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BACKGROUND: Artificial intelligence, particularly deep learning (DL), has immense potential to improve the interpretation of transthoracic echocardiography (TTE). Mitral regurgitation (MR) is the most common valvular heart disease and presents unique challenges for DL, including the integration of multiple video-level assessments into a final study-level classification. METHODS: A novel DL system was developed to intake complete TTEs, identify color MR Doppler videos, and determine MR severity on a 4-step ordinal scale (none/trace, mild, moderate, and severe) using the reading cardiologist as a reference standard. This DL system was tested in internal and external test sets with performance assessed by agreement with the reading cardiologist, weighted κ, and area under the receiver-operating characteristic curve for binary classification of both moderate or greater and severe MR. In addition to the primary 4-step model, a 6-step MR assessment model was studied with the addition of the intermediate MR classes of mild-moderate and moderate-severe with performance assessed by both exact agreement and ±1 step agreement with the clinical MR interpretation. RESULTS: A total of 61 689 TTEs were split into train (n=43 811), validation (n=8891), and internal test (n=8987) sets with an additional external test set of 8208 TTEs. The model had high performance in MR classification in internal (exact accuracy, 82%; κ=0.84; area under the receiver-operating characteristic curve, 0.98 for moderate/severe MR) and external test sets (exact accuracy, 79%; κ=0.80; area under the receiver-operating characteristic curve, 0.98 for moderate or greater MR). Most (63% internal and 66% external) misclassification disagreements were between none/trace and mild MR. MR classification accuracy was slightly higher using multiple TTE views (accuracy, 82%) than with only apical 4-chamber views (accuracy, 80%). In subset analyses, the model was accurate in the classification of both primary and secondary MR with slightly lower performance in cases of eccentric MR. In the analysis of the 6-step classification system, the exact accuracy was 80% and 76% with a ±1 step agreement of 99% and 98% in the internal and external test set, respectively. CONCLUSIONS: This end-to-end DL system can intake entire echocardiogram studies to accurately classify MR severity and may be useful in helping clinicians refine MR assessments.
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BACKGROUND AND AIMS: Early identification of cardiac structural abnormalities indicative of heart failure is crucial to improving patient outcomes. Chest X-rays (CXRs) are routinely conducted on a broad population of patients, presenting an opportunity to build scalable screening tools for structural abnormalities indicative of Stage B or worse heart failure with deep learning methods. In this study, a model was developed to identify severe left ventricular hypertrophy (SLVH) and dilated left ventricle (DLV) using CXRs. METHODS: A total of 71 589 unique CXRs from 24 689 different patients completed within 1 year of echocardiograms were identified. Labels for SLVH, DLV, and a composite label indicating the presence of either were extracted from echocardiograms. A deep learning model was developed and evaluated using area under the receiver operating characteristic curve (AUROC). Performance was additionally validated on 8003 CXRs from an external site and compared against visual assessment by 15 board-certified radiologists. RESULTS: The model yielded an AUROC of 0.79 (0.76-0.81) for SLVH, 0.80 (0.77-0.84) for DLV, and 0.80 (0.78-0.83) for the composite label, with similar performance on an external data set. The model outperformed all 15 individual radiologists for predicting the composite label and achieved a sensitivity of 71% vs. 66% against the consensus vote across all radiologists at a fixed specificity of 73%. CONCLUSIONS: Deep learning analysis of CXRs can accurately detect the presence of certain structural abnormalities and may be useful in early identification of patients with LV hypertrophy and dilation. As a resource to promote further innovation, 71 589 CXRs with adjoining echocardiographic labels have been made publicly available.
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Aprendizaje Profundo , Hipertrofia Ventricular Izquierda , Radiografía Torácica , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Radiografía Torácica/métodos , Femenino , Masculino , Persona de Mediana Edad , Ecocardiografía/métodos , Anciano , Insuficiencia Cardíaca/diagnóstico por imagen , Ventrículos Cardíacos/diagnóstico por imagen , Curva ROCRESUMEN
BACKGROUND: Aortic arch plaques are associated with an increased risk of ischemic stroke in patients with cryptogenic stroke or prior embolic events. However, this relationship is unclear in the community. We investigated (1) the long-term risk of stroke and cardiovascular events associated with arch plaques and (2) whether statin therapy prescribed for any indication modified the association. METHODS: A total of 934 stroke-free participants (72±9 years; 37% men) from the CABL study (Cardiovascular Abnormalities and Brain Lesion) were evaluated. Arch plaques were assessed by suprasternal transthoracic echocardiography; plaques ≥4 mm in thickness were classified as large plaques. The primary outcome was ischemic stroke; the secondary outcome was combined cardiovascular events (ischemic stroke, myocardial infarction, and cardiovascular