RESUMEN
In this review, we provide a comprehensive overview of the impact of the COVID-19 pandemic on adult heart transplantation. We highlight the decline in the number of adult transplantations performed throughout the pandemic as a consequence of restrictions imposed on individual programs and hospitals. There were challenges to maintaining cardiac transplant activity at multiple levels, including organ donation in intensive care units, logistical difficulties with organ procurement, and rapidly changing resource considerations at health system and jurisdictional levels. We also review the impact of COVID-19 on cardiac transplant recipients. Despite the high rates of morbidity and mortality observed during the initial phases of the pandemic among heart transplant patients infected with COVID-19, the availability of effective vaccines, pre-exposure prophylaxis, and specific antiviral therapies have drastically improved outcomes over time. Vaccines have proven to be safe and effective in reducing infections and illness severity, but specific considerations in the immunocompromised solid organ transplant population apply, including the need for additional booster doses to achieve sufficient immunisation. We further outline the strong rationale for vaccination before transplantation wherever possible. Finally, the COVID-19 response created a number of barriers to safe and efficient post-transplantation care. Given the need for frequent evaluation and monitoring, especially in the first several months after cardiac transplantation, the pandemic provided the impetus to improve virtual care delivery and explore noninvasive rejection surveillance through gene expression profiling. We hope that lessons learned will allow us to prepare and pivot effectively during future pandemics and health care emergencies.
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COVID-19 , Trasplante de Corazón , Trasplante de Órganos , Vacunas , Humanos , Adulto , COVID-19/epidemiología , Pandemias/prevención & controlRESUMEN
BACKGROUND: Cardiac retransplantation accounts for approximately 3% of cardiac transplantation and is considered a risk factor for increased mortality. However, factors inherent to retransplantation including previous sternotomy, sensitization, and renal dysfunction may account for the increased mortality. We assessed whether retransplantation was associated with all-cause mortality after adjusting for such patient risk factors. METHODS: We conducted a retrospective cohort study of adult and pediatric patients enrolled in the United Network for Organ Sharing database. We identified patients undergoing cardiac retransplantation based on transplant listing diagnosis and history of previous transplant. We used propensity-score matching to identify a matched cohort undergoing initial heart transplantation. RESULTS: In total, 62,112 heart transplant recipients were identified, with a mean age 46.6 ± 19.1 years. Of these, 2,202 (3.4%) underwent late cardiac retransplantation (>1 year after initial transplant and not for acute rejection). Compared with a matched group of patients undergoing initial heart transplantation, patients undergoing late retransplantation had comparable rates of all-cause mortality at 1 year (13.6% vs 13.8%, pâ¯=â¯0.733). In addition, overall mortality was not significantly different after matching (unadjusted hazard ratio [HR] 1.08, pâ¯=â¯0.084). In contrast, patients undergoing retransplantation within 1 year of initial transplant or for acute rejection remained at increased risk of mortality post-transplant after similar matching (unadjusted HR 1.79, p < 0.001). CONCLUSIONS: After matching for comorbidities, late retransplantation in the adult population was not associated with an increase in all-cause mortality. Our findings highlight the importance of assessing indication acuity and comorbid conditions when considering retransplant candidacy.
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Trasplante de Corazón/mortalidad , Reoperación/mortalidad , Adolescente , Adulto , Anciano , Causas de Muerte , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Naciones UnidasRESUMEN
Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent of the adult-onset muscular dystrophies. FSHD causes a loss of muscle mass and function, resulting in severe debilitation and reduction in quality of life. Currently, only the symptoms of FSHD can be treated, and such treatments have minimal benefit. The available options are not curative, and none of the treatments address the underlying cause of FSHD. The genetic, epigenetic, and molecular mechanisms triggering FSHD are now quite well-understood, and it has been shown that expression of the transcriptional regulator double homeobox 4 (DUX4) is necessary for disease onset and is largely thought to be the causative factor in FSHD. Therefore, we sought to identify compounds suppressing DUX4 expression in a phenotypic screen using FSHD patient-derived muscle cells, a zinc finger and SCAN domain-containing 4 (ZSCAN4)-based reporter gene assay for measuring DUX4 activity, and â¼3,000 small molecules. This effort identified molecules that reduce DUX4 gene expression and hence DUX4 activity. Among those, ß2-adrenergic receptor agonists and phosphodiesterase inhibitors, both leading to increased cellular cAMP, effectively decreased DUX4 expression by >75% in cells from individuals with FSHD. Of note, we found that cAMP production reduces DUX4 expression through a protein kinase A-dependent mode of action in FSHD patient myotubes. These findings increase our understanding of how DUX4 expression is regulated in FSHD and point to potential areas of therapeutic intervention.
