RESUMO
Performance evaluation of new dialysis membranes is primarily performed in vitro, which can lead to differences in clinical results. Currently, data on dialysis membrane performance and safety are available only for haemodialysis patients. Herein, we aimed to establish an in vivo animal model of dialysis that could be extrapolated to humans. We created a bilateral nephrectomy pig model of renal failure, which placed a double-lumen catheter with the hub exposed dorsally. Haemodialysis was performed in the same manner as in humans, during which clinically relevant physiologic data were evaluated. Next, to evaluate the utility of this model, the biocompatibility of two kinds of membranes coated with or without vitamin E used in haemodiafiltration therapy were compared. Haemodialysis treatment was successfully performed in nephrectomized pigs under the same dialysis conditions (4 h per session, every other day, for 2 weeks). In accordance with human clinical data, regular dialysis alleviated renal failure in pigs. The vitamin E-coated membrane showed a significant reduction rate of advanced oxidation protein products during dialysis than non-coated membrane. In conclusion, this model mimics the pathophysiology and dialysis condition of patients undergoing haemodialysis. This dialysis treatment model of renal failure will be useful for evaluating the performance and safety of dialysis membranes.
Assuntos
Modelos Animais de Doenças , Membranas Artificiais , Diálise Renal , Animais , Diálise Renal/instrumentação , Suínos , Vitamina E , Teste de Materiais , Materiais Revestidos Biocompatíveis , Nefrectomia , Hemodiafiltração/instrumentação , Hemodiafiltração/métodosRESUMO
OBJECTIVE: The primary care for acute coronary syndrome (ACS) includes the administration of nitroglycerin (GTN). This study aimed to investigate the association between the use of GTN before percutaneous coronary intervention (PCI) for ACS and clinical outcomes. METHODS: Nine-hundred and forty-seven patients who underwent PCI for ACS were examined and classified into two groups: those who were treated with GTN before PCI (GTN group) and those who were not (non-GTN group). The incidence of major adverse cardiovascular events (MACE), which consist of all-cause mortality, non-fatal myocardial infarction, stroke and rehospitalisation for heart failure at 1 year, was compared between the two groups. RESULTS: This study identified 289 patients with ACS who used GTN preceding PCI. Pre-PCI systolic blood pressure was significantly lower in the GTN group than in the non-GTN group (median (IQR); 132.0 (110.0-143.5) mm Hg vs 134.0 (112.0-157.0) mm Hg, respectively, p=0.03). Multivariate Cox regression analysis indicated that GTN use preceding PCI showed an independent association with the incidence of MACE (HR 1.57; 95% CI 1.09-2.28; p=0.016). Overall, the incidence of MACE 1 year after PCI for ACS was significantly higher in the GTN group than in the non-GTN group (log-rank test, p=0.024); however, this trend was consistently found in elderly patients aged ≥75 years (p=0.002) but not in non-elderly patients aged <75 years (p=0.773). CONCLUSIONS: GTN use preceding PCI for ACS is associated with lower blood pressure and adverse clinical outcomes in elderly patients.
Assuntos
Síndrome Coronariana Aguda , Infarto do Miocárdio , Intervenção Coronária Percutânea , Idoso , Humanos , Pessoa de Meia-Idade , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/terapia , Nitroglicerina/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Resultado do Tratamento , Infarto do Miocárdio/epidemiologiaRESUMO
PURPOSE: The purpose of this study was to investigate the morphological characteristics of the aortic valve and identify factors associated with the progression of aortic valve stenosis (AS) in osteoporosis patients. METHODS: In this single-center prospective cohort study, we recruited 10 patients (mean age: 75 ± 7 years, 90% female) who were taking anti-resorptive medicines at the outpatient clinic of University of Miyazaki Hospital, Japan. Baseline assessments, including transthoracic echocardiogram, blood sampling, and dual energy X-ray absorptiometry, were performed. Follow-up assessments were conducted at 6, 12, 18, and 24 months. RESULTS: During the 2-year follow-up, three patients with aortic valve peak flow velocity (AV PFV) ≥2 m/s at baseline developed moderate AS, which is defined as AV PFV ≥3 m/s. However, seven patients with AV PFV <2 m/s did not exhibit any progression of AS. There were significant variations in terms of bone mineral density, T-score values, and biomarkers associated with bone turnover (i.e., bone alkaline phosphatase, tartrate-resistance acid phosphatase-5b) among the enrolled patients, but none of these factors were found to be associated with the progression of AS. All patients exhibited low vitamin D status, with a median level of 16.1 ng/mL (25th percentile, 9.7 ng/mL; 75th percentile, 23 ng/mL). The baseline levels of AV PFV values were negatively correlated with 25-hydroxyvitamin D levels, determined by univariate linear regression analysis (beta coefficient = -0.756, 95% confidence interval, -0.136 ̶ -0.023, p = 0.011). CONCLUSION: Our data suggest that low vitamin D status might be a potential risk factor for the progression of AS in osteoporosis patients undergoing treatment with anti-resorptive medicines. Elderly patients with osteoporosis patients exhibited a subset of aortic valve stenosis. Our data suggest that the baseline aortic valve peak flow velocity predicts the progression of aortic valve stenosis, and there might be an association between the progression and the co-existing low vitamin D status in these patients.
