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1.
Physiol Rev ; 96(1): 253-305, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26676145

RESUMO

Dystrophin is a long rod-shaped protein that connects the subsarcolemmal cytoskeleton to a complex of proteins in the surface membrane (dystrophin protein complex, DPC), with further connections via laminin to other extracellular matrix proteins. Initially considered a structural complex that protected the sarcolemma from mechanical damage, the DPC is now known to serve as a scaffold for numerous signaling proteins. Absence or reduced expression of dystrophin or many of the DPC components cause the muscular dystrophies, a group of inherited diseases in which repeated bouts of muscle damage lead to atrophy and fibrosis, and eventually muscle degeneration. The normal function of dystrophin is poorly defined. In its absence a complex series of changes occur with multiple muscle proteins showing reduced or increased expression or being modified in various ways. In this review, we will consider the various proteins whose expression and function is changed in muscular dystrophies, focusing on Ca(2+)-permeable channels, nitric oxide synthase, NADPH oxidase, and caveolins. Excessive Ca(2+) entry, increased membrane permeability, disordered caveolar function, and increased levels of reactive oxygen species are early changes in the disease, and the hypotheses for these phenomena will be critically considered. The aim of the review is to define the early damage pathways in muscular dystrophy which might be appropriate targets for therapy designed to minimize the muscle degeneration and slow the progression of the disease.


Assuntos
Cálcio/metabolismo , Distrofina/metabolismo , Músculo Esquelético/metabolismo , Distrofias Musculares/metabolismo , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Animais , Sinalização do Cálcio , Distrofina/deficiência , Distrofina/genética , Regulação da Expressão Gênica , Humanos , Desenvolvimento Muscular , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofias Musculares/genética , Distrofias Musculares/patologia , Distrofias Musculares/fisiopatologia , Regeneração
2.
Hum Mol Genet ; 28(3): 386-395, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30256963

RESUMO

Syntrophins are a family of modular adaptor proteins that are part of the dystrophin protein complex, where they recruit and anchor a variety of signaling proteins. Previously we generated mice lacking α- and/or ß2-syntrophin but showed that in the absence of one isoform, other syntrophin isoforms can partially compensate. Therefore, in the current study, we generated mice that lacked α, ß1 and ß2-syntrophins [triple syntrophin knockout (tKO) mice] and assessed skeletal and cardiac muscle function. The tKO mice showed a profound reduction in voluntary wheel running activity at both 6 and 12 months of age. Function of the tibialis anterior was assessed in situ and we found that the specific force of tKO muscle was decreased by 20-25% compared with wild-type mice. This decrease was accompanied by a shift in fiber-type composition from fast 2B to more oxidative fast 2A fibers. Using echocardiography to measure cardiac function, it was revealed that tKO hearts had left ventricular cardiac dysfunction and were hypertrophic, with a thicker left ventricular posterior wall. Interestingly, we also found that membrane-localized dystrophin expression was lower in both skeletal and cardiac muscles of tKO mice. Since dystrophin mRNA levels were not different in tKO, this finding suggests that syntrophins may regulate dystrophin trafficking to, or stabilization at, the sarcolemma. These results show that the loss of all three major muscle syntrophins has a profound effect on exercise performance, and skeletal and cardiac muscle dysfunction contributes to this deficiency.


Assuntos
Proteínas de Ligação ao Cálcio/fisiologia , Proteínas Associadas à Distrofina/fisiologia , Proteínas de Membrana/fisiologia , Proteínas Musculares/fisiologia , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Distrofina/genética , Distrofina/fisiologia , Proteínas Associadas à Distrofina/genética , Coração/fisiologia , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Miocárdio/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia
3.
Intern Med J ; 50(7): 859-865, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31211489

