Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disorder manifesting as cardiac hypertrophy with myocyte disarray and an increased risk of sudden death. Mutations in five different loci cause FHC and 3 disease genes have been identified: beta cardiac myosin heavy chain, alpha tropomyosin and cardiac troponin T. Because these genes encode contractile proteins, other FHC loci are predicted also to encode sarcomere components. Two further FHC loci have been mapped to chromosomes 11p13-q13 (CMH4, ref. 6) and 7q3 (ref. 7). The gene encoding the cardiac isoform of myosin binding protein-C (cardiac MyBP-C) has recently been assigned to chromosome 11p11.2 and proposed as a candidate FHC gene. Cardiac MyBP-C is arrayed transversely in sarcomere A-bands and binds myosin heavy chain in thick filaments and titin in elastic filaments. Phosphorylation of MyBP-C appears to modulate contraction. We report that cardiac MyBP-C is genetically linked to CMH4 and demonstrate a splice donor mutation in one family with FHC and a duplication mutation in a second. Both mutations are predicted to disrupt the high affinity, C-terminal, myosin-binding domain of cardiac MyBP-C. These findings define cardiac MyBP-C mutations as the cause of FHC on chromosome 11p and reaffirm that FHC is a disease of the sarcomere.

Human heart and platelet actins are products of different genes.

The amino acid sequences of selected cyanogen bromide peptides from human blood platelet actin and human cardiac muscle actin were compared; it was found that, at position 129, platelet actin has threonine, and that cardiac muscle actin has valine. Thus human cytoplasmic and myofibrillar actins must be synthesized under the control of different genes.

Congenital heart disease caused by mutations in the transcription factor NKX2-5.

Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease. A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5, a Drosophila tinman homolog, is located. Three different NKX2-5 mutations were identified. Two are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding. These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life.

Distinguishing hypertrophic cardiomyopathy from athlete's heart physiological remodelling: clinical significance, diagnostic strategies and implications for preparticipation screening.

Sudden cardiac death in young competitive athletes is an important public health problem, although a relatively low-event-rate phenomenon. The single most common cardiovascular cause of these unexpected catastrophes is hypertrophic cardiomyopathy (HCM), accounting for about one-third of cases. Since the phenotypic expression of HCM is variable, and not uncommonly includes patients with mild and localised left ventricular hypertrophy, the differential diagnosis with physiological remodelling of athlete's heart not uncommonly arises. This review discusses those non-invasive strategies that are useful in distinguishing the benign consequences of systematic athletic training from pathological left ventricular hypertrophy with the potential for sudden cardiac death. Preparticipation screening in healthy general athlete populations may raise the suspicion of HCM, and ultimately lead to definitive diagnosis. However, recently controversy has arisen regarding the most effective and practical strategy for the screening of athletes. European investigators have promoted routine 12-lead ECGs as part of a national mandatory programme distinct from the customary practice in the US which is limited to history and physical examinations. Consensus criteria and recommendations for eligibility and disqualification of athletes with HCM (and other cardiovascular abnormalities) have proved useful to the practising community.

Spontaneously occurring arrhythmogenic right ventricular cardiomyopathy in the domestic cat: A new animal model similar to the human disease.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial disease of incompletely resolved pathogenesis and is a largely unappreciated cause of sudden death in the young. METHODS AND RESULTS: Clinical features of 12 domestic cats with ARVC (7 male; 1 to 20 years old, mean 7.3+/-5.2 years) were right-sided congestive heart failure (n=8), supraventricular tachyarrhythmias (n=5), ventricular tachycardia (n=3), polymorphic ventricular arrhythmias (n=6), and right bundle-branch block (n=5). ARVC was suspected in all 8 cats examined with echocardiography by marked enlargement of the right ventricle (RV) and right atrium and tricuspid regurgitation. Eight died of cardiovascular disease and 4 died of noncardiac conditions. At autopsy, hearts of ARVC cats were characterized grossly by moderate-to-severe RV cavity enlargement and wall thinning (n=12) and apical aneurysm formation (n=6). Histology demonstrated pronounced RV lesions in all 12 ARVC cats, including marked myocardial injury (myocyte death and atrophy) and repair (fibrous and/or fatty replacement). Injury and repair were also evident in the left ventricle (LV) in 10 cats, and 2 had involvement of both atria. Myocarditis was present in 10 of the 12 ARVC cats. Apoptosis was detected in 9 ARVC cats (mean apoptotic index, 28+/-23% RV, 21+/-19% LV, and 17+/-15% ventricular septum) but not in controls. CONCLUSIONS: In the common domestic cat, we identified a clinically relevant cardiomyopathy that closely mimics ARVC in humans. This unique feline model of human disease will be relevant to defining pathogenesis and investigating mechanisms responsible for disease progression in ARVC.

Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy.

BACKGROUND: Clinical impact of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) is largely unresolved. Thus, we analyzed the prognostic implications of AF in a large, community-based HCM population assembled from Italian and US cohorts. METHODS AND RESULTS: Occurrence of AF and outcome were assessed in 480 consecutive HCM patients (age at diagnosis, 45+/-20 years; 61% male) who were followed up for 9.1+/-6.4 years. AF occurred in 107 patients (22%; incidence, 2%/y) and was independently predicted by advancing age, congestive symptoms, and increased LA size at diagnosis. Patients with AF had increased risk for HCM-related death (OR, 3.7; P<0.002) because of excess heart failure-related mortality but not sudden, unexpected death. This risk associated with AF was substantially greater in patients with outflow obstruction or with earlier development of AF (

Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (M-PATHY).

BACKGROUND: Dual-chamber pacing (DDD) has been proposed as a treatment alternative to surgery for severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), based largely on uncontrolled studies. METHODS AND RESULTS: This prospective, multicenter trial assessed pacing in 48 symptomatic HCM patients with >/=50 mm Hg basal gradient, refractory to drug therapy. Patients were randomized to 3 months each of DDD pacing and pacing backup (AAI-30) in a double-blind, crossover study design, followed by an uncontrolled and unblinded 6-month pacing trial. With randomization, no significant differences were evident between pacing and no pacing for subjective or objective measures of symptoms or exercise capacity, including NYHA functional class, quality of life score, treadmill exercise time or peak oxygen consumption. After 6 additional months of unblinded pacing, functional class and quality of life score were improved compared with baseline (P<0.01), but peak oxygen consumption was unchanged. Outflow gradient decreased 40%, 82+/-32 mm Hg to 48+/-32 mm Hg (P<0. 001), and was reduced in 57% of patients but showed no change or an increase in 43%. At 12 months, 6 individual patients (12%) showed improved functional capacity; each was 65 to 75 years of age. Left ventricular wall thicknesses in the overall study group showed no remodeling between baseline (22+/-5 mm) and 12 months (21+/-5 mm; P=NS). CONCLUSIONS: (1) Pacing cannot be regarded as a primary treatment for obstructive HCM; (2) with randomization, perceived symptomatic improvement was most consistent with a substantial placebo effect; (3) longer, uncontrolled pacing periods were associated with some subjective benefit but unaccompanied by objective improvement in cardiovascular performance and should be interpreted cautiously; (4) modest reduction in outflow gradient was achieved in most patients; and (5) a small subset (12%) >/= 65 years of age showed a clinical response, suggesting that DDD pacing could be a therapeutic option for some elderly patients.

Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral-based patient population.

BACKGROUND: Death resulting from hypertrophic cardiomyopathy (HCM), particularly when sudden, has been reported to be largely confined to young persons. These data emanated from tertiary HCM centers with highly selected referral patterns skewed toward high-risk patients. METHODS AND RESULTS: The present analysis was undertaken in an international population of 744 consecutively enrolled and largely unselected patients more representative of the overall HCM spectrum. HCM-related death occurred in 86 patients (12%) over 8+/-7 years (mean+/-SD). Three distinctive modes of death were as follows: (1) sudden and unexpected (51%; age, 45+/-20 years); (2) progressive heart failure (36%; age, 56+/-19 years); and (3) HCM-related stroke associated with atrial fibrillation (13%; age, 73+/-14 years). Sudden death was most common in young patients, whereas heart failure- and stroke-related deaths occurred more frequently in midlife and beyond. However, neither sudden nor heart failure-related death showed a statistically significant, disproportionate age distribution (P=0.06 and 0.5, respectively). Stroke-related deaths did occur disproportionately in older patients (P=0.002). Of the 45 patients who died suddenly, most (71%) had no or mild symptoms, and 7 (16%) participated in moderate to severe physical activities at the time of death. CONCLUSIONS: HCM-related cardiovascular death occurred suddenly, or as a result of heart failure or stroke, largely during different phases of life in a prospectively assembled, regionally based, and predominantly unselected patient cohort. Although most sudden deaths occurred in adolescents and young adults, such catastrophes were not confined to patients of these ages and extended to later phases of life. This revised clinical profile suggests that generally held epidemiological tenants for HCM have been influenced considerably by skewed reporting from highly selected populations. These data are likely to importantly affect risk stratification and treatment strategies importantly for the prevention of sudden death in HCM.