Assuntos
Estenose da Valva Aórtica , Osteoporose , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Masculino , Valva Aórtica/diagnóstico por imagem , Estudos Prospectivos , Estenose da Valva Aórtica/diagnóstico por imagem , Vitamina D , Osteoporose/diagnóstico por imagem , Osteoporose/complicaçõesRESUMO
Excessive activation of the sympathetic nervous system is involved in cardiovascular damage including cardiac hypertrophy. Natriuretic peptides are assumed to exert protective actions for the heart, alleviating hypertrophy and/or fibrosis of the myocardium. In contrast to this assumption, we show in the present study that both atrial and C-type natriuretic peptides (ANP and CNP) potentiate cardiac hypertrophic response to noradrenaline (NA) in rats. Nine-week-old male Wistar rats were continuously infused with subcutaneous 30 micro-g/h NA without or with persistent intravenous administration of either 1.0 micro-g/h ANP or CNP for 14 days. Blood pressure (BP) was recorded under an unrestrained condition by a radiotelemetry system. Cardiac hypertrophic response to NA was evaluated by heart weight/body weight (HW/BW) ratio and microscopic measurement of myocyte size of the left ventricle. Mean BP levels at the light and dark cycles rose by about 20 mmHg following NA infusion for 14 days, with slight increases in HW/BW ratio and ventricular myocyte size. Infusions of ANP and CNP had no significant effects on mean BP in NA-infused rats, while two natriuretic peptides potentiated cardiac hypertrophic response to NA. Cardiac hypertrophy induced by co-administration of NA and ANP was attenuated by treatment with prazosin or atenolol. In summary, both ANP and CNP potentiated cardiac hypertrophic effect of continuously infused NA in rats, suggesting a possible pro-hypertrophic action of natriuretic peptides on the heart.
Assuntos
Fator Natriurético Atrial , Norepinefrina , Ratos , Animais , Masculino , Ratos Wistar , Norepinefrina/farmacologia , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , Pressão Sanguínea , Peptídeo Natriurético Tipo C/farmacologia , Peptídeo Natriurético Encefálico/farmacologiaRESUMO
The relationship between coronary artery calcium (CAC) and bleeding events after percutaneous coronary intervention (PCI) in patients with chronic coronary syndrome (CCS) is not well established. This study aimed to examine the association between CAC scores and clinical outcomes after PCI in patients with CCS. This retrospective observational study included 295 consecutive patients who underwent multidetector computer tomography and were scheduled for their first elective PCI. Patients were categorized into two groups based on the CAC scores (low: ≤ 400 or high: > 400). The bleeding risk was evaluated using the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria. The primary clinical outcome was a major bleeding event within 1 year after PCI, defined as Bleeding Academic Research Consortium (BARC) 3 or 5. The high CAC score group had a higher proportion of patients meeting the ARC-HBR criteria than the low CAC score group (52.7% vs. 31.3%, p < 0.001). Kaplan-Meier survival analysis showed that the incidence of major bleeding events was higher in the high CAC score group as compared to the low CAC score group (p < 0.001). Furthermore, multivariate Cox regression anal ysis revealed that a high CAC score was an independent determinant of major bleeding events during the first year after PCI. A high CAC score is significantly associated with the incidence of major bleeding events after PCI in CCS patients.
