Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease.

Recurrent myocardial ischemia can lead to left ventricular (LV) dysfunction in patients with coronary artery disease (CAD). In this observational cohort study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients undergoing coronary artery bypass grafting. During surgery, paired transmural LV biopsies were acquired on the beating heart from regions with and without evidence of inducible ischemia on preoperative stress perfusion cardiovascular magnetic resonance. From 33 patients, 63 biopsies were acquired, compared to analysis of LV samples from 11 donor hearts. The global myocardial adenosine triphosphate (ATP):adenosine diphosphate (ADP) ratio was reduced in patients with CAD as compared to donor LV tissue, with increased expression of oxidative phosphorylation (OXPHOS) genes encoding the electron transport chain complexes across multiple cell types. Paired analyses of biopsies obtained from LV segments with or without inducible ischemia revealed no significant difference in the ATP:ADP ratio, broader metabolic profile or expression of ventricular cardiomyocyte genes implicated in OXPHOS. Differential metabolite analysis suggested dysregulation of several intermediates in patients with reduced LV ejection fraction, including succinate. Overall, our results suggest that viable myocardium in patients with stable CAD has global alterations in bioenergetic and transcriptional profile without large regional differences between areas with or without inducible ischemia.

Genetic Architecture of Acute Myocarditis and the Overlap With Inherited Cardiomyopathy.

BACKGROUND: Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. METHODS: This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. RESULTS: Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with <1% of healthy controls (P=0.0097). In the London cohort (n=230; median age, 33 years; 84% men), patients were representative of national myocarditis admissions (median age, 32 years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% of cases versus 0.4% of controls; odds ratio, 8.2; P=0.001). This was driven predominantly by DSP-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age, 54 years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly TTN-tv, found in 7% (all with left ventricular ejection fraction <50%) compared with 1% in controls (odds ratio, 3.6; P=0.0116). Across both cohorts over a median of 5.0 years (interquartile range, 3.9-7.8 years), all-cause mortality was 5.4%. Two-thirds of deaths were cardiovascular, attributable to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype-negative patients versus 11.1% for genotype-positive patients (Padjusted=0.08). CONCLUSIONS: We identified DCM- or ACM-associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of DSP-tv in those with normal left ventricular ejection fraction and TTN-tv in those with reduced left ventricular ejection fraction. Despite differences between cohorts, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing should be considered in patients with acute myocarditis to help reassure the majority while improving the management of those with an underlying genetic variant.

Changes in clinical and imaging variables during withdrawal of heart failure therapy in recovered dilated cardiomyopathy.

AIMS: This study aimed to profile the changes in non-invasive clinical, biochemical, and imaging markers during withdrawal of therapy in patients with recovered dilated cardiomyopathy, providing insights into the pathophysiology of relapse. METHODS AND RESULTS: Clinical, biochemical, and imaging data from patients during phased withdrawal of therapy in the randomized or single-arm cross-over phases of TRED-HF were profiled. Clinical variables were measured at each study visit and imaging variables were measured at baseline, 16 weeks, and 6 months. Amongst the 49 patients [35% women, mean age 53.6 years (standard deviation 11.6)] who withdrew therapy, 20 relapsed. Increases in mean heart rate [7.6 beats per minute (95% confidence interval, CI, 4.5, 10.7)], systolic blood pressure [6.6 mmHg (95% CI 2.7, 10.5)], and diastolic blood pressure [5.8 mmHg (95% CI 3.1, 8.5)] were observed within 4-8 weeks of starting to withdraw therapy. A rise in mean left ventricular (LV) mass [5.1 g/m2 (95% CI 2.8, 7.3)] and LV end-diastolic volume [3.9 mL/m2 (95% CI 1.1, 6.7)] and a reduction in mean LV ejection fraction [-4.2 (95% CI -6.6, -1.8)] were seen by 16 weeks, the earliest imaging follow-up. Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) fell immediately after withdrawing beta-blockers and only tended to increase 6 months after beginning therapy withdrawal [mean change in log NT-proBNP at 6 months: 0.2 (95% CI -0.1, 0.4)]. CONCLUSIONS: Changes in plasma NT-proBNP are a late feature of relapse, often months after a reduction in LV function. A rise in heart rate and blood pressure is observed soon after withdrawing therapy in recovered dilated cardiomyopathy, typically accompanied or closely followed by early changes in LV structure and function.

