Ca2+ Cycling Impairment in Heart Failure Is Exacerbated by Fibrosis: Insights Gained From Mechanistic Simulations

[EN] Heart failure (HF) is characterized by altered Ca2+ cycling, resulting in cardiac contractile dysfunction. Failing myocytes undergo electrophysiological remodeling, which is known to be the main cause of abnormal Ca2+ homeostasis. However, structural remodeling, specifically proliferating fibroblasts coupled to myocytes in the failing heart, could also contribute to Ca2+ cycling impairment. The goal of the present study was to systematically analyze the mechanisms by which myocyte-fibroblast coupling could affect Ca2+ dynamics in normal conditions and in HF. Simulations of healthy and failing human myocytes were performed using established mathematical models, and cells were either isolated or coupled to fibroblasts. Univariate and multivariate sensitivity analyses were performed to quantify effects of ion transport pathways on biomarkers computed from intracellular [Ca2+] waveforms. Variability in ion channels and pumps was imposed and populations of models were analyzed to determine effects on Ca2+ dynamics. Our results suggest that both univariate and multivariate sensitivity analyses are valuable methodologies to shed light into the ionic mechanisms underlying Ca2+ impairment in HF, although differences between the two methodologies are observed at high parameter variability. These can result from either the fact that multivariate analyses take into account ion channels or non-linear effects of ion transport pathways on Ca2+ dynamics. Coupling either healthy or failing myocytes to fibroblasts decreased Ca2+ transients due to an indirect sink effect on action potential and thus on Ca2+ related currents. Simulations that investigated restoration of normal physiology in failing myocytes showed that Ca2+ cycling can be normalized by increasing SERCA and L-type Ca2+ current activity while decreasing Na+-Ca2+ exchange and SR Ca2+ leak. Changes required to normalize action potentials in failing myocytes depended on whether myocytes were coupled to fibroblasts. In conclusion, univariate and multivariate sensitivity analyses are helpful tools to understand how Ca2+ cycling is impaired in heart failure and how this can be exacerbated by coupling of myocytes to fibroblasts. The design of pharmacological actions to restore normal activity should take into account the degree of fibrosis in the failing heart.This work was partially supported by the National Science Foundation (MCB 1615677), the American Heart Association (15GRNT25490006), the "Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013-2016 from the Ministerio de Economia, Industria y Competitividad of Spain and Fondo Europeo de Desarrollo Regional (FEDER) DPI2016-75799-R (AEI/FEDER, UE)", and the "Programa de Ayudas de Investigacion y Desarrollo (PAID-01-17)" from the Universitat Politecnica de Valencia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Mora-Fenoll, MT.; Ferrero De Loma-Osorio, JM.; Gómez García, JF.; Sobie, EA.; Trenor Gomis, BA. (2018). Ca2+ Cycling Impairment in Heart Failure Is Exacerbated by Fibrosis: Insights Gained From Mechanistic Simulations. Frontiers in Physiology. 9. https://doi.org/10.3389/fphys.2018.01194S9Aguilar, M., Qi, X. Y., Huang, H., Comtois, P., & Nattel, S. (2014). Fibroblast Electrical Remodeling in Heart Failure and Potential Effects on Atrial Fibrillation. Biophysical Journal, 107(10), 2444-2455. doi:10.1016/j.bpj.2014.10.014R. ALPERT, N., HASENFUSS, G., J. LEAVITT, B., P. ITTLEMAN, F., PIESKE, B., & A. MULIERI, L. (2000). A Mechanistic Analysis of Reduced Mechanical Performance in Human Heart Failure. Japanese Heart Journal, 41(2), 103-116. doi:10.1536/jhj.41.103Bers, D. M. (2000). Calcium Fluxes Involved in Control of Cardiac Myocyte Contraction. 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Diagnostic accuracy of somatosensory evoked potential monitoring during scoliosis fusion

The goal of this review was to ascertain the diagnostic accuracy of intraoperative somatosensory evoked potential (SSEP) changes to predict perioperative neurological outcome in patients undergoing spinal deformity surgery to correct adolescent idiopathic scoliosis (AIS). The authors searched PubMed/MEDLINE and World Science databases to retrieve reports and/or experiments from January 1950 through January 2014 for studies on SSEP use during AIS surgery. All motor and sensory deficits were noted in the neurological examination administered after the procedure which was used to determine the effectiveness of SSEP as an intraoperative monitoring technique. Fifteen studies identified a total of 4763 procedures on idiopathic patients. The observed incidence of neurological deficits was 1.11% (53/4763) of the sample population. Of the patients with new postoperative neurological deficits 75.5% (40/53) showed significant SSEP changes, and 24.5% (13/53) did not show significant change. Pooled analysis using the bivariate model showed SSEP change with pooled sensitivity (average 84%, 95% confidence interval 59-95%) and specificity (average 98%, 95% confidence interval 97-99%). The diagnostic odds ratio of a patient who had a new neurological deficit with SSEP changes was a diagnostic odds ratio of 340 (95% confidence interval 125-926). Overall, detection of SSEP changes had excellent discriminant ability with an area under the curve of 0.99. Our meta-analysis covering 4763 operations on idiopathic patients showed that it is a highly sensitive and specific test and that iatrogenic spinal cord injury resulting in new neurological deficits was 340 times more likely to have changes in SSEP compared to those without any new deficits

