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The existence of naturally occurring ribosome heterogeneity is now a well-acknowledged phenomenon. However, whether this heterogeneity leads to functionally diverse 'specialized ribosomes' is still a controversial topic. Here, we explore the biological function of RPL3L (uL3L), a ribosomal protein (RP) paralogue of RPL3 (uL3) that is exclusively expressed in skeletal muscle and heart tissues, by generating a viable homozygous Rpl3l knockout mouse strain. We identify a rescue mechanism in which, upon RPL3L depletion, RPL3 becomes up-regulated, yielding RPL3-containing ribosomes instead of RPL3L-containing ribosomes that are typically found in cardiomyocytes. Using both ribosome profiling (Ribo-seq) and a novel orthogonal approach consisting of ribosome pulldown coupled to nanopore sequencing (Nano-TRAP), we find that RPL3L modulates neither translational efficiency nor ribosome affinity towards a specific subset of transcripts. In contrast, we show that depletion of RPL3L leads to increased ribosome-mitochondria interactions in cardiomyocytes, which is accompanied by a significant increase in ATP levels, potentially as a result of fine-tuning of mitochondrial activity. Our results demonstrate that the existence of tissue-specific RP paralogues does not necessarily lead to enhanced translation of specific transcripts or modulation of translational output. Instead, we reveal a complex cellular scenario in which RPL3L modulates the expression of RPL3, which in turn affects ribosomal subcellular localization and, ultimately, mitochondrial activity.
Ribosomes are macromolecular machines responsible for protein synthesis in all living beings. Recent studies have shown that ribosomes can be heterogeneous in their structure, possibly leading to a specialized function. Here, we focus on RPL3L, a ribosomal protein expressed exclusively in striated muscles. We find that the deletion of the Rpl3l gene in a mouse model triggers a compensation mechanism, in which the missing RPL3L protein is replaced by its paralogue, RPL3. Furthermore, we find that RPL3-containing ribosomes establish closer interactions with mitochondria, cellular organelles responsible for energy production, leading to higher energy production when compared with RPL3L-containing ribosomes. Finally, we show that the RPL3RPL3L compensation mechanism is also triggered in heart disease conditions, such as hypertrophy and myocardial infarction.
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Coração , Mitocôndrias , Proteínas Ribossômicas , Ribossomos , Animais , Camundongos , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Biossíntese de Proteínas , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Ribossomos/genética , Ribossomos/metabolismoRESUMO
The transient receptor potential melastatin 4 (TRPM4) channel contributes extensively to cardiac electrical activity, especially cardiomyocyte action potential formation. Mechanical stretch can induce changes in heart rate and rhythm, and the mechanosensitive channel Piezo1 is expressed in many cell types within the myocardium. Our previous study showed that TRPM4 and Piezo1 are closely co-localized in the t-tubules of ventricular cardiomyocytes and contribute to the Ca2+ -dependent signalling cascade that underlies hypertrophy in response to mechanical pressure overload. However, there was no direct evidence showing that Piezo1 activation was related to TRPM4 activation in situ. In the present study, we employed the HL-1 mouse atrial myocyte-like cell line as an in vitro model to investigate whether Piezo1-TRPM4 coupling can affect action potential properties. We used the small molecule Piezo1 agonist, Yoda1, as a surrogate for mechanical stretch to activate Piezo1 and detected the action potential changes in HL-1 cells using FluoVolt, a fluorescent voltage sensitive dye. Our results demonstrate that Yoda1-induced activation of Piezo1 changes the action potential frequency in HL-1 cells. This change in action potential frequency is reduced by Piezo1 knockdown using small intefering RNA. Importantly knockdown or pharmacological inhibition of TRPM4 significantly affected the degree to which Yoda1-evoked Piezo1 activation influenced action potential frequency. Thus, the present study provides in vitro evidence of a functional coupling between Piezo1 and TRPM4 in a cardiomyocyte-like cell line. The coupling of a mechanosensitive Ca2+ permeable channel and a Ca2+ -activated TRP channel probably represents a ubiquitous model for the role of TRP channels in mechanosensory transduction. KEY POINTS: The transient receptor potential melastatin 4 (TRPM4) and Piezo1 channels have been confirmed to contribute to the Ca2+ -dependent signalling cascade that underlies cardiac hypertrophy in response to mechanical pressure overload. However, there was no direct evidence showing that Piezo1 activation was related to TRPM4 activation in situ. We employed the HL-1 mouse atrial myocyte-like cell line as an in vitro model to investigate the effect of Piezo1-TRPM4 coupling on cardiac electrical properties. The results show that both pharmacological and genetic inhibition of TRPM4 significantly affected the degree to which Piezo1 activation influenced action potential frequency in HL-1 cells. Our findings provide in vitro evidence of a functional coupling between Piezo1 and TRPM4 in a cardiomyocyte-like cell line. The coupling of a mechanosensitive Ca2+ permeable channel and a Ca2+ -activated TRP channel probably represents a ubiquitous model for the role of TRP channels in mechanosensory transduction in various (patho)physiological processes.