death). The plaque-related risk of outcomes was also analyzed according to the presence of statin treatment. No plaque was used as a reference. RESULTS: Aortic arch plaques were present in 645 participants (69.1%), with large plaques in 114 (12.2%). During a mean follow-up of 11.3±3.6 years, 236 (25.3%) cardiovascular events occurred (76 ischemic strokes, 27 myocardial infarctions, and 133 cardiovascular deaths). Large arch plaques were independently associated with combined events (adjusted hazard ratio, 2.19 [95% CI, 1.40-3.43]) but not stroke alone (adjusted hazard ratio, 1.09 [95% CI, 0.50-2.38]). The association between large plaques and cardiovascular events was significant in participants receiving statins (adjusted hazard ratio, 2.57 [95% CI, 1.52-4.37]) but not in others; however, participants on statin treatment also had a worse risk profile (higher body mass index, greater frequencies of hypertension, diabetes, and coronary artery disease). CONCLUSIONS: Aortic arch plaques may be a marker of cardiovascular risk rather than a direct embolic stroke source in older adults without prior stroke. The efficacy of broader cardiovascular risk factors control, beyond cholesterol levels alone, for primary prevention of cardiovascular events in individuals with aortic arch plaques may require further investigation.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Accidente Cerebrovascular Isquémico , Infarto del Miocardio , Placa Aterosclerótica , Accidente Cerebrovascular , Masculino , Humanos , Anciano , Femenino , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Aorta Torácica/diagnóstico por imagen , Factores de Riesgo , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/etiología , Placa Aterosclerótica/complicaciones , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/tratamiento farmacológico , Infarto del Miocardio/epidemiología , Infarto del Miocardio/complicaciones , Accidente Cerebrovascular Isquémico/complicacionesRESUMEN
AIMS: The influence of social determinants of health (SDOH) on the prognosis of Heart Failure and reduced Ejection Fraction (HFrEF) is increasingly reported. We aim to evaluate the contribution of educational status on outcomes in patients with HFrEF. METHODS: We used data from the WARCEF trial, which randomized HFrEF patients with sinus rhythm to receive Warfarin or Aspirin; educational status of patients enrolled was collected at baseline. We defined three levels of education: low, medium and high level, according to the highest qualification achieved or highest school grade attended. We analysed the impact of the educational status on the risk of the primary composite outcome of all-cause death, ischemic stroke (IS) and intracerebral haemorrhage (ICH); components of the primary outcome were also analysed as secondary outcomes. RESULTS: 2295 patients were included in this analysis; of these, 992 (43.2%) had a low educational level, 947 (41.3%) had a medium education level and the remaining 356 (15.5%) showed a high educational level. Compared to patients with high educational level, those with low educational status showed a high risk of the primary composite outcome (adjusted hazard ratio [aHR]: 1.31, 95% confidence intervals [CI] 1.02-1.69); a non-statistically significant association was observed in those with medium educational level (aHR: 1.20, 95%CI: .93-1.55). Similar results were observed for all-cause death, while no statistically significant differences were observed for IS or ICH. CONCLUSION: Compared to patients with high educational levels, those with low educational status had worse prognosis. SDOH should be considered in patients with HFrEF. CLINICAL TRIAL REGISTRATION: NCT00041938.
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Insuficiencia Cardíaca , Accidente Cerebrovascular Isquémico , Humanos , Hemorragia Cerebral , Escolaridad , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/complicaciones , Pronóstico , Volumen Sistólico , WarfarinaRESUMEN
Mutations in LMNA encoding lamin A/C and EMD encoding emerin cause cardiomyopathy and muscular dystrophy. Lmna null mice develop these disorders and have a lifespan of 7-8 weeks. Emd null mice show no overt pathology and have normal skeletal muscle but with regeneration defects. We generated mice with germline deletions of both Lmna and Emd to determine the effects of combined loss of the encoded proteins. Mice without lamin A/C and emerin are born at the expected Mendelian ratio, are grossly normal at birth but have shorter lifespans than those lacking only lamin A/C. However, there are no major differences between these mice with regards to left ventricular function, heart ultrastructure or electrocardiographic parameters except for slower heart rates in the mice lacking both lamin A/C and emerin. Skeletal muscle is similarly affected in both of these mice. Lmna+/- mice also lacking emerin live to at least 1 year and have no significant differences in growth, heart or skeletal muscle compared to Lmna+/- mice. Deletion of the mouse gene encoding lamina-associated protein 1 leads to prenatal death; however, mice with heterozygous deletion of this gene lacking both lamin A/C and emerin are born at the expected Mendelian ratio but had a shorter lifespan than those only lacking lamin A/C and emerin. These results show that mice with combined deficiencies of three interacting nuclear envelope proteins have normal embryonic development and that early postnatal defects are primarily driven by loss of lamin A/C or lamina-associated polypeptide 1 rather than emerin.
