Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy.

AIMS: Left ventricular outflow tract obstruction (LVOTO) is associated with reduced survival in patients with hypertrophic cardiomyopathy (HCM). The influence of LVOTO on survival from SD in relation to other recognized clinical risk markers is unknown. METHODS AND RESULTS: A total of 917 patients with HCM (554 males, 43+/-15 years) were studied; 288 (31.4%) had LVOTO at rest (> or =30 mmHg). During follow-up [median 61 (30;99) months], 54 (5.9%) patients died suddenly (SD), survived ventricular fibrillation, or had an appropriate ICD discharge; 25 (2.7%) died from heart failure or were transplanted; 17 (1.8%) died from other cardiovascular causes. Five-year survival from all-cause death or cardiac transplantation was lower in patients with LVOTO [86.5% (95% CI: 81.7-91.2) vs. 90.1% (95% CI: 87.3-92.8), P=0.006], with a trend towards higher all-cause death and transplantation with increasing LVOTO [(RR per 20 mmHg=1.24 (95% CI: 1.08-1.42), P=0.003)]. In patients with obstruction, there was a significant relation between 5-year survival from all-cause death and functional limitation (NYHA class I: 91.0%; NYHA class II: 83.3%; NYHA class III/IV: 82.6%, P=0.002). LVOTO was associated with reduced survival from SD and ICD discharge (SD/ICD) [91.4% (95% CI: 87.4-95.3) vs. 95.7% (95% CI: 93.8-97.6), P=0.0004]. Magnitude of LVOTO was related to a higher occurrence of SD/ICD [RR per 20 mmHg=1.36 (95% CI: 1.12-1.65), P=0.001]. There was no relation between survival from SD/ICD, LVOTO, and NYHA class. The annual rate of SD/ICD in patients with LVOTO and no risk factors was 0.37% (95%CI: 0.05-1.35). There was a trend towards lower survival from SD/ICD, with increasing numbers of risk factors in patients with and without LVOTO (P=0.002 and P=0.002, respectively). Multivariable analysis demonstrated that LVOTO was an independent predictor of SD/ICD, with a 2.4-fold (P=0.003) increase in the risk of SD/ICD. CONCLUSION: LVOTO is associated with an increased risk of SD/ICD that is related to the severity of obstruction and the presence of other recognized risk factors for SD. The low sudden death mortality in asymptomatic patients with LVOTO and no other SD risk markers suggests that aggressive interventions to reduce LVOTO are unwarranted in this group. Further studies are required to determine the most appropriate treatment strategies (ICD or gradient reduction) in patients with additional risk factors.     

Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a primary cardiac disease with a diverse clinical spectrum, in which many of the abnormal structural and pathophysiologic features are consequences of inappropriate left ventricular hypertrophy. METHODS: We analyzed the amount, distribution and structure of the cardiac collagen network in transmural sections of the ventricular septum (thickness 17 to 40 mm, mean 25 mm) in 16 previously asymptomatic children and young adults with HCM (11 to 31 years of age, mean 20 years) who died suddenly. The morphologic appearance and volume fractions of interstitial (matrix) and perivascular (adventitial) collagen were analyzed with polarization microscopy and computerized videodensitometry in picrosirius red-stained sections. Findings were compared with 16 structurally normal hearts, 5 with systemic hypertension and 6 infants who died of HCM. RESULTS: Adults and young children with HCM had an eightfold greater amount of matrix collagen compared with normal controls (14.1 +/- 8.8% vs. 1.8 +/- 1% of the tissue section; p < 0.0001), and a threefold increase compared with patients with systemic hypertension (4.5 +/- 1.3%; p < 0.001) and infants with HCM (4.0 +/- 2.4%; p < 0.001). Compared with normal controls and hypertensives, adults and young children (and infants) with HCM showed increased numbers and thickness of each collagen fiber component of the matrix (perimysial coils, pericellular weaves and struts), which were often arranged in disorganized patterns. In HCM patients, the amount of collagen was not a consequence of other clinical, demographic and morphologic disease variables. CONCLUSIONS: Left ventricular collagen matrix in young, previously asymptomatic patients with HCM who died suddenly is morphologically abnormal and substantially increased in size. The enlarged matrix collagen compartment is present in HCM at an early age, further expands during growth, is partially responsible for increased ventricular septal thickness and likely represents a primary morphologic abnormality in this disease. These findings support the view that the complex HCM disease process is not confined to sarcomere protein abnormalities, but also involves connective tissue elements.     

