Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

BACKGROUND: Muscle fatigue and pain are key symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Although the pathophysiology is not yet fully understood, there is ample evidence for hypoperfusion which may result in electrolyte imbalance and sodium overload in muscles. Therefore, the aim of this study was to assess levels of sodium content in muscles of patients with ME/CFS and to compare these to healthy controls. METHODS: Six female patients with ME/CFS and six age, BMI and sex matched controls underwent 23Na-MRI of the left lower leg using a clinical 3T MR scanner before and after 3 min of plantar flexion exercise. Sodium reference phantoms with solutions of 10, 20, 30 and 40 mmol/L NaCl were used for quantification. Muscle sodium content over 40 min was measured using a dedicated plugin in the open-source DICOM viewer Horos. Handgrip strength was measured and correlated with sodium content. RESULTS: Baseline tissue sodium content was higher in all 5 lower leg muscle compartments in ME/CFS compared to controls. Within the anterior extensor muscle compartment, the highest difference in baseline muscle sodium content between ME/CFS and controls was found (mean ± SD; 12.20 ± 1.66 mM in ME/CFS versus 9.38 ± 0.71 mM in controls, p = 0.0034). Directly after exercise, tissue sodium content increased in gastrocnemius and triceps surae muscles with + 30% in ME/CFS (p = 0.0005) and + 24% in controls (p = 0.0007) in the medial gastrocnemius muscle but not in the extensor muscles which were not exercised. Compared to baseline, the increase of sodium content in medial gastrocnemius muscle was stronger in ME/CFS than in controls with + 30% versus + 17% to baseline at 12 min (p = 0.0326) and + 29% versus + 16% to baseline at 15 min (p = 0.0265). Patients had reduced average handgrip strength which was associated with increased average muscle tissue sodium content (p = 0.0319, R2 = 0.3832). CONCLUSION: Muscle sodium content before and after exercise was higher in ME/CFS than in healthy controls. Furthermore, our findings indicate an inverse correlation between muscle sodium content and handgrip strength. These findings provide evidence that sodium overload may play a role in the pathophysiology of ME/CFS and may allow for potential therapeutic targeting.

CARDIOKIN1: Computational Assessment of Myocardial Metabolic Capability in Healthy Controls and Patients With Valve Diseases.

BACKGROUND: Many heart diseases can result in reduced pumping capacity of the heart muscle. A mismatch between ATP demand and ATP production of cardiomyocytes is one of the possible causes. Assessment of the relation between myocardial ATP production (MVATP) and cardiac workload is important for better understanding disease development and choice of nutritional or pharmacologic treatment strategies. Because there is no method for measuring MVATP in vivo, the use of physiology-based metabolic models in conjunction with protein abundance data is an attractive approach. METHOD: We developed a comprehensive kinetic model of cardiac energy metabolism (CARDIOKIN1) that recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts, and in vivo studies with humans. We used the model to assess the energy status of the left ventricle of healthy participants and patients with aortic stenosis and mitral valve insufficiency. Maximal enzyme activities were individually scaled by means of protein abundances in left ventricle tissue samples. The energy status of the left ventricle was quantified by the ATP consumption at rest (MVATP[rest]), at maximal workload (MVATP[max]), and by the myocardial ATP production reserve, representing the span between MVATP(rest) and MVATP(max). RESULTS: Compared with controls, in both groups of patients, MVATP(rest) was increased and MVATP(max) was decreased, resulting in a decreased myocardial ATP production reserve, although all patients had preserved ejection fraction. The variance of the energetic status was high, ranging from decreased to normal values. In both patient groups, the energetic status was tightly associated with mechanic energy demand. A decrease of MVATP(max) was associated with a decrease of the cardiac output, indicating that cardiac functionality and energetic performance of the ventricle are closely coupled. CONCLUSIONS: Our analysis suggests that the ATP-producing capacity of the left ventricle of patients with valvular dysfunction is generally diminished and correlates positively with mechanical energy demand and cardiac output. However, large differences exist in the energetic state of the myocardium even in patients with similar clinical or image-based markers of hypertrophy and pump function. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03172338 and NCT04068740.

Abnormal aortic flow profiles persist after aortic valve replacement in the majority of patients with aortic valve disease: how model-based personalized therapy planning could improve results. A pilot study approach.

