Cardiopulmonary Exercise Testing for Surgical Risk Stratification in Adults with Congenital Heart Disease.

Adult congenital heart disease (ACHD) patients often require repeat cardiothoracic surgery, which may result in significant morbidity and mortality. Currently, there are few pre-operative risk assessment tools available. In the general adult population, pre-operative cardiopulmonary exercise testing (CPET) has a predictive value for post-operative morbidity and mortality following major non-cardiac surgery. The utility of CPET for risk assessment in ACHD patients requiring cardiothoracic surgery has not been evaluated. Retrospective chart review was conducted on 75 ACHD patients who underwent CPET less than 12 months prior to major cardiothoracic surgery at Children's Hospital of Wisconsin. Minimally invasive procedures, cardiomyopathy, acquired heart disease, single ventricle physiology, and heart transplant patients were excluded. Demographic information, CPET results, and peri-operative surgical data were collected. The study population was 56% male with a median age of 25 years (17-58). Prolonged post-operative length of stay correlated with increased ventilatory efficiency slope (VE/[Formula: see text] slope) (P = 0.007). Prolonged intubation time correlated with decreased peak HR (P = 0.008), decreased exercise time (P = 0.002), decreased heart rate response (P = 0.008) and decreased relative peak oxygen consumption (P = 0.034). Post-operative complications were documented in 59% of patients. While trends were noted between post-operative complications and some measurements of exercise capacity, none met statistical significance. Future studies may further define the relationship between exercise capacity and post-operative morbidity in ACHD patients.

Myocardial remodeling: cellular and extracellular events and targets.

The focus of this review is on translational studies utilizing large-animal models and clinical studies that provide fundamental insight into cellular and extracellular pathways contributing to post-myocardial infarction (MI) left ventricle (LV) remodeling. Specifically, both large-animal and clinical studies have examined the potential role of endogenous and exogenous stem cells to alter the course of LV remodeling. Interestingly, there have been alterations in LV remodeling with stem cell treatment despite a lack of long-term cell engraftment. The translation of the full potential of stem cell treatments to clinical studies has yet to be realized. The modulation of proteolytic pathways that contribute to the post-MI remodeling process has also been examined. On the basis of recent large-animal studies, there appears to be a relationship between stem cell treatment post-MI and the modification of proteolytic pathways, generating the hypothesis that stem cells leave an echo effect that moderates LV remodeling.

A novel method for the management of post-thyroidectomy or parathyroidectomy hematoma: a single-institution experience after over 4,000 central neck operations.

BACKGROUND: Cervical hematoma is a rare but serious complication of thyroid and parathyroid surgery that has historically required inpatient monitoring. With improved surgical technique and experience, operations are being performed increasingly as outpatient procedures. Therefore, a safe and systematic approach to cervical exploration of a postoperative hematoma needs to be defined. METHODS: From 1996 to 2013, a retrospective review was performed of 4,140 thyroid and parathyroid operations. Surgical outcomes data were recorded, specifically including the occurrence of a cervical hematoma, time interval to presentation, and methods of management. RESULTS: A total of 18 patients (0.43 %) developed a postoperative cervical hematoma that required surgical intervention. The occurrence of hematoma was 0.66 % (n = 11) for bilateral thyroid procedures, 0.21 % (n = 3) for unilateral thyroid procedures, and 0.13 % (n = 1) for parathyroid procedures. There were 3 (1.69 %) patients who had combined unilateral thyroid and parathyroid procedures and developed hematomas. Emergent bedside decompression was required for only two patients, both of whom suffered respiratory arrest in the postoperative anesthesia recovery unit. The remaining 16 patients were explored in the operating room, utilizing initial local anesthesia in the semi-upright position in 11 patients (69 %). CONCLUSIONS: From our experience, hematomas that caused significant airway compromise leading to respiratory arrest occurred in the postoperative anesthesia recovery room, and hematoma presentation after this time did not require emergent bedside decompression. Hematoma, when it occurs, can otherwise be managed safely in the operating room after inpatient or outpatient procedures using initial local anesthesia with the patient in the semi-upright position for hematoma evacuation.

Effect of Fontan fenestration on regional venous oxygen saturation during exercise: further insights into Fontan fenestration closure.

