Predictors of low-voltage zones in patients with persistent atrial fibrillation eligible for catheter ablation: An observational study.

INTRODUCTION: The presence of low-voltage zones (LVZs) in the left atrium (LA) is associated with the recurrence of atrial fibrillation (AF) following pulmonary vein isolation (PVI). However, there is variability and conflict in the data regarding predictors of LVZs as reported in previous studies. The objective of this study was to identify predictors for the presence of LVZs in a cohort of patients with persistent AF. METHODS: The study prospectively enrolled 439 patients with persistent AF who were scheduled for ablation. Voltage map of the LA was collected using a multipolar catheter. An LVZ was defined as an area of ≥3 cm2 exhibiting a peak-to-peak bipolar voltage of <0.5 mV. RESULTS: The mean age of the cohort was 65.3 ± 8.6 years and 26.4% were female. Additionally, 25.7% had significant LVZs, most frequently located in the anterior wall of the LA. Multivariable analysis identified the following independent predictors for LVZ: advanced age (OR [odds ratio] = 1.08, 95% CI [confidence interval] = 1.03-1.13, p = .002); female sex (OR = 4.83, 95% CI = 2.66-8.76, p < .001); coronary artery disease (CAD) (OR = 3.20, 95% CI = 1.32-7.77, p = .01) and enlarged LA diameter (OR = 1.10, 95% CI = 1.04-1.17, p = .001). The area under the curve (AUC) of the receiver operating characteristic (ROC) curve for the final model was 0.829. CONCLUSION: Approximately 25% of the patients with persistent AF had LVZs. Advanced age, female sex, CAD, and a larger LA were independent predictors for LVZs with the model demonstrating a very good AUC for the ROC curve. These findings hold the potential to be used to tailor the ablation procedure for the individual patient.

Risk assessment in patients with symptomatic and asymptomatic pre-excitation.

AIMS: Controversy remains as to whether the exercise stress test (EST) is sufficient for risk evaluation in patients with pre-excitation. This study aims to clarify the usefulness of EST in risk stratification in both asymptomatic and symptomatic patients presenting with pre-excitation. METHODS AND RESULTS: This prospective study includes consecutive asymptomatic and symptomatic patients with pre-excitation referred for risk assessment. All participants performed an incremental EST (bicycle) prior to an electrophysiology study (EPS). Primary data from the EST included loss of pre-excitation during exercise, and primary data from the EPS included the measurement of accessory pathway effective refractory period (APERP), shortest pre-excited RR interval (SPERRI), and inducible arrhythmia with the use of a beta-adrenergic receptor agonist if deemed necessary. One hundred and sixty-four patients (59 asymptomatic, 105 symptomatic) completed an EST and EPS. Forty-five patients (27%) demonstrated low-risk findings on EST, of which 19 were asymptomatic and 26 were symptomatic. Six patients with low-risk EST findings had SPERRI/APERP ≤ 250 ms at EPS, and two of them were asymptomatic. The sensitivity, specificity, positive predictive value, negative predictive value (NPV), and accuracy of low-risk EST for excluding patients with SPERRI/APERP ≤ 250 ms were 40, 91, 87, 51, and 60%, respectively. The number of patients with inducible arrhythmia at EPS was similar in the asymptomatic (36, 69%) and symptomatic (73, 61%) groups. CONCLUSION: Sudden loss of pre-excitation during EST has a low NPV in excluding high-risk APs. The EPS with the use of isoproterenol should be considered to accurately assess the risk of patients with pre-excitation regardless of symptoms (ClinicalTrials.gov Identifier: NCT03301935).

Low incidence of major complications after the first six hours post atrial fibrillation ablation: Is same-day discharge safe and feasible in most patients?