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Congenital heart disease (CHD) is the most common type of birth defect. In recent years, research has focussed on identifying the genetic causes of CHD. However, only a minority of CHD cases can be attributed to single gene mutations. In addition, studies have identified different environmental stressors that promote CHD, but the additive effect of genetic susceptibility and environmental factors is poorly understood. In this context, we have investigated the effects of short-term gestational hypoxia on mouse embryos genetically predisposed to heart defects. Exposure of mouse embryos heterozygous for Tbx1 or Fgfr1/Fgfr2 to hypoxia in utero increased the incidence and severity of heart defects while Nkx2-5+/- embryos died within 2 days of hypoxic exposure. We identified the molecular consequences of the interaction between Nkx2-5 and short-term gestational hypoxia, which suggest that reduced Nkx2-5 expression and a prolonged hypoxia-inducible factor 1α response together precipitate embryo death. Our study provides insight into the causes of embryo loss and variable penetrance of monogenic CHD, and raises the possibility that cases of foetal death and CHD in humans could be caused by similar gene-environment interactions.
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Interação Gene-Ambiente , Cardiopatias Congênitas/genética , Coração/embriologia , Proteína Homeobox Nkx-2.5/genética , Proteínas de Homeodomínio/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Animais , Apoptose , Proliferação de Células , Embrião de Mamíferos/metabolismo , Feminino , Predisposição Genética para Doença , Coração/diagnóstico por imagem , Heterozigoto , Proteína Homeobox Nkx-2.5/fisiologia , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oxigênio/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas com Domínio T/genética , Fatores de TempoRESUMO
Atrial septal aneurysms (ASAs) are often seen during routine cardiac imaging, though their clinical relevance has been poorly defined. The aneurysmal, and often mobile, inter-atrial septum is frequently associated with other clinically relevant structural cardiac abnormalities, particularly patent foramen ovale (PFO). Whilst ASAs have previously been considered an incidental finding, a well-endowed atrial septum provides more than visual interest, including insights into atrial function and intra-atrial pressures, and has important clinical implications in PFO-associated stroke, migraines, and arrhythmias. This review outlines diagnostic challenges when assessing ASAs using all imaging modalities and the clinical implications of this common anatomical variant.
