[Diagnostics and Treatment of Cardiac Sarcoidosis - Consensus Paper of the German Respiratory Society (DGP) and the German Cardiac Society (DGK)]. / Diagnostik und Therapie der kardialen Sarkoidose.

Sarcoidosis is a multisystemic granulomatous disorder which affects the respiratory system in the majority of the cases. Symptomatic cardiac manifestations are found in less than 10 % of the affected cohorts and show a large heterogeneity based on the ethnic background. Cardiac sarcoidosis is not only found in patients with rhythmogenic heart disease, such as atrial and ventricular fibrillation but also in all phenotypes of cardiomyopathy. The overall morbidity and mortality caused by cardiac sarcoidosis in Germany remains unclear and large prospective international observational studies.underline the importance of this disease entity. This consensus paper on diagnostic and therapeutic algorithms for cardiac sarcoidosis is based on a current literature search and forms an expert opinion statement under the auspices of the German Respiratory Society and the German Cardiac Society. The rationale of this statement is to provide algorithms to facilitate clinical decision-making based on the individual case situation.

Intermittent Hypoxia Contributes to the Lung Damage by Increased Oxidative Stress, Inflammation, and Disbalance in Protease/Antiprotease System.

INTRODUCTION: Intermittent hypoxia as a surrogate of obstructive sleep apnea is associated with different cardiovascular complications. However, the effects of intermittent hypoxia on the lung tissue are less known. Therefore, the aim of our present study was to investigate if intermittent hypoxia may influence oxidative stress, inflammation, and protease/antiprotease system in the lung. Additionally, potential protective properties of anti-inflammatory and anti-oxidative drugs have been evaluated. METHODS: 32 mice were divided into four groups: (1) intermittent hypoxia, (2) intermittent hypoxia with infliximab, (3) intermittent hypoxia with L-glutathione, and (4) normoxia. After 4 weeks, lungs and blood were collected. Levels of reactive oxygen species in the lung were calculated by L-O12-enhanced chemiluminescence. CD68-positive lung macrophages were detected by immunofluorescence. Concentrations of elastase and desmosine in lung and of alpha-1-antitrypsin in blood were calculated by means of enzyme-linked immunosorbent assay. RESULTS: Compared to a control, intermittent hypoxia augmented the release of free oxygen radicals, expression of CD68+ macrophages, and concentration of elastase in the lung tissue. Despite increased blood levels of protective alpha-1-antitrypsin, concentrations of desmosine-degradation product of elastin were higher versus control. The application of anti-inflammatory infliximab und anti-oxidative L-glutathione prevented at least partly the above-observed hypoxia-associated changes. CONCLUSIONS: Intermittent hypoxia contributes to the lung damage by increased oxidative stress, inflammation, and disbalance in protease/antiprotease system. Infliximab and L-glutathione may prevent adverse hypoxia-induced lung alternations.

Heart Rate Variability and Arrhythmic Burden in Pulmonary Hypertension.

A growing body of evidence indicates that sudden cardiac death constitutes a major cause of mortality in pulmonary hypertension (PH). As validated method to evaluate cardiac autonomic system dysfunction, alterations in heart rate variability (HRV) are predictive of arrhythmic events, particularly in left ventricular disease. Here, we sought to determine the clinical value of HRV assessment in PH. Sixty-four patients were allocated to different PH-subgroups in this prospectively conducted trial: 25 patients with pulmonary arterial hypertension (PAH), 11 patients with chronic thromboembolic PH (CTEPH), and 28 patients with COPD-induced PH. All patients underwent 24-h Holter electrocardiogram for HRV assessment by time- and frequency-domain analysis. Arrhythmic burden was evaluated by manual analysis and complementary automatic measurement of premature atrial and ventricular contractions. The results were compared to 31 healthy controls. The PAH patients offered a significantly higher mean heart rate (78.6 ± 10.4 bpm vs. 70.1 ± 10.3 bpm, p = 0.04), a higher burden of premature ventricular contractions (p < 0.01), and decreases in HRV (SDNN: p < 0.01; SDANN: p < 0.01; very low frequency: p < 0.01; low frequency/high frequency ratio: p < 0.01; total power: p = 0.02). In CTEPH patients, only the amount of premature ventricular contractions differed from controls (p < 0.01), whereas in COPD both premature atrial contraction count and frequency-domain-based HRV manifested significant differences. In conclusion, PAH appears to be primarily affected by HRV alterations and ventricular arrhythmic burden, indicating a high risk for malignant arrhythmic events.