AIMS: This study evaluates the incidence of procedural complications related to catheter ablation of atrial fibrillation (AF) to assess the potential feasibility and safety of same-day discharge in a large cohort. METHODS: We performed an analysis of prospectively collected data of complications of all patients staying overnight after undergoing AF ablation between 2001 and 2020 at a tertiary center. Using medical records, we analyzed complications occurring intraprocedurally until 6 h postablation and between 6 h postablation and discharge the day after the ablation procedure. RESULTS: In 5414 AF ablations, we identified a total of 108 (2.0%) major complications occurring intraprocedural or before discharge. Most major complications occurred intraprocedurally or within 6 h after the procedure (n = 96, 1.8%). Twelve (0.2%) major complications occurred between 6 h Postablation and discharge. The most common of these major complications were congestive heart failure (n = 6) and transient ischemic attack (TIA, n = 4). During this time span, 61 (1.1%) minor complications occurred. Factors independently associated with major complications intraprocedurally and until discharge were body mass index (BMI) ≥ 30 kg/m2 (p = .009), significant valvular disease (p = .001), cardiomyopathy (p < .001), prior stroke or TIA (p = .014), first-time procedure versus repeat procedure (p = .013), cryoablation versus radiofrequency (p < .001), and procedure duration (p < .001). CONCLUSION: After AF ablation, very few complications occurred between 6 h postprocedure and discharge the next day. Therefore, same-day discharge is a safe option for a majority of patients.

Cryoablation of atypical atrioventricular nodal reentry tachycardia.

AIM: Data on ablation for atypical recurrent atrioventricular nodal reentry tachycardia (AVNRT) and long-term follow-up are generally sparse. Furthermore, the rate of recurrence and safety of cryoablation for atypical AVNRT has not been established. We compared patients cryoablated for atypical AVNRT and typical AVNRT during long-term follow-up. METHODS: All patients (n = 2612) who underwent catheter ablation for AVNRT at the Karolinska University Hospital between January 2009 and August 2019 were analyzed. A total of 91 patients undergoing first-time cryoablation for atypical AVNRT were included. A control group with first-time cryoablation for typical AVNRT was matched in a 1:1 ratio. Patients were followed-up for recurrences for a median of 5.0 years (interquartile range: 3.1-7.5 years). RESULTS: After 5 years, AVNRT recurrence occurred in 10 patients (11.0%) in the atypical AVNRT group and in 8 patients (8.8%) in the typical AVNRT group (hazard ratio: 1.31 [95% confidence interval: 0.52-3.32]; p = 0.568). The duration of the index procedure was significantly longer for atypical compared to typical AVNRT ablation (132.1 ± 49.2 min vs. 110.1 ± 38.8 min; p = 0.001). Transient AV blocks occurred in a similar fashion in the atypical compared to typical group (11 [12.1%] vs. 4 [4.9%]; p = 0.103). However, no ablation induced persistent AV block developed in either group. CONCLUSION: Cryoablation for atypical AVNRT showed similar rate of recurrences and safety compared to typical AVNRT during long-term follow-up.

Is one month treatment with dabigatran before cardioversion of atrial fibrillation sufficient to prevent thromboembolism?

AIMS: The use of direct oral anticoagulants (DOACs) in patients undergoing elective direct current (DC) cardioversion of non-acute atrial fibrillation (AF) can potentially shorten the time from initiation of anticoagulation treatment to cardioversion, compared with warfarin. The safety of this strategy needs to be investigated. Data from subgroup analysis from clinical trials with DOAC do not clarify whether 4-week treatment with DOAC is sufficient to prevent thromboembolism (TE) after cardioversion. The aim of this retrospective study was to assess the incidence of TE in anticoagulant naive patients converted after one month's pre-treatment with dabigatran. METHODS AND RESULTS: We scrutinized the medical records of 631 patients where dabigatran had been used prior to elective DC cardioversion. Transoesophageal echocardiography was rarely performed. Thromboembolism within 30 days of cardioversion was the primary endpoint. A total of 570 patients were naive to OAC when dabigatran was initiated. The mean age in this group was 64.2 ± 11 years and 31.7% were women. The mean CHA2DS2-VASc score was 2.0 ± 1.5. The dose of dabigatran was 150 mg b.i.d. in 94% of the patients. The median time from initiation of dabigatran to cardioversion was 32.0 ± 15 days. In 91% cardioversion resulted in sinus rhythm. During the 30-day follow-up, three TE occurred for an incidence of 0.53% (0.18-1.54). CONCLUSION: In this retrospective study from clinical material, we found a low incidence of TE when dabigatran was used as TE prophylaxis in association with elective cardioversion. These results indicate that dabigatran is a safe alternative strategy to warfarin during cardioversion in patients with AF.

