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2.
J Cardiovasc Nurs ; 35(3): 253-261, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32221145

RESUMO

BACKGROUND: Cognitive impairment is common in older patients with heart failure (HF), leading to higher 30-day readmission rates than those without cognitive impairment. OBJECTIVES: The aim of this study was to determine whether increased readmissions in older adults with cognitive impairment are related to HF severity and whether readmissions can be modified by caregiver inclusion in nursing discharge education. METHODS: This study used prospective quality improvement program of cognitive testing and inclusion of caregivers in discharge education with chart review. Two hundred thirty-two patients older than 70 years admitted with HF were screened for cognitive impairment using the Mini-Cog; if score was less than 4, nurses were asked to include caregivers in education on 2 cardiovascular units with an enhanced discharge program. Individuals with ventricular assist device, transplant, or hospice were excluded. Measurements include Mini-Cog score, 30-day readmissions, readmission risk score, ejection fraction, brain natriuretic peptide, and medical comorbidities. RESULTS: Readmission Risk Scores for HF did not correlate with Mini-Cog scores, but admission brain natriuretic peptide levels were less abnormal in those with better Mini-Cog scores. Only for patients with cognitive impairment, involving caregivers in discharge teaching given by registered and advanced practice nurses was associated with decreased 30-day readmissions from 35% to 16% (P = .01). Readmission rates without/with cognitive impairment were 14.1% and 23.8%, respectively (P = .09). Abnormal Mini-Cog screen was associated with a significantly increased risk of 30-day readmission (odds ratio, 2.23; 95% confidence interval, 1.06-4.68; P = .03), whereas nurse documentation of education with family was associated with a significantly decreased risk of 30-day readmission (odds ratio, 0.46; 95% confidence interval, 0.24-0.90; P = .02). CONCLUSIONS: Involving caregivers in discharge education significantly reduced 30-day readmission rates for patients with HF and cognitive impairment. The Readmission Risk Score was similar between patients older than 70 years with and without cognitive impairment. We have hypothesis-generating evidence that identification of cognitive impairment and targeted caregiver engagement by nurses may be critical in the reduction of readmission rates for older patients with HF.

3.
J Pharm Pract ; 33(1): 21-29, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29909711

RESUMO

BACKGROUND: Older adults with cognitive impairment may have difficulty understanding and complying with medical or medication instructions provided during hospitalization which may adversely impact patient outcomes. OBJECTIVE: To evaluate the prevalence of cognitive impairment among patients aged 65 years and older within 24 hours of hospital admission using Mini-Cog™ assessments performed by advanced pharmacy practice experience (APPE) students. METHODS: Students on APPE rotations were trained to perform Mini-Cog™ assessments during routine medication education sessions from February 2017 to April 2017. The primary end point was the prevalence of cognitive impairment indicated by a Mini-Cog™ score of ≤3. Secondary end points were the average number of observed Mini-Cog™ practice assessments required for APPE students to meet competency requirements, caregiver identification, and 30-day hospital readmissions. RESULTS: Twelve APPE students completed the training program after an average of 4.4 (standard deviation [SD] = 1.0) graded Mini-Cog™ assessments. Of the 1159 admissions screened, 273 were included in the analysis. The prevalence of cognitive impairment was 55% (n = 149, 95% confidence interval [CI]: 48%-61%). A caregiver was identified for 41% (n = 113, 95% CI: 35%-47%) of patients, and 79 patients had a caregiver present at bedside during the visit. Hospital readmission within 30 days of discharge was 15% (n = 41, 95% CI: 11%-20%). CONCLUSION: Cognitive impairment could substantially impair a patient's ability to comprehend education provided during hospitalization. Pharmacy students can feasibly perform Mini-Cog™ assessments to evaluate cognitive function, thereby allowing them to tailor education content and involve caregivers when necessary.

