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While radiation therapy (RT) can improve cancer outcomes, it can lead to radiation-induced heart dysfunction (RIHD) in patients with thoracic tumors. This study examines the role of adaptive immune cells in RIHD. In Salt-Sensitive (SS) rats, image-guided whole-heart RT increased cardiac T-cell infiltration. We analyzed the functional requirement for these cells in RIHD using a genetic model of T- and B-cell deficiency (interleukin-2 receptor gamma chain knockout (IL2RG-/-)) and observed a complex role for these cells. Surprisingly, while IL2RG deficiency conferred protection from cardiac hypertrophy, it worsened heart function via echocardiogram three months after a large single RT dose, including increased end-systolic volume (ESV) and reduced ejection fraction (EF) and fractional shortening (FS) (p < 0.05). Fractionated RT, however, did not yield similarly increased injury. Our results indicate that T cells are not uniformly required for RIHD in this model, nor do they account for our previously reported differences in cardiac RT sensitivity between SS and SS.BN3 rats. The increasing use of immunotherapies in conjunction with traditional cancer treatments demands better models to study the interactions between immunity and RT for effective therapy. We present a model that reveals complex roles for adaptive immune cells in cardiac injury that vary depending on clinically relevant factors, including RT dose/fractionation, sex, and genetic background.
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Background The SNRK (sucrose-nonfermenting-related kinase) enzyme is critical for cardiac function. However, the underlying cause for heart failure observed in Snrk cardiac conditional knockout mouse is unknown. Methods and Results Previously, 6-month adult mice knocked out for Snrk in cardiomyocytes (CMs) displayed left ventricular dysfunction. Here, 4-month adult mice, on angiotensin II (Ang II) infusion, show rapid decline in cardiac systolic function, which leads to heart failure and death in 2 weeks. These mice showed increased expression of nuclear factor κ light chain enhancer of activated B cells (NF-κB), inflammatory signaling proteins, proinflammatory proteins in the heart, and fibrosis. Interestingly, under Ang II infusion, mice knocked out for Snrk in endothelial cells did not show significant systolic or diastolic dysfunction. Although an NF-κB inflammation signaling pathway was increased in Snrk knockout endothelial cells, this did not lead to fibrosis or mortality. In hearts of adult mice knocked out for Snrk in CMs, we also observed NF-κB pathway activation in CMs, and an increased presence of Mac2+ macrophages was observed in basal and Ang II-infused states. In vitro analysis of Snrk knockdown HL-1 CMs revealed similar upregulation of the NF-κB signaling proteins and proinflammatory proteins that was exacerbated on Ang II treatment. The Ang II-induced NF-κB pathway-mediated proinflammatory effects were mediated in part through protein kinase B or AKT, wherein AKT inhibition restored the proinflammatory signaling protein levels to baseline in Snrk knockdown HL-1 CMs. Conclusions During heart failure, SNRK acts as a cardiomyocyte-specific repressor of cardiac inflammation and fibrosis.