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Proteínas Portadoras/genética , Corazón/fisiopatología , Lamina Tipo A/genética , Proteínas de la Membrana/genética , Músculo Esquelético/fisiopatología , Distrofia Muscular de Emery-Dreifuss/genética , Mutación , Proteínas Nucleares/genética , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Femenino , Haploinsuficiencia , Masculino , Ratones , Ratones Noqueados , Músculo Esquelético/metabolismo , Distrofia Muscular de Emery-Dreifuss/fisiopatología , Miocardio/metabolismo , Miocardio/patologíaRESUMEN
X-linked scapuloperoneal myopathy (X-SM), one of Four-and-a-half LIM 1 (FHL1) related diseases, is an adult-onset slowly progressive myopathy, often associated with cardiomyopathy. We previously generated a knock-in mouse model that has the same mutation (c.365 G > C, p.W122S) as human X-SM patients. The mutant male mouse developed late-onset slowly progressive myopathy without cardiomyopathy. In this study, we observed that heterozygous (Het) and homozygous (Homo) female mice did not show alterations of skeletal muscle function or histology. In contrast, 20-month-old mutant female mice showed signs of cardiomyopathy on echocardiograms with increased systolic diameter [wild-type (WT): 2.74 ± 0.22 mm, mean ± standard deviation (SD); Het: 3.13 ± 0.11 mm, P < 0.01; Homo: 3.08 ± 0.37 mm, P < 0.05) and lower fractional shortening (WT: 31.1 ± 4.4%, mean ± SD; Het: 22.7 ± 2.5%, P < 0.01; Homo: 22.4 ± 6.9%, P < 0.01]. Histological analysis of cardiac muscle revealed frequent extraordinarily large rectangular nuclei in mutant female mice that were also observed in human cardiac muscle from X-SM patients. Western blot demonstrated decreased Fhl1 protein levels in cardiac muscle, but not in skeletal muscle, of Homo mutant female mice. Proteomic analysis of cardiac muscle from 20-month-old Homo mutant female mice indicated abnormalities of the integrin signaling pathway (ISP) in association with cardiac dysfunction. The ISP dysregulation was further supported by altered levels of a subunit of the ISP downstream effectors Arpc1a in Fhl1 mutant mice and ARPC1A in X-SM patient muscles. This study reveals the first mouse model of FHL1-related cardiomyopathy and implicates ISP dysregulation in the pathogenesis of FHL1 myopathy.
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Actinas/metabolismo , Cardiomiopatías/genética , Integrinas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas con Dominio LIM/genética , Proteínas Musculares/genética , Animales , Composición Corporal , Peso Corporal , Cardiomiopatías/patología , Ecocardiografía , Femenino , Heterocigoto , Homocigoto , Masculino , Ratones , Músculo Esquelético/patología , Enfermedades Musculares/genética , Distrofia Muscular de Emery-Dreifuss/genética , Mutación Missense , Miocardio/patología , Fenotipo , Proteómica , Transducción de SeñalRESUMEN
BACKGROUND: Insulin resistance carries increased risk of heart failure, although the pathophysiological mechanisms remain unclear. LV global longitudinal strain (LVGLS) assessed by speckle-tracking echocardiography has emerged as an important tool to detect early LV systolic abnormalities. This study aimed to investigate the association between insulin resistance and subclinical left ventricular (LV) dysfunction in a sample of the general population without overt cardiac disease. METHODS: We investigated 539 participants who voluntarily underwent extensive cardiovascular health check including laboratory test and speckle-tracking echocardiography. Glycemic profiles were categorized into 3 groups according to homeostatic model assessment of insulin resistance (HOMA-IR): absence of insulin resistance (HOMA-IR < 1.5), presence of insulin resistance (HOMA-IR ≥ 1.5) and diabetes mellitus (DM). Multivariable logistic regression models were conducted to evaluate the association between abnormal glucose metabolism and impaired LVGLS (> - 16.65%). RESULTS: Forty-five (8.3%) participants had DM and 66 (12.2%) had abnormal HOMA-IR. LV mass index and E/e' ratio did not differ between participants with and without abnormal HOMA-IR, whereas abnormal HOMA-IR group had significantly decreased LVGLS (- 17.6 ± 2.6% vs. - 19.7 ± 3.1%, p < 0.05). The prevalence of impaired LVGLS was higher in abnormal HOMA-IR group compared with normal HOMA-IR group (42.4% vs. 14.0%) and similar to that of DM (48.9%). In multivariable analyses, glycemic abnormalities were significantly associated with impaired LVGLS, independent of traditional cardiovascular risk factors and pertinent laboratory and echocardiographic parameters [adjusted odds ratio (OR) 2.38, p = 0.007 for abnormal HOMA-IR; adjusted OR 3.02, p = 0.003 for DM]. The independent association persisted even after adjustment for waist circumference as a marker of abdominal adiposity. Sub-group analyses stratified by body mass index showed significant association between abnormal HOMA-IR and impaired LVGLS in normal weight individuals (adjusted OR 4.59, p = 0.001), but not in overweight/obese individuals (adjusted OR 1.62, p = 0.300). CONCLUSIONS: In the general population without overt cardiac disease, insulin resistance carries independent risk for subclinical LV dysfunction, especially in normal weight individuals.
