Safety profiles of percutaneous left atrial appendage closure devices: An analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database from 2009 to 2016.

BACKGROUND: Percutaneous left atrial appendage closure (LAAC) is a viable option for AF patients who are unable to tolerate long-term oral anticoagulation (OAC). OBJECTIVE: We sought to assess the safety of two commonly used percutaneous devices for LAA closure in the United States by analysis of surveillance data from the FDA Manufacturer and User Facility Device Experience (MAUDE) database. METHODS: The MAUDE database was queried between May 1, 2006 and May 1, 2016 for LARIAT® (SentreHEART Inc., Redwood City, CA, USA) and WATCHMAN™ (Boston Scientific Corp., Marlborough, MA, USA) devices. Among 622 retrieved medical device reports, 356 unique and relevant reports were analyzed. The cumulative incidence of safety events was calculated over the study period and compared between the two devices. RESULTS: LAAC was performed with LARIAT in 4,889 cases. WATCHMAN was implanted in 2,027 patients prior to FDA approval in March 2015 and 3,822 patients postapproval. The composite outcome of stroke/TIA, pericardiocentesis, cardiac surgery, and death occurred more frequently with WATCHMAN (cumulative incidence, 1.93% vs. 1.15%; P = 0.001). The same phenomenon was observed when comparing the WATCHMAN pre- and postapproval experiences for the composite outcome, as well as device embolization, cardiac surgery, and myocardial infarction. CONCLUSIONS: MAUDE-reported data show that postapproval, new technology adoption is fraught with increased complications. Improved collaboration between operators, device manufacturers, and regulators can better serve patients through increased transparency and practical postmarket training and monitoring mechanisms.

Perioperative hematoma with subcutaneous ICD implantation: Impact of anticoagulation and antiplatelet therapies.

BACKGROUND: The safety of perioperative anticoagulation (AC) and antiplatelet (AP) therapy with subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation is unknown. The purpose of this study was to identify the risk factors associated with hematoma complicating S-ICD implantation. METHODS: Records were retrospectively reviewed from 200 consecutive patients undergoing S-ICD implantation at two academic medical centers. A hematoma was defined as a device site blood accumulation requiring surgical evacuation, extended hospital stay, or transfusion. RESULTS: Among 200 patients undergoing S-ICD implantation (age 49 ± 17 years, 67% men), 10 patients (5%) had a hematoma, which required evacuation in six patients (3%). Warfarin was bridged or uninterrupted in 12 and 13 patients, respectively (6% and 6.5%). Four of 12 patients with warfarin and bridging AC (33%) and two of 13 patients with uninterrupted warfarin (15%) developed a hematoma. Neither of the two patients with uninterrupted DOAC had a hematoma. No patients on interrupted AC without bridging (n = 26, 13 with warfarin, 13 with DOAC) developed a hematoma. A hematoma was also more likely with the use of clopidogrel (n = 4/10 vs 10/190, 40% vs 5.3%, P < 0.0001) in combination with aspirin in 12/14 patients. Any bridging AC (odds ratio [OR] 10.3, 1.8-60.8, P = 0.01), clopidogrel (OR 10.0, 1.7-57.7, P = 0.01), and uninterrupted warfarin without bridging (OR 11.1, 1.7-74.3, P = 0.013) were independently associated with hematoma formation. CONCLUSION: AC and/or AP therapy with clopidogrel appears to increase the risk for hematoma following S-ICD implantation. Interruption of AC without bridging should be considered when it is an acceptable risk to hold AC.

Replacing warfarin with a novel oral anticoagulant: Risk of recurrent bleeding and stroke in patients with warfarin ineligible or failure in patients with atrial fibrillation (The ROAR study).

