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1.
Genet Med ; 23(10): 1864-1872, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34050321

RESUMO

PURPOSE: Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). CTD features include developmental delay, seizures, and autism spectrum disorder. This study was designed to investigate CTD cardiac phenotype and sudden death risk. METHODS: We performed a cross-sectional analysis of CTD males between 2017 and 2020. Subjects underwent evaluation with electrocardiogram (ECG), echocardiography, and ambulatory ECG with comparable analysis in creatine transporter deficient mice (Slc6a8-/y) using ECG, echocardiography, exercise testing, and indirect calorimetry. RESULTS: Eighteen subjects with CTD (18 males, age 7.4 [3.8] years) were evaluated: seven subjects (39%) had QTc ≥ 470 milliseconds: 510.3 ± 29.0 vs. 448.3 ± 15.9, P < 0.0001. The QTc ≥ 470 milliseconds cohort had increased left ventricular internal dimension (diastole) ([LVIDd] Z-score: 0.22 ± 0.74, n = 7 vs. -0.93 ± 1.0, n = 11, P = 0.0059), and diminished left ventricular posterior wall dimension (diastole) ([LVPWDd, in mm]: 5.0 ± 0.6, n = 7 vs. 5.7 ± 0.8, n = 11, P = 0.0183), when compared to subjects with normal or borderline QTc prolongation. Similar ECG and echocardiographic abnormalities were seen in Slc6a8-/y mice. Additionally, Slc6a8-/y mice had diminished survival (65%). CONCLUSION: Prolonged QTc and abnormal echocardiographic parameters consistent with developing cardiomyopathy are seen in some male subjects with CTD. Slc6a8-/y mice recapitulated these cardiac abnormalities. Male CTD subjects may be at increased risk for cardiac dysfunction and sudden death.


Assuntos
Transtorno do Espectro Autista , Creatina , Animais , Encefalopatias Metabólicas Congênitas , Creatina/deficiência , Estudos Transversais , Morte Súbita , Humanos , Masculino , Deficiência Intelectual Ligada ao Cromossomo X , Camundongos , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência
2.
Am J Physiol Heart Circ Physiol ; 319(1): H3-H12, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32412778

RESUMO

Heart failure (HF) is characterized by autonomic imbalance with sympathetic hyperactivity and loss of parasympathetic tone. Intracardiac ganglia (ICG) neurons represent the final common pathway for vagal innervation of the heart and strongly regulate cardiac functions. This study tests whether ICG cholinergic neuron activation mitigates the progression of cardiac dysfunction and reduces mortality that occurs in HF. HF was induced by transaortic constriction (TAC) in male transgenic Long-Evans rats expressing Cre recombinase within choline acetyltransferase (ChAT) neurons. ChAT neurons were selectively activated by expression and activation of excitatory designer receptors exclusively activated by designer receptors (DREADDs) by clozapine-N-oxide (TAC + treatment and sham-treated groups). Control animals expressed DREADDs but received saline (sham and TAC groups). A separate set of animals were telemetry instrumented to record blood pressure (BP) and heart rate (HR). Acute activation of ICG neurons resulted in robust reductions in BP (∼20 mmHg) and HR (∼100 beats/min). All groups of animals were subjected to weekly echocardiography and treadmill stress tests from 3 to 6 wk post-TAC/sham surgery. Activation of ICG cholinergic neurons reduced the left ventricular systolic dysfunction (reductions in ejection fraction, fractional shortening, stroke volume, and cardiac output) and cardiac autonomic dysfunction [reduced HR recovery (HRR) post peak effort] observed in TAC animals. Additionally, activation of ICG ChAT neurons reduced mortality by 30% compared with untreated TAC animals. These data suggest that ICG cholinergic neuron activation reduces cardiac dysfunction and improves survival in HF, indicating that ICG neuron activation could be a novel target for treating HF.NEW & NOTEWORTHY Intracardiac ganglia form the final common pathway for the parasympathetic innervation of the heart. This study has used a novel chemogenetic approach within transgenic ChAT-Cre rats [expressing only Cre-recombinase in choline acetyl transferase (ChAT) neurons] to selectively increase intracardiac cholinergic parasympathetic activity to the heart in a pressure overload-induced heart failure model. The findings from this study confirm that selective activation of intracardiac cholinergic neurons lessens cardiac dysfunction and mortality seen in heart failure, identifying a novel downstream cardiac-selective target for increasing cardioprotective parasympathetic activity in heart failure.


