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    Prognostic

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    Prasetya Ismail Permadi
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    Him ORIGINAL CONTRIBUTION Incidence, Causes, and Outcomes of Dilated Cardiomyopathy in Children Jefirey A Towbin, MD) ox, MD, PhD arie, MD. MD Tharles Canter, MD James D. Wilkinson, MD tz, MD. = ARDIOMYOPATHIES ARE HEART muscle disorders that allect ventricular systolic fune- tion, diastolic function, or both. They are classified by the World Health Organization as (1) dilated ear- diomyopathy (DCM), (2) hyper- trophic cardiomyopathy, (3) restric live cardiomyopathy, and (4) arrhythmogenic right ventricular dys- plasia-cardiomyopathy.! Most pa- tients have “pure” forms of these dis- orders that fulfill strict diagnostic criteria, although some have overlap- ping disorders with mixed forms of di cease. Despite long-standing interest in these high-impact disorders, the de- mographics and underlying causes have been difficult toascertain, particularly in children. Dilated cardiomyopathy, a myocar dial disorder characterized by a dilated left ventricular (LV) chamber and sys- tolie dysfunction that commonly results in congestive heart failure (CHE),! is the most common form of cardiomyopathy and reason for car- (©2006 American Medical Assoc Downloaded From: on 10/22/2017 Context Dilated cardiomyopathy (DCM) isthe most common form of eardiomyop- aihy and cause of cardiac vansplantation in chidren. However, the eidemology and clnal course of DCM in chen ae not wel established. Objective To provide adetaled description ofthe incidence, causes, outcomes, and relled rs factors for DoM in chiren Design and Setting Longitudinal study based on a population-based, prospective cohot of elren dlegnosed as having DCM since January 1, 1996, t 89 pedatrc cardac centers and arevospecively collected cohor of paints seen primary atlarge tear are centers in North America and who had dagnoses between nua 1, 1990, and December 3, 1995, and were envlled through February 2003 Participants A total of 1426 chien from the United States and Canada diag- nosed as having DCM st younger than 18 yeas. Primary DCM was determined by Stic echocardlographle and/or pathologte eter. Patiens with disease due to en- docine,immunolog, drug tony, and other eauses were excluded Main Outcome Measures Annual incidence per 100000 children; mortality, ca- diac transplantation Results. The annul incidence of DEMn clon young: than 1 ets ws 037 Cases per 100000 per year over. The annual Ineldence was higher i Boys than in fs (0.66 50.47 eases per 100000, P00), in blacks than in whites (0.98 vs 0.46 Eases per 100000; P= 001), and in infants (1 year) than In chidren (40 vs 0.34 Cases pet 100000; P=.001). The majolyof children (66%) had dopathc disease. ‘The most common known causes were myocardits (46%) and neuromuscular ds ease (26%). The 1-and 5-year rats of death or transplantation were 31% and 46% respectively Independent tk factor at DCM diagnos for subsequent death or tan plantation were elder age, congestive heat alre ower lt venticuar action shor ning 2 score, and cause of DCM (P01 fora. Conelusions inchidren, DCMisa diverse disorder th outcomes that depend gly on cause, age, and heat fale stats at presentation, Race, sex, and age affect the Incidence of dase. Most chldren do not havea known cause of DCM, which ims the potential for disease specific therapies path 20052361867 1976 wacom diac transplantation in adults and chil- brio Tas Cnider’sHopt rCt a (eestor: aca i i dren. In some cases, right venricu- 8 et panna Vio as lar dysfunction als noted and may iam nD eet Cr ose aan to the clinical severity of disease. JEC°r4 mere) and Brigham and Women’s sad to the clinical severity of disease. F258 nt avai tase Sto, Soon, The estimated cost of caring for hss Gauyne Cun Canby sro A patients with this disorder is $4 billion Sa Mita Calg, Abany NY (Lune Colan ey Nn Yok era Wao {o $10 billion annwally in the United Southsea Sn use Coy States alone.