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Diabetes Mellitus/epidemiología , Resistencia a la Insulina , Obesidad/epidemiología , Disfunción Ventricular Izquierda/epidemiología , Anciano , Enfermedades Asintomáticas , Biomarcadores/sangre , Glucemia/metabolismo , Estudios Transversales , Diabetes Mellitus/sangre , Diabetes Mellitus/diagnóstico , Ecocardiografía Doppler , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/diagnóstico , Prevalencia , Medición de Riesgo , Factores de Riesgo , Tokio/epidemiología , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Mitochondrial permeability transition pore (mPTP) closure triggers cardiomyocyte differentiation during development while pathological opening causes cell death during myocardial ischemia-reperfusion and heart failure. Ubiquinone modulates the mPTP; however, little is known about its mechanistic role in health and disease. We previously found excessive proton leak in newborn Fmr1 KO mouse forebrain caused by ubiquinone deficiency and increased open mPTP probability. Because of the physiological differences between the heart and brain during maturation, we hypothesized that developing Fmr1 KO cardiomyocyte mitochondria would demonstrate dissimilar features. METHODS: Newborn male Fmr1 KO mice and controls were assessed. Respiratory chain enzyme activity, ubiquinone content, proton leak, and oxygen consumption were measured in cardiomyocyte mitochondria. Cardiac function was evaluated via echocardiography. RESULTS: In contrast to controls, Fmr1 KO cardiomyocyte mitochondria demonstrated increased ubiquinone content and decreased proton leak. Leak was cyclosporine (CsA)-sensitive in controls and CsA-insensitive in Fmr1 KOs. There was no difference in absolute mitochondrial respiration or cardiac function between strains. CONCLUSION: These findings establish the newborn Fmr1 KO mouse as a novel model of excess ubiquinone and closed mPTP in the developing heart. Such a model may help provide insight into the biology of cardiac development and pathophysiology of neonatal heart failure. IMPACT: Ubiquinone is in excess and the mPTP is closed in the developing FXS heart. Strengthens evidence of open mPTP probability in the normally developing postnatal murine heart and provides new evidence for premature closure of the mPTP in Fmr1 mutants. Establishes a novel model of excess CoQ and a closed pore in the developing heart. Such a model will be a valuable tool used to better understand the role of ubiquinone and the mPTP in the neonatal heart in health and disease.
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Modelos Animales de Enfermedad , Corazón Fetal/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/metabolismo , Ratones Noqueados , Mitocondrias Cardíacas/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Ubiquinona/metabolismo , Animales , Atractilósido/análogos & derivados , Atractilósido/farmacología , Ciclosporina/farmacología , Transporte de Electrón , Síndrome del Cromosoma X Frágil/genética , Guanosina Difosfato/farmacología , Masculino , Ratones , Mitocondrias Cardíacas/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Consumo de Oxígeno , Fuerza Protón-Motriz , Método Simple Ciego , Ubiquinona/análogos & derivados , Ubiquinona/farmacologíaRESUMEN
BACKGROUND AND AIMS: Obesity increases the risk for atrial fibrillation (AF), although the impact of abdominal fat distribution on left atrial (LA) morphology and functional remodeling remains unclear. This study aimed to investigate whether increased abdominal adiposity is independently associated with impaired LA function and/or LA enlargement in a sample of the general population and to evaluate the role of adipokines in this association. METHODS AND RESULTS: The study cohort consisted of 527 participants (362 men; 57 ± 10 years) without overt cardiac disease who underwent laboratory testing, abdominal computed tomographic examination and echocardiography. Abdominal adiposity was quantitatively assessed as visceral fat area (VFA) and subcutaneous fat area (SFA) at the level of the umbilicus. Speckle-tracking echocardiography was performed to assess LA phasic function including reservoir, conduit and pump strain. LA reservoir and conduit strain decreased with increasing VFA quartiles (both p < 0.05), whereas no significant differences were observed in LA volume index and pump strain. When stratified by SFA, there were no significant differences in LA size and function across the quartiles. In multivariable analysis, VFA was significantly associated with LA conduit strain independent of cardiovascular risk factors, and pertinent laboratory and echocardiographic parameters (standardized ß = -0.136, p = 0.019). VFA was correlated with serum adiponectin level (r = -0.51, p < 0.001), but there was no association between adiponectin level and three LA phasic strains. CONCLUSION: In a sample of the general population, VFA accumulation was independently associated with worse LA conduit strain, which may be involved in the pathophysiological mechanism of obesity-related AF.
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Función del Atrio Izquierdo , Grasa Intraabdominal , Anciano , Función del Atrio Izquierdo/fisiología , Estudios de Cohortes , Femenino , Humanos , Grasa Intraabdominal/fisiopatología , Masculino , Persona de Mediana EdadRESUMEN
Mutations in the lamin A/C gene (LMNA) encoding the nuclear intermediate filament proteins lamins A and C cause a group of tissue-selective diseases, the most common of which is dilated cardiomyopathy (herein referred to as LMNA cardiomyopathy) with variable skeletal muscle involvement. We previously showed that cardiomyocyte-specific overexpression of dual specificity protein phosphatase 4 (DUSP4) is involved in the pathogenesis of LMNA cardiomyopathy. However, how mutations in LMNA activate Dusp4 expression and whether it is necessary for the development of LMNA cardiomyopathy are currently unknown. We now show that female LmnaH222P/H222P mice, a model for LMNA cardiomyopathy, have increased Dusp4 expression and hyperactivation of extracellular signal-regulated kinase (ERK) 1/2 with delayed kinetics relative to male mice, consistent with the sex-dependent delay in the onset and progression of disease. Mechanistically, we show that the H222P amino acid substitution in lamin A enhances its binding to ERK1/2 and increases sequestration at the nuclear envelope. Finally, we show that genetic deletion of Dusp4 has beneficial effects on heart function and prolongs survival in LmnaH222P/H222P mice. These results further establish Dusp4 as a key contributor to the pathogenesis of LMNA cardiomyopathy and a potential target for drug therapy.
