Percutaneous Microwave Ablation versus Cryoablation for Small Renal Masses (≤4 cm): 12-Year Experience at a Single Center.

PURPOSE: To determine whether microwave ablation (MWA) has equivalent outcomes to those of cryoablation (CA) in terms of technical success, adverse events, local tumor recurrence, and survival in adult patients with solid enhancing renal masses ≤4 cm. MATERIALS AND METHODS: A retrospective review was performed of 279 small renal masses (≤4 cm) in 257 patients (median age, 71 years; range, 40-92 years) treated with either CA (n = 191) or MWA (n = 88) between January 2008 and December 2020 at a single high-volume institution. Evaluations of adverse events, treatment effectiveness, and therapeutic outcomes were conducted for both MWA and CA. Disease-free, metastatic-free, and cancer-specific survival rates were tabulated. The estimated glomerular filtration rate was employed to examine treatment-related alterations in renal function. RESULTS: No difference in patient age (P = .99) or sex (P = .06) was observed between the MWA and CA groups. Cryoablated lesions were larger (P < .01) and of greater complexity (P = .03). The technical success rate for MWA was 100%, whereas 1 of 191 cryoablated lesions required retreatment for residual tumor. There was no impact on renal function after CA (P = .76) or MWA (P = .49). Secondary analysis using propensity score matching demonstrated no significant differences in local recurrence rates (P = .39), adverse event rates (P = .20), cancer-free survival (P = .76), or overall survival (P = .19) when comparing matched cohorts of patients who underwent MWA and CA. CONCLUSIONS: High technical success and local disease control were achieved for both MWA and CA. Cancer-specific survival was equivalent. Higher adverse event rates after CA may reflect the tendency to treat larger, more complex lesions with CA.

Clinical translation of abdominal histotripsy: a review of preclinical studies in large animal models.

Histotripsy is an emerging noninvasive, non-thermal, and non-ionizing focused ultrasound (US) therapy that can be used to destroy targeted tissue. Histotripsy has evolved from early laboratory prototypes to clinical systems which have been comprehensively evaluated in the preclinical environment to ensure safe translation to human use. This review summarizes the observations and results from preclinical histotripsy studies in the liver, kidney, and pancreas. Key findings from these studies include the ability to make a clinically relevant treatment zone in each organ with maintained collagenous architecture, potentially allowing treatments in areas not currently amenable to thermal ablation. Treatments across organ capsules have proven safe, including in anticoagulated models which may expand patients eligible for treatment or eliminate the risk associated with taking patients off anti-coagulation. Treatment zones are well-defined with imaging and rapidly resorb, which may allow improved evaluation of treatment zones for residual or recurrent tumor. Understanding the effects of histotripsy in animal models will help inform physicians adopting histotripsy for human clinical use.

ACR Appropriateness Criteria® Management of Vertebral Compression Fractures: 2022 Update.

Vertebral compression fractures (VCFs) can have a variety of etiologies, including trauma, osteoporosis, or neoplastic infiltration. Osteoporosis related fractures are the most common cause of VCFs and have a high prevalence among all postmenopausal women with increasing incidence in similarly aged men. Trauma is the most common etiology in those >50 years of age. However, many cancers, such as breast, prostate, thyroid, and lung, have a propensity to metastasize to bone, which can lead to malignant VCFs. Indeed, the spine is third most common site of metastases after lung and liver. In addition, primary tumors of bone and lymphoproliferative diseases such as lymphoma and multiple myeloma can be the cause of malignant VCFs. Although patient clinical history could help raising suspicion for a particular disorder, the characterization of VCFs is usually referred to diagnostic imaging. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Thoracoabdominal Aortic Aneurysm or Dissection: Treatment Planning and Follow-Up.

As the incidence of thoracoabdominal aortic pathology (aneurysm and dissection) rises and the complexity of endovascular and surgical treatment options increases, imaging follow-up of patients remains crucial. Patients with thoracoabdominal aortic pathology without intervention should be monitored carefully for changes in aortic size or morphology that could portend rupture or other complication. Patients who are post endovascular or open surgical aortic repair should undergo follow-up imaging to evaluate for complications, endoleak, or recurrent pathology. Considering the quality of diagnostic data, CT angiography and MR angiography are the preferred imaging modalities for follow-up of thoracoabdominal aortic pathology for most patients. The extent of thoracoabdominal aortic pathology and its potential complications involve multiple regions of the body requiring imaging of the chest, abdomen, and pelvis in most patients. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Vertebral Body Bone Ablation with and without a Saline-Infused System in a Porcine Model.

