Cardiomyopathies, diseases of the heart muscle, are major causes of morbidity and mortality. A significant percentage of patients with cardiomyopathies have genetic-based, inheritable disease and, over the past two decades the genetic causes of these disorders have been increasingly discovered. The genes causing these disorders when they are mutated appear to encode proteins that frame a “final common pathway” for that specific disorder but the specifics of the phenotype, including age of onset, severity, and outcome is variable for reasons not yet understood. The “final common pathways” for the classified forms of cardiomyopathy include the sarcomere in the primarily diastolic dysfunction disorders hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM), the linkage of the sarcomere and sarcolemma in the systolic dysfunction disorder dilated cardiomyopathy (DCM), and the desmosome in arrhythmogenic cardiomyopathy (AVC). Left ventricular noncompaction cardiomyopathy (LVNC) is an overlap disorder and appears that any of these “final common pathways” can be involved depending on the specific form of LVNC. The genetics and mechanisms responsible for these clinical phenotypes will be described.
Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Taz-deficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS.
To determine the incidence of and predictors for recovery of normal echocardiographic function among children with idiopathic dilated cardiomyopathy (DCM).
Most children with idiopathic DCM have poor outcomes; however, some improve.
We studied children less than 18 years old in the Pediatric Cardiomyopathy Registry who had both depressed left ventricular (LV) function (fractional shortening [FS] or ejection fraction [EF] z-score <−2) and LV dilation (end-diastolic dimension [LVEDD] z-score >2) at diagnosis and who had at least one follow-up echocardiogram 30 days to 2 years from the initial echocardiogram. We estimated the cumulative incidence and predictors of normalization.
Among 868 children who met inclusion criteria, 741 (85%) had both echocardiograms. At 2 years, 22% had recovered normal LV function and size; 51% had died or undergone heart transplant (median, 3.2 months), and 27% had persistently abnormal echocardiograms. Younger age (hazard ratio, 0.90; 95% CI, 0.86 to 0.95) and lower LVEDD z-score (0.75; 95% CI, 0.68 to 0.84) independently predicted normalization. Nine children (9%) with normal LV function and size within 2 years of diagnosis later underwent heart transplant or died.
Despite marked LV dilation and depressed function initially, children with idiopathic DCM can recover normal LV size and function, particularly those younger and with less LV dilation at diagnosis. Investigations related to predictors for recovery, such as gene associations, serum markers, and the impact of medical therapy or ventricular unloading with assist devices are important next steps. Longer follow-up after normalization is warranted as cardiac failure can recur.
Clinical Trials Registration # NCT00005391
cardiomyopathy; pediatrics; heart failure; echocardiography
Marfan syndrome (MFS) is an autosomal dominant condition with pleiotropic manifestations involving the skeletal, ocular, and cardiovascular systems. The diagnosis is based primarily on clinical involvement of these and other systems, referred to as the Ghent criteria. We have identified three Hispanic families from Mexico with cardiovascular and ocular manifestations due to novel FBN1 mutations but with paucity of skeletal features. The largest family, hMFS001, had a frameshift mutation in exon 24 (3075delC) identified as the cause of aortic disease in the family. Assessment of eight affected adults revealed no major skeletal manifestation of MFS. Family hMFS002 had a missense mutation (R1530C) in exon 37. Four members fulfilled the criteria for ocular and cardiovascular phenotype but lacked skeletal manifestations. Family hMFS003 had two consecutive missense FBN1 mutations (C515W and R516G) in exon 12. Eight members fulfilled the ocular criteria for MFS and two members had major cardiovascular manifestations, however none of them met criteria for skeletal system. These data suggest that individuals of Hispanic descent with FBN1 mutations may not manifest skeletal features of the MFS to the same extent as Caucasians. We recommend that echocardiogram, ocular examination and FBN1 molecular testing be considered for any patients with possible MFS even in the absence of skeletal features, including Hispanic patients.
FBN1; fibrillin-1; Hispanic; Marfan syndrome
Left ventricular noncompaction is a rare type of cardiomyopathy, the genetics of which are poorly understood to date. Lamin A/C gene mutations have been associated with dilated cardiomyopathy and diseases of the conduction system, but rarely in left ventricular noncompaction cardiomyopathy. This report describes the cases of 4 family members with a lamin A/C gene mutation, 3 of whom had phenotypic expression of left ventricular noncompaction.
