayarao; June Yamrozik; Ronald Williams; Robert W Biederman

CARDIOLOGY DIVISION, Allegheny General Hosp, Pittsburgh, PA

BACKGROUND Hypertrophic cardiomyopathy (HCM) is a genetic disease that affects the cardiac sarcomere, resulting in myocardial hypertrophy and disarray. Affected patients have a predisposition for malignant ventricular tachyarrhythmias and, consequently, sudden cardiac death (SCD). In single center studies, late gadolinium enhancement (LGE) defined fibrosis has been linked to the substrate for VT/VF. However, despite innumerable investigations, SCD has not been definitely attributable to LGE. Explanations for this are believed to be related to insufficient statistical power.

OBJECTIVE To evaluate myocardial fibrosis as a risk factor for SCD in patients with HCM.

METHODS We performed an electronic search of MEDLINE, PubMED and CMR abstracts for original data published or presented between Jan 01 - Mar 11. Key search terms: HCM, LV fibrosis, SCD and LGE. Studies were screened for eligibility based on inclusion criteria: referral for CMR exam with LGE for HCM; and follow-up for incidence of VT/VF and SCD. Relevant studies were summarized and the following data were abstracted: socio-demographic information; study design; incidence of reported VT/VF; SCD. Categorical variables were evaluated between pt groups via Chi-square test.

RESULTS A total of 64 studies were initially identified. Of these, 4 (6.3%) were identified and included (n=1,063 pts, range 202 to 424). Three prospective and 1 retrospective studies were included. LGE was detected in 59.6% of pts. Mean follow-up was 43±14mo. Age 22-90 yrs (63% male). As expected, the presence of myocardial fibrosis was associated with VT/VF ( ²=6.5, p<0.05; OR 9.0 (95% CI 1.2 to 68.7). Moreover, myocardial fibrosis strongly predicted SCD ( ²=6.6, p<0.05; OR 3.3 (95% CI 1.2 to 9.7).

DISCUSSION Despite single center CMR studies, LGE has consistently predicted VT/VF while prediction of SCD has remained paradoxically unlinked. Although the lack of studies meeting our criteria limited our ability to perform a comprehensive meta-analysis, we have been able to demonstrate for the first time that LGE-defined fibrosis is a predictor of SCD in patients with HCM. This observation now demands a multi-center RCT for confirmation but supports the consideration of a primary indication of AICD implantation in HCM with LGE.

Diffuse Myocardial Fibrosis in Hypertrophic Cardiomyopathy Can be Detected by Cardiac MRI and Correlates with Left Ventricular Filling Pressure

Andris H Ellims; Leah Iles; James Hare; David Kaye; Andrew J Taylor Cardiology, The Alfred Hosp, Melbourne, Australia

Purpose:In patients with hypertrophic cardiomyopathy (HCM) the extent of diffuse myocardial fibrosis and its relationship to diastolic function has not been described. We used a contrast-enhanced cardiac magnetic resonance (CMR) T1 mapping technique to non-invasively determine the extent and location of diffuse myocardial fibrosis in patients with HCM. Furthermore, we evaluated the relationship between diffuse myocardial fibrosis and diastolic function.

Methods:We performed CMR on 44 subjects - 30 with asymmetric septal hypertrophy due to HCM (70% male, mean age 49±13 years) and 14 control patients. Chamber dimensions, wall thickness, systolic function and patterns of regional myocardial fibrosis were evaluated with cine imaging and late gadolinium enhancement (LGE). A prototype T1 mapping sequence was used (excluding areas of regional LGE) to determine the post-contrast myocardial T1 time as an index of diffuse myocardial fibrosis at the basal, mid and apical levels of the left ventricle (LV). Diastolic function (including septal, lateral and mean E/e') was assessed by transthoracic echocardiography.

Results:Regional myocardial fibrosis was observed in 87% of the HCM group. Global post-contrast myocardial T1 times were significantly shorter in patients with HCM compared to controls, consistent with the presence of diffuse myocardial fibrosis (494 ± 92 ms vs. 563 ± 52 ms, p<0.01). This difference was most pronounced at the basal level (436 ± 82 ms vs. 530 ± 87 ms, p<0.01). In HCM patients, the global LV T1 time correlated with mean E/e' (r=-0.47, p=0.01).

Conclusions:Patients with HCM have shorter myocardial T1 times, particularly at the basal level of the LV, consistent with the presence of diffuse myocardial fibrosis. The extent of diffuse fibrosis correlates with LV filling pressure, suggesting a mechanistic link between diffuse myocardial fibrosis and abnormal diastolic relaxation in HCM.