BACKGROUND: A significant proportion of patients treated with warfarin for atrial fibrillation (AF) become warfarin ineligible (WI) due to major bleeding events (MBE) or systemic thromboembolism (STE). We report a large multicenter real-world experience of the use of direct oral antagonists (DOACs) in these WI patients. METHODS: We report the outcomes of 263 WI patients treated with DOACs. The primary objective was to evaluate clinical outcomes of STE and MBE with DOACs. Secondary objective was to assess clinical predictors of repeat MBE and STE on DOACs. RESULTS: Note that 63% (166 of 263) patients had a repeat MBE on DOACs. Repeat MBE was significantly higher in patients with prior gastrointestinal bleeding (74.5% vs. 30%, P < 0.0001). Five percent (12 of 263) developed repeat STE. Higher mean CHA2DS2VASC (6.5 ± 1.7 vs. 3.3 ± 1.6 = 0.001) score was associated with repeat STE. About 34% (57 of 166) of patients had an intervention to manage repeat MBE. LAAO devices were successfully used in 67% (12 of 18) high-risk patients who underwent major interventions to manage MBE. CONCLUSION: In WI patients rechallenged with DOACs, a significant proportion developed repeat MBE. LAAO devices seem reasonable in those patients who undergo major interventions to manage MBE with cautious and temporary continuation of DOAC.

Catheter Ablation for Atrial Fibrillation in Patients With Watchman Left Atrial Appendage Occlusion Device: Results from a Multicenter Registry.

BACKGROUND: There have been an increasing number of atrial fibrillation (AF) patients with Watchman left atrial appendage occlusion (LAAO) device, requiring catheter ablation (CA) for maintenance of normal sinus rhythm. In this study, we describe our experience with the feasibility and safety of CA in patients with a preexisting Watchman LAAO device. METHODS: This was a retrospective multicenter AF registry of 60 patients with Watchman LAAO device who underwent CA for AF. Baseline clinical and procedural characteristics of the included subjects were retrieved from review of medical records and were analyzed. RESULTS: The mean age was 72.7 ± 4.9 years and the mean CHADS2 score was 2.3 ± 0.6. All patients had successful pulmonary vein isolation (PVI). The left atrial appendage (LAA) was electrically active in 34 (56%) while reentrant tachycardia and AF triggers were seen in 17 (28%) patients. Electrical isolation was attempted in these 17 patients with only 10 achieving complete LAA isolation. Repeat imaging showed new peri-device leaks in 30% (12/40) patients, while new significant peri-device leaks (≥5 mm) were noted in 10% (10/40) of patients after RFA, respectively, requiring continuation of oral anticoagulation. There were a higher proportion of patients with severe peri-device leaks (≥5 mm) after LAA isolation. However, >50% of those leaks sealed off on follow-up transesophageal echocardiogram. CONCLUSION: AF ablation is a feasible and safe in patients with preexisting Watchman LAAO device. Electrical isolation of the LAA could be difficult and when attempted can result in increased risk of short-term peri-device leak and recurrence of AT/AF in almost all patients.

Cardiac Implantable Electronic Device-Related Infection and Extraction Trends in the U.S.

BACKGROUND: Implantation of cardiac implanted electronic device (CIED) has surged lately. This resulted in a rise in cardiac device-related infections (CDI) and inevitably, lead extractions. We examined the recent national trend in the incidence of CIED infections and lead extractions in hospitalized patients and associated mortality. METHODS: Using the Nationwide Inpatient Sample for the years 2003-2011 we identified patients diagnosed with a CDI-associated infection as determined by discharge ICD-9 diagnostic codes. We examined the trend of device-related infections overall and in different subgroups. We studied mortality associated with device infections, lead extractions, associated costs, and length of stay. RESULTS: There is a significant increase in the number of hospitalizations due to CDI from 5,308 in the year 2003 to 9,948 in 2011. Males (68%), Caucasians (77%), and age group 65-84 years (56.4%) accounted for majority of CDI. The mortality associated with CDI was 4.5 %, and was worse in higher age groups (2.5% in 18-44 years compared to 5.3% in 85+ years, P < 0.001). Average length of stay was unchanged over the years remaining at 13.6 days; however, mean hospitalization charges increased from $91,348 in 2003 to $173,211 in 2011 (P < 0.001). Among all lead extraction procedures, the percentage of patients undergoing lead extraction secondary to CDI also increased from 2003 (59.1%) to 2011 (76.7%), P-value < 0.001. CONCLUSIONS: Healthcare burden associated with CDI infections and associated lead extractions has significantly increased in the recent years. Despite an increase in cost associated with CIED infections, mortality remains the same, and is higher in older patients.

Electromagnetic Interference in a Private Swimming Pool: Case report.

Although current lead design and filtering capabilities have greatly improved, Electromagnetic Interference (EMI) from environmental sources has been increasingly reported in patients with Cardiac Implantable Electronic Device (CIED) [1]. Few cases of inappropriate intracardiac Cardioverter Defibrillator (ICD) associated with swimming pool has been described [2]. Here we present a case of 64 year old male who presented with an interesting EMI signal that was subsequently identified to be related to AC current leak in his swimming pool.