** In adults, the incide 2nd Department of Pediatrics, University of Miami Miler Seer eae eens Be see i Be and tases pet 100000 population per year, Compondng Ator: fey A. Tobin, MO, Pe = per 100000 popula GONE ri sclera et a with a prevalence of 39 eases per ni he Boe Histon, B00 fh 100000 population. The underlying bxn'mc eda tion. Al rights reserved. (Reprinted) AMA, Och 18, 2006 Vol 296, No. 15 1867 DILATED CARDIOMYOPATHY IN CHILDREN cause in adults® is usually coronary artery disease, but other causes are also seen, including inflammatory hheart disease, myocardial toxins, and genetic defects® Approximately 30% lo 35% of patients are reported to have 4 genetic form of DCM." Infants and older children, however, appear to hhave a wider spectrum of causes," although identifying these causes has been dificult Relatively le information om the in- idence of cardiomyopathies in child- hhood has been published."* Arola et a reported an incidence of DCM of (0.34 cases per 100000 children per y and a prevalence of 2.6 cases per 100.000 children in Finland, a racially homogeneous population. A large per- centage of eases occurred in infants (<1 year of age; 3.8 per 100000 cases per year). Recently, our group, the Pediat- rie Cardiomyopathy Registry (PCMR), reported the incidence of pediatric car~ diomyopathy in 2 regions of the United States, New England and the central Southwest." A total of 467 cases of childhood cardiomyopathy were re- ported, yielding an annual incidence of 1.13 per 100000 infants and children overall, with differences by race, se and region, These data are supported by similar findings in Australis." The PCMR report defines the overall inci- dence of all forms of childhood cardi- ‘myopathy but has limited details re- ‘garding the eauses, risks, and outcomes fof specific forms of cardiomyopathy. However, more detailed information fo- cusing on particular forms of cardio- myopathy is required for clinicians to understand the clinical disorders of in- dividual patients The current report provides the most up-to-date estimates of the incidence of DCM in patients younger than 18 years living in 2 regions of the United States, as well as a detailed description of the causes, outcomes, and related risk fae- tots for DCM in children, METHODS: Study Design Two PMR cohorts were established, The first is a population-based, pro- $868 JAMA October 18, 2005 Vol 296, No 15 Rept Downloaded From: on 10/22/2017 spective cohort of patients younger than 18 years who have been diagnosed as having DCM between January 1, 1996, and February 25, 2003, at 98 pediatric cardise centers and is based on ident fication atthe time of diagnosis by pe- diatric cardiologist. Por this cohort, comprehensive patient enrollment was conducted in 2 geographically dis- tinct regions of the United States (New England and the central Southwest). Inaddition, a retrospective cohort of pa- dents seen primarily at 39 tertiary care centers in North America and who had diagnoses between January 1, 1990,and December 31, 1995, was identified by chart review. Both groups are fol- lowed up using annual chart review. and enrollment of newly diagnosed cases is ongoing. All participating PCM centers obtained institutional re- view board or ethics committee ap- proval with a waiver of consent autho- ization. The participating centers and associated investigators representing the PCM Study Group are detailed by Gre- rier et al. Eligibility Criteria All patients with cardiomyopathy were {identified by clinical presentation to a pediatric cardiologist with signs and symptoms of hear failure, sudden death or aborted sudden death, or evalua- tion for possible cardiomyopathy be- cause of familial inheritance. In add don, autopsy reports were evaluated in a retrospective case review. Sudden death was captured by review of the car- diology and pathology medical records. A variety of diagnostic exclusion ert- teria” were used, including endocrine disorders oF immunologic diseases known to cause heart muscle disease, treatment with doxorubietn, and in- flammation caused by human immu- nodeficiency virus (HIV) infection (or birth to an HIV-positive mother) or by Kawasaki disease ‘A patient is eligible for the PCM i{ he/she is younger than 18 years, strict quantitative echocardiographic criteria of LV dilation and systolic dysfunction are met, the pattern of cardiomyopathy conforms to a defined semiquantitative pattern, the diagnosis is confirmed by autopsy or tissue analysis, or the investigator has other compelling evidence