Stress perfusion cardiovascular magnetic resonance and serial fractional flow reserve assessment of the left anterior descending artery in patients undergoing right coronary artery chronic total occlusion revascularization.

BACKGROUND: Fractional flow reserve (FFR) assessment of remote arteries, in the context of a bystander chronic total occlusion (CTO), can lead to false positive results. Adenosine stress cardiovascular magnetic resonance (CMR) evaluates perfusion defects across the entire myocardium and may therefore be a reliable tool in the work-up of remote lesions in CTO patients. The IMPACT-CTO study investigated donor artery invasive physiology before, immediately post, and at 4 months following right coronary artery (RCA) CTO percutaneous coronary intervention (PCI). The aim of this subanalysis was to assess the concordance between baseline perfusion CMR and serial FFR evaluation of left anterior descending artery (LAD) ischemia in patients from the IMPACT-CTO study. METHODS: Baseline adenosine stress CMR examinations from 26 patients were analyzed for qualitative evidence of LAD ischemia. The results were correlated with the serial LAD FFR measurements. RESULTS: The present findings demonstrated that before RCA CTO PCI, there was 62% agreement between perfusion CMR and FFR (ischemic threshold £ 0.8) in the assessment of LAD ischemia (k = 0.29; fair concordance). At 4 months after revascularization, there was 77% agreement (k = 0.52; moderate concordance) between the index CMR assessment of LAD ischemia and the follow-up LAD FFR. Concordance was improved at a LAD FFR ischemic threshold of £ 0.75. CONCLUSIONS: In this hypothesis generating study, baseline CMR assessment of LAD ischemia correlated better with the 4 months LAD FFR data (threshold £ 0.8) as compared to the FFR measurements taken prior to RCA CTO revascularization.

Tourniquetless Total Knee Arthroplasty: History, Controversies, and Technique.

We present a literature review with technique for tourniquetless TKA for surgeons interested in transitioning away from the tourniquet. Tourniquet use provides a bloodless field and improved visualization with decreased intraoperative blood loss, but the arguments for tourniquet use of improved cement fixation and decreased overall blood loss have not been supported by the literature. Regarding recovery, tourniquetless TKA has demonstrated less postoperative pain and improved knee function. There is also the potential for patient harm with tourniquet use. The process of tourniquetless TKA begins preoperatively with anemia screening and treatment. Tranexamic acid decreases the overall blood loss and blood transfusion risk. We recommend preemptive analgesia. The surgery is performed with the knee flexed for a near bloodless field. For cementation, the knee irrigation removes lipids from the exposed bone along with meticulous cement technique. Tourniquetless TKA is able to be safely performed on a routine basis and brings potential benefits to the patient with no evident increased risk in comparison to tourniquet use.

Evaluating the Functionality of Conjunctiva Using a Rabbit Dry Eye Model.

Purpose. To assess the conjunctival functionality in a rabbit dry eye (DE) model. Methods. Nictitating membrane, lacrimal and Harderian glands were surgically excised from male New Zealand white rabbits using minimally invasive surgery. Fluorescein/rose Bengal staining of ocular surface (OS) and Schirmer test were done before (BE) and after excision (AE). The expression of interleukin- (IL-) 1ß, tumor necrosis factor- (TNF-) α, and MUC5AC proteins were estimated by immunoblotting from conjunctival impression cytology specimens. MUC5AC mRNA was quantified as well. The effect of epithelial sodium channel (ENaC) blockers on tear production and potential differences (PD) of OS were assessed under anesthesia in rabbits with and without surgery. Results. Increase in corneal and conjunctival staining was observed 1 month AE compared to BE. Schirmer tests failed to show decrease in tear production. Elevated IL-1ß, and TNF-α, 1 month AE indicated inflammation. MUC5AC expression was elevated 1 month AE. ENaC blockers did not improve tear production in rabbit eyes AE but characteristic changes in PD were observed in rabbits with surgery. Conclusions. DE biomarkers are important tools for OS assessment and MUC5AC expression is elevated in rabbit DE. PD measurement revealed significant electrophysiological changes in rabbits with surgery.

Disc Golf, a Growing Sport: Description and Epidemiology of Injuries.