4.
Cell Stem Cell ; 24(4): 579-591.e12, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30853557

RESUMO

Heart disease is a paramount cause of global death and disability. Although cardiomyocyte death plays a causal role and its suppression would be logical, no clinical counter-measures target the responsible intracellular pathways. Therapeutic progress has been hampered by lack of preclinical human validation. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is activated in failing human hearts and relevant rodent models. Using human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) and MAP4K4 gene silencing, we demonstrate that death induced by oxidative stress requires MAP4K4. Consequently, we devised a small-molecule inhibitor, DMX-5804, that rescues cell survival, mitochondrial function, and calcium cycling in hiPSC-CMs. As proof of principle that drug discovery in hiPSC-CMs may predict efficacy in vivo, DMX-5804 reduces ischemia-reperfusion injury in mice by more than 50%. We implicate MAP4K4 as a well-posed target toward suppressing human cardiac cell death and highlight the utility of hiPSC-CMs in drug discovery to enhance cardiomyocyte survival.


Assuntos
Doxorrubicina/farmacologia , Infarto/tratamento farmacológico , Infarto/patologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Humanos , Peróxido de Hidrogênio/farmacologia , Células-Tronco Pluripotentes Induzidas/citologia , Infarto/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-Atividade
5.
J Physiol ; 597(7): 1855-1872, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30730556

RESUMO

KEY POINTS: Impaired growth during fetal life can reprogramme heart development and increase the risk for long-term cardiovascular dysfunction. It is uncertain if the developmental window during which the heart is vulnerable to reprogramming as a result of inadequate nutrition extends into the postnatal period. We found that adult female mice that had been undernourished only from birth to 3 weeks of age had disproportionately smaller hearts compared to males, with thinner ventricle walls and more mononucleated cardiomyocytes. In females, but not males, cardiac diastolic function, and heart rate responsiveness to adrenergic stimulation were limited and maximal exercise capacity was compromised. These data suggest that the developmental window during which the heart is vulnerable to reprogramming by inadequacies in nutrient intake may extend into postnatal life and such individuals could be at increased risk for a cardiac event as a result of strenuous exercise. ABSTRACT: Adults who experienced undernutrition during critical windows of development are at increased risk for cardiovascular disease. The contribution of cardiac function to this increased disease risk is uncertain. We evaluated the effect of a short episode of postnatal undernutrition on cardiovascular function in mice at the whole animal, organ, and cellular levels. Pups born to control mouse dams were suckled from birth to postnatal day (PN) 21 on dams fed either a control (20% protein) or a low protein (8% protein) isocaloric diet. After PN21 offspring were fed the same control diet until adulthood. At PN70 V ̇ O 2 , max was measured by treadmill test. At PN80 cardiac function was evaluated by echocardiography and Doppler analysis at rest and following ß-adrenergic stimulation. Isolated cardiomyocyte nucleation and Ca2+ transients (with and without ß-adrenergic stimulation) were measured at PN90. Female mice that were undernourished and then refed (PUN), unlike male mice, had disproportionately smaller hearts and their exercise capacity, cardiac diastolic function, and heart rate responsiveness to adrenergic stimulation were limited. A reduced left ventricular end diastolic volume, impaired early filling, and decreased stored energy at the beginning of diastole contributed to these impairments. Female PUN mice had more mononucleated cardiomyocytes; under resting conditions binucleated cells had a functional profile suggestive of increased basal adrenergic activation. Thus, a brief episode of early postnatal undernutrition in the mouse can produce persistent changes to cardiac structure and function that limit exercise/functional capacity and thereby increase the risk for the development of a wide variety of cardiovascular morbidities.

