Left sinus of Valsalva aneurysm causing acute myocardial infarction with compression of the left main coronary trunk.

Sinus of Valsalva aneurysm (SVA) is a rare cardiac anomaly that commonly originates from the right or noncoronary sinuses and rarely from the left sinus. SVA is usually diagnosed in the setting of clinical sequelae of a rupture. We herein report a case of an unruptured left SVA presenting as acute myocardial infarction. A 54-year-old woman with a history of radical operation for patent ductus arteriosus in childhood was transferred to our hospital. An electrocardiogram indicated extensive myocardial ischemia with ST elevation. Urgent coronary angiography was performed but was unable to identify the left coronary artery. Subsequent aortography and computed tomography revealed a large SVA originating from the left sinus and compressing the left coronary artery. The patient died after approximately one month of intensive care, including mechanical circulatory support and coronary artery bypass grafting. Autopsy confirmed that the left main coronary trunk was stretched and compressed by the SVA and revealed unexpected atherosclerosis in the left anterior descending artery. Although a left SVA is an extremely rare anomaly, it occasionally provokes fatal myocardial infarction. Since an SVA might hinder performing percutaneous coronary intervention, cardiac surgery should be considered when myocardial ischemia is recognized. Learning objective: We herein report a case of an unruptured left sinus of Valsalva aneurysm (SVA) with acute myocardial infarction. Urgent percutaneous coronary intervention (PCI) was unsuccessful, as the left coronary artery was compressed by the SVA. The patient died after intensive care, including coronary artery bypass grafting (CABG). SVA, especially from the left sinus, is extremely rare but occasionally provokes myocardial infarction by compressing the coronary arteries. Because SVA might hinder PCI, CABG should be considered when myocardial ischemia is recognized.

Severe mitral regurgitation in chronic adult T-cell leukemia/lymphoma with granulomatous valvular inflammation.

Adult T-cell leukemia/lymphoma (ATLL) is a mature peripheral T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-1) infection. Besides the oncogenic property, HTLV-1 causes HTLV-1-associated myelopathy/tropical spastic paraparesis and certain inflammatory diseases via a complex host immune response to latent virus infection. Cardiac involvement of ATLL is rare, with the majority of cases being disclosed in postmortem autopsy in patients with advanced subtypes. We herein report the case of a 64-year-old female patient with indolent chronic ATLL with severe mitral regurgitation. Although the condition of ATLL was stable, dyspnea on exertion gradually progressed over the course of three years and echocardiography revealed marked thickening of the mitral valve. Finally, the patient experienced hemodynamic collapse with atrial fibrillation and underwent surgical valve replacement. The removed mitral valve was grossly edematous and swollen. A histological examination revealed a granulomatous reaction mimicking the active phase of rheumatic valvulitis, with the infiltration of ATLL cells that were immunohistochemically positive for CD3, CD4, FoxP3, HLA-DRα, and CCR4. The postoperative course was uneventful, with the exception that Sjögren's syndrome was noted. The history of rheumatic fever was unclear, and such unique valvular pathology was presumably related to autoimmune mechanisms associated with HTLV-1 infection. Learning objective: We report a case of chronic adult T-cell leukemia/lymphoma (ATLL) with isolated valvular infiltration with a unique histology of granulomatous reaction. Human T-cell leukemia virus type I infection may accelerate autoimmune reactions and cardiac inflammation, irrespective of indolent clinical subtype. Among ATLL cases, possible progression of valvular insufficiency and heart failure in patients with cardiac symptoms should be carefully evaluated.

Inappropriate subcutaneous implantable cardioverter defibrillator shock due to incomplete sealing of the seal plug: a case report.

Background: A subcutaneous implantable cardioverter defibrillator (S-ICD) has several advantages over the transvenous ICD, including a reduced risk of lead-related mechanical complications and infection. However, inappropriate shock therapy is one of the most common adverse events associated with S-ICDs. We herein report a case of inappropriate shock therapy of S-ICD due to incomplete sealing of the seal plug. Case summary: A 60-year-old man, who had been on haemodialysis with a history of myocardial infarction, was transferred to the hospital after successfully being resuscitated from ventricular fibrillation (VF). An S-ICD was implanted for secondary prevention. On the third and the seventh post-operative days, S-ICD shock therapy was delivered without any tachyarrhythmias. As device interrogation revealed reproducible noises in both the secondary and alternate vectors by tapping at the generator, the sensing vector was fixed to the primary vector. Two months after discharge, the patient died of VF after receiving appropriate S-ICD shock delivery seven times. The S-ICD was retrieved from the body, and it was revealed that the seal plug had incompletely sealed and returned to its normal closed position after reinsertion of a torque wrench. Discussion: Seal plug damage is a rare complication but should be considered if noise oversensing is provoked only at the secondary and/or alternate vectors. In the present case, the inappropriate shock therapy might have been prevented if we had checked the seal plug carefully. Therefore, we advocate confirming the seal plug routinely after the removal of the torque wrench.

