Harry M. Lever

Relationship of race to sudden cardiac death in competitive athletes with hypertrophic cardiomyopathy

OBJECTIVES The goal of this study was to determine the impact of race on identification of hypertrophic cardiomyopathy (HCM). BACKGROUND Sudden death in young competitive athletes is due to a variety of cardiovascular diseases (CVDs) and, most commonly, HCM. These catastrophes have become an important issue for African Americans, although HCM has been previously regarded as rare in this segment of the U.S. population. METHODS We studied the relationship of race to the prevalence of CVDs causing sudden death in our national athlete registry, and compared these findings with a representative multicenter hospital-based cohort of patients with HCM. RESULTS Of 584 athlete deaths, 286 were documented to be due to CVD at ages 17 +/- 3 years; 156 (55%) were white, and 120 (42%) were African American. Most were male (90%), and 67% participated in basketball and football. Among the 286 cardiovascular deaths, most were due to HCM (n = 102; 36%) or anomalous coronary artery of wrong sinus origin (n = 37; 13%). Of the athletes who died of HCM, 42 (41%) were white, but 56 (55%) were African American. In contrast, of 1,986 clinically identified HCM patients, only 158 (8%) were African American (p < 0.001). CONCLUSIONS In this autopsy series, HCM represented a common cause of sudden death in young and previously undiagnosed African American male athletes, in sharp contrast with the infrequent clinical identification of HCM in a hospital-based population (i.e., by seven-fold). This discrepancy suggests that many HCM cases go unrecognized in the African American community, underscoring the need for enhanced clinical recognition of HCM to create the opportunity for preventive measures to be employed in high-risk patients with this complex disease.

Outcome of patients with hypertrophic obstructive cardiomyopathy after percutaneous transluminal septal myocardial ablation and septal myectomy surgery.

OBJECTIVES This study was conducted to evaluate follow-up results in patients with hypertrophic obstructive cardiomyopathy (HOCM) who underwent either percutaneous transluminal septal myocardial ablation (PTSMA) or septal myectomy. BACKGROUND Controversy exists with regard to these two forms of treatment for patients with HOCM. METHODS Of 51 patients with HOCM treated, 25 were treated by PTSMA and 26 patients via myectomy. Two-dimensional echocardiograms were performed before both procedures, immediately afterwards and at a three-month follow-up. The New York Heart Association (NYHA) functional class was obtained before the procedures and at follow-up. RESULTS Interventricular septal thickness was significantly reduced at follow-up in both groups (2.3 +/- 0.4 cm vs. 1.9 +/- 0.4 cm for septal ablation and 2.4 +/- 0.6 cm vs. 1.7 +/- 0.2 cm for myectomy, both p < 0.001). Estimated by continuous-wave Doppler, the resting pressure gradient (PG) across the left ventricular outflow tract (LVOT) significantly decreased immediately after the procedures in both groups (64 +/- 39 mm Hg vs. 28 +/- 29 mm Hg for PTSMA, 62 +/- 43 mm Hg vs. 7 +/- 7 mm Hg for myectomy, both p < 0.0001). At three-month follow-up, the resting PG remained lower in the PTSMA and myectomy groups (24 +/- 19 mm Hg and 11 +/- 6 mm Hg, respectively, vs. those before procedures, both p < 0.0001). The NYHA functional class was also significantly improved in both groups (3.5 +/- 0.5 vs. 1.9 +/- 0.7 for PTSMA, 3.3 +/- 0.5 vs. 1.5 +/- 0.7 for myectomy, both p < 0.0001). CONCLUSIONS Both myectomy and PTSMA reduce LVOT obstruction and significantly improve NYHA functional class in patients with HOCM. However, there are benefits and drawbacks for each therapeutic method that must be counterbalanced when deciding on treatment for LVOT obstruction.

Cardiac magnetic resonance detection of myocardial scarring in hypertrophic cardiomyopathy: correlation with histopathology and prevalence of ventricular tachycardia.

