Effect of transcutaneous electrical nerve stimulation (TENS) on knee pain and physical function in patients with symptomatic knee osteoarthritis: the ETRELKA randomized clinical trial.

OBJECTIVE: To determine the effectiveness of TENS at relieving pain and improving physical function as compared to placebo TENS, and to determine its safety, in patients with knee osteoarthritis. METHODS: Multi-centre, parallel, 1:1 randomized, double-blind, placebo-controlled clinical trial conducted in six outpatient clinics in Switzerland. We included 220 participants with knee osteoarthritis recruited between October 15, 2012, and October 15, 2014. Patients were randomized to 3 weeks of treatment with TENS (n = 108) or placebo TENS (n = 112). Our pre-specified primary endpoint was knee pain at the end of 3-weeks treatment assessed with the WOMAC pain subscale. Secondary outcome measures included WOMAC physical function subscale and safety outcomes. RESULTS: There was no difference between TENS and placebo TENS in WOMAC pain at the end of treatment (mean difference -0.06; 95%CI -0.41 to 0.29; P = 0.74), nor throughout the trial duration (P = 0.98). Subgroup analyses did not indicate an interaction between patient/treatment characteristics and treatment effect on WOMAC pain at the end of treatment (P-interaction ≥0.22). The occurrence of adverse events was similar across groups, with 10.4% and 10.6% of patients reporting events in the TENS and placebo TENS groups, respectively (P = 0.95). No relevant differences were observed in secondary outcomes. CONCLUSIONS: TENS does not improve knee osteoarthritis pain when compared to placebo TENS. Therapists should consider other potentially more effective treatment modalities to decrease knee osteoarthritis pain and facilitate strengthening and aerobic exercise. Our findings are conclusive and further trials comparing TENS and placebo TENS in this patient population are not necessary.

Double-blind placebo-controlled trial of the effect of omalizumab on basophils in chronic urticaria patients.

BACKGROUND: Omalizumab has been shown to be effective in treating chronic spontaneous urticaria (CSU). The reduction in FcεRI receptor density on the surface of basophils and mast cells is thought to play a major role in its effectiveness. We conducted a double-blind, randomized, placebo-controlled trial to investigate the mode of action of omalizumab in patients with antihistamine-resistant CSU. METHODS: Thirty patients were randomized in a 2:1 ratio to receive either 300 mg omalizumab or placebo. Four monthly applications of omalizumab/placebo were followed up with a visit 2 months after the last injection. The primary endpoint was the FcεRI receptor density change on basophils. RESULTS: Omalizumab led to a significant reduction in FcεRI receptor density on basophils as soon as 1 week after the first injection: baseline omalizumab vs placebo group, 80.31 ± 47.18 × 10³ vs 78.29 ± 45.09 × 10³ receptors/basophil ± SD; 1 week, 72.89 ± 47.79 × 10³ vs 27.83 ± 20.87 × 10³, P = .001. This effect continued during the treatment phase and persisted for 2 months after the last injection: 93.81 ± 56.50 × 10³ vs 21.09 ± 15.23 × 10³, P = .002. Values for basophil "releasability" and the basophil activation test (CU-BAT) of patient serum using donor basophils were unchanged despite treatment: CU-BAT, CD63 10.75% (7.35) in the placebo group vs 8.35% (15.20) in the omalizumab group, P = .778. CONCLUSION: We demonstrated a rapid reduction of FcεRI receptor density on basophils following treatment with omalizumab. Because CU-BAT using well-characterized, omalizumab-naïve donor basophils did not change during the treatment phase, autoreactive serum factors seem to remain unaltered. This points towards a cellular effect of omalizumab on basophils. To predict the omalizumab response time and to monitor disease, FcεRI density and CU-BAT might be promising cellular-based assays.

Prevalence of cam and pincer-type deformities on hip MRI in an asymptomatic young Swiss female population: a cross-sectional study.