Assuntos
Neurônios Colinérgicos/fisiologia , Insuficiência Cardíaca/fisiopatologia , Coração/inervação , Função Ventricular , Animais , Sistema Nervoso Autônomo/fisiopatologia , Pressão Sanguínea , Colina O-Acetiltransferase/genética , Colina O-Acetiltransferase/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacologia , Coração/fisiopatologia , Insuficiência Cardíaca/etiologia , Frequência Cardíaca , Masculino , Ratos , Ratos Long-Evans , Obstrução do Fluxo Ventricular Externo/complicações
3.
Mol Cell Biochem ; 465(1-2): 175-185, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31853800

RESUMO

Cutaneous changes like rash and hair loss, as well as other neurogenic inflammation side effects, occur frequently during anticancer treatment with the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), erlotinib. These adverse events may be so severe that they impair the patient's compliance with the treatment or even cause its discontinuation. In the current preclinical study, rats (9.2 weeks) were treated with erlotinib (10 mg/kg/day) ± aprepitant (2 mg/kg/day) for 12 weeks. Visual changes in the development of facial skin lesions/hair loss and SP-receptor expression (immunohistochemically) in facial skin tissue were assessed; also changes in plasma magnesium, 8-isoprostane, substance P (SP), neutrophil superoxide production, and cardiac function (echocardiography) were measured. Erlotinib lowered plasma magnesium 14%, elevated SP 65%, caused 3.7-fold higher basal superoxide production, 2.5-fold higher 8-isoprostane levels, 11.6% lower cardiac systolic, and 10.9% lower diastolic function. Facial dermatological changes (alopecia, skin reddening, scabbing, nose crusting) occurred by 4 weeks (± + to ++) in erlotinib-treated rats, and progressively worsened (±++ to +++) by week 12. Facial skin SP-receptor upregulation (78% higher) occurred in epidermal and hair follicle cells. All adverse effects were substantially and significantly mitigated by aprepitant, including a 62% lowering of skin SP-receptors (p < 0.05). Elevated SP levels mediated the side effects of erlotinib treatment, but aprepitant's significant prevention of the systemic and cutaneous adverse events indicates a novel potential therapy against the side effects of this anticancer treatment.


Assuntos
Aprepitanto/farmacologia , Toxidermias , Cloridrato de Erlotinib/efeitos adversos , Doenças do Sistema Nervoso , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Animais , Toxidermias/tratamento farmacológico , Toxidermias/metabolismo , Toxidermias/patologia , Cloridrato de Erlotinib/farmacologia , Masculino , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Ratos , Ratos Sprague-Dawley
4.
Pediatr Cardiol ; 39(3): 478-483, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29188318

RESUMO

Duchenne muscular dystrophy (DMD) is an inherited X-linked disorder with an incidence of 1 in 3500 male births, and cardiomyopathy is becoming the leading cause of death. While Cardiac MRI (CMR) and late gadolinium enhancement (LGE) are important tools in recognizing myocardial involvement, myocardial strain imaging may demonstrate early changes and allow patients to avoid gadolinium contrast. We performed CMR feature tracking (FT) and echo-based speckle tracking (STE) strain measures on DMD patients and age/sex matched controls who had received a CMR with contrast and transthoracic echocardiogram. Data were collected for longitudinal strain in the apical four-chamber view and circumferential strain in the mid-papillary parasternal short axis. Segmental wall analysis was performed and compared with the presence of LGE. Data were analyzed using student's t tests or one-way ANOVA adjusting for multiple comparisons. We measured 24 subjects with DMD and 8 controls. Thirteen of 24 DMD subjects were LGE positive only in the lateral segments in short-axis views. Average circumferential strain (CS) measured by FT was significantly decreased in DMD compared to controls (- 18.8 ± 6.1 vs. - 25.5 ± 3.2; p < 0.001) and showed significant differences in the anterolateral, inferolateral, and inferior segments. Average CS by STE trended towards significance (p = 0.06) but showed significance in only the inferior segment. FT showed significant differences in the inferolateral segment between LGE positive (- 15.5 ± 9.0) and LGE negative (- 18.2 ± 8.3) in DMD subjects compared to controls (- 28.6 ± 7.3; p ≤ 0.04). FT also showed significant differences between anteroseptal and inferolateral segments within LGE-positive (p < 0.003) and LGE-negative (p < 0.03) DMD subjects while STE did not. There were no significant differences in longitudinal strain measures. CMR-FT-derived myocardial strain was able to demonstrate differences between subjects with DMD and controls not detected by STE. FT was also able to demonstrate differences in LGE-positive and LGE-negative segments within patients with DMD. FT may be able to predict LGE-positive segments in DMD without the use of gadolinium contrast.


