Dense Scar Research Articles

Lanthionine ketimine ester promotes locomotor recovery after spinal cord injury by reducing neuroinflammation and promoting axon growth

The mammalian central nervous system (CNS) has limited regenerative ability after injury, largely due to scar formation and axonal growth inhibitors. Experimental suppression of neuroinflammation encourages recovery from spinal cord injury (SCI), yet practical means for pharmacologically treating SCI have remained elusive. Lanthionine ketimine (LK) is a natural brain sulfur amino acid metabolite with demonstrated anti-neuroinflammatory and neurotrophic activities. LK and its synthetic brain-penetrating ethyl ester (LKE) promote growth factor-dependent neurite extension in cultured cell and suppress microglial activation in animal models of neurodegeneration. Thus far however, LKE has not been explored as a potential therapy for SCI. The present study investigated the hypothesis that systemic LKE could improve motor functional recovery after SCI in a mouse model. Intraperitoneal administration of LKE (100 mg/kg/d) after near-complete transect of spinal cord at the T7 level significantly improved motor function over a 4-week time course. Vehicle-treated mice, in contrast, demonstrated negligible functional recovery. In terms of histology, LKE treatment reduced pro-neuroinflammatory microglia/macrophage activation evidenced by quantitative Iba1 labeling and shifted the microglial phenotype toward a more neurotrophic M2 character evidenced by changes in the M2 marker arginase-1. This was correlated with less dense scar formation and more extensive axonal regrowth across the transection site demonstrated by 5-hydroxytryptamine (5HT) immunolabeling of raphespinal tract axons. These data provide evidence that LKE or similar compounds have potential therapeutic value for recovery after certain forms of SCI.

Left atrial fibrosis quantification by late gadolinium-enhanced magnetic resonance: a new method to standardize the thresholds for reproducibility.

Identification of left atrial (LA) fibrosis through late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) remains controversial due to the heterogeneity and lack of reproducibility of proposed methods. Our aim is to describe a normalized, reproducible, standardized method to evaluate LA fibrosis through LGE-CMR. Electrocardiogram- and respiratory-gated 3-Tesla LGE-CMR was performed in 10 healthy young volunteers and 30 patients with atrial fibrillation (AF): 10 with paroxysmal AF, 10 with persistent AF, and 10 with a previous AF ablation procedure. Local image intensity ratio (IIR) of the LA was calculated as the absolute pixel intensity to mean blood pool intensity ratio. The healthy atrial tissue threshold was defined in young healthy volunteers (upper limit of normality set at IIR tissue mean plus 2 SDs). Dense atrial scarring was characterized in patients with previous radiofrequency-induced scarring (post-AF ablation patients). Validation groups consisted of patients with paroxysmal and persistent AFs. The upper limit of normal IIR was 1.20; IIR values higher than 1.32 (60% of mean maximum pixel intensity in post-ablation patients) were considered dense scar. Image intensity ratio values between 1.2 and 1.32 identified interstitial fibrosis. Patients with paroxysmal and persistent AFs had less atrial fibrotic tissue compared with post-ablation patients. Endocardial bipolar voltage was correlated to IIR values. An IIR of 1.2 identifies the upper limit of normality in healthy young individuals. An IIR of >1.32 defines dense atrial fibrosis in post-ablation patients. Our results provide a consistent, comparable, and normalized tool to assess atrial arrhythmogenic substrate.