Arginine/genetics; cardiomyopathies/genetics; cysteine/genetics; echocardiography; genetic testing; genotype; lamin C/genetics; lamin type A/genetics; laminopathy; left ventricular noncompaction; magnetic resonance imaging; mutation; pedigree; phenotype; proteins/genetics
Treatment of children with hypertrophic cardiomyopathy might be improved if the risk of death or heart transplantation could be predicted by risk factors present at the time of diagnosis.
The Pediatric Cardiomyopathy Registry collected longitudinal data on 1085 children with hypertrophic cardiomyopathy from 1990 to 2006. The primary outcome was death or heart transplantation. Our goal is to understand how patient factors measured at the time of diagnosis will predict the subsequent risk of death or heart transplantation. The Kaplan-Meier method was used to calculate time-to-event rates from the time of diagnosis to the earlier of heart transplantation or death for children in each subgroup. Cox proportional-hazards regression was used to identify both univariable and multivariable predictors of death or heart transplantation within each aetiologic subgroup.
The poorest outcomes (death or transplant) were observed among children with inborn errors of metabolism, for whom the estimated rate of death or heart transplantation was 57% (95% CI: 45%, 69%) at 2 years. Children with mixed functional phenotypes also did poorly, with rates of death or heart transplantation of 45% (95% CI: 33%, 57%) at 2 years for children with mixed hypertrophic and dilated cardiomyopathy, and 38% (95% CI: 24%, 52%) at 2 years for children with mixed hypertrophic and restrictive cardiomyopathy. Excellent outcomes were observed among the 407 children who received a diagnosis of idiopathic hypertrophic cardiomyopathy at 1 year of age or older, with rates of death or heart transplantation of 3% (95% CI: 1%, 5·0%) at 2 years.
The risk factors for poor outcomes varied according to hypertrophic cardiomyopathy subgroup, but they generally included age, weight, congestive heart failure, lower left ventricular (LV) fractional shortening, or higher LV end-diastolic posterior wall thickness or end-diastolic ventricular septal thickness at the time of cardiomyopathy diagnosis. For all hypertrophic cardiomyopathy subgroups, the risk of death or heart transplantation is significantly increased when two or more risk factors are present and also as the number of risk factors increases.
Among children with hypertrophic cardiomyopathy, the risk of death or heart transplantation is greater for those who present as infants or with inborn errors of metabolism or with mixed hypertrophic and dilated or restrictive cardiomyopathy. Risk stratification by subgroup of cardiomyopathy, by characteristics such as lower weight, congestive heart failure, or abnormal echocardiographic findings, and by the presence of multiple risk factors allows for more informed clinical decision-making and prognosis at the time of diagnosis.
The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100 000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.
We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990–2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values.
292 982 (95% UI 261 017–327 792) maternal deaths occurred in 2013, compared with 376 034 (343 483–407 574) in 1990. The global annual rate of change in the MMR was −0·3% (−1·1 to 0·6) from 1990 to 2003, and −2·7% (−3·9 to −1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290–2866) maternal deaths were related to HIV in 2013, 0·4% (0·2–0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1–1262·8) in South Sudan to 2·4 (1·6–3·6) in Iceland.
Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.
Bill & Melinda Gates Foundation.
The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occurred since the Millennium Declaration.
To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010–13) of incidence, drug resistance, and coverage of insecticide-treated bednets.
Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.
Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS’s estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.
Bill & Melinda Gates Foundation.
Men and women with type-2 long QT syndrome (LQT2) exhibit time-dependent differences in the risk for cardiac events. We hypothesized that data regarding the location of the disease-causing mutation in the KCNH2 channel may affect gender-specific risk in LQT2
To risk stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information.
The risk for life-threatening cardiac events from birth through age 40 (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) years was assessed among 1,166 LQT2 males (n=490) and females (n=676) by the location of the LQTS-causing mutation in the KCNH2 channel (pre-specified in the primary analysis as pore-loop vs. nonpore-loop).
During follow-up, the cumulative probability of life-threatening cardiac events years was significantly higher among LQT2 women (26%) as compared with men (14%; p<0.001). Multivariate analysis showed that the risk for life-threatening cardiac events was not significantly different between women with and without pore-loop mutations (HR=1.20; p=0.33). In contrast, men with pore-loop mutations displayed a significant >2-fold higher risk of a first ACA or SCD as compared with those with nonpore-loop mutations (HR=2.18; p=0.01). Consistently, women experienced a high rate of life-threatening events regardless of mutation-location (pore-loop: 35%, nonpore-loop: 23%), whereas in men the rate of ACA or SCD was high among those with pore-loop mutations (28%) and relatively low among those with nonpore-loop mutations (8%).
Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in type-2 long QT syndrome.
long-QT syndrome; pore-loop mutations; sudden cardiac death; gender
The congenital long-QT syndrome (LQTS) is an important cause of sudden cardiac death (SCD) in children without structural heart disease. However, specific risk factors for life-threatening cardiac events in children with this genetic disorder have not been identified
Methods and Results
Cox proportional hazards regression modeling was used to identify risk factors for aborted cardiac arrest (ACA) or SCD in 3,015 LQTS children from the International LQTS Registry who were followed up from age 1 through 12 years. The cumulative probability of the combined end point was significantly higher in males (5%) than in females (1%; p<0.001). Risk factors for ACA or SCD during childhood included QTc duration >500 msec (HR=2.72 [95%CI 1.50 - 4.92]; p=0.001) and prior syncope (recent syncope [<2 years]: HR=6.16 [95%CI 3.41 - 11.15], p<0.001; remote syncope [≥2 years]: HR=2.67 [95% CI 1.22 - 5.85], p=0.01) in males, whereas prior syncope was the only significant risk factor among females (recent syncope: HR=27.82 [95%CI 9.72 - 79.60], p<0.001]; remote syncope: HR=12.04 [95%CI 3.79 - 38.26], p<0.001). β-blocker therapy was associated with a significant 53% reduction in the risk of ACA or SCD (p=0.01).
LQTS males experience a significantly higher rate of fatal or near-fatal cardiac events than females during childhood. A QTc duration >500 msec and a history of prior syncope identify risk in males, whereas prior syncope is the only significant risk factor among females. β-blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events during childhood.
long-QT syndrome; risk factors; sudden death
Patients with long QT syndrome (LQTS) who harbor multiple mutations (i.e. ≥ 2 mutations in ≥ 1 LQTS-susceptibility gene) may experience increased risk for life-threatening cardiac events.
The present study was designed to compare the clinical course of LQTS patients with multiple mutations to those with a single mutation.
The risk for life-threatening cardiac events (comprising aborted cardiac arrest, implantable defibrillator shock, or sudden cardiac death) from birth through age 40 years, by the presence of multiple vs. single mutations, was assessed among 403 patients from the LQTS Registry.
Patients with multiple mutations (n = 57) exhibited a longer QTc at enrollment compared with those with a single mutation (mean ± SD: 506 ± 72 vs. 480 ± 56 msec, respectively; p = 0.003) and had a higher rate of life threatening cardiac events during follow-up (23% vs. 11%, respectively; p < 0.001). Consistently, multivariate analysis demonstrated that patients with multiple mutations had a 2.3-fold (p = 0.015) increased risk for life threatening cardiac events as compared to patients with a single mutation. The presence of multiple mutations in a single LQTS gene was associated with a 3.2-fold increased risk for life threatening cardiac events (p = 0.010) whereas the risk associated with multiple mutation status involving > 1 LQTS gene was not significantly different from the risk associated with a single mutation (HR 1.7, p = 0.26).
LQTS patients with multiple mutations have a greater risk for life-threatening cardiac events as compared to patients with a single mutation.
Aborted cardiac arrest; Long QT syndrome; Mutation; Risk factor; Sudden cardiac death
The importance of clinical presentation and pre-transplantation course on outcome in children with dilated cardiomyopathy (DCM) listed for heart transplantation is not well defined.
Methods and Results
The impact of age, duration of illness, gender, race, ventricular geometry and the diagnosis of myocarditis on outcome in 261 DCM children enrolled in the Pediatric Cardiomyopathy Registry and Pediatric Heart Transplant Study was studied. Endpoints included: 1) listing as UNOS Status 1, 2) death while waiting and 3) death post-transplantation. The median age at the time of diagnosis was 3.4 years, and mean time from diagnosis to listing was 0.62±1.3 years. Risk factors associated with death while waiting were ventilator use and older age at listing in patients not mechanically ventilated (p=0.0006 and p=0.03, respectively). Shorter duration of illness (p=0.04) was associated with listing as UNOS Status 1. Death post-transplantation was associated with myocarditis at presentation (p=0.009), non-white race (p<0.0001) and a lower left ventricular end-diastolic dimension z-score at presentation (p=0.04). In the myocarditis group, 17% (4/23) died of acute rejection post-transplantation.
