Association of HbA1c and utilization of internal mammary arteries with wound infections in CABG.

Background: Deep sternal wound infection (DSWI) remains a serious complication after coronary artery bypass grafting (CABG). We herein aimed to stratify diabetic patients who underwent CABG using bilateral internal mammary artery (BIMA) for levels of glycated hemoglobin A1C (HbA1c) and compare postoperative outcomes. Methods: Between January 2010 and August 2020, 4,186 consecutive patients underwent isolated CABG at our center. In 3,229 patients, preoperative HbA1c levels were available. Primary endpoints were wound healing disorder (WHD), DSWI, and 30-day mortality. Patients were stratified according to preoperative HbA1c levels. Patients were further divided into subgroups according to utilization of BIMA. Results: After adjustment, no differences in mortality and stroke rates were seen between group 1 (HbA1c < 6.5%) vs. group 2 (HbA1c ≥ 6.5%). WHD was more frequent in group 2 [2.8 vs. 5.6%; adjusted p = 0.002; adjusted odds ratio (OR), 1.853 (1.243-2.711)] but not DSWI [1.0 vs. 1.5%; adjusted p = 0.543; adjusted OR, 1.247 (0.612-2.5409)]. BIMA use showed a higher rate of WHD [no BIMA: 3.0%; BIMA: 7.7%; adjusted p = 0.002; adjusted OR, 4.766 (1.747-13.002)] but not DSWI [no BIMA: 1.1%; BIMA: 1.8%; adjusted p = 0.615; adjusted OR, 1.591 (0.260-9.749)] in patients with HbA1c ≥ 6.5%. Conclusions: Intraoperative utilization of BIMA is not connected with an increase of DSWI but higher rates of WHD in patients with poor diabetic status and HbA1c ≥ 6.5%. Therefore, application of BIMA should be taken into consideration even in patients with poor diabetic status, while identification of special subsets of patients who are at particular high risk for DSWI is of paramount importance to prevent this serious complication.

Right ventricular and pulmonary artery pulse pressure variation and systolic pressure variation for the prediction of fluid responsiveness: an interventional study in coronary artery bypass surgery patients.

PURPOSE: Predicting fluid responsiveness is essential when treating surgical or critically ill patients. When using a pulmonary artery catheter, pulse pressure variation and systolic pressure variation can be calculated from right ventricular and pulmonary artery pressure waveforms. METHODS: We conducted a prospective interventional study investigating the ability of right ventricular pulse pressure variation (PPVRV) and systolic pressure variation (SPVRV) as well as pulmonary artery pulse pressure variation (PPVPA) and systolic pressure variation (SPVPA) to predict fluid responsiveness in coronary artery bypass (CABG) surgery patients. Additionally, radial artery pulse pressure variation (PPVART) and systolic pressure variation (SPVART) were calculated. The area under the receiver operating characteristics (AUROC) curve with 95%-confidence interval (95%-CI) was used to assess the capability to predict fluid responsiveness (defined as an increase in cardiac index of > 15%) after a 500 mL crystalloid fluid challenge. RESULTS: Thirty-three patients were included in the final analysis. Thirteen patients (39%) were fluid-responders with a mean increase in cardiac index of 25.3%. The AUROC was 0.60 (95%-CI 0.38 to 0.81) for PPVRV, 0.63 (95%-CI 0.43 to 0.83) for SPVRV, 0.58 (95%-CI 0.38 to 0.78) for PPVPA, and 0.71 (95%-CI 0.52 to 0.89) for SPVPA. The AUROC for PPVART was 0.71 (95%-CI 0.53 to 0.89) and for SPVART 0.78 (95%-CI 0.62 to 0.94). The correlation between pulse pressure variation and systolic pressure variation measurements derived from the different waveforms was weak. CONCLUSIONS: Right ventricular and pulmonary artery pulse pressure variation and systolic pressure variation seem to be weak predictors of fluid responsiveness in CABG surgery patients.

