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1.
Am J Cardiol ; 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32950468

RESUMO

Atrial fibrillation (AF) in hypertrophic cardiomyopathy (HC) is associated with significant symptomatic deterioration, heart failure, and thromboembolic disease. There is a need for better mechanistic insight and improved identification of at risk patients. We used cardiovascular magnetic resonance (CMR) to assess predictors of AF in HC, in particular the role of myocardial fibrosis. Consecutive patients with HC referred for CMR 2003 to 2013 were prospectively enrolled. CMR parameters including left ventricular volumes, presence and percentage of late gadolinium enhancement in the left ventricle (%LGE) and left atrial volume index (LAVi) were measured. Overall, 377 patients were recruited (age 62 ± 14 years, 73% men). Sixty-two patients (16%) developed new-onset AF during a median follow up of 4.5 (interquartile range 2.9 to 6.0) years. Multivariable analysis revealed %LGE (hazard ratio [HR] 1.3 per 10% (confidence interval: 1.0 to 1.5; p = 0.02), LAVi (HR 1.4 per 10 mL/m2[1.2 to 1.5; p < 0.001]), age at HC diagnosis, nonsustained ventricular tachycardia and diabetes to be independent predictors of AF. We constructed a simple risk prediction score for future AF based on the multivariable model with a Harrell's C-statistic of 0.73. In conclusion, the extent of ventricular fibrosis and LA volume independently predicted AF in patients with HC. This finding suggests a mechanistic relation between fibrosis and future AF in HC. CMR with quantification of fibrosis has incremental value over LV and LA measurements in risk stratification for AF. A risk prediction score may be used to identify patients at high risk of future AF who may benefit from more intensive rhythm monitoring and a lower threshold for oral anticoagulation.

2.
Nature ; 584(7822): 589-594, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32814899

RESUMO

The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development1,2. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization3,4. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.


Assuntos
Doenças Cardiovasculares/genética , Fractais , Predisposição Genética para Doença , Coração/anatomia & histologia , Coração/fisiologia , Miocárdio/metabolismo , Adulto , Idoso , Animais , Doenças Cardiovasculares/fisiopatologia , Citoesqueleto/genética , Citoesqueleto/fisiologia , Técnicas de Inativação de Genes , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Coração/embriologia , Hemodinâmica , Humanos , Pessoa de Meia-Idade , Miocárdio/citologia , Oryzias/embriologia , Oryzias/genética , Fenótipo
3.
J Am Coll Cardiol ; 75(10): 1196-1207, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32164893

RESUMO

Dilated cardiomyopathy (DCM) is a common condition, which carries significant mortality from sudden cardiac death and pump failure. Left ventricular ejection fraction has conventionally been used as a risk marker for sudden cardiac death, but has performed poorly in trials. There have been significant advances in the areas of cardiac magnetic resonance imaging and genetics, which are able to provide useful rick prediction in DCM. Biomarkers and cardiopulmonary exercise testing are well validated in the prediction of risk in heart failure; however, they have been tested less specifically in the DCM setting. This review will discuss these methods with a view toward multiparametric risk assessment in DCM with the hope of creating parametric risk models to predict sudden cardiac death and pump failure in the DCM population.