6.
FASEB J ; 33(1): 711-721, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30024790

RESUMO

Coordinated changes in signaling pathways and gene expression in hearts subjected to prolonged stress maintain cardiac function. Loss of steroid receptor coactivator-2 (SRC-2) results in a reversal to the fetal gene program and disrupts the response to pressure overload, accompanied by prominent effects on metabolism and growth signaling, including increased AMPK activation. We proposed that early metabolic stress driven by AMPK activation induces contractile dysfunction in mice lacking SRC-2. We used 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK transiently before transverse aortic constriction (TAC) in wild-type and cardiomyocyte-specific SRC-2 knockout (CKO) animals. In contrast to AMPK activities during stress, in unstressed hearts, AICAR induced a mild activation of Akt signaling, and, in SRC-2-CKO mice, partially relieved an NAD+ deficiency and increased antioxidant signaling. These molecular changes translated to a mild hypertrophic response to TAC with decreased maladaptive remodeling, including markedly decreased fibrosis. Additionally, preactivation of AMPK in SRC-2-CKO mice was accompanied by a dramatic improvement in cardiac function compared with saline-treated SRC-2-CKO mice. Our results show that altered molecular signaling before stress onset has extended effects on sustained cardiac stress responses, and prestress modulation of transient growth and metabolism pathways may control those effects.-Nam, D. H., Kim, E., Benham, A., Park, H.-K., Soibam, B., Taffet, G. E., Kaelber, J. T., Suh, J. H., Taegtmeyer, H., Entman, M. L., Reineke, E. L. Transient activation of AMPK preceding left ventricular pressure overload reduces adverse remodeling and preserves left ventricular function.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Cardiomegalia/prevenção & controle , Coativador 2 de Receptor Nuclear/fisiologia , Ribonucleotídeos/farmacologia , Função Ventricular Esquerda/fisiologia , Pressão Ventricular , Remodelação Ventricular/fisiologia , Proteínas Quinases Ativadas por AMP/genética , Aminoimidazol Carboxamida/farmacologia , Animais , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
7.
J Gerontol A Biol Sci Med Sci ; 73(9): 1167-1177, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-29538624

RESUMO

Metabolic, inflammatory, and functional changes occur in cardiovascular aging which may stem from oxidative stress and be remediable with antioxidants. Glutathione, an intracellular antioxidant, declines with aging, and supplementation with glutathione precursors, N-acetyl cysteine (NAC) and glycine (Gly), increases tissue glutathione. Thirty-month old mice were fed diets supplemented with NAC or NAC+Gly and, after 7 weeks, cardiac function and molecular studies were performed. The NAC+Gly supplementation improved diastolic function, increasing peak early filling velocity, and reducing relaxation time, left atrial volume, and left ventricle end diastolic pressure. By contrast, cardiac function did not improve with NAC alone. Both diet supplementations decreased cardiac levels of inflammatory mediators; only NAC+Gly reduced leukocyte infiltration. Several mitochondrial genes reduced with aging were upregulated in hearts by NAC+Gly diet supplementation. These Krebs cycle and oxidative phosphorylation enzymes, suggesting improved mitochondrial function, and permeabilized cardiac fibers from NAC+Gly-fed mice produced ATP from carbohydrate and fatty acid sources, whereas fibers from control old mice were less able to utilize fatty acids. Our data indicate that NAC+Gly supplementation can improve diastolic function in the old mouse and may have potential to prevent important morbidities for older people.


Assuntos
Acetilcisteína/metabolismo , Envelhecimento/fisiologia , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Dietoterapia/métodos , Suplementos Nutricionais , Glicina/metabolismo , Animais , Antioxidantes/metabolismo , Senescência Celular/fisiologia , Glutationa/metabolismo , Inflamação/metabolismo , Camundongos , Mitocôndrias/metabolismo , Estresse Oxidativo
8.
J Am Coll Cardiol ; 71(22): 2527-2536, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29535064

RESUMO

BACKGROUND: Current prevention guidelines recommend using the Pooled Cohort Equation (PCE) for 10-year atherosclerotic cardiovascular disease (CVD) risk assessment. However, the PCE has serious limitations in older adults: it excludes heart failure (HF) hospitalization, estimates 10-year risk, which may not be the most relevant time frame, and is not indicated for individuals age >79 years. OBJECTIVES: This study sought to determine whether adding biomarkers to PCE variables improves global CVD (coronary heart disease, stroke, and HF) risk prediction in older adults over a shorter time period. METHODS: Atherosclerosis Risk in Communities study participants without prevalent CVD including HF (n = 4,760; age 75.4 ± 5.1 years) were followed for incident global CVD events. Adding N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein to the PCE and a "lab model" with the biomarkers, age, race, and gender were assessed for prediction improvement. Area under the receiver operating characteristic curve (AUC) and net reclassification index (NRI) were calculated. RESULTS: Over median follow-up of ∼4 years, incident HF was the leading CVD event (n = 193 vs. 118 coronary heart disease and 81 stroke events). Compared to the PCE, each biomarker improved risk prediction. The largest improvement in risk prediction metrics was with the addition of all 3 biomarkers (ΔAUC 0.103; continuous NRI 0.484). The lab model also performed better than the PCE model (ΔAUC 0.091, continuous NRI 0.355). CONCLUSIONS: Adding biomarkers to the PCE or a simpler "lab model" improves short-term global CVD risk prediction and may be useful to inform short-term preventive strategies in older adults.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Saúde Global , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo
9.
J Biol Chem ; 292(52): 21643-21652, 2017 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-29127200