Coronary Artery Bypass Grafting in Patients With High Risk of Bleeding.

BACKGROUND: Postoperative bleeding after cardiac surgery is associated with increased morbidity and mortality. We tested the hypothesis that patients with a preoperatively estimated high risk of severe perioperative bleeding may have impaired early outcome after on-pump versus off-pump coronary artery bypass grafting (CABG). METHOD: Data from 7,352 consecutive patients who underwent isolated CABG from January 2015 to May 2017 were included in the multicentre European Coronary Artery Bypass Grafting registry. The postoperative bleeding risk was estimated using the WILL-BLEED risk score. Of all included patients, 3,548 had an increased risk of severe perioperative bleeding (defined as a WILL-BLEED score ≥4) and were the subjects of this analysis. We compared the early outcomes between patients who underwent on-pump or off-pump CABG using a multivariate mixed model for risk-adjusted analysis. RESULTS: Off-pump surgery was performed in 721 patients (20.3%). On-pump patients received more packed red blood cell units (on-pump: 1.41 [95% confidence interval {CI} 0.99-1.86]; off-pump: 0.86 [95% CI 0.64-1.08]; p<0.001), had a longer stay in the intensive care unit (on-pump: 4.4 [95% CI 3.6-8.1] days; off-pump: 3.2 [95% CI 2.0-4.4] days; p=0.049), and a higher rate of postoperative atrial fibrillation (on-pump: 46.5% [95% CI 34.9-58.1]; off-pump: 31.3% [95% CI 21.7-40.9]; p=0.025). Furthermore, on-pump patients showed a trend towards a higher rate of postoperative stroke (on-pump: 2.4% [95% CI 0.9-4.1]; off-pump: 1.1 [95% CI 0.2-2.7]; p=0.094). CONCLUSION: Our data suggest that in patients with an increased risk of bleeding, the use of cardiopulmonary bypass is associated with higher morbidity. These patients may benefit from off-pump surgery if complete revascularisation can be ensured.

Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia.

3',5'-cyclic guanosine monophosphate (cGMP) is a druggable second messenger regulating cell growth and survival in a plethora of cells and disease states, many of which are associated with hypoxia. For example, in myocardial infarction and heart failure (HF), clinical use of cGMP-elevating drugs improves disease outcomes. Although they protect mice from ischemia/reperfusion (I/R) injury, the exact mechanism how cardiac cGMP signaling is regulated in response to hypoxia is still largely unknown. By monitoring real-time cGMP dynamics in murine and human cardiomyocytes using in vitro and in vivo models of hypoxia/reoxygenation (H/R) and I/R injury combined with biochemical methods, we show that hypoxia causes rapid but partial degradation of cGMP-hydrolyzing phosphodiesterase-3A (PDE3A) protein via the autophagosomal-lysosomal pathway. While increasing cGMP in hypoxia prevents cell death, partially reduced PDE3A does not change the pro-apoptotic second messenger 3',5'-cyclic adenosine monophosphate (cAMP). However, it leads to significantly enhanced protective effects of clinically relevant activators of nitric oxide-sensitive guanylyl cyclase (NO-GC). Collectively, our mouse and human data unravel a new mechanism by which cardiac cGMP improves hypoxia-associated disease conditions.

Impella 5.0 therapy as a bridge-to-decision option for patients on extracorporeal life support with unclear neurological outcomes.