Fontan fenestration closure is a topic of great debate. The body of data regarding the risks and benefits of fenestration closure is limited yet growing. Previous studies have demonstrated that Fontan patients have less exercise capacity than those with normal cardiovascular anatomy. Differences also have been noted within various subgroups of Fontan patients such as whether Fontan is fenestrated or not. This study aimed to compare trends in regional oxygen saturations using near-infrared spectroscopy (NIRS) in patients with Fontan circulations during ramping exercise to further delineate differences between patients with and without a fenestration. It was hypothesized that Fontan patients with fenestrations have better exercise times, higher absolute regional oxygen venous saturations, and smaller arteriovenous differences than Fontan patients without fenestrations. For this study, 50 consecutive Fontan patients and 51 consecutive patients with normal cardiovascular anatomy were recruited. Placement of NIRS probes was performed to obtain regional oxygen saturations from the brain and the kidney. Readings were obtained at 1-min intervals during rest, exercise, and recovery. A standard Bruce protocol was used with a 5-min recovery period. Absolute regional tissue oxygenation values (rSO2) and arterial-venous oxygen saturation differences (AVDO2) calculated as arterial oxygen saturation (SPO2)--rSO2 for normal versus Fontan patients and for fenestrated versus unfenestrated Fontan patients were compared using independent t tests. When normal and Fontan patients were compared, the Fontan patients had a significantly shorter duration of exercise (9.3 vs 13.2 min; p < 0.001). No statistically significant difference in rSO2 change or AVDO2 was evident at the time of peak exercise, at 2 min into the recovery, or at 5 min into the recovery. A small oxygen debt also was paid back to the brain in the Fontan patients after exercise, as evidenced by a narrower AVDO2 than at baseline. The comparison of Fontan patients with and without fenestration showed no statistically significant difference in exercise time, rSO2 change, or AVDO2. The Fontan patients were noted to have shorter exercise times than the normal patients and also appeared to have an alteration in postexertional regional blood flow. However, when the various Fontan subtypes were compared by presence or absence of a fenestration, no significant differences were noted with regard to change in regional oxygen saturation or arteriovenous oxygen saturation. Thus, for patients with Fontan physiology, closure of the fenestration does not seem to have an impact on the dynamics of regional oxygen extraction during exercise or recovery.

Health-care reforms in the USA and England: areas for useful learning.

Two landmark and controversial bills reforming health care in the USA and England were recently passed. Despite the different history and context to health care in both countries, there is much room for mutual learning. This paper identifies three areas relating to financing, organisation, and information technology. For example, new payment mechanisms to encourage higher quality and efficiency are being developed and tested, particularly bundled payments, pay for performance, and value-based purchasing. In the USA, new national bodies to scrutinise payments in health care and to test promising new interventions to improve quality and efficiency will have lessons for the NHS. The faster adoption of electronic health records and their use in England to assess quality is a useful lesson for the USA. The new accountable care organisations and clinical commissioning groups have much to learn from each other as they develop.

Quick Response codes for surgical safety: a prospective pilot study.

BACKGROUND: Surgical safety programs have been shown to reduce patient harm; however, there is variable compliance. The purpose of this study is to determine if innovative technology such as Quick Response (QR) codes can facilitate surgical safety initiatives. METHODS: We prospectively evaluated the use of QR codes during the surgical time-out for 40 operations. Feasibility and accuracy were assessed. Perceptions of the current time-out process and the QR code application were evaluated through surveys using a 5-point Likert scale and binomial yes or no questions. RESULTS: At baseline (n = 53), survey results from the surgical team agreed or strongly agreed that the current time-out process was efficient (64%), easy to use (77%), and provided clear information (89%). However, 65% of surgeons felt that process improvements were needed. Thirty-seven of 40 (92.5%) QR codes scanned successfully, of which 100% were accurate. Three scan failures resulted from excessive curvature or wrinkling of the QR code label on the body. Follow-up survey results (n = 33) showed that the surgical team agreed or strongly agreed that the QR program was clearer (70%), easier to use (57%), and more accurate (84%). Seventy-four percent preferred the QR system to the current time-out process. CONCLUSIONS: QR codes accurately transmit patient information during the time-out procedure and are preferred to the current process by surgical team members. The novel application of this technology may improve compliance, accuracy, and outcomes.

Effect of telecare on use of health and social care services: findings from the Whole Systems Demonstrator cluster randomised trial.