Assuntos
Cardiomiopatias/diagnóstico por imagem , Ecocardiografia/métodos , Imagem Cinética por Ressonância Magnética/métodos , Distrofia Muscular de Duchenne/complicações , Adolescente , Cardiomiopatias/etiologia , Criança , Estudos Transversais , Feminino , Gadolínio , Humanos , Masculino , Miocárdio/patologia , Estudos Retrospectivos , Adulto Jovem
5.
Int J Mol Sci ; 19(8)2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111743

RESUMO

Chronic effects of a combination antiretroviral therapy (cART = tenofovir/emtricitatine + atazanavir/ritonavir) on systemic and cardiac oxidative stress/injury in HIV-1 transgenic (Tg) rats and protection by Mg-supplementation were assessed. cART (low doses) elicited no significant effects in normal rats, but induced time-dependent oxidative/nitrosative stresses: 2.64-fold increased plasma 8-isoprostane, 2.0-fold higher RBC oxidized glutathione (GSSG), 3.2-fold increased plasma 3-nitrotyrosine (NT), and 3-fold elevated basal neutrophil superoxide activity in Tg rats. Increased NT staining occurred within cART-treated HIV-Tg hearts, and significant decreases in cardiac systolic and diastolic contractile function occurred at 12 and 18 weeks. HIV-1 expression alone caused modest levels of oxidative stress and cardiac dysfunction. Significantly, cART caused up to 24% decreases in circulating Mg in HIV-1-Tg rats, associated with elevated renal NT staining, increased creatinine and urea levels, and elevated plasma substance P levels. Strikingly, Mg-supplementation (6-fold) suppressed all oxidative/nitrosative stress indices in the blood, heart and kidney and substantially attenuated contractile dysfunction (>75%) of cART-treated Tg rats. In conclusion, cART caused significant renal and cardiac oxidative/nitrosative stress/injury in Tg-rats, leading to renal Mg wasting and hypomagnesemia, triggering substance P-dependent neurogenic inflammation and cardiac dysfunction. These events were effectively attenuated by Mg-supplementation likely due to its substance P-suppressing and Mg's intrinsic anti-peroxidative/anti-calcium properties.


Assuntos
Antirretrovirais/efeitos adversos , Coração/efeitos dos fármacos , Magnésio/uso terapêutico , Inflamação Neurogênica/induzido quimicamente , Inflamação Neurogênica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Animais , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Cardiotoxinas/efeitos adversos , Expressão Gênica , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Coração/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Inflamação Neurogênica/fisiopatologia , Ativação de Neutrófilo/efeitos dos fármacos , Estresse Nitrosativo/efeitos dos fármacos , Ratos Endogâmicos F344 , Ratos Transgênicos
6.
Pediatr Cardiol ; 38(8): 1606-1612, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28821969

RESUMO

Duchenne muscular dystrophy (DMD) is a rare, fatal X-linked disorder characterized by the lack of dystrophin, a key sarcolemma muscle protein. Cardiac failure is a significant cause of death in DMD subjects. The purpose of our research was to identify potential cardiac serum biomarkers associated with DMD cardiomyopathy. This is an observational, case-controlled study using subjects from the CINRG DMD natural history study with cardiomyopathy (ejection fraction (EF) <55%; shortening fraction (SF) <28%), subjects without cardiomyopathy (EF ≥ 55%; SF ≥ 28%) compared to normal healthy volunteer subjects. The DMD with cardiomyopathy group had significantly lower average EF and SF (EF = 45 ± 10/SF = 25 ± 2%) than the DMD without cardiomyopathy group (EF = 58 ± 5% and SF = 32 ± 3%; p < 0.01). Among a selected set of potential biomarkers for cardiomyopathy (MMP9, BNP, GAL3, CRP, LEP, TNC, TLR4 and ST2) we validated ST2 as significantly elevated in the serum of DMD cardiomyopathy group (35,798 ± 4884 pg/mL) compared to normal controls (9940 ± 2680 pg/mL; p < 0.01; n = 6). Matrix metallopeptidase 9 (MMP9) levels were found significantly increased in both DMD groups compared to controls (p < 0.01). No significant differences were seen in BNP, GAL3, CRP, LEP, TNC or TLR4 levels. Increased ST2 levels were found in serum of DMD subjects compared to healthy volunteers and further elevated in DMD subjects with cardiomyopathy. Future studies correlating cardiomyopathy with ST2 levels may allow for improved non-invasive monitoring of cardiac disease in DMD subjects.