Inducible polymorphic ventricular tachycardia and ventricular fibrillation in a subgroup of patients with hypertrophic cardiomyopathy at high risk for sudden death

This investigation was undertaken to elucidate the underlying electrophysiologic substrate in hypertrophic cardiomyopathy and to identify possible predictors of sudden death in this patient population. Programmed stimulation was performed in 18 patients aged 14 to 64 years (mean 36) believed to be at high risk for sudden death on the basis of prior cardiac arrest or syncope, nonsustained ventricular tachycardia on Holter ambulatory electrocardiographic (ECG) monitoring or a family history of frequent sudden death. Polymorphic ventricular tachycardia that deteriorated to ventricular fibrillation was reproducibly induced in 8 (44%) of the 18 patients (Group A). This rhythm was induced in all three patients with a history of cardiac arrest. No sustained monomorphic ventricular tachycardia was induced. Group B comprised the 10 patients in whom a sustained arrhythmia could not be reproducibly initiated. The electrophysiologic substrate was distinctly different in patients with, than in those without, inducible sustained arrhythmia. The refractory period was shorter at the right ventricular outflow tract (232 +/- 22 ms) compared with the apex (264 +/- 12 ms) in Group A (p less than 0.005) whereas there was no difference in Group B (271 +/- 25 ms versus 271 +/- 13 ms). The local ventricular electrogram of most patients in both groups was prolonged and markedly multiphasic. However, 5 of the 8 Group A patients exhibited a double electrogram (V-V') with premature stimulation compared with 1 of the 10 patients in Group B (p less than 0.02). A positive R wave in lead aVR of the scalar ECG and poor R wave progression in the precordial leads were more common in Group A than in Group B (p less than 0.001 and p less than 0.001, respectively). The reason for the distinctly different electrophysiologic substrate and the high prevalence of inducible polymorphic arrhythmia is unclear. It may relate to the underlying myocardial architecture in these patients, characterized by myocardial cellular disarray and fibrosis.     

QT dispersion and risk factors for sudden cardiac death in patients with hypertrophic cardiomyopathy

This study examines the relation of QT dispersion (QTd) on a surface electrocardiogram (ECG) to clinical features and established risk factors of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HC). One hundred fifty-six consecutive patients with HC (91 men, mean age 41 ± 15 years, range 7 to 79) and 72 normal subjects (41 men, mean age 39 ± 9 years, range 20 to 60) were studied. Standard 12-lead ECGs were recorded from each subject using a MAC VU electrocardiograph. Patients with nonsinus rhythm, atrioventricular conduction block, QRS duration >120 ms, age <15 years, and low amplitude T waves were excluded from the analysis (n = 51). Another 22 patients who were receiving amiodarone and/or sotalol therapy were also excluded. QT interval and QTd were measured using automated analysis in the remaining 83 patients (46 men, age 40 ± 14 years, range 16 to 76). QT interval (406 ± 38 ms), QTc interval (432 ± 27 ms), and QTd (43 ± 25 ms) were significantly greater in patients with HC than in normal controls (386 ± 31 ms, 404 ± 16 ms, 26 ± 16 ms, respectively) (p <0.0001). QTd was significantly greater in patients with HC with chest pain compared with asymptomatic or mildly symptomatic patients (50 ± 28 ms vs 37 ± 20 ms, p = 0.02). Increased QTd was found in patients with dyspnea New York Heart Association functional classes II/III than in those with dyspnea New York Heart Association functional class I (50 ± 27 ms vs 38 ± 22 ms, p = 0.04). QTd was weakly correlated with maximum left ventricular wall thickness (r = 0.228, p = 0.038). No significant association was found between QTd and any risk factors for SCD. Thus, patients with HC have increased QTd. The QTd correlates with symptomatic status. Assessment of QTd might provide complementary clinical characterization of patients with HC but its relation to SCD remains uncertain.     