Assuntos
Células Endoteliais/metabolismo , Insuficiência Cardíaca/genética , Inflamação/genética , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/genética , Angiotensina II/farmacologia , Animais , Linhagem Celular , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Coração/efeitos dos fármacos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Técnicas In Vitro , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Knockout , Miocárdio/patologia , Vasoconstritores/farmacologia , Disfunção Ventricular EsquerdaRESUMO
In patients with sickle cell disease (SCD), poor outcome measures compromise the potential success of clinical trials. Contrast-enhanced ultrasound (CEUS) is a technique that can non-invasively quantify deep tissue microvascular blood flow. We tested the hypothesis that CEUS of forearm skeletal muscle could be used to: 1) assess microvascular abnormalities that occur during vaso-occlusive crisis; and 2) test new therapies for SCD that are targeted to improving the status of the microcirculation. We performed a prospective study, CEUS perfusion imaging of resting forearm muscle was performed in adults with SCD: 1) during and after a pain episode, and 2) before, during, and after a 24-hour infusion of the investigative agent, regadenoson, an adenosine A2A agonist. CEUS destruction-replenishment time-intensity data were analyzed to measure microvascular blood flow, as well as its components, microvascular blood volume and flux rate. Serial CEUS measurements were obtained in 32 adults with SCD. For the studies during crisis, there was a 30% reduction in microvascular blood flow compared to steady-state (p = 0.031), a reduction that was largely due to microvascular flux rate. For the regadenoson group, a non-significant 25% increase in flux rate and 9% increase in microvascular blood flow compared to baseline were detected during infusion. In a study of adults with SCD, CEUS detected changes in microvascular blood flow associated with vaso-occlusive crises. No changes were found during an infusion of the adenosine A2A agonist, regadenoson. This study provides preliminary evidence that CEUS could detect blood flow changes consistent with SCD physiology.
Assuntos
Anemia Falciforme/diagnóstico por imagem , Anemia Falciforme/fisiopatologia , Microcirculação/fisiologia , Ultrassonografia/métodos , Agonistas do Receptor A2 de Adenosina/farmacologia , Adulto , Meios de Contraste , Feminino , Antebraço/irrigação sanguínea , Antebraço/diagnóstico por imagem , Antebraço/fisiopatologia , Humanos , Aumento da Imagem , Masculino , Microcirculação/efeitos dos fármacos , Pessoa de Meia-Idade , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Estudos Prospectivos , Purinas/farmacologia , Pirazóis/farmacologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Adulto JovemRESUMO
OBJECTIVE: Bariatric surgery, including sleeve gastrectomy (SG), significantly improves cardiac geometry and function in patients with heart failure. In this study, we used the obese Zucker rat as an animal model of heart failure with preserved ejection fraction (HFpEF) to test the hypothesis that a SG will improve cardiac function independent of weight loss. METHODS AND RESULTS: Obese, male Zucker rats underwent SG, pair-fed sham, or ad-lib sham surgery. Lean Zucker rats also underwent ad-lib sham surgery. Echocardiograms were performed preoperatively and at 6 weeks postoperatively. Obese SG and obese pair-fed sham rats had similar body weights postoperatively. Obese SG and lean, ad-lib, sham rats had a significant increase in postoperative stroke volume, and left ventricular internal diameter in diastole and systole. SG preserved systolic function and significantly improved isovolumetric relaxation time (13.9 ± 2.4 to 11.1 ± 2.1 ms, Pâ¯=â¯.02) independent of weight loss. DISCUSSION: SG has a beneficial impact on both systolic and diastolic cardiac function in obese Zucker rats toward a lean phenotype independent of weight loss and caloric restriction. These findings may represent a weight-loss independent mechanism generated from the gastrointestinal tract that has the potential to improve diastolic dysfunction independent of obesity status and translate to patients with HFpEF.