Ventricular premature complexes successfully ablated from the non-coronary cusp: a case report.

Background: Ventricular premature complexes (VPCs) occasionally originate from the aortic sinus of Valsalva. Because the anterior part of the left coronary cusp (LCC) and right coronary cusp (RCC) are connected through the ventricular musculature at their bases, VPCs are more common in the LCC and the RCC than in the non-coronary cusp (NCC). We herein report a case in which VPCs were successfully ablated from the NCC, which is considered rare. Case summary: A 30-year-old woman was admitted to our hospital for the ablation of VPCs, which comprised 43% of the total heart beats. The clinical VPCs had an inferior axis and left bundle branch block morphology with a precordial transition between V4 and V5. Three-dimensional mapping of the target VPCs indicated that the earliest activation site was RCC. After radiofrequency (RF) energy application at the RCC, VPCs were temporally suppressed but recurred after 24 min. Remapping of the recurrent VPCs revealed that the earliest activation site shifted from the RCC to the His region. To avoid the risk of atrioventricular block, RF energy was applied from the NCC, which resulted in successful elimination of the VPCs without any complications. Discussion: The present case suggests that RF energy application from the NCC may be a safe and effective option for the ablation of VPCs with the earliest activation at the RCC and His region.

Effects of Patient Background and Treatment Strategy on Clinical Outcomes After Coronary Intervention for Calcified Nodule Lesions.

Background: The presence of a calcified nodule (CN) is associated with unfavorable clinical outcomes after percutaneous coronary intervention (PCI). This study clarified the optimal management of CNs by reassessing the PCI strategy in association with patient background characteristics and clinical outcomes. Methods and Results: Among 5,332 consecutive PCI cases managed using intra-coronary imaging, CNs were found in 167 lesions (3.1%). CNs were predominantly located at the proximal or mid-right coronary artery (RCA; 62%). More than half presented clinically as acute coronary syndrome (ACS; 56%). All-cause mortality and the target lesion revascularization (TLR) rate at 1 year were 13% and 23%, respectively. Multivariate analysis revealed that hemodialysis, diabetes, and ACS were independent risk factors for all-cause death, whereas hemodialysis and RCA location were independent risk factors for TLR. Regarding the PCI strategy, not using rotational atherectomy (RA) was significantly associated with restenosis, whereas placing a drug-eluting stent (DES) was not. Conclusions: Both hemodialysis and RCA location were strong predictors of poor outcomes after PCI for CN. Because not using RA was significantly associated with restenosis, it may be better to use RA whenever possible.

RR interval variability in the evaluation of ventricular tachycardia and effects of implantable cardioverter defibrillator therapy.

BACKGROUND: An implantable cardioverter defibrillator (ICD) is the most reliable therapeutic device for preventing sudden cardiac death in patients with sustained ventricular tachycardia (VT). Regarding its effectiveness, targeted VT is defined based on the tachyarrhythmia cycle length. However, variations in RR interval variability of VTs may occur. Few studies have reported on VT characteristics and effects of ICD therapy according to the RR interval variability. We aimed to identify the clinical characteristics of VTs and ICD therapy effects according to the RR interval variability. METHODS: We analyzed 821 VT episodes in 69 patients with ICDs or cardiac resynchronization therapy defibrillators. VTs were classified as irregular when the difference between two successive beats was >20 ms in at least one of 10 RR intervals; otherwise, they were classified as regular. We evaluated successful termination using anti-tachycardia pacing (ATP)/shock therapy, spontaneous termination, and acceleration between regular and irregular VTs. The RR interval variability reproducibility rates were evaluated. RESULTS: Regular VT was significantly more successfully terminated than irregular VT by ATP. No significant difference was found in shock therapy or VT acceleration between the regular and irregular VTs. Spontaneous termination occurred significantly more often in irregular than in regular VT cases. The reproducibility rates of RR interval variability in each episode and in all episodes were 89% and 73%, respectively. CONCLUSIONS: ATP therapy showed greater effectiveness for regular than for irregular VT. Spontaneous termination was more common in irregular than in regular VT. RR interval variability of VTs seems to be reproducible.