OBJECTIVES In hypertrophic cardiomyopathy (HCM) patients undergoing surgical myectomy, we sought to determine the association between pre-operative cardiac magnetic resonance (CMR) findings, small intramural coronary arteriole dysplasia (SICAD) on histopathology, and ventricular tachycardia (VT). BACKGROUND Myocardial scarring (fibrosis) and SICAD are frequently observed on histopathology in HCM patients. CMR measures wall thickness and detects scar. METHODS Sixty symptomatic HCM patients (62% men; mean age 51 +/- 14 years), with preserved ejection fraction (mean 64 +/- 5%) and no angiographic coronary disease underwent CMR (cine and delayed post-contrast) using a Siemens 1.5 T scanner, followed by septal myectomy. Maximal basal septal thickness was recorded on cine CMR. Scar was determined (percentage of total myocardium) on delayed post-contrast CMR images and quantified as none, mild (0% to 25%), moderate (26% to 50%), or severe (>50%). VT was assessed using Holter monitoring. Degree of SICAD was determined (normal, mild, moderate, and severe) on histopathology of surgical specimen. RESULTS SICAD and scar were seen in 45 (75%) and 38 (63%) patients, respectively. In 15 patients without SICAD, 12 (80%) had no scar; 23 (70%) patients with mild SICAD had mild scar on CMR. On multivariate analysis, degree of SICAD was independently associated with scar on CMR (Wald chi-square statistic: 6.8, p < 0.01). Patients with basal septal scar on CMR had higher VT frequency compared with those without (27% vs. 5%, p = 0.03). CONCLUSIONS A strong association exists between degree of SICAD and myocardial scarring seen on CMR.

Association Between Regional Ventricular Function and Myocardial Fibrosis in Hypertrophic Cardiomyopathy Assessed by Speckle Tracking Echocardiography and Delayed Hyperenhancement Magnetic Resonance Imaging

The relationship among myocardial fibrosis, segmental strains, and hypertrophic cardiomyopathy (HCM) in patients with preserved left ventricular ejection fraction is not known. We evaluated this relationship in 39 consecutive patients with HCM with transthoracic echocardiography and delayed hyperenhancement magnetic resonance imaging 20 minutes after injection of 0.2 mmol/kg of gadolinium. Speckle tracking echocardiography was used to assess left ventricle strains. Fibrosis was determined semiautomatically with magnetic resonance imaging, using a 12-segment short-axis left ventricular model. Myocardial fibrosis was detected in 23 of 39 patients with HCM. The mean end-systolic longitudinal strain correlated with the number of fibrotic segments (r = 0.47, P =.002) and total myocardial fibrosis (r = 0.46, P =.003). Fibrosis and wall thickness were both multivariate predictors of lower segmental longitudinal strain (P <.003). Longitudinal, circumferential, and radial strains are decreased in patients with HCM even in the absence of fibrosis. Myocardial fibrosis is associated with depressed longitudinal strain in patients with HCM.

Updated Meta-Analysis of Septal Alcohol Ablation Versus Myectomy for Hypertrophic Cardiomyopathy

OBJECTIVES The purpose of this study was to perform a systematic review and meta-analysis of comparative studies to compare outcomes of septal ablation (SA) with septal myectomy (SM) for treatment of hypertrophic obstructive cardiomyopathy (HOCM). BACKGROUND SM is considered the gold standard for treatment of HOCM. However, SA has emerged as an attractive therapeutic alternative. METHODS A Medline search using standard terms was conducted to determine eligible studies. Due to a lack of randomized control trials, we included observational studies for review. RESULTS Twelve studies were found eligible for review. No significant differences between short-term (risk difference [RD]: 0.01; 95% confidence interval [CI]: -0.01 to 0.03) and long-term mortality (RD: 0.02; 95% CI: -0.05 to 0.09) were found between the SA and SM groups. In addition, no significant differences could be found in terms of post-intervention functional status as well as improvement in New York Heart Association functional class, ventricular arrhythmia occurrence, re-interventions performed, and post-procedure mitral regurgitation. However, SA was found to increase the risk of right bundle branch block (RBBB) (pooled odds ratio [OR]: 56.3; 95% CI: 11.6 to 273.9) along with need for permanent pacemaker implantation post-procedure (pooled OR: 2.6; 95% CI: 1.7 to 3.9). Although the efficacy of both SA and SM in left ventricular outflow tract gradient (LVOTG) reduction seems comparable, there is a small yet significantly higher residual LVOTG amongst the SA group patients as compared with the SM group patients. CONCLUSION SA does seem to show promise in treatment of HOCM owing to similar mortality rates as well as functional status compared with SM; however, the caveat is increased conduction abnormalities and a higher post-intervention LVOTG. The choice of treatment strategy should be made after a thorough discussion of the procedures with the individual patient.