Assuntos
Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Humanos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/diagnóstico por imagem , Cálcio , Resultado do Tratamento , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Fatores de Risco , Hemorragia/etiologia , Hemorragia/induzido quimicamente , Síndrome , Inibidores da Agregação Plaquetária/efeitos adversosRESUMO
Objective: We reported that rats infused with angiotensin II (Ang II) are not only a model of hypertension but also of augmented 24 h blood pressure variability (BPV). In this study, we examined the mechanisms for Ang II-induced BPV, focusing on BP, heart rate (HR), baroreceptor reflex sensitivity (BRS), and medial area of the aortic arch. Methods: Nine-week-old male Wistar rats were infused with subcutaneous 5.2 µg/kg/h Ang II with or without oral administration with 30 mg/kg/day azelnidipine for 14 days. BP and HR were recorded every 15 min under an unrestrained condition by a radiotelemetry system, while BPV was evaluated by standard deviation of BP. BRS was quantified by a sequence analysis, and medial thickness of the aortic arch was measured by microscopic examination. Results: BPV increased at days 7 and 14 following continuous infusion of Ang II. Before the infusion, a positive correlation was found between BP and HR, but it became negative at day 7 and then weakened or disappeared at day 14. BRS was slightly impaired at day 7 and significantly lowered at day 14, a phenomenon accompanied by thickened medial area of the aortic arch in Ang II-infused rats. Those Ang II-induced alterations were all significantly attenuated by azelnidipine. Conclusions: The present findings suggest sequential changes in the mechanisms behind augmented BPV in rats continuously infused with Ang II over 14 days.
Assuntos
Angiotensina II , Hipertensão , Ratos , Masculino , Animais , Pressão Sanguínea , Angiotensina II/farmacologia , Ratos Wistar , Hipertensão/tratamento farmacológicoRESUMO
BACKGROUND: Bystander intervention in cases of out-of-hospital cardiac arrest (OHCA) is a key factor in bridging the gap between the event and the arrival of emergency health services at the site. This study investigated the implementation rate of bystander cardiopulmonary resuscitation (CPR) and automated external defibrillator (AED) and 1-month survival after OHCA in Miyazaki prefecture and Miyazaki city district as well as compared them with those of eight prefectures in the Kyushu-Okinawa region in Japan. In addition, we analyzed prehospital factors associated with survival outcomes in Miyazaki city district. METHODS: We used data from an annual report released by the Fire and Disaster Management Agency of Japan (n = 627,982) and the Utstein reporting database in Miyazaki city district (n = 1,686) from 2015 to 2019. RESULT: Despite having the highest rate of bystander CPR (20.8%), the 1-month survival rate (15.7%) of witnessed OHCA cases of cardiac causes in Miyazaki city district was comparable with that in the eight prefectures between 2015 and 2019. However, rates of survival (10.7%) in Miyazaki prefecture were lower than those in other prefectures. In 1,686 patients with OHCA (74 ± 18 years old, 59% male) from the Utstein reporting database identical to the 5-year study period in Miyazaki city district, binary logistic regression analysis demonstrated that age of the recipient [odds ratio (OR) 0.979, 95% confidential interval (CI) 0.964-0.993, p = 0.004)], witness of the arrest event (OR 7.501, 95% CI 3.229-17.428, p < 0.001), AED implementation (OR 14.852, 95% CI 4.226-52.201, p < 0.001), and return of spontaneous circulation (ROSC) before transport (OR 31.070, 95% CI 16.585-58.208, p < 0.001) predicted the 1-month survival with favorable neurological outcomes. In addition, chest compression at a public place (p < 0.001) and by nonfamily members (p < 0.001) were associated with favorable outcomes (p = 0.015). CONCLUSIONS: We found differences in 1-month survival rates after OHCA in the Kyushu-Okinawa region of Japan. Our results suggest that on-field ROSC with defibrillation performed by nonfamily bystanders who witnessed the event determines 1-month neurological outcomes after OHCA in Miyazaki city district. Continued education of citizens on CPR techniques and better access to AED devices may improve outcomes.
