Johannes Kastner

Sex differences in concentrations of exhaled nitric oxide and plasma nitrate

Nitric oxide (NO) is generally considered as an endogenous vasoprotective agent. Various studies indicate that the female sex hormone estradiol, that contributes to the well known gender differences in cardiovascular disease, may enhance NO-production. Thus we studied sex differences in NO-generation by measuring single breath NO-exhalation and plasma levels of nitrate (NO3), the stable endmetabolite of NO. In this observational trial 22 male and 21 female volunteers, 19 to 38 years of age, were studied on 3 days at weekly intervals. Median concentrations of NO were 20 parts per billion (95% CI: 16 to 32 ppb) in women and 34 ppb (95% CI: 31 to 58 ppb) in men. The median plasma concentrations of NO3 were 14 microM/L (95% CI: 11 to 23 microM/L) in women and 27 microM/L (95% CI: 24 to 47 microM/L) in men. Thus, men exhaled 59% more NO (p < 0.001) and had 99% higher NO3 levels than women (p < 0.0001). Even when exhaled NO concentrations were corrected for body weight, men exhaled 50% more NO than women (p = 0.024). No significant changes in measured endpoints were seen during the menstrual cycle (p > 0.05) in women. In view of the diversity of NO-actions, the finding of marked sex differences in NO-production is basic to the elucidation of gender differences in a number of (patho)-physiologic conditions.

Inhaled Nitric Oxide Reduces Pulmonary Vascular Resistance More Than Prostaglandin E1 During Heart Transplantation

Heart transplantation in patients with increased pulmonary vascular resistance is often associated with postbypass right heart failure. We therefore compared the abilities of prostaglandin E1 (PGE1) and inhaled nitric oxide to reduce pulmonary vascular resistance during heart transplantation. Patients undergoing orthotopic heart transplantation for congestive heart failure were randomly assigned to either a PGE1 infusion at a rate of 8 ng · kg· −1min−1 starting 10 min before weaning from cardiopulmonary bypass (CPB) (n = 34) or inhalation of 4 ppm nitric oxide starting just before weaning from CPB (n = 34). Both treatments were increased stepwise, if necessary, and were stopped 6 h postoperatively. Hemodynamic values were recorded after the induction of anesthesia, 10 and 30 min after weaning from CPB, and 1 h and 6 h postoperatively. Immediately after weaning from CPB, pulmonary vascular resistance was nearly halved in the nitric oxide group but reduced by only 10% in the PGE1 group. Pulmonary artery pressure was decreased approximately 30% during nitric oxide inhalation, but only approximately 16% during the PGE1 infusion. Six hours after surgery, pulmonary vascular resistance and pulmonary artery pressure were similar in the two groups. The ratio between pulmonary vascular resistance and systemic vascular resistance was significantly less in the nitric oxide patients at all postbypass times. In contrast, the pulmonary-to-systemic vascular resistance ratio increased approximately 30% in the patients given PGE1. Cardiac output, heart rate, mean arterial pressure, right atrial pressure, and pulmonary wedge pressure did not differ between the groups. Weaning from CPB was successful in all patients assigned to nitric oxide inhalation; in contrast, weaning failed in six patients assigned to PGE1 (P = 0.03). Implications: Nitric oxide inhalation selectively reduces pulmonary vascular resistance and pulmonary artery pressure immediately after heart transplantation which facilitates weaning from cardiopulmonary bypass.