Assuntos
Biomarcadores/sangue , Cardiomiopatias/sangue , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Distrofia Muscular de Duchenne/complicações , Adolescente , Adulto , Cardiomiopatias/etiologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Humanos , Modelos Lineares , Masculino , Distrofia Muscular de Duchenne/sangue , Volume Sistólico , Adulto Jovem
7.
J Cardiovasc Magn Reson ; 18(1): 72, 2016 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-27788681

RESUMO

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked, inherited disorder causing dilated cardiomyopathy with variable onset and progression. Currently we lack objective markers of the effect of therapies targeted towards preventing progression of subclinical cardiac disease. Thus, our aim was to compare the ability of native T1 and extracellular volume (ECV) measurements to differentiate risk of myocardial disease in DMD and controls. METHODS: Twenty boys with DMD and 16 age/gender-matched controls without history predisposing to cardiac fibrosis, but with a clinical indication for cardiovascular magnetic resonance (CMR) evaluation, underwent CMR with contrast. Data points collected include left ventricular ejection fraction (LVEF), left ventricular mass, and presence of late gadolinium enhancement (LGE). Native T1, and ECV regional mapping were obtained using both a modified Look-Locker (MOLLI) and saturation recovery single shot sequence (SASHA) on a 1.5T scanner. Using ordinal logistic regression models, controlling for age and LVEF, LGE-free septal we evaluated the ability native T1 and ECV assessments to differentiate levels of cardiomyopathy. RESULTS: Twenty DMD subjects aged 14.4 ± 4 years had an LVEF of 56.3 ± 7.4 %; 12/20 had LGE, all confined to the lateral wall. Sixteen controls aged 16.1 ± 2.2 years had an LVEF 60.4 ± 5.1 % and no LGE. Native T1 and ECV values were significantly higher in the DMD group (p < 0.05) with both MOLLI and SASHA imaging techniques. Native T1 demonstrated a 50 % increase in the ability to predict disease state (control, DMD without fibrosis, DMD with fibrosis). ECV demonstrated only the ability to predict presence of LGE, but could not distinguish between controls and DMD without fibrosis. CONCLUSIONS: LGE-spared regions of boys with DMD have significantly different native T1 and ECV values compared to controls. Native T1 measurements can identify early changes in DMD patients without the presence of LGE and help predict disease severity more effectively than ECV. Native T1 may be a novel outcome measure for early cardiac therapies in DMD and other cardiomyopathies.


Assuntos
Cardiomiopatia Dilatada/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Distrofia Muscular de Duchenne/complicações , Adolescente , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/fisiopatologia , Estudos de Casos e Controles , Meios de Contraste/administração & dosagem , Diagnóstico Diferencial , Desenho de Equipamento , Humanos , Interpretação de Imagem Assistida por Computador , Modelos Logísticos , Imageamento por Ressonância Magnética/instrumentação , Masculino , Distrofia Muscular de Duchenne/diagnóstico , Compostos Organometálicos/administração & dosagem , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Volume Sistólico , Função Ventricular Esquerda
8.
Pediatr Cardiol ; 37(7): 1290-6, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27314489

RESUMO

As treatments of the extra-cardiac complications of muscular dystrophy (MD) improve, males with MD are more likely to develop cardiac disease. The impact of cardiomyopathy or heart failure (HF) and ventricular tachycardia (VT) on hospitalizations and in hospital mortality are not known. We performed an analysis of inpatient admission data for patients with MD using the Pediatric Health Information System database. We selected males who were 6 years or older with diagnosis codes of MD and cardiac disease including cardiomyopathy/HF and VT between 2003 and 2013. We created a logistic regression model to identify predictors of subsequent cardiac arrest or death in MD patients. We also compared hospital charges, lengths of stay and ages among MD patients with or without cardiac disease. Our logistic regression model showed that VT (OR 5.41, 95 % CI 2.83, 10.34) and cardiomyopathy/HF (OR 1.79, 95 % CI 1.05, 3.04) were risk factors for cardiac arrest or death. Of the 84 cardiac arrests or deaths in 3363 MD patients, 49 (58 %) were related to cardiac disease. Nineteen (39 %) of these events occurred in MD patients with VT. The mean hospital charges and the mean length of stay were greater and longer in MD patients with VT compared to those without cardiac disease and those with only cardiomyopathy/HF (p < 0.05). Cardiac disease is a significant burden in hospitalized MD patients. Our results suggest that VT and cardiomyopathy/HF are associated with an increased risk of cardiac arrest or death in MD patients.


