Potential SCD Modifiers in HCM according to 2011 ACCF/AHA guidelines
Left Ventricular Outflow Tract Obstruction at Rest
Dynamic LVOTO is reported in approximately 25 % of patients during resting conditions.52,53 A study on 917 patients, including almost one-third with LVOTO, demonstrated an association between LVOTO and increased risk of SCD and appropriate ICD discharges over a 61-month median follow-up period.54 The risk of SCD was related to the severity of LVOTO and the presence of other recognised risk factors for SCD. Multivariable analysis demonstrated that LVOTO was an independent predictor of SCD/ICD discharge, with a 2.4-fold increase in the risk of SCD/ICD discharge.54 The role of provocable LVOTO with exercise is unclear and current guidelines do not recommend exercise-induced LVOTO in the risk stratification.30,55
Late Gadolinium Enhancement on CMR Study
The past decade has witnessed a burgeoning in the number of articles relating to the role of cardiovascular magnetic resonance (CMR) in HCM.56–76 In one study of 265 patients the quantification of LV mass correlated weakly with maximal wall thickness and was 100 % sensitive in predicting HCM-related mortality, but had a specificity of just 39 %.56 However, most of the interest in CMR is focused on the late enhancement after Gadolinium.57–72 Late Gadolinium enhancement (LGE) probably constitutes areas of myocardial replacement fibrosis and is detected in up to 60–70 % of HCM patients.57–63 As with all other aspects of the disease there is considerable heterogeneity in the extent and pattern of LGE.57–63 Fibrotic remodelling occurs early in disease pathogenesis of HCM but it may also be a secondary phenomenon related to microvascular ischaemia.13–17,64–66 Fibrous tissue represents a principal substrate for re-entrant ventricular arrhythmias and contributes to increased ventricular stiffness.59 A few studies have reported that the presence of LGE is significantly associated with heart failure death and all-cause mortality and is an independent predictor of adverse outcome and disease progression.59–62 In one study of 217 HCM patients the presence of fibrosis was associated with a 3.4-fold risk of major adverse events and the risk was proportional to the extent of LGE.59 Another study of 177 HCM patients showed that the presence of LGE may identify patients with increased susceptibility to ventricular tachyarrhythmias on the ambulatory Holter-monitoring (including a sevenfold increase in the risk of NSVT) and even small areas of LGE may be sufficient to promote arrhythmias.68 The significance of LGE in predicting arrhythmogenic SCD remains controversial. A recent metanalysis of four studies evaluating 1,053 patients, over an average follow-up of 3.1 years, concluded that LGE shows a trend towards significance for predicting SCD, but failed to shown a significant independent association.60 The high prevalence of LGE in HCM patients means that it would be impractical to consider it as a risk factor for SCD in isolation although extensive LGE has been shown to be associated with progressive ventricular dilatation and heart failure.58,59,69 Recently, two studies have provided conflicting results regarding the value of the extensive LGE in risk stratification for SCD.63,70 One study included 711 HCM patients, with a median follow-up of 3.5 years and 66 % of patients had LGE.63 The extent of LGE was found to be a strong univariable predictor of SCD, which was not maintained after adjustment for LV ejection fraction.63 The other study included 1,293 HCM patients, with a median follow-up of 3.3 years and presence of LGE in 42 % of patients. SCD events occurred in 37 patients (3 %), including 17 (1.3 %) with appropriate ICD discharge, which was considered equivalent to SCD.70 The extent of LGE was associated with an increased risk of SCD events and in particular LGE ≥15 % of the LV mass demonstrated a twofold increase in SCD event rate in those patients who would otherwise considered be at low risk. The authors concluded that extensive LGE provided additional information for assessing SCD event risk, particularly in HCM patients otherwise judged to be at low risk.70 The major criticism of this study was that even if the statistical analysis appeared to support this statement, the raw data did not.71 In the 20 patients that died suddenly or experienced aborted SCD only one revealed extensive LGE, while in the 17 patients experiencing an appropriate ICD shock, 13 patients had recognised conventional risk factors and from the rest only three had extensive LGE.70 In conclusion, the extent of LGE on CMR has some utility in predicting cardiovascular mortality, but the current data are contradictory and not conclusive in order to support the use of LGE in predicting the risk of arrhythmogenic SCD.30,71 Newer CMR techniques (as T1-mapping) may improve the characterisation of myocardial substrate of the arrhythmias.72–75
Additional Role of Genetics
Most sarcomere mutations capable of causing HCM are novel and limited to individual families; therefore, genetic screening is of limited value in risk stratification in most cases.4,5,29,30,76,77 The presence of multiple mutations or specific mutations encoding troponin T and lysosomal- associated membrane protein-2 (LAMP-2) may be indicative of a high risk of fatal events.78–83