4.
Cardiol J ; 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32037503

RESUMO

BACKGROUND: Fractional flow reserve (FFR) assessment of remote arteries, in the context of a bystander chronic total occlusion (CTO), can lead to false positive results. Adenosine stress cardiovascular magnetic resonance (CMR) evaluates perfusion defects across the entire myocardium and may therefore be a reliable tool in the work-up of remote lesions in CTO patients. The IMPACT-CTO study investigated donor artery invasive physiology before, immediately post, and at 4 months following right coronary artery (RCA) CTO percutaneous coronary intervention (PCI). The aim of this subanalysis was to assess the concordance between baseline perfusion CMR and serial FFR evaluation of left anterior descending artery (LAD) ischemia in patients from the IMPACT-CTO study. METHODS: Baseline adenosine stress CMR examinations from 26 patients were analyzed for qualitative evidence of LAD ischemia. The results were correlated with the serial LAD FFR measurements. RESULTS: The present findings demonstrated that before RCA CTO PCI, there was 62% agreement between perfusion CMR and FFR (ischemic threshold £ 0.8) in the assessment of LAD ischemia (k = 0.29; fair concordance). At 4 months after revascularization, there was 77% agreement (k = 0.52; moderate concordance) between the index CMR assessment of LAD ischemia and the follow-up LAD FFR. Concordance was improved at a LAD FFR ischemic threshold of £ 0.75. CONCLUSIONS: In this hypothesis generating study, baseline CMR assessment of LAD ischemia correlated better with the 4 months LAD FFR data (threshold £ 0.8) as compared to the FFR measurements taken prior to RCA CTO revascularization.

6.
Eur J Heart Fail ; 22(7): 1160-1170, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32056322

RESUMO

AIMS: There is an important need for better biomarkers to predict left ventricular (LV) remodelling in dilated cardiomyopathy (DCM). We undertook a comprehensive assessment of cardiac structure and myocardial composition to determine predictors of remodelling. METHODS AND RESULTS: Prospective study of patients with recent-onset DCM with cardiovascular magnetic resonance (CMR) assessment of ventricular structure and function, extracellular volume (T1 mapping), myocardial strain, myocardial scar (late gadolinium enhancement) and contractile reserve (dobutamine stress). Regression analyses were used to evaluate predictors of change in LV ejection fraction (LVEF) over 12 months. We evaluated 56 participants (34 DCM patients, median LVEF 43%; 22 controls). Absolute LV contractile reserve predicted change in LVEF (1% increase associated with 0.4% increase in LVEF at 12 months, P = 0.02). Baseline myocardial strain (P = 0.39 global longitudinal strain), interstitial myocardial fibrosis (P = 0.41), replacement myocardial fibrosis (P = 0.25), and right ventricular contractile reserve (P = 0.17) were not associated with LV reverse remodelling. There was a poor correlation between contractile reserve and either LV extracellular volume fraction (r = -0.22, P = 0.23) or baseline LVEF (r = 0.07, P = 0.62). Men were more likely to experience adverse LV remodelling (P = 0.01) but age (P = 0.88) and disease-modifying heart failure medication (beta-blocker, P = 0.28; angiotensin-converting enzyme inhibitor, P = 0.92) did not predict follow-up LVEF. CONCLUSIONS: Substantial recovery of LV function occurs within 12 months in most patients with recent-onset DCM. Women had the greatest improvement in LVEF. A low LV contractile reserve measured by dobutamine stress CMR appears to identify patients whose LVEF is less likely to recover.

7.
Am Heart J ; 221: 165-176, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31955812

RESUMO

AIMS: Patients with non-ischemic systolic heart failure have an increased risk of sudden cardiac death (SCD). Myocardial fibrosis, detected as late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR), has been shown to predict all-cause mortality. We hypothesized that LGE can identify patients with non-ischemic heart failure who will benefit from ICD implantation. METHODS AND RESULTS: In this prospective observational sub-study of the Danish Study to Assess the Efficacy of ICDs in Patients with Nonischemic Systolic Heart Failure on Mortality (DANISH), 252 patients underwent CMR. LGE was quantified by the full width/half maximum method. The primary endpoint was all-cause mortality. LGE could be adequately assessed in 236 patients, median age was 61 years and median duration of heart failure was 14 months; there were 108 patients (46%) randomized to ICD. Median follow-up time was 5.3 years. Median left ventricular ejection fraction on CMR was 35%. In all, 50 patients died. LGE was present in 113 patients (48%). The presence of LGE was an independent predictor of all-cause mortality (HR 1.82; 95% CI 1.002-3.29; P = .049) after adjusting for known cardiovascular risk factors. ICD implantation did not impact all-cause mortality, for either patients with LGE (HR 1.18; 95% CI 0.59-2.38; P = .63), or for patients without LGE (HR 1.00; 95% CI 0.39-2.53; P = .99), (P for interaction =0.79). CONCLUSION: In patients with non-ischemic systolic heart failure, LGE predicted all-cause mortality. However, in this cohort, LGE did not identify a group of patients who survived longer by receiving an ICD.