Assuntos
Cardiopatias , Parada Cardíaca , Humanos , Masculino , Distrofias Musculares , Taquicardia Ventricular
9.
J Cardiovasc Pharmacol ; 65(1): 54-61, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25343568

RESUMO

To determine whether the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib may cause hypomagnesemia, inflammation, and cardiac stress, erlotinib was administered to rats (10 mg · kg(-1)· d(-1)) for 9 weeks. Plasma magnesium decreased progressively between 3 and 9 weeks (-9% to -26%). Modest increases in plasma substance P (SP) occurred at 3 (27%) and 9 (25%) weeks. Neutrophil superoxide-generating activity increased 3-fold, and plasma 8-isoprostane rose 210%, along with noticeable appearance of cardiac perivascular nitrotyrosine. The neurokinin-1 (NK-1) receptor antagonist, aprepitant (2 mg · kg(-1) · d(-1)), attenuated erlotinib-induced hypomagnesemia up to 42%, reduced circulating SP, suppressed neutrophil superoxide activity and 8-isoprostane elevations; cardiac nitrotyrosine was diminished. Echocardiography revealed mild to moderately decreased left ventricular ejection fraction (-11%) and % fractional shortening (-17%) by 7 weeks of erlotinib treatment and significant reduction (-17.5%) in mitral valve E/A ratio at week 9 indicative of systolic and early diastolic dysfunction. Mild thinning of the left ventricular posterior wall suggested early dilated cardiomyopathy. Aprepitant completely prevented the erlotinib-induced systolic and diastolic dysfunction and partially attenuated the anatomical changes. Thus, chronic erlotinib treatment does induce moderate hypomagnesemia, triggering SP-mediated oxidative/inflammation stress and mild-to-moderate cardiac dysfunction, which can largely be corrected by the administration of the SP receptor blocker.


Assuntos
Receptores ErbB/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteínas Quinases/toxicidade , Quinazolinas/toxicidade , Animais , Aprepitanto , Ecocardiografia , Cloridrato de Erlotinib , Magnésio/sangue , Masculino , Morfolinas/farmacologia , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores da Neurocinina-1/efeitos dos fármacos , Receptores da Neurocinina-1/metabolismo , Substância P/sangue , Função Ventricular Esquerda/efeitos dos fármacos
10.
J Am Heart Assoc ; 13(9): e032960, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38686878

RESUMO

BACKGROUND: Cardiovascular disease is the leading cause of death among patients with Duchenne muscular dystrophy (DMD). Identifying patients at risk of early death could allow for increased monitoring and more intensive therapy. Measures that associate with death could serve as surrogate outcomes in clinical trials. METHODS AND RESULTS: Duchenne muscular dystrophy subjects prospectively enrolled in observational studies were included. Models using generalized least squares were used to assess the difference of cardiac magnetic resonance measurements between deceased and alive subjects. A total of 63 participants underwent multiple cardiac magnetic resonance imaging and were included in the analyses. Twelve subjects (19.1%) died over a median follow-up of 5 years (interquartile range, 3.1-7.0). Rate of decline in left ventricular ejection fraction was faster in deceased than alive subjects (P<0.0001). Rate of increase in indexed left ventricular end-diastolic (P=0.0132) and systolic (P<0.0001) volumes were higher in deceased subjects. Faster worsening in midcircumferential strain was seen in deceased subjects (P=0.049) while no difference in global circumferential strain was seen. The rate of increase in late gadolinium enhancement, base T1, and mid T1 did not differ between groups. CONCLUSIONS: Duchenne muscular dystrophy death is associated with the rate of change in left ventricular ejection fraction, midcircumferential strain, and ventricular volumes. Aggressive medical therapy to decrease the rate of progression may improve the mortality rate in this population. A decrease in the rate of progression may serve as a valid surrogate outcome for therapeutic trials.


Assuntos
Distrofia Muscular de Duchenne , Volume Sistólico , Função Ventricular Esquerda , Humanos , Distrofia Muscular de Duchenne/mortalidade , Distrofia Muscular de Duchenne/fisiopatologia , Distrofia Muscular de Duchenne/diagnóstico por imagem , Distrofia Muscular de Duchenne/complicações , Volume Sistólico/fisiologia , Masculino , Adolescente , Criança , Estudos Prospectivos , Imagem Cinética por Ressonância Magnética/métodos , Progressão da Doença , Imageamento por Ressonância Magnética , Adulto Jovem , Valor Preditivo dos Testes , Fatores de Risco , Fatores de Tempo , Prognóstico
11.
Am J Physiol Regul Integr Comp Physiol ; 305(10): R1102-11, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24049113