Hypertrophic cardiomyopathy in the elderly. Distinctions from the young based on cardiac shape.

The striking clinical and pathologic features of hypertrophic cardiomyopathy have been defined almost exclusively in the young. Little is known about this condition in the elderly, although it is assumed to be part of a single disease. Accordingly, we studied 28 patients who were 65 years of age and older (mean age, 72 +/- 6.4 years) who were diagnosed as having hypertrophic cardiomyopathy by M-mode, two-dimensional, and Doppler echocardiography and compared them with a group of 28 consecutive patients with this disease who were younger than 40 years of age (mean age, 26 +/- 9.5 years). No clinically detectable differences existed between the two groups, except for an increased incidence of mild hypertension in the elderly. Echocardiography in both groups showed hypertrophy with a small left ventricular cavity, and Doppler outflow tract velocity or cardiac catheterization in most patients showed systolic anterior motion of the mitral valve or a systolic outflow tract gradient or both. Significant differences existed between both groups, however, concerning left ventricular size and shape. The elderly group had a predominantly ovoid cavity contour with normal septal curvature. In contrast, in the young group, a markedly abnormal cardiac shape predominated (p less than 0.0001) with a crescent-shaped left ventricular cavity and a reversed curvature of the interventricular septum. The right ventricular free wall was prominent by echocardiography in the young compared with the elderly group (p less than 0.001). Apart from a more frequent history of mild hypertension in the elderly, likely related to age, these findings show that hypertrophic cardiomyopathy, when present in the elderly, has similar clinical features to that in the young.(ABSTRACT TRUNCATED AT 250 WORDS)

Homozygous Mutation in Cardiac Troponin T Implications for Hypertrophic Cardiomyopathy

BackgroundMutations in the gene that encode cardiac troponin T (cTnT) account for ≈15% of cases of familial hypertrophic cardiomyopathy (HCM). These mutations are associated with a particularly severe form of HCM characterized by a high incidence of sudden death and a poor overall prognosis, despite subclinical or mild left ventricular hypertrophy. Methods and ResultsWe evaluated a family with HCM and multiple occurrences of sudden death in children. DNA samples were isolated from peripheral blood or paraffin-embedded tissue, and all protein-encoding exons of the cTnT gene were sequenced. A mutation was identified in exon 11 and is predicted to substitute a phenylalanine-for-serine mutation at residue 179 (Ser179Phe) in cTnT. Both parents and 3 of 4 surviving and clinically unaffected children were heterozygous for this mutation; another clinically unaffected child did not carry the mutation. Genetic analysis of DNA from a child who died suddenly at age 17 years demonstrated he was homozygous for this mutation. A review of his echocardiogram revealed profound left and right ventricular hypertrophy. ConclusionsAn homozygous Ser179Phe mutation in cTnT causes a severe form of HCM characterized by striking morphological abnormalities and juvenile lethality. In contrast, the natural history of the heterozygous mutation is benign. These studies emphasize the relevance of genetic diagnosis in hypertrophic cardiomyopathy and provide a new perspective on the clinical consequences of troponin T mutations.

Abnormal Papillary Muscle Morphology Is Independently Associated With Increased Left Ventricular Outflow Tract Obstruction in Hypertrophic Cardiomyopathy

Background: Abnormal papillary muscles (PM) are often found in hypertrophic cardiomyopathy (HCM). Objective: To assess the relationship between morphological alterations of PM in patients with HCM and left ventricular outflow tract (LVOT) obstruction, using magnetic resonance imaging (MRI) and echocardiography. Methods: Fifty-six patients with HCM (mean age 42 years (interquartile range 27, 51), 70% male) and 30 controls (mean age (42 (30, 53) years, 80% male) underwent MRI on a 1.5 T scanner (Siemens, Erlangen, Germany). Standard cine images were obtained in short-axis (base to apex), along with two-, three- and four-chamber views. The presence of bifid PM (none, one or both) and anteroapical displacement of anterolateral PM was recorded by MRI and correlated with resting LVOT gradients obtained by echocardiography. Results: Double bifid PM (70% vs 17%) and anteroapical displacement of anterolateral PM (77% vs 17%) were more prevalent in patients with HCM than in controls (p<0.001). Subjects with anteroapically displaced PM and double bifid PM had higher resting LVOT gradients than controls (45 (6, 81) vs 12 (0, 12) mm Hg (p<0.01) and 42 (6, 64) vs 11 (0, 17) mm Hg (p = 0.02), respectively. In patients with HCM, the odds ratio of having significant (⩾30 mm Hg) peak resting gradient was 7.1 (95% CI 1.4 to 36.7) for anteroapically displaced anterolateral PM and 10.4 (95% CI 1.2 to 91.2) for double bifid PM (both p = 0.005), independent of septal thickness, use of β-blockers and/or calcium blockers and resting heart rate. Conclusions: Patients with HCM with abnormal PM have a higher degree of resting LVOT gradient, which is independent of septal thickness.