The purpose of this study was to evaluate the effect of bone radiofrequency (RF) ablation in the spine with and without controlled saline infusion. RF ablation with and without controlled saline infusion was performed in the vertebral bodies of 2 swine with real-time temperature and impedance recordings. Histology and magnetic resonance (MR) imaging results were reviewed to evaluate the ablation zone size, breach of spinal canal, and damage to the spinal cord and nerves. There was no difference in maximum and mean temperatures between controlled saline and noninfusion groups. The impedance and power output were not significantly different between the groups. MR imaging and histopathology demonstrated ablation zones confined within the vertebral bodies. Ablation zone size correlated on MR imaging and histopathology by groups. No ablation effect, breach of posterior cortex, spinal cord injury, or nerve or ganglion injury was observed at any level using MR imaging or histology. Controlled saline infusion does not appear to impact bone RF ablation and, specifically, does not increase the ablation zone size.

Role of Antiplatelet Therapy in Hemodialysis Arteriovenous Graft Secondary Patency Following Successful Percutaneous Thrombectomy.

PURPOSE: The purpose of this study was to elicit the relationship of antiplatelet therapy (AP) in maintaining arteriovenous graft (AVG) patency after successful percutaneous pharmacomechanical thrombectomy ("declot"). MATERIALS AND METHODS: This was an institutional review board-approved retrospective review of AVG declot procedures between July 2019 and August 2020. AVG characteristics, bleeding complications, anticoagulation and antiplatelet medication regimens, and thrombosis free survival were evaluated. Recurrent time-to-event analysis was performed using a Prentice-Williams-Peterson Gap time model was performed to evaluate AVG thrombosis free survival. RESULTS: A total of 109 declots were technically successful and performed in 63 individual patients. The majority of procedures were performed in upper arm grafts (71%, n = 45). Dual antiplatelet (DAPT) was prescribed after 52 declots (48%), single antiplatelet was prescribed after 36 declots (33%), and anticoagulation was prescribed after 31 declots (28%). Median thrombosis free survival was 37 days (range 1-412 days) in the no antiplatelet group, 84 days (range 1-427 days) in the single antiplatelet group, and 93 days (range 3-407 days) in the DAPT group. Anti-platelet medications trended towards protective of AVG thrombosis in multivariate analysis (hazard ratio 0.84, 95% confidence interval 0.60-1.19); however, this did not reach statistical significance (P = 0.33). A total of 4 major and 5 minor bleeding events occurred. CONCLUSION: The results of this study support further evaluation of AP therapy in preventing secondary rethrombosis of dialysis AVG.

ACR Appropriateness Criteria® Management of Liver Cancer: 2022 Update.

The treatment and management of hepatic malignancies can be complex because it encompasses a variety of primary and metastatic malignancies and an assortment of local and systemic treatment options. When to use each of these treatments is critical to ensure the most appropriate care for patients. Interventional radiologists have a key role to play in the delivery of a variety of liver directed treatments including percutaneous ablation, transarterial embolization with bland embolic particles alone, transarterial chemoembolization (TACE) with injection of a chemotherapeutic emulsion, and transarterial radioembolization (TARE). Based on 9 clinical variants, the appropriateness of each treatment is described in this document. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Hepatic Microwave Ablation in Challenging Locations.

In recent years, there has been increased utilization of microwave ablation (MWA) in the treatment of soft tissue tumors. MWA has several theoretical advantages over radiofrequency ablation (RFA) by achieving a more rapid and sustained heating of tissues, increased efficacy in tissues with poor thermal conductivity, and less susceptibility to heat sink effect. While its greater power output has led to appropriate caution when applying this energy to soft tissue tumors, many commonly held beliefs regarding contraindications to MWA are unsupported by data and have been passed along based on experience with RFA. The goal of this article is to review the use of MWA in challenging clinical situations along with the existing evidence for its use.