RESUMO

Use of protease inhibitors (PI) in HIV patients is associated with hyperlipidemia and increased risk of coronary heart disease. Chronic systemic and cardiac effects of ritonavir (RTV), a universal PI booster, and Mg supplementation were examined. RTV was administered (75 mg·kg(-1)·day(-1) po) to Lewis × Brown-Norway hybrid (LBNF1) rats for up to 8 wk; significant increases in plasma triglyceride and cholesterol occurred from 8 days to 8 wk. At 5 wk, the expression of selected hepatic genes (CYP7A1, CITED2, G6PC, and ME-1), which are key to lipid catabolism/synthesis, were altered toward lipogenesis. Dietary Mg supplementation (six-fold higher) completely reversed the altered expression of these genes and attenuated both hypertriglyceridemia and hypercholesterolemia. Neutrophils isolated from the RTV-treated rats displayed a three-fold higher basal and a twofold higher stimulated superoxide production; plasma isoprostane and red blood cell (RBC) GSSG levels were elevated two- to three-fold. All oxidative indices were normalized by Mg supplementation. After 5 wk, RTV caused significant decreases in cardiac left ventricular (LV) shortening fraction and LV ejection fraction; mitral valve early/late atrial ventricular filling (E/A) ratio was reduced accompanied by LV posterior wall thinning. Immunohistochemical staining revealed significant white blood cell (WBC) infiltration (5 wk) and prominent fibrosis (8 wk) in the RTV hearts. Mg supplementation attenuated RTV-induced declines in systolic and diastolic (improved mitral valve E/A ratio) function (>70%), lessened LV posterior wall thinning (by 75%), and substantially decreased the pathological markers. The known clinical hyperlipidemia effects of RTV can be mimicked in the LBNF1 rats; in association, systemic oxidative stress and progressive cardiac dysfunction occurred. Remarkably, Mg supplementation alone suppressed RTV-mediated hyperlipidemia, oxidative stress, and cardiac dysfunction.


Assuntos
Cardiopatias/induzido quimicamente , Hiperlipidemias/induzido quimicamente , Magnésio/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Ritonavir/toxicidade , Ração Animal , Animais , Dieta , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores da Protease de HIV/toxicidade , Cardiopatias/tratamento farmacológico , Masculino , Ratos , Aumento de Peso
12.
Pediatr Cardiol ; 39(1): 204-205, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29247334
13.
Circ Heart Fail ; 16(8): e010040, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37288563

RESUMO

BACKGROUND: Cardiopulmonary failure is the leading cause of death in Duchenne muscular dystrophy (DMD). Research into DMD-specific cardiovascular therapies is ongoing, but there are no Food and Drug Administration-approved cardiac end points. To adequately power a therapeutic trial, appropriate end points must be chosen and the rate of change for these end points reported. The objective of this study was to evaluate rate of change for cardiac magnetic resonance and blood biomarkers and to determine which measures associate with all-cause mortality in DMD. METHODS: Seventy-eight DMD subjects underwent 211 cardiac magnetic resonance studies analyzed for left ventricular (LV) ejection fraction, indexed LV end diastolic and systolic volumes, circumferential strain, late gadolinium enhancement presence and severity (global severity score, and full width half maximum), native T1 mapping, T2 mapping, and extracellular volume. Blood samples were analyzed for BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), and troponin I. Cox proportional hazard regression modeling was performed with all-cause mortality as the outcome. RESULTS: Fifteen subjects (19%) died. LV ejection fraction, indexed end systolic volumes, global severity score, and full width half maximum worsened at 1 and 2 years while circumferential strain and indexed LV end diastolic volumes worsened at 2 years. LV ejection fraction, indexed LV end diastolic and systolic volumes, late gadolinium enhancement full width half maximum, and circumferential strain associated with all-cause mortality (P<0.05). NT-proBNP was the only blood biomarker that associated with all-cause mortality (P<0.05). CONCLUSIONS: LV ejection fraction, indexed LV volumes, circumferential strain, late gadolinium enhancement full width half maximum, and NT-proBNP are associated with all-cause mortality in DMD and may be the best end points for use in cardiovascular therapeutic trials. We also report change over time of cardiac magnetic resonance and blood biomarkers.


Assuntos
Insuficiência Cardíaca , Distrofia Muscular de Duchenne , Humanos , Meios de Contraste , Gadolínio , Insuficiência Cardíaca/complicações , Função Ventricular Esquerda , Volume Sistólico , Biomarcadores
14.
Can J Physiol Pharmacol ; 90(8): 1145-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22646904

RESUMO

We determined whether the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) N-​(3-​chlorophenyl)-​6,​7-​dimethoxy-​4-​quinazolinamine (tyrphostin AG-1478) causes hypomagnesemia and cardiac dysfunction in rats. Tyrphostin was administered (3 times per week, intraperitoneal injection, to achieve 21.4 mg·(kg body mass)(-1)·day(-1)) to normomagnesemic rats for 5 weeks. Levels of magnesium in the plasma of the tyrphostin-treated rats decreased significantly by the following amount: 17% at week 1, 27% at week 2, and 26%-35% between weeks 3 to 5. Levels of the plasma lipid peroxidation marker 8-isoprostane rose significantly: by 58% at week 1, 168% at week 3, and 113% at week 5. At week 5, blood neutrophils from the tyrphostin-treated group displayed a 2.26-fold higher basal level of O(2)(·-) generation; the ratio of oxidized glutathione (glutathione disulfide; GSSG) to reduced glutathione (GSH) in the red blood cells increased 2.5-fold. At week 5, echocardiography revealed that TKI treatment resulted in significant cardiac systolic dysfunction, with impaired diastolic function and dilated cardiomyopathy. Since hypomagnesemia alone can trigger oxidative stress and cardiac injury, we suggest that inhibition of EGFR-TK caused magnesium wasting, which partly contributed to decreased cardiac contractility.


