Safety and care of no fasting prior to catheterization laboratory procedures: a non-inferiority randomized control trial protocol (SCOFF trial).

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.

Meta-Analysis of Intensive Lipid-Lowering Therapy in Patients With Polyvascular Disease.

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.

Targeting elevated left ventricular end-diastolic pressure following primary percutaneous coronary intervention for ST-segment elevation myocardial infarction - a phase one safety and feasibility study.

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.

Mycotic Coronary Aneurysms.

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.

Contemporary trends in stroke complicating cardiac catheterisation.

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.

Sedation and Analgesia for Cardiac Catheterisation and Coronary Intervention.

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.

Simvastatin provides long-term improvement of left ventricular function and prevents cardiac fibrosis in muscular dystrophy.

Duchenne muscular dystrophy (DMD), caused by absence of the protein dystrophin, is a common, degenerative muscle disease affecting 1:5000 males worldwide. With recent advances in respiratory care, cardiac dysfunction now accounts for 50% of mortality in DMD. Recently, we demonstrated that simvastatin substantially improved skeletal muscle health and function in mdx (DMD) mice. Given the known cardiovascular benefits ascribed to statins, the aim of this study was to evaluate the efficacy of simvastatin on cardiac function in mdx mice. Remarkably, in 12-month old mdx mice, simvastatin reversed diastolic dysfunction to normal after short-term treatment (8 weeks), as measured by echocardiography in animals anesthetized with isoflurane and administered dobutamine to maintain a physiological heart rate. This improvement in diastolic function was accompanied by increased phospholamban phosphorylation in simvastatin-treated mice. Echocardiography measurements during long-term treatment, from 6 months up to 18 months of age, showed that simvastatin significantly improved in vivo cardiac function compared to untreated mdx mice, and prevented fibrosis in these very old animals. Cardiac dysfunction in DMD is also characterized by decreased heart rate variability (HRV), which indicates autonomic function dysregulation. Therefore, we measured cardiac ECG and demonstrated that short-term simvastatin treatment significantly increased heart rate variability (HRV) in 14-month-old conscious mdx mice, which was reversed by atropine. This finding suggests that enhanced parasympathetic function is likely responsible for the improved HRV mediated by simvastatin. Together, these findings indicate that simvastatin markedly improves cardiac health and function in dystrophic mice, and therefore may provide a novel approach for treating cardiomyopathy in DMD.

Missed Acute Myocardial Infarction (MAMI) in a rural and regional setting.

BACKGROUND: Delay in treatment and/or failure to provide reperfusion in ST-segment elevation myocardial infarction (STEMI) impacts on morbidity and mortality. This occurs more often outside metropolitan areas yet the reasons for this are unclear. This study aimed to describe factors associated with missed diagnosis of acute myocardial infarction (MAMI) in a rural and regional setting. METHODS: Using a retrospective cohort design, patients who presented with STEMI and failed to receive reperfusion therapy within four hours were identified as MAMI. Univariate analyses were undertaken to identify differences in clinical characteristics between the treated STEMI group and the MAMI group. Mortality, 30-day readmission rates and length of hospital stay are reported. RESULTS: Of 100 patients identified as MAMI (70 male, 30 female), 24 died in hospital. Demographics and time from symptom onset were similar in the treated STEMI and MAMI groups. Of the MAMI patients who died, rural hospitals recorded the highest inpatient mortality (69.6% p = 0.008). MAMI patients compared to treated STEMI patients had higher 30 day readmission (31.6% vs 3.3%, p = 0.001) and longer length of stay (5.5 vs 4.3 days p = 0.029). Inaccurate identification of STEMI on electrocardiogram (72%) and diagnostic uncertainty (65%) were associated with MAMI. The Glasgow algorithm to identify STEMI was utilised on 57% of occasions, with 93% accuracy. CONCLUSION: Mortality following MAMI is high particularly in smaller rural hospitals. MAMI results in increased length of stay and readmission rate. Electrocardiogram interpretation and diagnostic accuracy require improvement to determine if this improves patient outcomes.

Specificity of Myocardial Perfusion Imaging: Issues With Proposed MBS Item Review.

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.

Mice lacking α-, ß1- and ß2-syntrophins exhibit diminished function and reduced dystrophin expression in both cardiac and skeletal muscle.

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.

Pulmonary hypertension in patients with a history of intravenous drug use.

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.

Drug-associated pulmonary arterial hypertension.