Pharmacological and ablative hybrid therapy of atrial fibrillation. Long-term effect on quality of life and arrhythmia-related symptoms.

UNLABELLED: The pharmacological and ablative hybrid therapy of atrial fibrillation (AF) consists of radiofrequency catheter ablation of antiarrhythmic drug-induced typical atrial flutter (AFl) and continuation of drug therapy. The purpose of this study was to determine the effect of this therapy on AF symptoms and quality of life (QoL). Forty-six patients were monitored after isthmus-ablation of drug-induced typical AFl and continuation of their antiarrhythmic drug treatment over a mean follow-up of 22.4+/-11.6 months. AF characteristics, symptoms and QoL before and after ablation were evaluated by the SF-36 question- naire, the Symptoms Checklist-Frequency and Severity Scale and the analysis of ECG recordings. 63% of patients demonstrated recurrences of AF. However, the frequency and duration of symptomatic episodes significantly decreased in 82.6 and 76% of patients. All categories of the SF-36 improved significantly and the AF symptomatology showed a relevant attenuation in 65.8% of the study population. CONCLUSION: The pharmacological and ablative hybrid therapy significantly reduced the mean number and the duration of symptomatic AF episodes as well as AF-correlated symptoms and was associated with significant QoL improvement.

Mayer-von Rokitansky-Küster-Hauser syndrome in association with a hitherto undescribed variant of the Holt-Oram syndrome with an aorto-pulmonary window.

We report on the association of Mayer-von Rokitansky-Küster-Hauser syndrome (MRKHS) with a unique form of Holt-Oram syndrome (HOS) with an aorto-pulmonary window. A 24-year-old Turkish woman was referred to our hospital because of primary amenorrhoea. Both her vagina and uterus were absent, and the diagnosis of MRKHS was established. Laparoscopic creation of a neovagina by the modified Vecchietti technique was performed. A rare congenital malformation of the heart, namely an aorto-pulmonary window, had required cardiac surgery when the patient was a 6-month-old infant. This cardiac malformation plus associated upper limb anomalies led to the clinical diagnosis of HOS. To the best of our knowledge, this is only the second report in the scientific literature on the concurrence of MRKHS and HOS, and the first published case of HOS with an aorto-pulmonary window as the cardiac malformation.

Heart rate variability in patients suffering from structural heart disease and decreased AV-nodal conduction capacity. Insights into the formation of heart rate variability.

METHODS: Time and frequency domain analysis were conducted during a period of 600 s each. We performed a special protocol consisting of five different "pacing" periods: 1) recording of normal sinus rhythm (SR1); 2) atrial pacing with a rate 15% higher than the intrinsic heart rate; 3) ventricular pacing triggered by atrial activation (VAT, with a short AV-delay of 80 ms); 4) AV-sequential pacing with an atrial rate 15% higher than the intrinsic heart rate and a very short AV delay of 80 ms (DDD); 5) normal sinus rhythm (SR2). Only patients with normal AV-nodal conduction or with AV-block I degrees were included. The influence of a structural heart disease as well as a non-sustained VT on Holter ECG and a depressed EF on HRV parameters were analyzed using a multivariate analysis. All patients were lying in a supine position. Blood pressure was measured continuously and the frequency of breathing was controlled. RESULTS: No differences in HRV between the two sinus rhythm periods SR1 versus SR2 could be detected. Neither SR1 vs VAT showed a significant difference for SDNN and r-MSSD. In contrast, HRV during SR1 compared to AAI, and HRV during VAT compared to AAI were significantly different (p < 0.001). When comparing HRV during DDD, which should be zero, and AAI, we found a significantly lower SDNN and r-MSSD (1.2 ms vs 4 ms, p < 0.04). The presence of structural heart disease, a non-sustained ventricular tachycardia, a depressed ejection fraction of less than 0.50 did not reveal a significant influence on the HRV parameters (multivariate analysis). The mean Wenckebach in patients with structural heart disease tended to be greater (437 ms vs 350 ms, p = 0.05); an increase in the Wenckebach was not correlated to a change in HRV parameters (p = ns). CONCLUSION: Heart rate variability derived from consecutive RR-intervals is predominantly caused by periodicity in sinus-node impulse formation. A conduction variability of the AV-node exists, but is very low. The presence of a structural heart disease, a non-sustained ventricular tachycardia on Holter ECG, as well as a depressed ejection fraction of less than 0.50 showed no significant influence on the HRV parameters. Therefore, one can apply the calculation of heart rate variability for risk stratification in patients suffering from structural heart disease and moderate AV-nodal conduction disturbances. Attenuation of the oscillation of the heart rate, i. e. heart rate variability (HRV), is associated with an increased risk for mortality in patients with structural heart disease. Many of these patients also suffer from conduction disturbances, e. g. AV-nodal conduction delays. Whether the calculation of HRV in those patients is recommendable has not been investigated yet. Therefore, we conducted a study consisting of 20 consecutive patients in order to determine the formation of HRV, the influence of structural heart disease, the presence of a nonsustained ventricular tachycardia (VT), and a reduced ejection fraction (EF) on the HRV parameters during an elective electrophysiologic study.

