Modeling risk of coronary obstruction during transcatheter aortic valve replacement.

OBJECTIVE: In this study we aimed to evaluate risk of coronary obstruction during transcatheter aortic valve replacement and develop improved criteria based on computational modeling. METHODS: Patient specific 3-dimensional models were constructed and validated for 28 patients out of 600 patients who were flagged as high risk for coronary obstruction (defined as meeting coronary ostium height < 14 mm and/or sinus of Valsalva diameter [SOVd] < 30 mm). The models consisted finite element analysis to predict the post- transcatheter aortic valve replacement native cusp apposition relative to the coronary ostium and were validated in vitro. The distance from cusp to coronary ostium (DLC) was derived from the 3-dimensional models and indexed with the coronary artery diameter to yield a fractional obstruction measure (DLC/d). RESULTS: Twenty-two out of 28 high-risk patients successfully underwent transcatheter aortic valve replacement without coronary obstruction and 6 did not. DLC/d between the 2 groups was significantly different (P < .00078), whereas neither coronary ostium height nor SOVd were significantly different (P > .32). A cutoff of DLC/d < 0.7 was predictive with 100% sensitivity and 95.7% specificity. The optimal sensitivity and specificity of coronary ostium height and SOVd in this high-risk group was only 60% and 40%, respectively, for cutoff coronary ostium height of 10 mm and SOVd of 30.5 mm. CONCLUSIONS: Three-dimensional modeling has the potential to enable more patients to be safely treated with transcatheter aortic valve replacement who have a low-lying coronary ostium or small SOVd. DLC/d is more predictive of obstruction than coronary ostium height and SOVd.

The beneficial effects of dichloroacetate in acute limb ischemia.

OBJECTIVE: The purpose of this study was to determine the effects of dichloroacetate (DCA) in acute limb ischemia. METHODS: Anterior tibialis muscle samples of DCA-treated and control animals (Sprague Dawley rats) were collected and assayed for pyruvate dehydrogenase activity, lactate, adenosine triphosphate, and creatine phosphate using spectrophotometry. A physiograph was used to measure fatigability. In an ischemia/reperfusion model using New Zealand rabbits, serum lactate and end-tidal CO2 were compared. Skeletal muscle was evaluated microscopically for muscle necrosis. RESULTS: DCA administration resulted in a 50% increase in pyruvate dehydrogenase activity (p = 0.025), reversal of the increase in lactate levels seen during acute limb ischemia (p = 0.41), a significant increase in the time to skeletal muscle fatigue (p = 0.05), a trend toward increased adenosine triphosphate (p = 0.07), and a significant increase in creatine phosphate (p < 0.02). DCA treatment resulted in a decrease in serum lactate (p < 0.01) and end-tidal CO2 (p < 0.001). CONCLUSION: In acute limb ischemia and reperfusion, DCA administration provides metabolic protection to skeletal muscle.

The effects of dichloroacetate in a rabbit model of acute hind-limb ischemia and reperfusion.

BACKGROUND: Dichloroacetate (DCA) is a drug that allows pyruvate dehydrogenase to remain active under anaerobic conditions by inhibiting the inactivating enzyme, pyruvate dehydrogenase kinase. We hypothesize that the administration of DCA during acute limb ischemia may have a beneficial effect by reducing the severity of anaerobic metabolism and lessening the irreversible injury. STUDY DESIGN: We studied a rabbit model using unilateral ligation of the iliac artery or femoral artery to evaluate two degrees of ischemia. After 2 hours of hind-limb ischemia, the animals were administered IV DCA (15 mg/kg) or an equivalent volume of saline. RESULTS: Higher serum lactate levels were seen after high compared to low ligation in control animals consistent with more severe ischemia. DCA treatment significantly reduced serum lactate levels after both high and low ligation. Similarly, the rise in percentage end-tidal CO(2) after reperfusion was less after DCA. All animals regained hind-limb function after the procedure, but ischemia or reperfusion resulted in appreciable muscle necrosis (> 10% area) in 50% of high- and 22% of low-ligation control animals. DCA treatment eliminated significant muscle necrosis in 100% of high-ligation animals. Muscle histology was similar in control and DCA-treated low-ligation animals. CONCLUSIONS: Treatment with DCA during acute arterial occlusion did significantly lower markers of anaerobic metabolism and reduced muscle necrosis in a rabbit model of acute hind-limb ischemia. DCA delivery through collateral blood flow may prolong the ischemia time interval before the onset of irreversible muscle injury and potential limb loss.