Assuntos
Reanimação Cardiopulmonar , Serviços Médicos de Emergência , Parada Cardíaca Extra-Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Reanimação Cardiopulmonar/métodos , Desfibriladores , Taxa de Sobrevida , Japão/epidemiologia , Sistema de RegistrosRESUMO
Background: Cardiac troponin-T (TNNT2) is exclusively present in cardiac muscle. Measurement of TNNT2 is used for diagnosing acute coronary syndrome. However, its expression may not be limited in myocardium. This study aimed at evaluating the expression of TNNT2 in neoplastic tissues. Methods and Results: We used paraffin-embedded blocks of 68 patients with lung cancer (age, 68 ± 11 years old; early-stage, 33; advance-stage, 35) at Miyazaki University Hospital, Japan between January 1, 2017, and March 31, 2019. We stained the slide sections with primary monoclonal antibody against TNNT2 protein, and assessed the frequency of positive staining, and its association with pathological severity. In addition, we examined whether TNNT2 gene is detected in lung cancer tissues of four patients using reverse transcription-polymerase chain reaction. Immunoreactivity for TNNT2 protein was present in the cytoplasm and nucleus of lung cancer cells. The frequency was 37% (25 of 68) in all patients and was irrespective of histologic type (six of 13, squamous cell carcinoma; 18 of 50, adenocarcinoma; 0 of 4, neuroendocrine cell carcinoma; 1 of 1, large cell carcinoma). The prevalence increased with pathological staging [9% (3 of 33) at early-stage (Stage 0-I); 63% (22 of 35) at advance-stage (Stage II-IV and recurrence)]. In addition, frequency of positive staining for TNNT2 increased with pleural (χ2 = 5.877, P = 0.015) and vascular (χ2 = 2.449, P = 0.118) invasions but decreased with lymphatic invasion (χ2 = 3.288, P = 0.070) in specimens performed surgical resection. Furthermore, TNNT2 mRNA was detected in the resected squamous cell carcinoma and adenocarcinoma tissues. Conclusions: Our data suggest the aberrant expression of TNNT2 in lung cancer and its prevalence increases with pathological severity.
RESUMO
Background The biological mechanism of action for osteoprotegerin, a soluble decoy receptor for the receptor activator of nuclear factor-kappa B ligand in the vascular structure, has not been elucidated. The study aim was to determine if osteoprotegerin affects aortic structural integrity in angiotensin II (Ang II)-induced hypertension. Methods and Results Mortality was higher (P<0.0001 by log-rank test) in 8-week-old male homozygotes of osteoprotegerin gene-knockout mice given subcutaneous administration of Ang II for 28 days, with an incidence of 21% fatal aortic rupture and 23% aortic dissection, than in age-matched wild-type mice. Ang II-infused aorta of wild-type mice showed that osteoprotegerin immunoreactivity was present with proteoglycan. The absence of osteoprotegerin was associated with decreased medial and adventitial thickness and increased numbers of elastin breaks as well as with increased periostin expression and soluble receptor activator of nuclear factor-kappa B ligand concentrations. PEGylated human recombinant osteoprotegerin administration decreased all-cause mortality (P<0.001 by log-rank test), the incidence of fatal aortic rupture (P=0.08), and aortic dissection (P<0.001) with decreasing numbers of elastin breaks, periostin expressions, and soluble receptor activator of nuclear factor-kappa B ligand concentrations in Ang II-infused osteoprotegerin gene-knockout mice. Conclusions These data suggest that osteoprotegerin protects against aortic rupture and dissection in Ang II-induced hypertension by inhibiting receptor activator of nuclear factor-kappa B ligand activity and periostin expression.
Assuntos
Dissecção Aórtica , Ruptura Aórtica , Hipertensão , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/genética , Angiotensina II/farmacologia , Animais , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/genética , Ruptura Aórtica/prevenção & controle , Modelos Animais de Doenças , Elastina , Hipertensão/induzido quimicamente , Hipertensão/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ligante RANK/genética , Ligante RANK/metabolismoRESUMO
BACKGROUND: Fabry disease (FD) is an X-chromosome-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. CASE SUMMARY: A 51-year-old Japanese woman with a previous diagnosis of FD presented with pericardial effusion. The exudative pericardial fluid contained globotriaosylsphingosine. Left ventricular hypertrophy progressed despite regular administration of agalsidase alfa every 2 weeks over a 7-year period, with increases in plasma levels of globotriaosylsphingosine and interleukin (IL)-18. In addition, the IL-6 level in the pericardial fluid was markedly higher than that in plasma. DISCUSSION: This case suggests that elevated IL-6 and IL-18 levels in pericardial fluid and plasma indicate the severity of FD cardiomyopathy.
