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1.
Am J Physiol Heart Circ Physiol ; 323(2): H285-H300, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35714177

RESUMO

The incidence of diastolic dysfunction increases with age in both humans and mice. This is characterized by increased passive stiffness and slower relaxation of the left ventricle. The stiffness arises at least partially from progressively increased interstitial collagen deposition because of highly secretory fibroblasts. In the past, we demonstrated that AMPK activation via the drug 5-aminoimidazole-4-carboxamide riboside (AICAR) in middle-aged mice reduced adverse remodeling after myocardial infarction. Therefore, as an attempt to normalize the fibroblast phenotype, we used 21-mo-old male and female mice and treated them with AICAR (0.166 mg/g body wt) where each mouse was followed in a functional study over a 3-mo period. We found sex-related differences in extracellular matrix (ECM) composition as well as heart function indices at baseline, which were further accentuated by AICAR treatment. AICAR attenuated the age-related increase in left atrial volume (LAV, an indicator of diastolic dysfunction) in female but not in male hearts, which was associated with reduced collagen deposition in the old female heart, and reduced the transcription factor Gli1 expression in cardiac fibroblasts. We further demonstrated that collagen synthesis was dependent on Gli1, which is a target of AMPK-mediated degradation. By contrast, AICAR had a minor impact on cardiac fibroblasts in the old male heart because of blunted AMPK phosphorylation. Hence, it did not significantly improve old male heart function indices. In conclusion, we demonstrated that male and female hearts are phenotypically different, and sex-specific differences need to be considered when analyzing the response to pharmacological intervention.NEW & NOTEWORTHY The aging heart develops diastolic dysfunction because of increased collagen deposition. We attempted to reduce collagen expression in the old heart by activating AMPK using AICAR. An improvement of diastolic function and reduction of cardiac fibrosis was found only in the female heart and correlated with decreased procollagen expression and increased degradation of the transcription factor Gli1. Male hearts display blunted AICAR-dependent AMPK activation and therefore this treatment had no benefits for the male mice.


Assuntos
Proteínas Quinases Ativadas por AMP , Cardiomiopatias , Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento/metabolismo , Aminoimidazol Carboxamida/farmacologia , Animais , Colágeno/metabolismo , Feminino , Fibrose , Masculino , Camundongos , Fenótipo , Proteína GLI1 em Dedos de Zinco/genética
2.
Age Ageing ; 50(3): 733-743, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33951145

RESUMO

OBJECTIVE: Detection of delirium in hospitalised older adults is recommended in national and international guidelines. The 4 'A's Test (4AT) is a short (<2 minutes) instrument for delirium detection that is used internationally as a standard tool in clinical practice. We performed a systematic review and meta-analysis of diagnostic test accuracy of the 4AT for delirium detection. METHODS: We searched MEDLINE, EMBASE, PsycINFO, CINAHL, clinicaltrials.gov and the Cochrane Central Register of Controlled Trials, from 2011 (year of 4AT release on the website www.the4AT.com) until 21 December 2019. Inclusion criteria were: older adults (≥65 years); diagnostic accuracy study of the 4AT index test when compared to delirium reference standard (standard diagnostic criteria or validated tool). Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Pooled estimates of sensitivity and specificity were generated from a bivariate random effects model. RESULTS: Seventeen studies (3,702 observations) were included. Settings were acute medicine, surgery, a care home and the emergency department. Three studies assessed performance of the 4AT in stroke. The overall prevalence of delirium was 24.2% (95% CI 17.8-32.1%; range 10.5-61.9%). The pooled sensitivity was 0.88 (95% CI 0.80-0.93) and the pooled specificity was 0.88 (95% CI 0.82-0.92). Excluding the stroke studies, the pooled sensitivity was 0.86 (95% CI 0.77-0.92) and the pooled specificity was 0.89 (95% CI 0.83-0.93). The methodological quality of studies varied but was moderate to good overall. CONCLUSIONS: The 4AT shows good diagnostic test accuracy for delirium in the 17 available studies. These findings support its use in routine clinical practice in delirium detection. PROSPERO REGISTRATION NUMBER: CRD42019133702.