Assuntos
Ecocardiografia/efeitos dos fármacos , Inibidores Enzimáticos/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinas/efeitos adversos , Erros Inatos do Transporte Tubular Renal/induzido quimicamente , Tirfostinas/efeitos adversos , Animais , Biomarcadores/sangue , Cálcio/sangue , Dinoprosta/análogos & derivados , Dinoprosta/sangue , Ecocardiografia/métodos , Ecocardiografia/estatística & dados numéricos , Glutationa/sangue , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Erros Inatos do Transporte Tubular Renal/sangue , Superóxidos/sangue
15.
Can J Physiol Pharmacol ; 90(9): 1257-68, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22913465

RESUMO

d-Propranolol (d-Pro: 2-8 mg·(kg body mass)(-1)·day(-1)) protected against cardiac dysfunction and oxidative stress during 3-5 weeks of iron overload (2 mg Fe-dextran·(g body mass)(-1)·week(-1)) in Sprague-Dawley rats. At 3 weeks, hearts were perfused in working mode to obtain baseline function; red blood cell glutathione, plasma 8-isoprostane, neutrophil basal superoxide production, lysosomal-derived plasma N-acetyl-ß-galactosaminidase (NAGA) activity, ventricular iron content, and cardiac iron deposition were assessed. Hearts from the Fe-treated group of rats exhibited lower cardiac work (26%) and output (CO, 24%); end-diastolic pressure rose 1.8-fold. Further, glutathione levels increased 2-fold, isoprostane levels increased 2.5-fold, neutrophil superoxide increased 3-fold, NAGA increased 4-fold, ventricular Fe increased 4.9-fold; and substantial atrial and ventricular Fe-deposition occurred. d-Pro (8 mg) restored heart function to the control levels, protected against oxidative stress, and decreased cardiac Fe levels. After 5 weeks of Fe treatment, echocardiography revealed that the following were depressed: percent fractional shortening (%FS, 31% lower); left ventricular (LV) ejection fraction (LVEF, 17%), CO (25%); and aortic pressure maximum (P(max), 24%). Mitral valve E/A declined by 18%, indicating diastolic dysfunction. Cardiac CD11b+ infiltrates were elevated. Low d-Pro (2 mg) provided modest protection, whereas 4-8 mg greatly improved LVEF (54%-75%), %FS (51%-81%), CO (43%-78%), P(max) (56%-100%), and E/A >100%; 8 mg decreased cardiac inflammation. Since d-Pro is an antioxidant and reduces cardiac Fe uptake as well as inflammation, these properties may preserve cardiac function during Fe overload.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Cardiopatias/prevenção & controle , Sobrecarga de Ferro/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Propranolol/uso terapêutico , Acetilglucosaminidase/sangue , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/química , Animais , Débito Cardíaco/efeitos dos fármacos , Progressão da Doença , Relação Dose-Resposta a Droga , Ecocardiografia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Glutationa , Cardiopatias/sangue , Cardiopatias/etiologia , Cardiopatias/metabolismo , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/metabolismo , Masculino , Miocárdio/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/enzimologia , Perfusão , Propranolol/administração & dosagem , Propranolol/química , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Superóxido Dismutase/metabolismo , Resultado do Tratamento
16.
Pediatr Cardiol ; 33(7): 1097-103, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22349679

