Biomedical subjects
Publications and source records attributed to B J Maron.
Left ventricular remodeling occurs spontaneously among patients with hypertrophic cardiomyopathy in several ways: (1) wall thickening in children; (2) wall thinning associated with cavity enlargement in midlife; and possibly (3) a very gradual wall thinning process occurring over long periods of time in adulthood.
BACKGROUND: Mutations in the gene for cardiac myosin-binding protein C account for approximately 15 percent of cases of familial hypertrophic cardiomyopathy. The spectrum of disease-causing mutations and the associated clinical features of these gene defects are unknown. METHODS: DNA sequences encoding cardiac myosin-binding protein C were determined in unrelated patients with familial hypertrophic cardiomyopathy. Mutations were found in 16 probands, who had 574 family members at risk of inheriting these defects. The genotypes of these family members were determined, and the clinical status of 212 family members with mutations in the gene for cardiac myosin-binding protein C was assessed. RESULTS: Twelve novel mutations were identified in probands from 16 families. Four were missense mutations; eight defects (insertions, deletions, and splice mutations) were predicted to truncate cardiac myosin-binding protein C. The clinical expression of either missense or truncation mutations was similar to that observed for other genetic causes of hypertrophic cardiomyopathy, but the age at onset of the disease differed markedly. Only 58 percent of adults under the age of 50 years who had a mutation in the cardiac myosin-binding protein C gene (68 of 117 patients) had cardiac hypertrophy; disease penetrance remained incomplete through the age of 60 years. Survival was generally better than that observed among patients with hypertrophic cardiomyopathy caused by other mutations in the genes for sarcomere proteins. Most deaths due to cardiac causes in these families occurred suddenly. CONCLUSIONS: The clinical expression of mutations in the gene for cardiac myosin-binding protein C is often delayed until middle age or old age. Delayed expression of cardiac hypertrophy and a favorable clinical course may hinder recognition of the heritable nature of mutations in the cardiac myosin-binding protein C gene. Clinical screening in adult life may be warranted for members of families characterized by hypertrophic cardiomyopathy.
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OBJECTIVES: Reliable prevalence data would be useful in assessing the impact of sudden cardiac death in young competitive athletes on the community and designing effective preparticipation screening strategies. BACKGROUND: The frequency with which these catastrophes occur is largely unknown. METHODS: We utilized a circumstance unique to Minnesota in which the precise number of participants and deaths due to cardiovascular disease could be ascertained over a substantial period of time based on a long-standing insurance program for catastrophic injury or death, mandatory for all student athletes engaged in interscholastic sports. RESULTS: Over the 12-year period, 1985/1986 to 1996/1997, inclusive, three sudden deaths due to cardiovascular disease occurred in competitive high school athletes (grades 10-12) during competition or practice. At autopsy, 1 each proved to be due to anomalous origin of the left main coronary artery from the right sinus of Valsalva, congenital aortic valve stenosis (with bicuspid valve) and myocarditis. All three athletes were white and male, 16 or 17 years of age; two competed in cross-country/track and one in basketball. During the study period there were 1,453,280 overall sports participations and 651,695 student athlete participants among the 27 high school sports. The calculated risk for sudden death was 1:500,000 participations and 1:217,400 participants per academic year (or 0.46/100,000, annually). Over a 3-year high school career for a student athlete the estimated risk was 1:72,500. CONCLUSIONS: The risk of sudden cardiac death in a population of high school student athletes was small, in the range of one in 200,000 per year, and was higher in male athletes. The rare occurrence of sudden cardiac death in competitive sports underlines the limitations implicit in structuring productive and cost-effective broad-based preparticipation screening strategies for high school athletes.
BACKGROUND: Amiodarone has been reported to reduce the likelihood of sudden death in patients with hypertrophic cardiomyopathy (HCM). However, data regarding the clinical course in HCM have traditionally come from selected referral populations biased toward assessment of high risk patients. AIMS: To evaluate antiarrhythmic treatment for sudden death in an HCM population not subject to tertiary referral bias, closely resembling the true disease state present in the community. METHODS: Cardiovascular mortality was assessed in relation to the occurrence of non-sustained ventricular tachycardia (NSVT) on 24 or 48 hour ambulatory Holter recording, a finding previously regarded as a marker for sudden death, particularly when the arrhythmia was frequent, repetitive or prolonged. 167 consecutive patients were analysed by multiple Holter ECG recordings (mean (SD) 157 (129) hours) and followed for a mean of 10 (5) years. Only patients with multiple repetitive NSVT were treated with amiodarone, and in relatively low. doses (220 (44) mg/day). RESULTS: Nine HCM related deaths occurred: 8 were the consequence of congestive heart failure, but only 1 was sudden and unexpected. Three groups of patients were segregated based on their NSVT profile: group 1 (n = 39), multiple (> or = 2 runs) and repetitive bursts (on > or = 2 Holters) of NSVT, or prolonged runs of ventricular tachycardia, included 4 deaths due to heart failure; group 2 (n = 38), isolated infrequent bursts of NSVT, included 1 sudden death; group 3 (n = 90), without NSVT, included 4 heart failure deaths. Kaplan-Meier survival analysis showed no significant differences in survival between the three groups throughout follow up. CONCLUSIONS: In an unselected patient population with HCM, isolated, non-repetitive bursts of NSVT were not associated with adverse prognosis and so this arrhythmia does not appear to justify chronic antiarrhythmic treatment. Amiodarone, administered in relatively low doses, did not carry an independent and additive risk for cardiac mortality. Amiodarone may have contributed to the absence of sudden cardiac death in patients believed to be at higher risk because of multiple repetitive NSVT.