 If There is LV Myocardial Fibrosis Should We Expect to Find RV Myocardial Fibrosis? A Cardiovascular MRI Study

Robert W Biederman¹; Saundra Grant¹; June Yamrozik¹; Ronald Williams¹; Vikas Rathi²; Mark Doyle¹

¹ Cardiology Div, Allegheny General Hosp, Pittsburgh, PA
² Cardiology Div, Bon Secours Heart and Vascular Institute, Richmond, VA

Introduction CMR has become the leading technique to detect hypertrophic cardiomyopathy (HCM) providing complete coverage of both ventricles with high spatial resolution. Late gadolinium enhancement (LGE) accurately identifies regions of myocardial fibrosis. Via CMR, innumerable studies have established LVH as the predominant phenotypic expression. It is well known that myocardial fibrosis can occur in pts with HCM and is independently linked to worse prognosis than those without fibrosis by CMR. The genotypic expressions would appear to affect the entire heart yet, conventionally; descriptions have been limited to the LV, likely due to the inability to image the smaller, thinner RV. Thus, little information is available about the RV in HCM.

Hypothesis We hypothesize there may be RV involvement in HCM when incorporating CMR analysis for RV hypertrophy and fibrosis.

Methods: Review of all pts referred for HCM was performed. SSFP/LGE was used to diagnose patients with HCM, using gadolinium administration (0.15mmol/kg, MultiHance, Bracco Diagnostics, Princeton, NJ). Post-injection LGE images were obtained via T1-weighted, IR preps. Regions of myocardium with abnormally high signals (>2SD) were designated as fibrotic. LV/RVMass Index was calculated.

Results: Via 99 pts referred for HCM from 2006-2011, 28 (28%) were confirmed to be HCM via CMR. Image quality was judged excellent in 27/28 (97%). The mean LVMI was 97±40gm² (> 2SDabove normal) while the mean RVMI was 22±5 gm² (>1SD > normal). All pts met formal LVH criteria while 17/28 (61%) met RVH criteria. LV fibrosis was evident in 24/28 (86%) while most, 19/28 (67%), also had evidence for RV fibrosis. No pt with RV fibrosis had absent LV fibrosis. In neither the LV nor RV did the degree of hypertrophy predict the likelihood for fibrosis (98±38 vs.84±26g/m² and 22±24 vs.21±25g/m², respectively).

Conclusions: The high frequency of RV fibrosis in the setting of HCM is unforeseen presumably as this phenomenon is not anticipated. However, given the genetic abnormalities, there is no reason to expect the phenotypic expression should be limited to just the LV. Interestingly, similar for LVH, the degree of RVH had little predictive power to define fibrosis.

Cardiovascular Magnetic Resonance Imaging Elucidates Genotype-Phenotype Relationships in Patients with Hypertrophic Cardiomyopathy

Shahriar Heidary¹; Matthew T Wheeler¹; Mihoko V Bennett²; Jaehoon Chung³; Aleksandra Pavlovic¹; Marie-Claude Parent¹; Rajesh Dash¹; Michael V McConnell¹; Euan A Ashley¹; Phillip C Yang¹

¹ Cardiovascular Medicine, Stanford Univ, Stanford, CA,
² Div of Immunology and Rheumatology, Stanford Univ, Stanford, CA,
³ Cardiovascular Medicine, Univ of Illinois at Chicago, Chicago, IL

Objectives: The purpose is to determine whether cardiovascular magnetic resonance (CMR) can characterize genotype-phenotype relationships in hypertrophic cardiomyopathy (HCM).

Background: CMR is the gold standard for quantifying left ventricular mass (LVM) and demonstrating late gadolinium enhancement (LGE) and may help characterize genotype-phenotype relationships in HCM.

Methods: 100 HCM patients (mean age: 55 ± 14 yrs) who underwent CMR with gadolinium contrast were enrolled. 56% completed genetic testing. LVM and LGE were measured. Patients were stratified into 4 groups (negative genetic test with normal LV mass (G-/LVM-), negative genetic test with abnormal LV mass (G-/LVM+), positive genetic test with normal LV mass (G+/LVM-), and positive genetic test with abnormal LV mass (G+/LVM+)) and followed for cardiovascular events (CVE = Progression of NYHA, Unplanned Cardiovascular Hospitalization, Appropriate ICD Firing, Sustained VT, SCD and CV Death). Clinical follow-up was over a period of 23 ± 12 months.

Results: 46% (n = 26) who completed genetic testing had a positive test. For G+/LVM+ patients, 9 out of 15 (60%) had LGE. In comparison to those without LGE, these 9 patients had smaller left ventricular stroke volume indexed for BSA (42.1 ± 13.5 ml/m2 vs. 56.8 ± 4.3 ml/m2, p = 0.025); lower frequency of zero risk factors for SCD (n = 0, 0% vs. n = 4, 66.7%, p = 0.011); and higher frequency of  2 risk factors for sudden cardiac death (n = 5, 55.6% vs. n = 0, 0%, p = 0.011) without any difference in CVE. Subset analysis revealed MYBPC3 mutation (n=8) was associated with a lower LVEF (65.1 ± 13.1% vs. 72.6 ± 9.0%, p = 0.046) without increased CVE. Overall, 53 patients (53%) had LGE which was associated with reverse curvature (37.7% in LGE+ vs. 10.6% in LGE-, p = 0.002) and higher frequency of  2 risk factors for sudden cardiac death (n = 18, 34% vs. n = 7, 15%, p = 0.028), without increased CVE. All of these relationships remained significant after multivariate analysis.