Assuntos
Delírio , Idoso , Delírio/diagnóstico , Serviço Hospitalar de Emergência , Avaliação Geriátrica , Humanos , Programas de Rastreamento , Sensibilidade e Especificidade
3.
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
4.
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.


Assuntos
Disfunção Cognitiva/enfermagem , Disfunção Cognitiva/reabilitação , Educação em Saúde/estatística & dados numéricos , Insuficiência Cardíaca/enfermagem , Insuficiência Cardíaca/reabilitação , Readmissão do Paciente/estatística & dados numéricos , Adaptação Psicológica , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/complicações , Feminino , Insuficiência Cardíaca/complicações , Humanos , Masculino , Estudos Prospectivos , Medição de Risco , Fatores de Risco
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 V̇O2,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.


Assuntos
Tolerância ao Exercício , Coração/fisiologia , Miocárdio/patologia , Envelhecimento , Ração Animal , Animais , Animais Recém-Nascidos , Dieta/veterinária , Dieta com Restrição de Proteínas , Feminino , Frequência Cardíaca , Masculino , Desnutrição , Fenômenos Fisiológicos da Nutrição Materna , Camundongos , Fatores Sexuais
6.
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
7.
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
8.
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
9.
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
10.
J Mol Cell Cardiol ; 70: 56-63, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24184998

RESUMO

Aging has been associated with adverse fibrosis. Here we formulate a new hypothesis and present new evidence that unresponsiveness of mesenchymal stem cells (MSC) and fibroblasts to transforming growth factor beta (TGF-ß), due to reduced expression of TGF-ß receptor I (TßRI), provides a foundation for cardiac fibrosis in the aging heart via two mechanisms. 1) TGF-ß promotes expression of Nanog, a transcription factor that retains MSC in a primitive state. In MSC derived from the aging heart, Nanog expression is reduced and therefore MSC gradually differentiate and the number of mesenchymal fibroblasts expressing collagen increases. 2) As TGF-ß signaling pathway components negatively regulate transcription of monocyte chemoattractant protein-1 (MCP-1), a reduced expression of TßRI prevents aging mesenchymal cells from shutting down their own MCP-1 expression. Elevated MCP-1 levels that originated from MSC attract transendothelial migration of mononuclear leukocytes from blood to the tissue. MCP-1 expressed by mesenchymal fibroblasts promotes further migration of monocytes and T lymphocytes away from the endothelial barrier and supports the monocyte transition into macrophages and finally into myeloid fibroblasts. Both myeloid and mesenchymal fibroblasts contribute to fibrosis in the aging heart via collagen synthesis. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium ".


Assuntos
Envelhecimento/metabolismo , Fibroblastos/metabolismo , Fibrose/metabolismo , Células-Tronco Mesenquimais/metabolismo , Envelhecimento/patologia , Diferenciação Celular , Colágeno/genética , Colágeno/metabolismo , Fibroblastos/patologia , Fibrose/patologia , Fibrose/fisiopatologia , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Células-Tronco Mesenquimais/patologia , Monócitos/metabolismo , Monócitos/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Proteína Homeobox Nanog , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
11.
FASEB J ; 27(4): 1761-71, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23303205

