As of February 2009, the PCMR included 1803 children diagnosed with DCM since 1990. Causes of DCM determined at presentation were: idiopathic disease (n = 1286), myocarditis (n = 255), neuromuscular disorder (n = 136), malformation syndrome (n = 10), familial isolated cardiomyopathy (n = 78), and inborn error of metabolism (n = 38). Mean age at diagnosis was 5.3±6.1 years. Mean LV end-diastolic dimension z-score was 4.3±2.7, LV fractional shortening was 16±9%, and LVEF (n = 597) was 28±14%. Median follow-up in patients with no death or transplant event was 2.6 years (interquartile range, 0.8 to 5.3 years; maximum, 16.7 years).
Of 280 deaths, the type of death was SCD in 35 (13%), non-SCD in 189 (68%), and unknown in 56 (20%). Thus, amongst patients with a known mode of death, 16% were SCD (35/224). Amongst the 1747 survivors and those with a known cause of death, SCD comprised 1.9%. The majority of SCDs, 74% (n = 26), occurred < 2 years after presentation. Most non-SCDs were caused by CHF.
The incidence rate of SCD was low, and the rates of transplant and non-SCD were high. The 1-, 3-, and 5-year cumulative incidence rates were 1.3%, 2.0%, and 2.4% (95% CI 1.7% to 3.4%) for SCD. The 1-, 3-, and 5-year cumulative incidence rates for non-SCD were 8.1%, 10.8%, and 12.1%; and for heart transplant, 22%, 27%, and 29% for heart transplant (). In addition, the 5-year incidence of death from unknown type (56 patients) was 4%. If the proportion of patients who had SCD in the group with an unknown cause of death is similar to that in the patients with a known cause of death (16%; 32/225), then we estimate that 9 additional patients died of SCD, and the 5-year cumulative incidence of SCD is 3.0%. This group of 56 patients is not included in risk factor analyses.
Figure 1 Competing risks analysis for sudden cardiac death, non-sudden cardiac death, unknown cause of death and cardiac transplantation among 1803 children with dilated cardiomyopathy (DCM) listed in the Pediatric Cardiomyopathy Registry. The 3, 5, and 10-year (more ...)
Risk Factors for Sudden Cardiac Death: Predictors from the Time of Cardiomyopathy Diagnosis
SCD was not associated with sex, race/ethnicity, or cause of DCM (). Children who experienced SCD were more likely to present with CHF (86%) at diagnosis than children who did not have SCD (73%; HR, 2.84; p = 0.03). In the first month after diagnosis, 47% of the SCD group and 22% of all other children were on anti-arrhythmic therapy (HR = 3.00; 95% CI 1.08 to 8.30, p = 0.03). Family history of SCD, family history of cardiomyopathy, NYHA class, and use of anticongestive or beta-blocker therapy in the first month after diagnosis were not associated with SCD. Among the subset of 548 patients who had information on ICD therapy, only 9 had an ICD, and none experienced SCD.
Patient Characteristics by Sudden Cardiac Death Status and Univariate Cox Regression Results
We examined echocardiographic parameters obtained at presentation (). Compared to patients without SCD, patients with SCD had a lower (log-transformed) LVPWT:EDD ratio, an index of ventricular remodeling that is a surrogate for LV end-diastolic wall stress, with a low ratio indicating insufficient LV hypertrophy (p = 0.02). A larger LV posterior wall thickness z-score was protective against SCD (HR = 0.86, p = 0.047). Fractional shortening z-score, was not a risk factor (p = 0.33).
We also examined ECG and Holter findings from the latest available follow-up. Of the 35 SCD cases, 13 had an ECG but only 5 had quantitative data, with a mean QTc interval of 449±72 msec. None of the 5 had any degree of AV block. One of the cases had a notation for wide complex tachycardia. These findings were qualitatively very similar to those in the 531 non-SCD patients who had QTc data (428±50 msec), with 5% (21/441) having AV block (none third-degree). Holter data were available for 5 of 35 SCD cases, with 3/5 (60%) having ventricular tachycardia and 60% having ventricular couplets. In the non-SCD group, 18% (52/294) had ventricular tachycardia and 25% (75/295) had ventricular couplets. No patients in either group had third-degree heart block or AV block. These limited data were not used in multivariable analysis.