Robotically-Assisted Sonic Therapy for Renal Ablation in a Live Porcine Model: Initial Preclinical Results.

PURPOSE: To demonstrate the feasibility of Robotically Assisted Sonic Therapy (RAST)-a noninvasive and nonthermal focused ultrasound therapy based on histotripsy-for renal ablation in a live porcine model. MATERIALS AND METHODS: RAST ablations (n = 11) were performed in 7 female swine: 3 evaluated at 1 week (acute) and 4 evaluated at 4 weeks (chronic). Treatment groups were acute bilateral (3 swine, 6 ablations with immediate computed tomography [CT] and sacrifice); chronic single kidney (3 swine, 3 ablations; CT at day 0, week 1, and week 4 after treatment, followed by sacrifice); and chronic bilateral (1 swine, 2 ablations). Treatments were performed using a prototype system (VortxRx; HistoSonics, Inc) and targeted a 2.5-cm-diameter sphere in the lower pole of each kidney, intentionally including the central collecting system. RESULTS: Mean treatment time was 26.4 minutes. Ablations had a mean diameter of 2.4 ± 0.3 cm, volume of 8.5 ± 2.4 cm3, and sphericity index of 1.00. Median ablation volume decreased by 96.1% over 4 weeks. Histology demonstrated complete lysis with residual blood products inside the ablation zone. Temporary collecting system obstruction by thrombus was observed in 4/11 kidneys (2 acute and 2 chronic) and resolved by 1 week. There were no urinary leaks, main vessel thromboses, or adjacent organ injuries on imaging or necropsy. CONCLUSIONS: In this normal porcine model, renal RAST demonstrated complete histologic destruction of the target renal tissue while sparing the urothelium.

Robotically Assisted Sonic Therapy (RAST) for Noninvasive Hepatic Ablation in a Porcine Model: Mitigation of Body Wall Damage with a Modified Pulse Sequence.

PURPOSE: Robotically assisted sonic therapy (RAST) is a nonthermal, noninvasive ablation method based on histotripsy. Prior animal studies have demonstrated the ability to create hepatic ablation zones at the focal point of an ultrasound therapy transducer; however, these treatments resulted in thermal damage to the body wall within the path of ultrasound energy delivery. The purpose of this study was to evaluate the efficacy and safety of a pulse sequence intended to mitigate prefocal body wall injury. MATERIALS AND METHODS: Healthy swine (n = 6) underwent hepatic RAST (VortxRx software version 1.0.1.3, HistoSonics, Ann Arbor MI) in the right hepatic lobe. A 3.0 cm spherical ablation zone was prescribed for each. Following treatment, animals underwent MRI which was utilized for ablation zone measurement, evaluation of prefocal injury, and assessment of complications. Each animal was euthanized, underwent necropsy, and the tissue was processed for histopathologic analysis of the ablation zone and any other sites concerning for injury. RESULTS: No prefocal injury was identified by MRI or necropsy in the body wall or tissues overlying the liver. Ablation zones demonstrated uniform cell destruction, were nearly spherical (sphericity index = 0.988), and corresponded closely to the prescribed size (3.0 × 3.1 × 3.4 cm, p = 0.70, 0.36, and 0.01, respectively). Ablation zones were associated with portal vein (n = 3, one occlusive) and hepatic vein thrombosis (n = 4, one occlusive); however, bile ducts remained patent within ablation zones (n = 2). CONCLUSIONS: Hepatic RAST performed with a modified ultrasound pulse sequence in a porcine model can mitigate prefocal body wall injuries while maintaining treatment efficacy. Further study of hepatic RAST appears warranted, particularly in tumor models.

Intranodal Glue Embolization for the Management of Postsurgical Groin Lymphocele and Lymphorrhea.

This report describes intranodal lymphatic embolization for treatment of groin lymphatic leaks following surgery or percutaneous vascular interventions. In 10 consecutive patients with groin lymphatic leak between 2015 and 2017, lymphangiography with embolization was performed by intranodal injection with dilute N-butyl cyanoacrylate (NBCA). Mean volume of dilute NBCA (1:3 with ethiodized oil) injected was 1 mL. Clinical success rate was 80%. Median time to resolution was 7 days. Intranodal lymphatic embolization for treatment of groin lymphatic leaks is a safe and effective treatment alternative to surgery resulting in a rapid time to resolution.