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Septo Interatrial , Forame Oval Patente , Aneurisma Cardíaco , Acidente Vascular Cerebral , Septo Interatrial/diagnóstico por imagem , Forame Oval Patente/diagnóstico , Forame Oval Patente/diagnóstico por imagem , Aneurisma Cardíaco/diagnóstico por imagem , Humanos , Fatores de RiscoRESUMO
The 'fight or flight' response to physiological stress involves sympathetic nervous system activation, catecholamine release and adrenergic receptor stimulation. In the heart, this induces positive inotropy, previously attributed to the ß1-adrenergic receptor subtype. However, the role of the α1A-adrenergic receptor, which has been suggested to be protective in cardiac pathology, has not been investigated in the setting of physiological stress. To explore this, we developed a tamoxifen-inducible, cardiomyocyte-specific α1A-adrenergic receptor knock-down mouse model, challenged mice to four weeks of endurance swim training and assessed cardiac outcomes. With 4-OH tamoxifen treatment, expression of the α1A-adrenergic receptor was knocked down by 80-89%, without any compensatory changes in the expression of other adrenergic receptors, or changes to baseline cardiac structure and function. Swim training caused eccentric hypertrophy, regardless of genotype, demonstrated by an increase in heart weight/tibia length ratio (30% and 22% in vehicle- and tamoxifen-treated animals, respectively) and an increase in left ventricular end diastolic volume (30% and 24% in vehicle- and tamoxifen-treated animals, respectively) without any change in the wall thickness/chamber radius ratio. Consistent with physiological hypertrophy, there was no increase in fetal gene program (Myh7, Nppa, Nppb or Acta1) expression. In response to exercise-induced volume overload, stroke volume (39% and 30% in vehicle- and tamoxifen-treated animals, respectively), cardiac output/tibia length ratio (41% in vehicle-treated animals) and stroke work (61% and 33% in vehicle- and tamoxifen-treated animals, respectively) increased, regardless of genotype. These findings demonstrate that cardiomyocyte α1A-adrenergic receptors are not necessary for cardiac adaptation to endurance exercise stress and their acute ablation is not deleterious.
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Adaptação Fisiológica , Modelos Biológicos , Miócitos Cardíacos/metabolismo , Condicionamento Físico Animal , Receptores Adrenérgicos alfa 1/metabolismo , Estresse Fisiológico , Animais , Biomarcadores , Débito Cardíaco , Cardiomegalia/diagnóstico , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Ecocardiografia sob Estresse , Genótipo , Hemodinâmica , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Modelos Animais , Contração Miocárdica , Receptores Adrenérgicos alfa 1/genéticaRESUMO
Multiple mouse lines lacking the orphan G protein-coupled receptor, GPR37L1, have elicited disparate cardiovascular phenotypes. The first Gpr37l1 knockout mice study to be published reported a marked elevation in systolic blood pressure (SBP; â¼60 mmHg), revealing a potential therapeutic opportunity. The phenotype differed from our own independently generated knockout line, where male mice exhibited equivalent baseline blood pressure to wild type. Here, we attempted to reproduce the first study by characterizing the cardiovascular phenotype of both the original knockout and transgenic lines alongside a C57BL/6J control line, using the same method of blood pressure measurement. The present study supports the findings from our independently developed Gpr37l1 knockout line, finding that SBP and diastolic blood pressure (DBP) are not different in the original Gpr37l1 knockout male mice (SBP: 130.9 ± 5.3 mmHg; DBP: 90.7 ± 3.0 mmHg) compared with C57BL/6J mice (SBP: 123.1 ± 4.1 mmHg; DBP: 87.0 ± 2.7 mmHg). Instead, we attribute the apparent hypertension of the knockout line originally described to comparison with a seemingly hypotensive transgenic line (SBP 103.7 ± 5.0 mmHg; DBP 71.9 ± 3.7 mmHg). Additionally, we quantified myocardial GPR37L1 transcript in humans, which was suggested to be downregulated in cardiovascular disease. We found that GPR37L1 has very low native transcript levels in human myocardium and that expression is not different in tissue samples from patients with heart failure compared with sex-matched healthy control tissue. These findings indicate that cardiac GPR37L1 expression is unlikely to contribute to the pathophysiology of human heart failure.NEW & NOTEWORTHY This study characterizes systolic blood pressure (SBP) in a Gpr37l1 knockout mouse line, which was previously reported to have â¼60 mmHg higher SBP compared with a transgenic line. We observed only a â¼27 mmHg SBP difference between the lines. However, when compared with C57BL/6J mice, knockout mice showed no difference in SBP. We also investigated GPR37L1 mRNA abundance in human hearts and observed no difference between healthy and failing heart samples.