OBJECTIVES: Femoroacetabular impingement is proposed to cause early osteoarthritis (OA) in the non-dysplastic hip. We previously reported on the prevalence of femoral deformities in a young asymptomatic male population. The aim of this study was to determine the prevalence of both femoral and acetabular types of impingement in young females. METHODS: We conducted a population-based cross-sectional study of asymptomatic young females. All participants completed a set of questionnaires and underwent clinical examination of the hip. A random sample was subsequently invited to obtain magnetic resonance images (MRI) of the hip. All MRIs were read for cam-type deformities, increased acetabular depths, labral lesions, and impingement pits. Prevalence estimates of cam-type deformities and increased acetabular depths were estimated, and relationships between deformities and signs of joint damage were examined using logistic regression models. RESULTS: The study included 283 subjects, and 80 asymptomatic females with a mean age of 19.3 years attended MRI. Fifteen showed some evidence of cam-type deformities, but none were scored to be definite. The overall prevalence was therefore 0% [95% confidence interval (95% CI) 0-5%]. The prevalence of increased acetabular depth was 10% (95% CI 5-19). No association was found between increased acetabular depth and decreased internal rotation of the hip. Increased acetabular depth was not associated with signs of labral damage. CONCLUSIONS: Definite cam-type deformities in women are rare compared to men, whereas the prevalence of increased acetabular depth is higher, suggesting that femoroacetabular impingement has different gender-related biomechanical mechanisms.

Risk factors for vertebral fractures and bone loss after denosumab discontinuation: A real-world observational study.

BACKGROUND: Denosumab discontinuation without subsequent bisphosphonates (BPs) is associated with bone loss and multiple vertebral fractures. OBJECTIVE: Identifying risk factors for bone loss and vertebral fractures after denosumab discontinuation. METHODS: This retrospective study measured the outcome of 219 women with osteoporosis who discontinued denosumab treatment and received subsequent treatment with zoledronate, other BPs or a selective estrogen receptor modulator (SERM), or no therapy. Fracture rate, longitudinal bone mineral density (BMD) changes and bone turnover markers (BTMs) within 2 years after denosumab discontinuation were analysed. Linear regression analysis evaluated loss of BMD and age, BMI (kg/m2), denosumab treatment duration, pre-treatment, prior fracture state, baseline T-scores, use of glucocorticoids or aromatase inhibitors and BMD gains under denosumab therapy. RESULTS: 171 women received zoledronate after denosumab discontinuation, 26 had no subsequent treatment and 22 received other therapies (other BPs or a SERM). Zoledronate was associated with the fewest vertebral fractures (hazard ratio 0.16, p = 0.02) and all subsequent therapies retained BMD at all sites to some extent. Higher BMD loss was associated with younger age, lower BMI, longer denosumab treatment, lack of prior antiresorptive treatment and BMD gain under denosumab treatment. BTM levels correlated with denosumab treatment duration and bone loss at the total hip, but not the lumbar spine. CONCLUSIONS: Compared to no subsequent therapy, zoledronate was associated with fewer vertebral fractures after denosumab. Further, BMD loss depended on denosumab treatment duration, age, prior BP therapy and BMD gain under denosumab therapy, whereas BTM levels were associated with bone loss at the total hip and denosumab treatment duration.

Increased radiographic progression of distal hand osteoarthritis occurring during biologic DMARD monotherapy for concomitant rheumatoid arthritis.