Assuntos
Gastrectomia , Insuficiência Cardíaca/terapia , Ventrículos do Coração/diagnóstico por imagem , Obesidade/cirurgia , Volume Sistólico , Disfunção Ventricular Esquerda/terapia , Animais , Colesterol/sangue , Modelos Animais de Doenças , Ecocardiografia , Período Pós-Operatório , Ratos ZuckerRESUMO
Radiation therapy is used in ~50% of cancer patients to reduce the risk of recurrence and in some cases improve survival. Despite these benefits, doses can be limited by toxicity in multiple organs, including the heart. The underlying causes and biomarkers of radiation-induced cardiotoxicity are currently unknown, prompting the need for experimental models with inherent differences in sensitivity and resistance to the development of radiation-induced cardiotoxicity. We have identified the parental SS (Dahl salt-sensitive/Mcwi) rat strain to be a highly-sensitized model of radiation-induced cardiotoxicity. In comparison, substitution of rat chromosome 3 from the resistant BN (Brown Norway) rat strain onto the SS background (SS-3BN consomic) significantly attenuated radiation-induced cardiotoxicity. SS-3BN rats had less radiation-induced cardiotoxicity than SS rats, as measured by survival, pleural and pericardial effusions, echocardiogram parameters, and histological damage. Mast cells, previously shown to have predominantly protective roles in radiation-induced cardiotoxicity, were increased in the more resistant SS-3BN hearts postradiation. RNA sequencing from SS and SS-3BN hearts at 1 wk postradiation revealed 5,098 differentially expressed candidate genes across the transcriptome and 350 differentially expressed genes on rat chromosome 3, which coincided with enrichment of multiple pathways, including mitochondrial dysfunction, sirtuin signaling, and ubiquitination. Upstream regulators of enriched pathways included the oxidative stress modulating transcription factor, Nrf2, which is located on rat chromosome 3. Nrf2 target genes were also differentially expressed in the SS vs. SS-3BN consomic hearts postradiation. Collectively, these data confirm the existence of heritable modifiers in radiation-induced cardiotoxicity and provide multiple biomarkers, pathways, and candidate genes for future analyses. NEW & NOTEWORTHY This novel study reveals that heritable genetic factors have the potential to modify normal tissue sensitivity to radiation. Gene variant(s) on rat chromosome 3 can contribute to enhanced cardiotoxicity displayed in the SS rats vs. the BN and SS-3BN consomic rats. Identifying genes that lead to understanding the mechanisms of radiation-induced cardiotoxicity represents a novel method to personalize radiation treatment, as well as predict the development of radiation-induced cardiotoxicity.
Assuntos
Mapeamento Cromossômico , Cromossomos de Mamíferos , Genes Modificadores , Variação Genética , Cardiopatias/genética , Lesões por Radiação/genética , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Cardiopatias/metabolismo , Cardiopatias/patologia , Masculino , Mastócitos/metabolismo , Mastócitos/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Lesões por Radiação/metabolismo , Lesões por Radiação/patologia , Ratos Endogâmicos BN , Ratos Endogâmicos Dahl , Transdução de SinaisRESUMO
Total-body irradiation causes acute and delayed toxicity to hematopoietic, pulmonary, cardiac, gastrointestinal, renal, and other organ systems. Angiotensin-converting enzyme inhibitors mitigate many of the delayed injuries to these systems. The purpose of this study was to define echocardiographic features in rats at two times after irradiation, the first before lethal radiation pneumonitis (50 d) and the second after recovery from pneumonitis but before lethal radiation nephropathy (100 d), and to determine the actions of the angiotensin-converting enzyme inhibitor lisinopril. Four groups of female WAG/RijCmcr rats at 11-12 wk of age were studied: nonirradiated, nonirradiated plus lisinopril, 13-Gy partial-body irradiation sparing one hind leg (leg-out partial-body irradiation), and 13-Gy leg-out partial-body irradiation plus lisinopril. Lisinopril was started 7 d after radiation. Echocardiograms were obtained at 50 and 100 d, and cardiac histology was assessed after 100 d. Irradiation without lisinopril demonstrated echocardiographic transient pulmonary hypertension by 50 d which was largely resolved by 100 d in survivors. Irradiated rats given lisinopril showed no increase in pulmonary artery pressures at 50 d but exhibited left ventricular remodeling. By 100 d these rats showed some signs of pulmonary hypertension. Lisinopril alone had no impact on echocardiographic end points at either time point in nonirradiated rats. Mild increases in mast cells and fibrosis in the heart were observed after 100 d following 13-Gy leg-out partial-body irradiation. These data demonstrate irradiation-induced pulmonary hypertension which was reversed in survivors of pneumonitis. Lisinopril modified cardiovascular remodeling to enhance survival in this model from 41% to 86% (p = 0.0013).