Development of a critical-sized ventral hernia model in the pig

BackgroundThe pig is commonly used as a preclinical model for ventral hernia repair. However, no study has verified that an unrepaired surgically induced hernia (control) in the pig does not heal spontaneously but rather develops a persistent hernia. Without such verification in any given model, one cannot draw conclusions on the efficacy of the repair technique investigated. Materials and methodsThree surgically induced hernia models with increasing severity were created in eight pigs. These included 10-cm retrorectus partial-thickness (model 1) and 15-cm preperitoneal full-thickness (model 2) incisional defects and an 8 × 8 cm preperitoneal full-thickness excisional defect (model 3). Postoperative management included use of an abdominal binder, and in some cases, suction drainage, for 2 wk to support the repair and prevent seroma. Models were evaluated for persistence of hernia at 5 wk using clinical and radiographic assessments. ResultsAll pigs developed clinical hernias after 2 wk of defect creation, but only models 1 and 3 had clinically persistent hernias at 5 wk. At 5 wk, the average defect area was 97 cm2 in model 1, 66 cm2 in model 2, and 245 cm2 in model 3. Dense fibrotic scarring was observed in the models with resolved hernias. ConclusionsOur results highlight the need to verify an unrepaired hernia injury model does not heal spontaneously prior to using it for hernia repair studies. The partial-thickness incisional model 1 and full-thickness excisional model 3 formed persistent hernias in pigs at 5 wk and should be further explored as models for investigating hernia repair strategies.

The Present and Future for Peripheral Nerve Regeneration.

Peripheral nerve injury can have a potentially devastating impact on a patient's quality of life, resulting in severe disability with substantial social and personal cost. Refined microsurgical techniques, advances in peripheral nerve topography, and a better understanding of the pathophysiology and molecular basis of nerve injury have all led to a decisive leap forward in the field of translational neurophysiology. Nerve repair, nerve grafting, and nerve transfers have improved significantly with consistently better functional outcomes. Direct nerve repair with epineural microsutures is still the surgical treatment of choice when a tension-free coaptation in a well-vascularized bed can be achieved. In the presence of a significant gap (>2-3 cm) between the proximal and distal nerve stumps, primary end-to-end nerve repair often is not possible; in these cases, nerve grafting is the treatment of choice. Indications for nerve transfer include brachial plexus injuries, especially avulsion type, with long distance from target motor end plates, delayed presentation, segmental loss of nerve function, and broad zone of injury with dense scarring. Current experimental research in peripheral nerve regeneration aims to accelerate the process of regeneration using pharmacologic agents, bioengineering of sophisticated nerve conduits, pluripotent stem cells, and gene therapy. Several small molecules, peptides, hormones, neurotoxins, and growth factors have been studied to improve and accelerate nerve repair and regeneration by reducing neuronal death and promoting axonal outgrowth. Targeting specific steps in molecular pathways also allows for purposeful pharmacologic intervention, potentially leading to a better functional recovery after nerve injury. This article summarizes the principles of nerve repair and the current concepts of peripheral nerve regeneration research, as well as future perspectives. [Orthopedics. 2017; 40(1):e141-e156.].

Recognition of Fibrotic Infarct Density by the Pattern of Local Systolic-Diastolic Myocardial Electrical Impedance

Myocardial electrical impedance is a biophysical property of the heart that is influenced by the intrinsic structural characteristics of the tissue. Therefore, the structural derangements elicited in a chronic myocardial infarction should cause specific changes in the local systolic-diastolic myocardial impedance, but this is not known. This study aimed to characterize the local changes of systolic-diastolic myocardial impedance in a healed myocardial infarction model. Six pigs were successfully submitted to 150 min of left anterior descending (LAD) coronary artery occlusion followed by reperfusion. 4 weeks later, myocardial impedance spectroscopy (1–1000 kHz) was measured at different infarction sites. The electrocardiogram, left ventricular (LV) pressure, LV dP/dt, and aortic blood flow (ABF) were also recorded. A total of 59 LV tissue samples were obtained and histopathological studies were performed to quantify the percentage of fibrosis. Samples were categorized as normal myocardium (<10% fibrosis), heterogeneous scar (10–50%) and dense scar (>50%). Resistivity of normal myocardium depicted phasic changes during the cardiac cycle and its amplitude markedly decreased in dense scar (18 ± 2 Ω·cm vs. 10 ± 1 Ω·cm, at 41 kHz; P < 0.001, respectively). The mean phasic resistivity decreased progressively from normal to heterogeneous and dense scar regions (285 ± 10 Ω·cm, 225 ± 25 Ω·cm, and 162 ± 6 Ω·cm, at 41 kHz; P < 0.001 respectively). Moreover, myocardial resistivity and phase angle correlated significantly with the degree of local fibrosis (resistivity: r = 0.86 at 1 kHz, P < 0.001; phase angle: r = 0.84 at 41 kHz, P < 0.001). Myocardial infarcted regions with greater fibrotic content show lower mean impedance values and more depressed systolic-diastolic dynamic impedance changes. In conclusion, this study reveals that differences in the degree of myocardial fibrosis can be detected in vivo by local measurement of phasic systolic-diastolic bioimpedance spectrum. Once this new bioimpedance method could be used via a catheter-based device, it would be of potential clinical applicability for the recognition of fibrotic tissue to guide the ablation of atrial or ventricular arrhythmias.

