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1.
Clin Obstet Gynecol ; 62(3): 491-504, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31344004

RESUMEN

Burnout afflicts a significant number of academic faculty and clinicians. There are many efforts the individual can undertake to prevent or lessen burnout. However, it not likely these will be successful without the institutional environment that promotes and atmosphere that assures self-efficacy, a sense of value and meaning and clear communication between leaders and members of the organization. This review discusses the factors that organizations and their leaders can leverage to create such an environment. Such measures are critically important not only for the health of the individual but to the organization as well.


Asunto(s)
Agotamiento Profesional/prevención & control , Ginecología/organización & administración , Obstetricia/organización & administración , Lugar de Trabajo/organización & administración , Lugar de Trabajo/psicología , Adulto , Femenino , Humanos , Liderazgo , Masculino , Persona de Mediana Edad , Embarazo , Autoeficacia
2.
J Mol Cell Cardiol ; 121: 81-93, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29981798

RESUMEN

BACKGROUND: In patients with end-stage heart failure, the primary etiology often originates in the left ventricle, and eventually the contractile function of the right ventricle (RV) also becomes compromised. RV tissue-level deficits in contractile force and/or kinetics need quantification to understand involvement in ischemic and non-ischemic failing human myocardium. METHODS AND RESULTS: The human population suffering from heart failure is diverse, requiring many subjects to be studied in order to perform an adequately powered statistical analysis. From 2009-present we assessed live tissue-level contractile force and kinetics in isolated myocardial RV trabeculae from 44 non-failing and 41 failing human hearts. At 1 Hz stimulation rate (in vivo resting state) the developed active force was not different in non-failing compared to failing ischemic nor non-ischemic failing trabeculae. In sharp contrast, the kinetics of relaxation were significantly impacted by disease, with 50% relaxation time being significantly shorter in non-failing vs. non-ischemic failing, while the latter was still significantly shorter than ischemic failing. Gender did not significantly impact kinetics. Length-dependent activation was not impacted. Although baseline force was not impacted, contractile reserve was critically blunted. The force-frequency relation was positive in non-failing myocardium, but negative in both ischemic and non-ischemic myocardium, while the ß-adrenergic response to isoproterenol was depressed in both pathologies. CONCLUSIONS: Force development at resting heart rate is not impacted by cardiac pathology, but kinetics are impaired and the magnitude of the impairment depends on the underlying etiology. Focusing on restoration of myocardial kinetics will likely have greater therapeutic potential than targeting force of contraction.


Asunto(s)
Insuficiencia Cardíaca/terapia , Ventrículos Cardíacos/fisiopatología , Corazón/fisiopatología , Miocardio/patología , Adulto , Anciano , Animales , Femenino , Insuficiencia Cardíaca/fisiopatología , Trasplante de Corazón , Humanos , Masculino , Persona de Mediana Edad , Contracción Miocárdica/fisiología , Terapia por Relajación , Donantes de Tejidos
3.
Pharm Res ; 34(8): 1648-1657, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28120175

RESUMEN

PURPOSE: Protein kinase C α (PRKCA) is involved in multiple functions and has been implicated in heart failure risks and treatment outcomes. This study aims to identify regulatory variants affecting PRKCA expression in human heart, and evaluate attributable risk of heart disease. METHODS: mRNA expression quantitative trait loci (eQTLs) were extracted from the Genotype and Tissue Expression Project (GTEx). Allelic mRNA ratios were measured in 51 human heart tissues to identify cis-acting regulatory variants. Potential regulatory regions were tested with luciferase reporter gene assays and further evaluated in GTEx and genome-wide association studies. RESULTS: Located in a region with robust enhancer activity in luciferase reporter assays, rs9909004 (T > C, minor allele frequency =0.47) resides in a haplotype displaying strong eQTLs for PRKCA in heart (p = 1.2 × 10-23). The minor C allele is associated with both decreased PRKCA mRNA expression and decreased risk of phenotypes characteristic of heart failure in GWAS analyses (QT interval p = 3.0 × 10-14). While rs9909004 is the likely regulatory variant, other variants in high linkage disequilibrium cannot be excluded. Distinct regulatory variants appear to affect expression in other tissues. CONCLUSIONS: The haplotype carrying rs9909004 influences PRKCA expression in the heart and is associated with traits linked to heart failure, potentially affecting therapy of heart failure.