Dichloroacetate increases skeletal muscle pyruvate dehydrogenase activity during acute limb ischemia.

The purpose of this study was to evaluate the effects of dichloroacetate sodium (DCA), a drug that inactivates pyruvate dehydrogenase kinase (PDH-K), on pyruvate dehydrogenase (PDH) activity, lactate level, and function of skeletal muscle in an experimental model of acute limb ischemia. Thirty-two male Sprague-Dawley rats underwent right iliac artery ligation to produce hindlimb ischemia. After 2 hours of ischemia, 16 animals received intravenous DCA (15 mg/100 g body weight) and 16 control animals received an equivalent volume of normal saline. After an additional 1 hour of ischemia (total 3 hours) tibialis anterior muscle from the ischemic limb and contralateral nonischemic limb was excised, rapidly freeze-clamped with Wallenberg tongs cooled in liquid nitrogen, and stored at -70 degrees C. Muscles specimens were subsequently assayed for PDH activity and lactate level by use of spectrophotometric techniques. An additional 16 animals (DCA-treated, n = 8; control, n = 8) underwent ex-vivo gastrocnemius muscle fatigue testing with a 10 g tension preload after 3 hours of limb ischemia. In ischemic hind limbs, DCA treatment significantly (p = 0.025) increased PDH activity (19.6 +/-1.6 micromol/min/g dry weight) compared to controls (13.1 +/-1.3 micromol/min/g dry weight). DCA treatment did not increase (p = 0.13) skeletal muscle PDH activity in the nonischemic limbs (9.6 +/-1.1 micromol/min/g dry weight, controls; 13.2 +/-1.3 micromol/min/g dry weight, DCA group). In DCA-treated animals, hind limb ischemia resulted in no significant increase in muscle lactate levels compared to the nonischemic limb, while control animals demonstrated a significant (p = 0.005) elevation in lactate level in ischemic limbs compared to contralateral nonischemic limb. Ischemia induced a significant decrease in time to muscle fatigue in both DCA-treated and control animals (p = 0.002 and 0.001, respectively). Time to muscle fatigue in DCA-treated animals was increased compared to controls (2.6 +/-0.3 versus 2 +/-0.6 minutes; p < 0.05)in ischemic limbs but was not significantly different in nonischemic limbs (DCA = 3.3 +/-0.5 minutes; control = 3.1 +/-0.6 minutes). Treatment with DCA during acute limb ischemia reduced the depression of PDH activity and lactate level of skeletal muscle. Ischemic muscle function was also improved by DCA treatment. Further investigation of the potential beneficial effects of DCA treatment on muscle injury during ischemia and reperfusion is warranted.

Successful management of long-term general anesthesia in rabbits used as an animal model of human disease.

The rabbit represents a popular animal model for basic science research, but projects requiring anesthesia and endotracheal intubation represent a technical challenge because of the difficulty in accessing the animal's airway and sensitivity to common anesthetic agents. We hypothesized that transoral intubation under direct visualization with guidewire assistance would improve airway access success and reduce perioperative mortality in the rabbit. Of the 39 New Zealand White rabbits that had passive inhalation anesthesia and were intubated using wire-guided assistance under direct laryngeal visualization, 33 were intubated using a flexible wire after the rigid guide had resulted in airway injury in three of the first six rabbits. Animals were then maintained under general anesthesia during a 4- to 5-h procedure. At the completion of the procedure, animals were recovered from anesthesia and extubated. All 39 animals were successfully intubated, mostly on the first attempt. There were two animal deaths, both in the first six animals; one death was a direct result of laryngeal injury from the rigid wire guide initially used. One additional animal in the first six had pulmonary difficulty after an airway injury but recovered and was successfully used in the experiment. Two animals developed gastric distention during anesthesia, which was alleviated with placement of an orogastric tube without adverse sequelae. No animals developed problems with oxygenation during the experiment, but over half (52.8%) had end-tidal CO2 (ETCO2) above 45 mmHg at least once during the surgery, and 13 rabbits were above this level for longer than 1 h. An average of 18 min elapsed between withdrawal of anesthesia and the time when spontaneous respirations and chewing movements returned. Animals then could be safely extubated. There was no correlation between high perioperative ETCO2 and time to recovery from anesthesia (P = 0.18, r = 0.23).