Successful Catheter Ablation for Multiple Atrial Arrhythmias in a Patient with Situs Inversus Totalis.

A 70-year-old woman with situs inversus totalis underwent catheter ablation for atrial fibrillation and atrial flutter. Although her morphologic left atrium (LA) was enlarged, we performed cryoballoon ablation and liner radiofrequency ablation of the cava-tricuspid isthmus without mapping atrial arrhythmias. However, a different form of atrial tachycardia (AT) recurred. We performed catheter ablation a second time using a three-dimensional electroanatomic mapping system. AT was not terminated by the liner ablation at the roof of morphologic LA and mitral isthmus but sustained by changing the atrial activation sequence and cycle length. Multipolar mapping catheter revealed that fractionated low-amplitude potentials were densely located in a limited area of the anterior morphologic LA, and an activation map demonstrated the presence of small-circuit reentry with an extremely slow conduction at the anterior morphologic LA. A single energy application targeting the fragmented potentials successfully terminated the AT. We successfully treated multiple ATs with a complex anatomy using a three-dimensional electroanatomic mapping system.

Evaluation of Coronary Artery Disease in Patients with Atrial Fibrillation by Cardiac Computed Tomography for Catheter Ablation: CADAF-CT Trial 2.

Objective We recently reported that routine cardiac computed tomography (CT) scans for radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) could steadily detect coronary artery lesions (CALs) and could accurately detect myocardial ischemia in 9% of patients with AF who underwent RFCA of AF. The aim of this study was to identify the independent risk factor (s) of myocardial ischemia in those patients. Methods Patient characteristics, blood test, CALs, Ordinal coronary calcium scoring (OCCS), and myocardial Ischemia (MI) were evaluated in 757 consecutive patients who underwent RFCA of AF. Results There were 685 and 72 patients without and with myocardial ischemia, respectively. A univariate analysis and multivariate statistical analysis revealed that a male gender (Odds ratio 2.11), a high number of co-existing coronary risk factors (NCCRF ≥3) (Odds ratio 2.03), an elevated brain natriuretic peptide level (BNP ≥100 pg/mL) (Odds ratio 3.37), an enlarged left atrial volume (≥90 mL) (Odds ratio 2.91), and a high OCCS (≥4) (Odds ratio 13.0) were independent risk factors of myocardial ischemia in patients undergoing RFCA of AF. Conclusion The high OCCS (≥4) by cardiac CT was the strongest independent risk factor of myocardial ischemia in those patients. However, physicians may be able to find the high risk patients of myocardial ischemia by evaluating a male gender, in the presence of a high NCCRF (≥3) and elevated BNP (≥100 pg/mL) without OCCS by cardiac CT in patients undergoing RFCA of AF.

Evaluation of coronary artery disease in patients with atrial fibrillation by cardiac computed tomography for catheter ablation: CADAF-CT trial.

Almost all institutions routinely perform cardiac computed tomography (CT) before radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) to evaluate the cardiac anatomy. The ideal timing of the CT image acquisition is different between for RFCA of AF and for evaluation of coronary artery lesions (CALs). Thus, the aim of this study was to assess whether 64- or 320-line routine cardiac CT scans before RFCA of AF could evaluate both coronary artery lesions and pulmonary veins (LA-PVs) anatomy at the timing of the image acquisition of the LA-PVs in patients with AF who underwent RFCA of AF. The CALs were evaluated in 606 consecutive patients who underwent RFCA of AF assessed by the ideal timing of the CT image acquisition for RFCA of AF, and myocardial ischemia (MI) was also evaluated in patients with severe coronary stenosis (≥ 50%) and unevaluable CALs due to their severe coronary calcification and banding artifact by additional examinations combined with exercise stress testing, 201Tl scintigraphy, and/or fractionated flow reserve measurements. This study revealed that, in patients with AF who underwent RFCA of AF, (1) both 64- and 320-line cardiac CT scans for RFCA of AF could evaluate CALs in 93% of those patients, (2) the prevalence of MI was 9%, (3) significant relationships between the CHADS2 score and prevalence of MI were observed (p = 0.003), and (4) the positive predict values of MI in patients with severe coronary stenosis (≥ 50%) and unevaluable CALs also significantly increased in accordance with the CHADS2 score (p = 0.003). The evaluation of CALs and MI by routine cardiac CT for RFCA of AF combined with the additional examinations may be one of the most feasible modalities for patients with AF.