Asunto(s)
Cardiopatías/genética , Proteína Quinasa C-alfa/genética , Proteína Quinasa C-alfa/metabolismo , Línea Celular , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Insuficiencia Cardíaca/metabolismo , Humanos , Mutación , Miocardio/metabolismo , Fenotipo , Polimorfismo de Nucleótido Simple
4.
Pharm Res ; 34(8): 1615-1625, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28181117

RESUMEN

PURPOSE: This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure. METHODS: Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n = 65) or metoprolol (n = 33). RESULTS: CYP2D6*4 was associated with lower maintenance dose of metoprolol (OR 0.13 [95% CI 0.02-0.75] p = 0.023), and a trend was observed between CYP2D6*4 and higher maintenance dose of carvedilol (OR 2.94 [95% CI 0.84-10.30] p = 0.093). None of the patients that carried CYP2D6*4 achieved the recommended target dose of metoprolol (200 mg/day). CONCLUSION: Consistent with the role of CYP2D6 in the metabolism of metoprolol, the tolerated maintenance dose of metoprolol was lower in CYP2D6*4 carriers compared to non-carriers. Consistent with the role of CYP2D6 in activation of carvedilol, tolerated maintenance dose of carvedilol was higher in CYP2D6*4 carriers compared to non-carriers. Further investigation is warranted to ascertain the potential of CYP2D6 as a potential predictive biomarker of beta-blocker maintenance dose in heart failure patients.


Asunto(s)
Antagonistas Adrenérgicos beta/administración & dosificación , Citocromo P-450 CYP2D6/genética , Insuficiencia Cardíaca/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carbazoles/administración & dosificación , Carvedilol , Citocromo P-450 CYP2D6/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Humanos , Masculino , Metoprolol/administración & dosificación , Persona de Mediana Edad , Fenotipo , Polimorfismo Genético , Propanolaminas/administración & dosificación , Estudios Retrospectivos
5.
Circulation ; 131(8): 695-708, 2015 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-25632041

RESUMEN

BACKGROUND: The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked to cardiac pathologies, including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction and cardiac electric activity is not well understood and often overlooked in the cardiac arrhythmia field. METHODS AND RESULTS: Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that ßII spectrin, an actin-associated molecule, is essential for the posttranslational targeting and localization of critical membrane proteins in heart. ßII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/ßII spectrin interaction, leading to severe human arrhythmia phenotypes. Mice lacking cardiac ßII spectrin display lethal arrhythmias, aberrant electric and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, ßII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes, including the Na/Ca exchanger, ryanodine receptor 2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in ßII spectrin-deficient mice. CONCLUSIONS: Our findings identify ßII spectrin as critical for normal myocyte electric activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.


Asunto(s)
Arritmias Cardíacas/patología , Arritmias Cardíacas/fisiopatología , Citoesqueleto/fisiología , Miocitos Cardíacos/patología , Miocitos Cardíacos/fisiología , Espectrina/fisiología , Secuencia de Aminoácidos , Animales , Ancirinas/genética , Ancirinas/fisiología , Arritmias Cardíacas/genética , Proteínas Portadoras/genética , Proteínas Portadoras/fisiología , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Humanos , Proteínas de la Membrana/fisiología , Ratones , Ratones Noqueados , Proteínas de Microfilamentos/deficiencia , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/fisiología , Microtúbulos/fisiología , Datos de Secuencia Molecular , Mutación/genética , Fenotipo , Espectrina/análisis , Espectrina/química
6.
Am J Physiol Heart Circ Physiol ; 310(11): H1583-91, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27106045

