Left Ventricular Assist Device Inflow Angle and Pump Positional Change Over Time Adverse Impact on Left Ventricular Assist Device Function.

BACKGROUND: This study investigates the impact of left ventricular assist device (LVAD) inflow cannula angulation, pump positional change over time, and the incidence of thrombotic pump dysfunction in a large cohort of HeartMate II (HM2) patients. METHODS: Patients (n = 326) who received primary HM2 LVAD between January 2008 and December 2013 at a single institution were retrospectively reviewed. Patients who underwent pump exchange (PE) for pump dysfunction, patients who had pump dysfunction (PD) but did not require pump exchange, and patients with normal LVAD pump dysfunction (NL) were compared. Pump positional change and angle of the inflow cannula with respect to the angle between inflow cannula and the LVAD body (IL angle) were measured from routine chest radiograph at postoperation, before discharge, and follow-up. Pump positional change was assessed based on pump positional differences between discharge and follow-up. Patients were also grouped by IL acute angulation (less than 65 degrees) and pump positional change. RESULTS: There were 21, 15, and 290 patients in the PE group, PD group, and NL group, respectively. There were significant differences in IL angle between PE and NL at all timepoints: postoperation (PD 63.6 ± 12.5, NL 70.6 ± 12.3; p = 0.018), before discharge (PD 64.4 ± 12.8, NL 69.5 ± 10.5; p = 0.039), and follow-up (PD 62.6 ± 14.2, NL 67.9 ± 11.2; p = 0.002). However, the IL angle was insignificant between PE and PD groups and between PD and NL groups. Sixty-seven percent of the PE group had pump positional change as opposed to 36% of the NL group (p = 0.019). Eighty-four of 101 patients with pump positional change and 75 of 91 patients with acute angulation at postoperation did not have pump dysfunction. CONCLUSIONS: Pump positional change may contribute to LVAD dysfunction or failure, but it does not entirely account for observed pump dysfunction or failure.

Does Tranexamic Acid Reduce Blood Loss and Transfusion Requirements Associated With the Periacetabular Osteotomy?

BACKGROUND: Tranexamic acid (TXA) has shown safety and efficacy in reducing blood loss associated with various surgical procedures. However, to our knowledge there are no studies evaluating the effect of TXA on blood loss and transfusion requirements associated with periacetabular osteotomy (PAO). QUESTIONS/PURPOSES: The main purpose of this study is to determine whether TXA reduces blood loss and transfusion use in patients undergoing PAO for symptomatic acetabular dysplasia. Our secondary purpose was to compare the frequency of symptomatic thromboembolic events between patients undergoing surgery with and without TXA. METHODS: A consecutive series of 100 periacetabular osteotomies performed by one surgeon was reviewed to compare the groups immediately before and after implementation of routine use of tranexamic acid (two retrospective cohorts). TXA dosing followed an established protocol with a standard dose of 1 g infused intravenously during 10 minutes before skin incision and an additional 1 g intravenously at wound closure. Outcome measures include total estimated blood loss perioperatively and transfusion requirements. Total estimated blood loss was calculated using a formula built from the National Surgical Quality Improvement Program data regarding surgical blood loss. RESULTS: The mean perioperative total estimated blood loss was less in the patients receiving TXA compared with blood loss in patients who did not receive TXA (706 mL versus 1021 mL; p<0.001; 95% CI, -495 to -134). Twenty-six (52%) of the 50 patients who did not receive TXA had postoperative blood transfusions compared with 15 (30%) of 50 who received TXA (odds ratio, 0.395; 95% CI, 0.174-0.899; p=0.0414). No symptomatic deep vein thromboses or symptomatic pulmonary emboli were identified in either group. CONCLUSIONS: TXA reduces estimated blood loss and the frequency of transfusions in patients undergoing PAO for treatment of symptomatic acetabular dysplasia. Future prospective studies should confirm our findings to determine whether patients undergoing PAO should receive routine perioperative TXA. LEVEL OF EVIDENCE: Level III, therapeutic study.

Relationship between mitochondrial matrix volume and cellular volume in response to stress and the role of ATP-sensitive potassium channel.