Clinical significance of abnormal electrocardiographic patterns in trained athletes.

BACKGROUND-The prevalence, clinical significance, and determinants of abnormal ECG patterns in trained athletes remain largely unresolved. METHODS AND RESULTS-We compared ECG patterns with cardiac morphology (as assessed by echocardiography) in 1005 consecutive athletes (aged 24+/-6 years; 75% male) who were participating in 38 sporting disciplines. ECG patterns were distinctly abnormal in 145 athletes (14%), mildly abnormal in 257 (26%), and normal or with minor alterations in 603 (60%). Structural cardiovascular abnormalities were identified in only 53 athletes (5%). Larger cardiac dimensions were associated with abnormal ECG patterns: left ventricular end-diastolic cavity dimensions were 56. 0+/-5.6, 55.4+/-5.7, and 53.7+/-5.7 mm (P<0.001) and maximum wall thicknesses were 10.1+/-1.4, 9.8+/-1.3, and 9.3+/-1.4 mm (P<0.001) in distinctly abnormal, mildly abnormal, and normal ECGs, respectively. Abnormal ECGs were also most associated with male sex, younger age (<20 years), and endurance sports (cycling, rowing/canoeing, and cross-country skiing). A subset of athletes (5% of the 1005) showed particularly abnormal or bizarre ECG patterns, but no evidence of structural cardiovascular abnormalities or an increase in cardiac dimensions. CONCLUSIONS-Most athletes (60%) in this large cohort had ECGs that were completely normal or showed only minor alterations. A variety of abnormal ECG patterns occurred in 40%; this was usually indicative of physiological cardiac remodeling. A small but important subgroup of athletes without cardiac morphological changes showed striking ECG abnormalities that suggested cardiovascular disease; however, these changes were likely an innocent consequence of long-term, intense athletic training and, therefore, another component of athlete heart syndrome. Such false-positive ECGs represent a potential limitation to routine ECG testing as part of preparticipation screening.

Selective activation of the K(+)(ATP) channel is a mechanism by which sudden death is produced by low-energy chest-wall impact (Commotio cordis).

BACKGROUND: Sudden death due to relatively innocent chest-wall impact has been described in young individuals (commotio cordis). In our previously reported swine model of commotio cordis, ventricular fibrillation (with T-wave strikes) and ST-segment elevation (with QRS strikes) were produced by 30-mph baseball impacts to the precordium. Because activation of the K(+)(ATP) channel has been implicated in the pathogenesis of ST elevation and ventricular fibrillation in myocardial ischemia, we hypothesized that this channel could be responsible for the electrophysiologic findings in our experimental model and in victims of commotio cordis. METHODS AND RESULTS: In the initial experiment, 6 juvenile swine were given 0.5 mg/kg IV glibenclamide, a selective inhibitor of the K(+)(ATP) channel, and chest impact was given on the QRS. The results of these strikes were compared with animals in which no glibenclamide was given. In the second phase, 20 swine were randomized to receive glibenclamide or a control vehicle (in a double-blind fashion), with chest impact delivered just before the T-wave peak. With QRS impacts, the maximal ST elevation was significantly less in those animals given glibenclamide (0.16+/-0.10 mV) than in controls (0.35+/-0.20 mV; P=0.004). With T-wave impacts, the animals that received glibenclamide had significantly fewer occurrences of ventricular fibrillation (1 episode in 27 impacts; 4%) than controls (6 episodes in 18 impacts; 33%; P=0.01). CONCLUSIONS: In this experimental model of commotio cordis, blockade of the K(+)(ATP) channel reduced the incidence of ventricular fibrillation and the magnitude of ST-segment elevation. Therefore, selective K(+)(ATP) channel activation may be a pivotal mechanism in sudden death resulting from low-energy chest-wall trauma in young people during sporting activities.