RESUMO

Pressure overload-induced cardiac stress induces left ventricular hypertrophy driven by increased cardiomyocyte mass. The increased energetic demand and cardiomyocyte size during hypertrophy necessitate increased fuel and oxygen delivery and stimulate angiogenesis in the left ventricular wall. We have previously shown that the transcriptional regulator steroid receptor coactivator-2 (SRC-2) controls activation of several key cardiac transcription factors and that SRC-2 loss results in extensive cardiac transcriptional remodeling. Pressure overload in mice lacking SRC-2 induces an abrogated hypertrophic response and decreases sustained cardiac function, but the cardiomyocyte-specific effects of SRC-2 in these changes are unknown. Here, we report that cardiomyocyte-specific loss of SRC-2 (SRC-2 CKO) results in a blunted hypertrophy accompanied by a rapid, progressive decrease in cardiac function. We found that SRC-2 CKO mice exhibit markedly decreased left ventricular vasculature in response to transverse aortic constriction, corresponding to decreased expression of the angiogenic factor VEGF. Of note, SRC-2 knockdown in cardiomyocytes decreased VEGF expression and secretion to levels sufficient to blunt in vitro tube formation and proliferation of endothelial cells. During pressure overload, both hypertrophic and hypoxic signals can stimulate angiogenesis, both of which stimulated SRC-2 expression in vitro Furthermore, SRC-2 coactivated the transcription factors GATA-binding protein 4 (GATA-4) and hypoxia-inducible factor (HIF)-1α and -2α in response to angiotensin II and hypoxia, respectively, which drive VEGF expression. These results suggest that SRC-2 coordinates cardiomyocyte secretion of VEGF downstream of the two major angiogenic stimuli occurring during pressure overload bridging both hypertrophic and hypoxia-stimulated paracrine signaling.


Assuntos
Coativador 2 de Receptor Nuclear/metabolismo , Indutores da Angiogênese/metabolismo , Angiotensina II/metabolismo , Animais , Ventrículos do Coração/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Neovascularização Patológica/metabolismo , Comunicação Parácrina/fisiologia , Ativação Transcricional , Fator A de Crescimento do Endotélio Vascular/metabolismo , Remodelação Ventricular
10.
Heart Fail Clin ; 13(3): 581-587, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28602373

RESUMO

Heart failure is a disease of poor prognosis marked by frequent hospitalizations, premature death, and impaired quality of life. Despite advances in medical therapy for patients with heart failure and reduced ejection fraction, mortality and hospitalizations with advanced disease are still increased and the quality of life continues to be poor in this population. The advent of cardiac resynchronization therapy has led to a significant improvement in both survival and symptom management in patients with heart failure and reduced ejection fraction. Its beneficial effects in the elderly population, however, are not well-defined.


Assuntos
Terapia de Ressincronização Cardíaca/métodos , Insuficiência Cardíaca/terapia , Fatores Etários , Idoso , Humanos , Pessoa de Meia-Idade
11.
Basic Res Cardiol ; 112(4): 34, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28478479