Symptoms of gastroesophageal reflux disease predicts low voltage zones in the posteroinferior left atrium in patients with persistent atrial fibrillation.

Background: The presence of low voltage zones (LVZs) in the left atrium (LA) is associated with the recurrence of atrial fibrillation (AF) after pulmonary vein isolation. Numerous studies have posited a link between gastroesophageal reflux disease (GERD) and AF, attributing this relationship to the anatomical proximity of the esophagus to the posteroinferior wall of the LA. Objective: The objective of this study was to investigate whether GERD can predict the presence of LVZs in the posteroinferior wall of the LA. Methods: Five hundred fifty-one patients with persistent AF, scheduled for their first AF ablation procedure, were prospectively enrolled. Voltage maps were collected using a multipolar catheter, and LVZs were defined as areas measuring ≥3 cm2 with a peak-to-peak bipolar voltage of <0.5 mV. Information on GERD symptoms was collected from the participants through a self-administered questionnaire. Results: Long-standing persistent AF was present in 22.3% of the total cohort. GERD was present in 29% of patients and LVZs in the posteroinferior wall in 12.7%. In the multivariable analysis, patients with GERD were found to have more than twice the odds (odds ratio 2.26; 95% confidence interval 1.24-4.13; P = .008) of exhibiting LVZs in the posteroinferior wall of the LA than patients without GERD. GERD was not associated with LVZs in any other region of the LA. Conclusion: GERD was found to be independently associated with LVZs in the posteroinferior LA. This association may be attributable to inflammation and may partly explain the link between GERD and AF.

Incidence of atrial fibrillation in patients with atrioventricular nodal re-entrant tachycardia and its association with long-term outcome.

Background: Atrioventricular nodal re-entrant tachycardia (AVNRT) is the most common paroxysmal supraventricular tachycardia. We sought to investigate the incidence of atrial fibrillation in patients with electrophysiologically confirmed/ablated AVNRT and its association with transient ischemic attack (TIA)/stroke as well as mortality during long-term follow-up. Methods: From the Karolinska Ablation Registry, 2855 consecutive patients with a first-time ablation for AVNRT between 2005 and 2018 were analyzed. Results: Patients were 52.1 ± 15.9 years old and 59.3% were women. During follow-up of up to 10 years (median 6.0 years; interquartile range 3.3 to 9.2 years), new onset or recurrence of atrial fibrillation occurred in 317 (11.1%) patients (incidence rate 19 cases per 1000 person-years). Excluding those with history of atrial fibrillation, new onset of atrial fibrillation occurred in 153 (6.1%) patients. In multivariable analysis, history of atrial fibrillation, arterial hypertension, history of TIA/stroke, and heart failure remained independently associated with new onset or recurrence of atrial fibrillation during follow-up. Death of any cause and TIA/stroke occurred in 141 (4.9%) patients and 107 (3.7%) patients, respectively. In multivariable analysis, occurrence of atrial fibrillation during follow-up remained independently associated with both outcomes. The prevalence of atrial fibrillation according to age at the end of follow-up was high among young patients (<60 years of age: 12.7%; 60-69 years of age: 10.6%). Conclusion: In this large cohort of patients with diagnosed AVNRT, the incidence of atrial fibrillation was high (11.1%) during long-term follow-up. Occurrence of atrial fibrillation during follow-up remained independently associated with death for any cause as well as with TIA/stroke. Therefore, a closer monitoring for atrial fibrillation in patients with AVNRT including those at young age is advisable.

Reduced dementia risk in patients with optimized anticoagulation therapy undergoing atrial fibrillation ablation.