BACKGROUND: Disc golf is a sport played much like traditional golf, but rather than using a ball and club, players throw flying discs with various throwing motions. It has been played by an estimated 8 to 12 million people in the United States. Like all sports, injuries sustained while playing disc golf are not uncommon. Although formalized in the 1970s, it has grown at a rapid pace; however, disc golf-related injuries have yet to be described in the medical literature. PURPOSE: To describe the most common injuries incurred by disc golf players while comparing the different types of throwing styles. STUDY DESIGN: Descriptive epidemiology study. METHODS: The data in this study were collected from 883 disc golf players who responded to an online survey collected over a 1-month period. Respondents answered 49 questions related to demographics, experience, style of play, and injury details. Using a chi-square analysis, common injuries sustained in players using backhand and forehand throwing styles were compared. RESULTS: More than 81% of respondents stated that they had sustained an injury playing disc golf, including injuries to the elbow (n = 325), shoulder (n = 305), back (n = 218), and knee (n = 199). The injuries were most commonly described as a muscle strain (n = 241), sprain (n = 162), and tendinitis (n = 145). The type of throw primarily used by players varied, with 86.2% using backhand, 12.7% using forehand, and 1.1% using an overhead throw. Players using a forehand throw were more likely to sustain an elbow injury (P = .014). Many players (n = 115) stated they had undergone surgery due to a disc golf-related injury, with the most common surgeries including meniscal, shoulder, spine, and foot/ankle surgeries. CONCLUSION: The majority of surveyed disc golfers sustained at least 1 injury while playing disc golf, with many requiring surgery. The types of injuries sustained by players varied by the types of throw primarily used. As the sport of disc golf continues to expand, health professionals should be aware of injuries sustained, with future studies focusing on injury prevention and education strategies.

Preoperative flexion does not influence postoperative flexion after rotating-platform total knee arthroplasty.

PURPOSE: Preoperative range of motion (ROM) has been regarded as one of the most important factors in predicting postoperative ROM following total knee arthroplasty (TKA). Mobile-bearing TKA designs have been suggested to possibly improve the knee kinematics compared to fixed-bearing designs. The purpose of this study was to examine the difference in postoperative flexion as a function of preoperative flexion in a consecutive series of TKAs done using a posterior-stabilized rotating-platform prosthesis. METHODS: ROM was assessed in 153 consecutive TKAs done using a rotating-platform posterior cruciate-substituting design. Patients were divided into two groups based on their preoperative ROM (Group 1 < 95°, Group 2 > 95°). The Knee Society Score (KSS) and ROM were assessed preoperatively, 3 months and 12 months postoperatively. RESULTS: There was no difference in flexion 12 months after surgery between groups (mean 120° and 123°, respectively. n.s.). After 3 month follow-up, no increase in ROM was experienced by either group. Patients in Group 1 experienced significantly greater increases in both ROM (p < 0.001) and KSS (p < 0.05). There was no difference in the KSS at 12 months after surgery between groups. CONCLUSION: In this series of patients undergoing TKA with a rotating-platform prosthesis, the preoperative ROM was not predictive of the postoperative ROM. Patients with stiff knees preoperatively may benefit from a mobile-bearing design prosthesis.

Robotic guidance in total hip arthroplasty: the shape of things to come.

Surgeons want to perform a perfect total hip arthroplasty (THA) with every operation. Human performance has limitations, especially when performing a mechanical operation in a biological environment. Recent suggested changes to improve outcomes have been large femoral heads and anterior incisions, but unfortunately, neither has resulted in any scientific data that change has been effected. The scientific data tell us that poor component positions and impingement are the source of increasing mechanical complications. Therefore, attempts have been made to improve the surgeon's performance by precise quantitative knowledge in the operating room. Robotic-guided navigation provides numerical data for cup inclination plus anteversion and center of rotation; femoral leg length and offset; and combined anteversion of the cup and stem. The acetabular bone preparation is done with a reamer connected to a robotic arm, which prevents human error by the surgeon of reaming off line or too deep. This technology provides predictable and reproducible results.

Wound healing in total joint arthroplasty.