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Cardiomiopatías/genética , Lamina Tipo A/genética , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteínas Tirosina Fosfatasas/genética , Sustitución de Aminoácidos/genética , Animales , Cardiomiopatías/fisiopatología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica , Humanos , Lamina Tipo A/economía , Sistema de Señalización de MAP Quinasas/genética , Masculino , Ratones , MutaciónRESUMEN
Myostatin (MSTN) is a transforming growth factor (TGF)-ß superfamily member that acts as a negative regulator of muscle growth and may play a role in cardiac remodeling. We hypothesized that inhibition of activin type II receptors (ACTRII) to reduce MSTN signaling would reduce pathological cardiac remodeling in experimental heart failure (HF). C57BL/6J mice underwent left anterior descending coronary artery ligation under anesthesia to induce myocardial infarction (MI) or no ligation (sham). MI and sham animals were each randomly divided into groups (n ≥ 10 mice/group) receiving an ACTRII or ACTRII/TGFß receptor-signaling inhibiting strategy: 1) myo-Fc group (weekly 10 mg/kg Myo-Fc) or 2) Fol + TGFi group (daily 12 µg/kg follistatin plus 2 mg/kg TGFß receptor inhibitor), versus controls. ACTRII/TGFBR signaling inhibition preserved cardiac function by echocardiography and prevented an increase in brain natriuretic peptide (BNP). ACTRII/TGFBR inhibition resulted in increased phosphorylation (P) of Akt and decreased P-p38 mitogen-activated protein kinase (MAPK) in MI mice. In vitro, Akt contributed to P-SMAD2,3, P-p38, and BNP regulation in cardiomyocytes. ACTRII/TGFBR inhibition increased sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) levels and decreased unfolded protein response (UPR) markers in MI mice. ACTRII/TGFBR inhibition was associated with a decrease in cardiac fibrosis and fibrosis markers, connective tissue growth factor (CTGF), type I collagen, fibronectin, α-smooth muscle actin, and matrix metalloproteinase (MMP)-12 in MI mice. MSTN exerted a direct regulation on the UPR marker eukaryotic translation initiation factor-2α (eIf2α) in cardiomyocytes. Our study suggests that ACTRII ligand inhibition has beneficial effects on cardiac signaling and fibrosis after ischemic HF.NEW & NOTEWORTHY Activin type II receptor ligand inhibition resulted in preserved cardiac function, a decrease in cardiac fibrosis, improved SERCA2a levels, and a prevention of the unfolded protein response in mice with myocardial infarction.
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Receptores de Activinas Tipo II/efectos de los fármacos , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/fisiopatología , Remodelación Ventricular/efectos de los fármacos , Animales , Ecocardiografía , Fibrosis , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Infarto del Miocardio/fisiopatología , Miocardio/patología , Miostatina/antagonistas & inhibidores , Miostatina/metabolismo , Péptido Natriurético Encefálico/metabolismo , Fosforilación , Resistencia Física , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is characterized by cardiac conduction abnormalities and left ventricular systolic dysfunction predisposing to heart failure. Previous cardiac transcriptional profiling of LmnaH222P/H222P mouse, a small animal model of LMNA cardiomyopathy, suggested decreased WNT/ß-catenin signalling. We confirmed decreased WNT/ß-catenin signalling in the hearts of these mice by demonstrating decreased ß-catenin and WNT proteins. This was correlated with increased expression of soluble Frizzled-related proteins that modulate the WNT/ß-catenin signalling pathway. Hearts of LmnaH222P/H222P mice also demonstrated lowered expression of the gap junction connexin 43. Activation of WNT/ß-catenin activity with 6-bromoindirubin-3'-oxime improved cardiac contractility and ameliorated intraventricular conduction defects in LmnaH222P/H222P mice, which was associated with increased expression of myocardial connexin 43. These results indicate that decreased WNT/ß-catenin contributes to the pathophysiology of LMNA cardiomyopathy and that drugs activating ß-catenin may be beneficial in affected individuals.
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Cardiomiopatía Dilatada/genética , Conexina 43/genética , Lamina Tipo A/genética , beta Catenina/genética , Animales , Cardiomiopatía Dilatada/tratamiento farmacológico , Cardiomiopatía Dilatada/fisiopatología , Conexina 43/biosíntesis , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Glicoproteínas/biosíntesis , Glicoproteínas/genética , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/fisiopatología , Humanos , Indoles/administración & dosificación , Péptidos y Proteínas de Señalización Intracelular , Ratones , Mutación , Oximas/administración & dosificación , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/fisiopatología , Proteínas Wnt/genética , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/biosíntesisRESUMEN
Homozygous mutations in the aromatic l-amino acid decarboxylase (AADC) gene result in a severe depletion of its namesake protein, triggering a debilitating and often fatal form of infantile Parkinsonism known as AADC deficiency. AADC deficient patients fail to produce normal levels of the monoamine neurotransmitters dopamine and serotonin, and suffer a multi-systemic disorder characterized by movement abnormalities, developmental delay and autonomic dysfunction; an absolute loss of dopamine is generally considered incompatible with life. There is no optimal treatment for AADC deficiency and few truly good models in which to investigate disease mechanisms or develop and refine therapeutic strategies. In this study, we introduced a relatively frequently reported but mildly pathogenic S250F missense mutation into the murine Aadc gene. We show that mutants homozygous for the mutation are viable and express a stable but minimally active form of the AADC protein. Although the low enzymatic activity of the protein resulted in only modestly reduced concentrations of brain dopamine, serotonin levels were markedly diminished, and this perturbed behavior as well as autonomic function in mutant mice. Still, we found no evidence of morphologic abnormalities of the dopaminergic cells in mutant brains. The striatum as well as substantia nigra appeared normal and no loss of dopamine expressing cells in the latter was detected. We conclude that even minute levels of active AADC are sufficient to allow for substantial amounts of dopamine to be produced in model mice harboring the S250F mutation. Such mutants represent a novel, mild model of human AADC deficiency.