BACKGROUND: Atrial fibrillation (AF) is associated with the development of dementia, and observational studies have shown that oral anticoagulation and catheter ablation reduce dementia risk. However, such studies did not consistently report on periprocedural anticoagulation and long-term oral anticoagulation coverage, for which reason the separate effect of AF ablation on dementia risk could not be established. OBJECTIVE: We evaluated the protective effect of AF ablation in a large cohort of patients who received optimized anticoagulation and compared them with patients who were managed medically. METHODS: We retrospectively included 5912 consecutive patients who underwent first-time catheter ablation for AF between 2008 and 2018 and compared them with 52,681 control individuals from the Swedish Patient Register. Propensity score matching produced 2 cohorts of equal size (n = 3940) with similar baseline characteristics. Dementia diagnosis was identified by International Classification of Diseases codes from the patient register. RESULTS: Most propensity score-matched patients were taking an oral anticoagulant at the start (94.5%) and end (75.0%) of the study. Mean follow-up was 4.9 ± 2.8 years. Catheter ablation was associated with lower risk for the dementia diagnosis compared with the control group (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.22-0.86; P = .017). The result was similar when including patients with a stroke diagnosis before inclusion (HR, 0.50; 95% CI, 0.28-0.89; P = .019) and after adjustment for the competing risk of death (HR, 0.41; 95% CI, 0.20-0.86; P = .018). CONCLUSION: Catheter ablation of AF in patients with optimized oral anticoagulation therapy was associated with a reduction in dementia diagnosis, even after adjustment for potential confounders and for competing risk of death.

Association between catheter ablation of atrial fibrillation and mortality or stroke.

OBJECTIVE: Catheter ablation of atrial fibrillation effectively reduces symptomatic burden. However, its long-term effect on mortality and stroke is unclear. We investigated if patients with atrial fibrillation who undergo catheter ablation have lower risk for all-cause mortality or stroke than patients who are managed medically. METHODS: We retrospectively included 5628 consecutive patients who underwent first-time catheter ablation for atrial fibrillation between 2008 and 2018 at three major Swedish electrophysiology units. Control individuals with an atrial fibrillation diagnosis but without previous stroke were selected from the Swedish National Patient Register, resulting in a control group of 48 676 patients. Propensity score matching was performed to produce two cohorts of equal size (n=3955) with similar baseline characteristics. The primary endpoint was a composite of all-cause mortality or stroke. RESULTS: Patients who underwent catheter ablation were healthier (mean CHA2DS2-VASc score 1.4±1.4 vs 1.6±1.5, p<0.001), had a higher median income (288 vs 212 1000 Swedish krona [KSEK]/year, p<0.001) and had more frequently received university education (45.1% vs 28.9%, p<0.001). Mean follow-up was 4.5±2.8 years. After propensity score matching, catheter ablation was associated with lower risk for the combined primary endpoint (HR 0.58, 95% CI 0.48 to 0.69). The result was mainly driven by a decrease in all-cause mortality (HR 0.51, 95% CI 0.41 to 0.63), with stroke reduction showing a trend in favour of catheter ablation (HR 0.75, 95% CI 0.53 to 1.07). CONCLUSIONS: Catheter ablation of atrial fibrillation was associated with a reduction in the primary endpoint of all-cause mortality or stroke. This result was driven by a marked reduction in all-cause mortality.

Validation of diagnostic accuracy of a handheld, smartphone-based rhythm recording device.

AIM: Evaluation of the diagnostic accuracy of a rhythm recording device, for detection of atrial tachyarrhythmia (ATA) and atrial fibrillation (AF) compared to 12-lead-electrocardiogram (12-L-ECG). RESEARCH DESIGN AND METHODS: Two hundred 12-L-ECGs (reference standard) and Coala Heart Monitor (CHM) recordings (index test) were collected from 189 patients. Two electrophysiologists independently performed manual analysis of all 12-L-ECGs and CHM recordings in random order. The CHM recordings were also analyzed by an automatic algorithm and compared to the results of the reference standard. RESULTS: Manual analysis of CHM for ATA showed a sensitivity of 98.9% (95% confidence interval (CI): 94.0-100) and a specificity of 100% (CI: 96.6-100). Manual analysis for AF had a sensitivity of 100% (CI: 95.3-100) and a specificity of 97.5% (CI: 93.0-99.5). Automatic analysis for ATA showed a sensitivity of 93.5% (CI: 86.3-97.6) and a specificity of 92.6% (CI: 85.9-96.7). Automatic analysis for AF showed a sensitivity of 97.4% (CI: 91.0-99.7) and a specificity of 86.1% (CI: 78.6-91.7). CONCLUSION: CHM has a very high accuracy for ATA and AF in manual analysis and a high accuracy for ATA and AF in automatic analysis, making the device suitable for screening.

Electrical cardioversion for early recurrences post pulmonary vein isolation.