Assuntos
Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis , Insuficiência Cardíaca Sistólica/terapia , Coração/diagnóstico por imagem , Miocárdio/patologia , Idoso , Dinamarca , Feminino , Fibrose , Humanos , Imagem por Ressonância Magnética , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mortalidade , Medição de Risco
8.
Circulation ; 141(5): 387-398, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31983221

RESUMO

BACKGROUND: Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 patients with DCM across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60 706 individuals to identify clinically interpretable genes robustly associated with dominant monogenic DCM. METHODS: We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 patients with DCM and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 patients with DCM sequenced in diagnostic laboratories and the Exome Aggregation Consortium database for replication and meta-analysis. RESULTS: Truncating variants in TTN and DSP were associated with DCM in all comparisons. Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM. Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult patients with DCM and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Although the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value because novel variants will be uninterpretable and their diagnostic yield is minimal. CONCLUSIONS: In the largest sequenced DCM cohort yet described, we observe robust disease association with 12 genes, highlighting their importance in DCM and translating into high interpretability in diagnostic testing. The other genes analyzed here will need to be rigorously evaluated in ongoing curation efforts to determine their validity as Mendelian DCM genes but have limited value in diagnostic testing in DCM at present. This data will contribute to community gene curation efforts and will reduce erroneous and inconclusive findings in diagnostic testing.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Cardiomiopatia Dilatada/genética , Predisposição Genética para Doença , Testes Genéticos , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Cardiomiopatia Dilatada/diagnóstico , Exoma/genética , Feminino , Heterogeneidade Genética , Humanos , Masculino , Adulto Jovem
9.
IEEE Trans Med Imaging ; 39(6): 2088-2099, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31944949

RESUMO

Quantification of anatomical shape changes currently relies on scalar global indexes which are largely insensitive to regional or asymmetric modifications. Accurate assessment of pathology-driven anatomical remodeling is a crucial step for the diagnosis and treatment of many conditions. Deep learning approaches have recently achieved wide success in the analysis of medical images, but they lack interpretability in the feature extraction and decision processes. In this work, we propose a new interpretable deep learning model for shape analysis. In particular, we exploit deep generative networks to model a population of anatomical segmentations through a hierarchy of conditional latent variables. At the highest level of this hierarchy, a two-dimensional latent space is simultaneously optimised to discriminate distinct clinical conditions, enabling the direct visualisation of the classification space. Moreover, the anatomical variability encoded by this discriminative latent space can be visualised in the segmentation space thanks to the generative properties of the model, making the classification task transparent. This approach yielded high accuracy in the categorisation of healthy and remodelled left ventricles when tested on unseen segmentations from our own multi-centre dataset as well as in an external validation set, and on hippocampi from healthy controls and patients with Alzheimer's disease when tested on ADNI data. More importantly, it enabled the visualisation in three-dimensions of both global and regional anatomical features which better discriminate between the conditions under exam. The proposed approach scales effectively to large populations, facilitating high-throughput analysis of normal anatomy and pathology in large-scale studies of volumetric imaging.