Mechanical ventilator use and older age at listing predicted death while waiting, while non-white race, smaller left ventricular dimension and myocarditis were associated with death post-transplantation. Although 97% of children with clinically or biopsy diagnosed myocarditis at presentation survived to transplantation, they had significantly higher mortality post-transplantation compared with children without myocarditis, raising the possibility that pre-existing viral infection or inflammation adversely affects graft survival.
dilated cardiomyopathy; heart transplantation; myocarditis; pediatrics
The left ventricular outflow tract (LVOT) defects aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart syndrome (HLHS) represent an embryologically related group of congenital cardiovascular malformations. They are common and cause substantial morbidity and mortality. Prior evidence suggests a strong genetic component in their causation.
We selected NRG1, ERBB3, and ERBB4 of the epidermal growth factor receptor (EGFR) signaling pathway as candidate genes for investigation of association with LVOT defects based on the importance of this pathway in cardiac development and the phenotypes in knockout mouse models. Single nucleotide polymorphism (SNP) genotyping was performed on 343 affected case-parent trios of European ancestry.
We identified a specific haplotype in intron 3 of ERBB4 that was positively associated with the combined LVOT defects phenotype (p = 0.0005) and in each anatomic defect AVS, COA, and HLHS separately. Mutation screening of individuals with an LVOT defect failed to identify a coding sequence or splice site change in ERBB4. RT-PCR on lymphoblastoid cells from LVOT subjects did not show altered splice variant ratios among those homozygous for the associated haplotype.
These results suggest ERBB4 is associated with LVOT defects. Further replication will be required in separate cohorts to confirm the consistency of the observed association.
genetics of cardiovascular disease; heart defects; congenital; congenital abnormalities; cardiovascular abnormalities; analysis; genetic association
AHA Scientific Statements; genetics
β-adrenergic stimulation is the main trigger for cardiac events in type-1 long QT syndrome (LQT1). We evaluated a possible association between ion channel response to β-adrenergic stimulation and clinical response to β-blocker therapy according to mutation location.
Methods and Results
The study sample comprised 860 patients with genetically-confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C-loops), membrane spanning domain, C/N-terminus, and non-missense mutations. There were 27 aborted cardiac arrest [ACA] and 78 sudden cardiac death [SCD] events from birth through age 40 years. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for ACA or SCD (hazard ratio [95% confidence interval] vs. non-missense mutations = 2.75 [1.29-5.86, P=0.009]). β-blocker therapy was associated with a significantly greater reduction in the risk of ACA or SCD among patients with C-loop mutations than among all other patients (hazard ratios = 0.12 [0.02-0.73, P=0.02] and 0.82 [0.31-2.13, P=0.68], respectively; P-for interaction = 0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to β-adrenergic stimulation.
Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high-risk for life-threatening events and derive a pronounced benefit from treatment with β-blockers. Reduced channel activation following sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.
beta-blockers; ion channels; long QT syndrome; mutation
Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families.
Methods and Results
Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 msec (interquartile-range: 402–442 msec). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) experienced ACA and none died suddenly during follow-up. Independent risk factors for syncope in genotype negative subjects included female gender (HR 1.60, p = 0.002), prolonged QTc (HR = 1.63 per 100 msec increment, p = 0.02), family history of ACA or SCD (HR = 1.89, p = 0.002), and LQT2 vs. LQT1 family mutation (HR = 1.41, p = 0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold (p = 0.001) increase in the risk of recurrent syncope in genotype negative subjects.
Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.
gene mutation; genetic polymorphisms; long-QT syndrome; sudden cardiac death arrhythmia; syncope
Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein–protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPNQ529X. Cardiac-restricted MYPNY20C Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein–protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.
Cardiomyopathy is a heterogeneous disease with a strong genetic component. A research-based pediatric cardiomyopathy registry (PCMR) identified familial, syndromic, or metabolic causes in 30% of children. However, these results pre-dated clinical genetic testing.