RESUMO

BACKGROUND: Stroke remains an important complication of diagnostic cardiac catheterisation and percutaneous coronary intervention and is associated with high rates of in-hospital mortality. AIMS: To evaluate the incidence of stroke over a 10-year period and assess the long-term influence of stroke following cardiac catheterisation and PCI on functional outcomes, based on modified Rankin score and mortality. METHODS: The study was performed using a case-control design in a single tertiary referral centre. Patients were identified by correlating those patients undergoing cardiac catheterisation between October 2006 and December 2016 with patients who underwent neuroimaging within 7 days to identify possible cases of suspected stroke or transient ischaemic attack. RESULTS: A total of 21 510 patients underwent cardiac catheterisation during the study period. Sixty (0.28%) patients experienced stroke or transient ischaemic attack. Compared to control patients, those who did experience cerebral ischaemic events were older (70.5 vs 64 years; P < 0.001), with higher rates of atrial fibrillation, hypertension and diabetes mellitus. Stroke complicating cardiac catheterisation was associated with an increased risk of readmission, with a significantly higher hazard of readmission for stroke noted. Despite minimal functional impairment based on modified Rankin score, stroke was associated with a significant risk of early and cumulative mortality. Stroke incidence remained stable over the study period despite changes in procedural practice. CONCLUSIONS: The incidence and functional severity of stroke remains low despite evolving procedural practice with a stable incidence over time despite changes in procedural practice; however, post-procedural stroke confirms an increased mortality hazard.


Assuntos
Ataque Isquêmico Transitório , Intervenção Coronária Percutânea , Acidente Vascular Cerebral , Cateterismo Cardíaco/efeitos adversos , Humanos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Resultado do Tratamento
4.
Heart Lung Circ ; 29(1): 128-136, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30686642

RESUMO

BACKGROUND: Mycotic coronary aneurysms (MCA) are rare but often lead to significant morbidity and mortality. Evidence on the topic is limited to case reports and small case series. A systematic review was performed to improve understanding of this challenging diagnosis. A case report prompting this review is also included. METHODS: Relevant articles were identified by searching databases Medline and Google Scholar for terms 'mycotic coronary aneurysm'. Manual searching from article references identified further case reports. RESULTS: Ninety-seven (97) published cases of MCA were identified between 1812 and 2017; 80 cases since the introduction of percutaneous coronary intervention (PCI) with stents in 1986. The most common associations were PCI (40.0%) and infective endocarditis (IE) (40.0%). Complications including aneurysm rupture (28.9%), pericardial effusion (37.3%) and myocardial infarction (39.8%) were frequent. Short-term mortality was high at 42.6%. The most common treatment was surgical resection of the aneurysm with bypass grafting. CONCLUSIONS: We present a case and the largest systematic review to date of this rare diagnosis, identifying 97 published case reports. Clinical scenarios in which to consider MCA include febrile illness after recent PCI, febrile illness (particularly infective endocarditis) with evidence of coronary ischaemia, and purulent pericarditis. Given the high rate of complications and mortality, immediate surgical referral is recommended.


Assuntos
Aneurisma Infectado , Aneurisma Coronário , Endocardite , Infarto do Miocárdio , Intervenção Coronária Percutânea , Derrame Pericárdico , Aneurisma Infectado/complicações , Aneurisma Infectado/epidemiologia , Aneurisma Infectado/cirurgia , Aneurisma Coronário/complicações , Aneurisma Coronário/epidemiologia , Aneurisma Coronário/cirurgia , Endocardite/epidemiologia , Endocardite/etiologia , Endocardite/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/cirurgia , Derrame Pericárdico/epidemiologia , Derrame Pericárdico/etiologia , Derrame Pericárdico/cirurgia
5.
Heart Lung Circ ; 29(2): 169-177, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31601511