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Hipertensão Pulmonar/etiologia , Lisinopril/uso terapêutico , Lesões Experimentais por Radiação/tratamento farmacológico , Pneumonite por Radiação/tratamento farmacológico , Remodelação Ventricular/efeitos da radiação , Animais , Ecocardiografia , Feminino , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/prevenção & controle , Miocárdio/patologia , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/prevenção & controle , Pneumonite por Radiação/complicações , Pneumonite por Radiação/prevenção & controle , RatosRESUMO
BACKGROUND: Augmentation of tissue blood flow by therapeutic ultrasound is thought to rely on convective shear. Microbubble contrast agents that undergo ultrasound-mediated cavitation markedly amplify these effects. We hypothesized that purinergic signaling is responsible for shear-dependent increases in muscle perfusion during therapeutic cavitation. METHODS: Unilateral exposure of the proximal hindlimb of mice (with or without ischemia produced by iliac ligation) to therapeutic ultrasound (1.3 MHz, mechanical index 1.3) was performed for 10 minutes after intravenous injection of 2×108 lipid microbubbles. Microvascular perfusion was evaluated by low-power contrast ultrasound perfusion imaging. In vivo muscle ATP release and in vitro ATP release from endothelial cells or erythrocytes were assessed by a luciferin-luciferase assay. Purinergic signaling pathways were assessed by studying interventions that (1) accelerated ATP degradation; (2) inhibited P2Y receptors, adenosine receptors, or KATP channels; or (3) inhibited downstream signaling pathways involving endothelial nitric oxide synthase or prostanoid production (indomethacin). Augmentation in muscle perfusion by ultrasound cavitation was assessed in a proof-of-concept clinical trial in 12 subjects with stable sickle cell disease. RESULTS: Therapeutic ultrasound cavitation increased muscle perfusion by 7-fold in normal mice, reversed tissue ischemia for up to 24 hours in the murine model of peripheral artery disease, and doubled muscle perfusion in patients with sickle cell disease. Augmentation in flow extended well beyond the region of ultrasound exposure. Ultrasound cavitation produced an ≈40-fold focal and sustained increase in ATP, the source of which included both endothelial cells and erythrocytes. Inhibitory studies indicated that ATP was a critical mediator of flow augmentation that acts primarily through either P2Y receptors or adenosine produced by ectonucleotidase activity. Combined indomethacin and inhibition of endothelial nitric oxide synthase abolished the effects of therapeutic ultrasound, indicating downstream signaling through both nitric oxide and prostaglandins. CONCLUSIONS: Therapeutic ultrasound using microbubble cavitation to increase muscle perfusion relies on shear-dependent increases in ATP, which can act through a diverse portfolio of purinergic signaling pathways. These events can reverse hindlimb ischemia in mice for >24 hours and increase muscle blood flow in patients with sickle cell disease. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT01566890.
Assuntos
Trifosfato de Adenosina/metabolismo , Músculo Esquelético/irrigação sanguínea , Purinérgicos/metabolismo , Ultrassonografia/métodos , Animais , Hemodinâmica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microbolhas , Transdução de SinaisRESUMO
BACKGROUND: Cardiac metabolism is critical for the functioning of the heart, and disturbance in this homeostasis is likely to influence cardiac disorders or cardiomyopathy. Our laboratory has previously shown that SNRK (sucrose nonfermenting related kinase) enzyme, which belongs to the AMPK (adenosine monophosphate-activated kinase) family, was essential for cardiac metabolism in mammals. Snrk global homozygous knockout (KO) mice die at postnatal day 0, and conditional deletion of Snrk in cardiomyocytes (Snrk cmcKO) leads to cardiac failure and death by 8 to 10 months. METHODS AND RESULTS: We performed additional cardiac functional studies using echocardiography and identified further cardiac functional deficits in Snrk cmcKO mice. Nuclear magnetic resonance-based metabolomics analysis identified key metabolic pathway deficits in SNRK knockdown cardiomyocytes in vitro. Specifically, metabolites involved in lipid metabolism and oxidative phosphorylation are altered, and perturbations in these pathways can result in cardiac function deficits and heart failure. A phosphopeptide-based proteomic screen identified ROCK (Rho-associated kinase) as a putative substrate for SNRK, and mass spec-based fragment analysis confirmed key amino acid residues on ROCK that are phosphorylated by SNRK. Western blot analysis on heart lysates from Snrk cmcKO adult mice and SNRK knockdown cardiomyocytes showed increased ROCK activity. In addition, in vivo inhibition of ROCK partially rescued the in vivo Snrk cmcKO cardiac function deficits. CONCLUSIONS: Collectively, our data suggest that SNRK in cardiomyocytes is responsible for maintaining cardiac metabolic homeostasis, which is mediated in part by ROCK, and alteration of this homeostasis influences cardiac function in the adult heart.