RESUMO

Aging is associated with increased cardiac interstitial fibrosis and diastolic dysfunction. Our previous study has shown that mesenchymal fibroblasts in the C57BL/6J (B6J) aging mouse heart acquire an inflammatory phenotype and produce higher levels of chemokines. Monocyte chemoattractant protein-1 (MCP-1) secreted by these aged fibroblasts promotes leukocyte uptake into the heart. Some of the monocytes that migrate into the heart polarize into M2a macrophages/myeloid fibroblasts. The number of activated mesenchymal fibroblasts also increases with age, and consequently, both sources of fibroblasts contribute to fibrosis. Here, we further investigate mechanisms by which inflammation influences activation of myeloid and mesenchymal fibroblasts and their collagen synthesis. We examined cardiac fibrosis and heart function in three aged mouse strains; we compared C57BL/6J (B6J) with two other strains that have reduced inflammation via different mechanisms. Aged C57BL/6N (B6N) hearts are protected from oxidative stress and fibroblasts derived from them do not develop an inflammatory phenotype. Likewise, these mice have preserved diastolic function. Aged MCP-1 null mice on the B6J background (MCP-1KO) are protected from elevated leukocyte infiltration; they develop moderate but reduced fibrosis and diastolic dysfunction. Based on these studies, we further delineated the role of resident versus monocyte-derived M2a macrophages in myeloid-dependent fibrosis and found that the number of monocyte-derived M2a (but not resident) macrophages correlates with age-related fibrosis and diastolic dysfunction. In conclusion, we have found that ROS and inflammatory mediators are necessary for activation of fibroblasts of both developmental origins, and prevention of either led to better functional outcomes.


Assuntos
Envelhecimento/patologia , Cardiomiopatias/patologia , Linhagem da Célula , Fibroblastos/patologia , Inflamação/patologia , Macrófagos/patologia , Miocárdio/patologia , Fatores Etários , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Comunicação Celular , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Diástole , Fibroblastos/metabolismo , Fibrose , Inflamação/genética , Inflamação/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Estresse Oxidativo , Fenótipo , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda
12.
J Vis Exp ; (120)2017 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-28287520

RESUMO

The present methodology teaches the investigator how to measure and use the LAV as a surrogate of chronic elevations in Left Ventricular diastolic pressure through echocardiography, as well as to obtain measurements of the Aorta and PA diameter in mice. Mice older than 10 d of age can be analyzed using the present technique. The technique is composed of 3 main steps: set-up, image acquisition, and image analysis. The set-up step consists of getting the mouse anesthetized with 1% isoflurane, shaving it, and taping it in a supine position to a heated EKG board where the image acquisition will take place. The image acquisition step consists of learning to identify the cardiac structures and obtaining all the required images with its correspondent probe and axis in order to be able to calculate volumes and diameters. The image analysis step consists of measuring the previously acquired images with the aid of computer software. Advantages of the proposed technique include a fast (15 min) procedure that would allow the researcher to evaluate interventions in a non-invasive, non-terminal approach and therefore follow the same mouse over time; each mouse can be used as its own control. This fact plus having the same operator perform all the acquisition and analysis for the entire experiment minimizes the limitation of operator-dependency. The present methodology is useful for mouse researchers in cardiovascular and pulmonary medicine.


Assuntos
Aorta Torácica/diagnóstico por imagem , Ecocardiografia/métodos , Átrios do Coração/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Animais , Camundongos , Modelos Animais
13.
J Am Geriatr Soc ; 64(11): 2296-2301, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27676328