RESUMO

BACKGROUND: While cardiac catheterisation is typically well tolerated, discomfort and anxiety are commonplace. Sedation using anxiolytic and analgesic medications has the potential to ameliorate such symptoms, however, is variably employed, with lack of standardised regimens and limited evidence. METHODS: We performed a review of the role of sedation for cardiac catheterisation, including current practices and summarising available evidence relevant to diagnostic and interventional coronary procedures in the cardiac catheterisation laboratory. RESULTS: Use of sedation and the medication regimens employed are highly variable. Available relevant studies are limited in number and mostly small. Sedation appears to modestly reduce anxiety and pain in most studies. The incidence of radial spasm and the consequent need to alter access site is reduced with procedural sedation. The majority of existing evidence applies to benzodiazepines and opioid use, which appear acceptably efficacious and safe when used with appropriate training and staffing; noting opioid medications reduce the absorption of loading doses of oral anti-platelet drugs. CONCLUSIONS: In conclusion, benzodiazepines and opioids result a modest reduction in pain, improved patient tolerability and reduced risk of radial artery spasm. The decision on whether to use sedation, and which agent(s) and dose, should be individualised based on patient factors, including need for oral antiplatelet therapy administration. Appropriate staffing and monitoring is essential.


Assuntos
Analgesia , Sedação Profunda , Intervenção Coronária Percutânea , Cateterismo Cardíaco , Feminino , Humanos , Masculino
6.
Proc Natl Acad Sci U S A ; 113(4): 1068-73, 2016 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-26755585

RESUMO

Facilitation and inactivation of P/Q-type calcium (Ca(2+)) currents through the regulation of voltage-gated Ca(2+) (CaV) 2.1 channels by Ca(2+) sensor (CaS) proteins contributes to the facilitation and rapid depression of synaptic transmission in cultured neurons that transiently express CaV2.1 channels. To examine the modulation of endogenous CaV2.1 channels by CaS proteins in native synapses, we introduced a mutation (IM-AA) into the CaS protein-binding site in the C-terminal domain of CaV2.1 channels in mice, and tested synaptic facilitation and depression in neuromuscular junction synapses that use exclusively CaV2.1 channels for Ca(2+) entry that triggers synaptic transmission. Even though basal synaptic transmission was unaltered in the neuromuscular synapses in IM-AA mice, we found reduced short-term facilitation in response to paired stimuli at short interstimulus intervals in IM-AA synapses. In response to trains of action potentials, we found increased facilitation at lower frequencies (10-30 Hz) in IM-AA synapses accompanied by slowed synaptic depression, whereas synaptic facilitation was reduced at high stimulus frequencies (50-100 Hz) that would induce strong muscle contraction. As a consequence of altered regulation of CaV2.1 channels, the hindlimb tibialis anterior muscle in IM-AA mice exhibited reduced peak force in response to 50 Hz stimulation and increased muscle fatigue. The IM-AA mice also had impaired motor control, exercise capacity, and grip strength. Taken together, our results indicate that regulation of CaV2.1 channels by CaS proteins is essential for normal synaptic plasticity at the neuromuscular junction and for muscle strength, endurance, and motor coordination in mice in vivo.


Assuntos
Canais de Cálcio Tipo N/fisiologia , Força Muscular , Plasticidade Neuronal/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Junção Neuromuscular/fisiologia , Condicionamento Físico Animal , Transmissão Sináptica
7.
Heart Lung Circ ; 28(3): e23-e25, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29891247

RESUMO

Myocardial perfusion scanning (MPS) is commonly used to assess patients with an intermediate to high risk of coronary artery disease. Concerns have been raised about the accuracy of this test. There is little recent data regarding the specificity of the MPS in the context of current medical therapy. The primary objective of this study is to determine the specificity of MPS in diagnosing obstructive coronary artery disease. A total of 184 patients fulfilled study criteria. The overall specificity of MPS for obstructive coronary artery disease was 54%.The only demographic variable that influenced specificity was gender: males with a specificity of 66% and females with a specificity of 29% (p-value=0.001). These results suggest that the real world specificity of MPS is lower than previously indicated, particularly in the female population. The limitations proposed by the Cardiac Services Committee Report are therefore unlikely to improve patient outcomes.