Assuntos
Células-Tronco Embrionárias/enzimologia , Metabolismo Energético , Insuficiência Cardíaca/enzimologia , Miócitos Cardíacos/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Quinases Associadas a rho/metabolismo , Animais , Células Cultivadas , Ecocardiografia , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/patologia , Metabolismo Energético/efeitos dos fármacos , Fibrose , Predisposição Genética para Doença , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Homozigoto , Células Endoteliais da Veia Umbilical Humana/enzimologia , Metabolismo dos Lipídeos , Espectroscopia de Ressonância Magnética , Metabolômica/métodos , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Fosforilação Oxidativa , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Transdução de Sinais , Transfecção , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
The ability of simvastatin to mitigate the increases in risk factors for and the occurrence of cardiac disease after 10 Gy total body irradiation (TBI) was determined. This radiation dose is relevant to conditioning for stem cell transplantation and threats from radiological terrorism. Male rats received single dose TBI of 10 Gy. Age-matched, sham-irradiated rats served as controls. Lipid profile, heart and liver morphology and cardiac mechanical function were determined for up to 120 days after irradiation. TBI resulted in a sustained increase in total- and LDL-cholesterol (low-density lipoprotein-cholesterol), and triglycerides. Simvastatin (10 mg/kg body weight/day) administered continuously from 9 days after irradiation mitigated TBI-induced increases in total- and LDL-cholesterol and triglycerides, as well as liver injury. TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis. Simvastatin mitigated these morphological injuries. TBI resulted in cardiac mechanical dysfunction. Simvastatin mitigated cardiac mechanical dysfunction 20-120 days following TBI. To determine whether simvastatin affects the ability of the heart to withstand stress after TBI, injury from myocardial ischemia/reperfusion was determined in vitro. TBI increased the severity of an induced myocardial infarction at 20 and 80 days after irradiation. Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI. It is concluded simvastatin mitigated the increases in risk factors for cardiac disease and the extent of cardiac disease following TBI. This statin may be developed as a medical countermeasure for the mitigation of radiation-induced cardiac disease.
RESUMO
To study the mechanisms of death following a single lethal dose of thoracic radiation, WAG/RijCmcr (Wistar) rats were treated with 15 Gy to the whole thorax and followed until they were morbid or sacrificed for invasive assays at 6 weeks. Lung function was assessed by breathing rate and arterial oxygen saturation. Lung structure was evaluated histologically. Cardiac structure and function were examined by echocardiography. The frequency and characteristics of pleural effusions were determined. Morbidity from 15 Gy radiation occurred in all rats 5 to 8 weeks after exposure, coincident with histological pneumonitis. Increases in breathing frequencies peaked at 6 weeks, when profound arterial hypoxia was also recorded. Echocardiography analysis at 6 weeks showed pulmonary hypertension and severe right ventricular enlargement with impaired left ventricular function and cardiac output. Histologic sections of the heart revealed only rare foci of lymphocytic infiltration. Total lung weight more than doubled. Pleural effusions were present in the majority of the irradiated rats and contained elevated protein, but low lactate dehydrogenase, when compared with serum from the same animal. Pleural effusions had a higher percentage of macrophages and large monocytes than neutrophils and contained mast cells that are rarely present in other pathological states. Lethal irradiation to rat lungs leads to hypoxia with infiltration of immune cells, edema and pleural effusion. These changes may contribute to pulmonary vascular and parenchymal injury that result in secondary changes in heart structure and function. We report that conditions resembling congestive heart failure contribute to death during radiation pneumonitis, which indicates new targets for therapy.