Mitral Valve Abnormalities in Hypertrophic Cardiomyopathy: Echocardiographic Features and Surgical Outcomes

BACKGROUND Functional and intrinsic mitral valve (MV) abnormalities are common in hypertrophic cardiomyopathy (HCM); however, morphologic characteristics constituting indications for surgical intervention are incompletely defined. This study was conducted to define the echocardiographic features of MV pathology in patients with HCM and relate these to repairability of the MV, MV procedures performed, durability of repair, and survival. METHODS From 1986 to 2003, 851 patients with HCM underwent operation, and 115 had a concomitant MV procedure. Detailed analysis of their 784 transthoracic and transesophageal echocardiograms, performed intraoperatively and postoperatively, was conducted. Outcomes were assessed by cross-sectional follow-up. RESULTS Sixty-seven patients (58%) underwent MV repair, and 48 (42%) had MV replacement. The mean left ventricular outflow tract peak gradient was 70 +/- 50 mm Hg. Systolic anterior motion was present in 95%. Valve abnormalities were degenerative in 36 (31%), myxomatous in 23 (20%), papillary muscle in 23 (20%), restrictive chordal in 22 (19%), restrictive leaflet in 80 (70%), and long leaflet in 64 (56%). Patients undergoing MV repair had higher prevalence of long leaflets and degenerative MV pathology. The anterior mitral leaflet was 3.0 +/- 0.49 cm in the repair group vs 2.5 +/- 0.40 cm in the replacement group (p = 0.0001). MV replacement patients were older, more symptomatic, and had more renal dysfunction and lower hematocrits. By 3 years, 91% of patients with a repair were free of reoperation. CONCLUSIONS Intrinsic MV pathology is frequently observed in HCM patients with symptomatic obstruction who undergo myectomy. Echocardiography can identify MV features predictive of successful valve repair. Repair, although durable, is feasible in only about half of patients.

Mechanism of Mitral Regurgitation in Hypertrophic Cardiomyopathy Mismatch of Posterior to Anterior Leaflet Length and Mobility

BACKGROUND In hypertrophic cardiomyopathy, a spectrum of mitral leaflet abnormalities has been related to the mechanism of mitral systolic anterior motion (SAM), which causes both subaortic obstruction and mitral regurgitation. In the individual patient, SAM and regurgitation vary in parallel; clinically, however, great interindividual differences in mitral regurgitation can occur for comparable degrees of SAM. We hypothesized that these differences relate to variations in posterior leaflet length and mobility, restricting its ability to follow the anterior leaflet (participate in SAM) and coapt effectively. METHODS AND RESULTS Different mitral geometries produced surgically in porcine valves were studied in vitro. Comparable degrees of SAM resulted in more severe mitral regurgitation for geometries characterized by limited posterior leaflet excursion. Mitral geometry was also analyzed in 23 patients with hypertrophic cardiomyopathy by intraoperative transesophageal echocardiography. All had typical anterior leaflet SAM with significant outflow tract gradients but considerably more variable mitral regurgitation; therefore, regurgitation did not correlate with obstruction. In contrast, mitral regurgitation correlated inversely with the length over which the leaflets coapted (r= -0.89), the most severe regurgitation occurring with a visible gap. Regurgitation increased with increasing mismatch of anterior to posterior leaflet length (r=0.77) and decreasing posterior leaflet mobility (r= -0.79). CONCLUSIONS SAM produces greater mitral regurgitation if the posterior leaflet is limited in its ability to move anteriorly, participate in SAM, and coapt effectively. This can explain interindividual differences in regurgitation for comparable degrees of SAM. Thus, the spectrum of leaflet length and mobility that affects subaortic obstruction also influences mitral regurgitation in patients with SAM.