OBJECTIVES: Complex blood flow profiles in the aorta are known to contribute to vessel dilatation. We studied flow profiles in the aorta in patients with aortic valve disease before and after surgical aortic valve replacement (AVR). METHODS: Thirty-four patients with aortic valve disease underwent 4-dimensional velocity-encoded magnetic resonance imaging before and after AVR (biological valve = 27, mechanical valve = 7). Seven healthy volunteers served as controls. Eccentricity (ES) and complex flow scores (CFS) were determined from the degree of helicity, vorticity and eccentricity of flow profiles in the aorta. Model-based therapy planning was used in 4 cases to improve in silico postoperative flow profiles by personalized adjustment of size, rotation and angulation of the valve as well as aorta diameter. RESULTS: Patients with aortic valve disease showed more complex flow than controls [median ES 2.5 (interquartile range (IQR) 2.3-2.7) vs 1.0 (IQR 1.0-1.0), P < 0.001, median CFS 4.7 (IQR 4.3-4.8) vs 1.0 (IQR 1.0-2.0), P < 0.001]. After surgery, flow complexity in the total patient cohort was reduced, but remained significantly higher compared to controls [median ES 2.3 (IQR 1.9-2.3) vs 1.0 (IQR 1.0-1.0), P < 0.001, median CFS 3.8 (IQR 3.0-4.3) vs 1.0 (IQR 1.0-2.0), P < 0.001]. In patients after mechanical AVR, flow complexity fell substantially and showed no difference from controls [median ES 1.0 (IQR 1.0-2.3) vs 1.0 (IQR 1.0-1.0), P = 0.46, median CFS 1.0 (IQR 1.0-3.3) vs 1.0 (IQR 1.0-2.0), P = 0.71]. In all 4 selected cases (biological, n = 2; mechanical, n = 2), model-based therapy planning reduced in silico complexity of flow profiles compared to the existing post-surgical findings [median ES 1.7 (IQR 1.4-1.7) vs 2.3 (IQR 2.3-2.3); CFS 1.7 (IQR 1.4-2.5) vs 3.8 (IQR 3.3-4.3)]. CONCLUSIONS: Abnormal flow profiles in the aorta more frequently persist after surgical AVR. Model-based therapy planning might have the potential to optimize treatment for best possible individual outcome. CLINICAL TRIAL REGISTRATION NUMBER: clinicaltrials.gov NCT03172338, 1 June 2017, retrospectively registered; NCT02591940, 30 October 2015, retrospectively registered.

Impact of predictive medicine on therapeutic decision making: a randomized controlled trial in congenital heart disease.

Computational modelling has made significant progress towards clinical application in recent years. In addition to providing detailed diagnostic data, these methods have the potential to simulate patient-specific interventions and to predict their outcome. Our objective was to evaluate to which extent patient-specific modelling influences treatment decisions in coarctation of the aorta (CoA), a common congenital heart disease. We selected three cases with CoA, two of which had borderline indications for intervention according to current clinical guidelines. The third case was not indicated for intervention according to guidelines. For each case, we generated two separate datasets. First dataset included conventional diagnostic parameters (echocardiography and magnetic resonance imaging). In the second, we added modelled parameters (pressure fields). For the two cases with borderline indications for intervention, the second dataset also included pressure fields after virtual stenting simulations. All parameters were computed by modelling methods that were previously validated. In an online-administered, invitation-only survey, we randomized 178 paediatric cardiologists to view either conventional (control) or add-on modelling (experimental) datasets. Primary endpoint was the proportion of participants recommending different therapeutic options: (1) surgery or catheter lab (collectively, "intervention") or (2) no intervention (follow-up with or without medication). Availability of data from computational predictive modelling influenced therapeutic decision making in two of three cases. There was a statistically significant association between group assignment and the recommendation of an intervention for one borderline case and one non-borderline case: 94.3% vs. 72.2% (RR: 1.31, 95% CI: 1.14-1.50, p = 0.00) and 18.8% vs. 5.1% (RR: 3.09, 95% CI: 1.17-8.18, p = 0.01) of participants in the experimental and control groups respectively recommended an intervention. For the remaining case, there was no difference between the experimental and control group and the majority of participants recommended intervention. In sub-group analyses, findings were not affected by the experience level of participating cardiologists. Despite existing clinical guidelines, the therapy recommendations of the participating physicians were heterogeneous. Validated patient-specific computational modelling has the potential to influence treatment decisions. Future studies in broader areas are needed to evaluate whether differences in decisions result in improved outcomes (Trial Registration: NCT02700737).

Development of a modeling pipeline for the prediction of hemodynamic outcome after virtual mitral valve repair using image-based CFD.

PURPOSE: Severe mitral valve regurgitation can either be treated by a replacement or a repair of the valve. The latter is recommended due to lower perioperative mortality and better long-term survival. On the other hand, recurrence rates after mitral valve repair are high compared to those after replacements and the repair intervention can cause induced mitral valve stenosis. So far, there are no methods to predict the hemodynamic outcome of a chosen treatment or to compare different treatment options in advance. To overcome this, diastolic mitral valve hemodynamics are simulated using computational fluid dynamics after different virtual treatments of the valve. METHODS: The left ventricular geometry of one patient was reconstructed using trans-esophageal echocardiography and computed tomography data. Pre-op hemodynamics are simulated using a referenced wall model to avoid expansive modeling of wall motion. Subsequently, the flow structures are compared to in vivo measurements. After manipulating the patient-specific geometry in order to mimic a restrictive mitral annuloplasty as well as a MitraClip intervention, hemodynamics results are calculated. RESULTS: Good agreements exist between calculated pre-op hemodynamics and in vivo measurements. The virtual annuloplasty did not result in any remarkable change of hemodynamics. Neither the pressure drop nor the velocity field showed strong differences. In contrast, the virtual MitraClip intervention led to a complete change in blood flow structures as well as an elevated pressure drop across the valve. CONCLUSION: The presented approach allows fast simulation of the diastolic hemodynamic situation before and after treatment of a mitral valve insufficiency. However, this approach is limited to the early diastolic phase of the cardiac cycle and needs to be validated using a larger sample size.