Assuntos
Derrame Pleural/fisiopatologia , Lesões por Radiação/fisiopatologia , Pneumonite por Radiação/fisiopatologia , Insuficiência Respiratória/fisiopatologia , Tórax/efeitos da radiação , Irradiação Corporal Total , Animais , Feminino , Insuficiência Cardíaca , Derrame Pleural/etiologia , Doses de Radiação , Lesões por Radiação/etiologia , Pneumonite por Radiação/etiologia , Ratos , Insuficiência Respiratória/etiologia , Taxa de SobrevidaRESUMO
Light chain amyloidosis (AL) involves multiorgan failure induced by amyloidogenic light chain proteins, and is associated with high mortality. We aimed to identify clinical, laboratory, and imaging parameters that would predict 1-year and long-term AL mortality. Forty-four biopsy-proven AL patients (61.5 ± 12 years, 20 females) underwent clinical evaluation including laboratory assays, echocardiography, and contrast cardiac magnetic resonance imaging (CMR, n = 31) prior to chemotherapy. Patients were prospectively followed for median duration of 62.7 months (interquartile range 35.5 months). Clinical and laboratory parameters were compared between 1-year survivors and nonsurvivors. Univariate Kaplan-Meier survival plots were calculated followed by stepwise logistic regression analysis to assess independent predictors of long-term survival. Eighteen (40.9 %) patients died within 1 year and an additional 10 subjects died during long-term follow-up. Patients who expired within 1 year presented with more advanced class of heart failure, higher alkaline phosphatase and uric acid, lower limb lead voltage on electrocardiography, shorter left ventricular ejection time (ET) on echocardiography, and a higher proportion of late gadolinium enhancement on CMR. On multivariable analysis, only ET ≤240 ms on echocardiography (hazard ratio (HR) 5.07, 95 % confidence interval (CI) 1.83-14.1, P = 0.002) and New York Heart Association functional class II-IV presentation (HR 1.0058, 95 % CI 1.0014-1.0103, P = 0.01) were independent predictors of AL mortality. In conclusion, AL amyloidosis is associated with high 1-year and long-term mortality. Among clinical, laboratory, and imaging parameters tested, an echocardiographic finding of ET ≤240 ms has independent and additive prognostic value to clinical heart failure evaluation in determining long-term survival of AL patients. This result may be important in the early identification of patients at risk.