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Blunt chest impact-induced cardiac arrest on the athletic field (commotio cordis) is not necessarily fatal. The 3 survivors reported here emphasize the importance of recognizing this syndrome so that emergency resuscitative measures are more likely to be implemented promptly, and such catastrophes avoided.
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OBJECTIVES: We studied the clinical and genetic features of familial hypertrophic cardiomyopathy (FHC) caused by an Asp175Asn mutation in the alpha-tropomyosin gene in affected subjects from three unrelated families. BACKGROUND: Correlation of genotype and phenotype has provided important information in FHC caused by beta-cardiac myosin and cardiac troponin T mutations. Comparable analyses of hypertrophic cardiomyopathy caused by alpha-tropomyosin mutations have been hampered by the rarity of these genetic defects. METHODS: The haplotypes of three kindreds with FHC due to an alpha-tropomyosin gene mutation, Asp175Asn, were analyzed. The cardiac histopathologic findings of this mutation are reported. Distribution of left ventricular hypertrophy in affected members was assessed by two-dimensional echocardiography, and patient survival rates were compared. RESULTS: Genetic studies defined unique haplotypes in the three families, demonstrating that independent mutations caused the disease in each. The Asp175Asn mutation caused cardiac histopathologic findings of myocyte hypertrophy, disarray and replacement fibrosis. The severity and distribution of left ventricular hypertrophy varied considerably in affected members from the three families (mean maximal wall thickness +/- SD: 24 +/- 4.5 mm in anterior septum of Family DT; 15 +/- 2.7 mm in anterior septum and free wall of Family DB; 18 +/- 2.1 mm in posterior septum of Family MI), but survival was comparable and favorable. CONCLUSIONS: Nucleotide residue 579 in the alpha-tropomyosin gene may have increased susceptibility to mutation. On cardiac histopathologic study, defects in this sarcomere thin filament component are indistinguishable from other genetic etiologies of hypertrophic cardiomyopathy. The Asp175Asn mutation can elicit different morphologic responses, suggesting that the hypertrophic phenotype is modulated not by genetic etiologic factors alone. In contrast, prognosis reflected genotype; near normal life expectancy is found in hypertrophic cardiomyopathy caused by the alpha-tropomyosin mutation Asp175Asn.
Spontaneous echocardiographic contrast (a swirling, smokelike haze that appears in blood during imaging) indicates a predisposition to thromboembolism, particularly in patients with atrial fibrillation and elevation of hematocrit, ESR, and serum fibrinogen.
Two concepts from pathologic descriptions of myocardial hypertrophy in trained individuals merit consideration: (1) The heart of the trained athlete can be twice the normal size, but histologic structure remains intact, and (2) the weight of the trained heart does not usually surpass the limit of 500 g, defined as the critical heart weight. Even though this threshold cannot be accepted dogmatically, the concept of an upper limit for physiologic cardiac remodeling is nevertheless relevant to the clinical question of distinguishing extreme expressions of athlete's heart from primary pathologic conditions. This morphologic distinction depends on whether the magnitude of cardiac remodeling in athletes exceeds that expected as a result of athletic conditioning alone. There has also been a great interest in understanding the impact that types of athletic conditioning and gender have on defining the upper limits to which such physiologic hypertrophy may extend.
There has been heightened interest in the design and role of preparticipation screening for high school and college athletes. An American Heart Association consensus panel, composed of cardiovascular specialists and other physician experts having extensive clinical experience with athletes of all ages as well as a legal expert, assessed the benefits and limitations of preparticipation screening for early detection of cardiovascular abnormalities in competitive athletes. The panel addressed cost-efficiency and feasibility issues as well as the medicolegal implications of screening; and developed consensus recommendations and guidelines for the most prudent, practical, and effective screening procedures and strategies.
OBJECTIVE: To assess the relation between P wave duration and the occurrence of atrial fibrillation in hypertrophic cardiomyopathy (HCM). DESIGN: High resolution signal averaged electrocardiography was used in 110 patients with HCM to determine whether patients at risk for paroxysmal atrial fibrillation could be detected during sinus rhythm by measuring P wave duration. Filtered P wave duration was measured manually, over an average of 300 beats per patient. RESULTS: During follow up, 18 patients (16%) had at least one one clinical episode of paroxysmal atrial fibrillation, including four patients whose initial episode followed the signal averaged electrocardiogram. The 18 patients with overt atrial fibrillation had greater P wave duration than the 69 patients who did not develop atrial fibrillation: 150 (SD 20) v 126 (14) ms; P < 0.001. Another 23 patients without clinically evident atrial fibrillation had prolonged bursts of the arrhythmia on Holter recording, and showed a P wave duration (138 (15) ms) intermediate between patients with and without clinical atrial fibrillation. In assessing risk for atrial fibrillation, P wave duration > or = 140 ms was associated with sensitivity, specificity, and positive predictive accuracy values of 56%, 83%, and 66%. Multivariate analysis showed that duration of the P wave was the only independent variable associated with occurrence of atrial fibrillation; if P wave duration > or = 140 ms was combined with left atrial enlargement > 40 mm, the specificity and positive predictive accuracy for atrial fibrillation increased to 93% and 78%. CONCLUSIONS: Measurement of P wave duration in sinus rhythm by high resolution signal averaged electrocardiography may be a useful non-invasive clinical tool for identifying patients with HCM likely to develop electrical instability and atrial fibrillation.
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