BACKGROUND: To study the association between timing and success of electrical cardioversion (ECV) for the treatment of early recurrences (ERs) of atrial fibrillation post pulmonary vein isolation (PVI) on long-term rhythm outcome. METHODS: Data of 133 patients ablated for paroxysmal or persistent atrial fibrillation receiving ECV for ERs, i.e., atrial tachyarrhythmia recurrences within 90 days post ablation were analyzed. During 1-year follow-up, patients were screened for late recurrences (LRs), i.e., recurrences after the blanking period. RESULTS: In 114 patients (85.7%), ECV was successful compared to 19 patients (14.3%) with failed ECV. A higher body mass index (odds ratio (OR) 1.19 (95% CI 1.02-1.39), p = 0.029), a lower left ventricular ejection fraction (OR 1.07 (95% CI 0.99-1.15), p = 0.079), and performance of ECV > 7 days from ER onset (OR 2.99 (95% CI 1.01-8.87), p = 0.048) remained independently associated with ECV failure. During 1-year follow-up, the rate of LR was significantly higher among patients with failed ECV as compared to patients with successful ECV (hazard ratio (HR) 3.00 (95% CI, 1.79-5.03), p < 0.001). Patients with ECV performed > 7 days from ER onset had a significantly higher risk of developing LR as compared to patients with ECV performed within ≤ 7 days from ER onset (HR 1.73 (95% CI 1.15-2.62), p = 0.009). Performance of ECV > 7 days from ER onset (HR 1.76 (95% CI 1.16-2.67), p = 0.008) and failed ECV (HR 3.32 (95% CI 1.96-5.64), p < 0.001) remained independently associated with LR. CONCLUSIONS: A failed ECV and performance of ECV > 7 days from ER onset were independently associated with LR.

Sinus heart rate post pulmonary vein ablation and long-term risk of recurrences.

PURPOSE: Cather ablation is known to influence the autonomic nervous system. This study sought to investigate the association of sinus heart rate pre-/post-ablation and recurrences in patients with atrial fibrillation undergoing pulmonary vein isolation (PVI). METHODS: Between January 2012 and December 2017, data of 482 patients undergoing their first PVI were included. Sinus heart rate was recorded before (PRE), directly post-ablation (POST) and 3 months post-ablation (3 M). All patients were screened for atrial tachyarrhythmia recurrences during the one-year follow-up. RESULTS: In the total study cohort, the mean resting sinus heart rate at PRE [mean 57.9 bpm (95% CI 57.1-58.7 bpm)] increased by over 10 bpm to POST [mean 69.4 bpm (95% CI 68.5-70.3 bpm); p < 0.001] followed by a slight decrease at 3 M [mean 67.3 bpm (95% CI 66.4-68.2 bpm)] but still remaining higher compared to PRE (p < 0.001). This pattern was observed in patients with and without recurrences at POST and 3 M (both p < 0.001 compared to PRE). However, at 3 M the mean sinus heart rate was significantly lower in patients with compared to patients without recurrences (p = 0.031). In this regard, patients with a heart rate change < 11 bpm (PRE to 3 M) or, as an alternative parameter, patients with a heart rate < 60 bpm at 3 M had a significantly higher risk of recurrences compared to the remaining patients (Hazard ratio (HR) 1.82 (95% CI 1.32-2.49), p < 0.001 and HR 1.64 (95% CI 1.20-2.25), p = 0.002, respectively). CONCLUSION: Our study confirms the impact of PVI on cardiac autonomic function with a significant sinus heart rate increase post-ablation. Patients with a sinus heart rate change < 11 bpm (PRE to 3 M) are at higher risk for recurrences during one-year post-PVI.

Distribution of intraportally implanted microspheres and fluorescent islets in mice.

The aim of the study was to evaluate the distribution of intraportally transplanted islets in mice. We initially administered 2000 polystyrene microspheres with a diameter of 50 microm intraportally into normoglycemic C57BL/6 mice. In separate experiments other mice were injected similarly with 300 microspheres each with a diameter of 100 or 200 microm. One week later the animals were killed, and the lungs and livers were removed and divided into lobes. The number of microspheres in each individual liver lobe and in the lungs was counted using a stereomicroscope. In other experiments, athymic C57BL/6 mice were similarly implanted with 250 islets isolated from transgenic mice expressing the enhanced yellow fluorescent protein in the islet cells. The distribution of microspheres and islets was independent of size, and fairly homogenous within the liver, with the exception of the caudate lobe, which contained fewer microspheres and islets, respectively. Approximately one third of all microspheres and islets were present as aggregates. Eighty-five to 90% of the implanted microspheres were identified in the liver sections, whereas 60-65% of the implanted islets were recovered. Aggregates or single fluorescent cells were observed in the liver of islet-implanted mice. We conclude that islets and microspheres implanted into the liver distribute fairly homogenously and quite a few of them exist as aggregates or, with respect to islets, as fragments.

