Purpose: To compare angiograms, considered the gold standard for diagnostic imaging of peripheral arterial disease (PAD), to the corresponding histological sections of popliteal and tibial vessels obtained after amputation to determine if angiography fails to define atheroma burden in “normal appearing” arteries in patients with PAD. Methods: Between 2004 and 2006, 69 patients underwent amputation of a lower extremity for severe tissue loss, gangrene, or pedal sepsis precluding limb salvage. Popliteal and tibial vessels were harvested, perfusion-fixed, and analyzed histologically. Thirty-four of these patients had pre-amputation angiography during attempted salvage procedures. Angiograms with patent or minimally diseased vessel segments (n=19) were assessed for stenoses, diameter, and calcification by 3 vascular surgeons (n=72 evaluations). These results were compared to corresponding cross-sectional histological slides (n=66) in a blinded manner. Results: Angiograms performed prior to above-knee (n=9) or below-knee (n=10) amputation revealed 24 stenoses with a mean (±SD) diameter-reducing stenosis of 19.5%±15.2%. Corresponding histological cross sections revealed greater linear stenoses measured via boundaries of the internal elastic lamina (IEL stenosis, 28.9%±20.2%, p=0.003 versus angiography) or via boundaries of the external elastic membrane (vessel stenosis, 43.1%±15.2%, p<0.0001). Stenosis calculated by area methods (IEL area) were greater and measured 39.2%±24.2% (p<0.0001) and 60.9%±15.2% (vessel area, p<0.0001). Popliteal arteries had greater discrepancy in stenosis measurement than tibial arteries (18.5%±14.6% versus 34.9%±21.0%, p=0.0005). However, evaluations of tibial arteries for concentricity of plaque (44% versus 69%, p=0.08) and calcification grade (1.6 versus 2.2, p=0.002) by angiography were discordant with histological analyses. Measurement of arterial diameter by histology for popliteal arteries (6.2±0.9 mm) and tibial arteries (3.1±0.7 mm) was greater than angiographic diameter determination (p<0.001). Conclusion: Angiography provides information on luminal characteristics of peripheral arteries but severely underestimates the extent of atherosclerosis in patients with PAD even in “normal appearing” vessels.

New-onset AF with RVR in the noncardiac postoperative patient is associated with a high mortality (21%). Amiodarone is the most effective treatment for rate and rhythm control. Failure to establish rate and rhythm control was associated with cardiac comorbidities. These results will help to form future algorithms for the treatment of AF with RVR in the SICU.

Objective-The aim of this study was to determine if significant differences in plaque composition exist between the popliteal and tibial vessels in patients with severe peripheral arterial disease (PAD).Methods-Forty-four patients with PAD required either above knee (n=38), below knee (n=5) or through knee (n=1) amputation for pedal sepsis/gangrene. The fifty-one vessels (anterior tibial, n=9; posterior tibial, n=10; peroneal, n=3; popliteal, n=29) were obtained, and underwent intravascular ultrasound (IVUS) evaluation ex vivo within 24 hours of amputation. Sequential IVUS data were obtained at known intervals throughout the vessel length, and then analyzed with radiofrequency techniques for quantification of plaque composition, plaque volume, and total vessel volume. Plaque composition was categorized as fibrous, fibro-fatty, necrotic core, and dense calcium. Clinical data was obtained via review of electronic records at the time of amputation. Two-sided t-tests were performed to compare components within each plaque. Results are expressed as mean percentage ±SEM.Results-Tibial vessels had more dense calcium within these plaques than popliteal arteries (33.8 ±5.6% v. 10.6±1.9%, P<0.001).Consequently, distal vessels had less fibro-fatty and fibrous plaque than popliteal arteries (7.7±1.4% v. 13.1±1.2%, P<0.005; 42.4±4.7% v. 61.4±2.2%, P<0.001), respectively. Necrotic core plaque composition was found to be similar when comparing tibial verses popliteal arteries (16.1% vs. 14.9%, p = NS). Clinical factors including diabetes, hyperlipidemia and chronic renal insufficiency were not associated with plaque composition differences using a univariate analysis.Conclusions-As we progress distally in the arterial tree of patients with PAD, calcium plaque content increases with decreasing burden of fibro-fatty plaque. Clinical and demographic factors with the exception of smoking were not found to be associated with atherosclerotic plaque composition.