Gene therapy for ischemic heart disease.

Current pharmacologic therapy for ischemic heart disease suffers multiple limitations such as compliance issues and side effects of medications. Revascularization procedures often end with need for repeat procedures. Patients remain symptomatic despite maximal medical therapy. Gene therapy offers an attractive alternative to current pharmacologic therapies and may be beneficial in refractory disease. Gene therapy with isoforms of growth factors such as VEGF, FGF and HGF induces angiogenesis, decreases apoptosis and leads to protection in the ischemic heart. Stem cell therapy augmented with gene therapy used for myogenesis has proven to be beneficial in numerous animal models of myocardial ischemia. Gene therapy coding for antioxidants, eNOS, HSP, mitogen-activated protein kinase and numerous other anti apoptotic proteins have demonstrated significant cardioprotection in animal models. Clinical trials have demonstrated safety in humans apart from symptomatic and objective improvements in cardiac function. Current research efforts are aimed at refining various gene transfection techniques and regulation of gene expression in vivo in the heart and circulation to improve clinical outcomes in patients that suffer from ischemic heart disease. In this review article we will attempt to summarize the current state of both preclinical and clinical studies of gene therapy to combat myocardial ischemic disease. This article is part of a Special Section entitled "Special Section: Cardiovascular Gene Therapy".

Hydrogen sulfide-mediated cardioprotection: mechanisms and therapeutic potential.

H2S (hydrogen sulfide), viewed with dread for more than 300 years, is rapidly becoming a ubiquitously present and physiologically relevant signalling molecule. Knowledge of the production and metabolism of H2S has spurred interest in delineating its functions both in physiology and pathophysiology of disease. Although its role in blood pressure regulation and interaction with NO is controversial, H2S, through its anti-apoptotic, anti-inflammatory and antioxidant effects, has demonstrated significant cardioprotection. As a result, a number of sulfide-donor drugs, including garlic-derived polysulfides, are currently being designed and investigated for the treatment of cardiovascular conditions, specifically myocardial ischaemic disease. However, huge gaps remain in our knowledge about this gasotransmitter. Only by additional studies will we understand more about the role of this intriguing molecule in the treatment of cardiovascular disease.

Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice.

OBJECTIVE: Humanin (HN), an endogenous antiapoptotic peptide, has previously been shown to protect against Alzheimer's disease and a variety of cellular insults. We evaluated the effects of a potent analog of HN (HNG) in an in vivo murine model of myocardial ischemia and reperfusion. METHODS AND RESULTS: Male C57BL6/J mice (8 to 10 week old) were subjected to 45 minutes of left coronary artery occlusion followed by a 24-hour reperfusion. HNG or vehicle was administered IP 1 hour prior or at the time of reperfusion. The extent of myocardial infarction per area-at-risk was evaluated at 24 hours using Evans Blue dye and 2-3-5-triphenyl tetrazolium chloride staining. Left ventricular function was evaluated at 1 week after ischemia using high-resolution, 2D echocardiography (VisualSonics Vevo 770). Myocardial cell signaling pathways and apoptotic markers were assessed at various time points (0 to 24 hours) following reperfusion. Cardiomyocyte survival and apoptosis in response to HNG were assessed in vitro. HNG reduced infarct size relative to the area-at-risk in a dose-dependent fashion, with a maximal reduction at the dose of 2 mg/kg. HNG therapy enhanced left ventricular ejection fraction and preserved postischemic left ventricular dimensions (end-diastolic and end-systolic), resulting in improved cardiac function. Treatment with HNG significantly increased phosphorylation of AMPK and phosphorylation of endothelial nitric oxide synthase in the heart and attenuated Bcl-2-associated X protein and B-cell lymphoma-2 levels following myocardial ischemia and reperfusion. HNG improved cardiomyocyte survival and decreased apoptosis in response to daunorubicin in vitro. CONCLUSIONS: These data show that HNG provides cardioprotection in a mouse model of myocardial ischemia and reperfusion potentially through activation of AMPK-endothelial nitric oxide synthase-mediated signaling and regulation of apoptotic factors. HNG may represent a novel agent for the treatment of acute myocardial infarction.

