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Mutations in X-linked lysosome-associated membrane protein gene (LAMP2; Danon disease) produce a cardiomyopathy in young patients that clinically mimics hypertrophic cardiomyopathy (HCM) due to sarcomere protein mutations. However, the natural history and phenotypic expression of this newly recognized disease is incompletely resolved and its identification may have important clinical implications.
To determine the clinical consequences of LAMP2 cardiomyopathy and the efficacy of diagnostic and management strategies.
Setting and Design
Clinical course and outcome were assessed prospectively in 7 young LAMP2 patients (6 males) previously identified in our laboratory from the time of diagnosis (ages 7–17; median 14) to October 2008. Phenotypic expression of this disease was assessed both clinically and at autopsy.
Implantable defibrillators, cardioactive medications, and heart transplantation.
Outcome measure
Progressive heart failure/cardiac death, and transplant.
Over 7.3 ± 3 (SD) years of follow-up, and by 12 to 24 years of age, the study patients developed LV systolic dysfunction (ejection fraction 25 ± 7[SD]%) and cavity enlargement, as well as particularly adverse clinical consequences including: progressive refractory heart failure and death (n = 4), sudden death (n = 1), aborted cardiac arrest (n = 1), or heart transplantation (n = 1). LV hypertrophy was particularly marked (maximum ventricular septum, 29–65 mm; mean 44±15[SD]) including 2 patients with massive thickness of 60 mm and 65 mm at ages 23 and 15 years, respectively. In 6 patients, at study entry a ventricular pre-excitation pattern was associated with markedly increased voltages for maximum R- or S-wave (40–145 mm; mean 74±38mm), and deeply inverted T-waves. Autopsy findings included a combination of histopathologic features consistent with a storage disease (i.e., clusters of vacuolated myocytes), but also typical of HCM due to sarcomere protein mutations (i.e., myocyte disarray, small vessel disease, myocardial scarring).
LAMP2 cardiomyopathy is a profound disease process characterized by rapid clinical deterioration leading to cardiac death in young patients < 25 years. These observations underscore the importance of timely molecular diagnosis for predicting prognosis, and early consideration of heart transplantation.
PMCID: PMC4106257  PMID: 19318653
4.  Ability of prospective assessment of personality profiles to predict the practice specialty of medical students 
Medical practice encompasses a diverse spectrum of specialties. Factors that impact selection of clinical disciplines by young physicians may have recently evolved associated with changes in medical school demographics. We assessed whether physicians gravitate to certain practice specialties due to preexisting personality traits. The Neuroticism-Extraversion-Openness Personality Inventory Revised Test was administered prospectively to 130 first-year students the week before they began medical school. Scores for five traits (neuroticism, extraversion, openness, agreeableness, conscientiousness) were compared with the selection among nine medical residencies at the conclusion of medical school. Personality scores for medical students selecting psychiatry residencies showed greater degrees of neuroticism (P < 0.01) and openness (P < 0.03). Students electing family practice also deviated from other specialties, showing a lower degree of neuroticism (P < 0.03). Unexpectedly, personality traits in prospective surgical residents did not differ from those of students choosing nonsurgical residencies. Personality profiles present before medical school appear to predict the selection of some residencies and clinical specialties but not others.
PMCID: PMC1769529  PMID: 17256038
5.  Inter-Association Task Force Recommendations on Emergency Preparedness and Management of Sudden Cardiac Arrest in High School and College Athletic Programs: A Consensus Statement 
Journal of Athletic Training  2007;42(1):143-158.
Objective: To assist high school and college athletic programs prepare for and respond to a sudden cardiac arrest (SCA). This consensus statement summarizes our current understanding of SCA in young athletes, defines the necessary elements for emergency preparedness, and establishes uniform treatment protocols for the management of SCA.
Background: Sudden cardiac arrest is the leading cause of death in young athletes. The increasing presence of and timely access to automated external defibrillators (AEDs) at sporting events provides a means of early defibrillation and the potential for effective secondary prevention of sudden cardiac death. An Inter-Association Task Force was sponsored by the National Athletic Trainers' Association to develop consensus recommendations on emergency preparedness and management of SCA in athletes.