RESUMO
Arrhythmogenic cardiomyopathy (ACM) caused by TMEM43 p.S358L is a fully penetrant heart disease that results in impaired cardiac function or fatal arrhythmia. However, the molecular mechanism of ACM caused by the TMEM43 variant has not yet been fully elucidated. In this study, we generated knock-in (KI) rats harboring a Tmem43 p.S358L mutation and established induced pluripotent stem cells (iPSCs) from patients based on the identification of TMEM43 p.S358L variant from a family with ACM. The Tmem43-S358L KI rats exhibited ventricular arrhythmia and fibrotic myocardial replacement in the subepicardium, which recapitulated the human ACM phenotype. The four-transmembrane protein TMEM43 with the p.S358L variant (TMEM43S358L ) was found to be modified by N-linked glycosylation in both KI rat cardiomyocytes and patient-specific iPSC-derived cardiomyocytes. TMEM43S358L glycosylation increased under the conditions of enhanced endoplasmic reticulum (ER) stress caused by pharmacological stimulation or age-dependent decline of the ER function. Intriguingly, the specific glycosylation of TMEM43S358L resulted from the altered membrane topology of TMEM43. Moreover, unlike TMEM43WT , which is mainly localized to the ER, TMEM43S358L accumulated at the nuclear envelope of cardiomyocytes with the increase in glycosylation. Finally, our comprehensive transcriptomic analysis demonstrated that the regional differences in gene expression patterns between the inner and outer layers observed in the wild type myocardium were partially diminished in the KI myocardium prior to exhibiting histological changes indicative of ACM. Altogether, these findings suggest that the aberrant accumulation of TMEM43S358L underlies the pathogenesis of ACM caused by TMEM43 p.S358L variant by affecting the transmural gene expression within the myocardium.
Assuntos
Cardiomiopatias , Proteínas de Membrana/fisiologia , Miocárdio/metabolismo , Adulto , Idoso , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Células Cultivadas , Feminino , Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação , Miócitos Cardíacos , RatosRESUMO
We herein report the cytokine expression at different stages for three patients who developed cardiac complications after immune checkpoint inhibitor (ICI) therapy. Case 1 with biopsy-proven myocarditis showed increased levels of interleukin (IL)-8, monocyte chemotactic and activating factor, and granulocyte macrophage colony-stimulating factor (GM-CSF) when he developed Takotsubo cardiomyopathy. Case 2 with subclinical myocarditis showed predominant activation of IL-8 during the progressive clinical course. Case 3 with cytokine-releasing syndrome showed substantial activations of IL-6, IL-8, GM-CSF, and interferon-γ. Our data suggest the development of unique cytokine activation in individual patients with cardiac complications after ICI therapy.
Assuntos
Citocinas , Inibidores de Checkpoint Imunológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Humanos , Interferon gama , Masculino , MonócitosRESUMO
We describe the case of a patient with neuroendocrine ethmoid sinus carcinoma, who exhibited markedly elevated levels of serum cardiac troponin-T and creatine kinase (CK)-MB isoenzyme without any symptom after the administration of nivolumab, immune checkpoint inhibitor. The repeated 12-leads-electrocardiogram did not show any changes in the ST-T segments or arrhythmias. The echocardiogram showed normal ranges of left ventricular contraction in the clinical course. Cardiac magnetic resonance imaging showed minimal myocardial edema and inflammation. Blood clots in the metastatic lesion of bone marrow aspirates exhibited positive staining for cardiac troponin-T and CK-MB in the cytoplasm and nucleoplasm of neoplastic cells. Although we did not perform a second cardiac magnetic resonance imaging and autopsy, we postulate that the attack of the neoplastic cells by the immune checkpoint inhibitor or the secretion from neoplastic cell-derived extracellular vesicles may have exacerbated the increase in concentrations of these molecules in the blood. Our case should warrant consideration a false-positive value of cardiac troponin-T and CK-MB can be obtained in cases with malignancy.