RESUMEN

ß2-Spectrin is critical for integrating membrane and cytoskeletal domains in excitable and nonexcitable cells. The role of ß2-spectrin for vertebrate function is illustrated by dysfunction of ß2-spectrin-based pathways in disease. Recently, defects in ß2-spectrin association with protein partner ankyrin-B were identified in congenital forms of human arrhythmia. However, the role of ß2-spectrin in common forms of acquired heart failure and arrhythmia is unknown. We report that ß2-spectrin protein levels are significantly altered in human cardiovascular disease as well as in large and small animal cardiovascular disease models. Specifically, ß2-spectrin levels were decreased in atrial samples of patients with atrial fibrillation compared with tissue from patients in sinus rhythm. Furthermore, compared with left ventricular samples from nonfailing hearts, ß2-spectrin levels were significantly decreased in left ventricle of ischemic- and nonischemic heart failure patients. Left ventricle samples of canine and murine heart failure models confirm reduced ß2-spectrin protein levels. Mechanistically, we identify that ß2-spectrin levels are tightly regulated by posttranslational mechanisms, namely Ca(2+)- and calpain-dependent proteases. Furthermore, consistent with this data, we observed Ca(2+)- and calpain-dependent loss of ß2-spectrin downstream effector proteins, including ankyrin-B in heart. In summary, our findings illustrate that ß2-spectrin and downstream molecules are regulated in multiple forms of cardiovascular disease via Ca(2+)- and calpain-dependent proteolysis.


Asunto(s)
Fibrilación Atrial/metabolismo , Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/metabolismo , Espectrina/metabolismo , Adulto , Anciano , Animales , Ancirinas/metabolismo , Fibrilación Atrial/fisiopatología , Calcio/metabolismo , Calpaína/metabolismo , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Perros , Regulación hacia Abajo , Femenino , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Proteolisis , Transducción de Señal , Volumen Sistólico , Función Ventricular Izquierda
8.
Am J Physiol Heart Circ Physiol ; 309(12): H2077-86, 2015 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-26453335

RESUMEN

Cross-bridge cycling rate is an important determinant of cardiac output, and its alteration can potentially contribute to reduced output in heart failure patients. Additionally, animal studies suggest that this rate can be regulated by muscle length. The purpose of this study was to investigate cross-bridge cycling rate and its regulation by muscle length under near-physiological conditions in intact right ventricular muscles of nonfailing and failing human hearts. We acquired freshly explanted nonfailing (n = 9) and failing (n = 10) human hearts. All experiments were performed on intact right ventricular cardiac trabeculae (n = 40) at physiological temperature and near the normal heart rate range. The failing myocardium showed the typical heart failure phenotype: a negative force-frequency relationship and ß-adrenergic desensitization (P < 0.05), indicating the expected pathological myocardium in the right ventricles. We found that there exists a length-dependent regulation of cross-bridge cycling kinetics in human myocardium. Decreasing muscle length accelerated the rate of cross-bridge reattachment (ktr) in both nonfailing and failing myocardium (P < 0.05) equally; there were no major differences between nonfailing and failing myocardium at each respective length (P > 0.05), indicating that this regulatory mechanism is preserved in heart failure. Length-dependent assessment of twitch kinetics mirrored these findings; normalized dF/dt slowed down with increasing length of the muscle and was virtually identical in diseased tissue. This study shows for the first time that muscle length regulates cross-bridge kinetics in human myocardium under near-physiological conditions and that those kinetics are preserved in the right ventricular tissues of heart failure patients.


Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Pruebas de Función Cardíaca/métodos , Contracción Miocárdica , Disfunción Ventricular Derecha/fisiopatología , Adulto , Anciano , Temperatura Corporal , Gasto Cardíaco , Femenino , Insuficiencia Cardíaca/patología , Humanos , Técnicas In Vitro , Cinética , Masculino , Persona de Mediana Edad , Músculos/fisiopatología , Miocardio/patología , Receptores Adrenérgicos beta , Malla Trabecular/fisiopatología , Disfunción Ventricular Derecha/patología , Adulto Joven
9.
J Cardiovasc Pharmacol ; 66(1): 80-5, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26164721