Recommendations: Comprehensive emergency planning is needed for high school and college athletic programs to ensure an efficient and structured response to SCA. Essential elements of an emergency action plan include establishment of an effective communication system, training of anticipated responders in cardiopulmonary resuscitation and AED use, access to an AED for early defibrillation, acquisition of necessary emergency equipment, coordination and integration of on-site responder and AED programs with the local emergency medical services system, and practice and review of the response plan. Prompt recognition of SCA, early activation of the emergency medical services system, the presence of a trained rescuer to initiate cardiopulmonary resuscitation, and access to early defibrillation are critical in the management of SCA. In any collapsed and unresponsive athlete, SCA should be suspected and an AED applied as soon as possible for rhythm analysis and defibrillation if indicated.
PMCID: PMC1896083  PMID: 17597956
sudden cardiac death; athletes; emergency action plan; automated external defibrillators
7.  Electrocardiographic Features of Sarcomere Mutations Carriers With versus Without Clinically Overt Hypertrophic Cardiomyopathy 
The American journal of cardiology  2011;108(11):1606-1613.
In hypertrophic cardiomyopathy (HC), ECG changes have been postulated to be an early marker of disease, detectable in sarcomere mutation carriers when LV wall thickness is still normal However, the ECG features of mutation carriers have not been fully characterized. Therefore, we systematically analyzed ECG’s in a genotyped HC population to: 1. Characterize ECG findings in mutation carriers (G+) with and without echocardiographic left ventricular hypertrophy (LVH), and 2. Evaluate the accuracy of the ECG to differentiate at- risk mutation carriers from genetically unaffected relatives during family screening. ECGs and echocardiograms were analyzed in 213 genotyped subjects (76 G+/LVH−, 57 G+/LVH+ overt HC, 80 genetically unaffected controls). Cardiac magnetic resonance imaging (CMR) was available on a subset. Q waves and repolarization abnormalities (QST) were highly specific (98%) markers for LVH− mutation carriers, present in 25% of G+/LVH− subjects and 3% of controls (p<0.001). QST ECG abnormalities remained independently predictive of carrying a sarcomere mutation after adjusting for age and impaired relaxation, another distinguishing feature of G+/LVH− subjects (OR 8.4, p=0.007). Myocardial scar or perfusion abnormalities were not detected on CMR in any G+/LVH− subjects, irrespective of ECG features. In overt HC, 75% had Q waves and/or repolarization changes but <25% demonstrated common isolated voltage criteria for LVH. In conclusion, Q waves and repolarization abnormalities are the most discriminating ECG features of sarcomere mutation carriers with and without LVH. However, due to the limited sensitivity of ECG and echocardiographic screening, genetic testing is required to definitively identify at-risk family members.
PMCID: PMC3215918  PMID: 21943931
Hypertrophic Cardiomyopathy; Electrocardiography; Genetics; Sarcomere
10.  Echocardiographic Strain Imaging to Assess Early and Late Consequences of Sarcomere Mutations in Hypertrophic Cardiomyopathy 
Genetic testing identifies sarcomere mutation carriers (G+) before clinical diagnosis of hypertrophic cardiomyopathy (HCM), allowing characterization of initial disease manifestations. Prior studies demonstrated that impaired relaxation develops before left ventricular hypertrophy (LVH). The precise impact of sarcomere mutations on systolic function in early and late disease is unclear.
Methods and Results
Comprehensive echocardiography with strain imaging was performed on 146 genotyped individuals with mutations in 5 sarcomere genes. Contractile parameters were compared in 68 preclinical (G+/LVH−), 40 overt (G+/LVH+) HCM subjects, and 38 mutation (−) normal control relatives. All subjects had normal LV ejection fraction (EF). In preclinical HCM, global and regional peak systolic strain (εsys) and longitudinal systolic strain rate (SSR) were not significantly different from controls, but early diastolic mitral annular velocity (Ea) was reduced by 13%. In overt HCM, there was a significant 27% and 14% decrease in global longitudinal εsys and SSR respectively, compared with both preclinical HCM and controls (p<0.013 for all comparisons), and a 33% reduction in Ea.