Systemic Octreotide Therapy in Prevention of Gastrointestinal Bleeds Related to Arteriovenous Malformations and Obscure Etiology in Atrial Fibrillation.

OBJECTIVES: The present study describes the use of octreotide (OCT) in patients with atrial fibrillation (AF) receiving oral anticoagulation (OAC) who have gastrointestinal (GI) bleeding related to arteriovenous malformations (AVMs), as well as its effect on OAC tolerance and subsequent rebleeding. BACKGROUND: AVMs cause significant GI bleeding, especially in patients with AF who are receiving OAC for stroke prevention. OCT has been shown to minimize recurrent GI bleeds related to AVMs. METHODS: In a multicenter, observational study, 38 AF patients with contraindications to OAC because of AVM-related GI bleeding were started on 100 µg of subcutaneous OCT twice daily. OAC was resumed in all patients within 48 h. Incidence of recurrent GI bleeds was calculated, and hemoglobin levels were recorded at enrollment and at 3 and 6 months' follow-up. RESULTS: After a median follow-up of 8 months, 36 patients (mean age 69 ± 8.0 years; mean CHA2DS2-VASc score 3 ± 1 and mean HAS-BLED score 3 ± 1) were available for analysis. All were able to successfully resume OAC, and 28 of 36 (78%) remained on OAC at the conclusion of the study, whereas 8 underwent left atrial appendage closure with subsequent OAC discontinuation. No systemic thromboembolic events occurred in follow-up. Of the 28 patients who continued receiving OAC, 19 (68%) were free of recurrent GI bleed, 4 had minor GI bleeds, 4 required transfusion, and 1 required colectomy for GI bleeding. Mean hemoglobin levels in all patients receiving OAC were significantly higher at 3- and 6-month follow-up than at baseline (p < 0.001). CONCLUSIONS: Subcutaneous OCT therapy is an attractive option in AF patients receiving OAC who have AVM-related GI bleeds. It allows successful reinitiation of OAC as a bridge to left atrial appendage exclusion or short-term relief from bleeding.

Impact of Radiofrequency Ablation of Atrial Fibrillation on Pulmonary Vein Cross Sectional Area: Implications for the Diagnosis of Pulmonary Vein Stenosis.

INTRODUCTION: Restoration of normal sinus rhythm by radiofrequency ablation (RFA) in atrial fibrillation (AF) patients can result in a reduction of left atrial (LA) volume and pulmonary vein (PV) dimensions. It is not clear if this PV size reduction represents a secondary effect of overall LA volume reduction or true PV stenosis. We assessed the relationship between LA volume reduction and PV orifice area pre- and post-RFA. METHODS: A retrospective cohort study was conducted at a tertiary care academic hospital. Pre- and post-RFA cardiac computed tomography (CT) studies of 100 consecutive AF patients were reviewed. Studies identifying obvious segmental PV narrowing were excluded. Left atrial volumes and PV orifice cross-sectional areas (PVOCA) were measured using proprietary software from the CT scanner vendor (GE Healthcare, Waukesha, WI). RESULTS: The cohort had a mean age of 60 ± 8 years, 73% were male, and 90% were Caucasian. Non-paroxysmal AF was present in 76% of patients with a mean duration from diagnosis to RFA of 55 ± 54 months. Mean procedural time was 244 ± 70 min. AF recurred in 27% at 3 month follow-up. Pre-RFA LA volumes were 132 ± 60 ml and mean PVOCA was 2.89 ± 2.32 cm2. In patients with successful ablation, mean LA volume decreased by 10% and PVOCA decreased by 21%. PVOCA was significantly reduced in patients with successful RFA compared to those who had recurrence (2.18 ± 1.12 vs. 2.8 ± 1.9 cm2, p = 0.04) but reduction in LA volume between groups was not significant (118 ± 42 vs. 133 ± 54 ml, p=0.15). CONCLUSIONS: The study demonstrates that both PV orifice dimensions and LA volume are reduced after successful AF ablation. These data warrant a reassessment of criteria for diagnosing PV stenosis based on changes in PV caliber alone, ideally incorporating LA volume changes.

Use of Oral Steroid and its Effects on Atrial Fibrillation Recurrence and Inflammatory Cytokines Post Ablation - The Steroid AF Study.