OBJECTIVES: A considerable proportion of patients with rheumatoid arthritis (RA) also suffer from hand osteoarthritis (OA). We here assess the association between conventional synthetic (cs) and biological (b) disease-modifying antirheumatic drugs (DMARDs) and radiographic distal interphalangeal-(DIP) OA in patients with RA. METHODS: Adult RA patients from a longitudinal Swiss registry of rheumatic diseases who had ≥ 2 hand radiographs were included at the first radiograph and followed until the outcome or the last radiograph. Patients were grouped into two cohorts based on whether DIP OA was present or absent at cohort entry (cohorts 1 and 2, respectively). Modified Kellgren-Lawrence scores (KLS) were obtained by evaluating DIP joints for the severity of osteophytes, joint space narrowing, subchondral sclerosis, and erosions. KLS ≥ 2 in ≥ 1 DIP joint indicated incident or existing OA, and increase of ≥ 1 in KLS in ≥ 1 DIP joint indicated progression in existing DIP OA. Time-varying Cox regression and generalized estimating equation (GEE) analyses were performed. We estimated hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CI) of DIP OA incidence (cohort 2), or progression (cohort 1), in bDMARD monotherapy, bDMARD/csDMARD combination therapy, and past or never DMARD use, when compared to csDMARD use. In post hoc analyses, we descriptively and analytically assessed the individual KLS features in cohort 1. RESULTS: Among 2234 RA patients with 5928 radiographs, 1340 patients had DIP OA at baseline (cohort 1). Radiographic progression of DIP OA was characterized by new or progressive osteophyte formation (666, 52.4%), joint space narrowing (379, 27.5%), subchondral sclerosis (238, 17.8%), or erosions (62, 4.3%). bDMARD monotherapy had an increased risk of radiographic DIP OA progression compared to csDMARD monotherapy (adjusted HR 1.34 [95% CI 1.07-1.69]). The risk was not significant in csDMARD/bDMARD combination users (HR 1.12 [95% CI 0.96-1.31]), absent in past DMARD users (HR 0.96 [95% CI 0.66-1.41]), and significantly lower among never DMARD users (HR 0.54 [95% CI 0.33-0.90]). Osteophyte progression (HR 1.74 [95% CI 1.11-2.74]) was the most significantly increased OA feature with bDMARD use compared to csDMARD use. In 894 patients without initial DIP OA (cohort 2), the risk of incident OA did not differ between the treatment groups. The results from GEE analyses corroborated all findings. CONCLUSIONS: These real-world RA cohort data indicate that monotherapy with bDMARDs is associated with increased radiographic progression of existing DIP OA, but not with incident DIP OA.

Does cartilage volume or thickness distinguish knees with and without mild radiographic osteoarthritis? The Framingham Study.

OBJECTIVES: To examine whether the quantity of cartilage or semiquantitative scores actually differ in knees with mild radiographic osteoarthritis compared with knees without osteoarthritis. METHODS: Framingham Osteoarthritis Study participants had knee tibiofemoral magnetic resonance imaging-based measurements of cartilage. Using three-dimensional FLASH-water excitation sequences, cartilage volume, thickness and subregional cartilage thickness were measured and cartilage scored semiquantitatively (using the whole-organ magnetic resonance imaging score; WORMS). Using weight-bearing radiographs, mild osteoarthritis was defined as Kellgren/Lawrence (K/L) grade 2 and non-osteoarthritis as K/L grade 0. Differences between osteoarthritis and non-osteoarthritis knees in median cartilage measurements were tested using the Wilcoxon rank sum test. RESULTS: Among 948 participants (one knee each), neither cartilage volume nor regional thickness were different in mild versus non-osteoarthritis knees. In mild osteoarthritis, cartilage erosions in focal areas were missed when cartilage was quantified over large regions such as the medial tibia. For some but not all subregions of cartilage, especially among men, cartilage thickness was lower (p<0.05) in mild osteoarthritis than non-osteoarthritis knees. Because semiquantitative scores captured focal erosions, median WORMS scores were higher in mild osteoarthritis than non-osteoarthritis (all p<0.05). In moderate/severe osteoarthritis (K/L grades 3 or 4), osteoarthritis knees had much lower cartilage thickness and higher WORMS scores than knees without osteoarthritis. CONCLUSIONS: In mild osteoarthritis, the focal loss of cartilage is missed by quantitative measures of cartilage volume or thickness over broad areas. Regional cartilage volume and thickness (eg, medial tibia) are not different in mild osteoarthritis versus non-osteoarthritis. Subregional thickness may be decreased in mild osteoarthritis. Semiquantitative scoring that assesses focal cartilage damage differentiates mild osteoarthritis from non-osteoarthritis.