Amiodarone-associated "torsade de pointes". Relevance of concomitant cardiovascular medication in a patient with atrial fibrillation and structural heart disease.

A 69 year old female with history of coronary heart disease, myocardial infarction and paroxysmal atrial fibrillation suffered from occipital apoplexy. Under treatment with amiodarone 600 mg daily and concomitant medication with beta-acetyldigoxine (0.1 mg daily) and bisoprolole (1.25 mg daily), significant QT-prolongation (max. 700 ms; QTc: 614 ms) could be documented. Out of normofrequent sinus rhythm but as well out of bradycardia, the patient developed repetitive short-lasting "torsade de pointes" tachycardias (320 bpm) which terminated spontaneously. Serum electrolytes, plasma levels of digoxine (1.76 ng/ml) and amiodarone (1.9 mcg/ml) were within therapeutic range. This case report is the first to describe induction of amiodarone-associated "torsade de pointes" tachycardia during concomitant beta-blocker and digitalis medication in a patient with atrial fibrillation and structural heart disease. This points towards an elevated risk for proarrhythmia under this triple therapy.

Biosynthesis of constitutive nitric oxide synthase-derived nitric oxide attenuates coronary vasoconstriction and myocardial depression in a model of septic heart failure induced by Staphylococcus aureus alpha-toxin.

OBJECTIVE: Myocardial depression, which frequently occurs in the course of septic shock, has been attributed to the cardiodepressant properties of nitric oxide (NO) generated by either the inducible NO synthase (iNOS) or the constitutive isoform (cNOS). We have previously demonstrated that alpha-toxin from Staphylococcus aureus induces thromboxane-mediated vasoconstriction accompanied by severe cardiodepression in isolated rat hearts. In the present study, we investigated the role of NO in the alpha-toxin-induced vascular and contractile abnormalities. DESIGN: Prospective, experimental study. SETTING: Research laboratory at a university hospital. SUBJECTS: Isolated hearts from male Wistar rats. INTERVENTIONS: Isolated hearts were perfused with purified staphylococcal alpha-toxin for 60 mins. MEASUREMENTS AND MAIN RESULTS: At a concentration of 0.25 and 0.5 microg/mL, alpha-toxin induced a rise in coronary perfusion pressure, depressed myocardial contractility, and caused edema formation. Simultaneously, a time- and dose-dependent rapid release of NO into the perfusate was noted as quantified by a chemiluminescence technique. L-NMMA, a nonselective inhibitor of NOS, but not PBITU, an iNOS-selective inhibitor, blocked NO synthesis, markedly increased the rise in coronary perfusion pressure and the loss in contractility, and enhanced edema formation in response to alpha-toxin. In contrast, zaprinast, a selective inhibitor of phosphodiesterase type V that is used for stabilization of cyclic guanosine monophosphate, attenuated the toxin-induced coronary vasoconstrictor response and the myocardial depression. L-arginine, the substrate of NOS, had similar, yet less potent, effects as zaprinast and slightly increased the release of NO caused by alpha-toxin. Immunohistochemical analysis of the myocardium at the end of the perfusion period demonstrated a positive staining for cNOS but not for iNOS. In addition, no up-regulation of iNOS mRNA was detected in the tissue of toxin-exposed hearts. CONCLUSIONS: Staphylococcal alpha-toxin provokes NO biosynthesis via activation of cNOS in rat hearts. NO partly antagonizes the deleterious effects of this pathogenicity factor on coronary vasoregulation and myocardial performance.