OBJECTIVE: to assess the impact of telecare on the use of social and health care. Part of the evaluation of the Whole Systems Demonstrator trial. PARTICIPANTS AND SETTING: a total of 2,600 people with social care needs were recruited from 217 general practices in three areas in England. DESIGN: a cluster randomised trial comparing telecare with usual care, general practice being the unit of randomisation. Participants were followed up for 12 months and analyses were conducted as intention-to-treat. DATA SOURCES: trial data were linked at the person level to administrative data sets on care funded at least in part by local authorities or the National Health Service. MAIN OUTCOME MEASURES: the proportion of people admitted to hospital within 12 months. Secondary endpoints included mortality, rates of secondary care use (seven different metrics), contacts with general practitioners and practice nurses, proportion of people admitted to permanent residential or nursing care, weeks in domiciliary social care and notional costs. RESULTS: 46.8% of intervention participants were admitted to hospital, compared with 49.2% of controls. Unadjusted differences were not statistically significant (odds ratio: 0.90, 95% CI: 0.75-1.07, P = 0.211). They reached statistical significance after adjusting for baseline covariates, but this was not replicated when adjusting for the predictive risk score. Secondary metrics including impacts on social care use were not statistically significant. CONCLUSIONS: telecare as implemented in the Whole Systems Demonstrator trial did not lead to significant reductions in service use, at least in terms of results assessed over 12 months.

Targeted regional injection of biocomposite microspheres alters post-myocardial infarction remodeling and matrix proteolytic pathways.

BACKGROUND: Although localized delivery of biocomposite materials, such as calcium hydroxyapatite (CHAM), have been demonstrated to potentially attenuate adverse left ventricular (LV) remodeling after myocardial infarction (MI), the underlying biological mechanisms for this effect remain unclear. This study tested the hypothesis that targeted CHAM injections would alter proteolytic pathways (matrix metalloproteinases [MMPs] and tissue inhibitors of MMPs [TIMPs]) and would be associated with parameters of post-MI LV remodeling. METHODS AND RESULTS: MI was induced in adult sheep followed by 20 targeted injections of a total volume of 1.3 mL (n=6) or 2.6 mL of CHAM (n=5) or saline (n=13) and LV end-diastolic volume (EDV) and MMP/TIMP profiles in the MI region were measured at 8 weeks after MI. LV EDV decreased with 2.6 mL CHAM versus MI only (105.4 ± 7.5 versus 80.6 ± 4.2 respectively, P<0.05) but not with 1.3 mL CHAM (94.5 ± 5.0, P=0.32). However, MI thickness increased by 2-fold in both CHAM groups compared with MI only (P<0.05). MMP-13 increased 40-fold in the MI only group (P<0.05) but fell by >6-fold in both CHAM groups (P<0.05). MMP-7 increased approximately 1.5-fold in the MI only group (P<0.05) but decreased to referent control values in both CHAM groups in the MI region (P<0.05). Collagen content was reduced by approximately 30% in the CHAM groups compared with MI only (P<0.05). CONCLUSIONS: Differential effects on LV remodeling and MMP/TIMP profiles occurred with CHAM. Thus, targeted injection of a biocomposite material can favorably affect the post-MI remodeling process and therefore holds promise as a treatment strategy in and of itself, or as a matrix with potentially synergistic effects with localized pharmacological or cellular therapies.

Access to care for children and young people diagnosed with localized scleroderma or juvenile SSc in the UK.

OBJECTIVES: To describe pathways of care and referral to paediatric rheumatology from onset of first symptom (noticed by the patient or their family) to diagnosis for children and young people diagnosed with localized scleroderma (LS) or juvenile SSc (jSSc). METHODS: Retrospective case note audit of patients under paediatric rheumatology care who presented during January 2005-January 2010. Data included disease subtype, sex, age at key points in the referral pathway and health care professional (HCP) contact. All patient and HCP data were pseudo-anonymized in accordance with good clinical practice. RESULTS: Data were from eight UK centres that saw 89 cases: 62 females, 26 males; 73 LS, 16 jSSc. Median time from first symptom to first HCP review was 4 (range 0-72) months (LS) and 1 (range 0-50) month (jSSc). Median time from first symptom to paediatric rheumatology review was 15 (range 1-103) months (LS) and 7 (range 0-50) months (jSSc). Median time from first HCP review to first paediatric rheumatology review was 11 (range 0-103) months (LS) and 2 (range 0-10) months. First HCP seen (74%) was usually a general practitioner. The referring HCP to paediatric rheumatology was usually a dermatologist (56%) for LS. Median time from first symptom to diagnosis was 13 (range 1-102) months (LS) and 8 (range 1-50) months (jSSc). CONCLUSION: A prolonged interval occurs from first symptom to definitive diagnosis, which may adversely affect outcome. There is a need to raise awareness of this rare diagnosis and facilitate earlier recognition.