Sarcomere mutations have disparate initial effects on diastolic and systolic function. Preclinical HCM is characterized by impaired relaxation but preserved systolic strain. In contrast, both diastolic and longitudinal systolic abnormalities are present in overt disease, despite normal EF. We propose that diastolic dysfunction is an early consequence of sarcomere mutations, whereas systolic dysfunction results from mutations combined with subsequent pathologic remodeling. Identifying mechanistic pathways triggered by these mutations may begin to reshape the clinical paradigm for treatment, based on early diagnosis and disease prevention.
PMCID: PMC2773504  PMID: 20031602
Genetics; Cardiomyopathy; Contractility; Hypertrophy; Echocardiography
11.  Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy 
European Heart Journal  2010;31(17):2111-2123.
Hypertrophic cardiomyopathy (HCM) is an important cause of heart failure-related disability over a wide range of ages. Profiles of severe progressive heart failure symptoms and death, or heart transplantation deserve more complete definition within large patient cohorts.
Methods and results
Clinical and morphological features of heart failure were assessed in 293 consecutive HCM patients over a median follow-up of 6 (inter-quartile range 2–11) years. Gross and histopathological features were analysed in 12 patients for whom the heart was available for inspection. Of the 293 patients, 50 (17%) developed severe progressive heart failure, including 18 who died or were transplanted. Three profiles of heart failure were identified predominantly associated with: (i) end-stage systolic dysfunction (ejection fraction <50%) (15; 30%); (ii) left ventricular (LV) outflow obstruction at rest (11; 22%); and (iii) non-obstructive with preserved systolic function (24; 48%). Overall, atrial fibrillation (AF) contributed to heart failure in 32 patients (64%) among the three profiles. Compared with other patients, those non-obstructive with preserved systolic function had earlier onset of heart failure symptoms mainly due to diastolic dysfunction, and the most accelerated progression to advanced heart failure and adverse outcome (P = 0.04). Thrombi were identified in the left atrial appendage of five gross heart specimens all belonging to patients with AF, including three of which were unrecognized clinically and had previously embolized. Extensive myocardial scarring with LV remodelling was evident in all end-stage patients; no or only focal scars were present in other patients.
Profiles of advanced heart failure in HCM are due to diverse pathophysiological mechanisms, including LV outflow obstruction and diastolic or global systolic ventricular dysfunction. Atrial fibrillation proved to be the most common disease variable associated with progressive heart failure. Recognition of the heterogeneous pathophysiology of heart failure in HCM is relevant, given the targeted management strategies necessary in this disease.
PMCID: PMC2930982  PMID: 20513729
Hypertrophic cardiomyopathy; Heart failure; Cardiovascular pathology; Atrial fibrillation; Cardiac transplant
12.  Commotio Cordis 
Sudden arrhythmic death as a result of a blunt chest wall blow has been termed Commotio Cordis (CC). CC is being reported with increasing frequency with more than 180 cases now described in the United States Commotio Cordis Registry. The clinical spectrum is diverse; however young athletes tend to be most at risk, with victims commonly being struck by projectiles regarded as standard implements of the sport. Sudden death is instantaneous and victims are most often found in ventricular fibrillation (VF). Chest blows are not of sufficient magnitude to cause any significant damage to overlying thoracic structures and autopsy is notable for the absence of any structural cardiac injury. Development of an experimental model has allowed for substantial insights into the underlying mechanisms of sudden death. In anesthetized juvenile swine, induction of VF is instantaneous following chest impacts that occur during a vulnerable window before the T wave peak. Other critical variables, including the impact velocity and location, and the hardness of the impact object have also been identified. Rapid left ventricular pressure rise following chest impact likely results in activation of ion channels via mechano-electric coupling. The generation of inward current through mechano-sensitive ion channels results in augmentation of repolarization and non-uniform myocardial activation, and is the cause of premature ventricular depolarizations that are triggers of VF in CC. Currently available chest protectors commonly used in sport are not adequately designed to prevent CC. The development of more effective chest protectors and the widespread availability of automated external defibrillators at youth sporting events could improve the safety of young athletes.