Combination transarterial chemoembolization and microwave ablation improves local tumor control for 3- to 5-cm hepatocellular carcinoma when compared with transarterial chemoembolization alone.

PURPOSE: To compare transarterial chemoembolization (TACE) monotherapy to combination TACE and microwave ablation (MWA) for local control of 3- to 5-cm hepatocellular carcinoma (HCC). METHODS: Patients with HCC between 3 and 5 cm treated with TACE monotherapy or combination TACE + MWA at a single institution between 2007 and 2016 were retrospectively reviewed. Twenty-four HCCs (median diameter 3.8 cm) in 16 patients (13 males; median age 64 years) were treated using TACE monotherapy. Combination TACE + MWA was used to treat 23 HCCs (median diameter 4.2 cm) in 22 patients (18 males; median age 61 years). Microwave ablation was performed at a target time of two weeks following TACE. Individual tumors were followed by serial contrast-enhanced CT or MR. Response to treatment was evaluated on a tumor-by-tumor basis using mRECIST criteria with the primary outcome being local tumor progression (LTP). Data were analyzed using Fisher's exact test for categorical variables and Wilcoxon rank sum test for continuous variables. Time to LTP was estimated with the Kaplan-Meier method. RESULTS: Relative to TACE monotherapy, TACE + MWA provided a trend toward both a lower rate of LTP (34.8% vs. 62.5%, p = 0.11) and a higher complete response rate (65.2% vs. 37.5%; p = 0.12). Time to LTP (22.3 months vs. 4.2 months; p = 0.001) was significantly longer in the TACE + MWA group compared to TACE monotherapy. CONCLUSIONS: Combination therapy with TACE and microwave ablation improves local control and increases time to LTP for 3-5 cm HCC.

Robotically Assisted Sonic Therapy as a Noninvasive Nonthermal Ablation Modality: Proof of Concept in a Porcine Liver Model.

Purpose To determine the feasibility of creating a clinically relevant hepatic ablation (ie, an ablation zone capable of treating a 2-cm liver tumor) by using robotically assisted sonic therapy (RAST), a noninvasive and nonthermal focused ultrasound therapy based on histotripsy. Materials and Methods This study was approved by the institutional animal use and care committee. Ten female pigs were treated with RAST in a single session with a prescribed 3-cm spherical treatment region and immediately underwent abdominal magnetic resonance (MR) imaging. Three pigs (acute group) were sacrificed immediately following MR imaging. Seven pigs (chronic group) were survived for approximately 4 weeks and were reimaged with MR imaging immediately before sacrifice. Animals underwent necropsy and harvesting of the liver for histologic evaluation of the ablation zone. RAST ablations were performed with a 700-kHz therapy transducer. Student t tests were performed to compare prescribed versus achieved ablation diameter, difference of sphericity from 1, and change in ablation zone volume from acute to chronic imaging. Results Ablation zones had a sphericity index of 0.99 ± 0.01 (standard deviation) (P < .001 vs sphericity index of 1). Anteroposterior and transverse dimensions were not significantly different from prescribed (3.4 ± 0.7; P = .08 and 3.2 ± 0.8; P = .29, respectively). The craniocaudal dimension was significantly larger than prescribed (3.8 ± 1.1; P = .04), likely because of respiratory motion. The central ablation zone demonstrated complete cell destruction and a zone of partial necrosis. A fibrous capsule surrounded the ablation zone by 4 weeks. On 4-week follow-up images, ablation zone volumes decreased by 64% (P < .001). Conclusion RAST is capable of producing clinically relevant ablation zones in a noninvasive manner in a porcine model. © RSNA, 2018.

Microwave Ablation of the Lung in a Porcine Model: Vessel Diameter Predicts Pulmonary Artery Occlusion.