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)     

Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients

OBJECTIVES: The aim of this study was to examine the characteristics of non-sustained ventricular tachycardia (NSVT) episodes during Holter monitoring and to determine their relationship to age and prognosis. BACKGROUND: It has been suggested that NSVT is only of prognostic importance in patients with hypertrophic cardiomyopathy (HCM) when repetitive, prolonged, or associated with symptoms. METHODS: We studied 531 patients with HCM (323 male, 39 +/- 15 years). All underwent ambulatory electrocardiogram monitoring (41 +/- 11 h). RESULTS: A total of 104 patients (19.6%) had NSVT. The proportion of patients with NSVT increased with age (p = 0.008). Maximum left ventricular wall thickness and left atrial size were greater in patients with NSVT. Mean follow-up was 70 +/- 40 months. Sixty-eight patients died, 32 from sudden cardiac death (SCD). Twenty-one patients received an implantable cardioverter defibrillator (ICD). There were four appropriate ICD discharges. In patients < or =30 years (but not >30), five-year freedom from sudden death was lower in those with NSVT (77.6% [95% confidence interval (CI): 59.8 to 95.4] vs. 94.1% [95% CI: 90.2 to 98.0]; p = 0.003). There was no relation between the duration, frequency, or rate of NSVT runs and prognosis at any age. The odds ratio of sudden death in patients < or =30 years of age with NSVT was 4.35 (95% CI: 1.54 to 12.28; p = 0.006) compared with 2.16 (95% CI: 0.82 to 5.69; p = 0.1) in patients >30 years of age. CONCLUSIONS: Non-sustained ventricular tachycardia is associated with a substantial increase in sudden death risk in young patients with HCM. A relation between the frequency, duration, and rate of NSVT episodes could not be demonstrated.     

Sudden death in hypertrophic cardiomyopathy with normal left ventricular mass.

An active, healthy, and symptom free 16 year old boy with a family history of hypertrophic cardiomyopathy died suddenly while walking home from school. Necropsy showed absence of left ventricular hypertrophy (that is, normal heart weight), though the characteristic histological abnormalities of hypertrophic cardiomyopathy, such as cardiac muscle cell disorganisation and abnormal intramural coronary arteries, were present. It is likely that this patient had hypertrophic cardiomyopathy and died before left ventricular hypertrophy developed.     

Left ventricular outflow tract obstruction and sudden death in hypertrophic cardiomyopathy.

We thank Maron et al. for their editorial on our paper.^1,2 Hypertrophic cardiomyopathy (HCM) is a capricious disorder,characterized by heterogeneity at all levels. Together withits relative rarity, this has resulted in a dearth of evidence-basedpractice. The authors suggest that cardiologists rely on guidancefrom a few major centres     

Sudden death (V). Identification and treatment of patients with hypertrophic cardiomyopathy at risk of sudden death

During the last 20 years, the principal objective in hypertrophic cardiomyopathy research has been the refinement of algorithms for the identification and treatment of patients at risk of sudden death. Sudden death is an important problem in hypertrophic cardiomyopathy, with an incidence of 4-6% in referral populations and approximately 1% in non-referral centers and because it affects young and often asymptomatic patients. We now know that hypertrophic cardiomyopathy is not a single disease, but a group of diseases caused by mutations in genes encoding different sarcomeric proteins. The phenotypic expression depends on multiple modifying genetic and environmental factors. Even though genetic testing is not presently a practical approach in hypertrophic cardiomyopathy risk stratification, it is important to consider new genetic data in the prognostic evaluation of patients. In this paper, we review the published data on risk stratification in hypertrophic cardiomyopathy and we set forth our opinion with regard to the available therapeutic options and their indications in the prevention of sudden death.     

