Yao-Chang Wang

Extracorporeal life support to terminate refractory ventricular tachycardia.

Objective:Extracorporeal life support (ECLS) has been applied successfully to patients with cardiopulmonary failure in extreme situations. Refractory ventricular tachycardia has high mortality and morbidity rates if not terminated in time. This study describes our preliminary experiences in using ECLS to treat patients with refractory ventricular tachycardia. Design:Retrospective chart review. Setting:Hospital. Patients:Eleven patients suffering from ventricular tachycardia refractory to antiarrhythmia agents and cardioversion attempts. Interventions:From January 2002 to December 2004, 11 patients suffering from ventricular tachycardia refractory to antiarrhythmia agents and cardioversion attempts were treated with ECLS. Mean patient age was 31 ± 21 yrs (range, 3–69 yrs). The triggering events were acute myocarditis (n = 8), coronary artery spasm (n = 1), and hypoxemia secondary to acute respiratory distress syndrome (n = 2). Nine (82%) patients received venoarterial mode support and the remaining two (18%) were supported with venovenous mode to correct hypoxemia. Pump flow was first maximized (mean, 3800 ± 1100 mL/min) to unload the heart, and an intra-aortic balloon pump was used to deal with the increased afterload (n = 8). Measurements and Main Results:Mean ventricular tachycardia duration before ECLS was 50 ± 16 mins (range, 20–75 mins) and soon converted to a sinus rhythm following ECLS deployment, including four patients who experienced spontaneous recovery without attempted cardioversion, in a mean of 7.4 mins (range, 1–20 mins). Four patients required temporary pacing but none needed a permanent pacemaker after recovery. Mean duration of ECLS support was 119 ± 69 hrs (range, 12–250 hrs). We excluded one patient who had permanent brain injury and another who succumbed to multiple organ failure. Nine (82%) patients were weaned and discharged with normal cardiac function. No recurrent ventricular tachycardia attack but one recurrent cardiomyopathy (ejection fraction = 15%) was reported during a mean 42-month follow-up. Conclusions:Using ECLS to terminate refractory ventricular tachycardia proved effective for selected patients when conventional therapeutic options were exhausted. Early deployment of ECLS to prevent secondary organ injury, maintain sufficient cardiac unloading, and avoid complications during ECLS support was central to successful outcomes.

HO-1 Activation Can Attenuate Cardiomyocytic Apoptosis via Inhibition of NF-κB and AP-1 Translocation Following Cardiac Global Ischemia and Reperfusion

BACKGROUND NF-kappaB and AP-1 play important roles in regulation of inflammatory responses that lead to cardiomyocytic injury following cardiopulmonary bypass (CPB) and cardiac global ischemia and reperfusion. It has been reported that heme oxygenase-1 (HO-1) can block those responses. Our aim was to determine whether HO-1 activation could decrease myocardial ischemia-reperfusion injury with cardioplegia during CPB and attenuate apoptosis of cardiomyocytes. MATERIALS AND METHODS Rabbits (10 in each group) were randomized to receive either bypass only (Group 1), CPB plus intravenous normal saline (Group 2), hemin (HO-1 inducer; Group 3), SnPP (HO-1 inhibitor; Group 4), or hemin + SnPP (Group 5) 2 d before CPB. In all groups except Group 1, cold (4 degrees C) antegrade intermittent crystalloid cardioplegia was delivered every 20 min for a total of 60 min of cardiac arrest, after CPB was established. Rabbits were weaned from CPB and reperfused for 4 h. Blood was sampled at various time points. The reperfused hearts were harvested for Western blotting and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) experiments. RESULTS The postoperative elevation of serum levels of IL-10, IL-6, and TNF-alpha were significantly decreased in Group 3, but HO-1 inhibitor abolished this effect (Group 4). Moreover in Group 3, the number of apoptotic cardiomyocytes, level of apoptosis-related activated fragments of caspase-3 and Akt, and level of nuclear NF-kappaB and AP-1 translocation were significantly decreased. CONCLUSIONS HO-1 activation can dampen the surge of inflammation-related cytokines during CPB and decrease the occurrence of cardiomyocytic apoptosis via inhibition of NF-kappaB and AP-1 translocation.

AMP-activated protein kinase activation during cardioplegia-induced hypoxia/reoxygenation injury attenuates cardiomyocytic apoptosis via reduction of endoplasmic reticulum stress.