Does land-based exercise reduce pain and disability associated with hip osteoarthritis? A meta-analysis of randomized controlled trials.

OBJECTIVE: To determine if clinical guidelines recommending therapeutic exercise for people with hip osteoarthritis (OA) are supported by rigorous scientific evidence. METHODS: A meta-analysis of randomized controlled trials (RCTs) recruiting people with hip OA and comparing some form of land-based exercise program (as opposed to exercises conducted in the water) with a non-exercise group in terms of hip pain and/or self-reported physical function. RESULTS: Thirty-two RCTs were identified, but only five met the inclusion criteria. Only one of the five included RCTs restricted recruitment to people with hip OA, the other four RCTs also recruiting participants with knee OA. The five included studies provided data on 204 and 187 hip OA participants for pain and physical function, respectively. Combining the results of the five included RCTs using a fixed-effects model demonstrated a small treatment effect for pain (standardized mean difference (SMD) -0.38; 95% confidence interval (CI) -0.67 to -0.09). No significant benefit in terms of improved self-reported physical function was detected (SMD -0.02; 95% CI -0.31 to 0.28). CONCLUSION: Currently there is only silver level evidence (one small RCT) supporting the benefit of land-based therapeutic exercise for people with symptomatic hip OA in terms of reduced pain and improved physical function. The limited number and small sample size of the included RCTs restricts the confidence that can be attributed to these results.

An examination chair to measure internal rotation of the hip in routine settings: a validation study.

OBJECTIVE: To determine the performance of a newly developed examination chair as compared with the clinical standard of assessing internal rotation (IR) of the flexed hip with a goniometer. METHODS: The examination chair allowed measurement of IR in a sitting position simultaneously in both hips, with hips and knees flexed 90 degrees, lower legs hanging unsupported and a standardized load of 5 kg applied to both ankles using a bilateral pulley system. Clinical assessment of IR was performed in supine position with hips and knees flexed 90 degrees using a goniometer. Within the framework of a population-based inception cohort study, we calculated inter-observer agreement in two samples of 84 and 64 consecutive, unselected young asymptomatic males using intra-class correlation coefficients (ICC) and determined the correlation between IR assessed with examination chair and clinical assessment. RESULTS: Inter-observer agreement was excellent for the examination chair (ICC right hip, 0.92, 95% confidence interval [CI] 0.89-0.95; ICC left hip, 0.90, 95% CI 0.86-0.94), and considerably higher than that seen with clinical assessment (ICC right hip, 0.65, 95% CI 0.49-0.77; ICC left hip, 0.69, 95% CI 0.54-0.80, P for difference in ICC between examination chair and clinical assessment

Gender inequity in the provision of care for hip disease: population-based cross-sectional study.

OBJECTIVES: To examine gender differences along the care pathway to total hip replacement. METHODS: We conducted a population-based cross-sectional study of 26,046 individuals aged 35 years and over in Avon and Somerset. Participants completed a questionnaire asking about care provision at five milestones on the pathway to total hip replacement. Those reporting hip disease were invited to a clinical examination. We estimated odds ratios (ORs) [95% confidence intervals (CI)] for provision of care to women compared with men. RESULTS: 3169 people reported hip pain, 2018 were invited for clinical examination, and 1405 attended (69.6%). After adjustment for age and disease severity, women were less likely than men to have consulted their general practitioner (OR 0.78, 95%-CI 0.61-1.00), as likely as men to have received drug therapy for hip pain in the previous year (OR 0.96, 95%-CI 0.74-1.24), but less likely to have been referred to specialist care (OR 0.53, 95%-CI 0.40-0.70), to have consulted an orthopaedic surgeon (OR 0.50, 95%-CI 0.32-0.78), or to be on a waiting list for total hip replacement (OR 0.41, 95%-CI 0.20-0.87). Differences remained in the 746 people who had sought care from their general practitioner, and after adjustment for willingness and fitness for surgery. CONCLUSIONS: There are gender inequalities in provision of care for hip disease in England, which are not fully accounted for by gender differences in care seeking and treatment preferences. Differences in referral to specialist care by general practitioners might unwittingly contribute to this inequity. Accurate information about availability, benefits and risks of hip replacement for providers and patients, and continuing education to ensure that clinicians interpret and correct patients' assumptions could help reduce inequalities.