BACKGROUND: Use of corticosteroids before and after atrial fibrillation (AF) ablation can decrease acute inflammation and reduce AF recurrence. PURPOSE: To assess the efficacy of oral prednisone in improving the outcomes of pulmonary vein isolation with radiofrequency ablation and its effect on inflammatory cytokine. METHODS: A total of 60 patients with paroxysmal AF undergoing radiofrequency ablation were randomized (1:1) to receive either 3 doses of 60 mg daily of oral prednisone or a placebo. Inflammatory cytokine levels (TNF-α, IL-1, IL6, IL-8) were measured at baseline, prior to ablation, immediately after ablation, and 24 hours post ablation. Patients underwent 30 day event monitoring at 3 months, 6 months and 12 months post procedure. RESULTS: Immediate post ablation levels of inflammatory cytokines were lower in the steroid group when compared to the placebo group; IL-6: 9.0 ±7 vs 15.8 ±13 p=0.031; IL-8: 10.5 ±9 vs 15.3 ±8; p=0.047 respectively. Acute PV reconnection rates during the procedure (7/23% vs 10/36%; p = 0.39), and RF ablation time (51±13 vs 56±11 min, p = 0.11) trended to be lower in the placebo group than the steroid group. There was no difference in the incidence of early recurrence of AF during the blanking period and freedom from AF off AAD at 12 months between both groups (5/17% vs 8/27%; p = 0.347 and 21/70% vs 18/60%; p=0.417 in placebo and steroid groups respectively). CONCLUSION: Although oral corticosteroids have significant effect in lowering certain cytokines, it did not impact the clinical outcomes of AF ablation.

Safety and Efficacy of Inpatient Initiation of Dofetilide versus Sotalol for atrial fibrillation.

BACKGROUND: We sought to investigate and compare the safety and efficacy of two commonly used antiarrhythmic drugs, Dofetilide (DF) and Sotalol (SL), during inpatient drug initiation in patients with symptomatic atrial fibrillation (AF). METHODS: We performed a single center retrospective study of consecutive patients, admitted for initiation of either DF or SL, for AF between 2012 and 2015. Rates of successful cardioversion, QT interval prolongation, adverse events and drug discontinuations were calculated and compared. A two-tailed p value less than 0.05 was considered statistically significant. RESULTS: Of 378 patients, 298 (78.8%) received DF and 80 (21.2%) SL, mean age was 64 ± 11 years, 90% were Caucasians and 66% were males. Among the patients who remained in AF upon admission (DF: 215/298 (72%) vs. SL: 48/80 (60%)), no significant differences were noted in pharmacological cardioversion rates (DF: 125/215(58%) vs. SL: 30/48 (62.5%); p = 0.58). Baseline QTc was similar between the groups, with higher dose dependent QTc prolongation with DF (472.25± 31.3 vs. 458± 27.03; p = 0.008). There were no significant differences in the rates of adverse events such as bradycardia (7.4% vs. 11.3%; p = 0.26), Torsades de pointes (1.3% vs. 1.2%; p = 1.00), and drug discontinuation (9.0% vs. 5.0%; p = 0.47) between the two groups.

Practice variation in the re-initiation of dofetilide: An observational study.

BACKGROUND: Dofetilide is a class III antiarrhythmic drug that has been reported to be safe and efficacious in the treatment of atrial dysrhythmias with a known initial risk of QT prolongation and torsades de pointes (TdP). As a result, the Federal Drug Administration (FDA) mandated in-hospital dofetilide initiation and adherence to a common dosing protocol. However, there is a lack of clarity on how to manage dofetilide re-initiation. METHODS: An observational survey was performed including 347 cardiologists in the United States and worldwide to evaluate the deviations from approved manufacturer's protocol during dofetilide initiation and re-initiation among practicing cardiologists. RESULTS: Most practicing cardiologists were cautious about outpatient dofetilide use and adhered to the manufacturer's in-patient dofetilide protocol during de-novo initiation and reported low incidence of TdP in clinical practice. There were substantial differences among practicing cardiologists with deviation from the manufacturer's protocol during re-initiation of dofetilide. About 21% cardiologists always admitted patients to the hospital while 37% admitted patients <10% of the time for dofetilide re-initiation. Only 4% reported major adverse events with outpatient dofetilide re-initiation. There was also wide variation regarding monitoring of electrolytes and QT interval as an outpatient with dofetilide. CONCLUSION: There is significant practice pattern variation in the use of dofetilide for the management of AF. This degree of variation noted is concerning and is a reflection of the current lack of substantial clinical evidence in the re-initiation dofetilide protocol to help direct the provider.