RESUMO

With age, the collagen content of the heart increases, leading to interstitial fibrosis. We have shown that CD44(pos) fibroblasts derived from aged murine hearts display reduced responsiveness to TGF-ß but, paradoxically, have increased collagen expression in vivo and in vitro. We postulated that this phenomenon was due to the defect in mesenchymal stem cell (MSC) differentiation in a setting of elevated circulating insulin levels and production that we observed in aging mice. We discovered that cultured fibroblasts derived from aged but not young cardiac MSCs of nonhematopoietic lineage displayed increased basal and insulin-induced (1 nM) collagen expression (2-fold), accompanied by increased farnesyltransferase (FTase) and Erk activities. In a quest for a possible mechanism, we found that a chronic pathophysiologic insulin concentration (1 nM) caused abnormal fibroblast differentiation of MSCs isolated from young hearts. Fibroblasts derived from these MSCs responded to insulin by elevating collagen expression as seen in untreated aged fibroblast cultures, suggesting a causal link between increased insulin levels and defective MSC responses. Here we report an insulin-dependent pathway that specifically targets collagen type I transcriptional activation leading to a unique mechanism of fibrosis that is TGF-ß and inflammation-independent in the aged heart.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Fibroblastos/citologia , Coração/efeitos dos fármacos , Insulina/farmacologia , Envelhecimento , Animais , Células Cultivadas , Colágeno/biossíntese , Colágeno Tipo I/metabolismo , Fibrose/metabolismo , Insulina/sangue , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Fator de Crescimento Transformador beta/metabolismo
12.
J Am Geriatr Soc ; 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39412893

RESUMO

BACKGROUND: Recruiting older adults into clinical trials can be particularly challenging. Our objective was to determine if targeted web-based advertising is an effective recruitment strategy. METHODS: We compared the recruitment rates of traditional and targeted web-based methods for three representative clinical trials involving older adults. All studies utilized traditional recruitment methods initially, but shifted toward primarily targeted web-based advertising after experiencing slow recruitment rates. RESULTS: We found that web-based advertising reached more individuals compared to traditional methods. Compared to traditional methods, web-based methods also had at least twice the rate of expressed interest, completion of telephone and in-person screening, eligibility, and enrollment. Additionally, the proportion of individuals excluded after the telephone screening did not differ according to whether targeted web-based advertising (STAMINA: 51%; Berries and Steps: 62%; ISTIM: 20%) or traditional methods (STAMINA: 48%; Berries and Steps: 69%; ISTIM: 23%) were used within each study. Those recruited using web-based advertisements tended to be younger compared to traditional methods, but were similar in racial distribution and education. CONCLUSION: Targeted web-based advertisements may be more effective in recruiting older adults for clinical trials at a faster rate than traditional recruitment methods, but need further evaluation of compatible study designs, potential population bias, and cost-effectiveness.

13.
Artigo em Inglês | MEDLINE | ID: mdl-39492659

RESUMO

Common features of the aging heart are dysregulated metabolism, inflammation, and fibrosis. Elevated oxidative stress is another hallmark of cardiac aging that can exacerbate each of these conditions. We hypothesize that by increasing natural antioxidant levels (glutathione), we will improve cardiac function. Twenty-one-month-old mice were fed Glycine and N-Acetyl Cysteine (GlyNAC) (glutathione precursors)-supplemented or control diets for 12 weeks. Heart function was monitored longitudinally, and the exercise performance was determined at the end of the study. We found that the GlyNAC diet was beneficial for old male but not old female mice, leading to an increase of Ndufb8 expression (a subunit of the mitochondrial respiratory chain complex), and higher enzymatic activity for CPT1b and CrAT, two carnitine acyltransferases that are critical to cardiomyocyte metabolism. Although no quantifiable change of collagen turnover was detected, hearts from GlyNAC-fed old males exhibited a slight but significant enrichment in Fmod, a protein that can inhibit collagen fibril formation, possibly reducing extracellular matrix (ECM) stiffness and thus improving diastolic function. Cardiac diastolic function was modestly improved in males but not females, and surprisingly GlyNAC-fed female mice showed a decline in exercise performance. In summary, our work supports the concept that aged male and female hearts are phenotypically different. These basic differences may affect the response to pharmacological and diet interventions, including antioxidants.