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Errores Innatos del Metabolismo de los Aminoácidos/genética , Descarboxilasas de Aminoácido-L-Aromático/deficiencia , Mutación Missense , Errores Innatos del Metabolismo de los Aminoácidos/enzimología , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Animales , Descarboxilasas de Aminoácido-L-Aromático/genética , Descarboxilasas de Aminoácido-L-Aromático/metabolismo , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Femenino , Terapia Genética , Humanos , Levodopa/metabolismo , Masculino , Ratones , Neostriado/metabolismo , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Serotonina/metabolismo , Sustancia Negra/metabolismoRESUMEN
BACKGROUND: A high pulse pressure (PP) is associated with adverse cardiovascular (CV) outcomes; however, this relationship may be reversed in patients with heart failure with reduced ejection fraction (HFREF). METHODS: Patients from the WARCEF trial with left ventricular ejection fraction ≤35% were included. PP was divided into tertiles: ≤42, 42-54 and >54 mm Hg. Age and ejection fraction adjusted Kaplan-Meier curves were generated to evaluate the relationship between PP and outcomes [mortality, CV mortality, stroke and HF hospitalizations (HFH)]. Cox proportional hazards models were created incorporating PP as a continuous variable. The interaction of PP with New York Heart Association (NYHA) functional class was examined. Linear and restricted cubic splines were used to study nonlinear association between PP and outcomes. RESULTS: We included 2,299 patients with a mean(±SD) follow-up of 3.5 ± 1.8 years. The lowest tertile of PP (≤42 mm Hg) was associated with significantly higher CV mortality and HFH. Cox proportional hazards models showed a reduction in CV death and HFH with higher PP, with adjusted hazard ratios (HR) of 0.91 (P = 0.02) and 0.93 (P = 0.04) per 10 mm Hg increase in PP. This relationship was more pronounced in subjects with NYHA functional class III-IV. Spline analysis showed that the association between PP and CV mortality and HFH was only seen at PP values lower than 40 mm Hg. CONCLUSIONS: In patients with advanced HFREF, a low PP (<40 mm Hg) portends a worse prognosis, whereas a high PP (>50 mm Hg) predicts a relatively favourable prognosis.
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BACKGROUND AND PURPOSE: Although increased heart rate (HR) is a predictor of cardiovascular events and mortality, its possible association with subclinical cerebrovascular disease, which is prevalent in the elderly, has not been evaluated. This study aimed to investigate the association of daytime, nighttime, 24-hour HR, and HR variability with subclinical cerebrovascular disease in an elderly cohort without history of stroke. METHODS: The study cohort consisted of 680 participants (mean age, 73±7 years; 42% men) in sinus rhythm who underwent 24-hour ambulatory blood pressure and HR monitoring, 2-dimensional echocardiography, and brain magnetic resonance imaging as part of the CABL study (Cardiac Abnormalities and Brain Lesion). Subclinical cerebrovascular disease was defined as silent brain infarcts and white matter hyperintensity volume (WMHV). The relationship of HR measures with the presence of silent brain infarct and upper quartile of log WMHV (log WMHV4) was analyzed. RESULTS: Presence of silent brain infarct was detected in 93 participants (13.7%); mean log WMHV was -0.92±0.93 (median, -1.05; min, -5.88; max, 1.74). Multivariate analysis showed that only nighttime HR (adjusted odds ratio, 1.29 per 10 bpm; 95% confidence interval, 1.03-1.61; P=0.026) was significantly associated with log WMHV4, independent of traditional cardiovascular risk factors, ambulatory systolic blood pressure, and echocardiographic parameters. No similar association was observed for daytime HR and HR variability. There was no significant association between all HR measures and silent brain infarct. CONCLUSIONS: In a predominantly elderly cohort, elevated nighttime HR was associated with WMHV, suggesting an independent role of HR in subclinical cerebrovascular disease.