Obtaining primary wound healing in total joint arthroplasty is essential to a good result. Wound healing problems can occur and the consequences can be devastating. Determination of the host healing capacity can be useful in predicting complications. Cierney and Mader classified patients as type A, no healing compromises; and type B, systemic or local healing compromising factors present. Local factors include traumatic arthritis, multiple previous incisions, extensive scarring, lymphedema, poor vascular perfusion. Systemic compromising factors include diabetes, rheumatic diseases, renal or liver disease, immunocompromise, steroids, smoking, and poor nutrition. In high-risk patients, the surgeon should encourage positive choices such as smoking cessation and nutritional supplementation to elevate the total lymphocyte count and total albumin. Careful planning of incisions, particularly in patients with scarring or multiple previous operations, is productive. Around the knee the vascular viability is better in the medial flap. Thus, use the most lateral previous incision, do minimal undermining, and handle tissue meticulously. We perform all potentially complicated total knee arthroplasties without tourniquet to enhance blood flow and tissue viability. The use of perioperative anticoagulation will increase wound problems. If wound drainage or healing problems occur, immediate action is required. Deep sepsis can be ruled out with a joint aspiration and cell count (>2000), differential (>50% polys), and negative culture and sensitivity. All hematomas should be evacuated and necrosis or dehiscence should be managed by debridement to obtain a live wound.

Tissue-Dependent Expression of Estrogen Receptor ß in 17ß-Estradiol-Mediated Attenuation of Autoimmune CNS Inflammation.

Treatment strategies using therapeutic estrogen are being developed and tested for multiple sclerosis (MS). MS is an autoimmune inflammatory disease that attacks the central nervous system, damages myelin and produces neurode-generative changes associated with periodic and chronic progression of functional neurological deficit. Experimental studies in chimeric bone marrow transplant mice treated with 17ß-estradiol (E2) have revealed that the estrogen receptor-1 (Esr-1, or -alpha) expressed exclusively within the non-hematopoietic tissue compartment is sufficient for mediating a beneficial neuroprotective therapeutic response in mice lacking Esr-1 expression on T lymphocytes or other bone marrow-derived cells. Less is known regarding requirements for estrogen receptor-2 (Esr-2, or -beta) expression in E2-mediated therapy. Here, we tested and compared requirements for Esr-2 expression within distinct tissue compartments in bone marrow transplant mice. Our studies support a crucial role for Esr-1 in E2 treatment and demonstrate that Esr-2 expressed by non-bone marrow-derived cells plays a role in sustaining the neuroprotective response mediated through Esr-1.

Bone marrow lacking integrin expression facilitates an enhanced susceptibility to EAE in the xenogeneic bone marrow chimeras.

Xenotransplantation of rat bone marrow cells (BMC) into immunodeficient (SCID) mice generates chimeric mice susceptible to paralytic autoimmune CNS inflammation. Herein, we identified a disease relevant subset of transplantable BMC lacking expression of CD11b/c and CD49d. Moreover, disease susceptibility was enhanced in the presence of non-myelin specific T-cells. Only the CD11b/c negative population of BM retained the capability to populate the blood, spleen and spinal cord of recipients and matured after transplant to express CD11b/c. These results indicate non-myelin T cells in combination with integrin negative BM represent pre-pathogenic determinants of an enhanced disease susceptibility to myelin reactive T cells.

Functional recovery of muscles after minimally invasive total hip arthroplasty.

Whether mini-incision total hip arthroplasty is associated with accelerated postoperative recovery is a subject of considerable controversy. A study was conducted to compare objective outcomes using gait analysis as a measure for recovery of function in patients treated with three different minimally invasive surgical approaches and the traditional posterior approach. Sixty-nine patients underwent instrumented gait analysis at self-selected and fast velocities preoperatively and at 6 weeks and 3 months postoperatively. Four surgical groups were studied-30 treated with posterior mini-incisions, 11 anterolateral, 10 anterior Judet, and 18 traditional posterior long incisions. Overall, gait velocity increased slightly at 6 weeks and significantly at 3 months. However, there were no significant differences between groups for velocity, cadence, stride length, single-limb support time, or double-limb support time at 6 weeks or 3 months postoperatively. These data indicate that patients undergoing total hip arthroplasty with any of these surgical approaches recover muscle function, as measured by gait analysis, to preoperative levels within 6 weeks postoperatively. No advantage was shown with the use of any of the three different small-incision approaches. This finding suggests that the amount of muscle, or the particular muscle cut, does not have a significant effect on the recovery of postoperative gait function.

Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice.

