Effects of Long-Term Nitroglycerin Treatment on Endothelial Nitric Oxide Synthase (NOS III) Gene Expression, NOS III–Mediated Superoxide Production, and Vascular NO Bioavailability

Abstract —Long-term nitroglycerin (NTG) treatment has been shown to be associated with cross-tolerance to endothelium-dependent vasodilators. It may involve increased production of reactive oxygen species (such as superoxide, O 2 ·− ) that rapidly inactivate the nitric oxide (NO) released from the endothelial cells. It remains to be elucidated, however, whether long-term treatment with NTG alters the activity and expression of the endothelial NO synthase (NOS III) and whether this enzyme can contribute to O 2 ·− formation. We studied the influence of long-term NTG treatment on the expression of NOS III as assessed by RNase protection assay and Western blot. Tolerance was measured ex vivo i…

Nebivolol inhibits superoxide formation by NADPH oxidase and endothelial dysfunction in angiotensin II-treated rats.

Nebivolol is a β 1 -receptor antagonist with vasodilator and antioxidant properties. Because the vascular NADPH oxidase is an important superoxide source, we studied the effect of nebivolol on endothelial function and NADPH oxidase activity and expression in the well-characterized model of angiotensin II–induced hypertension. Angiotensin II infusion (1 mg/kg per day for 7 days) caused endothelial dysfunction in male Wistar rats and increased vascular superoxide as detected by lucigenin-derived chemiluminescence, as well as dihydroethidine staining. Vascular NADPH oxidase activity, as well as expression at the mRNA and protein level, were markedly upregulated, as well as NOS III uncoupled, …

Primary Persistent Atrial Fibrillation: A Distinct Arrhythmia Subentity of an Ablation Population

INTRODUCTION Persistent atrial fibrillation (persAF) can occur either as a sustained arrhythmia that has progressed from initially paroxysmal AF or as primary persAF without a history of any spontaneously terminated episode. There is a paucity of data differentiating between the 2 different persAF entities. Thus, we prospectively evaluated baseline characteristics, electrophysiological features, and ablation outcome in these 2 patient cohorts. METHODS AND RESULTS A total number of 154 consecutive persAF patients (63 ± 10 years, f = 42, longstanding persAF = 60) were characterized in terms of having primary persAF (P-persAF group) or persAF that secondarily progressed from paroxysmal AF (S-p…

Reduction of ICD Shock Burden by Eliminating Back-Up Pacing Induced Ventricular Tachyarrhythmias

ICD Shock Reduction by Subthreshold Pacing Introduction Implantable cardioverter defibrillators (ICD) may have the capacity to provoke or worsen ventricular tachyarrhythmias (VT). It has been reported that ICD shocks by itself can increase mortality. This study aimed to determine the role of back-up pacing-induced VT (PIT) in the overall ICD shock burden by avoiding pause-related ventricular back-up pacing. Methods and Results A population of 550 single-chamber ICD patients was studied. Of them, 17 (3%, 69 ± 16 years, 14 male) patients had documented episodes of PIT. A total of 431 VT episodes were documented including 89 (21%) due to PIT. In 3 patients, VT events were exclusively PITs. Aft…

Anti-oxidative effects in response to pentaerithrityl tetranitrate (PETN) treatment are mediated by heme oxygenase-1 and ferritin induction and prevent the development of nitrate tolerance and cross-tolerance in vivo

Mitochondrial oxidative stress and nitrate tolerance – comparison of nitroglycerin and pentaerithrityl tetranitrate in Mn-SOD+/- mice

Abstract Background Chronic therapy with nitroglycerin (GTN) results in a rapid development of nitrate tolerance which is associated with an increased production of reactive oxygen species (ROS). According to recent studies, mitochondrial ROS formation and oxidative inactivation of the organic nitrate bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) play an important role for the development of nitrate and cross-tolerance. Methods Tolerance was induced by infusion of wild type (WT) and heterozygous manganese superoxide dismutase mice (Mn-SOD+/-) with ethanolic solution of GTN (12.5 μg/min/kg for 4 d). For comparison, the tolerance-free pentaerithrityl tetranitrate (PETN, 1…

The Oxidative Stress Concept of Nitrate Tolerance and the Antioxidant Properties of Hydralazine

The hemodynamic and anti-ischemic effects of nitroglycerin (NTG) are rapidly blunted as a result of the development of nitrate tolerance. With initiation of NTG therapy, it is possible to detect neurohormonal activation and intravascular volume expansion. These so-called pseudotolerance mechanisms may compromise the vasodilatory effects of NTG. Long-term nitrate treatment also is associated with decreased vascular responsiveness caused by changes in intrinsic mechanisms of the tolerant vasculature itself. According to the oxidative stress concept, increased vascular superoxide (O 2 − ) production and an increased sensitivity to vasoconstrictors secondary to activation of protein kinase C co…