Near infrared spectroscopy describes physiologic payback associated with excess postexercise oxygen consumption in healthy controls and children with complex congenital heart disease.

Exercise creates a physiologic burden with recovery from such effort crucial to adaptation. Excess postexercise oxygen consumption (EPOC) refers to the body's increased metabolic need after work. This investigation was designed to determine the role of near infrared spectroscopy (NIRS) in the description of exercise recovery in healthy controls (NL) and children with congenital heart disease (CHD). Subjects were recruited with exercise testing performed to exhaustion. Exercise time (EXT), heart rate (HR), and oxygen consumption (VO(2)) were measured. Four-site NIRS (brain, kidney, deltoid, and vastus lateralis) were measured during exercise and into recovery to establish trends. Fifty individuals were recruited for each group (NL = 26 boys and 24 girls; CHD = 33 boys and 17 girls). Significant differences existed between EXT, VO(2), and peak HR (P < 0.01). NIRS values were examined at four distinct intervals: rest, peak work, and 2 and 5 min after exercise. Significant cerebral hyperemia was seen in children with CHD post exercise when compared to normal individuals in whom redistribution patterns were directed to somatic muscles. These identified trends support an immediate compensation of organ systems to re-establish homeostasis in peripheral beds through enhanced perfusion. Noninvasive NIRS monitoring helps delineate patterns of redistribution associated with EPOC in healthy adolescents and children with CHD.

Near-infrared spectroscopic monitoring during cardiopulmonary exercise testing detects anaerobic threshold.

Cardiopulmonary exercise testing (CPET) provides assessment of the integrative responses involving the pulmonary, cardiovascular, and skeletal muscle systems. Application of exercise testing remains limited to children who are able to understand and cooperate with the exercise protocol. Near-infrared spectroscopy (NIRS) provides a noninvasive, continuous method to monitor regional tissue oxygenation (rSO2). Our specific aim was to predict anaerobic threshold (AT) during CPET noninvasively using two-site NIRS monitoring. Achievement of a practical noninvasive technology for estimating AT will increase the compatibility of CPET. Patients without structural or acquired heart disease were eligible for inclusion if they were ordered to undergo CPET by a cardiologist. Data from 51 subjects was analyzed. The ventilatory anaerobic threshold (VAT) was computed on [Formula: see text] and respiratory quotient post hoc using the standard V-slope method. The inflection points of the regional rSO2 time-series were identified as the noninvasive regional NIRS AT for each of the two monitored regions (cerebral and kidney). AT calculation made using an average of kidney and brain NIRS matched the calculation made by VAT for the same patient. Two-site NIRS monitoring of visceral organs is a predictor of AT.

The predictive ability of the Lacey Assessment of Preterm Infants (LAPI), Cranial Ultrasound (cUS) and General Movements Assessment (GMA) for Cerebral Palsy (CP): A prospective, clinical, single center observational study.

BACKGROUND AND AIM: The LAPI, cUS and GMA are assessments used clinically in the UK to identify preterm infants at high risk of neurodevelopmental disabilities such as cerebral palsy. This study investigated the ability of these assessments to predict cerebral palsy at 2 years corrected gestational age. METHODS: Design: Prospective longitudinal cohort study including infants born <30 weeks' gestation from a single tertiary neonatal intensive care unit. The LAPI and cUS were undertaken as part of routine care before term equivalent age and the GMA was undertaken at 11-18 weeks corrected gestational age. RESULTS: There were 123 eligible infants and 95 infants (77.2%) were included. Thirteen infants (13.7%) had a diagnosis of CP at 2 years. There was no significant difference in gestational age, gender, or birth weight between the groups with and without a diagnosis of CP. The highest accuracy of prediction of CP was achieved by an aberrant, absent fidgety general movements classification with a sensitivity of 92.3% and specificity of 98.9%. Combining the GMA to include the cUS or LAPI did not increase the predictive accuracy. CONCLUSION: The GMA when undertaken in clinical practice had high accuracy for predicting CP at 2 years corrected age in infants born <30 weeks gestation; LAPI and cUS did not improve this accuracy.