Isoform-Specific Modulation of Inflammation Induced by Adenoviral Mediated Delivery of Platelet-Derived Growth Factors in the Adult Mouse Heart.

Platelet-derived growth factors (PDGFs) are key regulators of mesenchymal cells in vertebrate development. To what extent PDGFs also exert beneficial homeostatic or reparative roles in adult organs, as opposed to adverse fibrogenic responses in pathology, are unclear. PDGF signaling plays critical roles during heart development, during which forced overexpression of PDGFs induces detrimental cardiac fibrosis; other studies have implicated PDGF signaling in post-infarct myocardial repair. Different PDGFs may exert different effects mediated through the two PDGF receptors (PDGFRα and PDGFRβ) in different cell types. Here, we assessed responses induced by five known PDGF isoforms in the adult mouse heart in the context of adenovirus vector-mediated inflammation. Our results show that different PDGFs have different, in some cases even opposing, effects. Strikingly, whereas the major PDGFRα agonists (PDGF-A and -C) decreased the amount of scar tissue and increased the numbers of PDGFRα-positive fibroblasts, PDGFRβ agonists either induced large scars with extensive inflammation (PDGF-B) or dampened the adenovirus-induced inflammation and produced a small and dense scar (PDGF-D). These results provide evidence for PDGF isoform-specific inflammation-modulating functions that may have therapeutic implications. They also illustrate a surprising complexity in the PDGF-mediated pathophysiological responses.

Directional Influences of Ventricular Activation on Myocardial Scar Characterization: Voltage Mapping With Multiple Wavefronts During Ventricular Tachycardia Ablation.

The effects of varying the wavefront of activation on ventricular scar characterization has not been systematically assessed. Patients referred for ablation of scar-related ventricular tachycardia underwent voltage maps during a minimum of 2 wavefronts of activation. The bipolar and unipolar low-voltage areas were compared, and direct electrogram analysis was performed in regions where discrepancies were seen. Concordance between wavefronts was measured by calculating percentage of overlap between maps. Sixty endocardial voltage maps (360±147 points) were performed in 29 patients during 2 distinct wavefronts, with 3 wavefronts in 7 patients. With median bipolar and unipolar low-voltage areas of 37 and 116 cm(2), respectively, 22% and 14% variability in median scar area was observed with a different activation wavefront. Concordance between wavefronts was lower in patients with mixed scar compared to those with dense scar (52% [interquartile range, 29%-70%] versus 84% [interquartile range, 71%-87%]), with septal scars exhibiting the lowest concordance [(27% (interquartile range, 21%-56%)]. Among 16 critical sites for ventricular tachycardia, 3 (18%) were in a discordant region of scar, with one of the wavefronts showing voltage >1.5 mV. Significant differences in bipolar and unipolar low-voltage characterization of scar were observed with different ventricular activation wavefronts, particularly in septal locations and in patients without dense scar. In patients with a paucity of dense, low-voltage regions identified during substrate mapping, an alternate activation wavefront may increase the sensitivity to detect arrhythmogenic substrate and critical sites for ventricular tachycardia.