RESUMEN

Our objective was to evaluate the associations of genetic variants affecting simvastatin (SV) and simvastatin acid (SVA) metabolism [the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)*22 and the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5)*3] and transport [the gene encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) T521C] with 12-hour plasma SV and SVA concentrations. The variants were genotyped, and the concentrations were quantified by high performance liquid chromatography-tandem mass spectrometry in 646 participants of the Cholesterol and Pharmacogenetics clinical trial of 40 mg/d SV for 6 weeks. The genetic variants were tested for association with 12-hour plasma SV, SVA, or the SVA/SV ratio using general linear models. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentration. CYP3A4*1/*22 participants had 58% higher 12-hour plasma SV concentration compared with CYP3A4*1/*1 participants (P = 0.006). SLCO1B1 521T/C and 521C/C participants had 71% (P < 0.001) and 248% (P < 0.001) higher 12-hour plasma SVA compared with SLCO1B1 521T/T participants, respectively. CYP3A4 and SLCO1B1 genotypes combined categorized participants into low (<1), intermediate (≈1), and high (>1) SVA/SV ratio groups (P = 0.001). In conclusion, CYP3A4*22 and SLCO1B1 521C were significantly associated with increased 12-hour plasma SV and SVA concentrations, respectively. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentrations. The combination of CYP3A4*22 and SLCO1B1 521C was significantly associated with SVA/SV ratio, which may translate into different clinical SV risk/benefit profiles.


Asunto(s)
Citocromo P-450 CYP3A/genética , Variación Genética/genética , Transportadores de Anión Orgánico/genética , Simvastatina/análogos & derivados , Simvastatina/sangre , Adulto , Anciano , Femenino , Estudios de Asociación Genética/métodos , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado , Masculino , Persona de Mediana Edad
10.
J Biol Chem ; 288(2): 1032-46, 2013 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-23204520

RESUMEN

Kinase/phosphatase balance governs cardiac excitability in health and disease. Although detailed mechanisms for cardiac kinase regulation are established, far less is known regarding cardiac protein phosphatase 2A (PP2A) regulation. This is largely due to the complexity of the PP2A holoenzyme structure (combinatorial assembly of three subunit enzyme from >17 subunit genes) and the inability to segregate "global" PP2A function from the activities of multiple "local" holoenzyme populations. Here we report that PP2A catalytic, regulatory, and scaffolding subunits are tightly regulated at transcriptional, translational, and post-translational levels to tune myocyte function at base line and in disease. We show that past global read-outs of cellular PP2A activity more appropriately represent the collective activity of numerous individual PP2A holoenzymes, each displaying a specific subcellular localization (dictated by select PP2A regulatory subunits) as well as local specific post-translational catalytic subunit methylation and phosphorylation events that regulate local and rapid holoenzyme assembly/disassembly (via leucine carboxymethyltransferase 1/phosphatase methylesterase 1 (LCMT-1/PME-1). We report that PP2A subunits are selectively regulated between human and animal models, across cardiac chambers, and even within specific cardiac cell types. Moreover, this regulation can be rapidly tuned in response to cellular activation. Finally, we report that global PP2A is altered in human and experimental models of heart disease, yet each pathology displays its own distinct molecular signature though specific PP2A subunit modulatory events. These new data provide an initial view into the signaling pathways that govern PP2A function in heart but also establish the first step in defining specific PP2A regulatory targets in health and disease.


Asunto(s)
Miocardio/enzimología , Proteína Fosfatasa 2/metabolismo , Animales , Secuencia de Bases , Cartilla de ADN , Perros , Humanos , Inmunoprecipitación , Ratones , Reacción en Cadena de la Polimerasa , Biosíntesis de Proteínas , Proteína Fosfatasa 2/genética , Transducción de Señal , Transcripción Genética
11.
N Engl J Med ; 364(17): 1617-25, 2011 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-21463153

RESUMEN

BACKGROUND: The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a survival benefit. However, the efficacy of this approach is uncertain. METHODS: In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds. RESULTS: Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval [CI], 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53). CONCLUSIONS: The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595.).