Utility of 99 mTc-Pyrophosphate Scintigraphy in Diagnosing Transthyretin Cardiac Amyloidosis in Real-World Practice.

Background: Amyloid transthyretin (ATTR) cardiac amyloidosis has now been recognized as one of the major causes of heart failure, especially in elderly patients. The purpose of the present study was to validate the usefulness of technetium-99 m (99 mTc)-pyrophosphate (99 mTc-PYP) scintigraphy in the screening diagnosis for ATTR amyloidosis in daily clinical practice. Methods and Results: Ninety-eight patients underwent 99 mTc-PYP scintigraphy in the previous 3 years (PYP positive/negative, 18/80), of whom 29 underwent concomitant endomyocardial biopsy (ATTR positive/negative, 9/20). The sensitivity and specificity of 99 mTc-PYP scintigraphy for the diagnosis of biopsy-proven ATTR amyloidosis were 0.889 and 0.950, respectively. Age, gender, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level, or electrocardiogram findings did not differ significantly between PYP-positive and PYP-negative patients. Left ventricular (LV) wall thickness was significantly greater in PYP-positive than in PYP-negative patients, but LV ejection fraction or prevalence of atrial fibrillation was similar between groups. In the PYP-positive patients, higher uptake of PYP correlated with younger age and lower NT-proBNP. Conclusions: 99 mTc-PYP scintigraphy was useful, with high sensitivity and specificity in the screening diagnosis for ATTR cardiac amyloidosis, which is difficult to diagnose on clinical characteristics alone. 99 mTc-PYP scintigraphy should be considered to elucidate the underlying causes of heart failure, especially in elderly patients based on the higher prevalence of ATTR cardiac amyloidosis in this population.

CORRIGENDUM: Utility of 99 mTc-Pyrophosphate Scintigraphy in Diagnosing Transthyretin Cardiac Amyloidosis in Real-World Practice.

[This corrects the article DOI: 10.1253/circrep.CR-19-0015.].

Successful percutaneous retrieval of a micra transcatheter pacing system at 8 weeks after implantation.

An 86-year-old woman suffering from repeated methicillin-resistant Staphylococcus aureus (MRSA) bacteremia underwent percutaneous lead extraction using an excimer laser. Since negative blood cultures were confirmed three times after lead extraction under intravenous infusion of anti-MRSA drugs, a Micra transcatheter pacing system (Micra TPS) was implanted 7 days after the lead extraction. Although infusion of anti-MRSA drugs was continued for 5 weeks, MRSA was isolated in four separate samples of blood cultures 3 weeks after the discontinuation of the anti-MRSA therapy. The micra TPS was successfully retrieved using a steerable sheath and snare at 8 weeks after implantation.

Very late perforation by a Riata implantable cardioverter-defibrillator lead-A case report.

Cardiac perforation by a transvenous lead is an uncommon but serious complication. We herein present a case of very late perforation of a Riata implantable cardioverter-defibrillator lead, which occurred 8 years after implantation. The patient was successfully treated with percutaneous lead extraction using an excimer laser. Lead perforation should be considered, even after years from implantation.

Successful bipolar ablation for ventricular tachycardia with potential substrate identification by pre-procedural cardiac magnetic resonance imaging.

Cardiac magnetic resonance imaging (MRI) is a useful tool for detecting the arrhythmogenic substrate in cardiac sarcoidosis. We herein present a case of bipolar radiofrequency catheter ablation for ventricular tachycardia (VT) complicated with cardiac sarcoidosis, guided by pre-procedural cardiac MRI. Neither echocardiography nor endocardial voltage mapping suggested a septal VT substrate. However, MRI alone detected intramural lesions in the septum. Although application of endocardial energy failed to treat the VT, bipolar ablation targeting the potential substrate identified by MRI successfully eliminated the VT. Even when no abnormalities are depicted on echocardiography and endocardial voltage mapping, intramural scar tissue identified by cardiac MRI could be critical for VT.

Superior Rhythm Discrimination With the SmartShock Technology Algorithm　- Results of the Implantable Defibrillator With Enhanced Features and Settings for Reduction of Inaccurate Detection (DEFENSE) Trial.