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Pressão Sanguínea , Insuficiência Cardíaca/metabolismo , Hipertensão/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adulto , Animais , Estudos de Casos e Controles , Feminino , Genótipo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Fenótipo , Receptores Acoplados a Proteínas G/genética , Especificidade da EspécieRESUMO
Echocardiography is an invaluable tool for characterizing cardiac structure and function in vivo. Technological advances in high-frequency ultrasound over the past 3 decades have increased spatial and temporal resolution, and facilitated many important clinical and basic science discoveries. Successful reverse translation of established echocardiographic techniques, including M-mode, B-mode, color Doppler, pulsed-wave Doppler, tissue Doppler and, most recently, myocardial deformation imaging, from clinical cardiology into the basic science laboratory has enabled researchers to achieve a deeper understanding of myocardial phenotypes in health and disease. With high-frequency echocardiography, detailed evaluation of ventricular systolic function in a range of small animal models is now possible. Furthermore, improvements in frame rate and the advent of diastolic strain rate imaging, when coupled with the use of select pulsed-wave Doppler parameters, such as isovolumic relaxation time and E wave deceleration, have enabled nuanced interpretation of ventricular diastolic function. Comparing pulsed-wave Doppler indices of atrioventricular inflow during early and late diastole with parameters that describe the simultaneous myocardial deformation (e.g., tissue Doppler é and á, global longitudinal strain rate and global longitudinal velocity) may yield additional insights related to myocardial compliance. This review will provide a historical perspective of the development of high-frequency echocardiography and consider how ongoing innovation will help future-proof this important imaging modality for 21st century translational research.
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Ecocardiografia/tendências , Animais , Diagnóstico por Imagem/métodos , Ecocardiografia/instrumentação , Ecocardiografia/métodos , Ecocardiografia Doppler de Pulso , Coração/diagnóstico por imagem , Humanos , Camundongos , Pesquisa/instrumentação , Pesquisa/tendências , Peixe-ZebraRESUMO
We present a case of a complex congenital coronary artery fistula between the right coronary artery, left anterior descending artery, and the main pulmonary artery complicated by massive aneurysms and a left-to-right shunt. We highlight the multimodality approach to assessment and the importance of individualized management of complex coronary fistulas.
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Contemporary echocardiographic criteria for grading aortic stenosis severity have remained relatively unchanged, despite significant advances in noninvasive imaging techniques over the last 2 decades. More recently, attention has shifted to the ventricular response to aortic stenosis and how this might be quantified. Global longitudinal strain, semiautomatically calculated from standard two-dimensional echocardiographic images, has been the focus of extensive research. Global longitudinal strain is a sensitive marker of subtle hypertrophy-related impairment in left ventricular function and has shown promise as a relatively robust prognostic marker, both independently and when added to severity classification systems. Herein we review the pathophysiological basis underpinning the potential utility of global longitudinal strain in the assessment of aortic stenosis, as well as its potential role in quantifying myocardial recovery and prognostic discrimination following aortic valve replacement.
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Estenose da Valva Aórtica , Humanos , Estenose da Valva Aórtica/diagnóstico por imagem , Função Ventricular Esquerda/fisiologia , Ecocardiografia/métodos , Valva Aórtica/diagnóstico por imagem , Prognóstico , Índice de Gravidade de DoençaRESUMO
Aims: The morphology and function of the left atrium (LA) are intimately tied to left ventricular loading conditions. Data pertaining to the effect of transcatheter aortic valve replacement (TAVR) on LA function and geometry are scarce. The aim of the study was to quantify associations between TAVR and LA remodelling by pooling available data from published observational studies. Methods and results: A systematic review and meta-analysis were performed. Studies reporting serial LA speckle-tracking echocardiographic (STE) data, before and after TAVR, were included. Other outcome data included LA area and indexed volume (LAVi) and standard chamber measurements. Outcomes were stratified by timing of follow-up echocardiography: early (<6 months) or late (≥6 months). Twelve studies were included, comprising 1066 patients. The mean reduction in LAVi was 2.72â mL/m2 [95% confidence interval (CI) 1.37-4.06, P < 0.01]. LA reservoir function improved overall by a mean difference (MD) of 3.71% (95% CI 1.82-5.6, P < 0.01), although there was significant heterogeneity within the pooled studies (I 2 = 87.3%). Significant improvement in reservoir strain was seen in both early follow-up (MD 3.1%, P < 0.01) and late follow-up studies (MD 4.48%, P = 0.03), but heterogeneity remained high (I 2 = 65.23 and 94.4%, respectively). Six studies reported a change in LA contractile function, which recovered in the early follow-up studies (MD 2.26, P < 0.01), but not in the late group (MD 1.41, P = 0.05). Pooled improvement in LA booster function was 1.96% (95% CI 1.11-2.8, P < 0.01). Conclusion: TAVR is associated with significant negative LA remodelling, and an improvement in LA mechanics, quantified by STE. The prognostic implications of these findings require further study.