PURPOSE: To determine the size of pulmonary artery (PA) at risk for occlusion during percutaneous microwave ablation and to assess the effect of vessel diameter, number, and patency, on ablation zone volume. MATERIALS AND METHODS: Computed tomography (CT) fluoroscopy-guided percutaneous microwave ablations were performed in 8 pigs under general anesthesia. All ablations were performed at 65 W for 5 min with a single 17-gauge antenna positioned in the central third of the lungs. A CT pulmonary angiogram was performed immediately after the ablations. The maximum diameter, number and patency of PA branches within each ablation zone were recorded. Ablation volumes were measured at gross dissection and with CT. Student's t test was used to compare ablation zone volumes among groups. RESULTS: Twenty-one pulmonary ablations were performed. Six of the ablation zones (29%) contained at least 1 occluded PA branch. The mean diameter of the occluded PA branches in the ablation zones (2.4 mm; range, 2.0-2.8 mm) was significantly smaller than non-occluded PA branches (3.7 mm; range: 2.1-6.9 mm; p = 0.009). No PA branches ≥3 mm in size were occluded. There was no significant difference in volume of gross ablation zones that contained occluded versus non-occluded PAs (p = 0.42), one versus multiple PAs (p = 0.71), or PAs <3 mm versus ≥3 mm in diameter (p = 0.44). CONCLUSIONS: PAs ≥3 mm in size have a low risk for iatrogenic occlusion during percutaneous microwave ablation. The presence of multiple adjacent PA branches, an occluded PA branch, and a vessel diameter ≥3 mm within the ablation zone had no observed effect on ablation zone volume.

Safety and Efficacy of Percutaneous Microwave Hepatic Ablation Near the Heart.

PURPOSE: To evaluate safety and efficacy of percutaneous hepatic microwave (MW) ablation performed near the heart. MATERIALS AND METHODS: This study reviewed 118 consecutive peripheral (ablation zone margins within 5 mm of liver capsule) percutaneous MW hepatic ablations performed between June 2010 and August 2015. Ablation zones of 27 tumors (22.8%) extended to ≤ 5 mm from myocardium, and these ablations comprised the study group; the remaining ablations formed the control group. The study cohort included 14 men and 10 women (mean age, 59 y) with 16 hepatocellular carcinomas, 9 metastases, and 2 hemangiomas. Periprocedural imaging was used to evaluate tumor size and distance from the heart, ablation zone size, and complications. Mean tumor size and distance to myocardium were 2.6 cm ± 1.7 and 1.1 cm ± 1.1, respectively. The electronic medical record was used to retrospectively assess local tumor progression (LTP) and electrocardiogram and hemodynamic alterations during and after ablation. Statistical analysis was performed with Fisher exact test and t test. RESULTS: Median follow-up was 13.6 months (range, 1.2-38.7 months). No arrhythmias occurred during or after ablation in the follow-up period (0/27). There was no difference between groups in frequency of alterations in periprocedural blood pressure (25.9% vs 29.6%, p=0.81) or heart rate (18.5% vs 24.2%, P = .61) or rate of LTP (12.0% vs 10.8%, P = 1.0). CONCLUSIONS: Percutaneous MW ablation near the heart may be safe and effective, without increased risk of cardiac complications and with similar rates of LTP, compared with a control group of peripheral liver ablations.

Radiofrequency and microwave ablation of subcapsular hepatocellular carcinoma accessed by direct puncture: Safety and efficacy.

OBJECTIVES: Direct puncture of subcapsular hepatocellular carcinoma (HCC) for tumor ablation has been considered high risk due to a perceived increased incidence of hemorrhage or tumor seeding. The purpose of this retrospective multicenter study was to identify the rate of tumor seeding, hemorrhage and local tumor progression (LTP) associated with direct puncture radiofrequency (RF) and microwave (MW) ablation of subcapsular HCC. METHODS: A multicenter, retrospective review of direct-puncture RF and MW performed on subcapsular HCC was conducted. Complications and local tumor progression were documented. Data was analyzed using Kaplan-Meier and log-rank tests. RESULTS: The study group consisted of 60 cirrhotic patients (M/F=43/17; mean age 69.6 years) with 67 subcapsular HCC (mean diameter 2.3 cm ± 1.0 cm) that were directly punctured for RF (n=40) or MW (n=27) under ultrasound (US) guidance. The mean follow-up period was 30.8 months. There were no hemorrhagic complications. The overall LTP rate was 13.4%. There was one case of tumor tract seeding in a patient who had undergone a percutaneous biopsy two weeks prior to RF. CONCLUSIONS: Thermal ablation of HCC by direct puncture appears safe and effective. There were no cases of intraperitoneal hemorrhage, and tumor seeding was seen in a single case in which a preceding percutaneous biopsy had been performed.