Cardioplegic-induced H/R injury results in cardiomyocytic apoptosis. AMPK has been shown to reduce ER stress and the unfolded protein response (UPR). Whether AMPK activation can attenuate cardiomyocytic apoptosis after cardioplegia-induced H/R injury is unknown. Cardiomyocytes were exposed to simulated ischemia by incubation in a hypoxic chamber with intermittent cold cardioplegia solution infusion at 20-minute intervals and subsequently reoxygenated in a normoxic environment. Various doses of AMPK activators (AICAR or metformin) were given 2 days before H/R injury. The cardiomyocytes were harvested after reoxygenation for subsequent examination. With both AMPK activators, the antiapoptotic genes of ER stress and UPR, the subsequent production of proapoptotic proteins was attenuated, and the antiapoptotic proteins were elevated. The activity of the apoptotic effectors of ER stress was also reduced with AMPK activation. Moreover, TUNEL staining showed that AMPK activation significantly reduced the percentage of apoptotic cardiomyocytes after cardioplegia-induced H/R injury. Our results revealed that AMPK activation during cardioplegia-induced H/R injury attenuates cardiomyocytic apoptosis, via enhancement of antiapoptotic and reduction of proapoptotic responses, resulting from lessening ER stress and the UPR. AMPK activation may serve as a future pharmacological target to reduce H/R injury in the clinical setting.

Direct Revascularization With the Angiosome Concept for Lower Limb Ischemia: A Systematic Review and Meta-Analysis.

AbstractThe angiosome concept provides practical information regarding the vascular anatomy of reconstructive and vascular surgery for the treatment of peripheral arterial occlusive disease and, particularly, critical lower limb ischemia.The aim of the study was to confirm the efficacy of direct revascularization with the angiosome concept (DR) for lower limb ischemia.Complementary manual searches were performed through the Pubmed, Cochrane Library, and EMBASE databases.We searched all randomized and nonrandomized studies (NRSs) comparing DR with indirect revascularization (IR) (without the angiosome concept) for lower limb ischemia. Only 9 nonrandomized controlled retrospective cohort studies were found and included. Trials published in any language were included.Primary endpoints were time to limb amputation and time to wound healing. Data extraction and trial quality assessment were performed by two authors independently. A third author was consulted for disagreements settlement and quality assurance.Five NRSs involving 779 lower limbs revealed that DR significantly improved the overall survival of limbs (hazard ratio [HR] 0.61; 95% confidence interval [CI] = 0.46–0.80; P < 0.001; I2 = 0%). In addition, DR significantly improved time to wound healing (HR 1.38; 95% CI = 1.13–1.69; P = 0.002; I2 = 0%, in 5 studies including 605 limbs).All included studies were retrospective comparative studies, and no consensus was obtained in describing wound conditions in the included studies.Our results suggested that treatment of lower limb ischemia using DR is more effective in salvaging limbs and healing wounds than IR is. Additional randomized controlled studies are necessary to confirm these results.

Microrna-27a Regulates Cardiomyocytic Apoptosis During Cardioplegia-induced Cardiac Arrest by Targeting Interleukin 10–related Pathways

ABSTRACT In this study, experiments were designed to determine whether microRNAs (miRNAs) play a role in the regulation or modulation of cardiomyocytic reactions under cardioplegia-induced cardiac arrest during cardiopulmonary bypass. MicroRNAs play powerful and unexpected roles in numerous cardiovascular diseases. MicroRNA-based therapeutics may provide a unique opportunity to translate this knowledge into the clinical setting. Sprague-Dawley rats (10 per group) were randomly divided into three groups: control, perfusion, and arrest groups. In the perfusion group, isolated hearts were perfused with oxygenated physiologic buffered solution for 3 h using a Langendorff apparatus. In the arrest group, cold crystalloid cardioplegia solution was used to induce and maintain cardiac arrest for 1 h; hearts were reperfused for 2 h with warm oxygenated phosphate-buffered saline solution. Cardiac miRNAs and protein expression patterns were detected using miRNA arrays and two-dimensional fluorescence difference gel electrophoresis followed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Of 103 different miRNAs and 222 different proteins expressed in the three groups, miRNA-27a was the one considered to be related to the regulation of cardiomyocyte apoptosis by targeting the interleukin 10 pathway. Transfection of H9c2 cardiomyocytes with pre-miRNA-27a, which significantly decreased the mRNA and protein levels of interleukin 10 and increased expression of nuclear factor &kgr;B and its downstream cytokines during hypoxia/reperfusion injury, could activate caspase 3 and apoptosis. Our study demonstrated the altered expression of miRNAs in cardiomyocytes during cardioplegia-induced cardiac arrest. The involvement of miRNAs in cardiomyocytic apoptosis adds another level of complexity to gene regulation, which could open up novel avenues for cardiac protection strategies during cardiac surgery.