Structural features of the athlete heart as defined by echocardiography.

The morphologic concepts of the "athlete heart" have been enhanced and clarified over the last 10 years by virtue of M-mode echocardiographic studies performed on more than 1,000 competitive athletes. Long-term athletic training produces relatively mild but predictable alterations in cardiac structure that result in an increase in calculated left ventricular mass. This increase in mass observed in highly trained athletes is due to a mild increase in either transverse end-diastolic dimension of the left ventricle or left ventricular wall thickness, or both. Cardiac dimensions in athletes compared with matched control subjects show increases of about 10% for left ventricular end-diastolic dimension, about 15 to 20% for wall thickness and about 45% for calculated left ventricular mass. Furthermore, there is evidence that the modest degree of "physiologic" left ventricular hypertrophy (both the cavity dilation and wall thickening) observed in athletes is dynamic in nature, that is, it may develop rapidly within weeks or months after the initiation of vigorous conditioning and may be reversed in a similar time period after the cessation of training. Several echocardiographic studies also suggest that the precise alterations in cardiac structure associated with training may differ depending on the type of athletic activity undertaken (that is, whether training is primarily dynamic [isotonic] or static [isometric]). Although the ventricular septal to free wall thickness ratio (on M-mode echocardiogram) is almost always within normal limits (less than 1.3), occasionally an athlete will show mild asymmetric thickening of the anterior basal septum (usually 13 to 15 mm). This circumstance may mimic certain pathologic conditions characterized by primary left ventricular hypertrophy such as nonobstructive hypertrophic cardiomyopathy. The long-term significance of increased left ventricular mass in trained athletes has not been conclusively defined. However, there is no evidence at this time suggesting that this form of hypertrophy is itself deleterious to the athlete or predisposes to (or prevents) the natural occurrence of cardiovascular disease later in life.

Hypertrophic cardiomyopathy with extreme increase in left ventricular wall thickness: functional and morphologic features and clinical significance.

Clinical and morphologic features of 34 patients with hypertrophic cardiomyopathy and particularly marked left ventricular hypertrophy were analyzed. Only patients with a ventricular septal thickness of at least 35 mm (range to 52 mm) were selected for the study; 31 (90%) had a diffuse pattern of hypertrophy also involving substantial portions of the left ventricular free wall. Despite similar left ventricular morphology, these patients exhibited a broad spectrum of clinical findings and natural history. Ten patients (29%) had hemodynamic or echocardiographic evidence of basal subaortic obstruction (average gradient, 63 mm Hg); however, the majority (24 [71%]) had no evidence of obstruction at rest, despite substantial hypertrophy of the basal anterior portions of septum and free wall. Although the electrocardiograms of most patients (76%) showed patterns of left ventricular hypertrophy, the magnitude of precordial QRS complexes was not markedly increased (S wave in lead V1 or V2, 27 +/- 15 mm; R wave in lead V5 or V6, 21 +/- 9 mm). The clinical course was variable in 30 patients who were followed up for at least 1 year (mean 6 years). Although no patient died, nine (30%) have exhibited clinical deterioration, including two who spontaneously developed complete heart block and one who collapsed with ventricular fibrillation but survived. However, the clinical condition of the majority of patients (21 [70%]) remained unchanged or improved. At the most recent evaluation, 20 (67%) of the 30 patients were asymptomatic or only mildly symptomatic, including 7 who remained without symptoms throughout the period of follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Sudden death and the competitive athlete: perspectives on preparticipation screening studies.