Methods and Results
We determined the prevalence of familial, syndromic, or metabolic causes in eighty-three consecutive unrelated patients referred for genetic evaluation of cardiomyopathy from 2006–2009. Seventy-six percent of probands (n=63) were categorized as familial, syndromic, or metabolic. Forty-three percent (n=18) of hypertrophic cardiomyopathy (HCM) patients had mutations in sarcomeric genes, with MYH7 and MYBPC3 mutations predominating. Syndromic (17%, n=7) and metabolic (26%, n=11) causes were frequently identified in HCM patients. The metabolic subgroup was differentiated by decreased endocardial shortening fraction on echocardiography. Dilated cardiomyopathy (DCM) patients had similar rates of syndromic (20%, n=5) and metabolic (16%, n=4) causes, but fewer familial cases (24%, n=6) than HCM patients.
The cause of cardiomyopathy is identifiable in a majority of affected children. An underlying metabolic or syndromic cause is identified in greater than 35% of children with HCM or DCM. Identification of etiology is important for management, family based risk assessment, and screening.
cardiomyopathy; heart failure; genetics; mutation; genetic testing
To establish the incidence of, and risk factors for, SCD in pediatric DCM.
The incidence of SCD in children with DCM is unknown. The ability to predict patients at high risk for SCD will help define who may benefit most from ICDs.
The cohort was 1803 children in the PCMR diagnosed with DCM from 1990-2009. Cumulative incidence competing-risks event rates were estimated. We achieved risk stratification using CART methodology.
Five-year incidence rates were 29% for heart transplant, 12.1% non-sudden cardiac death (non-SCD), 4.0% death from unknown cause, and 2.4% for SCD. Of 280 deaths, 35 were SCD and cause was unknown for 56. The 5-year rate for SCD incorporating a subset of the unknown deaths is 3%. Patients receiving anti-arrhythmic medication were at higher risk of SCD (hazard ratio 3.0, 95% CI 1.1-8.3, p =0.025). A risk stratification model based on most recent echocardiographic values had 86% sensitivity and 57% specificity. Thirty of 35 SCDs occurred in patients who met all of these criteria: LV end-systolic dimension z score > 2.6, age at diagnosis <14.3 years, and ratio of LVPWT:EDD <0.14. Sex, ethnicity, cause of DCM, and family history were not associated with SCD.
The 5-year incidence of SCD in children with DCM is 3%. A risk stratification rule (86% sensitivity) included diagnosis age < 14.3 years, LV dilation, and LV posterior wall thinning. Patients who consistently meet these criteria should be considered for ICD placement.
death, sudden; cardiomyopathy; pediatrics; heart failure
This study was designed to evaluate the clinical and prognostic aspects of long QT syndrome-related cardiac events that occur in the first year of life (infancy).
The clinical implications for patients with long QT syndrome who experience cardiac events in infancy have not been studied previously.
The study population of 3,323 patients with QTc ≥ 450 ms enrolled in the International LQTS Registry involved 20 patients with sudden cardiac death (SCD), 16 patients with aborted cardiac arrest (ACA), 34 patients with syncope, and 3,253 patients who were asymptomatic during the first year of life.
The risk factors for a cardiac event among 212 patients who had an ECG recorded in the first year of life included QTc≥500ms, heart rate ≤100bpm, and female sex. ACA before age 1 year was associated with a hazard ratio of 23.4 (p<0.01) for ACA or SCD during age 1-10 years. During the 10-year follow-up after infancy, beta-blocker therapy was associated with a significant reduction in ACA/SCD only in those with a syncopal episode within 2 years before ACA/SCD, but not for those who survived ACA in infancy.
Patients with LQTS who experience ACA during the first year of life are at very high-risk for subsequent ACA or death during their next 10 years of life, and beta-blockers may not be effective in preventing fatal or near fatal cardiac events in this small but high-risk subset.
Long QT Syndrome; Genetics; Infants; Risk Stratification
Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by recurrent infections of the upper and lower respiratory tract, reduced fertility in males and situs inversus in about 50% of affected individuals (Kartagener syndrome). It is caused by motility defects in the respiratory cilia that are responsible for airway clearance, the flagella that propel sperm cells and the nodal monocilia that determine left-right asymmetry1. Recessive mutations that cause PCD have been identified in genes encoding components of the outer dynein arms, radial spokes and cytoplasmic pre-assembly factors of axonemal dyneins, but these mutations account for only about 50% of cases of PCD. We exploited the unique properties of dog populations to positionally clone a new PCD gene, CCDC39. We found that loss-of-function mutations in the human ortholog underlie a substantial fraction of PCD cases with axonemal disorganization and abnormal ciliary beating. Functional analyses indicated that CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex.