of cardiomyopathy. This analysis focuses on pure DCM, defined as the presence of DCM at di- agnosis, excluding any additional over- lapping cardiac phenotype (n=1426). Cases of mixed functional DCM, including a combination of DCM. with hypertrophic, restrictive, arhyth- mogenic, noncompaction without gene mapping, or other functional types of cardiac disorder, were excluded. A sul- ficient number of significant differ ences in characteristics at diagnosis ‘were found between patients in these 2 categories, and genetic and clinical studies indicate that mixed functional lypes of DCM have different causes than, pure DCM and therefore are not re resentative of DCM as a classification, In addition, classification schemes for cardiomyopathy were developed on the basis of pure DCM." Data Collection Following patient identification, con- lirmation of eligibility and enrollment are established by chart review per- formed by study personnel using a unique study identifier to ensure con- Iidentiality. Supplemental informa- tion on clinical history, procedures, and ‘outcomes is obtained annually for all patients, and information on family his- tory, results of laboratory studies, and therapies administered is additionally collected for retrospective cohort pa- Lients, All patients are seen by thelr pri- mary pediatric cardiologist in follow- up, and data reported are based on ‘comprehensive chart review of each pa- Statistical Methods The clinical components ofthis report include all patients who were enrolled in the PCMR as of February 25, 2003, and the incidence rates are based on all cardiomyopathy diagnoses in the New England and central Southwest re- flons between January 1, 1996, and De- cember 31, 2002. The retrospective co- (©2006 American Medical Association, All rights reserved. hhort cannot be confirmed to include all ceases and, therefore, was not used for incidence estimates. Population de- rominalors used for ineidence rate eal culations were obtained from the state- specific US census counts for 1996 through 2002, Race/ethnicity was assessed to cre- tea subgroup factor for ineidence rates and clinical outcomes, Asa result of di ferences between race/ethnicity defini- tions in the US Census and the PCMR, both an upperand a lower estimate for incidence rates are given for white, black, and Hispanic children. The PCMR data on race/ethnicity consist of single question with choi black, Hispanic, Native American, Asian/Pacific Islander, or other. How ofwhite, fever, the census data on race/ethnicity ceros-tabullates Hispanic status by r= cial category. Therefore, we caleu- lated both lower-hound and upper- bound estimates of race-specilic incidence rates. The lower-bound e Limate includes all white Hispanics and black Hispanics in the white and black population counts, respectively, and the upper bound includes none ofthe white Hispanics and black Hispanics in the white and black population counts, re spectively. The lower-bound estimate for the Hispanic rate includes all His- panics of any race (white, black, or other race) in the population count, and the upper-bound estimate for the His panic rate includes only Hispanics with ‘racial background not classified as white or black in the population Descriptive statistics are presented as percentages or means and standard de- vlations, with skewed continuous data summarized as medians and interquar- lile ranges. The distributions of cat cegorical variables were compared us- ing the Fisher exact test, except for comparisons by cause, for which the X° statistic was used. Two groups of nor- mally distributed variables were com- pared using the f test, and analysis of variance was used to compare more than 2 groups. Skewed data were ana- lyzed using the Wilcoxon rank-sum test and the Kruskal-Wallis test. The Man- (©2006 American Medical Assoc Downloaded From: on 10/22/2017 1, All rights reserved. DILATED CARDIOMYOPATHY IN CHILDREN Figure 1. Esumstea Freedom From Death or Trarspaaiaton for Patents Wit Pure Distea Cardiomyopathy by Cohort eee eeeee ievospecve: diagnosed 1990 lo 1995 491 plenty prospective: dagosed 1996 io 2002 935 patents tel-Haenszel test for linear trend was used to examine age at diagnosis of car- diomyopathy grouped categorically by Left ventricular end-diastolic