A randomised controlled trial of spinal manipulative therapy in acute low back pain.

OBJECTIVE: To determine whether treatment with spinal manipulative therapy (SMT) administered in addition to standard care is associated with clinically relevant early reductions in pain and analgesic consumption. METHODS: 104 patients with acute low back pain were randomly assigned to SMT in addition to standard care (n = 52) or standard care alone (n = 52). Standard care consisted of general advice and paracetamol, diclofenac or dihydrocodeine as required. Other analgesic drugs or non-pharmacological treatments were not allowed. Primary outcomes were pain intensity assessed on the 11-point box scale (BS-11) and analgesic use based on diclofenac equivalence doses during days 1-14. An extended follow-up was performed at 6 months. RESULTS: Pain reductions were similar in experimental and control groups, with the lower limit of the 95% CI excluding a relevant benefit of SMT (difference 0.5 on the BS-11, 95% CI -0.2 to 1.2, p = 0.13). Analgesic consumptions were also similar (difference -18 mg diclofenac equivalents, 95% CI -43 mg to 7 mg, p = 0.17), with small initial differences diminishing over time. There were no differences between groups in any of the secondary outcomes and stratified analyses provided no evidence for potential benefits of SMT in specific patient groups. The extended follow-up showed similar patterns. CONCLUSIONS: SMT is unlikely to result in relevant early pain reduction in patients with acute low back pain.

The association of bone attrition with knee pain and other MRI features of osteoarthritis.

OBJECTIVE: To determine whether bone attrition (flattening or depression of the subchondral bone) was associated with the presence and severity of knee pain and to evaluate the coexistence of attrition and other MRI features likely associated with pain. METHODS: Participants in the Framingham Osteoarthritis Study, a community cohort unselected for OA, answered questions about knee pain and underwent knee x rays and MRI. Attrition, bone marrow lesions (BMLs) and effusions were scored on MRI using the WORMS scale. We assessed attrition in knees with and without pain, and using logistic regression examined its association with pain adjusting for age, gender, Kellgren-Lawrence (K-L)grade, BMI, BML and effusion. We also explored the relation between attrition, pain severity and nocturnal pain. RESULTS: Attrition (Grade >2) was present in 28% (167/592) of painful knees and in 10% (106/1035) of nonpainful knees (adjusted OR 1.6 (95% CI 1.1 to 2.2)). Of knees with OA (n=368), 74% had pain if attrition was present and 58% if it was absent (adjusted OR 1.2 (95%CI 0.7 to 2.0)). Of knees without OA (n=1222), pain was reported in 39% of knees with attrition and in 27%without it (adjusted OR 2.1 (95% CI 1.1 to 4.0)). We found no association between either attrition/pain severity or attrition/nocturnal pain. Attrition often co-occurred with other OA features associated with pain such as BMLs and effusions. CONCLUSIONS: Attrition was associated independently with knee pain. Unlike knees without OA, the association was lost in OA knees where other pathological features that may cause pain also coexisted.

Prevalence of bone attrition on knee radiographs and MRI in a community-based cohort.