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Trastornos Cerebrovasculares/complicaciones , Frecuencia Cardíaca/fisiología , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Monitoreo Ambulatorio de la Presión Arterial/métodos , Infarto Encefálico/diagnóstico por imagen , Trastornos Cerebrovasculares/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/etiologíaRESUMEN
Cardiomyopathy caused by lamin A/C gene mutations (LMNA cardiomyopathy) is characterized by increased myocardial fibrosis, which impairs left ventricular relaxation and predisposes to heart failure, and cardiac conduction abnormalities. While we previously discovered abnormally elevated extracellular signal-regulated kinase 1/2 (ERK1/2) activities in heart in LMNA cardiomyopathy, its role on the development of myocardial fibrosis remains unclear. We now showed that transforming growth factor (TGF)-ß/Smad signaling participates in the activation of ERK1/2 signaling in LMNA cardiomyopathy. ERK1/2 acts on connective tissue growth factor (CTGF/CCN2) expression to mediate the myocardial fibrosis and left ventricular dysfunction. Studies in vivo demonstrate that inhibiting CTGF/CCN2 using a specific antibody decreases myocardial fibrosis and improves the left ventricular dysfunction. Together, these findings show that cardiac ERK1/2 activity is modulated in part by TGF-ß/Smad signaling, leading to altered activation of CTGF/CCN2 to mediate fibrosis and alter cardiac function. This identifies a novel mechanism in the development of LMNA cardiomyopathy.
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Cardiomiopatías/genética , Factor de Crecimiento del Tejido Conjuntivo/genética , Fibrosis/genética , Lamina Tipo A/genética , Factor de Crecimiento Transformador beta/genética , Animales , Cardiomiopatías/patología , Fibrosis/patología , Humanos , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Noqueados , Miocardio/metabolismo , Miocardio/patología , Proteínas Smad/genética , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/patologíaRESUMEN
Clinical and experimental studies have suggested that the duration of left ventricular assist device (LVAD) support may affect remodeling of the failing heart. We aimed to 1) characterize the changes in Ca2+/calmodulin-dependent protein kinase type-IIδ (CaMKIIδ), growth signaling, structural proteins, fibrosis, apoptosis, and gene expression before and after LVAD support and 2) assess whether the duration of support correlated with improvement or worsening of reverse remodeling. Left ventricular apex tissue and serum pairs were collected in patients with dilated cardiomyopathy ( n = 25, 23 men and 2 women) at LVAD implantation and after LVAD support at cardiac transplantation/LVAD explantation. Normal cardiac tissue was obtained from healthy hearts ( n = 4) and normal serum from age-matched control hearts ( n = 4). The duration of LVAD support ranged from 48 to 1,170 days (median duration: 270 days). LVAD support was associated with CaMKIIδ activation, increased nuclear myocyte enhancer factor 2, sustained histone deacetylase-4 phosphorylation, increased circulating and cardiac myostatin (MSTN) and MSTN signaling mediated by SMAD2, ongoing structural protein dysregulation and sustained fibrosis and apoptosis (all P < 0.05). Increased CaMKIIδ phosphorylation, nuclear myocyte enhancer factor 2, and cardiac MSTN significantly correlated with the duration of support. Phosphorylation of SMAD2 and apoptosis decreased with a shorter duration of LVAD support but increased with a longer duration of LVAD support. Further study is needed to define the optimal duration of LVAD support in patients with dilated cardiomyopathy. NEW & NOTEWORTHY A long duration of left ventricular assist device support may be detrimental for myocardial recovery, based on myocardial tissue experiments in patients with prolonged support showing significantly worsened activation of Ca2+/calmodulin-dependent protein kinase-IIδ, increased nuclear myocyte enhancer factor 2, increased myostatin and its signaling by SMAD2, and apoptosis as well as sustained histone deacetylase-4 phosphorylation, structural protein dysregulation, and fibrosis.
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Cardiomiopatía Dilatada/terapia , Insuficiencia Cardíaca/terapia , Ventrículos Cardíacos/metabolismo , Corazón Auxiliar , Miocardio/metabolismo , Función Ventricular Izquierda , Apoptosis , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Cardiomiopatía Dilatada/complicaciones , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/fisiopatología , Estudios de Casos y Controles , Femenino , Fibrosis , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/fisiopatología , Histona Desacetilasas/metabolismo , Humanos , Factores de Transcripción MEF2/metabolismo , Masculino , Persona de Mediana Edad , Miostatina/metabolismo , Fosforilación , Diseño de Prótesis , Recuperación de la Función , Proteínas Represoras/metabolismo , Transducción de Señal , Proteína Smad2/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Remodelación VentricularRESUMEN
A member of the four-and-a-half-LIM (FHL) domain protein family, FHL1, is highly expressed in human adult skeletal and cardiac muscle. Mutations in FHL1 have been associated with diverse X-linked muscle diseases: scapuloperoneal (SP) myopathy, reducing body myopathy, X-linked myopathy with postural muscle atrophy, rigid spine syndrome (RSS) and Emery-Dreifuss muscular dystrophy. In 2008, we identified a missense mutation in the second LIM domain of FHL1 (c.365 G>C, p.W122S) in a family with SP myopathy. We generated a knock-in mouse model harboring the c.365 G>C Fhl1 mutation and investigated the effects of this mutation at three time points (3-5 months, 7-10 months and 18-20 months) in hemizygous male and heterozygous female mice. Survival was comparable in mutant and wild-type animals. We observed decreased forelimb strength and exercise capacity in adult hemizygous male mice starting from 7 to 10 months of age. Western blot analysis showed absence of Fhl1 in muscle at later stages. Thus, adult hemizygous male, but not heterozygous female, mice showed a slowly progressive phenotype similar to human patients with late-onset muscle weakness. In contrast to SP myopathy patients with the FHL1 W122S mutation, mutant mice did not manifest cytoplasmic inclusions (reducing bodies) in muscle. Because muscle weakness was evident prior to loss of Fhl1 protein and without reducing bodies, our findings indicate that loss of function is responsible for the myopathy in the Fhl1 W122S knock-in mice.