49-05: Defining arrhythmogenic ventricular scar using time- and voltage-domain mapping (V-T-mapping): a new approach to ventricular tachycardia channel localization during sinus rhythm

Aims: In ventricular scar, the impulse spread is slow as it traverses multiple split and zigzag channels of surviving muscle. We aimed to evaluate electrograms in the scar to determine their local delay in relation to the onset of ventricular activation (activation time) and inequality in voltage splitting (entropy), and their relationship to channels. We reasoned that unlike innocuous bystander channels, which are often short with multiple side branches, ventricular tachycardia (VT) supporting channels have very slow impulse spread and possess low entropy due to their longer protected length and relative lack of side branching. Methods: Patients with ischemic cardiomyopathy and multiple inducible VT were studied. In the initial mapping stage (16 patients, 58 VTs), left ventricular endocardial mapping was performed in sinus rhythm. Detailed pace mapping was used to identify VT channels, and confirmed, when feasible, by entrainment. The scar electrograms were analyzed in time- and voltage-domains to determine mean activation time, dispersion in activation time and entropy. The predictive performances of these properties to detect VT channels were tested. In the application stage (7 patients, 20 VTs), these properties were prospectively tested to guide catheter ablation. Results: A mean of 763 ± 203 sampling points per-patient were taken, 451 ± 145 points in dense scar. From 1770 pace maps, 174 channels were identified, and 47 corresponded to inducible VTs. A combination of scar electrograms with the latest mean activation time and minimum entropy, in a high activation dispersion region, accurately recognized regions containing VT channels (kappa = 0.89, sensitivity = 86%, specificity = 100%, positive predictive value = 93%, and negative predictive value = 100%). Finally, focused ablation within the prospective channel regions eliminated 18/20 inducible VTs. Conclusion: Activation time and entropy mapping in the scar accurately identifies VT channels during sinus rhythm. This can expedite recognition of VT channels without pace mapping or mapping during VT and minimize extensive ablation.

High-Resolution Mapping of Ventricular Scar

Mapping resolution is influenced by electrode size and interelectrode spacing. The aims of this study were to establish normal electrogram criteria for 1-mm multielectrode-mapping catheters (Pentaray) in the ventricle and to compare its mapping resolution within scar to standard 3.5-mm catheters (Smart-Touch Thermocool). Three healthy swine and 11 swine with healed myocardial infarction underwent sequential mapping of the left ventricle with both catheters. Bipolar voltage amplitude in healthy tissue was similar between 3.5- and 1-mm multielectrode catheters with a 5th percentile of 1.61 and 1.48 mV, respectively. In swine with healed infarction, the total area of low bipolar voltage amplitude (defined as <1.5 mV) was 22.5% smaller using 1-mm multielectrode catheters (21.7 versus 28.0 cm2; P=0.003). This was more evident in the area of dense scar (bipolar amplitude <0.5 mV) with a 47% smaller very low-voltage area identified using 1-mm electrode catheters (7.1 versus 15.2 cm(2); P=0.003). In this region, 1-mm multielectrode catheters recorded higher voltage amplitude (0.72±0.81 mV versus 0.30±0.12 mV; P<0.001). Importantly, 27% of these dense scar electrograms showed distinct triphasic electrograms when mapped using a 1-mm multielectrode catheter compared with fractionated multicomponent electrogram recorded with the 3.5-mm electrode catheter. In 8 mapped reentrant ventricular tachycardias, the circuits included regions of preserved myocardial tissue channels identified with 1-mm multielectrode catheters but not 3.5-mm electrode catheters. Pacing threshold within the area of low voltage was lower with 1-mm electrode catheters (0.9±1.3 mV versus 3.8±3.7 mV; P=0.001). Mapping with small closely spaced electrode catheters can improve mapping resolution within areas of low voltage.