Cardiomyocytic apoptosis limited by bradykinin via restoration of nitric oxide after cardioplegic arrest.

BACKGROUND Our previous studies revealed that cardioplegia-induced cardiac arrest under cardiopulmonary bypass (CPB) decreased cardiomyocytic nitric oxide and increased apoptosis. We hypothesized that pretreatment with bradykinin (BK) would improve the profile of anti-apoptotic proteins and inhibit cardiomyocytic apoptosis. MATERIALS AND METHODS New Zealand white rabbits received total CPB. Rabbits were weaned from CPB and reperfused for 4 h. Blood was sampled at various time points. Bradykinin and/or nitric oxide synthase (NOS) inhibitors or BK-receptor antagonists were infused systemically 30 min before beginning of CPB, and continued throughout the procedure. The ascending aorta was cross-clamped for 60 min while cold crystalloid cardioplegic solution was intermittently infused into the aortic root. The hearts were harvested and studied for evidence of apoptosis and ischemia/reperfusion induced inflammation-related cytokine production by cardiomyocytes. RESULTS Our results revealed that bradykinin supplementation during cardioplegia could prevent I/R-induced inflammatory and apoptotic effects, which could be reversed with a NOS inhibitor. BK antagonists and NOS inhibitors worsened the inflammatory and apoptotic responses of cardiomyocytes, which could be reversed with an exogenous NO donor. CONCLUSIONS Restoring the NO concentration after cardioplegia-induced cardiac arrest (CCA) under CPB with bradykinin could modulate (1) the nuclear translocation of NF-kappaB, (2) the plasma levels of inflammation-related cytokines, (3) the Bcl-2/Bax ratio, and (4) the occurrence of apoptosis. Exogenous bradykinin administration was associated with the myocardial apoptotic response by inhibition of NF-kappaB translocation, inflammatory cytokine production, Akt activation, and elevation of the Bcl-2/Bax ratio via a NO-mediated pathway.

Carvedilol treatment after myocardial infarct decreases cardiomyocytic apoptosis in the peri-infarct zone during cardioplegia-induced cardiac arrest.

ABSTRACT Objective: In this study, experiments were designed to determine which parts and how carvedilol provided protection of the failed hearts under cardioplegia-induced hypoxia/reperfusion (H/R) insult. Background: Carvedilol could improve the perioperative and postoperative prognosis of the heart failure patients. The mechanism of carvedilol in prevention of the occurrence of cardiomyocytic apoptosis and preservation of cardiac function had been rarely studied. Methods: Fifty Sprague-Dawley rats treated with placebo or daily carvedilol after coronary artery ligation were divided into five groups (ligation only—group 2; ligation followed with cardioplegia-induced cardiac arrest—group 3; daily oral carvedilol treatment at 0.1, 1.0, or 10.0 mg/kg after ligation followed with cardioplegia-induced cardiac arrest—groups 4, 5, and 6), whereas another 10 animals received sham operation only (group 1), 30 days before ex vivo H/R injury. Failed hearts were harvested and received 1-h cardiac hypoxia with intermittent cold cardioplegia infusion and followed by 2-h reperfusion with warm oxygenated phosphate-buffered saline solution using a Langendorff apparatus. Perfusate was sampled at various time points. After H/R injury, the myocardium was carefully dissected into infarct, peri-infarct, and remote zones, which were used for further studies. In vitro H/R studies were carried on HL-1 cardiomyocytes to further explore the possible downstream pathways. Results: Carvedilol could reduce the H/R-induced cardiomyocytic apoptosis and related proteins expression, especially in the peri-infarct zone, in a dose-dependent pattern. Carvedilol could also preserve cardiac contractility via modulation of the tumor necrosis factor &agr; and interleukin 8 mRNA expression and reduction of Bcl-2 and cytochrome c protein production and decrease the occurrence of apoptosis ex vivo. In vitro experiments revealed that carvedilol exerted its antiapoptotic effect by way of phosphatidylinositol 3-kinase and MEK (mitogen-activated protein-kinase kinase), instead of protein kinase A, pathways. Conclusions: In the failed heart, pretreatment with carvedilol could preserve cardiac contractility during cardioplegia-induced myocardial H/R injury by lessening inflammation-related genes and expression of cytokines, decreasing apoptosis-related proteins production and diminishing the occurrence of cardiomyocytic apoptosis in the peri-infarct zone. The cardinal pathways of the antiapoptotic mechanism of carvedilol were PI3K- and MEK-related pathways.