Sudden death in healthy athletes is uncommon but, when it occurs, the primary mechanism is cardiovascular. The major cause of sudden death in the young athlete is hypertrophic cardiomyopathy or related conditions characterized by left ventricular hypertrophy, aortic rupture due to cystic medial necrosis and congenital coronary artery abnormalities. In the middle-aged or older athlete, coronary artery disease is the most significant cause of sudden death. Noninvasive screening procedures are currently available that can detect most subjects at risk of sudden death. However, although some potentially lethal diseases can be excluded by a relatively simple screening program, other diseases require expensive procedures, such as echocardiography and exercise electrocardiographic stress testing. This means that the sensitivity of detecting diseases leading to sudden death increases in proportion to the financial resources that can be applied to the screening program. Thus, when a screening program designed to identify all cardiac diseases that have the potential to cause sudden death is planned by a community, school or nonprofessional athletic team, the costs will almost undoubtedly be considered prohibitive. The practicality of applying a community- or school-initiated screening program can be questioned because of the very low incidence of sudden unexpected death in young healthy individuals. It is therefore likely that comprehensive screening programs will be confined to individuals or organizations with adequate financial resources. Less expensive, limited screening can be undertaken by individuals or groups to identify some subjects at risk of sudden death during athletic competition.

Elderly patients with hypertrophic cardiomyopathy: a subset with distinctive left ventricular morphology and progressive clinical course late in life.

This report describes a subgroup of 52 elderly patients with obstructive hypertrophic cardiomyopathy in whom certain clinical and morphologic features differed importantly from those of many other patients with this disease. Ages ranged from 60 to 84 years (mean 69) and 45 [87%] were women. Echocardiographic examination showed a relatively small heart, having only modest ventricular septal hypertrophy associated with marked distortion of left ventricular outflow tract morphology. By virtue of selection, left ventricular outflow tract size at end-diastole was substantially reduced, and anterior displacement of the mitral valve within the left ventricular cavity was particularly marked. Sizable deposits of calcium in the region of the mitral anulus, posterior to the mitral valve, appeared to contribute to the outflow tract narrowing. Systolic anterior motion of the mitral valve was severe (with apposition of the mitral valve and ventricular septum) in 32 patients and more moderate in 20. The mechanism by which systolic contact between the mitral valve and septum occurred in most patients appeared to differ from that observed more typically in many other patients with hypertrophic cardiomyopathy; in most elderly study patients, anterior excursion of the mitral valve leaflets was relatively restricted, and systolic apposition between the mitral valve and septum resulted from a combination of anterior motion of the mitral valve and posterior excursion of the septum. The vast majority (50 of 52) of the patients remained asymptomatic (or only mildly symptomatic) for most of their lives and often did not develop severe and intractable symptoms until the 6th or 7th decade (ages 56 to 81 years; mean 66). Of the 49 patients with at least 1 year follow-up study, only 12 had improvement with pharmacologic therapy; however, 14 of the 18 patients who underwent ventricular septal myotomy-myectomy or mitral valve replacement obtained symptomatic benefit from operation. In conclusion, obstructive hypertrophic cardiomyopathy in many elderly (and predominantly female) patients may assume a distinctive morphologic appearance and a progressive clinical course. This subgroup of patients appears to constitute an important segment of the disease spectrum of hypertrophic cardiomyopathy of cardiac disease in the elderly that previously has not been precisely defined nor fully appreciated.

Relation between extent of left ventricular hypertrophy and diastolic filling abnormalities in hypertrophic cardiomyopathy.

In hypertrophic cardiomyopathy, the relation between left ventricular diastolic impairment and magnitude of left ventricular hypertrophy has not been clearly defined. In the present study, Doppler echocardiographic indexes of left ventricular diastolic filling were compared in 78 patients with hypertrophic cardiomyopathy and in 72 normal control subjects of similar age, and the relation between abnormalities of diastolic filling and magnitude of left ventricular hypertrophy was assessed. In patients with hypertrophic cardiomyopathy, isovolumic relaxation was prolonged (94 +/- 25 ms); peak early diastolic flow velocity (53 +/- 18 cm/s), deceleration of flow velocity in early diastole (341 +/- 142 cm/s2) and the ratio between early and late peaks of flow velocity (1.6 +/- 0.9) were reduced; and peak late diastolic flow velocity was increased (38 +/- 15 cm/s) compared with values in control subjects (76 +/- 12 ms, 65 +/- 12 cm/s, 512 +/- 131 cm/s2, 2.3 +/- 0.8 and 30 +/- 7 cm/s, respectively; p less than 0.001). Individual patient analysis showed that diastolic filling was abnormal in 52 (67%) of the 78 patients with hypertrophic cardiomyopathy. However, within the patient group, none of the Doppler diastolic indexes showed a significant correlation with maximal left ventricular wall thickness or the wall thickness index (correlation coefficients ranged from -0.15 to 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertrophic cardiomyopathy characterized by marked hypertrophy of the posterior left ventricular free wall: significance and clinical implications.