Asunto(s)
Puente de Arteria Coronaria , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/cirugía , Miocardio/patología , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/cirugía , Anciano , Enfermedades Cardiovasculares/mortalidad , Terapia Combinada , Enfermedad de la Arteria Coronaria/complicaciones , Ecocardiografía de Estrés , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/cirugía , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Isquemia Miocárdica , Modelos de Riesgos Proporcionales , Estadísticas no Paramétricas , Tomografía Computarizada de Emisión de Fotón Único , Disfunción Ventricular Izquierda/etiología
12.
J Surg Res ; 191(2): 302-8, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24932840

RESUMEN

BACKGROUND: There has been a steady increase of patients living in the community with Left Ventricular Assist Devices (LVADs). There is a significant gap in our fund of knowledge with respect to the impact that insurance and socioeconomic status has on outcomes for LVAD patients. We thus hypothesize that low neighborhood socioeconomic status and receipt of Medicaid, respectively, lead to earlier readmissions, earlier death, as well as longer time to transplantation among LVAD patients. METHODS: This was a retrospective review of 101 patients using existing data in the medical information warehouse database at The Ohio State University Medical Center. Primary outcomes measured included time to first event (first readmission or death), death, and time to rehospitalization. Our secondary outcome of interest included time from LVAD implantation to cardiac transplantation. RESULTS: Recipients of Medicaid did not have an increased risk of adverse events compared with patients without Medicaid coverage. Low Median Household Income (MHI) was associated with an increased risk of readmission (log-rank P = 0.0069) and time to first event (log-rank P = 0.0088). Bridge to transplantation was the only independent predictor of time to death (Hazard Ratio 2.1, [95% confidence interval = 1.03-4.37]). Low MHI and a history of atherosclerosis were both significant predictors for readmission and time to first event. Aldosterone antagonist use decreased the risk of readmission or time to first event by 46%. CONCLUSIONS: LVAD recipients with a low MHI were more likely to be readmitted to the hospital after LVAD implantation. Whether these patients are adequately monitored on an outpatient basis remains unclear.


Asunto(s)
Corazón Auxiliar , Medicaid , Medicare , Clase Social , Adulto , Anciano , Femenino , Humanos , Renta , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estados Unidos
13.
J Am Heart Assoc ; 13(7): e031117, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38506666

RESUMEN

BACKGROUND: There is conflicting evidence as to the impact of mental health treatment on outcomes in patients with heart disease. The aim of this study was to examine whether individuals who received mental health treatment for anxiety or depression after being hospitalized for ischemic disorders or heart failure had a reduced frequency of rehospitalizations, emergency department visits, or mortality compared with those who did not receive treatment. METHODS AND RESULTS: A population-based, retrospective, cohort design was used to examine the association between psychotherapy or antidepressant medication prescription and health service utilization and mortality in patients with coronary artery disease or heart failure and comorbid anxiety or depression. Those receiving versus not receiving mental health treatment were compared based on the frequency of rehospitalization, emergency department visits, and mortality. The study sample included 1563 patients who had a mean age of 50.1 years. Individuals who received both forms of mental health treatment for anxiety or depression were 75% less likely to be rehospitalized, 74% less likely to have an emergency department visit, and 66% less likely to die from any cause. CONCLUSIONS: Mental health treatment for anxiety or depression has a significant impact on outcomes in patients with cardiovascular disease consisting of reduced hospitalizations, emergency department visits, and in some conditions improved survival.


Asunto(s)
Insuficiencia Cardíaca , Isquemia Miocárdica , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Salud Mental , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/terapia , Psicoterapia , Servicio de Urgencia en Hospital
14.
J Biol Chem ; 287(36): 30268-81, 2012 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-22778271