BackgroundRecent evidence suggests that drugs targeting Kv7 channels could be used to modulate vascular function and blood pressure. Here, we studied whether Kv7 channel inhibitors can be utilized to stabilize hemodynamics and reduce resuscitation fluid requirements after hemorrhagic shock.MethodsAnesthetized male Sprague-Dawley rats were instrumented with arterial and venous catheters for blood pressure monitoring, hemorrhage and fluid resuscitation. Series 1: Linopirdine (Kv7 channel blocker, 0.1–6 mg/kg) or retigabine (Kv7 channel activator, 0.1–12 mg/kg) were administered to normal animals. Series 2: Animals were hemorrhaged to a MAP of 25 mmHg for 30 min, followed by fluid resuscitation with normal saline (NS) to a MAP of 70 mmHg until t = 75 min. Animals were treated with single bolus injections of vehicle, linopirdine (1–6 mg/kg), XE-991 (structural analogue of linopirdine with higher potency for channel blockade, 1 mg/kg) prior to fluid resuscitation. Series 3: Animals were resuscitated with NS alone or NS supplemented with linopirdine (1.25–200 μg/mL). Data were analyzed with 2-way ANOVA/Bonferroni post-hoc testing.ResultsSeries 1: Linopirdine transiently (10–15 min) and dose-dependently increased MAP by up to 15%. Retigabine dose-dependently reduced MAP by up to 60%, which could be reverted with linopirdine. Series 2: Fluid requirements to maintain MAP at 70 mmHg were 65 ± 34 mL/kg with vehicle, and 57 ± 13 mL/kg, 22 ± 8 mL/kg and 22 ± 11 mL/kg with intravenous bolus injection of 1, 3 and 6 mg/kg linopirdine, respectively. XE-991 (1 mg/kg), reduced resuscitation requirements comparable to 3 mg/kg linopirdine.Series 3: When resuscitation was performed with linopirdine-supplemented normal saline (NS), fluid requirements to stabilize MAP were 73 ± 12 mL/kg with NS alone and 72 ± 24, 61 ± 20, 36 ± 9 and 31 ± 9 mL/kg with NS supplemented with 1.25, 6.25, 12.5 and 200 μg/mL linopirdine, respectively.ConclusionsOur data suggest that Kv7 channel blockers could be used to stabilize blood pressure and reduce fluid resuscitation requirements after hemorrhagic shock.

Activation of C-X-C motif chemokine receptor 4 (CXCR4) has been reported to result in lung protective effects in various experimental models. The effects of pharmacological CXCR4 modulation on the development of acute respiratory distress syndrome (ARDS) after lung injury, however, are unknown. Thus, we studied whether blockade and activation of CXCR4 influences development of ARDS in a unilateral lung ischaemia-reperfusion injury rat model. Anaesthetized, mechanically ventilated animals underwent right lung ischaemia (series 1, 30 minutes; series 2, 60 minutes) followed by reperfusion for 300 minutes. In series 1, animals were treated with vehicle or 0.7 μmol/kg of AMD3100 (CXCR4 antagonist) and in series 2 with vehicle, 0.7 or 3.5 μmol/kg ubiquitin (non-cognate CXCR4 agonist) within 5 minutes of reperfusion. AMD3100 significantly reduced PaO /FiO ratios, converted mild ARDS with vehicle treatment into moderate ARDS (PaO /FiO ratio<200) and increased histological lung injury. Ubiquitin dose-dependently increased PaO /FiO ratios, converted moderate-to-severe into mild-to-moderate ARDS and reduced protein content of bronchoalveolar lavage fluid (BALF). Measurements of cytokine levels (TNFα, IL-6, IL-10) in lung homogenates and BALF showed that AMD3100 reduced IL-10 levels in homogenates from post-ischaemic lungs, whereas ubiquitin dose-dependently increased IL-10 levels in BALF from post-ischaemic lungs. Our findings establish a cause-effect relationship for the effects of pharmacological CXCR4 modulation on the development of ARDS after lung ischaemia-reperfusion injury. These data further suggest CXCR4 as a new drug target to reduce the incidence and attenuate the severity of ARDS after lung injury.

Background Recent evidence suggests transient postoperative atrial fibrillation leads to future cardiovascular events, even in noncardiac surgery. The long-term effects of postoperative atrial fibrillation in gastrectomy patients are unknown. Methods The Healthcare Cost and Utilization Project State Inpatient Databases identified patients undergoing gastrectomy for malignancy between 2007 and 2010. Patients were matched by propensity scores based on various factors. Adjusted Kaplan-Meier and Cox proportional hazards models assessed the effect of postoperative atrial fibrillation on cardiovascular events. Results A higher incidence of cardiovascular events occurred over the 1st year in patients who developed postoperative atrial fibrillation. Cox proportional hazards regression confirmed an increased risk of cardiovascular events in postoperative atrial fibrillation patients. Conclusions Our results demonstrate that patients undergoing gastrectomy for malignancy who develop postoperative atrial fibrillation are at increased risk of cardiovascular events within 1 year. Physicians should be vigilant in assessing postoperative atrial fibrillation, given the increased risk of cardiovascular morbidity.