Guillain-Barré syndrome during childhood: particular clinical and electrophysiological features

Introduction Guillain–Barré syndrome (GBS) has some specific characteristics in children. Methods In this study we reviewed the clinical, laboratory, electrophysiological, and prognosis features of the 19 children diagnosed with GBS at Nantes University Hospital from 2000 to 2011. Results Gait disturbance and leg pain were the most frequent presenting symptoms. Electrophysiological examinations revealed significant abnormalities even when performed within the first week after onset. Decreased distal CMAP amplitude was noted in 89% of cases. The pattern indicated an acute inflammatory demyelinating polyneuropathy in 95% of cases and acute motor axonal neuropathy in the remaining 5%. About two-thirds of the children were treated with intravenous immunoglobulin. After >1 year of follow-up, 17 patients had complete recovery. Conclusion Gait disorder, leg pain, a high rate of distal conduction block, and a good prognosis are among the main specific features of GBS in childhood. Muscle Nerve, 48: 247–251, 201

Current treatment practice of Guillain-Barré syndrome

Objective: To define the current treatment practice of Guillain-Barré syndrome (GBS). Methods: The study was based on prospective observational data from the first 1,300 patients included in the International GBS Outcome Study. We described the treatment practice of GBS in general, and for (1) severe forms (unable to walk independently), (2) no recovery after initial treatment, (3) treatment-related fluctuations, (4) mild forms (able to walk independently), and (5) variant forms including Miller Fisher syndrome, taking patient characteristics and hospital type into account. Results: We excluded 88 (7%) patients because of missing data, protocol violation, or alternative diagnosis. Patients from Bangladesh (n = 189, 15%) were described separately because 83% were not treated. IV immunoglobulin (IVIg), plasma exchange (PE), or other immunotherapy was provided in 941 (92%) of the remaining 1,023 patients, including patients with severe GBS (724/743, 97%), mild GBS (126/168, 75%), Miller Fisher syndrome (53/70, 76%), and other variants (33/40, 83%). Of 235 (32%) patients who did not improve after their initial treatment, 82 (35%) received a second immune modulatory treatment. A treatment-related fluctuation was observed in 53 (5%) of 1,023 patients, of whom 36 (68%) were re-treated with IVIg or PE. Conclusions: In current practice, patients with mild and variant forms of GBS, or with treatment-related fluctuations and treatment failures, are frequently treated, even in absence of trial data to support this choice. The variability in treatment practice can be explained in part by the lack of evidence and guidelines for effective treatment in these situations

Ataluren delays loss of ambulation and respiratory decline in nonsense mutation Duchenne muscular dystrophy patients

Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulation (LoA) and respiratory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) versus patients with DMD on SoC alone. / Patients & methods: Study 019 was a long-term Phase III study of ataluren safety in nmDMD patients with a history of ataluren exposure. Propensity score matching identified Study 019 and CINRG DNHS patients similar in disease progression predictors. / Results & conclusion: Ataluren plus SoC was associated with a 2.2-year delay in age at LoA (p = 0.0006), and a 3.0-year delay in decline of predicted forced vital capacity to <60% in nonambulatory patients (p = 0.0004), versus SoC. Ataluren plus SoC delays disease progression and benefits ambulatory and nonambulatory patients with nmDMD. / ClinicalTrials.gov: NCT01557400

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion

Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion.

Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist

Muscle activation during gait in children with Duchenne muscular dystrophy

The aim of this prospective study was to investigate changes in muscle activity during gait in children with Duchenne muscular Dystrophy (DMD). Dynamic surface electromyography recordings (EMGs) of 16 children with DMD and pathological gait were compared with those of 15 control children. The activity of the rectus femoris (RF), vastus lateralis (VL), medial hamstrings (HS), tibialis anterior (TA) and gastrocnemius soleus (GAS) muscles was recorded and analysed quantitatively and qualitatively. The overall muscle activity in the children with DMD was significantly different from that of the control group. Percentage activation amplitudes of RF, HS and TA were greater throughout the gait cycle in the children with DMD and the timing of GAS activity differed from the control children. Significantly greater muscle coactivation was found in the children with DMD. There were no significant differences between sides. Since the motor command is normal in DMD, the hyper-activity and co-contractions likely compensate for gait instability and muscle weakness, however may have negative consequences on the muscles and may increase the energy cost of gait. Simple rehabilitative strategies such as targeted physical therapies may improve stability and thus the pattern of muscle activity