OBJECTIVES: Peripheral venoarterial extracorporeal life support (ECLS) for the treatment of cardiogenic shock has shown to improve survival but is associated with complications. However, if the patient cannot be weaned from ECLS, their therapy options are limited. Although durable left ventricular assist device implantation might be an option in such cases, an unclear neurological outcome is often a contraindication. We hypothesize that Impella 5.0 therapy provides sufficient circulatory support while avoiding ECLS-related complications, thereby allowing for an adequate evaluation of a patient's neurological state and facilitating further treatment options. METHODS: We retrospectively reviewed data from 22 ECLS patients (mean age 56.5 ± 10.7 years) with an unclear neurological status who underwent Impella 5.0 implantation between January 2016 and July 2018 in our institution. Neurological status was evaluated on a daily basis using the cerebral performance category score and the modified Rankin scale. RESULTS: Sixteen patients (72.7%) were resuscitated before ECLS implantation and 13 patients (59.1%) had acute myocardial infarction. The mean duration on ECLS before Impella 5.0 implantation was 9.3 ± 1.7 days. All patients were successfully weaned from ECLS by Impella 5.0 implantation via the axillary artery. The mean duration on Impella 5.0 was 16.3 ± 4.7 days. In surviving patients, both quantitative measurements of cerebral performance improved after 30 days compared to the baseline (P < 0.01). Six patients (27.3%) were bridged to a durable left ventricular assist device. In 9 patients (40.9%), myocardial function recovered during Impella 5.0 support and the device was successfully explanted. The 30-day survival rate was 68.2%. CONCLUSIONS: Impella 5.0 support provides a bridge-to-decision option for patients following ECLS implantation and leads to left ventricular unloading. It allows further evaluation of a patient's neurological situation and facilitates further therapy. About two-thirds of patients survived with acceptable neurological outcomes.

Safety of Simultaneous Coronary Artery Bypass Grafting and Carotid Endarterectomy Versus Isolated Coronary Artery Bypass Grafting: A Randomized Clinical Trial.

BACKGROUND AND PURPOSE: The optimal operative strategy in patients with severe carotid artery disease undergoing coronary artery bypass grafting (CABG) is unknown. We sought to investigate the safety and efficacy of synchronous combined carotid endarterectomy and CABG as compared with isolated CABG. METHODS: Patients with asymptomatic high-grade carotid artery stenosis ≥80% according to ECST (European Carotid Surgery Trial) ultrasound criteria (corresponding to ≥70% NASCET [North American Symptomatic Carotid Endarterectomy Trial]) who required CABG surgery were randomly assigned to synchronous carotid endarterectomy+CABG or isolated CABG. To avoid unbalanced prognostic factor distributions, randomization was stratified by center, age, sex, and modified Rankin Scale. The primary composite end point was the rate of stroke or death at 30 days. RESULTS: From 2010 to 2014, a total of 129 patients were enrolled at 17 centers in Germany and the Czech Republic. Because of withdrawal of funding after insufficient recruitment, enrolment was terminated early. At 30 days, the rate of any stroke or death in the intention-to-treat population was 12/65 (18.5%) in patients receiving synchronous carotid endarterectomy+CABG as compared with 6/62 (9.7%) in patients receiving isolated CABG (absolute risk reduction, 8.8%; 95% confidence interval, -3.2% to 20.8%; PWALD=0.12). Also for all secondary end points at 30 days and 1 year, there was no evidence for a significant treatment-group effect although patients undergoing isolated CABG tended to have better outcomes. CONCLUSIONS: Although our results cannot rule out a treatment-group effect because of lack of power, a superiority of the synchronous combined carotid endarterectomy+CABG approach seems unlikely. Five-year follow-up of patients is still ongoing. CLINICAL TRIAL REGISTRATION: URL: https://www.controlled-trials.com. Unique identifier: ISRCTN13486906.

Reversed Frozen Elephant Trunk Technique to Treat a Type II Thoracoabdominal Aortic Aneurysm.

