RESUMO
BACKGROUND: The myocardial longitudinal relaxation time (T1) on cardiac magnetic resonance imaging (CMR) can quantify myocardial fibrosis in the presence or absence of visually detectable late gadolinium (Gd) enhancement (LGE). Mineralocorticoid receptor antagonist (MRA) treatment produces beneficial remodeling in nonischemic dilated cardiomyopathy (NIDCM). We assessed the hypothesis that interstitial myocardial fibrosis measured with the use of CMR predicts left ventricular (LV) beneficial remodeling in NIDCM after heart failure (HF) treatment including MRAs. METHODS AND RESULTS: Twelve patients with NIDCM, on stable beta-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor-blocking therapy, were studied before and after 6-29 months of treatment with MRAs, by means of CMR assessment of LV structure, function, and T1 from standard Look-Locker sequences (T1LL). All patients had depressed cardiac function, dilated left ventricles, and no visual LGE. After adding MRA to HF treatment, the LV ejection fraction increased and the LV end-systolic volume index (LV end-systolic volume/m2) decreased in all patients (P < .0001). This this was inversely proportional to the baseline myocardial T1LL (r = -0.65; P = .02). CONCLUSION: Myocardial T1LL, in the absence of visually detectable LGE, was quantitatively related to the degree of beneficial LV remodeling achieved in response to adding MRA to a HF regimen.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/diagnóstico , Imagem Cinética por Ressonância Magnética/métodos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Miocárdio/patologia , Remodelação Ventricular/fisiologia , Adulto , Quimioterapia Combinada , Feminino , Seguimentos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de TempoAssuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , Imageamento por Ressonância Magnética/métodos , Miocardite/diagnóstico por imagem , Miocardite/etiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , RNA Mensageiro , Estudos Retrospectivos , SARS-CoV-2 , Adulto JovemRESUMO
BACKGROUND: Elevated levels of plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of urokinase plasminogen activator and tissue plasminogen activator, are implicated in the pathogenesis of tissue fibrosis. Paradoxically, lack of PAI-1 in the heart is associated with the development of cardiac fibrosis in aged mice. However, the molecular basis of cardiac fibrosis in aged PAI-1-deficient mice is unknown. Here, we investigated the molecular and cellular bases of myocardial fibrosis. METHODS AND RESULTS: Histological evaluation of myocardial tissues derived from aged PAI-1-deficient mice revealed myocardial fibrosis resulting from excessive accumulation of collagen. Immunohistochemical characterization revealed that the levels of matrix metalloproteinase-2, matrix metalloproteinase-9, and transforming growth factor-ß1/2 and the number of Mac3-positive and fibroblast specific protein-1-positive cells were significantly elevated in aged PAI-1-deficient myocardial tissues compared with controls. Zymographic analysis revealed that matrix metalloproteinase-2 enzymatic activity was elevated in PAI-1-deficient mouse cardiac endothelial cells. Real-time quantitative polymerase chain reaction analyses of RNA from myocardial tissues revealed the upregulation of profibrotic markers in aged PAI-1-deficient mice. The numbers of phosphorylated Smad2-, phosphorylated Smad3-, and phosphorylated ERK1/2 MAPK-, but not pAkt/PKB-, positive cells were significantly increased in PAI-1-deficient myocardial tissues. Western blot and immunocytochemical analysis revealed that PAI-1-deficient mouse cardiac endothelial cells were more susceptible to endothelial-to-mesenchymal transition in response to transforming growth factor-ß2. CONCLUSIONS: These results indicate that spontaneous activation of both Smad and non-Smad transforming growth factor-ß signaling may contribute to profibrotic responses in aged PAI-1-deficient mice hearts and establish a possible link between endothelial-to-mesenchymal transition and cardiac fibrosis in PAI-1-deficient mice.