Assuntos
Doença da Artéria Coronariana/diagnóstico , Medicare/estatística & dados numéricos , Imagem de Perfusão do Miocárdio/métodos , Idoso , Angiografia Coronária , Doença da Artéria Coronariana/economia , Eletrocardiografia , Teste de Esforço , Feminino , Seguimentos , Humanos , Masculino , Imagem de Perfusão do Miocárdio/economia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Estados Unidos
8.
Hum Mol Genet ; 25(1): 158-66, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26604149

RESUMO

Nitric oxide (NO) is a key regulator of skeletal muscle function and metabolism, including vasoregulation, mitochondrial function, glucose uptake, fatigue and excitation-contraction coupling. The main generator of NO in skeletal muscle is the muscle-specific form of neuronal nitric oxide synthase (nNOSµ) produced by the NOS1 gene. Skeletal muscle nNOSµ is predominantly localized at the sarcolemma by interaction with the dystrophin protein complex (DPC). In Duchenne muscular dystrophy (DMD), loss of dystrophin leads to the mislocalization of nNOSµ from the sarcolemma to the cytosol. This perturbation has been shown to impair contractile function and cause muscle fatigue in dystrophic (mdx) mice. Here, we investigated the effect of restoring sarcolemmal nNOSµ on muscle contractile function in mdx mice. To achieve this, we designed a modified form of nNOSµ (NOS-M) that is targeted to the sarcolemma by palmitoylation, even in the absence of the DPC. When expressed specifically in mdx skeletal muscle, NOS-M significantly attenuates force loss owing to damaging eccentric contractions and repetitive isometric contractions (fatigue), while also improving force recovery after fatigue. Expression of unmodified nNOSµ at similar levels does not lead to sarcolemmal association and fails to improve muscle function. Aside from the benefits of sarcolemmal-localized NO production, NOS-M also increased the surface membrane levels of utrophin and other DPC proteins, including ß-dystroglycan, α-syntrophin and α-dystrobrevin in mdx muscle. These results suggest that the expression of NOS-M in skeletal muscle may be therapeutically beneficial in DMD and other muscle diseases characterized by the loss of nNOSµ from the sarcolemma.


Assuntos
Contração Muscular , Óxido Nítrico Sintase Tipo I/metabolismo , Sarcolema/metabolismo , Animais , Proteínas Associadas à Distrofina/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos mdx , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Utrofina/metabolismo
9.
Echocardiography ; 35(4): 575-577, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29457263

RESUMO

A young woman presented with fulminant heart failure. Transthoracic echocardiography revealed severe left ventricular dysfunction with a mass adjacent to the basal anterior wall, near the left ventricular outflow tract (LVOT). The cause of the acute heart failure and mass was unclear. Transesophageal echocardiography, with contrast, and cardiac magnetic resonance imaging findings were consistent with thrombus near the LVOT. Cardiac biopsy suggested giant cell myocarditis. The patient was treated with anticoagulation, steroids, and heart failure medications with resolution of the thrombus. This case was remarkable for the location of thrombus at the base of the ventricle.


Assuntos
Trombose Coronária/complicações , Trombose Coronária/diagnóstico por imagem , Ecocardiografia Transesofagiana/métodos , Insuficiência Cardíaca/complicações , Miocardite/complicações , Miocardite/diagnóstico por imagem , Doença Aguda , Adulto , Anticoagulantes , Angiografia por Tomografia Computadorizada , Trombose Coronária/tratamento farmacológico , Diagnóstico Diferencial , Feminino , Glucocorticoides , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Ventrículos do Coração/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Miocardite/tratamento farmacológico , Prednisona , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/tratamento farmacológico
10.
Proc Natl Acad Sci U S A ; 112(41): 12864-9, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26417069

RESUMO

Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fibras Musculares Esqueléticas , Força Muscular/efeitos dos fármacos , Distrofia Muscular de Duchenne , Sinvastatina/farmacologia , Animais , Creatina Quinase/sangue , Masculino , Camundongos , Camundongos Endogâmicos mdx , Complexos Multienzimáticos/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular de Duchenne/fisiopatologia , NADH NADPH Oxirredutases/metabolismo , Oxirredução/efeitos dos fármacos
12.
J Physiol ; 594(24): 7215-7227, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27570057