Efficacy of two methods for reducing postbypass afterdrop

Background Afterdrop, defined as the precipitous reduction in core temperature after cardiopulmonary bypass, results from redistribution of body heat to inadequately warmed peripheral tissues. The authors tested two methods of ameliorating afterdrop: (1) forced-air warming of peripheral tissues and (2) nitroprusside-induced vasodilation. Methods Patients were cooled during cardiopulmonary bypass to approximately 32°C and subsequently rewarmed to a nasopharyngeal temperature near 37°C and a rectal temperature near 36°C. Patients in the forced-air protocol (n = 20) were assigned randomly to forced-air warming or passive insulation on the legs. Active heating started with rewarming while undergoing bypass and was continued for the remainder of surgery. Patients in the nitroprusside protocol (n = 30) were assigned randomly to either a control group or sodium nitroprusside administration. Pump flow during rewarming was maintained at 2.5 l · m−2 · min−1 in the control patients and at 3.0 l · m−2 · min−1 in those assigned to sodium nitroprusside. Sodium nitroprusside was titrated to maintain a mean arterial pressure near 60 mmHg. In all cases, a nasopharyngeal probe evaluated core (trunk and head) temperature and heat content. Peripheral compartment (arm and leg) temperature and heat content were estimated using fourth-order regressions and integration over volume from 18 intramuscular needle thermocouples, nine skin temperatures, and “deep” hand and foot temperature. Results In patients warmed with forced air, peripheral tissue temperature was higher at the end of warming and remained higher until the end of surgery. The core temperature afterdrop was reduced from 1.2 ± 0.2°C to 0.5 ± 0.2°C by forced-air warming. The duration of afterdrop also was reduced, from 50 ± 11 to 27 ± 14 min. In the nitroprusside group, a rectal temperature of 36°C was reached after 30 ± 7 min of rewarming. This was only slightly faster than the 40 ± 13 min necessary in the control group. The afterdrop was 0.8 ± 0.3°C with nitroprusside and lasted 34 ± 10 min which was similar to the 1.1 ± 0.3°C afterdrop that lasted 44 ± 13 min in the control group. Conclusions Cutaneous warming reduced the core temperature afterdrop by 60%. However, heat-balance data indicate that this reduction resulted primarily because forced-air heating prevented the typical decrease in body heat content after discontinuation of bypass, rather than by reducing redistribution. Nitroprusside administration slightly increased peripheral tissue temperature and heat content at the end of rewarming. However, the core-to-peripheral temperature gradient was low in both groups. Consequently, there was little redistribution in either case.

Unexplained syncope in patients with structural heart disease and no documented ventricular arrhythmias: value of electrophysiologically guided implantablecardioverter defibrillator therapy

AIMS To evaluate electrophysiologically guided implantable cardioverter defibrillator (ICD) therapy in patients with syncope, structural heart disease and no documented sustained ventricular tachycardia (sVT). METHODS AND RESULTS Programmed ventricular stimulation (PVS) was performed in 52 patients (age 62+/-10 years): 40 patients had ischaemic and 12 patients had idiopathic dilated cardiomyopathy. On PVS sVT and ventricular fibrillation were induced in seven and four patients, respectively, and two patients spontaneously experienced symptomatic sVT. These patients received an ICD (ICD group, n=13). Non-inducible patients were left on conventional therapy (non-ICD group, n=39). During 5+/-2.8 years five ICD patients received therapies, all appropriate. There were seven non-sudden deaths and overall survival analysis revealed no significant difference. Recurrent syncope occurred in five ICD and four non-ICD patients and did not correlate well with sVT. The positive and negative predictive values of PVS for tachyarrhythmias or sudden death were 36 and 98%, respectively. CONCLUSION Syncope per se does not necessarily herald a bad prognosis. PVS identifies high-risk patients. Induction of ventricular fibrillation with double or triple extrastimuli is of limited value. Patients with poor left ventricular function and bad clinical condition benefit most from an ICD. Syncope and sVT are not necessarily correlated during follow-up, which may merit consideration.

Tissue heat content and distribution during and after cardiopulmonary bypass at 17°C