Oxidative stress may play a key role in Alzheimer's disease (AD) neuropathology. Here, the effects of the antioxidant, alpha-lipoic acid (ALA) were tested on the Tg2576 mouse, a transgenic model of cerebral amyloidosis associated with AD. Ten-month old Tg2576 and wild type mice were fed an ALA-containing diet (0.1%) or control diet for 6 months and then assessed for the influence of diet on memory and neuropathology. ALA-treated Tg2576 mice exhibited significantly improved learning, and memory retention in the Morris water maze task compared to untreated Tg2576 mice. Twenty-four hours after contextual fear conditioning, untreated Tg2576 mice exhibited significantly impaired context-dependent freezing. ALA-treated Tg2576 mice exhibited significantly more context freezing than the untreated Tg2576 mice. Assessment of brain soluble and insoluble beta-amyloid levels revealed no differences between ALA-treated and untreated Tg2576 mice. Brain levels of nitrotyrosine, a marker of nitrative stress, were elevated in Tg2576 mice, while F2 isoprostanes and neuroprostanes, oxidative stress markers, were not elevated in the Tg2576 mice relative to wild type. These data indicate that chronic dietary ALA can reduce hippocampal-dependent memory deficits of Tg2576 mice without affecting beta-amyloid levels or plaque deposition.

The infected knee: all my troubles now.

Infection after total knee arthroplasty poses formidable challenges to the surgeon. Once an infection is diagnosed, the identification of the organism and its sensitivity to antibiotics is essential. The host's healing capacity is vital. Supplemental nutrition and cessation of smoking can improve wound healing. Surgical goals include debridement of necrotic tissue and elimination of the dead space. Intravenous antibiotics and a 2-stage protocol are the standard of care. At our institution, the first stage is performed with an implant and antibiotic-cement composite. This articulating spacer maintains limb length and tissue compliance. The patient can maintain a functional status between stages. Definitive reconstruction is more readily accomplished with this method in contrast to the static spacer approach. The clinical efficacy of this protocol has been well documented in the literature.

What would you do? Case challenges in knee surgery.

Six cases representing a variety of orthopedic issues were presented to a panel of senior surgeons. These included the following: (1) developmental patella baja with degenerative arthritis, (2) high valgus knee with attenuated medial collateral ligament, (3) degenerative arthritis with near-ankylosis, (4) depressed tibial plateau fracture with degenerative arthritis, (5) degenerative arthritis with laterally dislocating patella, and (6) degenerative arthritis with distal femoral malunion.

Mobile bearings in revision total knee arthroplasty.

Mobile-bearing hinged knee replacement systems were used early on for primary and revision knee arthroplasty, but they were associated with high failure rates. Third-generation modular rotating platform hinged knee replacement systems have evolved with modular diaphyseal engaging slotted and splined stems and metaphyseal filling and loading sleeves. Additionally, significant improvement of the articulation between the rotating hinge mechanism and tibial component with broad congruent surfaces has decreased the deleterious stresses that contributed to the failures of earlier designs. The excellent mid-term results of the S-ROM modular mobile-bearing hinge and modular rotating plaform nonlinked knee replacement systems provide solid evidence for expanding the indications for rotating platform revision systems.

T lymphocytes do not directly mediate the protective effect of estrogen on experimental autoimmune encephalomyelitis.

Gender influences mediated by 17 beta-estradiol (E2) have been associated with susceptibility to and severity of autoimmune diseases such as diabetes, arthritis, and multiple sclerosis. In this regard, we have shown that estrogen receptor-alpha (Esr1) is crucial for the protective effect of 17 beta-estradiol (E2) in murine experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis. The expression of estrogen receptors among various immune cells (eg, T and B lymphocytes, antigen-presenting cells) suggests that the therapeutic effect of E2 is likely mediated directly through specific receptor binding. However, the target immune cell populations responsive to E2 treatment have not been identified. In the current study, we induced EAE in T-cell-deficient, severe combined immunodeficient mice or in immunocompetent mice with encephalitogenic T cells from wild-type Esr1+/+ or Esr1 knockout (Esr1-/-) donors and compared the protective E2 responses. The results showed that E2-responsive, Esr1+/+ disease-inducing encephalitogenic T cells were neither necessary nor sufficient for E2-mediated protection from EAE. Instead, the therapeutic response appeared to be mediated through direct effects on nonlymphocytic, E2-responsive cells and down-regulation of the inflammatory response in the central nervous system. These results provide the first demonstration that the protective effect of E2 on EAE is not mediated directly through E2-responsive T cells and raise the alternative possibility that nonlymphocytic cells such as macrophages, dendritic cells, or other nonlymphocytic cells are primarily responsive to E2 treatment in EAE.