BACKGROUND: Cardiac myocytes demonstrate significant swelling and associated reduced contractility in response to stress that is prevented by the ATP-sensitive potassium channel opener, diazoxide (DZX) via an unknown mechanism. One proposed mechanism of cardioprotection is mitochondrial matrix swelling. To establish the relationship between mitochondrial and cellular volume during stress, this study examined the effect of DZX on mitochondrial volume. METHODS AND RESULTS: Isolated mouse mitochondria were exposed to the following solutions: Tyrode, isolation buffer, cardioplegia (CPG)±DZX±ATP-sensitive potassium channel inhibitor, 5-hydroxydecanoate, and metabolic inhibition (MI) ± DZX ± 5-hydroxydecanoate. Mitochondrial volume was measured. DZX resulted in significant mitochondrial swelling (P<0.0001 versus Tyrode). MI and CPG resulted in significant mitochondrial swelling compared with baseline volume. The addition of DZX did not alter the response of mitochondrial volume to CPG (P=0.912) but increased swelling in response to MI (P=0.036). The addition of 5-hydroxydecanoate to MI + DZX or CPG+DZX significantly reduced mitochondrial swelling (P<0.003 MI+DZX versus MI + DZX + 5HD; P<0.001 CPG+DZX versus CPG + DZX + 5HD). CONCLUSIONS: Both cellular and mitochondrial volume increased during exposure to MI and CPG. DZX did not alter mitochondrial volume during CPG; however, it was associated with an increase in mitochondrial volume during MI. 5-Hydroxydecanoate reduced mitochondrial volume during exposure to both stresses with DZX, supporting a role for a mitochondrial ATP-sensitive potassium channel in the mechanism of cardioprotection by DZX.

Cardioprotective mechanism of diazoxide involves the inhibition of succinate dehydrogenase.

BACKGROUND: The adenosine triphosphate-sensitive potassium (KATP) channel opener, diazoxide, preserves myocyte volume homeostasis and contractility during stress via an unknown mechanism. Pharmacologic overlap has been suggested between succinate dehydrogenase (SDH) activity and KATP channel modulators. Diazoxide may be cardioprotective due to the inhibition of SDH which may form a portion of the mitochondrial KATP channel. To determine the role of inhibition of SDH in diazoxide's cardioprotection, this study utilized glutathione to prevent the inhibition of SDH. METHODS: SDH activity was measured in isolated mitochondria exposed to succinate (control), malonate (inhibitor of succinate dehydrogenase), diazoxide, and varying concentrations of glutathione alone or in combination with diazoxide. Enzyme activity was measured by spectrophotometric analysis. To evaluate myocyte volume and contractility, cardiac myocytes were superfused with Tyrode's physiologic solution (Tyrode's) (20 minutes), followed by test solution (20 minutes), including Tyrode's, hyperkalemic cardioplegia (stress), cardioplegia + diazoxide, cardioplegia + diazoxide + glutathione, or glutathione alone; followed by Tyrode's (20 minutes). Myocyte volume and contractility were recorded using image grabbing software. RESULTS: Both malonate and diazoxide inhibited succinate dehydrogenase. Glutathione prevented the inhibition of succinate dehydrogenase by diazoxide in a dose-dependent manner. The addition of diazoxide prevented the detrimental myocyte swelling due to cardioplegia alone and this benefit was lost with the addition of glutathione. However, glutathione elicited an independent cardioprotective effect on myocyte contractility. CONCLUSIONS: The ability of diazoxide to provide beneficial myocyte homeostasis during stress involves the inhibition of succinate dehydrogenase, which may also involve the opening of a purported mitochondrial adenosine triphosphate sensitive potassium channel.

Inhibition of Succinate Dehydrogenase by Diazoxide Is Independent of the ATP-Sensitive Potassium Channel Subunit Sulfonylurea Type 1 Receptor.

BACKGROUND: Diazoxide maintains myocyte volume and contractility during stress via an unknown mechanism. The mechanism of action may involve an undefined (genotype unknown) mitochondrial ATP-sensitive potassium channel and is dependent on the ATP-sensitive potassium channel subunit sulfonylurea type 1 receptor (SUR1). The ATP-sensitive potassium channel openers have been shown to inhibit succinate dehydrogenase (SDH) and a gene for a portion of SDH has been found in the SUR intron. Diazoxide may be cardioprotective via inhibition of SDH, which can form part of an ATP-sensitive potassium channel or share its genetic material. This study investigated the role of inhibition of SDH by diazoxide and its relationship to the SUR1 subunit. STUDY DESIGN: Mitochondria were isolated from wild-type and SUR1 knockout mice. Succinate dehydrogenase activity was measured by spectrophotometric analysis of 2,6-dichloroindophenol reduction for 20 minutes as the relative change in absorbance over time. Mitochondria were treated with succinate (20 mM), succinate + 1% dimethylsulfoxide, succinate + malonate (8 mM) (competitive inhibitor of SDH), or succinate + diazoxide (100 µM). RESULTS: Both malonate and diazoxide inhibit SDH activity in mitochondria of wild-type mice and in mice lacking the SUR1 subunit (p < 0.05 vs control). CONCLUSIONS: The ability of DZX to inhibit SDH persists even after deletion of the SUR1 gene. Therefore, the enzyme complex SDH is not dependent on the SUR1 gene. The inhibition of SDH by DZX can play a role in the cardioprotection afforded by DZX; however, this role is independent of the ATP-sensitive potassium channel subunit SUR1.