BACKGROUND: Shocks delivered by implanted anti-tachyarrhythmia devices, even when appropriate, lower the quality of life and survival. The new SmartShock Technology®(SST) discrimination algorithm was developed to prevent the delivery of inappropriate shock. This prospective, multicenter, observational study compared the rate of inaccurate detection of ventricular tachyarrhythmia using the SST vs. a conventional discrimination algorithm.Methods and Results:Recipients of implantable cardioverter defibrillators (ICD) or cardiac resynchronization therapy defibrillators (CRT-D) equipped with the SST algorithm were enrolled and followed up every 6 months. The tachycardia detection rate was set at ≥150 beats/min with the SST algorithm. The primary endpoint was the time to first inaccurate detection of ventricular tachycardia (VT) with conventional vs. the SST discrimination algorithm, up to 2 years of follow-up. Between March 2012 and September 2013, 185 patients (mean age, 64.0±14.9 years; men, 74%; secondary prevention indication, 49.5%) were enrolled at 14 Japanese medical centers. Inaccurate detection was observed in 32 patients (17.6%) with the conventional, vs. in 19 patients (10.4%) with the SST algorithm. SST significantly lowered the rate of inaccurate detection by dual chamber devices (HR, 0.50; 95% CI: 0.263-0.950; P=0.034). CONCLUSIONS: Compared with previous algorithms, the SST discrimination algorithm significantly lowered the rate of inaccurate detection of VT in recipients of dual-chamber ICD or CRT-D.

Verapamil-Sensitive Upper Septal Idiopathic Left Ventricular Tachycardia: Prevalence, Mechanism, and Electrophysiological Characteristics.

OBJECTIVES: This study sought to demonstrate the prevalence, mechanism, and electrocardiographic and electrophysiological characteristics of upper septal idiopathic left fascicular ventricular tachycardia (US-ILVT). BACKGROUND: ILVT is classified into left anterior and posterior types with no clear data about US-ILVT. METHODS: Among 193 ILVT patients, we identified 12 patients (6.2%; age 41 ± 22 years, 7 men) with US-ILVT. RESULTS: Of 12 patients with US-ILVT, 6 patients (50%) had previous history of radiofrequency catheter ablation for common ILVT. Sustained VT (cycle length: 349 ± 53 ms) was seen in all patients with a QRS interval slightly wider (104 ± 18 ms) than that during sinus rhythm (90 ± 19 ms). The VT exhibited an identical QRS configuration as sinus rhythm in 6 (50%) and incomplete right bundle branch block configuration in another 6. His-ventricular interval during VT was always shorter than that during sinus rhythm (27 ± 5 ms vs. 47 ± 10 ms). Purkinje potentials were activated in a reverse direction to that of common ILVT; namely, the diastolic potential (P1) was activated retrogradely but the pre-systolic potential (P2) was activated antegradely. At the left upper-middle ventricular septum, P1 potential was recorded during VT, preceding the QRS by 54 ± 20 ms. Radiofrequency catheter ablation at that site eliminated the VT with no recurrence during a 58 ± 35 months of follow-up. CONCLUSIONS: US-ILVT is an identifiable VT that shares common criteria with ILVT and has a narrow QRS interval. Some US-ILVT cases appeared after common ILVT ablation. It is a reverse type of common ILVT (orthodromic form) with baseline morphological abnormalities that might provide a potential substrate for such VT.

Ratio of eicosapentaenoic acid to arachidonic acid is a critical risk factor for acute coronary syndrome in middle-aged older patients as well as younger adult patients.

BACKGROUND: Coronary risk factors for the onset of acute coronary syndrome (ACS), including polyunsaturated fatty acids (PUFAs), in younger adult patients may be different from those in older patients. METHODS AND RESULTS: We enrolled 578 patients who underwent coronary angiography at Fukuoka Saiseikai Hospital, and divided them into a younger adult group (YG) (<50 years, n=47) and a middle-aged older group (OG) (≥50 years, n=531). In a multivariate analysis, lower levels of high-density lipoprotein cholesterol and the ratio of eicosapentaenoic acid (EPA) to arachidonic acid (AA) (EPA/AA), and less aspirin, oral hypoglycemic agent, and calcium channel blocker (CCB) use were independent risk factors for ACS in all patients. In YG, lower levels of EPA/AA and less angiotensin II receptor blocker/angiotensin-converting enzyme inhibitor use were the independent risk factors. In OG, smoking, lower levels of EPA/AA, less aspirin and CCB use were the risk factors. While lower levels of EPA/AA was the only risk factor for ACS that was common to all patients, YG and OG, docosahexaenoic acid/AA was not associated with ACS in YG and OG. CONCLUSIONS: Lower level of EPA/AA is a common critical risk factor for ACS in middle-aged older patients as well as younger adult patients. Some of the risk factors for the onset of ACS in younger patients were different from those in older patients.