Microwave Ablation for the Treatment of Hepatic Adenomas.

Microwave (MW) ablation was used to treat 12 hepatocellular adenomas in six patients (five women and one man; mean age, 39.6 y). Mean treated tumor size was 2.7 cm ± 2.0. Tumor response was evaluated with serial cross-sectional imaging for a mean follow-up of 12.6 months ± 7.1. Primary treatment effectiveness and local tumor control were 100%. There were no instances of hemorrhage, malignant transformation, new hepatic tumors, or extrahepatic metastases. This early experience of treatment of hepatic adenomas by MW ablation demonstrates it to be a safe and feasible treatment modality at short-term follow-up. Continued investigation, including comparison with other treatment modalities, is warranted.

Microwave ablation of hepatic tumors abutting the diaphragm is safe and effective.

OBJECTIVE: The purpose of this study was to evaluate the incidence of clinically significant diaphragmatic injuries and local tumor progression after microwave ablation of hepatic tumors abutting the diaphragm. MATERIALS AND METHODS: This retrospective study included 55 peripheral hepatic tumors abutting the diaphragm treated by microwave ablation versus a control group of 15 centrally located tumors. Treated tumors were further subdivided according to the use of artificial ascites (fluid vs no fluid) and whether instilled fluid achieved displacement of the liver surface away from the diaphragm (displaced vs nondisplaced). Measurements of tumor size, distance to the diaphragm, ablation zone size, displacement distance, length of the ablation zone along the liver capsule, diaphragm thickness, diaphragmatic hernia, and local tumor progression were made on pre- and postablation CT and MRI. The electronic medical record was reviewed for patient self-reported pain scores and other symptoms. Data were analyzed by use of the Kruskal-Wallis and Fisher exact tests. RESULTS: There were no cases of diaphragmatic hernia in peripheral or central tumors. Postablation diaphragm thickness was higher in peripheral hepatic tumors than in control tumors. Peripheral tumors had an overall higher incidence of postprocedure shoulder pain (18% vs 0%) and local tumor progression (5.5% vs 0%) compared with control tumors, but these differences did not achieve statistical significance (p = 0.2 and p = 1, respectively). CONCLUSION: Our study shows that microwave ablation of peridiaphragmatic hepatic tumors is safe, without incidence of diaphragmatic hernia, and can be performed with a low rate of local tumor progression.

Protein kinase C upregulates intercellular adhesion molecule-1 and leukocyte-endothelium interactions in hyperglycemia via activation of endothelial expressed calpain.

OBJECTIVE: We tested the hypothesis of a role for the calcium-dependent protease calpain in the endothelial dysfunction induced by hyperglycemic activation of protein kinase C (PKC). METHODS AND RESULTS: Chronic hyperglycemia with insulin deficiency (type 1 diabetes) was induced in rats by streptozotocin. Total PKC and calpain activities, along with activity and expression level of the 2 endothelial-expressed calpains isoforms, µ- and m-calpain, were measured in vascular tissue homogenates by enzymatic assays and Western blot analysis, respectively. Intravital microscopy was used to measure and correlate leukocyte-endothelium interactions with calpain activity in the microcirculation. Expression levels and endothelial localization of the inflammatory adhesion molecule intercellular adhesion molecule-1 were studied by Western blot analysis and immunofluorescence, respectively. The mechanistic role of hyperglycemia alone in the process of PKC-induced calpain activation and actions was also investigated. We found that in the type 1 diabetic vasculature, PKC selectively upregulates the activity of the µ-calpain isoform. Mechanistic studies confirmed a role for hyperglycemia and PKCß in this process. The functional implications of PKC-induced calpain activation were upregulation of endothelial expressed intercellular adhesion molecule-1 and leukocyte-endothelium interactions. CONCLUSIONS: Our results uncover the role of µ-calpain in the endothelial dysfunction of PKC. Calpain may represent a novel molecular target for the treatment of PKC-associated diabetic vascular disease.