RESUMO

KEY POINTS: Duchenne muscular dystrophy (DMD) is a severe, degenerative muscle disease that is commonly studied using the mdx mouse. The mdx diaphragm muscle closely mimics the pathophysiological changes in DMD muscles. mdx diaphragm force is commonly assessed ex vivo, precluding time course studies. Here we used ultrasonography to evaluate time-dependent changes in diaphragm function in vivo, by measuring diaphragm movement amplitude. In mdx mice, diaphragm amplitude decreased with age and values were much lower than for wild-type mice. Importantly, diaphragm amplitude strongly correlated with ex vivo specific force values. Micro-dystrophin administration increased mdx diaphragm amplitude by 26% after 4 weeks. Diaphragm amplitude correlated positively with ex vivo force values and negatively with diaphragm fibrosis, a major cause of DMD muscle weakness. These studies validate diaphragm ultrasonography as a reliable technique for assessing time-dependent changes in mdx diaphragm function in vivo. This technique will be valuable for testing potential therapies for DMD. ABSTRACT: Duchenne muscular dystrophy (DMD) is a severe, degenerative muscle disease caused by dystrophin mutations. The mdx mouse is a widely used animal model of DMD. The mdx diaphragm muscle most closely recapitulates key features of DMD muscles, including progressive fibrosis and considerable force loss. Diaphragm function in mdx mice is commonly evaluated by specific force measurements ex vivo. While useful, this method only measures force from a small muscle sample at one time point. Therefore, accurate assessment of diaphragm function in vivo would provide an important advance to study the time course of functional decline and treatment benefits. Here, we evaluated an ultrasonography technique for measuring time-dependent changes of diaphragm function in mdx mice. Diaphragm movement amplitude values for mdx mice were considerably lower than those for wild-type, decreased from 8 to 18 months of age, and correlated strongly with ex vivo specific force. We then investigated the time course of diaphragm amplitude changes following administration of an adeno-associated viral vector expressing Flag-micro-dystrophin (AAV-µDys) to young adult mdx mice. Diaphragm amplitude peaked 4 weeks after AAV-µDys administration, and was 26% greater than control mdx mice at this time. This value decreased slightly to 21% above mdx controls after 12 weeks of treatment. Importantly, diaphragm amplitude again correlated strongly with ex vivo specific force. Also, diaphragm amplitude and specific force negatively correlated with fibrosis levels in the muscle. Together, our results validate diaphragm ultrasonography as a reliable technique for assessing time-dependent changes in dystrophic diaphragm function in vivo, and for evaluating potential therapies for DMD.


Assuntos
Diafragma/diagnóstico por imagem , Diafragma/fisiopatologia , Distrofia Muscular Animal/diagnóstico por imagem , Distrofia Muscular Animal/fisiopatologia , Animais , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/diagnóstico por imagem , Distrofia Muscular de Duchenne/fisiopatologia , Reprodutibilidade dos Testes , Ultrassonografia
13.
J Pathol ; 228(1): 77-87, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22653783

RESUMO

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy caused by mutations in the dystrophin gene. Loss of dystrophin initiates a progressive decline in skeletal muscle integrity and contractile capacity which weakens respiratory muscles including the diaphragm, culminating in respiratory failure, the leading cause of morbidity and mortality in DMD patients. At present, corticosteroid treatment is the primary pharmacological intervention in DMD, but has limited efficacy and adverse side effects. Thus, there is an urgent need for new safe, cost-effective, and rapidly implementable treatments that slow disease progression. One promising new approach is the amplification of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signalling pathways with phosphodiesterase 5 (PDE5) inhibitors. PDE5 inhibitors serve to amplify NO signalling that is attenuated in many neuromuscular diseases including DMD. We report here that a 14-week treatment of the mdx mouse model of DMD with the PDE5 inhibitor sildenafil (Viagra(®), Revatio(®)) significantly reduced mdx diaphragm muscle weakness without impacting fatigue resistance. In addition to enhancing respiratory muscle contractility, sildenafil also promoted normal extracellular matrix organization. PDE5 inhibition slowed the establishment of mdx diaphragm fibrosis and reduced matrix metalloproteinase-13 (MMP-13) expression. Sildenafil also normalized the expression of the pro-fibrotic (and pro-inflammatory) cytokine tumour necrosis factor α (TNFα). Sildenafil-treated mdx diaphragms accumulated significantly less Evans Blue tracer dye than untreated controls, which is also indicative of improved diaphragm muscle health. We conclude that sildenafil-mediated PDE5 inhibition significantly reduces diaphragm respiratory muscle dysfunction and pathology in the mdx mouse model of Duchenne muscular dystrophy. This study provides new insights into the therapeutic utility of targeting defects in NO-cGMP signalling with PDE5 inhibitors in dystrophin-deficient muscle.