Assuntos
Envelhecimento/patologia , Endotélio Vascular/patologia , Cardiopatias/genética , Cardiopatias/patologia , Mesoderma/patologia , Serpinas/genética , Fator de Crescimento Transformador beta/metabolismo , Animais , Diferenciação Celular/fisiologia , Colágeno/metabolismo , Modelos Animais de Doenças , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Cardiopatias/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Proteína A4 de Ligação a Cálcio da Família S100 , Proteínas S100/metabolismo , Serpina E2 , Serpinas/deficiência , Serpinas/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Importance: The utility of cardiac magnetic resonance imaging (MRI) as a screening tool for myocarditis in competitive student athletes returning to training after recovering from coronavirus disease 2019 (COVID-19) infection is unknown. Objective: To describe the prevalence and severity of cardiac MRI findings of myocarditis in a population of competitive student athletes recovering from COVID-19. Design, Setting, and Participants: In this case series, an electronic health record search was performed at our institution (University of Wisconsin) to identify all competitive athletes (a consecutive sample) recovering from COVID-19, who underwent gadolinium-enhanced cardiac MRI between January 1, 2020, and November 29, 2020. The MRI findings were reviewed by 2 radiologists experienced in cardiac imaging, using the updated Lake Louise criteria. Serum markers of myocardial injury and inflammation (troponin-I, B-type natriuretic peptide, C-reactive protein, and erythrocyte sedimentation rate), an electrocardiogram, transthoracic echocardiography, and relevant clinical data were obtained. Exposures: COVID-19 infection, confirmed using reverse transcription-polymerase chain reaction testing. Main Outcomes and Measures: Prevalence and severity of MRI findings consistent with myocarditis among young competitive athletes recovering from COVID-19. Results: A total of 145 competitive student athletes (108 male and 37 female individuals; mean age, 20 years; range, 17-23 years) recovering from COVID-19 were included. Most patients had mild (71 [49.0%]) or moderate (40 [27.6%]) symptoms during the acute infection or were asymptomatic (24 [16.6%]). Symptoms were not specified or documented in 10 patients (6.9%). No patients required hospitalization. Cardiac MRIs were performed a median of 15 days (range, 11-194 days) after patients tested positive for COVID-19. Two patients had MRI findings consistent with myocarditis (1.4% [95% CI, 0.4%-4.9%]). Of these, 1 patient had marked nonischemic late gadolinium enhancement and T2-weighted signal abnormalities over multiple segments, along with an abnormal serum troponin-I level; the second patient had 1-cm nonischemic mild late gadolinium enhancement and mild T2-weighted signal abnormalities, with normal laboratory values. Conclusions and Relevance: In this case series study, based on MRI findings, there was a low prevalence of myocarditis (1.4%) among student athletes recovering from COVID-19 with no or mild to moderate symptoms. Thus, the utility of cardiac MRI as a screening tool for myocarditis in this patient population is questionable.
Assuntos
COVID-19/complicações , Técnicas de Imagem Cardíaca , Imageamento por Ressonância Magnética , Miocardite/diagnóstico por imagem , Miocardite/etiologia , Volta ao Esporte , Adolescente , Meios de Contraste , Feminino , Gadolínio , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Miocardite/epidemiologia , Prevalência , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Mineralocorticoid receptor antagonist (MRA) treatment produces beneficial left ventricular (LV) remodeling in nonischemic dilated cardiomyopathy (NIDCM). This study addressed the timing of maximal beneficial LV remodeling in NIDCM when adding MRA. MATERIALS AND METHODS: We studied 12 patients with NIDCM on stable ß-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor-blocking therapy who underwent cardiac magnetic resonance imaging before and after 6-31 months of continuous MRA therapy. RESULTS: At baseline, the LV ejection fraction (LVEF) was 24% (19-27); median [interquartile range]. The LV end-systolic volume index (LVESVI) was 63 ml (57-76) and the LV stroke volume index (LVSVI) was 19 ml (14-21), all depressed. After adding MRA to the HF regimen, the LVEF increased to 47% (42-52), with a decrease in LVESVI to 36 ml (33-45) and increase in LVSVI to 36 ml (28-39) (for each, P < 0 .0001). Using generalized least squares analysis, the maximal beneficial remodeling (defined by maximal increase in LVEF, the maximal decrease in LVESVI and maximal increase in LVSVI) was achieved after approximately 12-16 months of MRA treatment. CONCLUSIONS: Adding MRA to a standard medical regimen for NIDCM resulted in beneficial LV remodeling. The maximal beneficial remodeling was achieved with 12-16 months of MRA therapy. These results have implications for the timing of other advanced therapies, such as placing internal cardioverter-defibrillators.
Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Imageamento por Ressonância Magnética , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Volume Sistólico/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Antagonistas Adrenérgicos beta/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/tratamento farmacológico , Cardiomiopatia Dilatada/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Fatores de TempoRESUMO
OBJECTIVES: This study examined plasma levels of certain matrix metalloproteinase (MMP) and tissue inhibitor of matrix metalloproteinase (TIMP) species before and after alcohol-induced myocardial infarction (MI) in patients with hypertrophic obstructive cardiomyopathy (HOCM). BACKGROUND: Matrix metalloproteinases contribute to tissue remodeling, and endogenous control of MMP activity is achieved by the concordant release and binding of TIMPs. Animal models of MI have demonstrated a role for MMP activation in myocardial remodeling. However, the temporal relationship of MMP and TIMP release following a controlled myocardial injury in humans remains unknown. METHODS: Plasma levels for the gelatinases MMP-2 and MMP-9, and for the collagenases MMP-8 and MMP-13, as well as TIMP-1 profiles were examined (by enzyme-linked immunosorbent assay) at baseline and serially up to 60 h following alcohol injection into the septal perforator artery in order to induce an MI in 51 patients with HOCM (age 55 +/- 2 years). RESULTS: Plasma creatine kinase (MB isoform), indicating myocardial injury, increased 2,150% 18 h post-MI (p < 0.05). Plasma MMP-9 increased by over 400% and MMP-8 by over 100% from baseline values by 12 h post-MI (p < 0.05 vs. baseline). A similar temporal profile was not observed for MMP-2 and MMP-13. In addition, a concomitant increase in plasma TIMP-1 levels did not occur post-MI. As a result, MMP/TIMP stoichiometry (MMP-9/TIMP-1 ratio) increased significantly post-MI, suggestive of reduced TIMP-1 mediated MMP-9 inhibition, which would potentially enhance extracellular myocardial remodeling. CONCLUSIONS: These unique results demonstrated that induction of a controlled myocardial injury in humans, specifically through alcohol-induced MI, caused species- and time-dependent perturbations of MMP/TIMP stoichiometry that would facilitate myocardial remodeling in the early post-MI setting.
Assuntos
Álcoois/uso terapêutico , Cardiomiopatia Hipertrófica/sangue , Metaloproteinases da Matriz/sangue , Infarto do Miocárdio/induzido quimicamente , Inibidores Teciduais de Metaloproteinases/sangue , Área Sob a Curva , Cardiomiopatia Hipertrófica/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangueRESUMO
A milestone in the progression of congestive heart failure (CHF) is myocardial remodeling. Left ventricular (LV) remodeling during the progression of CHF is accompanied by changes in the structure of the myocardial extracellular matrix. Recent clinical and experimental studies have noted that increased release of tumor necrosis factor alpha (TNF-alpha) can contribute to LV myocardial remodeling. Experimental studies have noted that the induction of TNF-alpha can result in LV dilation and proceed to LV pump dysfunction. The biological effects of TNF-alpha are mediated through TNF receptors that are present on all nucleated cells in the heart. TNF receptor activation can induce a number of cellular and molecular events which contribute to LV remodeling in CHF, and include changes in myocyte size and viability and alterations in myocardial structure/composition. In vitro studies have demonstrated that TNF receptor activation can cause the induction of a proteolytic system. This proteolytic system, the matrix metalloproteinases (MMPs), is upregulated in models of LV dysfunction and possesses the capacity to degrade a wide variety of extracellular matrix components. Therefore, one pathway by which TNF-alpha can influence LV myocardial remodeling is through the induction of a specific portfolio of MMP species. Future basic and clinical studies which directly alter TNF receptor activity and measure myocardial MMP species and the relation to LV remodeling will provide new insight into this disease process and future therapeutic modalities.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Fator de Necrose Tumoral alfa/fisiologia , Remodelação Ventricular , Animais , Progressão da Doença , Humanos , Metaloproteinases da Matriz/fisiologia , Transdução de SinaisRESUMO