RESUMEN

Ankyrins (ankyrin-R, -B, and -G) are adapter proteins linked with defects in metazoan physiology. Ankyrin-B (encoded by ANK2) loss-of-function mutations are directly associated with human cardiovascular phenotypes including sinus node disease, atrial fibrillation, ventricular tachycardia, and sudden cardiac death. Despite the link between ankyrin-B dysfunction and monogenic disease, there are no data linking ankyrin-B regulation with common forms of human heart failure. Here, we report that ankyrin-B levels are altered in both ischemic and non-ischemic human heart failure. Mechanistically, we demonstrate that cardiac ankyrin-B levels are tightly regulated downstream of reactive oxygen species, intracellular calcium, and the calcium-dependent protease calpain, all hallmarks of human myocardial injury and heart failure. Surprisingly, ß(II)-spectrin, previously thought to mediate ankyrin-dependent modulation in the nervous system and heart, is not coordinately regulated with ankyrin-B or its downstream partners. Finally, our data implicate ankyrin-B expression as required for vertebrate myocardial protection as hearts deficient in ankyrin-B show increased cardiac damage and impaired function relative to wild-type mouse hearts following ischemia reperfusion. In summary, our findings provide the data of ankyrin-B regulation in human heart failure, provide insight into candidate pathways for ankyrin-B regulation in acquired human cardiovascular disease, and surprisingly, implicate ankyrin-B as a molecular component for cardioprotection following ischemia.


Asunto(s)
Ancirinas/biosíntesis , Regulación de la Expresión Génica , Insuficiencia Cardíaca/metabolismo , Proteínas Musculares/metabolismo , Miocardio/metabolismo , Animales , Ancirinas/genética , Calcio/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Células Cultivadas , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Humanos , Ratones , Ratones Mutantes , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Proteínas Musculares/genética , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patología , Miocardio/patología , Especies Reactivas de Oxígeno/metabolismo , Síndrome del Seno Enfermo/genética , Síndrome del Seno Enfermo/metabolismo , Síndrome del Seno Enfermo/patología
15.
Circulation ; 126(17): 2084-94, 2012 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-23008441

RESUMEN

BACKGROUND: Human gene variants affecting ion channel biophysical activity and/or membrane localization are linked to potentially fatal cardiac arrhythmias. However, the mechanism for many human arrhythmia variants remains undefined despite more than a decade of investigation. Posttranslational modulation of membrane proteins is essential for normal cardiac function. Importantly, aberrant myocyte signaling has been linked to defects in cardiac ion channel posttranslational modifications and disease. We recently identified a novel pathway for posttranslational regulation of the primary cardiac voltage-gated Na(+) channel (Na(v)1.5) by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). However, a role for this pathway in cardiac disease has not been evaluated. METHODS AND RESULTS: We evaluated the role of CaMKII-dependent phosphorylation in human genetic and acquired disease. We report an unexpected link between a short motif in the Na(v)1.5 DI-DII loop, recently shown to be critical for CaMKII-dependent phosphorylation, and Na(v)1.5 function in monogenic arrhythmia and common heart disease. Experiments in heterologous cells and primary ventricular cardiomyocytes demonstrate that the human arrhythmia susceptibility variants (A572D and Q573E) alter CaMKII-dependent regulation of Na(v)1.5, resulting in abnormal channel activity and cell excitability. In silico analysis reveals that these variants functionally mimic the phosphorylated channel, resulting in increased susceptibility to arrhythmia-triggering afterdepolarizations. Finally, we report that this same motif is aberrantly regulated in a large-animal model of acquired heart disease and in failing human myocardium. CONCLUSIONS: We identify the mechanism for 2 human arrhythmia variants that affect Na(v)1.5 channel activity through direct effects on channel posttranslational modification. We propose that the CaMKII phosphorylation motif in the Na(v)1.5 DI-DII cytoplasmic loop is a critical nodal point for proarrhythmic changes to Na(v)1.5 in congenital and acquired cardiac disease.