Image Integration to Guide Catheter Ablation in Scar‐Related Ventricular Tachycardia

Although multi-detector computed tomography (MDCT) and cardiac magnetic resonance (CMR) can assess the structural substrate of ventricular tachycardia (VT) in ischemic cardiomyopathy (ICM), non-ICM (NICM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), the usefulness of systematic image integration during VT ablation remains undetermined. A total of 116 consecutive patients (67 ICM; 30 NICM; 19 ARVC) underwent VT ablation with image integration (MDCT 91%; CMR 30%; both 22%). Substrate was defined as wall thinning on MDCT and late gadolinium-enhancement on CMR in ICM/NICM, and as myocardial hypo-attenuation on MDCT in ARVC. This substrate was compared to mapping and ablation results with the endpoint of complete elimination of local abnormal ventricular activity (LAVA), and the impact of image integration on procedural management was analyzed. Imaging-derived substrate identified 89% of critical VT isthmuses and 85% of LAVA, and was more efficient in identifying LAVA in ICM and ARVC than in NICM (90% and 90% vs. 72%, P < 0.0001), and when defined from CMR than MDCT (ICM: 92% vs. 88%, P = 0.026, NICM: 88% vs. 72%, P < 0.001). Image integration motivated additional mapping and epicardial access in 57% and 33% of patients. Coronary and phrenic nerve integration modified epicardial ablation strategy in 43% of patients. The impact of image integration on procedural management was higher in ARVC/NICM than in ICM (P < 0.01), and higher in case of epicardial approach (P < 0.0001). Image integration is feasible in large series of patients, provides information on VT substrate, and impacts procedural management, particularly in ARVC/NICM, and in case of epicardial approach.

Cell proliferation in the amputated limb of lizard leading to scarring is reduced compared to the regenerating tail

AbstractAfter amputation, the tail of lizards regenerates while the limb forms a short scarring outgrowth. Using phospho‐histone‐H3 immunohistochemistry the mitotic activity of limb tissues at 12–25 days after amputation has been studied, when a limb outgrowth of 0.5–2 mm in length is covered by wound epidermis and the underlying connective is turning into a dense scar. In comparison with a regenerating tail of 3–5 mm in length, the number of dividing cells is reduced of 40–70% in different tissues of the scarring limb 1–2 mm in length at 18 days postamputation. Dividing cells are still present at 12–25 days postamputation in the cartilaginous epiphyses of the transected tibia and fibula and of the untransected femur. Also, the injured muscles present at the base of the scarring outgrowth still contain sparse dividing cells after 25 days postamputation of the limb. Together previous studies, the present observations suggest that after the initial proliferation of fibroblasts deriving from the injured tissues, especially from the dermis and intermuscle connectives during the initial 7–15 days postinjury, these cells cover the injured tissues underneath the wound epidermis, but rapidly produce high levels of collagen turning the initial blastema into a scar.

Analysis of Activation-Recovery Intervals from Intracardiac Electrograms in Normal and Infarcted Porcine Hearts

Mapping of intracardiac electrical signals is a well-established clinical method used to identify the foci of abnormal heart rhythms associated with chronic myocardial infarct (a major cause of death). These foci reside in the ‘border zone’ (BZ) between healthy tissue and dense collagenous scar, and are the targets of ablation therapy. In this work we analyzed detailed features of the electrical signals recorded in a translational animal model of chronic infarct. Specifically, three-dimensional activation maps and bipolar voltages were recorded in vivo from 8 pigs at 5-6 weeks following infarct creation, as well as 7 control (normal) pigs. Endocardial and epicardial maps were obtained during normal sinus rhythm and/or pacing conditions via a catheter-based electro-anatomical CARTO-XP mapping system (Biosense, Webster). Next, depolarization and repolarization maps were derived through manual annotation of electro-cardiogram waves, where the peak of the QRS wave marked the time of depolarization and the peak of the T wave marked the recovery time. Then, at each recording point, activation-recovery intervals (ARI) were found by subtracting activation times from repolarization times. Such ARI maps are important clinical surrogates of action potential duration. Overall, we observed that ARI values in the BZ have recovered from the acute stage and were close to ARI values in normal tissue. Furthermore, in both infarcted and normal cases we observed: i) a weak negative correlation between the activation times and ARI values, and ii) not a significant variation (p<0.5) between mean ARI values in the BZ area and those in the healthy areas. Our future work will focus on personalizing mathematical models from these electrical maps per individual hearts, to enable accurate predictions of cardiac wave propagation and the inducibility of scar-related abnormal rhythms.