Focal multiple sclerosis lesions abound in 'normal appearing white matter'.

BACKGROUND: The 'normal appearing white matter' (NAWM) in multiple sclerosis (MS) is known to be abnormal using quantitative magnetic resonance (MR) techniques. The aetiology of the changes in NAWM remains debatable. OBJECTIVE: To investigate whether high-field and ultra high-field T(1)-weighted magnetization prepared rapid acquisition gradient echo (MPRAGE) MRI enables detection of MS white matter lesions in areas defined as NAWM using high-field T(2)-weighted fluid attenuation inversion recovery (FLAIR) MRI; that is, to ascertain whether undetected lesions are likely contributors to the burden of abnormality in similarly defined NAWM. METHODS: Fourteen MS patients underwent MRI scans using 3T FLAIR and MPRAGE and 7 Tesla (7T) MPRAGE sequences. Independent observers identified lesions on 3T FLAIR and (7T and 3T) MPRAGE images. The detection of every individual lesion was then compared for each image type. RESULTS: We identified a total of 812 white matter lesions on 3T FLAIR. Using 3T MPRAGE, 186 additional lesions were detected that were not detected using 3T FLAIR. Using 7T MPRAGE, 231 additional lesions were detected that were not detected using 3T FLAIR. CONCLUSIONS: MRI with 3T and 7T MPRAGE enables detection of MS lesions in areas defined as NAWM using 3T FLAIR. Focal MS lesions contribute to the abnormalities known to exist in the NAWM.

Continuous localized monitoring of plasmin activity identifies differential and regional effects of the serine protease inhibitor aprotinin: relevance to antifibrinolytic therapy.

BACKGROUND: Antifibrinolytic therapy, such as the use of the serine protease inhibitor aprotinin, was a mainstay for hemostasis after cardiac surgery. However, aprotinin was empirically dosed, and although the pharmacological target was the inhibition of plasmin activity (PLact), this was never monitored, off-target effects occurred, and led to withdrawn from clinical use. The present study developed a validated fluorogenic microdialysis method to continuously measure PLact and tested the hypothesis that standardized clinical empirical aprotinin dosing would impart differential and regional effects on PLact. METHODS/RESULTS: Pigs (30 kg) were instrumented with microdialysis probes to continuously measure PLact in myocardial, kidney, and skeletal muscle compartments (deltoid) and then randomized to high-dose aprotinin administration (2 mKIU load/0.5 mKIU/hr infusion; n = 7), low-dose aprotinin administration (1 mKIU load/0.250 mKIU/hr infusion; n = 6). PLact was compared with time-matched vehicle (n = 4), and PLact was also measured in plasma by an in vitro fluorogenic method. Aprotinin suppressed PLact in the myocardium and kidney at both high and low doses, indicative that both doses exceeded a minimal concentration necessary for PLact inhibition. However, differential effects of aprotinin on PLact were observed in the skeletal muscle, indicative of different compartmentalization of aprotinin. CONCLUSIONS: Using a large animal model and a continuous method to monitor regional PLact, these unique results demonstrated that an empirical aprotinin dosing protocol causes maximal and rapid suppression in the myocardium and kidney and in turn would likely increase the probability of off-target effects and adverse events. Furthermore, this proof of principle study demonstrated that continuous monitoring of determinants of fibrinolysis might provide a novel approach for managing fibrinolytic therapy.

Predicting who will use intensive social care: case finding tools based on linked health and social care data.

BACKGROUND: the costs of delivering health and social care services are rising as the population ages and more people live with chronic diseases. OBJECTIVES: to determine whether predictive risk models can be built that use routine health and social care data to predict which older people will begin receiving intensive social care. DESIGN: analysis of pseudonymous, person-level, data extracted from the administrative data systems of local health and social care organisations. SETTING: five primary care trust areas in England and their associated councils with social services responsibilities. SUBJECTS: people aged 75 or older registered continuously with a general practitioner in five selected areas of England (n = 155,905). METHODS: multivariate statistical analysis using a split sample of data. RESULTS: it was possible to construct models that predicted which people would begin receiving intensive social care in the coming 12 months. The performance of the models was improved by selecting a dependent variable based on a lower cost threshold as one of the definitions of commencing intensive social care. CONCLUSIONS: predictive models can be constructed that use linked, routine health and social care data for case finding in social care settings.