10.
JACC Cardiovasc Imaging ; 13(2 Pt 2): 559-561, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31864986
11.
Open Heart ; 6(2): e001115, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31673393

RESUMO

Objectives: Ultra-small superparamagnetic particles of iron oxide (USPIO)-enhanced MRI can detect cellular inflammation within tissues and may help non-invasively identify cardiac transplant rejection. Here, we aimed to determine the normal reference values for USPIO-enhanced MRI in patients with a prior cardiac transplant and examine whether USPIO-enhanced MRI could detect myocardial inflammation in patients with transplant rejection. Methods: Ten volunteers and 11 patients with cardiac transplant underwent T2, T2* and late gadolinium enhancement 1.5T MRI, with further T2* imaging at 24 hours after USPIO (ferumoxytol, 4 mg/kg) infusion, at baseline and 3 months. Results: Ten patients with clinically stable cardiac transplantation were retained for analysis. Myocardial T2 values were higher in patients with cardiac transplant versus healthy volunteers (53.8±5.2 vs 48.6±1.9 ms, respectively; p=0.003). There were no differences in the magnitude of USPIO-induced change in R2* in patients with transplantation (change in R2*, 26.6±7.3 vs 22.0±10.4 s-1 in healthy volunteers; p=0.28). After 3 months, patients with transplantation (n=5) had unaltered T2 values (52.7±2.8 vs 52.12±3.4 ms; p=0.80) and changes in R2* following USPIO (29.42±8.14 vs 25.8±7.8 s-1; p=0.43). Conclusion: Stable patients with cardiac transplantation have increased myocardial T2 values, consistent with resting myocardial oedema or fibrosis. In contrast, USPIO-enhanced MRI is normal and stable over time suggesting the absence of chronic macrophage-driven cellular inflammation. It remains to be determined whether USPIO-enhanced MRI may be able to identify acute cardiac transplant rejection. Trial registration number: NCT02319278349 (https://clinicaltrials.gov/ct2/show/NCT02319278) Registered 03.12.2014 EUDraCT 2013-002336-24.

12.
PLoS Comput Biol ; 15(10): e1007421, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658247

RESUMO

This paper presents a morphological analysis of fibrotic scarring in non-ischemic dilated cardiomyopathy, and its relationship to electrical instabilities which underlie reentrant arrhythmias. Two dimensional electrophysiological simulation models were constructed from a set of 699 late gadolinium enhanced cardiac magnetic resonance images originating from 157 patients. Areas of late gadolinium enhancement (LGE) in each image were assigned one of 10 possible microstructures, which modelled the details of fibrotic scarring an order of magnitude below the MRI scan resolution. A simulated programmed electrical stimulation protocol tested each model for the possibility of generating either a transmural block or a transmural reentry. The outcomes of the simulations were compared against morphological LGE features extracted from the images. Models which blocked or reentered, grouped by microstructure, were significantly different from one another in myocardial-LGE interface length, number of components and entropy, but not in relative area and transmurality. With an unknown microstructure, transmurality alone was the best predictor of block, whereas a combination of interface length, transmurality and number of components was the best predictor of reentry in linear discriminant analysis.


Assuntos
Arritmias Cardíacas/patologia , Cardiomiopatia Dilatada/fisiopatologia , Cicatriz/patologia , Arritmias Cardíacas/etiologia , Estudos de Coortes , Simulação por Computador , Humanos , Interpretação de Imagem Assistida por Computador , Modelos Lineares , Imagem por Ressonância Magnética/métodos , Modelos Teóricos , Infarto do Miocárdio/patologia , Isquemia Miocárdica/patologia , Miocárdio/patologia
13.
JACC Cardiovasc Imaging ; 12(11 Pt 2): 2357-2368, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31542527

RESUMO

Pathological left ventricular hypertrophy is a common feature of many cardiac diseases. It results from both myocyte hypertrophy and interstitial expansion. Interstitial expansion is most commonly secondary to the accumulation of mature cross-linked collagen fibers due to dysregulated metabolism, known as interstitial fibrosis. This occurs secondary to a variety of stimuli including ischemic, toxic, metabolic, infective, genetic, and hemodynamic factors. Less commonly, interstitial expansion may occur because of the accumulation of misfolded amyloid protein or interstitial edema. It is now well recognized that the presence and extent of interstitial disease are associated with adverse outcomes. There is therefore interest in the development of novel therapies that target the pathways that drive these disease processes. With the emergence of such therapies, it is becoming increasingly important to be able to characterize the type and extent of interstitial disease to enable the use of such targeted therapies in a personalized manner.