PMCID: PMC2018736  PMID: 17957272
Commotio cordis; Ventricular Fibrillation; Athletes; Sudden Death; Mechano-electric coupling
13.  Role of Implantable Cardioverter Defibrillators in the Treatment of Hypertrophic Cardiomyopathy 
Hypertrophic cardiomyopathy (HCM) is an important cardiovascular disease with sudden cardiac death as the most devastating presentation. Implantable cardioverter defibrillators (ICD) are the optimal therapy for prevention of sudden death from ventricular tachycardia or fibrillation of any cause. While there is no controversy with implanting ICDs in patients who have already survived a cardiac arrest, identifying high-risk patients for primary prevention in this disease remains a challenge. Implanting ICDs in patients with HCM is an important clinical consideration since many individuals could achieve normal or near-normal lifespans with this protection.
PMCID: PMC1513528  PMID: 16943946
Hypertrophic cardiomyopathy; implantable defibrillator; sudden cardiac death
14.  Drug-Induced Toxic Myocarditis 
Texas Heart Institute Journal  2003;30(1):76-79.
A 66-year-old woman presented with new-onset complete left bundle branch block and congestive heart failure. She had had chronic paranoid schizophrenia for 35 years and had been taking medications to control her psychiatric disorder for the past 10 years. A 2-dimensional echocardiogram performed at the onset of congestive heart failure showed dilated cardiomyopathy with global impairment of left ventricular function (ejection fraction <0.25). Despite withdrawal of the medications most likely responsible for the heart problems (perphenazine, 2 mg; and amitriptyline, 25 mg), the patient died of refractory congestive heart failure 2 years later. Histologic examination at autopsy showed evidence of persistent toxic myocarditis with fibrosis of the heart and persistent chronic hepatitis. These autopsy findings were considered to be drug related. (Tex Heart Inst J 2003;30:76–9)
PMCID: PMC152844  PMID: 12638679
Cardiomyopathy, congestive/pathology; myocarditis, toxic/complications/diagnosis/etiology/pathology/therapy
15.  Usefulness of Doppler echocardiographic assessment of diastolic filling in distinguishing “athlete's heart” from hypertrophic cardiomyopathy 
British Heart Journal  1992;68(3):296-300.
Objective—In some athletes with a substantial increase in left ventricular wall thickness, it may be difficult to distinguish with certainty physiological hypertrophy due to athletic training from hypertrophic cardiomyopathy. The purpose of the present investigation was to determine whether assessment of left ventricular filling could differentiate between these two conditions.
Design—Doppler echocardiography was used to obtain transmitral flow velocity waveforms from which indices of left ventricular diastolic filling were measured. Normal values were from 35 previously studied control subjects.
Setting—Athletes were selected mostly from the Institute of Sports Science (Rome, Italy), and patients with hypertrophic cardiomyopathy were studied at the National Institutes of Health (Bethesda, Maryland).
Participants—The athlete group comprised 16 young competitive athletes with an increase in left ventricular wall thickness (range 13–16 mm; mean 14). For comparison, 12 symptom free patients with non-obstructive hypertrophic cardiomyopathy were selected because their ages and degree of hypertrophy were similar to those of the athletes.
Results—In the athlete group, values for deceleration of flow velocity in early diastole, peak early and late diastolic flow velocities, and their ratio were not significantly different from those obtained in untrained normal subjects; furthermore, Doppler diastolic indices were normal in each of the 16 athletes. Conversely, in patients with hypertrophic cardiomyopathy, mean values for Doppler diastolic indices were significantly different from both normal subjects and athletics (p = 0·01 to 0·003), and one or more indices were abnormal in 10 (83%) of the 12 patients.
Conclusions—Doppler echocardiographic indices of left ventricular filling may aid in distinguishing between pronounced physiological hypertrophy due to athletic training and pathological hypertrophy associated with hypertrophic cardiomyopathy.
PMCID: PMC1025074  PMID: 1389762

Results 1-15 (15)