Improving the quality of care in health systems: towards better strategies.

Improving the quality of health care across a nation is complex and hard. Countries often rely on multiple single national level programmes to make progress. But the key is to use a framework to develop a balanced overall strategy, and evaluate the main elements continuously and over time. Achieving that requires having a critical mass of leaders who collectively can see the bigger picture now, envision a roadmap for the future to chart an intelligent course, and course correct regularly. This is a long-term agenda requiring commitment, careful stewardship, different perspectives, trust, and the building of knowledge and experience over time. It is also almost completely at odds with much current policymaking which is short term, reactive and demands hard results. Many countries are making progress. But the rapid introduction of new types of care during the COVID 19 pandemic, such as online and digital, the use of new technologies which could soon revolutionalise the way care is delivered, experienced and evaluated, and the huge pressures on spending on health care in future mean we will have to do better. Achieving system-wide quality of care requires having a critical mass of leaders who collectively can see the bigger picture now, envision a roadmap for the future to chart a balanced intelligent course. For the Israeli health system, the recent IJHPR article by Dreiher et al. will help, but it will be important, in the future, to analyse how Israel measures up on the framework outlined above. This ideally would be supplemented with a survey of key leaders for their assessment, and both would be a regular (say 5 yearly) exercise and would help inform future strategies.

Mesenchymal cell transplantation and myocardial remodeling after myocardial infarction.

BACKGROUND: Targeted delivery of mesenchymal precursor cells (MPCs) can modify left ventricular (LV) cellular and extracellular remodeling after myocardial infarction (MI). However, whether and to what degree LV remodeling may be affected by MPC injection post-MI, and whether these effects are concentration-dependent, remain unknown. METHODS AND RESULTS: Allogeneic MPCs were expanded from sheep bone marrow, and direct intramyocardial injection was performed within the borderzone region 1 hour after MI induction (coronary ligation) in sheep at the following concentrations: 25x10(6) (25 M, n=7), 75x10(6) (75 M, n=7), 225x10(6) (225 M, n=10), 450x10(6) (450 M, n=8), and MPC free media only (MI Only, n=14). LV end diastolic volume increased in all groups but was attenuated in the 25 and 75 M groups. Collagen content within the borderzone region was increased in the MI Only, 225, and 450 M groups, whereas plasma ICTP, an index of collagen degradation, was highest in the 25 M group. Within the borderzone region matrix metalloproteinases (MMPs) and MMP tissue inhibitors (TIMPs) also changed in a MPC concentration-dependent manner. For example, borderzone levels of MMP-9 were highest in the 25 M group when compared to the MI Only and other MPC treatment group values. CONCLUSIONS: MPC injection altered collagen dynamics, MMP, and TIMP levels in a concentration-dependent manner, and thereby influenced indices of post-MI LV remodeling. However, the greatest effects with respect to post-MI remodeling were identified at lower MPC concentrations, thus suggesting a therapeutic threshold exists for this particular cell therapy.

Heterogeneity in MT1-MMP activity with ischemia-reperfusion and previous myocardial infarction: relation to regional myocardial function.

After a myocardial infarction (MI), an episode of ischemia-reperfusion (I/R) can result in a greater impairment of left ventricular (LV) regional function (LVRF) than that caused by an initial I/R episode in the absence of MI. Membrane type-I matrix metalloproteinase (MT1-MMP) proteolytically processes the myocardial matrix and is upregulated in LV failure. This study tested the central hypothesis that a differential induction of MT1-MMP occurs and is related to LVRF after I/R in the context of a previous MI. Pigs with a previous MI [3 wk postligation of the left circumflex artery (LCx)] or no MI were randomized to undergo I/R [60-min/120-min left anterior descending coronary artery (LAD) occlusion] or no I/R as follows: no MI and no I/R (n = 6), no MI and I/R (n = 8), MI and no I/R (n = 8), and MI and I/R (n = 8). Baseline LVRF (regional stroke work, sonomicrometry) was lower in the LAD region in the MI group compared with no MI (103 ± 12 vs. 188 ± 26 mmHg·mm, P < 0.05) and remained lower with peak ischemia (35 ± 8 vs. 88 ± 17 mmHg·mm, P < 0.05). Using a novel interstitial microdialysis method, MT1-MMP was directly measured and was over threefold higher in the LCx region and over twofold higher in the LAD region in the MI group compared with the no MI group at baseline. MT1-MMP fluorogenic activity was persistently elevated in the LCx region in the MI and I/R group but remained unchanged in the LAD region. In contrast, no changes in MT1-MMP occurred in the LCx region in the no MI and I/R group but increased in the LAD region. MT1-MMP mRNA was increased by over threefold in the MI region in the MI and I/R group. In conclusion, these findings demonstrate that a heterogeneous response in MT1-MMP activity likely contributes to regional dysfunction with I/R and that a subsequent episode of I/R activates a proteolytic cascade within the MI region that may contribute to a continued adverse remodeling process.