Multivariable CART analysis based on predictors from the time of DCM diagnosis demonstrated that the LV posterior wall thickness z
-score, age at diagnosis and LV septal thickness z
-score and antiarrhythmic therapy are the most important discriminators between SCD and non-SCD (). Overall, 2% of subjects had SCD. Two of the five subgroups in the regression tree have at least twice the risk of SCD (e.g., > 4 %). These include:
- Patients with LV posterior wall thickness z-score < −1.7; and
- Patients with LV posterior wall thickness z-score ≥ −1.7, age at diagnosis < 13.1 years, septal thickness z-score < −0.8 and who were prescribed antiarrhythmic therapy within a month of presentation with DCM.
This model classified 24% of patients as high-risk, i.e., 20/35 deaths occurred in these groups, yielding 57% sensitivity and 78% specificity. Due to the very low prevalence of SCD, positive predictive value (% SCD among those identified as high risk) was only 5%, while negative predictive value (% non-SCD among those identified as lower risk) was 99%.
Figure 2 Classification and Regression Tree for Sudden Cardiac Death (SCD): Predictors from Time of Cardiomyopathy Diagnosis (Total N=1747, 35 sudden cardiac deaths). Red boxes denote high-risk patient groups. Bold black boxes denote lower-risk patient subgroups. (more ...)
Risk Factors for Sudden Cardiac Death: Predictors from Last Available Follow-up
Since treatment decisions are made based on the most current status of the patient, we also examined the predictive strength of the latest available measures of LV size and function. Over three-quarters (78%) of subjects had at least one follow-up measurement (range, 1 to 17). For the remainder, their value from the time of diagnosis was used.
Univariate analysis () shows that a higher hazard of SCD was significantly associated with all echocardiographic parameters except for LV posterior wall and septal thicknesses. For LV end-diastolic dimension and mass, a unit increase in z-score was associated with a 1.2- to 1.3-fold increase in risk. Similarly, a 5-unit decrease in LV fractional shortening (%) or LVEF (%) imparted a 1.4- to 1.5-fold increase in risk of SCD. The LVPWT:EDD ratio was again highly predictive (p < 0.001). At least moderate mitral (3% of patients) or tricuspid (8% of patients) regurgitation was also associated with SCD.
Patient Characteristics by Sudden Cardiac Death Status using Measurements from The Last Follow-up and Univariate Cox Regression Results
Multivariable CART analysis that considered echocardiographic measurements from the most recent follow-up (except for LVEF, see Methods) in addition to age and presence of CHF at diagnosis demonstrated that LV end-systolic dimension z-score, age at diagnosis and ratio of LVPWT:EDD are the most important discriminators between SCD and non-SCD (). The tree had four terminal nodes. Three nodes had a below-average rate of SCD (0% to 1.8%). A single node captured 30 of the 35 SCD. This subgroup (44% of patients) with the highest SCD rate (3.9%, 30/766) met all three of the following criteria: 1) LV end-systolic dimension z-score > 2.6; 2) DCM diagnosis at age < 14.3 years, and 3) LVPWT:EDD ratio < 0.14. This patient subset produced high sensitivity of 30/35 = 86%, and specificity of 981/1712 = 57%; albeit with a positive predictive value of 4% and a negative predictive value of 99%.
Figure 3 Classification and Regression Tree for Sudden Cardiac Death (SCD): Predictors from Time of Last Follow-up (Total N=1747, 35 sudden cardiac deaths). Red box denotes the high-risk patient group. Bold black boxes denote lower-risk patient subgroups. Sensitivity=86%, (more ...)
Despite LVEF from follow-up being available for only 46% of patients, we examined the predictive strength of a commonly used threshold, LVEF < 35%, and assessed its validity by comparing it to the equivalent value of LV fractional shortening < 18%. The results for these two thresholds were similar (). If LVEF < 35% is used as an indication for ICD placement, sensitivity is only 73% (compared to the regression tree result in with 86% sensitivity). Specificity using LVEF < 35% was the same as that yielded by the regression tree (57%).