RESUMO
Juvenile Paget disease (JPD1), an autosomal-recessive disorder, is characterized by extremely rapid bone turnover due to osteoprotegerin deficiency. Its extra-skeletal manifestations, such as hypertension and heart failure, suggest a pathogenesis with shared skeletal and cardiovascular system components. In spite of this, the effects of anti-hypertensive drugs on bone morphometry remain unknown. We administered an angiotensin II type 1 receptor blocker, olmesartan (5 mg/kg/day) to 8-week-old male mice lacking the osteoprotegerin gene, with and without 1 µg/kg/min of angiotensin II infusion for 14 days. Olmesartan treatment decreased systolic blood pressure, and echocardiography showed increased left ventricular systolic contractility. Three-dimensional micro-computed tomography scans demonstrated that olmesartan treatment increased trabecular bone volume (sham, +176%; angiotensin II infusion, +335%), mineral density (sham, +150%; angiotensin II infusion, +313%), and trabecular number (sham, +407%; angiotensin II infusion, +622%) in the tibia. Olmesartan increased cortical mineral density (sham, +19%; angiotensin II infusion, +24%), decreased the cortical bone section area (sham, -16%; angiotensin II infusion, -18%), decreased thickness (sham, -18%; angiotensin II infusion, -31%), and decreased the lacunar area (sham, -41%; angiotensin II infusion, -27%) in the tibia. Similar trend was observed in the femur. Moreover, olmesartan decreased angiotensin II-induced increases in tartrate-resistant acid phosphatase concentrations in plasma, but it affected neither type I procollagen N-terminal propeptides, nor the receptor activator of nuclear factor kappa-B ligand. Our data suggest that blockade of the angiotensin II type 1 receptor improves bone vulnerability, and helps to maintain the heart's structural integrity in osteoprotegerin-deficient mice.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Densidade Óssea/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/fisiopatologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Fêmur/efeitos dos fármacos , Fêmur/patologia , Fêmur/fisiopatologia , Hipertrofia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Osteíte Deformante/metabolismo , Osteíte Deformante/patologia , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Ligante RANK/sangue , Sístole/efeitos dos fármacos , Sístole/fisiologia , Fosfatase Ácida Resistente a Tartarato/sangueRESUMO
Adrenomedullin (AM), a peptide isolated from an extract of human pheochromocytoma, comprises 52 amino acids with an intramolecular disulfide bond and amidation at the carboxy-terminus. AM is present in various tissues and organs in rodents and humans, including the heart. The peptide concentration increases with cardiac hypertrophy, acute myocardial infarction, and overt heart failure in the plasma and the myocardium. The principal function of AM in the cardiovascular system is the regulation of the vascular tone by vasodilation and natriuresis via cyclic adenosine monophosphate-dependent or -independent mechanism. In addition, AM may possess unique properties that inhibit aldosterone secretion, oxidative stress, apoptosis, and stimulation of angiogenesis, resulting in the protection of the structure and function of the heart. The AM receptor comprises a complex between calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP) 2 or 3, and the AM-CLR/RAMP2 system is essential for heart development during embryogenesis. Small-scale clinical trials have proven the efficacy and safety of recombinant AM peptide therapy for heart failure. Gene delivery and a modified AM peptide that prolongs the half-life of the native peptide could be an innovative method to improve the efficacy and benefit of AM in clinical settings. In this review, we focus on the pathophysiological roles of AM and its receptor system in the heart and describe the advances in AM and proAM-derived peptides as diagnostic biomarkers as well as the therapeutic application of AM and modified AM for cardioprotection.
Assuntos
Adrenomedulina/metabolismo , Animais , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Cardiomegalia/metabolismo , Insuficiência Cardíaca/metabolismo , Humanos , Proteína 2 Modificadora da Atividade de Receptores/metabolismo , Proteína 3 Modificadora da Atividade de Receptores/metabolismoRESUMO
RATIONALE: Kawasaki disease (KD) is an acute febrile illness predominantly affecting children less than 5 years of age and characterized by systemic inflammation in all medium-sized arteries. Adult-onset KD (AKD) is rare with only 105 case reports published. Recently, the efficacy of infliximab (IFX) for patients with refractory KD has been demonstrated. PATIENT CONCERNS: A previously healthy 24-year-old man was admitted because of a persistent fever, and elevated serum level of AST, ALT, LDH, and CRP. DIAGNOSIS: The patients met the diagnostic criteria for KD based on the findings of persistent fever, polymorphous exanthema, unilateral cervical lymphadenopathy, non-purulent palpebral conjunctivitis and membranous desquamation. Echocardiogram revealed the dilatation at the proximal sites of the right coronary artery (7.9âmm) and left anterior descending artery (5âmm). The patient was treated with high-dose intravenous immunoglobulin (1âg/kg/day for 2 days) and ASA (100âmg daily). However, his fever and arthralgia persisted. INTERVENTIONS: He was administered single 5âmg/kg doses of IFX. OUTCOMES: He became afebrile the next day and his arthralgia improved. LESSONS: We report the first case of administration of IFX in a patient with AKD refractory to intravenous immunoglobulin (IVIG), and successful reduction of systemic inflammation. However, the effectiveness of IFX in the regression of coronary artery aneurysm remains to be determined.