We examined the hypothesis that insulin resistance (IR) decreases circulating concentrations of N-terminal (NT)-probrain natriuretic peptide (BNP). Obesity, despite being a risk factor for heart failure (HF), is paradoxically associated with lower concentrations of BNP, a marker of myocardial stress. Low BNP in obesity is postulated to be due to IR; however, it has been difficult to define the role of IR independent of obesity. IR in rheumatoid arthritis (RA) is increased, independent of obesity, thus allowing potential mechanistic insights into the relationship between IR and BNP. We measured demographic factors, traditional cardiovascular risk factors, body mass index (BMI), markers of inflammation (interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor α (TNFα)), NT-proBNP, and IR by the homeostatic model assessment (HOMA) in 140 patients with RA and 82 control subjects. Patients with heart failure and coronary artery disease were excluded. We used multiple linear regression models to examine the relationship between HOMA and NT-proBNP in RA and controls and in RA alone, the additional effect of inflammation. As previously reported, NT-proBNP concentrations were higher in RA (median 80.49 pg/mL, IQR (23.67-167.08 pg/mL)) than controls (17.84 pg/mL (3.28-36.28 pg/mL)) (P < 0.001), and the prevalence of IR, defined by HOMA > 2.114, was higher among RA than controls (53 % vs. 15%, P > 0.001). HOMA was positively correlated with NT-proBNP (rho = 0.226, P = 0.007) in RA, but not in controls (rho = -0.154, P = 0.168). In a multivariable model adjusted for age, race, and sex, we found that increasing HOMA was statistically associated with increasing NT-proBNP concentrations in RA (P = 0.001), but not controls (P = 0.543) (P for interaction = 0.036). In RA subjects, when IL-6 was further included in the model, IL-6 (P = 0.0014), but not HOMA (P = 0.43), remained significantly associated with NT-proBNP, suggesting that IL-6 may be mechanistically involved in the relationship between IR and NT-proBNP in RA. We conclude that in patients with RA, insulin resistance is associated with higher, rather than the expected lower, concentrations of NT-proBNP and that this may be related to increased IL-6.
Assuntos
Artrite Reumatoide/imunologia , Resistência à Insulina/fisiologia , Interleucina-6/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Feminino , Humanos , Inflamação/imunologia , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Obesidade/imunologia , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVES: We examined the hypothesis that cardiac-specific troponin-I (cTn-I), a biomarker of myocardial injury, is elevated in patients with rheumatoid arthritis (RA). BACKGROUND: RA patients have an increased incidence of heart failure (HF). Chronic myocardial injury in RA may be a mechanism for the development of HF. METHODS: We compared cTn-I concentrations measured by high-sensitivity immunoassay in 164 patients with RA and 90 controls, excluding prior or active heart failure. We examined the relationship between cTn-I concentrations and cardiovascular risk factors, inflammation, and coronary artery calcium score (CACS), a measure of coronary atherosclerosis. RESULTS: cTn-I concentrations were 49% higher in patients with RA (median 1.15 pg/mL [IQR 0.73-1.92] than controls (0.77 pg/mL [0.49-1.28](P<0.001). The difference remained statistically significant after adjustment for demographic characteristics (P = 0.002), further adjustment for cardiovascular (CV) risk factors (P = 0.004), inflammatory markers (P = 0.008), and in a comprehensive model of CV risk factors and inflammatory markers (P = 0.03). In patients with RA, cTn-I concentrations were positively correlated with age (rho = 0.359), Framingham risk score (FRS) (rho = 0.366), and systolic blood pressure (rho = 0.248 (all P values ≤ 0.001)), but not with measures of inflammation or RA drug therapies. cTn-I was significantly correlated with CACS in RA in univariate analysis, but not after adjustment for age, race, sex and FRS (P = 0.79). Further model adjustments for renal function and coronary artery disease confirmed the significance of the findings. CONCLUSION: High-sensitivity cTn-I concentrations are elevated in patients with RA without heart failure, independent of cardiovascular risk profile and inflammatory markers. Elevated troponin concentrations in RA may indicate subclinical, indolent myocardial injury.