dimen- sion, posterior wall thickness, septal thickness, and mass were measured and expressed conditional on body surface area Fractional shorteningisamea- sure of LY contractility and is defined by the ratio of the difference between the end-diastolic dimension (LVEDD) and end-systolic dimension (LVESD) to the LVEDD, expressed as fractional short- ening=(LVEDD-LVESD)/LVEDD 100. Quantitative right ventricular structure and function data were not collected, ‘Outcome measures were death, car- diac transplantation, and the compos- fie end point of death or transplanta Won, Because of varying amounts of follow-up, survival figures and esti- mates were calculated using the Kaplan- Meier method and were compared with the log-rank test, with time from DCM. diagnosis as the origin. Cox regres sion modeling was used to find predic~ tors of death or transplantation in pa tients with pure DCM, excluding those with neuromuscular disease and in bor errors of metabolism, To control for the large number of subgroup analyses as well as multiple comparisons, only P-<.01 was eonsid- cred to be statistically significant. All analyses were conducted using SAS ver- sion 9.1 (SAS Institute Ine, Cary, NC) and S-Plus version 6.1 (Insightful Corp, Seattle, Wash). RESULTS Registry Characteristics A total of 1426 patients with pure DCM were enrolled as of February 25, 2003, including 491 (34%) enrolled retro- spectively and 935 (66%) enrolled pro- spectively. These patients resided in New England (n1=105 [14%]), the ce tral Southwest (n=397 [28%]), and the remainder of North America (n=834 [58%6]) at the time of diagnosis. Cohort Differences The retrospective and prospective co- hhortsare similar with respect to sex, age, region, cause, presence of CHF at di- agnosis, and outcome (FIGURE 1), Therefore, although there were statis- tical differences according to race (slightly more white children were rolled in the retrospective cohort: 61% [298/485] vs 54% [497/918] and rate of idiopathic disease (67% [33/491] vs 70% [710/034] for retrospective vs pro- spective), these 2 cohorts were com- bined for all other analyses. (Reprinted) JAMA, Cxies 18,2006 Vo 296, No. 15 1869 DILATED CARDIOMYOPATHY IN CHILDREN (20% [12/125]) muscular dystrophy, t "T. Pediatne Cardomnjopalhy Reghty Annual Inadence of Pure Dated Cardiomyopathy in 422 Patients Diagnosed Between 1996 and 2002 in the New England both caused by mutations in dys- Sd Cena soutowet Regions ofthe Ued States” trophin, Three children (2%) had io. of Annual eenae pa T0000 CHan PF _Emery-Dreifuss muscular dystrophy Characteristics Patients: The majority of patients with famil- [sal 8 ial DCM (14% [66/485]) had autoso- Feaert mal dominant inherltance (68% [45/ Men Ea ie Set Se O75) 09 66]), and 24% (16/66) had autosomal, Sara eet e ose J recessive inheritance. The remainder had Mle 20 086,056-075) ] oor Bile ibertene 2% othe Feral 7 a7 (ADDIS) complex phenotype of LV noncompac- Fazeetnany tion with gene mapping (6% [466)) An He, overpoe 207 03/046 020-0380.40-05 aaditional 48 cases had LV noncompac- Sak oe Tos ETAT ] <0) ee ee Feri, kweripper Y00 0.599299 OA 07027 08-0 DCM; ofthese, 45 remained idiopathic Fee re and 2 had unspecified chromosomal d a 12 400 078.509 = we sours J] <00t fects and 1 had Barth syndrome as the a _PTimary cause of DEM. Causative gene jrepmaens 32 abnormalities were identified in 4 famni- lies with autosomal dominant disease including mutations in 8-sarcoglyean in ‘Sarma er hearer by etre Hogan The ae corenermeepermnterormertack 2 families and ZASP (Z-band alterna- ‘Ssrtod coos auf: fe ont coment pare tively spiced PDZ domain protein) in 2 families, In addition, mutations in 2 ‘Annual Incidence of DCM. Echocardiogram results were avail-__ families with LV noncompaction (ZASP) Incidence rates were based on 422 cases able for 97% of patients (1378/1419). and in 2 with X-linked disease (dystro- of DCM diagnosed from 1996 10 2002 ‘The mean LVEDD Z score was 4.17 phin mutation in 1 and tafazzin muta in 2 regions of the United States. The (SD, 2.70), whereas the mean LVESD _ tion in 1) were also identified." overall rate of pure DCM in childhood _ Z score was 5.96 (SD, 2.86) (Table 2). Among the 54 patients with inborn was 0.57 cases per 100.000 per year. Lelt ventricular fractional shortening errors of