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Purpose To assess the correlation between noninvasive cardiac MRI-derived parameters with pressure-volume (PV) loop data and evaluate changes in left ventricular function after myocardial infarction (MI). Materials and Methods Sixteen adult female swine were induced with MI, with six swine used as controls and 10 receiving platelet-derived growth factor-AB (PDGF-AB). Load-independent measures of cardiac function, including slopes of end-systolic pressure-volume relationship (ESPVR) and preload recruitable stroke work (PRSW), were obtained on day 28 after MI. Cardiac MRI was performed on day 2 and day 28 after infarct. Global longitudinal strain (GLS) and global circumferential strain (GCS) were measured. Ventriculo-arterial coupling (VAC) was derived from PV loop and cardiac MRI data. Pearson correlation analysis was performed. Results GCS (r = 0.60, P = .01), left ventricular ejection fraction (LVEF) (r = 0.60, P = .01), and cardiac MRI-derived VAC (r = 0.61, P = .01) had a significant linear relationship with ESPVR. GCS (r = 0.75, P < .001) had the strongest significant linear relationship with PRSW, followed by LVEF (r = 0.67, P = .005) and cardiac MRI-derived VAC (r = 0.60, P = .01). GLS was not significantly correlated with ESPVR or PRSW. There was a linear correlation (r = 0.82, P < .001) between VAC derived from cardiac MRI and from PV loop data. GCS (-3.5% ± 2.3 vs 0.5% ± 1.4, P = .007) and cardiac MRI-derived VAC (-0.6 ± 0.6 vs 0.3 ± 0.3, P = .001) significantly improved in the animals treated with PDGF-AB 28 days after MI compared with controls. Conclusion Cardiac MRI-derived parameters of MI correlated with invasive PV measures, with GCS showing the strongest correlation. Cardiac MRI-derived measures also demonstrated utility in assessing therapeutic benefit using PDGF-AB. Keywords: Cardiac MRI, Myocardial Infarction, Pressure Volume Loop, Strain Imaging, Ventriculo-arterial Coupling Supplemental material is available for this article. © RSNA, 2024.
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Modelos Animais de Doenças , Infarto do Miocárdio , Animais , Feminino , Suínos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Função Ventricular Esquerda/fisiologia , Volume Sistólico/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética/métodosRESUMO
BACKGROUND: Aggressive dose reduction strategies for cardiac CT require the prospective selection of limited cardiac phases. At lower heart rates, the period of mid-diastole is typically selected for image acquisition. We aimed to identify the effect of heart rate on the optimal CT acquisition phase within the period of mid-diastole. METHODS: We utilized high temporal resolution tissue Doppler to precisely measure coronary motion within diastole. Tissue-Doppler waveforms of the myocardium corresponding to the location of the circumflex artery (100 patients) and mid-right coronary arteries (50 patients) and the duration and timing of coronary motion were measured. Using regression analysis an equation was derived for the timing of the period of minimal coronary motion within the RR interval. In a validation set of 50 clinical cardiac CT examinations, we assessed coronary motion artifact and the effect of using a mid-diastolic imaging target that was adjusted according to heart rate vs a fixed 75% phase target. RESULTS: Tissue Doppler analysis shows the period of minimal cardiac motion suitable for CT imaging decreases almost linearly as the RR interval decreases, becoming extinguished at an average heart rate of 91 bpm for the circumflex (LCX) and 78 bpm for the right coronary artery (RCA). The optimal imaging phase has a strong linear relationship with RR duration (R2 = 0.92 LCX, 0.89 RCA). The optimal phase predicted by regression analysis of the tissue-Doppler waveforms increases from 74% at a heart rate of 55 bpm to 77% at 75 bpm. In the clinical CT validation set, the optimal CT acquisition phase similarly occurred later with increasing heart rate. When the selected cardiac phase was adjusted according to heart rate the result was closer to the optimal phase than using a fixed 75% phase. While this effect was statistically significant (p < 0.01 RCA/LCx), the mean effect of heart-rate adjustment was minor relative to typical beat-to-beat variability and available precision of clinical phase selection. CONCLUSION: High temporal resolution imaging of coronary motion can be used to predict the optimal acquisition phase in cardiac CT. The optimal phase for cardiac CT imaging within mid-diastole increases with increasing heart rate although the magnitude of change is small.