Peri-Infarction Zone as a Risk Marker for Patients With Postmyocardial Infarction

IntroductionThe role of contrast-enhanced (ce) cardiac magnetic resonance in risk stratification of patients with depressed left ventricle (LV) function is widely studied. In this study, we investigated the myocardial infarct size and characteristics by ce-magnetic resonance imaging (MRI) and its relationship with spontaneous ventricular arrhythmia occurrence during follow-up of in patients with mild LV systolic dysfunction and nonsustained ventricular tachycardia (VT). Materials and MethodsThis study enrolled 32 patients with postmyocardial infarction with an LV ejection fraction between 40% and 50% and nonsustained VT. Cardiac MRI performed to identify cardiac scar size and characteristics. Dense scar, peri-infarction zone and total infarct masses were calculated, these values to LV mass ratios were obtained. All patients were followed up 48 ± 6 months. Cardiac magnetic resonance data compared among patients with (n = 6) and without spontaneous sustained VT (n = 26). ResultsDuring follow-up, 6 patients experienced sustained VT (VT+ group), whereas 26 patients had no sustained ventricular arrhythmia (VT− group). The groups had similar baseline clinical characteristics. The LV masses, volumes and ejection fractions did not differ significantly between 2 groups. For the VT+ group versus VT− group dense scar to LV mass were similar (3.1 ± 0.3% versus 3.3 ± 0.9%, P = not significant). Ratio of peri-infarction zone to LV mass (30.9 ± 6.1% versus 21.3 ± 7.5%, P = 0.007) and total infarct to LV mass (34.1 ± 6.1% versus 24.6 ± 7.9%, P = 0.011) were larger in patients with sustained VT. ConclusionsThis small study supports the potential utility of ce-MRI to identify patients with postmyocardial infarction prone to develop serious ventricular arrhythmias.

Management of postburn contractures of upper extremities: A general surgeon's perspective

Introduction: Postburn contracture (PBC) is one of the common sequelae encountered after burns in general surgical practice. Surgical management of such deformities involves release of contracture followed by cover by skin graft or skin flap. Optimum management of PBCs has always been a challenge to the surgeon because of paucity of adequate healthy skin in the affected areas. Various operative techniques are available, and the surgeon has to decide which particular technique will be more suitable for a particular patient. We have employed the techniques of release by Z-plasty, and release and skin grafting in managing PBC involving upper extremity, and this study is based on our experience with these techniques. Aims and Objective: The study was carried out to evaluate the frequency of different PBCs involving upper extremities and comparing the relatively simpler techniques of release of contracture and cover by skin grafting and Z-plasty, which can be undertaken by a general surgeon as well. Materials and Methods: A total of 100 cases having PBC of upper extremities of more than 6 months duration were included in this study. Complex contractures of hands involving tendons and joints were excluded from this study. Linear contractures were managed by single or multiple Z-plasty techniques whereas patients having wider and dense scars were managed by release/excision of scar and cover by skin grafting. Observations: The mean visual analog score for patient satisfaction was 8.06 for Z-plasty group versus 5.33 for split skin grafting (SSG) group. The mean stay for patients who had undergone Z-plasty was 9.40 days as compared to 15 days for SSG. Conclusion: Contracture release with local flap cover was better technique in relation to patient satisfaction, recurrence of deformity, hospital stay, and time taken for rehabilitation.

Femtosecond laser-assisted phototherapeutic keratectomy for the treatment of dense corneal scarring

Femtosecond laser-assisted phototherapeutic keratectomy for the treatment of dense corneal scarring

Treating spinal cord injury via sustained drug delivery from calcium phosphate coatings.

Spinal cord injury (SCI) is a devastating trauma that leaves approximately 10,000 to 20,000 people paralyzed every year in the United States. The majority of these cases are young people that will live to almost a full life expectancy, however, their quality of life is significantly reduced. After SCI there is loss of both sensory and motor function below the level of injury. Due to this loss of function SCI patients are often unable to care for themselves and rely on friends and family to serve as their primary caregivers. The Christopher Reeve Foundation found that more than 50 million people each year provide this care in the U.S., the value of which is estimated to be $306 billion annually. Along with the financial burden, SCI patients have emotional stress and continued health care problems throughout their lives most predominately renal complications and pressure sores. These facts demonstrate the overwhelming need to restore function after SCI.