PURPOSE: To describe a hybrid technique of reversed frozen elephant trunk to treat thoracoabdominal aortic aneurysms (TAAA) through an abdominal only approach. TECHNIQUE: The technique is demonstrated in a 29-year-old Marfan patient with a chronic type B aortic dissection previously treated with a thoracic stent-graft who presented with a thoracoabdominal false lumen aneurysm. Through an open distal retroperitoneal approach to the abdominal aorta, a frozen elephant trunk graft was implanted over a super-stiff wire upside down with the stent-graft component in the thoracic aorta. Following deployment of the stent-graft proximally and preservation of renovisceral perfusion in a retrograde manner, the renovisceral vessels were sequentially anastomosed to the elephant trunk graft branches, thus reducing the ischemia time of the end organs. The aortic sac was then opened, and the distal part of the hybrid graft was anastomosed with a further bifurcated graft to the iliac vessels. CONCLUSION: The reversed frozen elephant trunk technique is feasible for hybrid treatment of TAAAs via an abdominal approach only. This has the benefit of substantially reducing the trauma of thoracic exposure, thus preserving major benefits of open thoracoabdominal surgery, such as the presence of short bypasses to the renovisceral vessels and reimplantation of lumbar arteries to reduce spinal cord ischemia.

Reduction of clinically irrelevant alarms in patient monitoring by adaptive time delays.

The problem of high rates of false alarms in patient monitoring in anesthesiology and intensive care medicine is well known but remains unsolved. False alarms desensitize the medical staff, leading to ignored true alarms and reduced quality of patient care. A database of intra-operative monitoring data was analyzed to find characteristic alarm patterns. The original data were re-evaluated to find relevant events and to rate the severity of these events. Based on this analysis an adaptive time delay was developed that individually delays the alarms depending on the grade of threshold deviation. The conventional threshold algorithm led to 4893 alarms. 3515 (71.84 %) of these alarms were annotated as clinically irrelevant. In total 81.0 % of all clinically irrelevant alarms were caused by only mild and/or brief threshold violations. We implemented the new algorithm for selected parameters. These parameters equipped with adaptive validation delays led to 1729 alarms. 931 (53.85 %) alarms were annotated as clinically irrelevant. 632 alarms indicated the 645 clinically relevant events. The positive predictive value of occurring alarms improved from 28.16 % (conventional algorithm) to 46.15 % (new algorithm). 13 events were missed. The false positive alarm reduction rate of the algorithm ranged from 33 to 86.75 %. The overall reduction was 73.51 %. The implementation of this algorithm may be able to suppress a large percentage of false alarms. The effect of this approach has not been demonstrated but shows promise for reducing alarm fatigue. Its safety needs to be proven in a prospective study.

Trends in Surgical Aortic Valve Replacement in More Than 3,000 Consecutive Cases in the Era of Transcatheter Aortic Valve Implantations.

Objectives Biological prostheses for surgical aortic valve replacement (sAVR) are increasingly being considered in patients < 60 years of age. Likely, preserving the option of performing a transcatheter valve-in-valve (ViV) procedure in cases of structural valve deterioration has contributed to this development. We assessed the use pattern in sAVR over an 11-year period. Methods From 2002 through 2012, a total of 3,172 patients underwent sAVR at our center. Results Mean age was 70.4 ± 10.6 years and mortality was 1.9%. From 2002 to 2012, mean manufacturer given valve size increased from 22.8 ± 1.7 to 23.9 ± 2.0 mm (p < 0.001). Mean true internal diameter and effective orifice area increased from 19.6 to 20.3 mm (p = 0.027) and 1.41 to 1.56 cm(2) (p < 0.001), respectively. Use of mechanical valves decreased from 10.9 to 1.8% (p < 0.001), and patients were younger in 2012 than in 2002 (52.8 ± 16.5 vs. 41.0 ± 14.3 years; p = 0.028). Conclusion Profound change of use pattern in sAVR was observed as indication for biological prostheses became more liberal. Larger prostheses were implanted during the observational period. Especially in younger patients, optimal sizing is essential to preserve the option for subsequent ViV procedures.

Distinction of non-ischemia inducing versus ischemia inducing coronary stenosis by fluorescent cardiac imaging.