RESUMO

OBJECTIVES: To determine whether 30-day readmissions were associated with presence of cognitive impairment more in elderly adults with heart failure (HF) than in those with other diagnoses and whether medical teams recognized cognitive impairment. DESIGN: One-year prospective cohort quality improvement program of cognitive screening and retrospective chart review of documentation and outcomes. SETTING: Academic tertiary care hospital medical unit with a cardiovascular focus and an enhanced discharge program of individualized patient education. PARTICIPANTS: Individuals aged 70 and older screened before home discharge (241 admission encounters; 121 with HF as a primary diagnosis, 120 without). The HF cohort included individuals with preserved and reduced ejection fraction. Individuals who had undergone transplantation, ventricular assist device implantation, or hemodialysis or who had a primary oncology diagnosis or hospice referral were excluded. MEASUREMENTS: Mini-Cog administered 48 hours or less before discharge, 30-day all-cause readmission rates, documentation of dementia or cognitive impairment, and caregiver education. RESULTS: Mini-Cog scores were less than 4 (indicating cognitive impairment) in 157 encounters (82 (67.7%) with HF, 75 (62.5%) without). Mini-Cog scores were similar in rate and distribution between groups. Individuals with HF and cognitive impairment had a significantly higher 30-day readmission rate than did the other groups (26.8% vs 13.2%; P = .01; HF, no cognitive impairment, 12.8%; no HF, no cognitive impairment, 13.3%; cognitive impairment, no HF, 13.3%). In individuals with HF and cognitive impairment, those with documented caregiver education had lower readmission rates than those without (14.3% vs 36.2%; P = .03). Fewer than 9% had documentation of cognitive impairment in the medical record. CONCLUSION: Cognitive impairment, which is frequently undocumented, may indicate greater risk of readmission for individuals with HF than those without. Screening for cognitive impairment, adapting discharge for it, and involving family and caregivers in discharge education may help reduce readmissions.


Assuntos
Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico , Insuficiência Cardíaca/complicações , Readmissão do Paciente/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Feminino , Avaliação Geriátrica , Humanos , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Texas
14.
Physiol Rep ; 4(8)2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27125666

RESUMO

Angiotensin-II (Ang-II) infusion is associated with the development of interstitial fibrosis in both heart and kidney as a result of chemokine-dependent uptake of monocytes and subsequent development of myeloid fibroblasts. This study emphasizes on the synergistic role of tumor necrosis factor (TNF) on the time course of Ang-II-induced fibrosis and inflammation in heart and kidney. In wild-type (WT) hearts, Ang-II-induced fibrosis peaked within 1 week of infusion and remained stable over a 6-week period, while the myeloid fibroblasts disappeared; TNF receptor-1-knockout (TNFR1-KO) hearts did not develop a myeloid response or cardiac fibrosis during this time. WT hearts developed more accelerated cardiac hypertrophy and remodeling than TNFR1-KO In the kidney, 1-week Ang-II infusion did not evoke a fibrotic response; however, after 6 weeks, WT kidneys displayed modest but significant tubulointerstitial collagen deposition associated with the appearance of myeloid cells and profibrotic gene activation. Renal fibrosis was not seen in Ang-II-infused TNFR1-KO By contrast, while hypertension increased and cardiac function decreased more slowly in TNFR1-KO than WT, they were equivalently abnormal at 6 weeks. Similarly, serum markers for renal dysfunction were not different after 6 weeks. In conclusion, Ang-II infusion initiated fibroinflammatory responses with different time courses in heart and kidney, both requiring TNFR1 signaling, and both associated with monocyte-derived myeloid fibroblasts. TNFR1 deletion obviated the fibroinflammatory effects of Ang-II, but did not alter changes in blood pressure and cardiorenal function after 6 weeks. Thus, the synergy of TNF with Ang-II targets the fibroinflammatory component of Ang-II signaling.


Assuntos
Angiotensina II/metabolismo , Cardiopatias/metabolismo , Nefropatias/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Angiotensina II/farmacologia , Animais , Ensaio de Imunoadsorção Enzimática , Fibroblastos/efeitos dos fármacos , Fibrose/metabolismo , Fibrose/patologia , Citometria de Fluxo , Coração/efeitos dos fármacos , Cardiopatias/patologia , Inflamação/metabolismo , Inflamação/patologia , Rim/efeitos dos fármacos , Nefropatias/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Tipo I de Fatores de Necrose Tumoral/deficiência , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/farmacologia
15.
J Cardiovasc Transl Res ; 9(3): 184-93, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26891844

RESUMO

C-reactive protein (CRP) as an indicator of cardiovascular disease (CVD) has shown limited sensitivity. We demonstrate that two isoforms of CRP (pentameric, pCRP and monomeric, mCRP) present in soluble form or on microparticles (MPs) have different biological effects and are not all measured by clinical CRP assays. The high-sensitivity CRP assay (hsCRP) did not measure pCRP or mCRP on MPs, whereas flow cytometry did. MPs derived from endothelial cells, particularly those bearing mCRP, were elevated in peripheral artery disease (PAD) patients compared to controls. The numbers of mCRP(+) endothelial MPs did not correlate with hsCRP measurements of soluble pCRP, indicating their independent modulation. In controls, statins lowered mCRP(+) endothelial MPs. In a model of vascular inflammation, mCRP induced endothelial shedding of MPs and was proinflammatory, while pCRP was anti-inflammatory. mCRP on endothelial MPs may be both an unmeasured indicator of, and an amplifier of, vascular disease, and its detection might improve risk sensitivity.