metabolism, the largest sub- The incidence was higher in boys than was severely depressed, with amedian groups were mitochondrial disorders In girls (0.66 vs 0.47 per 100000 per Z score of -9.16 (interquartile range, (46% [20/54]), Barth syndrome (24% year; P=.006), inblacks than in whites 11.0810 -6.10).Leftventricular end-_[13/54]), and primary or systemic car- (0.98-1.05 vs 0.33-0-46 per 100000 per diastolic posterior wall thickness and _nitine deficiency (119% [7/54]. Mal- year; P<.001),and in infants (<1 year) septal wall thickness were, on aver- formation syndromes were the least, than in older children (4.40 vs0.34 per age, normal, but LV mass was mildly common cause of DCM, and these dis- 100.000 per year; P<.001) (Tapte 1). abnormal, witha mean Z score of 2.34 orders affected 15 patients, with Al- (SD, 289). strom syndrome occurring in 5 cases (63%) and a chromosomal defect oc- ‘curring in 7 cases (47%), Clinical Presentation Clinical findings, therapy, and out- CAUSES of DCA tomes are based on the entire cohort ‘The cause of DCM was identified in of 1426 patients with pure DCM un- 34% of patients (Table 2). Of the 485 Therapy lessoiherwise specified, Themedian age patients with a known cause the most At the time of diagnosis of DCM, 82% a diagnosis wns L3 years (ierquar- Common cases were myecardils of patients (1120/1370) were pre- tile range, 3-113 years) CTamte 2). (40% [222/485] and neuromuscular scrbedan anticongesiveagentand 64% ‘Age younger than 1 ear was the most disease (26% (125/495). Hall of myo- 0778) an angotensinconvertingen- Common age at diagnosis of DCM carditis cases (2% [116/223]) met zyme inhibitor, with 38% (183/478) (n=561 [1%)). Thee-oyoungerthan strict Dallas histopathologic criteria. ceiving an antiarrhythmic agent, 15% Tyearold age group was the least Specille vial or ether eauses were (67/136) using Leafiinesuppkene common (2194 14%) age at initial Known for very ew eases Because cul tatlon, and 13% (63/487) having other Giagnosts. Themmaorty ofpaientshad sues and polymerase chain reaction dietary modification. Antithrombotic clinical evidence of CHE at diagnosis information were not available in therapy was prescribed In 19% of eases (71% [1999/1415], with 27% G6l/ most cases The majority of children andinouopesin 1% Therewaclow use 967) overall classified as having class with neuromuscular disorders had of calcium channel blockers (3% [12/ TV heart ailures"2"" Duchenne (0% [100/125) of Becker 473) and Prblockers (6 (17/4741) 4870 JAMA October 18, 2005 Vol 296, No 15 Rept (©2006 American Medical Association. All ights reserved. Downloaded From: on 10/22/2017 DILATED CARDIOMYOPATHY IN CHILDREN Pacemaker and balloon pump use at di- tion was 4.0 years, and the median age 5-year survival of 77%, and 10-year sur- agnosis was rare (1% each [7/480 and at transplantation was 4.8 years. Death vival of 70% (Table 3). Similarly, the 7/480, respectively]), as was use of an occurred (for all patients who died) ata_rate of freedom from transplantation at (deft or right ventricular) assist device median age of 3.0 years, Median fol- 1, 2, 5, and 10 years was 70%, 74%, (2% [9/486]) and extracorporeal mem- low-up time from diagnosis of DCM 70%, and 66%, respectively. Freedom brane oxygenation (3% [13/486)). among survivors who did not undergo from death or transplantation was 60% transplantation was 1.6 years, with 25% at L year, 61%at2 years, 544bat5 years, Clinical Outcomes having more than 4 years of follow-up. and 46% at 10 years. Themedianageofthe patientsatthe time -Kaplan-Meieranalysisofsurvival af Kaplan-Meier estimates showed sig- ‘of diagnosis was 1.5 years (TABLE3),the ter DCM diagnosis revealed L-year sur- nificant differences in survival, {ree- median age at listing for transplanta- vival of 87%, 2-year survival of 83%, dom from transplantation, and the ‘Table 2. Characterstes at Diagnosis of 1426 Patients With Pure DCM From the Pecatic Cardiomyopathy Registry, by Cause” agora oats alan Ghencwii —«Maie Wopaticbew abe Bane ranlgew tues “Sisane” p Be “AYR MENT) ea, aN St) valet ee aa pq wg ey yn aan Sansom ea aa) ee aia | Covariates No, (esc, Valoot (estech) Valet geal cagness oTECMIS or ea 001 =O Toxbwecty DOS TETAA oF 2 Bociwaty Ta (0-187 OF = aT Wo

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