INTRODUCTION: While pulmonary arterial hypertension remains an uncommon diagnosis, various therapeutic agents are recognized as important associations. These agents are typically categorized into "definite", "likely", "possible", or "unlikely" to cause pulmonary arterial hypertension, based on the strength of evidence. OBJECTIVE: This review will focus on those therapeutic agents where there is sufficient literature to adequately comment on the role of the agent in the pathogenesis of pulmonary arterial hypertension. METHODS: A systematic search was conducted using PubMed covering the period September 1970- 2017. The search term utilized was "drug induced pulmonary hypertension". This resulted in the identification of 853 peer-reviewed articles including case reports. Each paper was then reviewed by the authors for its relevance. The majority of these papers (599) were excluded as they related to systemic hypertension, chronic obstructive pulmonary disease, human immunodeficiency virus, pulmonary fibrosis, alternate differential diagnosis, treatment, basic science, adverse effects of treatment, and pulmonary hypertension secondary to pulmonary embolism. Agents affecting serotonin metabolism (and related anorexigens): Anorexigens, such as aminorex, fenfluramine, benfluorex, phenylpropanolamine, and dexfenfluramine were the first class of medications recognized to cause pulmonary arterial hypertension. Although most of these medications have now been withdrawn worldwide, they remain important not only from a historical perspective, but because their impact on serotonin metabolism remains relevant. Selective serotonin reuptake inhibitors, tryptophan, and lithium, which affect serotonin metabolism, have also been implicated in the development of pulmonary arterial hypertension. Interferon and related medications: Interferon alfa and sofosbuvir have been linked to the development of pulmonary arterial hypertension in patients with other risk factors, such as human immunodeficiency virus co-infection. Antiviral therapies: Sofosbuvir has been associated with two cases of pulmonary artery hypertension in patients with multiple risk factors for its development. Its role in pathogenesis remains unclear. Small molecule tyrosine kinase inhibitors: Small molecule tyrosine kinase inhibitors represent a relatively new class of medications. Of these dasatinib has the strongest evidence in drug-induced pulmonary arterial hypertension, considered a recognized cause. Nilotinib, ponatinib, carfilzomib, and ruxolitinib are newer agents, which paradoxically have been linked to both cause and treatment for pulmonary arterial hypertension. Monoclonal antibodies and immune regulating medications: Several case reports have linked some monoclonal antibodies and immune modulating therapies to pulmonary arterial hypertension. There are no large series documenting an increased prevalence of pulmonary arterial hypertension complicating these agents; nonetheless, trastuzumab emtansine, rituximab, bevacizumab, cyclosporine, and leflunomide have all been implicated in case reports. Opioids and substances of abuse: Buprenorphine and cocaine have been identified as potential causes of pulmonary arterial hypertension. The mechanism by which this occurs is unclear. Tramadol has been demonstrated to cause severe, transient, and reversible pulmonary hypertension. Chemotherapeutic agents: Alkylating and alkylating-like agents, such as bleomycin, cyclophosphamide, and mitomycin have increased the risk of pulmonary veno-occlusive disease, which may be clinically indistinct from pulmonary arterial hypertension. Thalidomide and paclitaxel have also been implicated as potential causes. Miscellaneous medications: Protamine appears to be able to cause acute, reversible pulmonary hypertension when bound to heparin. Amiodarone is also capable of causing pulmonary hypertension by way of recognized side effects. CONCLUSIONS: Pulmonary arterial hypertension remains a rare diagnosis, with drug-induced causes even more uncommon, accounting for only 10.5% of cases in large registry series. Despite several agents being implicated in the development of PAH, the supportive evidence is typically limited, based on case series and observational data. Furthermore, even in the drugs with relatively strong associations, factors that predispose an individual to PAH have yet to be elucidated.

Acute myocarditis with thrombus near left ventricular outflow tract.

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.

ST elevation myocardial infarction in patients with anomalous left main coronary artery: Case series and review of the literature.

Anomalous left main coronary artery is rare. We present four cases where anomalous left main coronary artery was diagnosed during emergent cardiac catheterization for ST elevation myocardial infarction. Procedural characteristics, technical challenges, and relevant literature are discussed.

Anterolateral papillary muscle rupture in Staphylococcus aureus endocarditis due to direct bacterial invasion of papillary muscle.

Rupture of papillary muscles due to infective endocarditis is a very rare event. We report a case of anterolateral papillary muscle rupture caused by Staphylococcus aureus endocarditis, due to direct bacterial invasion of the papillary muscle, resulting in severe mitral regurgitation.

Validation of ultrasonography for non-invasive assessment of diaphragm function in muscular dystrophy.

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.

Simvastatin offers new prospects for the treatment of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is the most common and severe inherited neuromuscular disorder. DMD is caused by mutations in the gene encoding the dystrophin protein in muscle fibers. Dystrophin was originally proposed to be a structural protein that protected the sarcolemma from stresses produced during contractions. However, more recently, experimental evidence has revealed a far more complicated picture, with the loss of dystrophin causing dysfunction of multiple muscle signaling pathways, which all contribute to the overall disease pathophysiology. Current gene-based approaches for DMD are conceptually appealing since they offer the potential to restore dystrophin to muscles, albeit a partially functional, truncated form of the protein. However, given the cost and technical challenges facing these genetic approaches, it is important to consider if relatively inexpensive, clinically used drugs may be repurposed for treating DMD. Here, we discuss our recent findings showing the potential of simvastatin as a novel therapy for DMD.

Enhanced autophagy as a potential mechanism for the improved physiological function by simvastatin in muscular dystrophy.

Autophagy has recently emerged as an important cellular process for the maintenance of skeletal muscle health and function. Excessive autophagy can trigger muscle catabolism, leading to atrophy. In contrast, reduced autophagic flux is a characteristic of several muscle diseases, including Duchenne muscular dystrophy, the most common and severe inherited muscle disorder. Recent evidence demonstrates that enhanced reactive oxygen species (ROS) production by CYBB/NOX2 impairs autophagy in muscles from the dmd/mdx mouse, a genetic model of Duchenne muscular dystrophy. Statins decrease CYBB/NOX2 expression and activity and stimulate autophagy in skeletal muscle. Therefore, we treated dmd/mdx mice with simvastatin and showed decreased CYBB/NOX2-mediated oxidative stress and enhanced autophagy induction. This was accompanied by reduced muscle damage, inflammation and fibrosis, and increased muscle force production. Our data suggest that increased autophagy may be a potential mechanism by which simvastatin improves skeletal muscle health and function in muscular dystrophy.

Altered short-term synaptic plasticity and reduced muscle strength in mice with impaired regulation of presynaptic CaV2.1 Ca2+ channels.

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.