This report describes a subgroup of 17 patients with hypertrophic cardiomyopathy and an unusual and distinctive pattern of left ventricular hypertrophy characterized on echocardiography by marked thickening of the posterior left ventricular free wall and virtually normal or only modestly increased ventricular septal thickness. This distribution of hypertrophy often created a distinctive pattern of "inverted" asymmetry of the posterior wall relative to the septum. The thickness of the posterior wall was 20 to 42 mm (mean 25), while that of the basal ventricular septum was only 12 to 24 mm (mean 17). The left ventricular outflow tract was narrowed because of anterior displacement of the mitral valve within the small left ventricular cavity. Systolic anterior motion of the mitral valve was present in 16 of the 17 patients. The patients ranged in age from 13 to 54 years (mean 31) at most recent evaluation; most (11 of 17, 65%) were severely symptomatic and had experienced important symptoms early in life (before age 40). The condition of only 4 of these 11 patients improved with medical therapy over an average follow-up period of 9 years; however, 6 of the 7 patients who had unsuccessful medical treatment and underwent operation with mitral valve replacement (5 patients) or ventricular septal myotomy-myectomy (1 patient) experienced symptomatic benefit from surgery. The subgroup of patients described in this report underscores the morphologic and clinical diversity that exists within the overall disease spectrum of hypertrophic cardiomyopathy. Characteristically, the patients were young, severely symptomatic and demonstrated evidence of outflow obstruction and an "inverted" asymmetric pattern of posterior free wall left ventricular hypertrophy. (ABSTRACT TRUNCATED AT 250 WORDS)

Relation between extent of left ventricular hypertrophy and occurrence of sudden cardiac death in hypertrophic cardiomyopathy.

Sudden unexpected death can be the first clinical manifestation of hypertrophic cardiomyopathy and is the most devastating feature of the natural history of the disease. Left ventricular hypertrophy appears to be an important determinant of many clinical features of hypertrophic cardiomyopathy, but the relation between its magnitude and the occurrence of sudden cardiac death has not been clearly defined. In this study, the magnitude of hypertrophy was assessed with two-dimensional echocardiography in 29 asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy who subsequently died suddenly or experienced cardiac arrest with documented ventricular fibrillation. Findings were compared with those obtained in a control group of 95 patients of similar age and symptomatic state. Maximal left ventricular wall thickness was significantly greater in patients with sudden death (26 +/- 7 mm) than in control patients (21 +/- 5 mm, p less than 0.001). Left ventricular wall thickness index, a quantitative expression of the overall extent of hypertrophy, was also greater in patients with sudden death (76 +/- 20 mm) than in surviving control patients (62 +/- 13 mm, p less than 0.001). Particularly marked and diffuse hypertrophy, with maximal wall thickness greater than or equal to 30 mm or wall thickness greater than or equal to 25 mm in two or more of the four segments into which the left ventricle had been divided, was eight times more common in patients with sudden death (11 [38%] of 29) than in control patients (5 [5%] of 95, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between extent of left ventricular hypertrophy and age in hypertrophic cardiomyopathy.