OBJECTIVES: Bone attrition probably constitutes remodeling of the bone, resulting in flattening or depression of the articular surfaces. Defining bone attrition is challenging because it is an accentuation of the normal curvature of the tibial plateaus. We aimed to define bone attrition on magnetic resonance imaging (MRI) of the knee using information from both radiographs and MRIs, and to assess whether bone attrition is common prior to end stage disease osteoarthritis (OA) in the tibio-femoral joint. METHODS: All knees of participants in the community-based sample of the Framingham OA Study were evaluated for bone attrition in radiographs and MRIs. Radiographs were scored based on templates designed to outline the normal contours of the tibio-femoral joint. MRIs were analyzed using the semi-quantitative Whole-Organ Magnetic Resonance Imaging Scoring (WORMS) method. The prevalence of bone attrition was calculated using two different thresholds for MRI scores. RESULTS: Inter-observer agreement for identification of bone attrition was substantial for the radiographs (kappa=0.71, 95% CI 0.67-0.81) and moderate for MRI (kappa=0.56, 95% CI 0.40-0.72). Of 964 knees, 5.7% of the radiographs showed bone attrition. Of these, 91% of MRIs were also read as showing bone attrition. We selected a conservative threshold for bone attrition on MRI scoring (> or = 2 on a 0-3 scale) based on agreement with attrition on the radiograph or when bone attrition on MRI co-occurred with cartilage loss on OA. Using this threshold for bone attrition on MRI, bone attrition was common in knees with OA. For example, in knees with mild OA but no joint space narrowing, 13 of 88 MRIs (14.8%) showed bone attrition. CONCLUSIONS: Using MRI we found that many knees with mild OA without joint narrowing on radiographs had bone attrition, even using conservative definitions. The validity of our definition of bone attrition should be evaluated in further studies. Bone attrition may occur in milder OA and at earlier stages of disease than previously thought.

Role of the nicotinic acid group in NAADP receptor selectivity.

Nicotinic acid adenine dinucleotide phosphate (NAADP) has been shown to be an intracellular Ca2+-releasing messenger in a wide variety of systems to date. Its actions are both potent and highly specific despite differing structurally from the endogenous cellular co-factor and its precursor, NADP, only in the substitution of a hydroxyl for the amine group at the 3' position of the pyridine ring. This substitution allows NAADP to bind to a membrane-localized binding site in sea urchin egg homogenates with an IC50 at least 1000-fold greater than that of NADP as measured by competition radioligand binding assays. This suggests that the NAADP receptor protein must include certain features in the NAADP binding site that regulate this specificity. In order to investigate this interaction, we synthesised a series of NAADP analogues differing from NAADP at the 3' position of the pyridine ring that included both simple carboxylic acid analogues as well as a series of chemical isosters. We then investigated both their affinity for the NAADP binding site in sea urchin egg homogenates and their ability to activate the NAADP sensitive Ca2+ channel. We hereby show that a negative charge at the 3' position is an important determinant of affinity but the protein displays a large tolerance for the size of the group. Furthermore, the protein does not easily accommodate multiple charged groups or large uncharged groups.

A versatile intracorporeal ventricular assist device based on the thoratec VAD system.

BACKGROUND: As patients are supported for longer durations with paracorporeal Thoratec left ventricular and biventricular assist devices (longest durations: 515 and 457 days, respectively), there is a need for implantable options. METHODS: We are developing a small, simple, and versatile intracorporeal ventricular assist device (IVAD) for left, right, or biventricular support as an alternative to the large, implantable, pulsatile left ventricular assist device (LVAD) systems available today. The new device is based on the Thoratec paracorporeal VAD that has been used in more than 1,400 patients weighing from 17 to 144 kg and for durations exceeding 1 year including patient discharge (using the portable driver). RESULTS: The IVAD has the same blood flow path and Thoralon polyurethane blood pumping sac as the paracorporeal VAD, but the housing is a smooth contoured, polished titanium alloy. The IVAD has a new sensor to detect when the pump is full and empty, and is controlled with the Thoratec TLC-II portable VAD driver, which is a small, briefcase-sized, battery-powered, pneumatic control unit. A small flexible (9 mm OD) percutaneous pneumatic driveline for each VAD is tunneled out of the body from the LVAD or right VAD in a pre- or intraperitoneal position. Small size and simplicity are the major advantages of the new device. The IVAD weight (339 g) and implanted volume (252 mL) are approximately one-half that of the current implantable pulsatile electromechanical LVAD systems. CONCLUSIONS: The small size of the IVAD should not only allow support of a large range of patient sizes and body habitus, but also provide options for implantable left, right, or biventricular support. By implanting only the mechanically simple blood pump, the more complex control unit is external, where it can be serviced and replaced without surgery. The IVAD with the portable driver will be a viable alternative to large implanted electromechanical systems and should address a larger segment of the physically diverse patient population.