Oxidative Inhibition of the Mitochondrial Aldehyde Dehydrogenase Promotes Nitroglycerin Tolerance in Human Blood Vessels

Objectives We tested the hypothesis of whether an inhibition of the nitroglycerin (GTN) bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) contributes to GTN tolerance in human blood vessels. Background The hemodynamic effects of GTN are rapidly blunted by the development of tolerance, a phenomenon associated with increased formation of reactive oxygen species (ROS). Recent studies suggest that ROS-induced inhibition of ALDH-2 accounts for tolerance in animal models. Methods Segments of surgically removed arteria mammaria and vena saphena from patients undergoing coronary bypass surgery were used to examine the vascular responsiveness to GTN and the endothelium-dependent vas…

Effects of a nitrate-free interval on tolerance, vasoconstrictor sensitivity and vascular superoxide production

Abstract OBJECTIVES In the present study, we tested whether a nitrate-free interval is able to prevent increases in vascular superoxide (O2•−) and the development of hypersensitivity to vasoconstrictors and whether this may result in restoration of vascular nitroglycerin (NTG) sensitivity. BACKGROUND Intermittent NTG-patch treatment (12 h patch on/patch off) has been shown to increase ischemic periods in patients with stable coronary arteries, suggesting a rebound-like situation during the patch-off period. Recently, we demonstrated that long-term treatment with NTG induces tolerance, which was in part related to increases in vascular O2•− and increased vasoconstrictor sensitivity. METHODS …

Crucial role for Nox2 and sleep deprivation in aircraft noise-induced vascular and cerebral oxidative stress, inflammation, and gene regulation

Abstract Aims Aircraft noise causes endothelial dysfunction, oxidative stress, and inflammation. Transportation noise increases the incidence of coronary artery disease, hypertension, and stroke. The underlying mechanisms are not well understood. Herein, we investigated effects of phagocyte-type NADPH oxidase (Nox2) knockout and different noise protocols (around-the-clock, sleep/awake phase noise) on vascular and cerebral complications in mice. Methods and results C57BL/6j and Nox2 −/− (gp91phox −/−) mice were exposed to aircraft noise (maximum sound level of 85 dB(A), average sound pressure level of 72 dB(A)) around-the-clock or during sleep/awake phases for 1, 2, and 4 days. Adverse effec…

Cardiac arrhythmias in patients with Danon disease.

Aims Different cardiac arrhythmias have been suggested to be associated with Danon disease, e.g. Wolff–Parkinson–White syndrome. However, a systematic electrophysiological investigation of patients with Danon disease is lacking thus far. Methods and results Seven patients with Danon disease (4 males, 35.8 ± 10.8 years; 3 females, 51.3 ± 19.9 years) from 3 different families were studied. In all patients, the presence of Danon disease was confirmed by western blot of biopsy material or genetic testing. The patients were characterized by 12-lead electrocardiogram (ECG), Holter ECG, echocardiography, and serial implantable cardioverter defibrillator (ICD) interrogations (in ICD recipients). Al…

Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins.

Recruitment and activation of polymorphonuclear neutrophils (PMNs) reflects a primary immunological response to invading pathogens and has also emerged as a hallmark of vascular inflammation. One of the principal enzymes released upon PMN activation is myeloperoxidase (MPO), a heme protein that not only generates cytotoxic oxidants but also impacts deleteriously on nitric oxide-dependent signaling cascades within the vasculature. Because MPO also associates with the membrane of PMN, we evaluated whether MPO could also function as an autocrine modulator of PMN activation. The extent of PMN membrane-associated MPO was elevated in patients with acute inflammatory vascular disease compared with…

The Incidence of Audible Steam Pops Is Increased and Unpredictable With the ThermoCool® Surround Flow Catheter During Left Atrial Catheter Ablation: A Prospective Observational Study

Audible Steam Pops During Left Atrial Catheter AblationIntroduction Open irrigated radiofrequency (RF) ablation catheters with a porous tip (56 holes, TC-SF) permit delivering RF energy in a temperature-controlled mode without temperature rise. This prospective observational study investigated the association of different catheter parameters on the occurrence of audible steam pops during left atrial (LA) ablation. Methods and Results A total of 226 patients underwent TC-SF catheter ablation for atrial fibrillation. RF power delivery, impedance and catheter tip temperature were continually recorded throughout the ablation. Pulmonary vein isolation was performed with a maximum of 27 W and LA …

Vascular Dysfunction and Oxidative Stress in Diabetic Rats - Comparison of Beneficial Effects of AT1- Receptor Blockade, Calcium Antagonist, or Combination Therapy

In vitro comparison of platinum-iridium and gold tip electrodes: lesion depth in 4 mm, 8 mm, and irrigated-tip radiofrequency ablation catheters