Assuntos
Diafragma/efeitos dos fármacos , Fibrose/tratamento farmacológico , Debilidade Muscular/tratamento farmacológico , Distrofia Muscular de Duchenne/tratamento farmacológico , Inibidores da Fosfodiesterase 5/farmacologia , Piperazinas/farmacologia , Sulfonas/farmacologia , Animais , Creatina Quinase/sangue , GMP Cíclico/metabolismo , Diafragma/metabolismo , Diafragma/patologia , Modelos Animais de Doenças , Azul Evans/metabolismo , Fibrose/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Contração Muscular/efeitos dos fármacos , Fadiga Muscular/efeitos dos fármacos , Fadiga Muscular/fisiologia , Debilidade Muscular/etiologia , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/patologia , Óxido Nítrico/metabolismo , Purinas/farmacologia , Citrato de Sildenafila
14.
Eur Heart J Open ; 3(6): oead111, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38025651

RESUMO

Aims: Cardiac catheterization procedures are typically performed with local anaesthetic and proceduralist guided sedation. Various fasting regimens are routinely implemented prior to these procedures, noting the absence of prospective evidence, aiming to reduce aspiration risk. However, there are additional risks from fasting including patient discomfort, intravascular volume depletion, stimulus for neuro-cardiogenic syncope, glycaemic outcomes, and unnecessary fasting for delayed/cancelled procedures. Methods and results: This is an investigator-initiated, multicentre, randomized trial with a prospective, open-label, blinded endpoint (PROBE) assessment based in New South Wales, Australia. Patients will be randomized 1:1 to fasting (6 h solid food and 2 h clear liquids) or to no fasting requirements. The primary outcome will be a composite of hypotension, hyperglycaemia, hypoglycaemia, and aspiration pneumonia. Secondary outcomes will include patient satisfaction, contrast-induced nephropathy, new intensive care admission, new non-invasive or invasive ventilation requirement post procedure, and 30-day mortality and readmission. Conclusions: This is a pragmatic and clinically relevant randomised trial designed to compare fasting verse no fasting prior to cardiac catheterisation procedures. Routine fasting may not reduce peri-procedural adverse events in this setting.

15.
J Am Heart Assoc ; 10(5): e017948, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33586467

RESUMO

Background Polyvascular atherosclerotic disease is associated with an increased risk of future cardiovascular events. Intensive lipid-lowering therapy (ILT) may mitigate this risk. The aims of this study-level meta-analysis were to examine the effects of ILT in patients with polyvascular disease and whether baseline low-density lipoprotein cholesterol (LDL-C) may determine the level of benefit. Methods and Results Electronic databases were searched through January 2020 to identify randomized controlled trials of treatments targeting upregulation of LDL-C receptors (ie, statins, ezetimibe, and PCSK9 [proprotein convertase subtilisin-kexin type 9] inhibitors). The primary end point was major adverse vascular events as defined by the included studies. A total of 94 362 patients (14 821 [18.6%] with polyvascular disease) from 7 studies were included. In patients with monovascular disease, ILT was associated with a 13% reduction in the primary end point (rate ratio [RR] 0.87; 95% CI, 0.81-0.93 [P=0.0002]) (absolute RR, 1.8%) compared with less ILT, while patients with polyvascular disease had 15% relative RR (0.85; 95% CI, 0.80-0.90 [P<0.00001]) (absolute RR, 6.5%) (P=0.66 for interaction). When factoring LDL-C, unlike patients with monovascular disease, the relative benefits of ILT, compared with less ILT, in patients with polyvascular disease were comparable with LDL-C >100 mg/dL (RR, 0.85; 95% CI, 0.80-0.90 [P<0.00001]) and LDL-C <100 mg/dL (RR, 0.88; 95% CI, 0.81-0.96 [P=0.003]) (P=0.23 for interaction). Conclusions Patients with polyvascular disease experienced comparable benefits to those with monovascular disease in response to ILT. The benefits of ILT in patients with polyvascular disease were not dependent on baseline LDL-C, challenging the approach of using LDL-C as a prerequisite to commence ILT for this high-risk subgroup.