UNLABELLED We measured afterdrop and peripheral tissue temperature distribution in eight patients cooled to approximately 17 degrees C during cardiopulmonary bypass and subsequently rewarmed to 36.5 degrees C. A nasopharyngeal probe evaluated trunk and head temperature and heat content. Peripheral tissue temperature (arm and leg temperature) and heat content were estimated using fourth-order regressions and integration over volume from 30 tissue and skin temperatures. Peripheral tissue temperature decreased to 19.7+/-0.9 degrees C during bypass and subsequently increased to 34.3+/-0.7 degrees C during 104+/-18 min of rewarming. The core-to-peripheral tissue temperature gradient was -5.9+/-0.9 degrees C at the end of cooling and 4.7+/-1.5 degrees C at the end of rewarming. The core-temperature afterdrop was 2.2+/-0.4 degrees C and lasted 89+/-15 min. It was associated with 1.1+/-0.7 degrees C peripheral warming. At the end of cooling, temperatures at the center of the upper and lower thigh were (respectively) 8.0+/-5.2 degrees C and 7.3+/-4.2 degrees C cooler than skin temperature. On completion of rewarming, tissue at the center of the upper and lower thigh were (respectively) 7.0+/-2.2 degrees C and 6.4+/-2.3 degrees C warmer than the skin. When estimated systemic heat loss was included in the calculation, redistribution accounted for 73% of the afterdrop, which is similar to the contribution observed previously in nonsurgical volunteers. IMPLICATIONS Temperature afterdrop after bypass at 17 degrees C was 2.2+/-0.4 degrees C, with approximately 73% of the decrease in core temperature resulting from core-to-peripheral redistribution of body heat. Cooling and rewarming were associated with large radial tissue temperature gradients in the thigh.

Effects of nitroglycerin and sodium nitroprusside on endexpiratory concentrations of nitric oxide in healthy humans.

The cellular origin of nitric oxide (NO) in exhaled air of healthy humans is unknown. It is currently not known, whether changes in NO concentrations that originate from pulmonary vessels, can be detected as changes in exhaled NO. Thus, we have studied the effects of increased intravascular NO generation on endexpiratory NO-levels. Twenty-four young healthy volunteers received nitroglycerin (GTN), sodium nitroprusside (SNP) or placebo i.v. in a randomized, double blind cross-over trial. Diastolic blood pressure decreased from 59 mmHg (95% confidence interval: 56-62) during placebo to 48 mmHg (CI: 45-51) and to 48 mmHg (CI: 45-50) after infusions of GTN and SNP, respectively. Heart rate increased from 69 (CI: 65-73) during placebo to 78 (CI: 72-84) and to 84 (CI: 77-92) after infusions of GTN and SNP, respectively (p<0.01 for all comparisons). However, no increase in exhaled NO was detected: endexpiratory NO-concentrations averaged 6.1 ppb (CI: 4.9-7.4), 5.7 ppb (CI: 4.4-7.0) and 6.4 ppb (CI: 5.3-7.6) under placebo, GTN and SNP infusions, respectively (Friedman ANOVA p=0.328). NO release from within the pulmonary vasculature does not significantly contribute to endexpiratory NO concentrations in non-intubated healthy humans suggesting that such NO measurements quantify NO production mainly from non-vascular pulmonary cells.

Evaluation of the short- and long-term safety and therapy outcomes of the everolimus-eluting bioresorbable vascular scaffold system in patients with coronary artery stenosis: Rationale and design of the German-Austrian ABSORB RegIstRy (GABI-R).

BACKGROUND Third-generation drug-eluting metal stents are the gold standard for treatment of coronary artery disease. The permanent metallic caging of the vessel, however, can result in limited vasomotion, chronic inflammation, and late expansive remodeling, conditions that can lead to late and very late stent thrombosis. The development of bioresorbable scaffolds (BRSs) promises advantages over metal stents due to complete biodegradation within 2-4years. Theoretically, since vessel scaffolding is temporary and no permanent implant remains in the vessel, BRSs, as opposed to metal stents, once degraded would no longer be potential triggers for stent-related adverse events or side effects. METHODS/DESIGN The short- and long-term outcome after implantation of an everolimus-eluting, poly-L-lactic acid-based bioresorbable scaffold system (ABSORB, Abbott Vascular, Santa Clara, CA, USA) in the world-wide greatest all-comers cohort will be evaluated in the prospective, non-interventional, multicenter German-Austrian ABSORB RegIstRy (GABI-R). GABI-R will include over 5000 patients from about 100 study sites in Austria and Germany. Safety endpoints such as cardiac death, myocardial infarction, and clinically driven percutaneous or surgical target lesion and vessel revascularization will be evaluated during hospitalization and in the follow-up period (minimum of 5years). CONCLUSION Although two randomized controlled trials and several registries have documented safety and efficacy as well as non-inferiority of this everolimus-eluting ABSORB device compared with drug-eluting metal stents, the current knowledge regarding clinical application, treatment success, and long-term safety of using this BRS in daily routine is limited. Thus, the goal of GABI-R is to address this lack of information.