Pediatric dilated cardiomyopathy (DCM) is the leading indication for heart transplantation after age 1 year. Risk factors by etiology at clinical presentation have not been determined separately for death and transplantation in population-based studies. Competing risks analysis may inform patient prioritization for transplantation listing.
Methods and Results
The Pediatric Cardiomyopathy Registry enrolled 1731 children diagnosed with DCM from 1990-2007. Etiologic, demographic and echocardiographic data collected at diagnosis were analyzed with competing risks methods stratified by DCM etiology to identify predictors of death and transplantation. For idiopathic DCM (n=1192), diagnosis after age 6, congestive heart failure (CHF), and lower left ventricular (LV) fractional shortening (FS) z-score were independently associated with both death and transplantation equally. In contrast, increased LV end-diastolic dimension (EDD) z-score was associated only with transplantation while lower height-for-age z-score was associated only with death. For neuromuscular disease (n=139), lower LVFS was associated equally with both endpoints, but increased LVEDD was associated only with transplantation. The risks of death and transplantation were increased equally for older age at diagnosis, CHF, and increased LVEDD among those with myocarditis (n=272) and for CHF and decreased LVFS among those with familial DCM (n=79).
Risk factors for death and transplantation in children varied by DCM etiology. For idiopathic DCM, increased LVEDD was associated with increased transplantation risk but not mortality. Conversely, short stature was significantly related to death but not transplantation. This may present an opportunity to improve the transplantation selection algorithm.
cardiomyopathy; pediatrics; cardiac transplantation; heart failure
The survival benefit of heart transplantation in adult heart failure is greatest for the sickest patients and negligible for patients not requiring inotropic or mechanical support. We hypothesized a similar survival benefit of heart transplantation for childhood cardiomyopathies with heart failure.
A merged dataset of children registered in both the Pediatric Cardiomyopathy Registry and the Pediatric Heart Transplant Study was used to assess differences in mortality before and after transplant in patients with different levels of heart failure severity. Severity was scored 2 if mechanical ventilatory or circulatory support was required, 1 if intravenous inotropes were required, or 0 if no support was required.
For 332 eligible children, 12-month mortality after listing was 9% for those with a severity score of 0 (n=105), 16% with a score of 1 (n=118), and 26% with a score of 2 (n=109; P=0.002) with a 3%, 8%, and 20% mortality with severity scores at listing of 0, 1, and 2, respectively, occurring before transplant. Patients listed with a score of 0 frequently deteriorated: 50% were transplanted or died prior to transplant with severity scores of 1 or 2. The risk of deterioration increased with previous surgery (relative risk, 3.84; P=0.03) in the short-term and with lower left ventricular mass z-score at time of presentation (relative risk, 1.74; P=0.003) in the longer-term.
Pediatric cardiomyopathy patients who require high levels of support receive a survival benefit from heart transplantation that is not shared by patients not requiring intravenous inotropic or mechanical support.
cardiomyopathy; pediatrics; heart transplantation
Women with congenital long-QT syndrome (LQTS) experience increased risk for cardiac events after the onset of adolescence, that is more pronounced among carriers of the LQT2 genotype. We hypothesized that the hormonal changes associated with menopause may affect clinical risk in this population.
Methods and Results
We used a repeated events analysis to evaluate the risk for recurrent syncope during the menopause-transition and post-menopausal periods (5-years before and after the age at onset of menopause, respectively) among 282 LQT1 (n=151) and LQT2 (n=131) women enrolled in the LQTS Registry. Multivariate analysis showed that the risk for recurrent syncope (n=150) among LQT2 women was significantly increased during both menopause-transition (HR = 3.38 [p = 0.005]) and the post-menopausal period (HR = 8.10 [p < 0.001]) as compared with the reproductive period. The risk increase was evident among women who did or did not receive estrogen therapy. In contrast, among LQT1 women the onset of menopause was associated with a reduction in the risk for recurrent syncope (HR = 0.19 [p = 0.05]; p-value for genotype-by-menopause interaction = 0.02). Only 22 women (8%) experienced aborted cardiac arrest (ACA) or sudden cardiac death (SCD) during follow-up. The frequency of ACA/SCD showed a similar genotype-specific association with the onset of menopause.
The onset of menopause is associated with a significant increase in the risk of cardiac events (dominated by recurrent episodes of syncope) in LQT2 women, suggesting that careful follow-up and continued long-term therapy are warranted in this population.
long-QT syndrome; women; estrogen; testosterone