Aims We compared a newly developed irrigated gold tip electrode ablation catheter and a gold tip 4 and 8 mm catheter with the corresponding platinum–iridium (Pt) tip catheters in an in vitro setting. Methods and results In a flow chamber simulating physiological flow conditions, radiofrequency catheter ablation was performed on tissue samples of porcine endomyocardium and liver. Lesion depth, energy and temperature delivery, and popping frequency were determined. Two hundred and fifty-three ablations were conducted. Four and eight millimetre, gold tip electrode catheters produced significantly deeper lesions compared with the Pt tip electrode (liver 4 mm: 4.67 ± 1.7 vs. 2.9 ± 1.0 mm, P < 0.…

Arrhythmia Termination Versus Elimination of Dormant Pulmonary Vein Conduction as a Procedural End Point of Catheter Ablation for Paroxysmal Atrial Fibrillation: A Prospective Randomized Trial.

Background— Pulmonary vein isolation (PVI) is still associated with a substantial number of arrhythmia recurrences in paroxysmal atrial fibrillation (AF). This prospective, randomized study aimed to compare 2 different procedural strategies. Methods and Results— A total of 152 patients undergoing de novo ablation for paroxysmal AF were randomized to 2 different treatment arms. The procedure in group A consisted of PVI exclusively. In this group, all isolated PVs were challenged with adenosine to reveal and ablate dormant conduction. In group B, PVI was performed with the patient either in spontaneous or in induced AF. If AF did not terminate with PVI, ablation was continued by targeting ex…

Heme oxygenase-1: a novel key player in the development of tolerance in response to organic nitrates.

Objective— Nitrate tolerance is likely attributable to an increased production of reactive oxygen species (ROS) leading to an inhibition of the mitochondrial aldehyde dehydrogenase (ALDH-2), representing the nitroglycerin (GTN) and pentaerythrityl tetranitrate (PETN) bioactivating enzyme, and to impaired nitric oxide bioactivity and signaling. We tested whether differences in their capacity to induce heme oxygenase-1 (HO-1) might explain why PETN and not GTN therapy is devoid of nitrate and cross-tolerance. Methods and Results— Wistar rats were treated with PETN or GTN (10.5 or 6.6 μg/kg/min for 4 days). In contrast to GTN, PETN did not induce nitrate tolerance or cross-tolerance as assess…

Mechanisms of Increased Vascular Superoxide Production in an Experimental Model of Idiopathic Dilated Cardiomyopathy

Objective— In the present study, we sought to identify mechanisms underlying increased oxidative stress in vascular tissue in an experimental animal model of chronic congestive heart failure (CHF). Methods and Results— Superoxide and nitric oxide (NO) was measured in vessels from cardiomyopathic hamsters (CHF hamsters) and golden Syrian hamsters. We also determined expression of endothelial nitric oxide synthase (NOSIII), the soluble guanylyl cyclase, the cGMP-dependent kinase, and the NADPH oxidase. To analyze the contribution of the renin-angiotensin system to oxidative stress, CHF hamsters were treated with the angiotensin-converting enzyme inhibitor captopril for 200 days (120 mg · kg …

High Degree of Realism in Teaching Percutaneous Coronary Interventions by Combining a Virtual Reality Trainer With a Full Scale Patient Simulator

The virtual reality coronary angiography simulator "CATHI" (Catheter Instruction System, Mannheim, Germany) simulates coronary arteries with implemented vessel lesions in virtual patients. Like similar systems the software model runs on common PC systems, which are linked to the mechanical device for manual training. We combined the advantages of this skill trainer with the near to reality assembly of a cardiac catheterization laboratory (Cath-lab) by connecting it to a full scale simulator (HPS, METI, Sarasota, FL). We present two methods of synchronizing the heartbeat between both simulation devices. Method A-the hardware solution-uses the electrocardiogram-synchronization signal of the H…

First Evidence for a Crosstalk Between Mitochondrial and NADPH Oxidase-Derived Reactive Oxygen Species in Nitroglycerin-Triggered Vascular Dysfunction

Chronic nitroglycerin treatment results in development of nitrate tolerance associated with endothelial dysfunction (ED). We sought to clarify how mitochondria- and NADPH oxidase (Nox)-derived reactive oxygen species (ROS) contribute to nitrate tolerance and nitroglycerin-induced ED. Nitrate tolerance was induced by nitroglycerin infusion in male Wistar rats (100 microg/h/4 day) and in C57/Bl6, p47(phox/) and gp91(phox/) mice (50 microg/h/4 day). Protein and mRNA expression of Nox subunits were unaltered by chronic nitroglycerin treatment. Oxidative stress was determined in vascular rings and mitochondrial fractions of nitroglycerin-treated animals by L-012 enhanced chemiluminescence, revea…