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Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Regulación hacia Abajo , Activación Enzimática , Proteínas de Homeodominio/genética , Fibras Musculares Esqueléticas/metabolismo , Distrofia Muscular Facioescapulohumeral/genética , Agonistas Adrenérgicos beta/farmacología , Células Cultivadas , AMP Cíclico/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Descubrimiento de Drogas , Activación Enzimática/efectos de los fármacos , Humanos , Fibras Musculares Esqueléticas/efectos de los fármacos , Distrofia Muscular Facioescapulohumeral/tratamiento farmacológico , Distrofia Muscular Facioescapulohumeral/metabolismoRESUMEN
Left ventricular systolic dysfunction is a significant cause of morbidity among cancer patients in whom this unfortunate complication develops. Investigation and management of chemotherapy- and radiation-induced cardiomyopathy in the emerging field of cardio-oncology involves a multidisciplinary approach between cardiology and oncology departments. The purpose of this article is to provide a practical approach to the cardiologist's assessment and management of cancer treatment-related cardiomyopathies.
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Cardiomiopatías/terapia , Conducta Cooperativa , Insuficiencia Cardíaca/terapia , Comunicación Interdisciplinaria , Neoplasias/terapia , Disfunción Ventricular Izquierda/terapia , Enfermedad Aguda , Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Quimioradioterapia , Diagnóstico Diferencial , Estudios de Seguimiento , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/etiología , Humanos , Neoplasias/complicaciones , Pronóstico , Factores de Riesgo , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/etiologíaRESUMEN
BACKGROUND: In diabetes mellitus the morbidity and mortality of cardiovascular disease is increased and represents an important independent mechanism by which heart disease is exacerbated. The pathogenesis of diabetic cardiomyopathy involves the enhanced activation of PPAR transcription factors, including PPARα, and to a lesser degree PPARß and PPARγ1. How these transcription factors are regulated in the heart is largely unknown. Recent studies have described post-translational ubiquitination of PPARs as ways in which PPAR activity is inhibited in cancer. However, specific mechanisms in the heart have not previously been described. Recent studies have implicated the muscle-specific ubiquitin ligase muscle ring finger-2 (MuRF2) in inhibiting the nuclear transcription factor SRF. Initial studies of MuRF2-/- hearts revealed enhanced PPAR activity, leading to the hypothesis that MuRF2 regulates PPAR activity by post-translational ubiquitination. METHODS: MuRF2-/- mice were challenged with a 26-week 60% fat diet designed to simulate obesity-mediated insulin resistance and diabetic cardiomyopathy. Mice were followed by conscious echocardiography, blood glucose, tissue triglyceride, glycogen levels, immunoblot analysis of intracellular signaling, heart and skeletal muscle morphometrics, and PPARα, PPARß, and PPARγ1-regulated mRNA expression. RESULTS: MuRF2 protein levels increase ~20% during the development of diabetic cardiomyopathy induced by high fat diet. Compared to littermate wildtype hearts, MuRF2-/- hearts exhibit an exaggerated diabetic cardiomyopathy, characterized by an early onset systolic dysfunction, larger left ventricular mass, and higher heart weight. MuRF2-/- hearts had significantly increased PPARα- and PPARγ1-regulated gene expression by RT-qPCR, consistent with MuRF2's regulation of these transcription factors in vivo. Mechanistically, MuRF2 mono-ubiquitinated PPARα and PPARγ1 in vitro, consistent with its non-degradatory role in diabetic cardiomyopathy. However, increasing MuRF2:PPARγ1 (>5:1) beyond physiological levels drove poly-ubiquitin-mediated degradation of PPARγ1 in vitro, indicating large MuRF2 increases may lead to PPAR degradation if found in other disease states. CONCLUSIONS: Mutations in MuRF2 have been described to contribute to the severity of familial hypertrophic cardiomyopathy. The present study suggests that the lack of MuRF2, as found in these patients, can result in an exaggerated diabetic cardiomyopathy. These studies also identify MuRF2 as the first ubiquitin ligase to regulate cardiac PPARα and PPARγ1 activities in vivo via post-translational modification without degradation.
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Cardiomiopatías/prevención & control , Dieta Alta en Grasa , Proteínas Musculares/metabolismo , Miocardio/enzimología , Obesidad/etiología , PPAR gamma/metabolismo , Aumento de Peso , Animales , Cardiomiopatías/enzimología , Cardiomiopatías/etiología , Cardiomiopatías/genética , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Genotipo , Resistencia a la Insulina , Masculino , Ratones Noqueados , Proteínas Musculares/deficiencia , Proteínas Musculares/genética , Obesidad/enzimología , Obesidad/genética , PPAR gamma/genética , Fenotipo , ARN Mensajero/metabolismo , Transducción de Señal , Factores de Tiempo , UbiquitinaciónRESUMEN
Molecular mechanisms underlying sarcopenia, the age-related loss of skeletal muscle mass and function, remain unclear. To identify molecular changes that correlated best with sarcopenia and might contribute to its pathogenesis, we determined global gene expression profiles in muscles of rats aged 6, 12, 18, 21, 24, and 27 months. These rats exhibit sarcopenia beginning at 21 months. Correlation of the gene expression versus muscle mass or age changes, and functional annotation analysis identified gene signatures of sarcopenia distinct from gene signatures of aging. Specifically, mitochondrial energy metabolism (e.g., tricarboxylic acid cycle and oxidative phosphorylation) pathway genes were the most downregulated and most significantly correlated with sarcopenia. Also, perturbed were genes/pathways associated with neuromuscular junction patency (providing molecular evidence of sarcopenia-related functional denervation and neuromuscular junction remodeling), protein degradation, and inflammation. Proteomic analysis of samples at 6, 18, and 27 months confirmed the depletion of mitochondrial energy metabolism proteins and neuromuscular junction proteins. Together, these findings suggest that therapeutic approaches that simultaneously stimulate mitochondrogenesis and reduce muscle proteolysis and inflammation have potential for treating sarcopenia.