Assuntos
Artrite Reumatoide/diagnóstico , Biomarcadores/metabolismo , Calcinose/diagnóstico , Doença da Artéria Coronariana/diagnóstico , Insuficiência Cardíaca/diagnóstico , Inflamação/diagnóstico , Troponina I/metabolismo , Artrite Reumatoide/complicações , Artrite Reumatoide/metabolismo , Calcinose/etiologia , Calcinose/metabolismo , Estudos de Casos e Controles , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Método Simples-CegoRESUMO
Reproductive age women (5-10%) are affected by the polycystic ovarian syndrome (PCOS), a diagnosis which confers lifelong cardiovascular and reproductive health implications. Plasminogen activator inhibitor-1 (PAI-1), the main physiological inhibitor of plasminogen activation, is consistently elevated in women with PCOS, regardless of metabolic status. Interestingly, the plasminogen system has long been implicated in proteolytic processes within the dynamic ovary. A non-physiologic elevation in PAI-1 may thus contribute systemically to endothelial dysfunction and locally to abnormal ovarian phenotype and function. We herein characterize the phenotypic alterations in ovaries from transgenic mice, which constitutively express a stable form of human PAI-1 and determine the plasma testosterone level in these mice as opposed to their unaffected counterparts. Over half of the ovaries from transgenic mice were found to contain large cystic structures, in contrast to wild-type controls of the same genetic background (53% (N = 17) vs 5% (N = 22); P = 0.001). Plasma testosterone was nearly twofold elevated in transgenic female mice versus wild-type females (0.312 ng/ml +/- 0.154 (N = 10) vs 0.181 ng/ml +/- 0.083 (N = 8); P = 0.014). An elevation in PAI-1 therefore appears to predispose mice to the development of this abnormal architecture, which in turn is associated with an increase in plasma testosterone. Therefore, we propose that an inappropriate elevation in PAI-1 contributes to the development of polycystic structures; these findings may thus reorient the efforts aimed at the development of therapeutic agents for the treatment of this increasingly common syndrome.
Assuntos
Inibidor 1 de Ativador de Plasminogênio/genética , Síndrome do Ovário Policístico/genética , Animais , Endotelina-1/genética , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Ovário/patologia , Ovário/fisiologia , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/patologia , Regiões Promotoras Genéticas , Valores de Referência , Testosterona/sangueRESUMO
The cytokine tumor necrosis factor (TNF)-alpha has been causally linked to left ventricular (LV) remodeling, but the molecular basis for this effect is unknown. Matrix metalloproteinases (MMPs) have been implicated in cardiac remodeling and can be regulated by TNF-alpha. This study tested the central hypothesis that administration of a TNF-alpha blocking protein would prevent the induction of MMPs and alter the course of myocardial remodeling in developing LV failure. Adult dogs were randomly assigned to the following groups: 1) chronic pacing (250 beats/min, 28 days, n = 12), 2) chronic pacing with concomitant administration of a TNF-alpha blocking protein (TNF block) using a soluble p75 TNF receptor fusion protein (TNFR:Fc; administered at 0.5 mg/kg twice a week subcutaneously, n = 7), and 3) normal controls (n = 10). LV end-diastolic volume increased from control with chronic pacing (83 +/- 12 vs. 118 +/- 10 ml, P < 0.05) and was reduced with TNF block (97 +/- 9 ml, P < 0.05). MMP zymographic levels (92 kDa, pixels) increased from control with chronic pacing (36,848 +/- 9,593 vs. 87,247 +/- 12,912, P < 0.05) and was normalized by TNF block. Myocardial MMP-9 and MMP-13 levels by immunoblot increased with chronic pacing relative to controls (130 +/- 10% and 118 +/- 6%, P < 0.05) and was normalized by TNF block. These results provide evidence to suggest that TNF-alpha contributes to the myocardial remodeling process in evolving heart failure through the local induction of specific MMPs.