Assuntos
Amiloidose , Gadolínio DTPA , Insuficiência Cardíaca , Cadeias Leves de Imunoglobulina/sangue , Idoso , Proteínas Amiloidogênicas/sangue , Amiloidose/sangue , Amiloidose/complicações , Amiloidose/diagnóstico , Amiloidose/mortalidade , Biópsia , Meios de Contraste , Ecocardiografia/métodos , Eletrocardiografia/métodos , Feminino , Seguimentos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Humanos , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Medição de RiscoRESUMO
Myocardial remodeling and dysfunction are serious complications of type 2 diabetes mellitus (T2DM). Factors controlling their development are not well established. To specifically address the role of the mitochondrial genome, we developed novel conplastic rat strains, i.e. strains with the same nuclear genome but a different mitochondrial genome. The new animals were named T2DN(mtFHH) and T2DN(mtWistar), where the acronym T2DN denotes their common nuclear genome (type 2 diabetic nephropathy (T2DN) rats) and mtFHH or mtWistar the origin of their mitochondria, Fawn Hooded Hypertensive (FHH) or Wistar rats, respectively. The T2DN(mtFHH) and T2DN(mtWistar) showed a similar progression of diabetes as determined by HbA1c, cholesterol, and triglycerides with normal blood pressure, thus enabling investigation of the specific role of the mitochondrial genome in cardiac function without the confounding effects of obesity or hypertension found in other models of diabetes. Echocardiographic analysis of 12-week-old animals showed no abnormalities, but at 12 months of age the T2DN(mtFHH) showed left ventricular remodeling that was verified by histology. Decreased complex I and complex IV but not complex II activity within the electron transport chain was found only in T2DN(mtFHH), which was not explained by differences in protein content. Decreased cardiac ATP levels in T2DN(mtFHH) were in agreement with a lower ATP synthetic capacity by isolated mitochondria. Together, our data provide experimental evidence that mtDNA sequence variations have an additional role in energetic heart deficiency. The mitochondrial DNA background may explain the increased susceptibility of certain T2DM patients to develop myocardial dysfunction.
Assuntos
DNA Mitocondrial/genética , Complicações do Diabetes/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Cardiopatias/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Ecocardiografia/métodos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Variação Genética , Teste de Tolerância a Glucose , Cardiopatias/complicações , Masculino , Microscopia Eletrônica de Transmissão/métodos , Mitocôndrias/metabolismo , Mutação , Miocárdio/patologia , Ratos , Ratos WistarRESUMO
PURPOSE: To determine the impact of 10 Gy total body irradiation (TBI) or local thorax irradiation, a dose relevant to a radiological terrorist threat, on lipid and liver profile, coronary microvasculature and ventricular function. MATERIALS AND METHODS: WAG/RijCmcr rats received 10 Gy TBI followed by bone marrow transplantation, or 10 Gy local thorax irradiation. Age-matched, non-irradiated rats served as controls. The lipid profile and liver enzymes, coronary vessel morphology, nitric oxide synthase (NOS) isoforms, protease activated receptor (PAR)-1 expression and fibrinogen levels were compared. Two-dimensional strain echocardiography assessed global radial and circumferential strain on the heart. RESULTS: TBI resulted in a sustained increase in total and low density lipoprotein (LDL) cholesterol (190 +/- 8 vs. 58 +/- 6; 82 +/- 8 vs. 13 +/- 3 mg/dl, respectively). The density of small coronary arterioles was decreased by 32%. Histology revealed complete blockage of some vessels while cardiomyocytes remained normal. TBI resulted in cellular peri-arterial fibrosis whereas control hearts had symmetrical penetrating vessels with less collagen and fibroblasts. TBI resulted in a 32 +/- 4% and 28 +/- 3% decrease in endothelial NOS and inducible NOS protein, respectively, and a 21 +/- 4% and 35 +/- 5% increase in fibrinogen and PAR-1 protein respectively, after 120 days. TBI reduced radial strain (19 +/- 8 vs. 46 +/- 7%) and circumferential strain (-8 +/- 3 vs. -15 +/- 3%) compared to controls. Thorax-only irradiation produced no changes over the same time frame. CONCLUSIONS: TBI with 10 Gy, a dose relevant to radiological terrorist threats, worsened lipid profile, injured coronary microvasculature, altered endothelial physiology and myocardial mechanics. These changes were not manifest with local thorax irradiation. Non-thoracic circulating factors may be promoting radiation-induced injury to the heart.