Left Atrial Appendage Closure for Stroke Prevention: Devices, Techniques, and Efficacy.

Left atrial appendage closure can be performed either surgically or percutaneously. Surgical approaches include direct suture, excision and suture, stapling, and clipping. Percutaneous approaches include endocardial, epicardial, and hybrid endocardial-epicardial techniques. Left atrial appendage anatomy is highly variable and complex; therefore, preprocedural imaging is crucial to determine device selection and sizing, which contribute to procedural success and reduction of complications. Currently, the WATCHMAN is the only device that is approved for left atrial appendage closure in the United States.

Malignancy Associated Iatrogenic Iliopsoas Abscess -Venous Access Complication From Ablation Procedure.

Iliopsoas abscess is a rare condition with a high rate of mortality and morbidity if left untreated. It can occur from hematogenous or lymphatic spread from distant structures or as a result of contiguous spread from adjacent structures. The disease typically occurs in patients with immunocompromised status and the symptoms can be non-specific.1,2 Generally, infectious complications from venous access during atrial fibrillation (AF) procedure are uncommon, and an iatrogenic iliopsoas abscess from percutaneous cardiac procedures has never been reported. We present the first case of iliopsoas abscess from an ablation procedure.

Five years of keeping a watch on the left atrial appendage-how has the WATCHMAN fared?

Left atrial appendage closure (LAAC) is a promising site-directed therapy for stroke prevention in patients with non-valvular atrial fibrillation (AF) who are ineligible or contraindicated for long-term oral anticoagulation. A variety of LAAC modalities are available, including percutaneous endocardial occluder devices such as WATCHMANTM (Boston Scientific Corp., Marlborough, MA, USA), and an ever-increasing body of evidence is helping to define the optimal use of each technique. Similarly increased experience with LAAC has revealed challenges such as device-related thrombi and peri-device leaks for which the long-term significance and appropriate management are areas of active investigation. We review the evolution and long-term outcomes with the WATCHMANTM device with particular emphasis on the nuances of its use and its role in the broader landscape of appendageology.

Beta3-adrenoreceptor stimulation ameliorates myocardial ischemia-reperfusion injury via endothelial nitric oxide synthase and neuronal nitric oxide synthase activation.

OBJECTIVES: This paper examined whether nebivolol protects the heart via nitric oxide (NO) synthase and NO-dependent signaling in an in vivo model of acute myocardial infarction. BACKGROUND: Beta(3)-adrenergic receptor (AR) activation promotes endothelial nitric oxide synthase (eNOS) activity and NO bioavailability. We hypothesized that specific beta(3)-AR agonists would attenuate myocardial ischemia-reperfusion (MI/R) injury via eNOS activation and increased NO bioavailability. METHODS: Mice were subjected to 45 min of myocardial ischemia in vivo followed by 24 h of reperfusion (R). Nebivolol (500 ng/kg), CL 316243 (1 µg/kg), BRL-37344 (1 µg/kg), or vehicle (VEH) was administered at the time of R. Myocardial area-at-risk (AAR) and infarct size (INF)/AAR was measured at 24 h of R. Cardiac tissue and plasma were collected to evaluate eNOS phosphorylation, neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase expression, and nitrite and nitrosothiol levels. RESULTS: Nebivolol (500 ng/kg) reduced INF/AAR by 37% (p < 0.001 vs. VEH) and serum troponin-I levels from 41 ± 4 ng/ml to 25 ± 4 ng/ml (p < 0.05 vs. VEH). CL 316243 and BRL-37344 reduced INF by 39% and 42%, respectively (p < 0.001 vs. VEH). Nebivolol and CL 316243 increased eNOS phosphorylation at Ser-1177 (p < 0.05 vs. VEH) and increased nitrite and total nitrosylated protein levels. Nebivolol and CL 316243 significantly increased myocardial nNOS expression. Nebivolol failed to reduce INF after MI/R in beta(3)-AR (-/-), eNOS(-/-), and in nNOS(-/-) mice. CONCLUSIONS: Our results indicate that beta(3)-AR agonists protect against MI/R injury. Furthermore, the cardioprotective effects of beta(3)-AR agonists are mediated by rapid eNOS and nNOS activation and increased NO bioavailability.