RESUMO

We sought to study the impact of the 2004 American Heart Association guidelines on diagnosis and treatment of patients with Kawasaki disease (KD). We reviewed patient records from July 2000 to June 2002 (group 1) and July 2007 to June 2009 (group 2) at a tertiary children's hospital. The proportion of patients with incomplete KD in group 2 (56 of 118 [47%]) was significantly higher than that in group 1 (20 of 85 [24%], p = 0.001). Median age (months) and interquartile ranges for group 1 was 26 (range 12.5-52) and for group 2 was 38.5 (range 18-63; p = 0.072). The number of patients diagnosed with KD having just 2 symptoms other than fever was significantly higher in group 2 (2.4 vs. 16.9%, p < 0.001). Erythrocyte sedimentation rate, albumin, and alanine aminotransferase levels were obtained in a significantly greater number of patients with KD after the guidelines were published. Thirty-two of the 203 patients studied had coronary artery (CA) involvement (15.8%), 4 of whom had CA aneurysms (2%) and 28 had CA ectasia only (13.8%). CA involvement was seen in 13 of 85 (15.3%) patients in group 1 and 19 of 118 (16.1%; p = 1) patients in group 2. After publication of the 2004 AHA guidelines, diagnoses of incomplete KD and laboratory use increased at our center; however, the rate of CA involvement remained stable. There also was a trend towards older age in children diagnosed with KD. Laboratory parameters and CA involvement between incomplete KD and classic KD were comparable.


Assuntos
Síndrome de Linfonodos Mucocutâneos/epidemiologia , Guias de Prática Clínica como Assunto , American Heart Association , Distribuição de Qui-Quadrado , Pré-Escolar , Feminino , Hospitais Pediátricos , Humanos , Incidência , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/terapia , Estudos Retrospectivos , Estatísticas não Paramétricas , Estados Unidos
17.
Clin Med Insights Cardiol ; 16: 11795468221116838, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36046180

RESUMO

The purpose of this study was to determine whether the longitudinal progression of decline in left ventricular ejection fraction (LVEF) in Duchenne muscular dystrophy (DMD) patients is moderated by ADRB1 genotype and whether the efficacy of ß-blocker therapy is influenced by genotype status. About 147 DMD patients (6-34 years.) were analyzed with a focus on ß1 adrenergic receptor (ADRB1) genotype variants. Patients were grouped by ADRB1 genotype resulting in Gly389 patients and Arg389 patients. A generalized additive mixed effects model was used to examine differences in the nonlinear trend of LVEF across patient ages between genotype groups and for ß-blocker use. Both genotype groups displayed a progressive decline in LVEF starting around the mean age of ambulation loss (~12 years). However, there was no difference between genotype groups in the progression of decline in LVEF. There was a significant effect of ß-blocker use on longitudinal LVEF, wherein patients on ß-blockers had systematically lower LVEF when compared to patients not on ß-blockers. However, the effect of ß-blocker therapy on LVEF was not affected by ADRB1 genotype. The current study did not demonstrate an influence of patient ADRB1 genotype on longitudinal LVEF in our cohort. Despite previous literature suggesting a positive influence of ß-blocker use on cardiac function in DMD patients and of an ADRB1 genotypic difference in responsiveness to ß-blocker use, we did not observe this in our cohort. Interestingly, our cohort did not demonstrate a positive influence of ß-blocker use on LVEF measures.

18.
Circulation ; 131(18): 1590-8, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-25940966
19.
Muscle Nerve ; 44(1): 8-19, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21674516

RESUMO

Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy and occurs in 1 in 3500 male births. Improved survival due to improvements in clinical care of the musculoskeletal and respiratory systems has led to an increased incidence of cardiomyopathy. Cardiac-related deaths are now seen in approximately 20% of DMD patients. Our current understanding of DMD cardiomyopathy has increased significantly over the past 10 years, but further research is required to improve cardiac treatment and outcomes in DMD. This review provides a summary of the current literature and discussion of potential new therapies for DMD cardiomyopathy.


Assuntos
Cardiomiopatias/diagnóstico , Cardiomiopatias/terapia , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/terapia , Animais , Cardiomiopatias/complicações , Compreensão , Eletrocardiografia/métodos , Previsões , Humanos , Masculino , Força Muscular/fisiologia , Distrofia Muscular de Duchenne/complicações
20.
Muscle Nerve ; 44(2): 174-8, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21698649

RESUMO

INTRODUCTION: Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin-deficient muscle. METHODS: We performed an open-label, "add-on" pilot study of CoQ10 in thirteen 5-10-year-old DMD patients on steroids. The primary outcome measure was the total quantitative muscle testing (QMT) score. RESULTS: Twelve of 16 children (mean age 8.03 ± 1.64 years) completed the trial. Target serum levels of CoQ10 (≥2.5 µg/ml) were shown to be subject- and administration-dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in an 8.5% increase in muscle strength (P = 0.03). CONCLUSIONS: Addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD.


Assuntos
Corticosteroides/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Ubiquinona/análogos & derivados , Vitaminas/uso terapêutico , Criança , Pré-Escolar , Progressão da Doença , Quimioterapia Combinada , Feminino , Humanos , Masculino , Força Muscular/efeitos dos fármacos , Projetos Piloto , Estudos Prospectivos , Resultado do Tratamento , Ubiquinona/administração & dosagem , Ubiquinona/uso terapêutico
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