Potent cardioprotection from ischemia–reperfusion injury by a two‐domain fusion protein comprising annexin V and Kunitz protease inhibitor

Considerable evidence suggests that coagulation proteases (tissue factor [TF]/activated factor VII [FVIIa]/FXa/thrombin) and their target protease activated receptors (PAR‐1/PAR‐2) play important roles in myocardial ischemia–reperfusion (I‐R) injury. We hypothesized that localized inhibition of TF/FVIIa on the membrane surfaces of ischemic cells could effectively block coagulation cascade and subsequent PAR‐1/PAR‐2 cell signaling, thereby protecting the myocardium from I‐R injury.

Effects of Antiplatelet Medication on Arteriovenous Fistula Patency After Surgical Thrombectomy

OBJECTIVES To study the effect of antiplatelet agents on preventing arteriovenous (AV) fistulae thrombosis in hemodialysis (HD) patients after surgical thrombectomy (ST) for acute AV fistulae occlusion. Whether post-operative antiplatelet drugs have similar effects on the patency of AV fistula after surgical thrombectomy in patients with end-stage renal disease who undergo HD has not been investigated. DESIGN, MATERIALS AND METHODS We employed the Taiwan National Health Insurance Research Database (NHIRD) from 1999 to 2010 to assess the recurrent occlusion requiring ST and longevity of AV fistula after ST in 1049 patients on regular HD, with or without antiplatelet drugs. RESULTS From the propensity-score (PS)-matched NHIRD, Multivariate Cox model demonstrated that concomitant antiplatelet medication in the HD patients who received the first ST significantly reduced the duration of recurrent ST (adjusted hazard ratio (HR) 1.69; 95% confidence interval (CI) 1.22-2.35, p=0.002) and the longevity of the fistula (adjusted HR 1.79; 95% CI 1.31-2.46, p<0.001). CONCLUSION Treatment with antiplatelet drugs in HD patients did not prevent recurrent thrombosis requiring further ST, but significantly jeopardized the longevity of AV fistula after ST.

Initiation of antiplatelet medication after surgical thrombectomy jeopardized arteriovenous graft longevity

Introduction The efficacy of antiplatelet agents in preventing thrombosis in newly formed arteriovenous graft (AVG) in hemodialysis (HD) patients has been extensively examined. The aim of this study was to investigate the possible effect of initiation of antiplatelet medications on preventing AVG thrombosis recurrence after surgical thrombectomy for acute occlusion in HD patients. Whether post-operatively antiplatelet medications have protective effects on the patency or longevity of AVG after surgical thrombectomy in HD patients has not been investigated. Methods We conducted a 4-year quasi-randomized study of the unassisted patency and AVG longevity for 213 HD patients with or without initiating antiplatelet drugs after receiving surgical thrombectomy for first episode of acute AVG thrombosis. Results From the propensity-score-matched quasi-randomized study, initiation of antiplatelet drugs after first surgical thrombectomy in HD patients did not prevent the recurrence of surgical thrombectomy (log-rank p = 0.81), but significantly decreased the longevity of the access (log-rank p = 0.034). Multivariate Cox model demonstrated that prescription of antiplatelet drugs significantly increased the risk of graft failure (adjusted hazard ratio 2.13, p = 0.025). Conclusions Adjunctive prescription with antiplatelet medications in HD patients after surgical thrombectomy did not prevent recurrent thrombosis of AV access, but significantly jeopardized the longevity of AVG after surgical thrombectomy.