Asunto(s)
Arritmias Cardíacas/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/fisiología , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Animales , Arritmias Cardíacas/enzimología , Arritmias Cardíacas/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Células Cultivadas , Citoplasma/enzimología , Citoplasma/genética , Citoplasma/metabolismo , Perros , Variación Genética , Células HEK293 , Humanos , Ratones , Canal de Sodio Activado por Voltaje NAV1.5/genética , Fosforilación , Procesamiento Proteico-Postraduccional/genética
16.
Clin Transl Sci ; 15(7): 1764-1775, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35488487

RESUMEN

There are limited comparison data throughout the dosing interval for generic versus brand metoprolol extended-release (ER) tablets. We compared the pharmacokinetics (PKs) and pharmacodynamics of brand name versus two generic formulations (drugs 1 and 2) of metoprolol ER tablets with different time to maximum concentration (Tmax ) in adults with hypertension. Participants were randomized to equal drug doses (50-150 mg/day) administered in one of two sequences (brand-drug1-brand-drug2 or brand-drug2-brand-drug1) and completed 24-h PK, digital heart rate (HR), ambulatory blood pressure (BP), and HR studies after taking each formulation for greater than or equal to 7 days. Metoprolol concentrations were determined by liquid chromatography tandem mass spectrometry, with noncompartmental analysis performed to obtain PK parameters in Phoenix WinNonlin. Heart rate variability (HRV) low-to-high frequency ratio was determined per quartile over the 24-h period. Thirty-six participants completed studies with the brand name and at least one generic product. Among 30 participants on the 50 mg dose, the primary PK end points of area under the concentration-time curve and Cmax were similar between products; Tmax was 6.1 ± 3.6 for the brand versus 3.5 ± 4.9 for drug 1 (p = 0.019) and 9.6 ± 3.2 for drug 2 (p < 0.001). Among all 36 participants, 24-h BPs and HRs were similar between products. Mean 24-h HRV low-to-high ratio was also similar for drug 1 (2.04 ± 1.35), drug 2 (1.86 ± 1.35), and brand (2.04 ± 1.77), but was more sustained over time for the brand versus drug 1 (drug × quartile interaction p = 0.017). Differences in Tmax between metoprolol ER products following repeated doses may have implications for drug effects on autonomic balance over the dosing interval.


Asunto(s)
Monitoreo Ambulatorio de la Presión Arterial , Metoprolol , Adulto , Área Bajo la Curva , Estudios Cruzados , Medicamentos Genéricos/uso terapéutico , Humanos , Metoprolol/farmacocinética , Comprimidos
17.
Heart Fail Clin ; 7(1): 69-74, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21109209

RESUMEN

Depression occurring concurrently with cardiovascular diseases is associated with poor outcomes. Several review articles have examined the link between established indices of depression and prognosis in individuals with known coronary heart disease (CHD). These studies have demonstrated relatively consistent results and suggest an important connection between cardiovascular morbidity and mortality in patients with depressive symptoms or major depression. This article discusses the current best practices for the screening, identification, and treatment of depression in patients with CHD and coronary heart failure, as well as the financial aspects associated with care management.


Asunto(s)
Enfermedad de la Arteria Coronaria/complicaciones , Depresión/diagnóstico , Insuficiencia Cardíaca/complicaciones , Adaptación Psicológica , Enfermedad de la Arteria Coronaria/psicología , Depresión/etiología , Depresión/psicología , Progresión de la Enfermedad , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/psicología , Humanos , Prevalencia , Pronóstico , Psicometría , Factores de Riesgo , Estrés Psicológico , Encuestas y Cuestionarios , Estados Unidos
18.
CPT Pharmacometrics Syst Pharmacol ; 9(12): 678-685, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33067866

RESUMEN

Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S-metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/minute) vs. 2-2.25 (8.3 ± 0.6 mL/minute; P = 0.012), similar between an AS of 1 and 1.25-1.5 (7.8 ± 0.5 mL/minute; P = 0.702), and lower with an AS of 1.25-1.5 vs. 2-2.25 (P = 0.03). There was also a greater reduction in heart rate with metoprolol among study participants with AS of 1 (-10.8 ± 5.5) vs. 2-2.25 (-7.1 ± 5.6; P < 0.001) and no significant difference between those with an AS of 1 and 1.25-1.5 (-9.2 ± 4.7; P = 0.095). These data highlight linear trends among CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice.


Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Citocromo P-450 CYP2D6/genética , Genotipo , Metoprolol/farmacocinética , Administración Oral , Antagonistas de Receptores Adrenérgicos beta 1/administración & dosificación , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Metoprolol/administración & dosificación , Persona de Mediana Edad , Farmacogenética , Fenotipo , Polimorfismo de Nucleótido Simple , Estudios Prospectivos
19.
Circulation ; 117(11): 1414-22, 2008 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-18316483

RESUMEN

BACKGROUND: Protein kinase A signaling has long been known to play an important role in cardiac function. Dysregulation of the protein kinase A system, caused by mutation of the protein kinase A regulatory subunit gene PRKAR1A, causes the inherited tumor syndrome Carney complex, which includes cardiac myxomas as one of its cardinal features. Mouse models of this genetic defect have been unsatisfactory because homozygote null animals die early in development and heterozygotes do not exhibit a cardiac phenotype. METHODS AND RESULTS: To study the cardiac-specific effects resulting from complete loss of Prkar1a, we used cre-lox technology to generate mice lacking this protein specifically in cardiomyocytes. Conditional knockout mice died at day 11.5 to 12.5 of embryogenesis with thin-walled, dilated hearts. These hearts showed elevated protein kinase A activity and decreased cardiomyocyte proliferation before demise. Analysis of the expression of transcription factors required for cardiogenesis revealed downregulation of key cardiac transcription factors such as the serum response factor, Gata4, and Nkx2-5. Although heart wall thickness was reduced overall, specific areas exhibited morphological changes consistent with myxomatous degeneration in the walls of knockout hearts. CONCLUSIONS: Loss of Prkar1a from the heart causes a failure of proper myocardial development with subsequent cardiac failure and embryonic demise. These changes appear to be due to suppression of cardiac-specific transcription by increased protein kinase A activity. These biochemical changes lead to myxoma-like changes, indicating that these mice may be a good model with which to study the formation of these tumors.


Asunto(s)
Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/deficiencia , Corazón Fetal/patología , Neoplasias Cardíacas/genética , Mixoma/genética , Animales , Apoptosis , División Celular , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/fisiología , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Regulación hacia Abajo , Muerte Fetal/enzimología , Muerte Fetal/genética , Corazón Fetal/enzimología , Corazón Fetal/ultraestructura , Genes Letales , Neoplasias Cardíacas/patología , Integrasas , Ratones , Ratones Noqueados , Modelos Animales , Miocitos Cardíacos/enzimología , Mixoma/patología , Síndromes Neoplásicos Hereditarios/enzimología , Síndromes Neoplásicos Hereditarios/genética , Especificidad de Órganos , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética
20.
Cardiology ; 112(1): 69-73, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-18580063

RESUMEN

Four patients with chronically well-compensated, non-ischemic dilated cardiomyopathy (NIDC) presented with occlusive atherosclerotic coronary artery disease as the cause of subacute decompensation (FC III-IV heart failure) 8-13 years following the diagnosis of NIDC. In addition to the atherogenic condition of heart failure, 3 of the patients acquired major atherosclerotic risk factors (dyslipidemia, diabetes mellitus) during the interval between the diagnoses of NIDC and problematic atherosclerotic coronary disease. For each patient, dyspnea on exertion was the primary symptom during the subacute decompensation. Only 1 patient noted precordial chest pain in the form of atypical angina during some of the dyspneic events. The diagnosis of occlusive coronary artery disease was made by coronary angiography, followed by angioplasty-stent deployment in 3 patients and coronary artery bypass surgery in 1; all improved to their baseline FC I-II status following these coronary interventions. As survival of patients with NIDC increases, occlusive coronary artery disease may enter an otherwise stable clinical course to provoke unanticipated decompensation (principally dyspnea), and can do so without causing angina pectoris as a heralding symptom.


Asunto(s)
Angina de Pecho/etiología , Cardiomiopatía Dilatada/etiología , Enfermedad de la Arteria Coronaria/complicaciones , Insuficiencia Cardíaca/etiología , Adulto , Angina de Pecho/epidemiología , Cardiomiopatía Dilatada/epidemiología , Enfermedad de la Arteria Coronaria/epidemiología , Progresión de la Enfermedad , Femenino , Insuficiencia Cardíaca/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo
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