14.
Curr Probl Cardiol ; 49(1 Pt C): 102131, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37866417

RESUMO

BACKGROUND: Reduction of diastolic blood pressure (DBP) below 70 mmHg may decrease perfusion to the heart and worsen cardiovascular (CV) outcomes. AIMS: Explore the association between low DBP and CV outcomes. METHODS: We searched the online databases until August 2023 for studies reporting the risk of all-cause mortality (ACM) or CV outcomes in patients with low versus normal DBP (70-80mm Hg). RESULTS: Inclusion of 10 studies (n = 1,998,223 patients) found that a mean achieved DBP < 60 mmHg was associated with an increased risk of all-cause mortality (HR 1.48; 95 % CI [1.26-1.74]), especially in patients with pre-existing CV disease. It was also associated to a higher risk of major adverse cardiovascular events (HR 1.84; [1.28-2.65]) and myocardial infarction (HR 1.49; [1.13-1.97]). A DBP of 60-69 mmHg was associated with an increased risk of all-cause mortality (HR 1.11; [1.03-1.20]). CONCLUSION: Reduction of DBP, particularly below 60 mmHg, is associated with increased risk of ACM.


Assuntos
Doenças Cardiovasculares , Insuficiência Cardíaca , Hipertensão , Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Pressão Sanguínea/fisiologia , Hipertensão/complicações , Hipertensão/epidemiologia , Acidente Vascular Cerebral/etiologia , Infarto do Miocárdio/etiologia , Insuficiência Cardíaca/complicações , Doenças Cardiovasculares/epidemiologia
15.
bioRxiv ; 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38798364

RESUMO

Alzheimer's Disease (AD) is a global health issue, affecting over 6 million in the United States, with that number expected to increase as the aging population grows. As a neurodegenerative disorder that affects memory and cognitive functions, it is well established that AD is associated with cardiovascular risk factors beyond only cerebral decline. However, the study of cerebrovascular techniques for AD is still evolving. Here, we provide reproducible methods to measure impedance-based pulse wave velocity (PWV), a marker of arterial stiffness, in the systemic vascular (aortic PWV) and in the cerebral vascular (cerebral PWV) systems. Using aortic impedance and this relatively novel technique of cerebral impedance to comprehensively describe the systemic vascular and the cerebral vascular systems, we examined the sex-dependent differences in 5x transgenic mice (5XFAD) with AD under normal and high-fat diet, and in wild-type mice under a normal diet. Additionally, we validated our method for measuring cerebrovascular impedance in a model of induced stress in 5XFAD. Together, our results show that sex and diet differences in wildtype and 5XFAD mice account for very minimal differences in cerebral impedance. Interestingly, 5XFAD, and not wildtype, male mice on a chow diet show higher cerebral impedance, suggesting pathological differences. Opposingly, when we subjected 5XFAD mice to stress, we found that females showed elevated cerebral impedance. Using this validated method of measuring impedance-based aortic and cerebral PWV, future research may explore the effects of modifying factors including age, chronic diet, and acute stress, which may mediate cardiovascular risk in AD.