Assuntos
Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Doenças Vasculares/tratamento farmacológico , Biomarcadores/sangue , Humanos , Doenças Vasculares/sangue
16.
Can J Physiol Pharmacol ; 88(2): 83-91, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20237582

RESUMO

Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease caused by the absence of the cytoskeletal protein dystrophin. Experiments on the mdx mouse, a model of DMD, have shown that mdx muscles are particularly susceptible to stretch-induced damage. In this review, we discuss evidence showing that a series of stretched contractions of mdx muscle fibres causes a prolonged increase in resting intracellular calcium concentration ([Ca2+]i). The rise in [Ca2+]i is caused by Ca2+ entry through a class of stretch-activated channels (SACNSC) for which one candidate gene is TRPC1. We review the evidence for activation of SACNSC in muscle by reactive oxygen species (ROS) and suggest that stretch-induced ROS production is part of the pathway that triggers increased channel activity. When the TRPC1 gene was transfected into C2 myoblasts, expression occurred throughout the cell. Only when the TRPC1 gene was coexpressed with caveolin-3 did the TRPC1 protein express in the membrane. When TRPC1 was expressed in the membrane, it could be activated by ROS to produce Ca2+ entry and this entry was inhibited by PP2, an inhibitor of src kinase. These results suggest that stretched contractions activate ROS production, which activates src kinase. Activity of this kinase causes opening of SACNSC and allows Ca2+ entry. This pathway appears to be a significant cause of muscle damage in DMD.


Assuntos
Sinalização do Cálcio/fisiologia , Cálcio/fisiologia , Distrofia Muscular de Duchenne/metabolismo , Animais , Cálcio/química , Cálcio/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/patologia , Mioblastos/citologia , Mioblastos/metabolismo , Mioblastos/fisiologia , Transdução de Sinais/fisiologia , Canais de Cátion TRPC/química , Canais de Cátion TRPC/fisiologia
17.
Adv Exp Med Biol ; 682: 297-313, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20824533

RESUMO

One component of stretch-induced muscle damage is an increase in the permeability of the cell membrane. As a result soluble myoplasmic proteins leak out of the muscle into the plasma, extracellular proteins can enter the muscle, and extracellular ions, including calcium, are driven down their electrochemical gradient into the myoplasm. In Duchenne muscular dystrophy, caused by the absence of the cytoskeletal protein dystrophin, stretch-induced membrane damage is much more severe. The most popular theory to explain the occurrence of stretch-induced membrane damage is that stretched-contractions cause transient mechanically-induced defects in the membrane (tears or rips). Dystrophin, which is part of a mechanical link between the contractile machinery and the extracellular matrix, is thought to contribute to membrane strength so that in its absence mechanically-induced defects are worse. In our view the evidence that stretch-induced muscle damage causes increased membrane permeability is overwhelming but the evidence that the increased permeability is caused by mechanically-induced defects is weak. Instead we review the substantial evidence that the membrane permeability is a secondary consequence of the mechanical events in which elevated intracellular calcium and reactive oxygen species are important intermediaries.