14.
Heart ; 105(23): 1818-1824, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31467152

RESUMO

OBJECTIVES: To investigate sex differences in left ventricular remodelling and outcome in patients undergoing surgical or transcatheter aortic valve replacement (SAVR/TAVR). METHODS: In this multicentre, observational, outcome study with imaging core-lab analysis, patients with severe aortic stenosis (AS) listed for intervention at one of six UK centres were prospectively recruited and underwent cardiovascular magnetic resonance imaging. The primary endpoint was all-cause mortality and secondary endpoint was cardiovascular mortality. RESULTS: 674 patients (425 men, 249 women, age 75±14 years) were included: 399 SAVR, 275 TAVR. Women were older, had higher surgical risk scores and underwent TAVR more frequently (53% vs 33.6%, p<0.001). More men had bicuspid aortic valves (BAVs) (26.7% vs 14.9%, p<0.001) and demonstrated more advanced remodelling than women. During a median follow-up of 3.6 years, 145 (21.5%) patients died, with no significant sex difference in all-cause mortality (23.3% vs 20.5%, p=0.114), but higher cardiovascular mortality in women (13.7% vs 8.5%, p=0.012). There were no significant sex-related differences in outcome in the SAVR or TAVR subgroups, or after excluding those with BAV. Factors independently associated with all-cause mortality were age, left ventricular ejection fraction (LVEF), BAV (better) and myocardial fibrosis detected with late gadolinium enhancement (LGE) in men, and age, LVEF and LGE in women. Age and LGE were independently associated with cardiovascular mortality in both sexes. CONCLUSIONS: Men demonstrate more advanced remodelling in response to a similar severity of AS. The higher cardiovascular mortality observed in women following AVR is accounted for by women having less BAV and higher risk scores resulting in more TAVR. LGE is associated with a worse prognosis in both sexes.

17.
Dis Model Mech ; 12(8)2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31324689

RESUMO

Hemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Epicutaneous treatment of mice with the Toll-like receptor 7 (TLR-7) agonist Resiquimod induces auto-antibodies and systemic tissue damage, including in the heart, and is used as an inducible mouse model of systemic lupus erythematosus (SLE). Here, we show that overactivation of the TLR-7 pathway of viral recognition by Resiquimod treatment of CFN mice induces severe thrombocytopenia and internal bleeding, which manifests most prominently as hemorrhagic myocarditis. We optimized a cardiac magnetic resonance (CMR) tissue mapping approach for the in vivo detection of diffuse infiltration, fibrosis and hemorrhages using a combination of T1, T2 and T2 * relaxation times, and compared results with ex vivo histopathology of cardiac sections corresponding to CMR tissue maps. This allowed detailed correlation between in vivo CMR parameters and ex vivo histopathology, and confirmed the need to include T2 * measurements to detect tissue iron for accurate interpretation of pathology associated with CMR parameter changes. In summary, we provide detailed histological and in vivo imaging-based characterization of acute hemorrhagic myocarditis as an acute cardiac complication in the mouse model of Resiquimod-induced SLE, and a refined CMR protocol to allow non-invasive longitudinal in vivo studies of heart involvement in acute inflammation. We propose that adding T2 * mapping to CMR protocols for myocarditis diagnosis improves diagnostic sensitivity and interpretation of disease mechanisms.This article has an associated First Person interview with the first author of the paper.