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Envejecimiento/genética , Mitocondrias/metabolismo , Unión Neuromuscular/patología , Proteoma/análisis , Sarcopenia/patología , Transcriptoma , Envejecimiento/metabolismo , Animales , ADN Mitocondrial/genética , Metabolismo Energético , Perfilación de la Expresión Génica , Inmunohistoquímica , Modelos Lineales , Masculino , Análisis por Micromatrices , Mitocondrias/genética , Mitocondrias/patología , Fuerza Muscular/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Unión Neuromuscular/genética , Unión Neuromuscular/metabolismo , Cambios Post Mortem , Proteómica , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Regulación hacia ArribaRESUMEN
Skeletal muscle atrophy occurs as a side effect of treatment with synthetic glucocorticoids such as dexamethasone (DEX) and is a hallmark of cachectic syndromes associated with increased cortisol levels. The E3 ubiquitin ligase MuRF1 (muscle RING finger protein 1) is transcriptionally upregulated by DEX treatment. Differentiated myotubes treated with DEX undergo depletion of myosin heavy chain protein (MYH), which physically associates with MuRF1. This loss of MYH can be blocked by inhibition of MuRF1 expression. When wild-type and MuRF1(-/-) mice are treated with DEX, the MuRF1(-/-) animals exhibit a relative sparing of MYH. In vitro, MuRF1 is shown to function as an E3 ubiquitin ligase for MYH. These data identify the mechanism by which MYH is depleted under atrophy conditions and demonstrate that inhibition of a single E3 ligase, MuRF1, is sufficient to maintain this important sarcomeric protein.
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Dexametasona/farmacología , Proteínas Musculares/metabolismo , Músculo Esquelético/efectos de los fármacos , Cadenas Pesadas de Miosina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Western Blotting , Línea Celular , Expresión Génica/efectos de los fármacos , Glucocorticoides/farmacología , Leupeptinas/farmacología , Ratones , Ratones Noqueados , Músculo Esquelético/metabolismo , Oligopéptidos/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma , Unión Proteica , Isoformas de Proteínas/metabolismo , Interferencia de ARN , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas/genética , UbiquitinaciónRESUMEN
Skeletal muscle size depends upon a dynamic balance between anabolic (or hypertrophic) and catabolic (or atrophic) processes. Previously, no link between the molecular mediators of atrophy and hypertrophy had been reported. We demonstrate a hierarchy between the signals which mediate hypertrophy and those which mediate atrophy: the IGF-1/PI3K/Akt pathway, which has been shown to induce hypertrophy, prevents induction of requisite atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1. Moreover, the mechanism for this inhibition involves Akt-mediated inhibition of the FoxO family of transcription factors; a mutant form of FOXO1, which prevents Akt phosphorylation, thereby prevents Akt-mediated inhibition of MuRF1 and MAFbx upregulation. Our study thus defines a previously uncharacterized function for Akt, which has important therapeutic relevance: Akt is not only capable of activating prosynthetic pathways, as previously demonstrated, but is simultaneously and dominantly able to suppress catabolic pathways, allowing it to prevent glucocorticoid and denervation-induced muscle atrophy.
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Factor I del Crecimiento Similar a la Insulina/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Proteínas Serina-Treonina Quinasas , Transducción de Señal/genética , Factores de Transcripción/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Línea Celular , Desnervación/efectos adversos , Dexametasona/farmacología , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead , Glucocorticoides/farmacología , Factor I del Crecimiento Similar a la Insulina/farmacología , Ratones , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/crecimiento & desarrollo , Músculo Esquelético/patología , Atrofia Muscular/inducido químicamente , Atrofia Muscular/patología , Mutación/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Proteínas Ligasas SKP Cullina F-box/genética , Proteínas Ligasas SKP Cullina F-box/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/genética , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas/genética , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
Extracto de un trabajo presentado en el XVIII congreso interamericano de ingeniería sanitaria, que muestra la visión europea de este tipo de pretratamiento
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Filtración LentaRESUMEN
Extracto de un trabajo presentado en el XVIII congreso interamericano de ingeniería sanitaria, que muestra la visión europea de este tipo de pretratamiento