Avoidable costs of stenting for aortic coarctation in the United Kingdom: an economic model.

BACKGROUND: Undesirable outcomes in health care are associated with patient harm and substantial excess costs. Coarctation of the aorta (CoA), one of the most common congenital heart diseases, can be repaired with stenting but requires monitoring and subsequent interventions to detect and treat disease recurrence and aortic wall injuries. Avoidable costs associated with stenting in patients with CoA are unknown. METHODS: We developed an economic model to calculate potentially avoidable costs in stenting treatment of CoA in the United Kingdom over 5 years. We calculated baseline costs for the intervention and potentially avoidable complications and follow-up interventions and compared these to the costs in hypothetical scenarios with improved treatment effectiveness and complication rates. RESULTS: Baseline costs were £16 688 ($25 182) per patient. Avoidable costs ranged from £137 ($207) per patient in a scenario assuming a 10% reduction in aortic wall injuries and reinterventions at follow-up, to £1627 ($2455) in a Best-case scenario with 100% treatment success and no complications. Overall costs in the Best-case scenario were 90.2% of overall costs at Baseline. Reintervention rate at follow-up was identified as most influential lever for overall costs. Probabilistic sensitivity analysis showed a considerable degree of uncertainty for avoidable costs with widely overlapping 95% confidence intervals. CONCLUSIONS: Significant improvements in the treatment effectiveness and reductions in complication rates are required to realize discernible cost savings. Up to 10% of total baseline costs could be avoided in the best-case scenario. This highlights the need to pursue patient-specific treatment approaches which promise optimal outcomes.

Bicuspid aortic valve disease: systematic review and meta-analysis of surgical aortic valve repair.

Aortic valve repair is still emerging, and its role in the treatment of bicuspid aortic valve disease (BAVD) is not yet fully understood. Our objective is to synthesise available evidence on outcomes after surgical aortic valve repair in patients with BAVD. We conducted a systematic review of clinical studies using prespecified methods for searching, identifying and selecting eligible studies in 4 databases, and synthesising results (PROSPERO 2014:CRD42014014415). 2 researchers independently reviewed full-text articles and extracted data. The results of included studies were quantitatively synthesised in frequentist meta-analyses. We included 11 aortic valve repair studies or study arms with a total of 2010 participants. Pooled estimates for the proportion of patients surviving at 30 days, 1 year, 5 years and 10 years were 0.995 (95% CI 0.991 to 0.995), 0.994 (0.989 to 0.999), 0.945 (0.898 to 0.993) and 0.912 (0.845 to 0.979), respectively. The pooled proportion of late deaths from valve-related causes was 0.008 (0.000 to 0.019) at a mean follow-up of 3.5 years. Proportion of patients with valve-related reinterventions was 0.075 (0.037 to 0.113) at a mean follow-up of 3.9 years, and the linearised reintervention rate was 1.3 (0.7 to 1.9) per 100 patient-years. Outcome reporting was insufficient to pool the results for a number of predefined outcomes. In conclusion, existing evidence on aortic valve repair in BAVD is limited to mostly small case series, case-control and small retrospective cohort studies. Despite the low quality, available evidence suggests favourable survival outcomes after aortic valve repair in selected patients with BAVD. Valve-related reinterventions at follow-up are common in all patients undergoing repair surgery.

Interactive virtual stent planning for the treatment of coarctation of the aorta.

PURPOSE: The coarctation of the aorta (CoA), a local narrowing of the aortic arch, accounts for 7 % of all congenital heart defects. Stenting is a recommended therapy to reduce the pressure gradient. This procedure is associated with complications such as the development of adverse flow conditions. A computer-aided treatment planning based on flow simulations can help to predict possible complications. The virtual stent planning is an important, intermediate step in the treatment planning pipeline. We present a novel approach that automatically suggests a stent setup and provides a set of intuitive parameters that allow for an interactive adaption of the suggested stent placement and induced deformation. METHODS: A high-quality mesh and a centerline are automatically generated. The stent-induced deformation is realized through a deformation of the centerline and a vertex displacement with respect to the deformed centerline and additional stent parameters. The parameterization is automatically derived from the underlying data and can be optionally altered through a condensed set of clinically sound parameters. RESULTS: The automatic deformation can be generated in about 25 s on a consumer system. The interactive adaption can be performed in real time. Compared with manual expert reconstructions of the stented vessel section, the mean difference of vessel path and diameter is below 1 mm. CONCLUSION: Our approach enables a medical user to easily generate a plausibly deformed vessel mesh which is necessary as input for a simulation-based treatment planning of CoA.