Assuntos
Doença da Artéria Coronariana/etiologia , Raios gama/efeitos adversos , Coração/fisiopatologia , Coração/efeitos da radiação , Miocárdio/patologia , Doses de Radiação , Irradiação Corporal Total/efeitos adversos , Animais , Transplante de Medula Óssea , Colágeno/metabolismo , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/patologia , Modelos Animais de Doenças , Fibrinogênio/metabolismo , Fibroblastos/metabolismo , Lipídeos/sangue , Masculino , Óxido Nítrico Sintase/química , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos Wistar , Receptor PAR-1/metabolismo , Fatores de RiscoRESUMO
OBJECTIVE: Light chain amyloidosis (AL) is associated with high mortality. The aim was to identify echocardiographic parameters that predict AL long-term mortality. METHODS: Forty-two subjects with biopsy-proven AL (43% were female; aged 61 +/- 12 years) underwent echocardiography and were followed 29 +/- 16 months (median 29.4 months). Standard echocardiographic and clinical parameters and heart failure (HF) class were tested using univariate/multivariable Cox proportional hazard regression analyses to identify markers of mortality. RESULTS: Twenty-three subjects died, with a 1-year mortality of 44%. Univariate predictors of mortality were HF class (P < .001), left ventricular systolic ejection time (ET) (P = .002), alkaline phosphatase (P < .001), and aspartate and alanine aminotransferase (P = .003 each). On multivariable analysis, only HF class (hazard ratio [HR] 4.86; 95% confidence interval [CI], 1.58-14.9; P = .006), ET (10 ms increase; HR 0.87; CI, 0.78-0.97; P = .01), and alkaline phosphatase (10 U/L increase; HR 1.04; CI, 1.01-1.06; P = .01) were prognostic. ET Assuntos
Amiloidose/diagnóstico por imagem
, Amiloidose/mortalidade
, Ecocardiografia/métodos
, Gestão da Segurança
, Volume Sistólico
, Análise de Sobrevida
, Disfunção Ventricular Esquerda/diagnóstico por imagem
, Disfunção Ventricular Esquerda/mortalidade
, Amiloidose/genética
, Comorbidade
, Feminino
, Alemanha/epidemiologia
, Humanos
, Cadeias Leves de Imunoglobulina/genética
, Estudos Longitudinais
, Masculino
, Pessoa de Meia-Idade
, Prevalência
, Reprodutibilidade dos Testes
, Medição de Risco/métodos
, Fatores de Risco
, Sensibilidade e Especificidade
, Taxa de Sobrevida
, Disfunção Ventricular Esquerda/genética
RESUMO
BACKGROUND: Light chain amyloidosis (AL) is a rare but often fatal disease due to intractable heart failure. Amyloid deposition leads to diastolic dysfunction and often preserved ejection fraction. We hypothesize that AL is associated with regional systolic dyssynchrony. The aim is to compare left ventricular (LV) regional synchrony in AL subjects versus healthy controls using 16-segment dyssynchrony index measured from 3-dimension-al (3D) echocardiography. METHODS: Cardiac 3D echocardiography full volumes were acquired in 10 biopsy-proven AL subjects (60 +/- 3 years, 5 females) and 10 healthy controls (52 +/- 1 years, 5 females). The LV was subdivided into 16 segments and the time from end-diastole to the minimal systolic volume for each of the 16 segments was expressed as a percent of the cycle length. The standard deviations of these times provided a 16-segment dyssynchrony index (16-SD%). 16-SD% was compared between healthy and AL subjects. RESULTS: Left ventricular ejection fraction was comparable (control vs. AL: 62.4 +/- 0.6 vs. 58.6 +/- 2.8%, p = NS). 16-SD% was significantly higher in AL versus healthy subjects (5.93 +/- 4.4 vs. 1.67 +/- 0.87%, p = 0.003). 16-SD% correlated with left ventricular mass index (R 0.45, p = 0.04) but not to left ventricular ejection fraction. CONCLUSION: Light chain amyloidosis is associated with left ventricular regional systolic dyssynchrony. Regional dyssynchrony may be an unrecognized mechanism of heart failure in AL subjects.