Intraoperative fluorescent cardiac imaging (FCI) can quantitatively assess myocardial perfusion abnormalities produced by graded flow-limiting coronary stenosis (FLS), but there are no data to distinguish FLS from non flow-limiting stenosis (NFLS) to determine their functional significance. The aim of the study was to evaluate whether non-ischemia inducing NFLS can be quantified and differentiated from FLS by FCI technology. Data are compared to gold standard fluorescent microspheres (FM). 11 domestic pigs of either sex underwent sternotomy. Left anterior descending coronary artery blood-flow was recorded by transit-time flow measurements. After baseline and Adenosine-induced hyperemia, two stenosis of low severity (50 and 90 % NFLS) were produced, followed by FLS (50 %) and total vessel occlusion. Time-dependent fluorescence intensity curves were recorded by FCI. Slope of fluorescence intensity (SFI) and background-subtracted peak fluorescence (BSFI) intensity were calculated and data compared to myocardial blood flow measurements using FM. All NFLS and FLS reduced myocardial perfusion as quantified by FCI showing decreased normalized BSFI and SFI (P < 0.001). Box-plot analysis showed significant difference between NFLS (50 and 90 %) and FLS (50 %) assessed by BSFI (P < 0.001) and SFI (P < 0.001). In each animal, a linear correlation between FM-derived myocardial blood flow and FCI-derived BSFI (r = 0.936, P < 0.001) or SFI (r = 0.942, P < 0.001) was observed during baseline, hyperemia, graded NFLS, and FLS. Both, BSFI (r = 0.789, P < 0.001) and SFI (r = 0.802, P < 0.001) significantly correlated with transit-time flow measurements. FCI quantitative technology is capable of distinguishing between non-ischemia inducing NFLS and ischemia inducing FLS showing a good correlation compared to fluorescent microspheres.

Initial experience of pacemaker and implantable cardioverter defibrillator lead extraction with the new GlideLight 80 Hz laser sheaths.

OBJECTIVES: Laser lead extraction is a challenging procedure, especially in patients with old or multiple pacemaker (PM) or implantable cardioverter defibrillator (ICD) leads. The mechanical force is a leading cause of complications during the extraction procedure. Use of new laser sheaths, which deliver a rate of 80 pulses per second, may probably reduce intraoperative adverse events by reduction of extraction force. METHODS: Between January 2012 and April 2013, 76 PM and ICD leads were treated in 38 patients using GlideLight 80 Hz laser sheaths. Indications for lead removals were pocket infection (42.1%), septicaemia or endocarditis (23.7%), lead dysfunction (31.6%) and upgrade from PM to ICD (2.6%). Data on procedural success rates, intra- and postoperative outcomes, as well as 30-day mortality were collected into a database and analysed retrospectively. RESULTS: The mean patient age was 62.0 ± 17.7 years (range 18-83), and 73.7% were male. The mean time from initial lead implantation was 96.0 ± 58.3 months (range 24-288). Thirty-seven (48.7%) PM and 39 (51.3%) ICD leads had to be extracted. The mean procedural time was 68.3 ± 27.3 min (range 35-115). Seventy-two of 76 leads (94.8%) were completely removed, partial removal was achieved in 2 (2.6%) leads and a failure of extraction occurred in 2 (2.6%) leads. The overall complication rate was 5.2%, including one major (superior vena cava perforation) (2.6%) and one minor (pocket haematoma) (2.6%) complication. No death occurred during the 30-day follow-up. CONCLUSIONS: The GlideLight 80 Hz laser sheath allows safe and effective removal of chronically implanted PM and ICD leads, combining high procedural success with low complication rates.

Transcutaneous lead implantation connected to an externalized pacemaker in patients with implantable cardiac defibrillator/pacemaker infection and pacemaker dependency.