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Técnicas de Imagem de Sincronização Cardíaca/métodos , Angiografia Coronária/métodos , Vasos Coronários/fisiologia , Ecocardiografia/métodos , Técnicas de Imagem por Elasticidade/métodos , Frequência Cardíaca/fisiologia , Tomografia Computadorizada por Raios X/métodos , Diástole , Feminino , Humanos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Movimento , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Double inter-atrial septum is an exceedingly rare congenital cardiac abnormality. We describe a case of transient ischaemic attack in a 53 year-old female found to have double inter-atrial septa on transthoracic and transoesophageal echocardiography. The midline inter-atrial chamber enclosed by the two septa was found to be continuous with the left atrium, with stasis in this accessory chamber predisposing to thrombus formation and cardio-embolic events. The case highlights the importance of transoesophageal echocardiography in the investigation of stroke, particularly in younger individuals.
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Ecocardiografia Transesofagiana , Comunicação Interatrial , Embolia Intracraniana , Acidente Vascular Cerebral , Ecocardiografia , Feminino , Comunicação Interatrial/complicações , Comunicação Interatrial/diagnóstico por imagem , Humanos , Embolia Intracraniana/diagnóstico por imagem , Embolia Intracraniana/etiologia , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologiaAssuntos
Doença da Artéria Coronariana/tratamento farmacológico , Vasos Coronários/diagnóstico por imagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Placa Aterosclerótica/tratamento farmacológico , Remodelação Vascular/efeitos dos fármacos , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Vasos Coronários/fisiopatologia , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Placa Aterosclerótica/diagnóstico , Resultado do Tratamento , Ultrassonografia de IntervençãoRESUMO
BACKGROUND: A high coronary calcium burden may adversely affect image quality of CT coronary angiography (CTCA). The ability to rule out clinically significant disease in this setting is uncertain. METHODS: We examined CTCA findings in patients with a calcium score of >600. Utilising a search of death notices, structured patient interview and medical records, downstream investigations, cardiovascular events, revascularisation and mortality were recorded. RESULTS: Sixty patients with a calcium score >600 had CTCA performed on the same day. Coronary disease findings were: mild 28%, moderate 33%, severe 32% and non-diagnostic 7%. During a median 1.75-year follow-up, 31 (53%) of patients underwent further assessment for coronary disease, eight patients (13%) underwent revascularisation and there were two non-cardiovascular and one cardiovascular deaths. No patient with mild or moderate disease at CTCA had subsequently demonstrated ischaemia, was deemed to require PCI or suffered cardiac mortality. The negative predictive value of CTCA for subsequent PCI and all-cause mortality was 97% (100% for cardiac mortality only). The positive predictive value of CTCA for revascularisation or CV death was 42%. CONCLUSION: In patients with an elevated coronary calcium score, a negative CTCA implies an excellent short-term outcome and appears to exclude clinically significant coronary disease.