Assuntos
Hemorragia/diagnóstico por imagem , Imageamento por Ressonância Magnética Multiparamétrica , Miocardite/diagnóstico por imagem , Receptor 7 Toll-Like/agonistas , Animais , Feminino , Hemorragia/complicações , Hemorragia/patologia , Humanos , Imidazóis , Inflamação/complicações , Inflamação/patologia , Ferro/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miocardite/complicações , Miocardite/patologia , Trombocitopenia/complicações , Trombocitopenia/patologia
19.
JAMA Netw Open ; 2(6): e196520, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31251381

RESUMO

Importance: There is a need for better arrhythmic risk stratification in nonischemic dilated cardiomyopathy (DCM). Titin-truncating variants (TTNtvs) in the TTN gene are the most common genetic cause of DCM and may be associated with higher risk of arrhythmias in patients with DCM. Objective: To determine if TTNtv status is associated with the development of life-threatening ventricular arrhythmia and new persistent atrial fibrillation in patients with DCM and implanted cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) devices. Design, Setting, and Participants: This retrospective, multicenter cohort study recruited 148 patients with or without TTNtvs who had nonischemic DCM and ICD or CRT-D devices from secondary and tertiary cardiology clinics in the United Kingdom from February 1, 2011, to June 30, 2016, with a median (interquartile range) follow-up of 4.2 (2.1-6.5) years. Exclusion criteria were ischemic cardiomyopathy, primary valve disease, congenital heart disease, or a known or likely pathogenic variant in the lamin A/C gene. Analyses were performed February 1, 2017, to May 31, 2017. Main Outcome and Measures: The primary outcome was time to first device-treated ventricular tachycardia of more than 200 beats/min or first device-treated ventricular fibrillation. Secondary outcome measures included time to first development of persistent atrial fibrillation. Results: Of 148 patients recruited, 117 adult patients with nonischemic DCM and an ICD or CRT-D device (mean [SD] age, 56.9 [12.5] years; 76 [65.0%] men; 106 patients [90.6%] with primary prevention indications) were included. Having a TTNtv was associated with a higher risk of receiving appropriate ICD therapy (shock or antitachycardia pacing) for ventricular tachycardia or fibrillation (hazard ratio [HR], 4.9; 95% CI, 2.2-10.7; P < .001). This association was independent of all covariates, including midwall fibrosis measured by late gadolinium enhancement on cardiac magnetic resonance images (adjusted HR, 8.3; 95% CI, 1.8-37.6; P = .006). Having a TTNtv was also associated with the risk of receiving a shock (HR, 3.6; 95% CI, 1.1-11.6; P = .03). Individuals with a TTNtv and fibrosis had a greater rate of receiving appropriate device therapy than those with neither (HR, 16.6; 95% CI, 3.5-79.3; P < .001). Having a TTNtv was also a risk factor for developing new persistent atrial fibrillation (HR, 3.9; 95% CI, 1.3-12.0; P = .01). Conclusions and Relevance: Having a TTNtv was an important risk factor for clinically significant arrhythmia in patients with DCM and ICD or CRT-D devices. Having a TTNtv, especially in combination with midwall fibrosis confirmed with cardiovascular magnetic resonance imaging, may provide a risk stratification approach for evaluating the need for ICD therapy in patients with DCM. This hypothesis should be tested in larger studies.


Assuntos
Arritmias Cardíacas/genética , Cardiomiopatia Dilatada/genética , Conectina/genética , Adulto , Idoso , Arritmias Cardíacas/fisiopatologia , Cardiomiopatia Dilatada/fisiopatologia , Desfibriladores Implantáveis , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos
20.
Circulation ; 140(1): 31-41, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-30987448

RESUMO

BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. METHODS: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P<0.002, respectively). CONCLUSIONS: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.


Assuntos
Antineoplásicos/efeitos adversos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/genética , Variação Genética/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Adulto , Idoso , Animais , Cardiomiopatias/epidemiologia , Estudos de Coortes , Feminino , Variação Genética/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Estudos Prospectivos , Estudos Retrospectivos
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