Evidence of functional impairment of syngeneically transplanted mouse pancreatic islets retrieved from the liver.

A drawback in pancreatic islet transplantation is the large number of islets needed to obtain insulin independence in patients with diabetes. This most likely reflects extensive posttransplantation islet cell death and functional impairment of the remaining endocrine cells. We aimed to develop an experimental method to retrieve transplanted islets from the mouse liver, which would enable comparisons of transplanted and endogenous islets and provide valuable information on functional changes induced by intraportal transplantation. Transplanted islets were obtained by retrograde perfusion of the liver with collagenase. The identity of retrieved tissue as transplanted islets was confirmed by intravital staining, immunohistochemistry, and electron microscopy. The retrieved islets, irrespective of whether they had resided in diabetic or nondiabetic recipients, had a markedly lower insulin content and glucose-stimulated insulin release when compared with isolated endogenous islets. The glucose oxidation rate was also markedly lower in the retrieved islets, suggesting mitochondrial dysfunction. These disturbances in insulin content, insulin release, and glucose oxidation rate were not reversed by a few days of culture after retrieval. The results implicate changes in islet function after intraportal transplantation. Such dysfunction may contribute to the high number of islets needed for successful transplantation in diabetic individuals.

Pancreatic islet function in a transgenic mouse expressing fluorescent protein.

Pancreatic islet function and glucose homeostasis have been characterized in the transgenic YC-3.0 mouse, which expresses the yellow chameleon 3.0 (YC-3.0) protein under the control of the beta-actin and the cytomegalovirus promoters. Fluorescence from the enhanced yellow fluorescent protein (EYFP), one part of the yellow chameleon protein, was used as a reporter of transgene expression. EYFP was expressed in different quantities throughout most cell types, including islet endocrine and stromal cells. No adverse effects of the transgene on animal health, growth or fertility were observed. Likewise, in vivo glucose homeostasis, mean arterial blood pressure and regional blood flow values were normal. Furthermore, the transgenic YC-3.0 mouse had a normal beta-cell volume and mass as well as glucose-stimulated insulin release in vitro, compared with the C57BL/6 control mouse. Isolated islets from YC-3.0 animals continuously expressed the transgene and reversed hyperglycemia when transplanted under the renal capsule of alloxan-diabetic nude mice. We conclude that isolated pancreatic islets from YC-3.0 animals implanted into recipients without any EYFP expression, constitute a novel and versatile model for studies of islet engraftment.

Blood glucose-lowering activity of a hyaluronan-insulin complex after oral administration to rats with diabetes.

BACKGROUND: Several covalently modified insulin derivatives or formulations with absorption enhancers have been shown to decrease the blood glucose concentration after oral administration in animals with diabetes. The aim of this study was to investigate the biological activity of a novel hyaluronan-insulin complex. METHODS: The efficacy of the complexed insulin after oral and subcutaneous administration was evaluated by analysis of blood glucose concentrations in rats with streptozotocin-induced diabetes. RESULTS: The complexed insulin significantly decreased blood glucose concentrations within 1 h after oral administration in eight of 10 rats in the dose interval 1.5-4.7 mg (3.1-14.5 mg/kg). Oral administration of native insulin or non-complexed insulin plus hyaluronan using similar doses failed to decrease blood glucose concentrations. The lowest oral dose of complexed insulin achieving a statistically significant decrease in blood glucose concentrations was 1.2-1.5 mg (about 4 mg/kg), and the threshold dose after subcutaneous administration was 0.08-0.12 mg (0.25 mg/kg). CONCLUSIONS: The hyaluronan-insulin complex was active after oral administration and decreased blood glucose concentrations in rats with streptozotocin-induced diabetes. The ratio between the oral and subcutaneous threshold doses was about 16.