16.
J Mol Cell Cardiol ; 63: 26-36, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23871790

RESUMO

We have demonstrated that scar formation after myocardial infarction (MI) is associated with an endogenous pool of CD44(pos)CD45(neg) multipotential mesenchymal stem cells (MSC). MSC differentiate into fibroblasts secreting collagen that forms a scar and mature into myofibroblasts that express alpha smooth muscle actin (α-SMA) that stabilizes the scar. In the aging mouse, cardiac repair after MI is associated with impaired differentiation of MSC; MSC derived from the aged hearts form dysfunctional fibroblasts that deposit less collagen in response to transforming growth factor beta-1 (TGF-ß1) and poorly mature into myofibroblasts. We found in vitro that the defect in myofibroblast maturation can be remedied by AICAR, which activates non-canonical TGF-ß signaling through AMP-activated protein kinase (AMPK). In the present study, we injected aged mice with AICAR and subjected them to 1h occlusion of the left anterior descending artery (LAD) and then reperfusion for up to 30days. AICAR-dependent AMPK signaling led to mobilization of an endogenous CD44(pos)CD45(neg) MSC and its differentiation towards fibroblasts and myofibroblasts in the infarct. This was accompanied by enhanced collagen deposition and collagen fiber maturation in the scar. The AICAR-treated group has demonstrated reduced adverse remodeling as indicated by improved apical end diastolic dimension but no changes in ejection fraction and cardiac output were observed. We concluded that these data indicate the novel, previously not described role of AMPK in the post-MI scar formation. These findings can potentially lead to a new therapeutic strategy for prevention of adverse remodeling in the aging heart.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Cicatriz/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Ribonucleotídeos/farmacologia , Aminoimidazol Carboxamida/administração & dosagem , Aminoimidazol Carboxamida/farmacologia , Animais , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Masculino , Camundongos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Fosforilação/efeitos dos fármacos , Ribonucleotídeos/administração & dosagem , Remodelação Ventricular/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
17.
J Mol Cell Cardiol ; 57: 59-67, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23337087

RESUMO

Angiotensin-II (Ang-II) is associated with many conditions involving heart failure and pathologic hypertrophy. Ang-II induces the synthesis of monocyte chemoattractant protein-1 that mediates the uptake of CD34(+)CD45(+) monocytic cells into the heart. These precursor cells differentiate into collagen-producing fibroblasts and are responsible for the Ang-II-induced development of non-adaptive cardiac fibrosis. In this study, we demonstrate that in vitro, using a human monocyte-to-fibroblast differentiation model, Ang-II required the presence of tumor necrosis factor-alpha (TNF) to induce fibroblast maturation from monocytes. In vivo, mice deficient in both TNF receptors did not develop cardiac fibrosis in response to 1week Ang-II infusion. We then subjected mice deficient in either TNF receptor 1 (TNFR1-KO) or TNF receptor 2 (TNFR2-KO) to continuous Ang-II infusion. Compared to wild-type, in TNFR1-KO, but not in TNFR2-KO hearts, collagen deposition was greatly attenuated, and markedly fewer CD34(+)CD45(+) cells were present. Quantitative RT-PCR demonstrated a striking reduction of key fibrosis-related, as well as inflammation-related mRNA expression in Ang-II-treated TNFR1-KO hearts. TNFR1-KO animals also developed less cardiac remodeling, cardiac hypertrophy, and hypertension compared to wild-type and TNFR2-KO in response to Ang-II. Our data suggest that TNF induced Ang-II-dependent cardiac fibrosis by signaling through TNFR1, which enhances the generation of monocytic fibroblast precursors in the heart.


Assuntos
Angiotensina II/fisiologia , Cardiomegalia/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais , Animais , Cardiomegalia/patologia , Diferenciação Celular , Tamanho Celular , Células Cultivadas , Técnicas de Cocultura , Colágeno/metabolismo , Citocinas/genética , Citocinas/metabolismo , Fibrose , Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Migração Transendotelial e Transepitelial , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/fisiologia
18.
Circulation ; 125(22): 2751-61, 2012 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-22570371

RESUMO

BACKGROUND: Delineating the role of microRNAs (miRNAs) in the posttranscriptional gene regulation offers new insights into how the heart adapts to pathological stress. We developed a knockout of miR-22 in mice and investigated its function in the heart. METHODS AND RESULTS: Here, we show that miR-22-deficient mice are impaired in inotropic and lusitropic response to acute stress by dobutamine. Furthermore, the absence of miR-22 sensitized mice to cardiac decompensation and left ventricular dilation after long-term stimulation by pressure overload. Calcium transient analysis revealed reduced sarcoplasmic reticulum Ca(2+) load in association with repressed sarcoplasmic reticulum Ca(2+) ATPase activity in mutant myocytes. Genetic ablation of miR-22 also led to a decrease in cardiac expression levels for Serca2a and muscle-restricted genes encoding proteins in the vicinity of the cardiac Z disk/titin cytoskeleton. These phenotypes were attributed in part to inappropriate repression of serum response factor activity in stressed hearts. Global analysis revealed increased expression of the transcriptional/translational repressor purine-rich element binding protein B, a highly conserved miR-22 target implicated in the negative control of muscle expression. CONCLUSION: These data indicate that miR-22 functions as an integrator of Ca(2+) homeostasis and myofibrillar protein content during stress in the heart and shed light on the mechanisms that enhance propensity toward heart failure.