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Cálcio/metabolismo , Angiografia Coronária , Doença da Artéria Coronariana , Miocárdio/metabolismo , Tomografia Computadorizada por Raios X , Idoso , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Background: Moderate severity aortic stenosis (AS) is poorly understood, is associated with subclinical myocardial dysfunction, and can lead to adverse outcome rates that are comparable to severe AS. Factors associated with progressive myocardial dysfunction in moderate AS are not well described. Artificial neural networks (ANNs) can identify patterns, inform clinical risk, and identify features of importance in clinical datasets. Methods: We conducted ANN analyses on longitudinal echocardiographic data collected from 66 individuals with moderate AS who underwent serial echocardiography at our institution. Image phenotyping involved left ventricular global longitudinal strain (GLS) and valve stenosis severity (including energetics) analysis. ANNs were constructed using two multilayer perceptron models. The first model was developed to predict change in GLS from baseline echocardiography alone and the second to predict change in GLS using data from baseline and serial echocardiography. ANNs used a single hidden layer architecture and a 70%:30% training/testing split. Results: Over a median follow-up interval of 1.3 years, change in GLS (≤ or >median change) could be predicted with accuracy rates of 95% in training and 93% in testing using ANN with inputs from baseline echocardiogram data alone (AUC: 0.997). The four most important predictive baseline features (reported as normalized % importance relative to most important feature) were peak gradient (100%), energy loss (93%), GLS (80%), and DI < 0.25 (50%). When a further model was run including inputs from both baseline and serial echocardiography (AUC 0.844), the top four features of importance were change in dimensionless index between index and follow-up studies (100%), baseline peak gradient (79%), baseline energy loss (72%), and baseline GLS (63%). Conclusions: Artificial neural networks can predict progressive subclinical myocardial dysfunction with high accuracy in moderate AS and identify features of importance. Key features associated with classifying progression in subclinical myocardial dysfunction included peak gradient, dimensionless index, GLS, and hydraulic load (energy loss), suggesting that these features should be closely evaluated and monitored in AS.
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Congenital heart defects (CHD) are collectively the most common form of congenital malformation. Studies of human cases and animal models have revealed that mutations in several genes are responsible for both familial and sporadic forms of CHD. We have previously shown that a mutation in MYH6 can cause an autosomal dominant form of atrial septal defect (ASD), whereas others have identified mutations of the same gene in patients with hypertrophic and dilated cardiomyopathy. In the present study, we report a mutation analysis of MYH6 in patients with a wide spectrum of sporadic CHD. The mutation analysis of MYH6 was performed in DNA samples from 470 cases of isolated CHD using denaturing high-performance liquid chromatography and sequence analysis to detect point mutations and small deletions or insertions, and multiplex amplifiable probe hybridization to detect partial or complete copy number variations. One non-sense mutation, one splicing site mutation and seven non-synonymous coding mutations were identified. Transfection of plasmids encoding mutant and non-mutant green fluorescent protein-MYH6 fusion proteins in mouse myoblasts revealed that the mutations A230P and A1366D significantly disrupt myofibril formation, whereas the H252Q mutation significantly enhances myofibril assembly in comparison with the non-mutant protein. Our data indicate that functional variants of MYH6 are associated with cardiac malformations in addition to ASD and provide a novel potential mechanism. Such phenotypic heterogeneity has been observed in other genes mutated in CHD.
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Miosinas Cardíacas/genética , Cardiopatias Congênitas/genética , Comunicação Interatrial/genética , Miofibrilas/metabolismo , Cadeias Pesadas de Miosina/genética , Animais , Miosinas Cardíacas/metabolismo , Cardiomiopatia Dilatada/genética , Cromatografia Líquida de Alta Pressão , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Estudos de Associação Genética , Humanos , Camundongos , Mutação , Mioblastos/citologia , Miofibrilas/genética , Cadeias Pesadas de Miosina/metabolismo , Plasmídeos , TransfecçãoRESUMO
RATIONALE: The cardiac gene regulatory network (GRN) is controlled by transcription factors and signaling inputs, but network logic in development and it unraveling in disease is poorly understood. In development, the membrane-tethered signaling ligand Neuregulin (Nrg)1, expressed in endocardium, is essential for ventricular morphogenesis. In adults, Nrg1 protects against heart failure and can induce cardiomyocytes to divide. OBJECTIVE: To understand the role of Nrg1 in heart development through analysis of null and hypomorphic Nrg1 mutant mice. METHODS AND RESULTS: Chamber domains were correctly specified in Nrg1 mutants, although chamber-restricted genes Hand1 and Cited1 failed to be activated. The chamber GRN subsequently decayed with individual genes exhibiting decay patterns unrelated to known patterning boundaries. Both trabecular and nontrabecular myocardium were affected. Network demise was spatiotemporally dynamic, the most sensitive region being the central part of the left ventricle, in which the GRN underwent complete collapse. Other regions were partially affected with graded sensitivity. In vitro, Nrg1 promoted phospho-Erk1/2-dependent transcription factor expression, cardiomyocyte maturation and cell cycle inhibition. We monitored cardiac pErk1/2 in embryos and found that expression was Nrg1-dependent and levels correlated with cardiac GRN sensitivity in mutants. CONCLUSIONS: The chamber GRN is fundamentally labile and dependent on signaling from extracardiac sources. Nrg1-ErbB1/4-Erk1/2 signaling critically sustains elements of the GRN in trabecular and nontrabecular myocardium, challenging our understanding of Nrg1 function. Transcriptional decay patterns induced by reduced Nrg1 suggest a novel mechanism for cardiac transcriptional regulation and dysfunction in disease, potentially linking biomechanical feedback to molecular pathways for growth and differentiation.