Recently, we demonstrated that Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements in short-term rat models of haemorrhagic shock. The aim of the present study was to further delineate the therapeutic potential and side effect profile of the Kv7 channel blocker linopirdine in various rat models of severe haemorrhagic shock over clinically relevant time periods. Intravenous administration of linopirdine, either before (1 or 3 mg/kg) or after (3 mg/kg) a 40% blood volume haemorrhage, did not affect blood pressure and survival in lethal haemorrhage models without fluid resuscitation. A single bolus of linopirdine (3 mg/kg) at the beginning of fluid resuscitation after haemorrhagic shock transiently reduced early fluid requirements in spontaneously breathing animals that were resuscitated for 3.5 hours. When mechanically ventilated rats were resuscitated after haemorrhagic shock with normal saline (NS) or with linopirdine-supplemented (10, 25 or 50 μg/mL) NS for 4.5 hours, linopirdine significantly and dose-dependently reduced fluid requirements by 14%, 45% and 55%, respectively. Lung and colon wet/dry weight ratios were reduced with linopirdine (25/50 μg/mL). There was no evidence for toxicity or adverse effects based on measurements of routine laboratory parameters and inflammation markers in plasma and tissue homogenates. Our findings support the concept that linopirdine-supplementation of resuscitation fluids is a safe and effective approach to reduce fluid requirements and tissue oedema formation during resuscitation from haemorrhagic shock.

ImportanceThe number of older patients (80 years and older) diagnosed with locally advanced rectal cancer (LARC) is expected to increase. Although current guidelines recommend neoadjuvant chemoradiation therapy (NACRT) followed by resection, little is known about management and outcomes in this older population.ObjectiveTo assess the trends in management of older patients diagnosed with LARC who had a surgical resection.Design, Setting, and ParticipantsPatients 80 years and older who had a surgical resection for LARC were identified in the 2004-2016 National Cancer Database. Patients were grouped based on therapy sequence: (1) surgery followed by adjuvant therapy (AT), ie, chemotherapy or radiation; (2) surgery alone; or (3) NACRT followed by surgical resection. Data were analyzed in May 2021.ExposuresNACRT followed by surgery, and surgery with or without AT.Main Outcomes and MeasuresOverall survival (OS) was assessed using Kaplan-Meier analyses with inverse probability of treatment weighting (IPTW) and Cox proportional hazards regression were performed to examine the association of NACRT with the risk of death.ResultsOf 3868 patients with LARC who underwent surgical resection, 2042 (52.8%) were male, and the mean (SD) age was 83.4 (3.0) years. A total of 2273 (58.8%) received NACRT followed by surgical resection. Factors independently associated with NACRT were more recent diagnosis, age 80 to 85 years (vs 86 years and older), fewer comorbidities, larger tumors, and node-positive disease. The Kaplan-Meier analyses with IPTW showed that 3-year and 5-year OS for NACRT (3-year: 68.9%; 95% CI, 67.0-70.8; 5-year: 51.1%; 95% CI, 49.0-53.4) vs surgery with AT (3-year: 64.4%; 95% CI, 59.0-70.2; 5-year: 43.0%; 95% CI, 37.4-49.5) vs surgery alone (3-year: 55.8%; 95% CI, 52.0-60.0; 5-year: 34.7%; 95% CI, 30.8-39.0) was significantly different (P &amp;lt; .001). After adjusting for confounders, patients who received NACRT were more likely to undergo an R0 resection (adjusted odds ratio, 2.16; 95% CI, 1.62-2.88), which independently improved OS (P &amp;lt; .001). Moreover, receipt of NACRT was independently associated with a 25% decreased risk of death (adjusted hazard ratio, 0.75; 95% CI, 0.69-0.82) compared with alternative treatment sequences.Conclusions and RelevanceApproximately 40% of older patients with LARC did not receive the current standard of care. In this cohort, NACRT was associated with a higher likelihood of an R0 resection and improved OS. Clinicians should advocate for receipt of NACRT in older patients with LARC.