Abstract 17049: Computer Simulation to Study the Effect of Structural Remodeling on Atrial Fibrillation Using Clinically-obtained Cardiac MRIs

Introduction: Structural remodeling of the atria in the form of fibrosis is known to be a contributing factor for the initiation and maintenance of atrial fibrillation (AF). Hypothesis: Using computer simulation based on clinically-obtained MRIs, we tested the hypothesis that both dense and diffuse fibrosis play significant roles in the inducibility of AF and the effectiveness of pulmonary vein (PV) ablation. Methods: Magnetic resonance angiograms and delayed enhancement MRIs (DEMRIs) of the left atrium from 34 AF patients were used to construct the models for the computer simulations. Using the Fenton-Karma action potential model, three conditions were tested for AF inducibility: 1) no fibrosis, 2) diffuse fibrosis, and 3) diffuse and dense fibrosis. AF induction was attempted at each of the four PVs and episodes lasting &gt;30 s were considered sustained. Wide area PV ablation was simulated on all sustained episodes. Results: With no fibrosis, sustained AF was achieved in 55.9±32.0% of induction attempts. This percentage was significantly increased to 92.6±15.7% and 93.4±12.8% with diffuse fibrosis and combined dense and diffuse fibrosis, respectively (p&lt;0.0001 for both). PV ablation terminated 75% of episodes induced with no fibrosis, 62% with diffuse fibrosis and 60% with combined dense and diffuse fibrosis. Organized reentry usually formed after ablation with dense scar providing an anchor for reentry in episodes where dense scar is present. Conclusions: Both diffuse and dense fibrosis significantly increases the likelihood for AF induction and maintenance in the computer model with dense fibrosis providing additional anchor points in the left atrium for reentrant circuits.

Value of cardiac magnetic resonance imaging in the setting of familiar cardiomyopathy: A step toward pre-clinical diagnosis

A 24-years-old asymptomatic man was referred to our Institution for screening of familiar idiopathic dilated cardiomyopathy (CMP) due to the important family history of dilated CMP with associated severe burden of ventricular arrhythmias (Fig. 1). His father and a first-degree father's cousin were indeed both affected by idiopathic dilated CMP, which was diagnosed in their third decade after an episode of sustained ventricular tachycardia (VT); both underwent implantable cardioverter defibrillator (ICD) implantation for secondary prevention of sudden cardiac death (SCD) and subsequently experienced multiple appropriate ICD interventions. Due to further dilatation and dysfunction of the left ventricle (LV) and worsening of the arrhythmic burden as well as heart failure symptoms despite optimal medical therapy, they were finally referred to heart transplantation at the age of 40 and 45 years, respectively. In addition, two more first-degree father's cousins died suddenly at the age of 14 and 47 years. The histologic examination of the explanted heart of proband's father showed multiple areas of dense fibrosis with intra-myocardial and sub-epicardial patchy distribution (Fig. 2A –B, Mallory trichromic stain: blue areas); myocyte apoptotic and degenerative phenomena were also observed (Fig. 2C–D, arrows). Of note, a strong family history of breast cancer was also present in the family (Fig. 1). Fig. 2Cardiomyopathy-related myocardial morphological changes are shown in histological sections of the explanted heart of the proband's father. They consist of a spectrum of changes beginning with focal degeneration and necrosis of cardiomyocytes with no or minimal cellular response, followed by myofiber loss and replacement of the cardiomyocytes with varying degrees of fibrosis. Low magnification shows intra-myocardial (A) and sub-epicardial (B) areas of dense fibrotic scar with patchy distribution (blue with Mallory trichromic stain). Higher magnification reveals foci of myocardial degeneration with vacuolization of cardiomyocytes (panel C–D, arrows, Hematoxylin and Eosin stain). Necrotic cardiomyocytes exhibit homogeneously brightly eosinophilic sarcoplasm with pyknotic or karyorrhectic nuclei (panels C–D, arrows). View Large Image Figure Viewer Download Hi-res image

Mammographic imaging after partial breast reconstruction: Impact of a bioabsorbable breast implant.