Assuntos
Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , MicroRNAs/genética , MicroRNAs/metabolismo , Contração Miocárdica/fisiologia , Estresse Fisiológico/fisiologia , Animais , Cálcio/metabolismo , Cardiomiopatia Dilatada/patologia , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/fisiologia , Homeostase/fisiologia , Masculino , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Fator de Resposta Sérica/metabolismo
19.
J Gerontol A Biol Sci Med Sci ; 78(1): 75-89, 2023 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-35975308

RESUMO

BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial. METHODS: Twenty-four OA and 12 young adults (YA) were studied. OA was randomized to receive either GlyNAC (N = 12) or isonitrogenous alanine placebo (N = 12) for 16-weeks; YA (N = 12) received GlyNAC for 2-weeks. Participants were studied before, after 2-weeks, and after 16-weeks of supplementation to assess GSH concentrations, OxS, MFO, molecular regulators of energy metabolism, inflammation, endothelial function, IR, aging hallmarks, gait speed, muscle strength, 6-minute walk test, body composition, and blood pressure. RESULTS: Compared to YA, OA had GSH deficiency, OxS, mitochondrial dysfunction (with defective molecular regulation), inflammation, endothelial dysfunction, IR, multiple aging hallmarks, impaired physical function, increased waist circumference, and systolic blood pressure. GlyNAC (and not placebo) supplementation in OA improved/corrected these defects. CONCLUSION: GlyNAC supplementation in OA for 16-weeks was safe and well-tolerated. By combining the benefits of glycine, NAC and GSH, GlyNAC is an effective nutritional supplement that improves and reverses multiple age-associated abnormalities to promote health in aging humans. Clinical Trials Registration Number: NCT01870193.


Assuntos
Acetilcisteína , Resistência à Insulina , Humanos , Camundongos , Animais , Idoso , Acetilcisteína/farmacologia , Acetilcisteína/metabolismo , Glicina/metabolismo , Promoção da Saúde , Estresse Oxidativo , Envelhecimento/fisiologia , Glutationa , Suplementos Nutricionais , Resistência à Insulina/fisiologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mitocôndrias/metabolismo
20.
J Am Coll Cardiol ; 82(7): 631-647, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37389519

RESUMO

Geroscience posits that cardiovascular disease (CVD) and other chronic diseases result from progressive erosion of the effectiveness of homeostatic mechanisms that oppose age-related accumulation of molecular damage. This hypothetical common root to chronic diseases explains why patients with CVD are often affected by multimorbidity and frailty and why older age negatively affects CVD prognosis and treatment response. Gerotherapeutics enhance resilience mechanisms that counter age-related molecular damage to prevent chronic diseases, frailty, and disability, thereby extending healthspan. Here, we describe the main resilience mechanisms of mammalian aging, with a focus on how they can affect CVD pathophysiology. We next present novel gerotherapeutic approaches, some of which are already used in management of CVD, and explore their potential to transform care and management of CVD. The geroscience paradigm is gaining traction broadly in medical specialties, with potential to mitigate premature aging, reduce health care disparities, and improve population healthspan.


Assuntos
Doenças Cardiovasculares , Fragilidade , Geriatria , Idoso , Humanos , Envelhecimento/fisiologia , Doenças Cardiovasculares/prevenção & controle , Doença Crônica , Gerociência
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