Progressive left ventricular remodeling in patients with hypertrophic cardiomyopathy and severe left ventricular hypertrophy

OBJECTIVES: The aim of this study was to determine the natural history of patients with hypertrophic cardiomyopathy (HCM) and severe left ventricular hypertrophy (LVH) (i.e., maximal left ventricular wall thickness [MLVWT] >/=30 mm) and whether changes in cardiac morphology influence the course of the disease. BACKGROUND: Severe LVH is common in young and rare among elderly patients with HCM. This has been explained by a high incidence of sudden death. We hypothesized that this age-related difference might be explained by left ventricular wall thinning. METHODS: A total of 106 (age 33 +/- 15 years; 71 males) consecutive patients with severe LVH underwent history taking, examination, electrocardiography, echocardiography, cardiopulmonary exercise testing, and Holter analysis. Survival data were collected at subsequent clinic visits or by communication with patients and their general practioners. In order to assess morphologic and functional changes, 71 (67.0%) patients (mean age 31 +/- 15 years; 47 males) followed at our institution underwent serial (>/=1 year) assessment. RESULTS: Of the 106 patients, the majority (78 [71.6%]) were <40 years of age. During follow-up (92 +/- 50 months [range 1 to 169]), 18 (17.0%) patients died or underwent heart transplantation (13 sudden cardiac deaths, 2 heart failure deaths, 1 heart transplantation, 1 stroke, 1 postoperative death). Five-year survival from sudden death was 90.1% (95% confidence interval [CI] 84.0% to 96.3%), and that from heart failure death or transplantation was 97.7% (95% CI 94.5 to 100). In patients serially evaluated over 85 +/- 51 months, there was an overall reduction in MLVWT of 0.6 mm/year (95% CI 0.31 to 0.81, p = 0.00004). Wall thinning >/=5 mm was observed in 41 patients (57.7%; age 35 +/- 13 years; 28 males). On multivariate analysis, the follow-up duration only predicted wall thinning (0.6 mm/year, 95% CI 0.38 to 0.85, p < 0.00001). CONCLUSIONS: Left ventricular remodeling is common in patients with severe LVH and contributes to the low prevalence of severe LVH seen in middle age and beyond.     

Relation of left ventricular thickness to age and gender in hypertrophic cardiomyopathy

Left ventricular (LV) wall thickening is the most consistent clinical marker of hypertrophic cardiomyopathy (HC), and characteristically increases substantially during adolescence. In this study, we used 2-dimensional echocardiography to develop a cross-sectional profile of LV wall thicknesses in adult patients with HC. We studied a regional community-based cohort of 239 consecutively enrolled patients (aged 18 to 91 years). On average, maximum LV wall thickness decreased relative to increasing age (p = 0.007) within 4 age groups: 22.8 +/- 5.1 mm (18 to 39 years) to 22.1 +/- 5.1 mm (40 to 59 years) to 21.1 +/- 3.7 mm (60 to 74 years) to 20.8 +/- 3.6 mm (>or=75 years). The LV thickness index (summation of wall thicknesses in all 4 segments) also decreased with age (p = 0.017): 63.0 +/- 12.2 mm to 59.8 +/- 11.9 mm to 58.3 +/- 10.4 mm to 57.9 +/- 9.8 mm. Decreasing magnitude of LV hypertrophy was independently associated with increasing age, but not with other relevant disease variables, such as symptoms and outflow obstruction. However, when separated by gender, this inverse relation between age and LV wall thickness was statistically significant only for women (p = 0.007). In conclusion, in an unselected HC cohort, cross-sectional analysis showed a modest but statistically significant inverse relation between age and LV hypertrophy that was largely gender-specific for women. This association constitutes another facet of the natural history of this complex and heterogenous disease and may reflect disproportionate occurrence of premature death in young patients with HC with marked hypertrophy or possibly gradual LV remodeling.     

Mitral valve abnormalities in decedents of sudden cardiac death due to hypertrophic cardiomyopathy and idiopathic left ventricular hypertrophy

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QT dispersion and left ventricular morphology in patients with hypertrophic cardiomyopathy

Objective: To evaluate the relation between QT variables and disproportion of left ventricular wall hypertrophy in patients with hypertrophic cardiomyopathy.