Assuntos
Redes Reguladoras de Genes/fisiologia , Coração/fisiologia , Miocárdio/metabolismo , Neuregulina-1/fisiologia , Animais , Bovinos , Células Cultivadas , Coração/embriologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Miocárdio/química , Miocárdio/citologia , Transdução de Sinais/fisiologiaRESUMO
RATIONALE: Mutations in the LMNA gene, which encodes the nuclear lamina proteins lamin A and lamin C, are the most common cause of familial dilated cardiomyopathy (DCM). Mechanical stress-induced apoptosis has been proposed as the mechanism underpinning DCM in lamin A/C-deficient hearts, but supporting in vivo evidence has been lacking. OBJECTIVE: Our aim was to study interventions to modify mechanical stress in heterozygous Lmna knockout (Lmna(+/-)) mice. METHODS AND RESULTS: Cardiac structure and function were evaluated before and after exercise training, thoracic aortic constriction, and carvedilol treatment. Lmna(+/-) mice develop adult-onset DCM with relatively more severe disease in males. Lmna(+/-) cardiomyocytes show altered nuclear morphology and perinuclear desmin organization, with enhanced responses to hypo-osmotic stress indicative of cytoskeletal instability. Despite these structural defects that provide a template for mechanical stress-induced damage, young Lmna(+/-) mice subjected to 6 weeks of moderate or strenuous exercise training did not show induction of apoptosis or accelerated DCM. In contrast, regular moderate exercise attenuated DCM development in male Lmna(+/-) mice. Sustained pressure overload generated by thoracic aortic constriction depressed ventricular contraction in young wild-type and Lmna(+/-) mice with no sex or genotype differences in the time-course or severity of response. Treatment of male Lmna(+/-) mice from 12 to 40 weeks with the beta-blocker, carvedilol, prevented the dilatation and contractile dysfunction that was observed in placebo-treated mice. CONCLUSIONS: These data suggest that factors other than mechanical stress-induced apoptosis contribute to DCM and provide the first demonstration that regular moderate exercise and carvedilol can modify disease progression in lamin A/C-deficient hearts.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Carbazóis/uso terapêutico , Cardiomiopatia Dilatada/genética , Coração/fisiopatologia , Lamina Tipo A/deficiência , Miocárdio/patologia , Propanolaminas/uso terapêutico , Estresse Mecânico , Animais , Aorta Torácica , Apoptose , Cardiomiopatia Dilatada/tratamento farmacológico , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Carvedilol , Constrição , Desmina/análise , Feminino , Genótipo , Lamina Tipo A/genética , Masculino , Camundongos , Camundongos Knockout , Pressão Osmótica , Condicionamento Físico Animal , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
Computed tomography coronary angiography (CTCA) has been shown in multicentre trials to be reliable in ruling out significant coronary artery disease (CAD). It is used most appropriately in symptomatic patients with low to intermediate pretest probability of CAD. It should not be used in asymptomatic subjects, patients with known significant CAD or patients with a high pretest probability of CAD. The radiation dose of CTCA was previously two to three times that of invasive coronary angiography but with modern protocols, it is similar or lower. Patients generally need to be in sinus rhythm, tolerate Β-blockers and nitrates, have a heart rate < 65 beats per minute, be able to hold their breath for 10 seconds, and have normal renal function.