3 Tesla and 7 Tesla MRI of multiple sclerosis cortical lesions.

Cortical lesions are prevalent in multiple sclerosis but are poorly detected using MRI. The double inversion recovery (DIR) sequence is increasingly used to explore the clinical relevance of cortical demyelination. Here we evaluate the agreement between imaging sequences at 3 Tesla (T) and 7T for the presence and appearance of individual multiple sclerosis cortical lesions. Eleven patients with demyelinating disease and eight healthy volunteers underwent MR imaging at 3T (fluid attenuated inversion recovery [FLAIR], DIR, and T(1)-weighted magnetization prepared rapid acquisition gradient echo [MP-RAGE] sequences) and 7T (T(1)-weighted MP-RAGE). There was good agreement between images for the presence of mixed cortical lesions (involving both gray and white matter). However, agreement between imaging sequences was less good for purely intracortical lesions. Even after retrospective analysis, 25% of cortical lesions could only be visualized on a single MRI sequence. Several DIR hyperintensities thought to represent cortical lesions were found to correspond to signal arising from extracortical blood vessels. High-resolution 7T imaging appeared useful for confidently classifying the location of lesions in relation to the cortical/subcortical boundary. We conclude that DIR, FLAIR, and MP-RAGE imaging sequences appear to provide complementary information during the detection of multiple sclerosis cortical lesions. High resolution 7T imaging may facilitate anatomical localization of lesions in relation to the cortical boundary.

Temporally and regionally disparate differences in plasmin activity by tranexamic acid.

BACKGROUND: A major complication associated with cardiac surgery is excessive and prolonged bleeding in the perioperative period. Improving coagulation by inhibiting fibrinolysis, primarily through inhibition of plasmin activity (PLact) with antifibrinolytics such as tranexamic acid (TXA), has been a pharmacological mainstay in cardiac surgical patients. Despite its almost ubiquitous use, the temporal and regional modulation of PLact profiles by TXA remains unexplored. Accordingly, we developed a fluorogenic-microdialysis system to measure in vivo dynamic changes in PLact after TXA administration in a large animal model. METHODS: Pigs (25-35 kg) were randomly assigned to receive TXA (30 mg/kg, diluted into 50 mL normal saline; n = 9) or vehicle (50 mL normal saline; n = 7). Microdialysis probes were placed in the liver, myocardium, kidney, and quadriceps muscle compartments. The microdialysate infusion contained a validated plasmin-specific fluorogenic peptide. The fluorescence emission (standard fluorogenic units [SFU]) of the interstitial fluid collected from the microdialysis probes, which directly reflects PLact, was determined at steady-state baseline and 30, 60, 90, and 120 min after TXA/vehicle infusion. Plasma PLact was determined at the same time points using the same fluorogenic substrate approach. RESULTS: TXA reduced plasma PLact at 30 min after infusion by >110 SFU compared with vehicle values (P < 0.05). Specifically, there was a decrease in liver PLact at 90 and 120 min after TXA infusion of >150 SFU (P < 0.05) and 175 SFU (P < 0.05), respectively. The decrease in liver PLact occurred 60 min after the maximal decrease in plasma PLact. In contrast, kidney, heart, and quadriceps PLact transiently increased followed by an overall decrease at 120 min. CONCLUSIONS: Using a large animal model and in vivo microdialysis measurements of PLact, the unique findings from this study were 2-fold. First, TXA induced temporally distinct PLact profiles within the plasma and selected interstitial compartments. Second, TXA caused region-specific changes in PLact profiles. These temporal and regional differences in the effects of TXA may have important therapeutic considerations when managing fibrinolysis in the perioperative period.