AIMS: Systemic cardiac implantable electronic device (CIED) infection is a serious complication, especially in patients with pacemaker (PM) dependency. In those patients after infectious device removal temporary pacing is necessary, to obtain adequate haemodynamics. In this study, a new therapy option with temporary pacing by ipsilateral implantation of a new active-fixation right ventricular (RV)-lead was evaluated. METHODS AND RESULTS: Between September 2009 and November 2011, infectious lead removal was performed in 17 patients with systemic CIED infection. Temporary pacing was achieved by simultaneous implantation of a new active-fixation RV-lead, which then was connected extracorporally to the old CIED device. Antibiotic therapy was initiated. When laboratory infection parameters were in normal range and blood culture samples showed negative results, new CIED was implanted on contralateral side and temporary RV-lead was removed. Mean patients' age was 71.3 ± 9.1 years. Mean C-reactive protein values were 79.3 mg/dL, and mean leucocytes counts were 12.6 × 10(3). After lead extraction, temporary pacing was necessary in all patients due to severe bradycardia. Mean duration of temporary pacing was 12.7 (6-24) days. No major procedure-related peri- or post-operative adverse events occurred. Mean time of hospitalization was 20.8 (10-48) days. Mean follow-up time was 21.1 months (12-36), showing survival rate of 100% and freedom from reinfection in all patients. CONCLUSION: Ipsilateral implantation of a temporary active-fixation RV-lead connected to an externalized PM and pursued antibiotic therapy seems to be a good option for patients with CIED infection and PM dependency, showing no temporary pacing-related complications and no reinfection after mean follow-up time of 21.1 months.

Customized transapical thoracic endovascular repair for acute type A dissection.

A 67-year-old patient with severe comorbidities and acute type A aortic dissection with pericardial tamponade was treated with an endograft introduced through a mini-thoracotomy and puncture of the left ventricular apex. Final angiography showed complete coverage of the dissection. Early and 6-month follow-up computed tomography showed full apposition of the endograft without residual dissection. Transapical thoracic endovascular repair of acute type A aortic dissection appears to be feasible and is associated with minimal physiologic compromise. It may provide a less invasive alternative for patients with increased operative mortality.

Myeloperoxidase deficiency preserves vasomotor function in humans.

AIMS: Observational studies have suggested a mechanistic link between the leucocyte-derived enzyme myeloperoxidase (MPO) and vasomotor function. Here, we tested whether MPO is systemically affecting vascular tone in humans. METHODS AND RESULTS: A total of 12 135 patients were screened for leucocyte peroxidase activity. We identified 15 individuals with low MPO expression and activity (MPO(low)), who were matched with 30 participants exhibiting normal MPO protein content and activity (control). Nicotine-dependent activation of leucocytes caused attenuation of endothelial nitric oxide (NO) bioavailability in the control group (P < 0.01), but not in MPO(low) individuals (P = 0.12); here the MPO burden of leucocytes correlated with the degree of vasomotor dysfunction (P = 0.008). To directly test the vasoactive properties of free circulating MPO, the enzyme was injected into the left atrium of anaesthetized, open-chest pigs. Myeloperoxidase plasma levels peaked within minutes and rapidly declined thereafter, reflecting vascular binding of MPO. Blood flow in the left anterior descending artery and the internal mammary artery (IMA) as well as myocardial perfusion decreased following MPO injection when compared with albumin-treated animals (P < 0.001). Isolated IMA-rings from animals subjected to MPO revealed markedly diminished relaxation in response to acetylcholine (P < 0.01) and nitroglycerine as opposed to controls (P < 0.001). CONCLUSION: Myeloperoxidase elicits profound effects on vascular tone of conductance and resistance vessels in vivo. These findings not only call for revisiting the biological functions of leucocytes as systemic and mobile effectors of vascular tone, but also identify MPO as a critical systemic regulator of vasomotion in humans and thus a potential therapeutic target.

First successful use of the new ab5000 portable circulatory support console as bridge to recovery in a case of dilated cardiomyopathy.