Assuntos
Antirreumáticos/administração & dosagem , Infliximab/administração & dosagem , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Idade de Início , Humanos , Masculino , Resultado do Tratamento , Adulto JovemRESUMO
Mutations in cardiac myosin-binding protein C (cMyBP-C) are a major cause of familial hypertrophic cardiomyopathy. Although cMyBP-C has been considered to regulate the cardiac function via cross-bridge arrangement at the C-zone of the myosin-containing A-band, the mechanism by which cMyBP-C functions remains unclear. We identified formin Fhod3, an actin organizer essential for the formation and maintenance of cardiac sarcomeres, as a cMyBP-C-binding protein. The cardiac-specific N-terminal Ig-like domain of cMyBP-C directly interacts with the cardiac-specific N-terminal region of Fhod3. The interaction seems to direct the localization of Fhod3 to the C-zone, since a noncardiac Fhod3 variant lacking the cMyBP-C-binding region failed to localize to the C-zone. Conversely, the cardiac variant of Fhod3 failed to localize to the C-zone in the cMyBP-C-null mice, which display a phenotype of hypertrophic cardiomyopathy. The cardiomyopathic phenotype of cMyBP-C-null mice was further exacerbated by Fhod3 overexpression with a defect of sarcomere integrity, whereas that was partially ameliorated by a reduction in the Fhod3 protein levels, suggesting that Fhod3 has a deleterious effect on cardiac function under cMyBP-C-null conditions where Fhod3 is aberrantly mislocalized. Together, these findings suggest the possibility that Fhod3 contributes to the pathogenesis of cMyBP-C-related cardiomyopathy and that Fhod3 is critically involved in cMyBP-C-mediated regulation of cardiac function via direct interaction.
Assuntos
Cardiomiopatia Hipertrófica/metabolismo , Proteínas de Transporte/metabolismo , Proteínas dos Microfilamentos/metabolismo , Miocárdio/metabolismo , Sarcômeros/metabolismo , Animais , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Proteínas de Transporte/genética , Forminas , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Miocárdio/patologia , Ligação Proteica , Domínios Proteicos , Transporte Proteico , Sarcômeros/genética , Sarcômeros/patologiaRESUMO
It is debated whether carbohydrate restriction has metabolic advantage for its variable weight loss. Five-week-old male mice fed a high-fat diet and receiving a glycolytic inhibitor, 2-deoxyglucose, died within 9 days. They exhibited greater decreases in rectal temperature, appetite, and decline in body weight accompanied by increasing total cholesterol level than the other groups. This study suggests that carbohydrate is necessary for adequate physical and metabolic performance when lipid-rich diet is loaded.
Assuntos
Desoxiglucose/farmacologia , Dieta com Restrição de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Glicólise/efeitos dos fármacos , Animais , Regulação do Apetite/efeitos dos fármacos , Biomarcadores/sangue , Regulação da Temperatura Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Fatores de Tempo , Redução de Peso/efeitos dos fármacosAssuntos
Dissecção Aórtica/diagnóstico por imagem , Fluordesoxiglucose F18/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Idoso de 80 Anos ou mais , Humanos , Inflamação/diagnóstico por imagem , Inflamação/metabolismo , Masculino , Fatores de Tempo , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/patologiaRESUMO
Transient left ventricular contractile dysfunction (TLVCD) is often observed as a result of stress-related cardiomyopathy; however, recent reports suggest that rhabdomyolysis and eating disorders can also induce the development of TLVCD. We report a 52-year-old malnourished man who developed acute heart failure on day 4 of treatment for rhabdomyolysis. Transthoracic echocardiogram revealed severe hypokinesis at the apical and mid-ventricular segments, except for the basal segments of the left ventricular wall, which recovered within one week. We discuss the pathogenesis of TLVCD with sympathetic nerve activation in association with rhabdomyolysis or refeeding syndrome.