Influence of different racing positions on metabolic cost in elite cyclists.

The spectacular improvements of the 1-h world record in cycling in the last four years have highlighted the importance of aerodynamics in modern bicycle racing. We have investigated the metabolic consequences of the low-crouched aero-positions necessary to reduce air drag. In this study, 14 elite male bicycle racers (24.0 +/- 1.0 yr, VO2max 69.4 +/- 0.5 mL.kg-1.min-1) were tested for oxygen consumption (VO2) and heart rate (HR) at 70% (302.6 +/- 5.3 W) of their individual VO2max in three different riding positions during a single test run. The subjects rode their racing bicycles on a wind braked roller; the sequence of the three following positions was randomized: 1) upright cycling (UP), cadence 90 rpm; 2) hands on drops (DP), 90 rpm; and 3) hands on clip-on aero-handlebars (AP), 90 rpm. VO2 and HR values in AP were significantly higher by 1.5 mL.kg-1.min-1 and 5 beats.min-1, respectively, compared with UP. We concluded that riding a bicycle in an extreme aero-position increases the metabolic cost of cycling when wind resistance is not taken into account. However, when the mechanical power losses of 9 W (estimated by the VO2 increase) are compared with the expected aerodynamic power savings of approximately 100 W, it appears that aerodynamic advantages by far outweight their metabolic cost.

Characterization and work optimization of skeletal muscle as a VAD power source.

Powering a ventricular assist device (VAD) with skeletal muscle in a linear configuration will require the understanding of basic muscle mechanics and efficient use of available power. Accordingly, a mathematical model incorporating aspects of the Hill equation has been developed. This model relates whole muscle length, force, velocity, and time during cyclic contraction to investigate coupling with a hydraulically actuated VAD. Parameters of the model have been determined from in vivo isometric and isotonic measurements of electrically stimulated pig latissimus dorsi with the humerus insertion reattached to a hydraulic loading system. The in vivo results show an exponential passive force-length relationship and active isometric forces increasing from 2 to 8 kgf over a 5 cm change in length. The maximum shortening velocity extrapolated from isotonic data in 85 cm/sec. With the experimentally determined parameters, the model system of differential equations was optimized computationally. Predicted maximum cycle work and corresponding muscle force are nonlinear functions of contraction duration; an increase in duration yields little improvement in work output for longer contraction times. The model helps clarify VAD system design parameters for optimal muscle coupling; for example, the model predicts that operating at maximum instantaneous power does not optimize stroke work.

Mechanical advantage of skeletal muscle as a cardiac assist power source.

The insertion of unconditioned latissimus dorsi muscle at the humerus was reattached in anesthetized goats to the first stage piston of a two stage mechanical-to-hydraulic energy convertor for a skeletal muscle powered ventricular assist device. To study a range of forces, pistons of different cross sectional areas were evaluated during thoracodorsal nerve stimulation. Each energy convertor piston was coupled hydraulically to an actuator on a Thoratec VAD (Thoratec Laboratories, Berkeley, CA) in a mock circulatory loop. Maximum force (70.1 +/- 10.8 N) was greatest for the largest piston, and stroke length (4.0 +/- 0.7 cm) was greatest for the smallest piston. However, maximum stroke work (1.2 +/- 0.5 J) and muscle powered VAD ejected stroke volume (45 +/- 17 ml) were greatest for the middle size piston. These results are consistent with a biomechanical model of whole muscle contraction that predicts that there is an optimum force that produces maximum cycle work. Thus, with a two stage energy convertor, by changing the ratio of the cross sectional areas of the energy convertor and muscle powered VAD actuator pistons, the effective mechanical advantage for the muscle can be optimized to produce more work output and muscle powered VAD flow. Skeletal muscle powered devices using such an energy convertor could provide completely implantable circulatory support free from batteries and other power conditioning hardware required with electromechanical systems.