Assuntos
Proteína C-Reativa/metabolismo , Micropartículas Derivadas de Células/metabolismo , Células Endoteliais/metabolismo , Mediadores da Inflamação/sangue , Doença Arterial Periférica/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Micropartículas Derivadas de Células/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/tratamento farmacológico , Projetos Piloto , Regulação para Cima
16.
J Gerontol A Biol Sci Med Sci ; 71(9): 1141-50, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26511013

RESUMO

Impaired cardiac diastolic function occurs with aging in many species and may be difficult to measure noninvasively. In humans, left atrial (LA) volume is a robust measure of chronic diastolic function as the LA is exposed to increased left ventricular filling pressures. We hypothesized that LA volume would be a useful indicator of diastolic function in aging mice. Further, we asked whether pressures were propagated backwards affecting pulmonary arteries (PAs) and right ventricle (RV). We measured LA, PA, and RV infundibulum dimensions with echocardiography and used mouse-specific Doppler systems and pressure catheters for noninvasive and invasive measures. As C57BL/6 mice aged from 3 to 29-31 months, LA volume almost tripled. LA volume increases correlated with traditional diastolic function measures. Within groups of 14- and 31-month-old mice, LA volume correlated with diastolic function measured invasively. In serial studies, mice evaluated at 20 and 24 months showed monotonic increases in LA volume; other parameters changed less predictably. PA diameters, larger in 30-month-old mice than 6-month-old mice, correlated with LA volumes. Noninvasive LA volume and PA diameter assessments are useful and state independent measures of diastolic function in mice, correlating with other measures of diastolic dysfunction in aging. Furthermore, serial measurements over 4 months demonstrated consistent increases in LA volume suitable for longitudinal cardiac aging studies.


Assuntos
Envelhecimento , Função do Átrio Esquerdo , Átrios do Coração , Insuficiência Cardíaca Diastólica , Artéria Pulmonar , Animais , Diástole , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/patologia , Insuficiência Cardíaca Diastólica/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos C57BL , Valor Preditivo dos Testes , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/patologia , Sensibilidade e Especificidade , Ultrassonografia Doppler/métodos
17.
J Clin Invest ; 125(7): 2759-71, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26075818

RESUMO

Ischemic heart disease is the leading cause of heart failure. Both clinical trials and experimental animal studies demonstrate that chronic hypoxia can induce contractile dysfunction even before substantial ventricular damage, implicating a direct role of oxygen in the regulation of cardiac contractile function. Prolyl hydroxylase domain (PHD) proteins are well recognized as oxygen sensors and mediate a wide variety of cellular events by hydroxylating a growing list of protein substrates. Both PHD2 and PHD3 are highly expressed in the heart, yet their functional roles in modulating contractile function remain incompletely understood. Here, we report that combined deletion of Phd2 and Phd3 dramatically decreased expression of phospholamban (PLN), resulted in sustained activation of calcium/calmodulin-activated kinase II (CaMKII), and sensitized mice to chronic ß-adrenergic stress-induced myocardial injury. We have provided evidence that thyroid hormone receptor-α (TR-α), a transcriptional regulator of PLN, interacts with PHD2 and PHD3 and is hydroxylated at 2 proline residues. Inhibition of PHDs increased the interaction between TR-α and nuclear receptor corepressor 2 (NCOR2) and suppressed Pln transcription. Together, these observations provide mechanistic insight into how oxygen directly modulates cardiac contractility and suggest that cardiac function could be modulated therapeutically by tuning PHD enzymatic activity.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Miocárdio/metabolismo , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Receptores Adrenérgicos beta/metabolismo , Animais , Sinalização do Cálcio , Proteínas de Ligação ao Cálcio/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Feminino , Humanos , Hidroxilação , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/deficiência , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Contração Miocárdica/fisiologia , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Correpressor 2 de Receptor Nuclear/metabolismo , Pró-Colágeno-Prolina Dioxigenase/deficiência , Pró-Colágeno-Prolina Dioxigenase/genética , Ratos , Estresse Fisiológico , Receptores alfa dos Hormônios Tireóideos/metabolismo
19.
J Mol Cell Cardiol ; 83: 73-87, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25754674