Conclusions: LGE was associated with high-risk features, particularly in G+/LM+ subjects, and MYBPC3 was associated with decreased LVEF. CMR was successful in characterizing genotype-phenotype relationships in HCM.

Prediction of Major Adverse Cardiac Events in Patients with Hypertrophic Cardiomyopathy by Quantitative Late Enhancement Volume in Left Ventricular Myocardium by Cardiac Magnetic Resonance

Hiroyuki Takaoka¹; Nobusada Funabashi¹; Masae Uehara¹; Michiko Daimon¹; Yasunori Iida²; Yoshio Kobayashi¹

¹ Cardiovascular Medicine, Chiba Univ Hosp, Chiba, Japan
² Vascular Surgery Dept, Stanford Univ Hosp, Stanford, CA

Purpose: To predict major adverse cardiac events (MACE) in patients with hypertrophic cardiomyopathy (HCM), we measured focal late enhancement volume (LEV) in left ventricular myocardium (LVM) by cardiac magnetic resonance (MR) quantitatively and followed patients for a median of 21 months.

Material and methods: 30 consecutive subjects with HCM (20 males, 65.8±11.8 years old, Maron HCM type 1, 1; type 2, 7; type 3, 10; type 4, 4; and type 5, 8) who underwent cardiac MRI (1.5T Intra achieva) were recruited and followed for a median of 20.8±12.6 months. Cardiac MR was acquired 15 minutes after injection of Gadopentetate dimeglumine for detecting LEV in LVM quantitatively, and the optimal cut off value of LEV was determined based on Receiver Operating Curved (ROC) analysis for prediction of MACE. Using optimal cut off value, we compared risks of MACE between groups with high and low LEV using a Kaplan Meier analysis.

Result: MFs were detected in 25 patients, and LEV was 35.7±26.7 cm3. Three (10%) had MACE, and their LEV (68.8±29.2cm3) was significantly greater than in subjects without MACE (32.0±24.3cm3; p<0.05). According to ROC analysis, at a cutoff of 49.8cm3, sensitivity and specificity for detection of MACE were 100% and 81.5%, respectively. HCM subjects were then divided into two groups on the basis of LEV  49.8cm3 and <49.8cm3, regarded as optimal cut-off value. MACE was observed more frequently in subjects with LEV  49.8cm3 (37.5%) than in those with LEV <49.8cm3 (0%; p=0.02) during observation period. A significant difference between the subjects with LEV  49.8cm3 and <49.8cm3 was also seen at each time point and when the whole period of follow up was compared with a Kaplan Meier analysis and log rank test (p<0.01). Inter observer variability of LEV was evaluated by two observers and its Pearson's correlation coefficient was 0.77 (p<0.05).

Conclusion: Risk of MACE was significantly higher in subjects with LEV  49.8cm3 than in those with LEV <49.8cm3 following a median of 21 months.

Factors Affecting the Decision to Undergo Genetic Testing in Patients with Hypertrophic Cardiomyopathy

Patricia L Arscott¹; Christina M Rigelsky¹; Rocio T Moran¹; Maran Thamilarasan²; Nicholas G Smedira³; Bruce W Lytle⁴; Harry M Lever²; Milind Y Desai²

¹ Cntr for Personalized Genetic Healthcare, Cleveland Clinic, Cleveland, OH
² Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH
³ Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, OH
⁴ Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH

Introduction: Genetic testing for hypertrophic cardiomyopathy (HCM) has emerged as an important tool to identify at-risk family members who would potentially benefit from periodic cardiac screening for development of overt HCM phenotype. We sought to identify potential factors that play a role in the decision-making to pursue genetic testing in a HCM proband.

Methods: This study included 108 consecutive adults with HCM seen for genetic counseling between 12/2009 and 4/2011. We collected data on demographics, children, siblings, type of health insurance, family history of sudden cardiac death (SCD) and HCM, presence of internal defibrillator (ICD), need for surgical myectomy and whether they had commercially available genetic testing for at least 11 genes most commonly associated with HCM.

Results: The mean age of the study population at presentation was 52 ± 14 years with 75 (69 %) males. Overall, 20 (18 %) and 52 (48 %) patients had family history of HCM and SCD, respectively. The mean number of children and siblings were 2 ± 1 and 3 ± 2, respectively. Thus far, 62 (58 %) patients have undergone surgical myectomy and 23 (21 %) patients have had an ICD placed. Two (2 %) patients had no insurance, 21 (19 %) had medicare/medicaid and 85 (79 %) had private insurance. Of the 55 (51 %) probands that underwent genetic testing, 16 (31 %) were gene positive, while 5 (9 %) had a variant of unknown significance and 33 (60 %) were negative. Of the 16 gene-positive individuals, family history of HCM and SCD were absent in 8 (50 %) and 7 (44 %), respectively. Logistic regression analyses of potential factors associated with the decision to undergo genetic testing are shown in the Figure.

Conclusion: The decision to undergo genetic testing was independently associated with a younger age at presentation, number of children, presence of ICD and a family history of SCD. The type of health insurance did not play a significant role in the decision-making to undergo genetic testing.