Passive characteristics of conditioned skeletal muscle for ventricular assistance.

Systems to drive a ventricular assist device (VAD) with power from skeletal muscle have been proposed and are under development. During VAD filling, these systems must counter passive muscle force to control the precontraction length and optimize power output. To determine how muscle conditioning with electrical stimulation alters basic biomechanical characteristics and influences available power, goat latissimus dorsi were evaluated in vivo after an 8 week training protocol with an implanted myostimulator. Conditioned muscles displayed increased passive stiffness. After conditioning, the slope of the exponential passive force-length relation, at a passive force of 10 N, significantly increased from 5.1 to 7.6 N/cm (p = 0.003). Similarly, for a passive force of 10 N, the length relative to the zero developed force length decreased from 5.5 to 4.2 cm (p < 0.014). The linear relationship between slope (dF/dL) and force (F) also demonstrated a significant intercept shift. The latter relationship is independent of absolute length. Consistent with other studies, conditioning also resulted in fatigue resistance, fiber type transformation, and reductions in maximum developed force and shortening velocity. In the context of available power for cardiac assist, the results demonstrate that the influence of passive characteristics is accentuated after conditioning and has a substantial effect on available power.

In vivo measurements of skeletal muscle in a linear configuration powering a hydraulically actuated VAD.

Linear contracting skeletal muscle can provide more power and physiologic efficiency for cardiac assistance than muscle wrapping configurations. In this study, the insertion of the porcine latissimus dorsi muscle was removed from the humerus and reattached to a muscle powered ventricular assist device (MVAD), consisting of a mechanical to hydraulic piston energy convertor coupled to a Thoratec VAD. Effects of muscle preload stretch and thoracodorsal nerve stimulation parameters on in vivo unconditioned muscle work and MVAD stroke volume were studied. Stroke work increased linearly with muscle preload, and the slope of this relationship (Mprsw) provided an index of muscle "contractility," similar to the preload-recruitable stroke work relationship for the heart. With 5 V, 220 microseconds stimulation pulses over a 200 msec contraction period at 60 bpm, the Mprsw increased with stimulation frequencies from 0.055 J/cm at 30 Hz to 0.149 J/cm at 60 Hz, and to 0.212 J/cm at 90 Hz. Stroke work up to 1 J was achieved during muscle shortening of 2.5 cm with forces up to 6 kgf and energy convertor pressure of 112 psi (approximately 760 kPa). This produced an ejected MVAD stroke volume of 40 ml into a systolic pressure of 92 mmHg on a mock loop, at a filling pressure of 10 mmHg. The MVAD is designed as an alternative to cardiac transplantation, to provide completely implantable circulatory support free from batteries and other power conditioning hardware required with electromechanical systems.

In vivo studies of an implantable energy convertor for skeletal muscle powered cardiac assist.

A device that harnesses the mechanical energy of skeletal muscle contracting in a linear configuration has been implanted in goats. This energy convertor transforms muscle work to hydraulic energy that could drive a variety of cardiac assist devices. The device is mounted with a rib clamp and plate affixed to the sternum by cortical bone screws. A transcutaneous hydraulic line carries a silicon based working fluid to an external system that controls the muscle load. In 60 to 70 kg goats, the latissimus dorsi insertion was reattached to the energy convertor. A Telectronics myostimulator with intramuscular electrodes stimulated the latissimus dorsi. In acute implants, hydraulic pressures in excess of 150 psi were obtained. Chronic implantation of the device allowed system evaluation in the conscious unanesthetized animal. Two weeks after implant, hydraulic pressures in excess of 200 psi were obtained and energy transferred to the external loading system exceeded 1 J per contraction. Six weeks after implant, the device continued to cycle freely. These initial results are very promising and suggest an implantable energy convertor is feasible. Development of an energy convertor is an important step toward tether-free skeletal muscle powered cardiac assist devices.