A case of acute coronary syndrome caused by a giant saddle thrombus at left main coronary artery bifurcation.

An 87-year-old woman who had metastatic lung cancer presented with intermittent chest discomfort. The emergent coronary angiogram showed a giant saddle thrombus at the left main coronary artery bifurcation without flow limitation. We performed thrombolysis with unfractionated heparin and warfarin under careful observation of the thrombus with a 320-row area detector computed tomography (ADCT). Ten days later, the second examination with ADCT revealed complete resolution of the saddle thrombus. During the follow-up, neither chest pain nor enzymatic cardiac damage was reported. In this carefully observed case, a less invasive strategy instead of catheter intervention or strong thrombolysis might have led to a favorable clinical outcome.

High salt intake enhances blood pressure increase during development of hypertension via oxidative stress in rostral ventrolateral medulla of spontaneously hypertensive rats.

High salt intake increases blood pressure (BP) in spontaneously hypertensive rats (SHR), and central neural mechanisms are suggested to be involved. Increased generation of reactive oxygen species (ROS) in the rostral ventrolateral medulla (RVLM) contributes to the neural mechanism of hypertension in SHR. We sought to examine whether high salt intake increases hypertension in SHR and whether the increased ROS in the RVLM contributes to this mechanism. Male SHR and Wistar-Kyoto rats (WKY) (6 weeks old) were fed a high-salt diet (8%: HS-S; HS-W) or a regular-salt diet (0.5%: RS-S; RS-W) for 6 weeks. Systolic BP was significantly higher in HS-S than in RS-S at 12 weeks of age (244+/-5 vs. 187+/-7 mmHg, n=8; p<0.05). Urinary norepinephrine excretion was significantly higher in HS-S than in RS-S. Thiobarbituric acid-reactive substances levels in the RVLM were significantly higher in HS-S than in RS-S (9.9+/-0.5 vs. 8.1+/-0.6 mumol/g wet wt, n=5; p<0.05). Microinjection of tempol or valsartan into the RVLM induced significantly greater BP reduction in HS-S than in RS-S. The increase in angiotensin II type 1 receptor (AT(1)R) expression and the increase in reduced nicotinamide-adenine dinucleotide phosphate (NAD(P)H) oxidase activity in the RVLM were significantly greater in HS-S than in RS-S. These findings indicate that high salt intake exacerbates BP elevation and sympathetic nervous system activity during the development of hypertension in SHR. These responses are mediated by increased ROS generation that is probably due to upregulation of AT(1)R/NAD(P)H oxidase in the RVLM. (Hypertens Res 2008; 31: 2075-2083).

Mitochondria-derived reactive oxygen species mediate sympathoexcitation induced by angiotensin II in the rostral ventrolateral medulla.

OBJECTIVES: Reactive oxygen species (ROS) in the central nervous system are thought to contribute to sympathoexcitation in cardiovascular diseases such as hypertension and heart failure. Nicotinamide adenine dinucleotide phosphate oxidase is a major source of ROS in the central nervous system, which acts as a key mediator (mediators) of angiotensin II (AngII). It is not clear, however, whether mitochondria-derived ROS in the central nervous system also participate in sympathoexcitation. METHODS: In an in-vivo study, we investigated whether the AngII-elicited pressor response in the rostral ventrolateral medulla, which controls sympathetic nerve activity, is attenuated by adenovirus-mediated gene transfer of a mitochondria-derived antioxidant (Mn-SOD). In an in-vitro study, using differentiated PC-12 cells with characteristics similar to those of sympathetic neurons, we examined whether AngII increases mitochondrial ROS production. RESULTS: Overexpression of Mn-SOD attenuated the AngII-induced pressor response and also suppressed AngII-induced ROS production, as evaluated by microdialysis in the rostral ventrolateral medulla. Using reduced MitoTracker red, we showed that AngII increased mitochondrial ROS production in differentiated PC-12 cells in vitro. Overexpression of Mn-SOD and rotenone, a mitochondrial respiratory complex I inhibitor, suppressed AngII-induced ROS production. Depletion of extracellular Ca2+ with ethylene glycol bis-N,N,N',N'-tetraacetate (EGTA) and administration of p-trifluoromethoxycarbonylcyanide phenylhydrazone, which prevents further Ca2+ uptake into the mitochondria, blocked AngII-elicited mitochondrial ROS production. CONCLUSION: These results indicate that AngII increases the intracellular Ca2+ concentration and that the increase in mitochondrial Ca2+ uptake leads to mitochondrial ROS production.