111 Background: Marking the site of the excised tumor bed during partial mastectomy is critical for radiation targeting and surveillance for breast cancer recurrence. However, delineating the lumpectomy cavity margins is challenging, and dense fibrosis and scarring often present obstacles when reviewing post-operative mammograms for signs of early recurrence. To determine whether implantation of a "mini" breast implant used for partial breast reconstruction adversely affected post-operative breast imaging, we reviewed clinical imaging of 100 patients that had been implanted with a new bioabsorbable breast implant over a three year period. Methods: Following informed consent, 110 patients were implanted at the time of partial mastectomy with a bioabsorbable implant with a primary purpose of marking the surgical site of tumor excision for radiotherapy. In each case, the surgeon sutured the implant into the cavity at the location believed to be at greatest risk for recurrence. Implants were used for partial breast reconstruction, a guide for radiation treatment planning and routine mammographic follow-up. Mammograms were reviewed for implant visibility, presence of artifacts and other diagnostic criteria. Results: In all cases the implant was rated as easily visible on mammography and CT without appreciable artifact or interference with diagnostic capabilities. In addition, there was notably less dense fibrotic tissue visualized on mammographic imaging at the tumor excision site containing the implant. In some cases, the marker clips coalesced in the center of the surgical cavity. The marker was also seen on US and MRI during routine follow-up. Conclusions: Mammographic imaging in patients implanted with this new device was not adversely affected by its presence. The implant visually assisted with verification of the excised tumor bed without introducing any artifact or diagnostic interference and there was notable in-growth of normal breast tissue clearly seen on mammography. In this group of patients there were no abnormal calcifications in or around the implant and there were no recurrent cancers detected within this 36 month period.

Local Delivery of High-Dose Chondroitinase ABC in the Sub-Acute Stage Promotes Axonal Outgrowth and Functional Recovery after Complete Spinal Cord Transection.

Chondroitin sulfate proteoglycans (CSPGs) are glial scar-associated molecules considered axonal regeneration inhibitors and can be digested by chondroitinase ABC (ChABC) to promote axonal regeneration after spinal cord injury (SCI). We previously demonstrated that intrathecal delivery of low-dose ChABC (1 U) in the acute stage of SCI promoted axonal regrowth and functional recovery. In this study, high-dose ChABC (50 U) introduced via intrathecal delivery induced subarachnoid hemorrhage and death within 48 h. However, most SCI patients are treated in the sub-acute or chronic stages, when the dense glial scar has formed and is minimally digested by intrathecal delivery of ChABC at the injury site. The present study investigated whether intraparenchymal delivery of ChABC in the sub-acute stage of complete spinal cord transection would promote axonal outgrowth and improve functional recovery. We observed no functional recovery following the low-dose ChABC (1 U or 5 U) treatments. Furthermore, animals treated with high-dose ChABC (50 U or 100 U) showed decreased CSPGs levels. The extent and area of the lesion were also dramatically decreased after ChABC treatment. The outgrowth of the regenerating axons was significantly increased, and some partially crossed the lesion site in the ChABC-treated groups. In addition, retrograde Fluoro-Gold (FG) labeling showed that the outgrowing axons could cross the lesion site and reach several brain stem nuclei involved in sensory and motor functions. The Basso, Beattie and Bresnahan (BBB) open field locomotor scores revealed that the ChABC treatment significantly improved functional recovery compared to the control group at eight weeks after treatment. Our study demonstrates that high-dose ChABC treatment in the sub-acute stage of SCI effectively improves glial scar digestion by reducing the lesion size and increasing axonal regrowth to the related functional nuclei, which promotes locomotor recovery. Thus, our results will aid in the treatment of spinal cord injury.