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Miembro Anterior/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas con Dominio LIM/genética , Proteínas con Dominio LIM/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/patología , Distrofia Muscular de Emery-Dreifuss/patología , Miocardio/patología , Edad de Inicio , Animales , Modelos Animales de Enfermedad , Femenino , Técnicas de Sustitución del Gen , Hemicigoto , Heterocigoto , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Distrofia Muscular de Emery-Dreifuss/epidemiología , Distrofia Muscular de Emery-Dreifuss/genética , Distrofia Muscular de Emery-Dreifuss/metabolismo , Mutación MissenseRESUMEN
BACKGROUND: Although abnormal left ventricular geometric patterns have prognostic value for morbidity and mortality, their possible association with silent cerebrovascular disease has not been extensively evaluated. METHODS: We examined 665 participants in the CABL study who underwent transthoracic echocardiography and brain magnetic resonance imaging. Participants were divided into 4 geometric patterns: normal geometry (n=397), concentric remodeling (n=89), eccentric hypertrophy (n=126), and concentric hypertrophy (n=53). Subclinical cerebrovascular disease was defined as silent brain infarcts (SBIs) and white matter hyperintensity volume (WMHV; expressed as log-transformed percentage of the total cranial volume). RESULTS: Silent brain infarcts were observed in 94 participants (14%). Mean log-WMHV was -0.97±0.93. Concentric hypertrophy carried the greatest risk for both SBI (adjusted odds ratio [OR] 3.39, P<.001) and upper quartile of log-WMHV (adjusted OR 3.35, P<.001), followed by eccentric hypertrophy (adjusted ORs 2.52 [P=.001 for SBI] and 1.96 [P=.004] for log-WMHV). Concentric remodeling was not associated with subclinical brain disease. In subgroup analyses, concentric and eccentric hypertrophies were significantly associated with SBI and WMHV in both genders and nonobese participants, but differed for SBI by age (all ages for eccentric hypertrophy, only patients ≥70years for concentric hypertrophy) and by race-ethnicity (Hispanics for eccentric hypertrophy, blacks for concentric hypertrophy; no association in whites). CONCLUSIONS: Left ventricular hypertrophy, with both eccentric and concentric patterns, was significantly associated with subclinical cerebrovascular disease in a multiethnic stroke-free general population. Left ventricular geometric patterns may carry different risks for silent cerebrovascular disease in different sex, age, race-ethnic, and body size subgroups.
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Enfermedades Asintomáticas , Infarto Encefálico/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Leucoencefalopatías/diagnóstico por imagen , Remodelación Ventricular , Anciano , Anciano de 80 o más Años , Población Negra/estadística & datos numéricos , Infarto Encefálico/epidemiología , Trastornos Cerebrovasculares/diagnóstico por imagen , Trastornos Cerebrovasculares/epidemiología , Estudios de Cohortes , Diabetes Mellitus/epidemiología , Ecocardiografía , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/patología , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Hipertensión/epidemiología , Hipertrofia Ventricular Izquierda/epidemiología , Leucoencefalopatías/epidemiología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Ciudad de Nueva York/epidemiología , Oportunidad Relativa , Tamaño de los Órganos , Población Blanca/estadística & datos numéricosRESUMEN
BACKGROUND: Although high resting heart rate (RHR) is known to be associated with an increased risk of mortality and hospital admission in patients with heart failure, the relationship between RHR and ischemic stroke remains unclear. This study is aimed at investigating the relationship between RHR and ischemic stroke in patients with heart failure in sinus rhythm. METHODS: We examined 2,060 patients with systolic heart failure in sinus rhythm from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial. RHR was determined from baseline electrocardiogram, and was examined as both a continuous variable and a categorical variable using quartiles. Ischemic strokes were identified during follow-up and adjudicated by physician review. RESULTS: During 3.5 ± 1.8 years of follow-up, 77 patients (5.3% from Kaplan-Meier [KM] curve) experienced an ischemic stroke. The highest incidence of ischemic stroke (21/503 [KM 6.9%]) was observed in the lowest RHR quartile (RHR <64 beats/min) compared to other groups; 22/573 (KM 5.3%) in 64-70 beats/min, 13/465 (KM 3.5%) in 71-79 beats/min, and 21/519 (KM 5.4%) in RHR >79 beats/min (p = 0.693). Multivariable Cox proportional hazards analysis revealed that RHR was significantly associated with ischemic stroke (hazard ratio per unit decrease: 1.07, 95% CI 1.02-1.13, when RHR <64/beats/min; p = 0.038), along with a history of stroke or transient ischemic attack and left ventricular ejection fraction. CONCLUSIONS: In contrast to its beneficial effect on mortality and hospital re-admissions, lower RHR may increase the risk of ischemic stroke in patients with systolic heart failure in sinus rhythm.