Assuntos
Distrofina/deficiência , Distrofia Muscular de Duchenne/fisiopatologia , Animais , Membrana Celular/fisiologia , Permeabilidade da Membrana Celular , Distrofina/metabolismo , Matriz Extracelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Contração Muscular/fisiologia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia , Estresse Mecânico , Cromossomo X/genética
18.
Eur Heart J Acute Cardiovasc Care ; 9(7): 758-763, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30569736

RESUMO

INTRODUCTION: Elevated left ventricular end diastolic pressure (LVEDP) is an independent predictor of mortality and heart failure in patients with ST-segment elevation myocardial infarction (STEMI). Whether lowering elevated LVEDP improves outcomes remains unknown. METHODS: This non-randomized, single blinded study with prospective enrolment and sequential group allocation recruited patients undergoing primary percutaneous coronary intervention for STEMI with LVEDP ⩾ 20 mmHg measured immediately after primary percutaneous coronary intervention. The intervention arm (n=10) received furosemide 40 mg intravenous bolus plus escalating doses of glyceryl trinitrate (100 µg per min to a maximum of 1000 µg) during simultaneous measurement of LVEDP. The control group (n=10) received corresponding normal saline boluses with simultaneous measurement of LVEDP (10 readings over 10 min). Efficacy endpoints were final LVEDP achieved, and the dose of glyceryl trinitrate needed to reduce LVEDP by ⩾ 20%. Safety endpoint was symptomatic hypotension (systolic blood pressure < 90 mmHg). RESULTS: From 1 April 2017 to 23 August 2017 we enrolled 20 patients (age: 64±9 years, males: 60%, n=12, anterior STEMI: 65%, n=13). The mean LVEDP for the whole cohort (n=20) was 29±4 mmHg (intervention group: 28±3 mmHg vs. control group: 31±5 mmHg; p=0.1). The LVEDP dropped from 28±3 to 16±2 mmHg in the glyceryl trinitrate + furosemide group (p <0.01) but remained unchanged in the control group. The median dose of glyceryl trinitrate required to produce ⩾ 20% reduction in LVEDP in the intervention group was 200 µg (range: 100-800). One patient experienced asymptomatic decline in systolic blood pressure to below 90 mmHg. There was no correlation between LVEDP and left ventricular ejection fraction. CONCLUSION: The administration of glyceryl trinitrate plus furosemide in patients with elevated LVEDP following primary percutaneous coronary intervention for STEMI safely reduces LVEDP.


Assuntos
Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Pressão Ventricular/fisiologia , Idoso , Diástole , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Estudos Prospectivos , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia
20.
Curr Med Res Opin ; 35(6): 1097-1101, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30550348

RESUMO

OBJECTIVE: Pulmonary hypertension may be a consequence of intrinsic elevation in pulmonary vasculature resistance or complicate numerous other conditions affecting the cardiac and respiratory systems. In this review we sought to explore the relationship between pulmonary hypertension and intravenous drug use. METHODS: A narrative review was conducted using PubMed MeSH search with further papers identified using a standard PubMed search with relevant key terms and various synonyms. RESULTS: HIV infection may be associated with pulmonary hypertension due to indirect consequences of viral infection, venous thromboembolism or its therapies. Anti-retroviral infection may also influence plasma concentrations of commonly used treatments for pulmonary hypertension. Intravenous drug use is acknowledged as an important portal for the acquisition of hepatitis virus C infection, with portopulmonary hypertension a potential complication associated with poor prognosis. Interferon based therapy, used in treatment of chronic hepatitis C infection, may also play a causal role in the development of pulmonary hypertension. More recently, sofosbuvir has been linked to development or exacerbation of pulmonary arterial hypertension. Certain drugs of abuse may cause pulmonary hypertension due to properties that result in direct injury to the pulmonary vasculature. The potential for embolic phenomena, complicating venous thromboembolism, recurrent embolization of particulate matter or because of right-sided endocarditis, resulting in pulmonary hypertension is an important contributing factor in the pathophysiology in this unique cohort. CONCLUSIONS: Eliciting a history of intravenous drug use is important and may be associated with a number of less common etiologies, each with specific diagnostic and therapeutic implications.


Assuntos
Hipertensão Pulmonar/etiologia , Abuso de Substâncias por Via Intravenosa/complicações , Humanos
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