Impaired revascularization of transplanted mouse pancreatic islets is chronic and glucose-independent.

BACKGROUND: Pancreatic islets are avascular immediately after transplantation and depend on revascularization. Recently, the authors found decreased vascular density in mouse islets 1 month after implantation into nondiabetic recipients. This study investigated possible differences in revascularization between islets implanted into nondiabetic and diabetic recipients, and also evaluated changes in vascular density up to 6 months posttransplantation. METHODS: Islets were syngenically transplanted beneath the renal capsule of normoglycemic or alloxan-diabetic C57BL/6 mice. One to 6 months later, the animals were killed and the grafts removed. Histologic slides were prepared and stained with Bandeiraea simplicifolia. RESULTS: The vascular density in all transplanted islets was decreased compared with native islets. There were no differences in the islet graft vascular density between nondiabetic and diabetic animals. No improvement over time occurred. CONCLUSIONS: The vascular density is decreased in islets implanted to cure diabetic recipients. No improvement occurs in transplanted islets after 1 month posttransplantation.

Microdialysis measurements demonstrate a shift to nonoxidative glucose metabolism in rat pancreatic islets transplanted beneath the renal capsule.

BACKGROUND: We aimed to use microdialysis to assess, for the first time, the internal milieu of pancreatic islet grafts. METHODS: One month after transplantation, microdialysis probes were inserted into syngeneic rat islet transplants (500-700 islets) placed beneath the renal capsule of nondiabetic or diabetic recipients. The number of grafted islets was purposely chosen not to cure the diabetic recipients. RESULTS: During an intravenous glucose challenge, insulin concentrations increased in parallel in serum and in the graft interstitium of nondiabetic animals suggesting the existence of a functionally well-established vascularization. Diabetic recipients had both a lower serum and dialysate insulin concentration than normoglycemic animals. The lactate/pyruvate ratios were determined in the dialysates as a measure of the degree of anaerobic metabolism in the islet grafts. Lactate/pyruvate ratios were between 50 and 100 in grafts of both nondiabetic and diabetic recipients, and they almost doubled in response to the intravenous glucose challenge in the grafts of nondiabetic recipients. In comparison, lactate/pyruvate ratios were approximately 12 in the medium of cultured islets incubated at low glucose (5.6 mmol/L) or high glucose (16.7 mmol/L) concentrations. CONCLUSIONS: The microdialysis technique has proven to be a valuable tool for evaluating the internal environment of islet transplants. Moreover, the high lactate/pyruvate ratio suggests that islet grafts have an increased anaerobic glucose metabolism.

The effect of capsule composition in the reversal of hyperglycemia in diabetic mice transplanted with microencapsulated allogeneic islets.

The transplantation of microencapsulated islets may allow reversal of hyperglycemia in the absence of immunosuppression. Poly-L-lysine (PLL) on capsules may potentiate the fibrotic reaction against implanted capsules. The aims of this study were to investigate how the biocompatibility of such capsules affects their function in vivo and to compare their efficacy relative to naked islets after intraperitoneal transplantation to nude or immune competent mice. Alloxan-diabetic C57BL/6 wild-type or nude (nu/nu) mice were transplanted with naked BALB/c islets, empty capsules, or microencapsulated BALB/c islets. Three types of capsules were used, one containing a high guluronic acid (G) alginate and PLL, one with a high mannuronic acid (M) alginate and PLL, and one high M alginate capsule with no PLL. Hyperglycemia in nude mice was reversed after transplantation of naked islets or islets encapsulated in a capsule containing high M alginate. Nude mice transplanted with islets encapsulated in the high G capsules showed only a transient reversal of hyperglycemia. In an allogeneic system, naked BALB/c islets were rejected by day 10 after transplantation, whereas the islets encapsulated in high M capsules continued to function for at least a month. When PLL was excluded from the capsules, the grafts functioned for up to 8 weeks. Islets microencapsulated in high G alginate capsules fail to reverse hyperglycemia for more than a few days in nude mice. However, islets in high M alginate capsules can reverse hyperglycemia in nude and immune competent mice. Islets microencapsulated in PLL-free high M alginate capsules function for 8 weeks in immune competent mice.