INTRODUCTION: Growing clinical experience and improved technology have led to more widespread use of ventricular assist devices in patients with end-stage heart failure. METHODS: We report the case of a patient with preexisting cardiomyopathy who arrived at our center in cardiogenic shock and received a biventricular assist device. RESULTS: The new compact Abiomed Portable Circulatory Support Console facilitated mobilization of the patient which was particularly advantageous in the face of transient hemiparesis. After recovery from cardiogenic shock, device removal was performed following a bridge-to-recovery concept. He was discharged in a state of full cardiac recompensation and is back to everyday life with stable cardiac function up to 24 months after the incident. CONCLUSIONS: This is the first report describing successful clinical use of the AB5000 assist device in combination with the portable console. Furthermore, it underlines the potential of temporary circulatory support to induce permanent myocardial recovery even in cases of preexisting cardiomyopathy.

Ten-year follow up after autologous rectus abdominis fascia sheath patch repair of aortic root abscess.

The infection of aortic annular tissue is a life-threatening complication of aortic valve endocarditis, the survival of which is usually with immediate surgical intervention. Optimal surgical techniques include aortic valve replacement with an aortic or pulmonary homograft, and reconstruction of cardiac structures with autologous pericardium. Here, two cases are reported with extensive aortic root infection and partial left ventricular-aortic dehiscence, who underwent left ventricular outflow tract reconstruction using a rectus abdominis fascia patch and aortic valve replacement with a Carpentier-Edwards porcine bioprosthetic graft. Both patients did well perioperatively and for 10 years postoperatively. The results may encourage alternative surgical strategies to be used when aortic valve homografts or autologous pericardium are unavailable. Notably, autologous rectus fascia patches showed excellent performance in the reconstruction of left ventricular outflow tract destruction associated with aortic root abscess.

Surgical revision of an uncommonly dislocated self-expanding Amplatzer septal occluder device.

Open heart surgery is the standard procedure for closure of ostium secundum atrial septal defects. Recently, percutaneous transcatheter procedures emerged as therapeutic alternatives for closure of both atrial septal defects and patent foramen ovale. Unfortunately, however, such percutaneous procedures may require surgical intervention for early or late complications. We report a case with emergent surgery for dislocation of the Amplatzer septal occluder into the aortic arch diagnosed 30 days after percutaneous closure of an atrial septal defect.

Functional and biochemical analysis of endothelial (dys)function and NO/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment.

BACKGROUND: In experimental animal models, long-term in vivo treatment with nitroglycerin (NTG) induces both endothelial dysfunction and tolerance to nitrates. However, it is still controversial whether nitrate tolerance in humans is associated with both endothelial dysfunction and impaired vascular response to nitrovasodilator-derived NO. METHODS AND RESULTS: Patients undergoing elective bypass surgery were randomized to receive 48 hours of continuous NTG infusion (NTG group) or no nitrate therapy (control group). Segments of surgically removed arteria mammaria, vena saphena, and arteria radialis not required for the bypass procedure were used to examine (1) the vascular responsiveness to NTG and the endothelium-dependent vasodilator acetylcholine; (2) the expression of the NO target, the soluble guanylyl cyclase; (3) the expression of the soluble guanylyl cyclase/cGMP effector target, the cGMP-dependent protein kinase (cGK); and (4) the cGK activity as assessed by the phosphorylation state of its vascular substrate, the vasodilator-stimulated phosphoprotein at serine(239) (P-VASP). NTG treatment caused a marked degree of nitrate tolerance in all 3 vessel types studied and a significant cross-tolerance to the endothelium-dependent vasodilator acetylcholine in A. mammaria and A. radialis. Although soluble guanylyl cyclase, cGK-I, and VASP expression levels were not modified by NTG treatment, a marked decrease of P-VASP, a surrogate parameter for in-vivo cGK-I activity, was observed. CONCLUSIONS: We conclude that long-term NTG treatment induces endothelial dysfunction and impaired vascular NO/cGMP signaling in humans, which can be monitored by measuring P-VASP levels.