This investigation was undertaken to determine whether a relation could be identified between left ventricular wall thickness and age in a large population of symptomatic patients with hypertrophic cardiomyopathy. Extent of left ventricular hypertrophy was assessed with two-dimensional echocardiography in 173 patients with hypertrophic cardiomyopathy who ranged in age from 21 to 74 years (mean 45) and had mild to severe cardiac symptoms. The overall study group was classified into five age subgroups (each corresponding to a decade); maximal left ventricular wall thickness and wall thickness index (a quantitative expression of the overall extent of hypertrophy) were assessed in each group. These two indexes were significantly higher in patients 21 to 30 years of age than in patients in each of the other four older age groups. The two indexes of left ventricular hypertrophy were also significantly higher in patients 31 to 40 years of age than in patients who were 61 to 74 years old. Multivariate regression analysis showed that the relation between wall thickness and age was not influenced by other clinical variables such as severity of symptoms, presence of subaortic obstruction, left ventricular cavity dimension and gender. In conclusion, the findings indicate that, in a population of symptomatic adult patients with hypertrophic cardiomyopathy, left ventricular hypertrophy is considerably more severe in younger than in older patients and that there is an inverse relation between left ventricular wall thickness and age.

Absence of progression of left ventricular hypertrophy in adult patients with hypertrophic cardiomyopathy.

Development or progression of left ventricular hypertrophy has recently been described in children with hypertrophic cardiomyopathy. To determine whether similar changes in magnitude and distribution of left ventricular hypertrophy may also occur in adult patients with this disease, serial assessment of left ventricular wall thickness was obtained with M-mode and two-dimensional echocardiography in 65 patients with hypertrophic cardiomyopathy who were 23 to 50 years of age. The follow-up period was 3 to 6 years (mean 4). None of the 65 patients showed a substantial increase (greater than or equal to 5 mm) in left ventricular wall thickness; however, 9 (14%) demonstrated a substantial decrease (5 to 9 mm). Wall thinning most commonly involved the anterior ventricular septum (seven patients), but was also identified in the posterior septum (six patients), lateral free wall (two patients) and posterior free wall (one patient). In the nine patients with wall thinning, left ventricular end-diastolic diameter increased significantly (from 44 +/- 6 to 51 +/- 6 mm; p less than 0.001); however, in seven of the nine, absolute cavity size remained within normal limits (less than or equal to 52 mm) at the most recent evaluation. Eight of the nine patients with left ventricular wall thinning and relative cavity enlargement were severely symptomatic and one was mildly symptomatic. In conclusion, substantial progression of left ventricular hypertrophy was not identified in any of the study patients. Hence, if such progression occurs in adults with hypertrophic cardiomyopathy, it is probably rare. Conversely, an important minority of adult patients with hypertrophic cardiomyopathy may show progressive left ventricular wall thinning and relative cavity enlargement, which are usually associated with severe cardiac symptoms.

Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients.

OBJECTIVES: This study sought to achieve an understanding of the true structural heterogeneity of hypertrophic cardiomyopathy. BACKGROUND: The diversity and clinical significance of the morphologic expression of hypertrophic cardiomyopathy have not been fully defined within this broad disease spectrum. METHODS: Patterns of left ventricular hypertrophy were characterized by two-dimensional echocardiography in a large study cohort of 600 patients (7 to 79 years old, mean age 45; 393 [66%] men) consecutively studied at two referral centers. RESULTS: Left ventricular wall thickness was 15 to 52 mm (mean [+/- SD] 22.3 +/- 5). A multitude of patterns of asymmetric left ventricular hypertrophy were identified, with the most common showing diffuse involvement of substantial portions of both ventricular septum and free wall. Of 16 possible patterns of left ventricular hypertrophy, 12 (78%) were identified among the 600 patients. Hypertrophy most commonly involved two left ventricular segments (228 patients [38%]) or three or more segments (202 patients [34%]), but was also localized to one segment in a substantial number of patients (170 [28%]). The anterior portion of the ventricular septum was the region of the left ventricle that most frequently showed thickening (573 patients [96%]), and was also the predominant site of hypertrophy in most patients (492 patients [83%]). Patterns of wall thickening that were either concentric (i.e., symmetric) or confined to the apex were particularly uncommon (in 1% each). CONCLUSIONS: 1) In hypertrophic cardiomyopathy, the distribution of left ventricular hypertrophy is characteristically asymmetric and particularly heterogeneous, encompassing most possible patterns of wall thickening, from extensive and diffuse to mild and segmental, and with no single morphologic expression considered typical or classic. 2) A greater extent of left ventricular hypertrophy was associated with younger age and more marked mitral valve systolic anterior motion and outflow obstruction but showed no relation to either magnitude of symptoms or gender.