RESUMO

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure (HF) in older adults, particularly women, and is increasing in prevalence as the population ages. With morbidity and mortality on par with HF with reduced ejection fraction, it remains a most challenging clinical syndrome for the practicing clinician and basic research scientist. Originally considered to be predominantly caused by diastolic dysfunction, more recent insights indicate that HFpEF in older persons is typified by a broad range of cardiac and non-cardiac abnormalities and reduced reserve capacity in multiple organ systems. The globally reduced reserve capacity is driven by: 1) inherent age-related changes; 2) multiple, concomitant co-morbidities; 3) HFpEF itself, which is likely a systemic disorder. These insights help explain why: 1) co-morbidities are among the strongest predictors of outcomes; 2) approximately 50% of clinical events in HFpEF patients are non-cardiovascular; 3) clinical drug trials in HFpEF have been negative on their primary outcomes. Embracing HFpEF as a true geriatric syndrome, with complex, multi-factorial pathophysiology and clinical heterogeneity could provide new mechanistic insights and opportunities for progress in management. This article is part of a Special Issue entitled CV Aging.


Assuntos
Envelhecimento/patologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/terapia , Idoso , Envelhecimento/metabolismo , Animais , Enalapril/uso terapêutico , Terapia por Exercício , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Proteínas Recombinantes/uso terapêutico , Relaxina/uso terapêutico , Fatores de Risco , Volume Sistólico/efeitos dos fármacos , Rigidez Vascular/efeitos dos fármacos
20.
Biomed Res Int ; 2015: 645153, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25821814

RESUMO

Viral-myocarditis is an important cause of heart failure for which no specific treatment is available. We previously showed the neuropeptide substance P (SP) is associated with the pathogenesis of murine myocarditis caused by encephalomyocarditis virus (EMCV). The current studies determined if pharmacological inhibition of SP-signaling via its high affinity receptor, NK1R and downstream G-protein, Ras homolog gene family, member-A (RhoA), will be beneficial in viral-myocarditis. Aprepitant (1.2 mg/kg), a SP-receptor antagonist, or fasudil (10 mg/kg), a RhoA inhibitor, or saline control was administered daily to mice orally for 3 days, prior to, or 5 days following, intraperitoneal infection with and without 50 PFU of EMCV, following which disease assessment studies, including echocardiogram and cardiac Doppler were performed in day 14 after infection. Pretreatment and posttreatment with aprepitant significantly reduced mortality, heart and cardiomyocyte size, and cardiac viral RNA levels (P < 0.05 all, ANOVA). Only aprepitant pretreatment improved heart functions; it significantly decreased end systolic diameter, improved fractional shortening, and increased peak aortic flow velocity (P < 0.05 all, ANOVA). Pre- or posttreatment with fasudil did not significantly impact disease manifestations. These findings indicate that SP contributes to cardiac-remodeling and dysfunction following ECMV infection via its high affinity receptor, but not through the Rho-A pathway. These studies suggest that SP-receptor antagonism may be a novel therapeutic-option for patients with viral-myocarditis.


Assuntos
Infecções por Cardiovirus/tratamento farmacológico , Infecções por Cardiovirus/fisiopatologia , Miocardite/tratamento farmacológico , Miocardite/fisiopatologia , Antagonistas do Receptor de Neuroquinina-1/uso terapêutico , Receptores da Neurocinina-1/metabolismo , Animais , Infecções por Cardiovirus/virologia , Estudos de Viabilidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocardite/virologia , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
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