Nitric oxide concentration in the gas phase of the gastrointestinal tract in man

Nitric oxide (NO) has been implicated in various aspects of physiological regulation in the gastrointestinal tract. Hence, measurement of luminal NO concentrations is of interest for studying physiological and pathophysiological alterations in NO generation; however, at present, no reliable measurement techniques are available. Here we describe novel approaches for measurement of NO concentrations directly in the gas phase of the stomach and colon in healthy subjects and patients. Studies were conducted in young healthy volunteers (n = 13), intensive care patients (n = 8) and patients undergoing gastroscopy (n = 8) or colonoscopy (n = 8). NO concentrations were measured by chemolumininescence detection in air obtained through a nasogastric tube, after inflation into the stomach of a defined volume of air, or directly in the air suctioned from the endoscope. The mean NO concentration obtained from the stomach of healthy volunteers studied under baseline conditions was 18.0 ± 2.8 (SEM) p.p.m. Day‐to‐day reproducibility of NO measurements was high. Tube feeding with a nitrite‐ and nitrate‐free feeding solution left gastric NO concentrations unchanged, but standardized bicycle exercise caused an ≈30% decrease in NO levels. NO concentrations in intensive care patients were ≈2 log cycles lower than in healthy volunteers. NO levels in the colon were similar to those in the stomach. We have described two readily applicable techniques for direct, uncontaminated measurement of NO concentrations in the lumen of the gastrointestinal tract. Our finding of a striking reduction in gastric NO concentrations in intensive care patients requires further study.

Everolimus-eluting bioresorbable scaffolds in patients with coronary artery disease: results from the German-Austrian ABSORB RegIstRy (GABI-R)

AIMS The aim of this study was to analyse the procedural results and midterm safety of everolimus-eluting bioresorbable vascular scaffolds (BVS) used for percutaneous coronary intervention in a large all-comers cohort from the German-Austrian ABSORB RegIstRy (GABI-R). METHODS AND RESULTS A total of 3,231 patients were included in this prospective, observational, multicentre study (ClinicalTrials.gov NCT02066623) of consecutive patients undergoing BVS implantation between November 2013 and January 2016. Endpoints were major adverse cardiac events (MACE; a composite endpoint of death, target vessel revascularisation, and myocardial infarction), and target lesion failure (TLF; a composite endpoint of cardiac death, target vessel myocardial infarction, and target lesion revascularisation). Scaffold thrombosis was a further endpoint. Of all patients, 51.5% presented with acute coronary syndrome. Predilatation and post-dilatation were performed in 91.5% and 71.9% of patients, respectively. Procedural success was 98.9%. After six months, the incidence of MACE was 4.1% and of TLF 2.4%. The rate of target vessel MI was 1.5%, and target lesion revascularisation was performed in 1.8%. Definite/ probable scaffold thrombosis was documented in 1.4% of patients. CONCLUSIONS GABI-R, the largest registry to provide data regarding safety after BVS implantation in a real-world setting, reveals high procedural success and low six-month event rates.

Interventional Treatment of LVAD Outflow Graft Stenosis by Introduction of Bare Metal Stents.

Left ventricular assist device outflow graft stenosis is a rare but life-threatening complication of mechanical cirulatory support therapy. Current treatment modalities (pump exchange or systemic thrombolytic therapy) are associated with significant mortality and morbidity. Implantation of bare metal stents within the stenosed outflow graft is an alternative. Herein, we describe a series of three cases with successful stent placement. This seems to be safe and successful; however, correct and early diagnosis of outflow stenosis can be challenging. Information provided by the HeartWare ventricular assist device (HVAD) logfiles is extremely helpful for diagnosis.