Abnormal thyroid function is common in takotsubo syndrome and depends on two distinct mechanisms: results of a multicentre observational study.

BACKGROUND: Several reports have described Takotsubo syndrome (TTS) secondary to thyrotoxicosis. A complex interaction of central and peripheral catecholamines with thyroid homeostasis has been suggested. In this study, we analysed sequential thyroid hormone profiles during the acute phase of TTS. METHODS: Thyrotropin (TSH), free T4 (FT4) and free T3 (FT3) concentrations were analysed at predefined time points in 32 patients presenting with TTS or acute coronary syndrome (ACS, n = 16 in each group) in a 2-year period in two German university hospitals. Data were compared to age- and sex-matched controls (10 samples, each of 16 subjects), and an unsupervised machine learning (ML) algorithm identified patterns in the hormone signature. Subjects with thyroid disease and patients receiving amiodarone were excluded from follow-up. RESULTS: Among patients with TTS, FT4 concentrations were significantly higher when compared to controls or ACS. Four subjects (25%) suffered from subclinical or overt thyrotoxicosis. Two additional patients developed subclinical or overt thyrotoxicosis during stay in hospital. In four subjects (25%), FT4 concentrations were increased, despite nonsuppressed TSH concentration, representing an elevated set point of thyroid homeostasis. The thyroid hormone profile was normal in only six patients (38%) presenting with TTS. CONCLUSION: Abnormal thyroid function is frequent in patients with TTS. Primary hyperthyroidism and an elevated set point of thyroid homeostasis are common in TTS, suggesting a stress-dependent endocrine response or type 2 thyroid allostasis. Thyroid function may be a worthwhile target in treating or preventing TTS.

The number of regulatory T cells correlates with hemodynamic improvement in patients with inflammatory dilated cardiomyopathy after immunoadsorption therapy.

Inflammatory DCM (iDCM) may be related to autoimmune processes. An immunoadsorption (IA) has been reported to improve cardiac hemodynamics. The benefit of IA is probably related to the removal of autoantibodies. A recent study suggests additional effects of IA on the T cell-mediated immune reactions, especially on regulatory T cells (Tregs). In this prospective study, the correlation between the level of Tregs and improvement of myocardial contractility in response to IA in patients with iDCM was investigated. Patients (n = 18) with iDCM, reduced left ventricular (LV) ejection fraction (<35%), were enrolled for IA. Before and 6 months after IA, LV systolic function was assessed by echocardiography, and blood levels of Tregs were quantified by FACS analysis. Patients (n = 12) with chronic ischaemic heart failure and comparable reduced LV-EF served as controls. IA improved LV-EF in 12 of 18 patients at 6-month follow-up. These patients were classified as 'IA responder'. In 6 patients, LV-EF remained unchanged. At baseline, IA responder and non-responder subgroups showed similar values for C-reactive protein, white blood cells, lymphocytes and T helper cells, but they differ for the number of circulating Tregs (responder: 2.32 ± 1.38% versus non-responder: 4.86 ± 0.28%; P < 0.01). Tregs increased significantly in the IA responders, but remained unchanged in the IA non-responders. In patients with ischaemic cardiomyopathy, none of these values changed over time. A low level of Tregs in patients with chronic iDCM may characterize a subset of patients who do best respond to IA therapy.

Myocardial fractional flow reserve. Its role in guiding PCI in stable coronary artery disease.

Revascularization of coronary artery lesions should be based on objective evidence of ischemia, as recommended by the guidelines of the European Society of Cardiology. However, even in the case of stable coronary artery disease and elective percutaneous coronary intervention (PCI), pre-procedural noninvasive stress test results are available in a minority of patients only. It is common practice for physicians to make decisions on revascularization in the catheterization laboratory after a cursory review of the angiogram, despite the well-recognized inaccuracy of such an approach. Myocardial fractional flow reserve (FFR) measured by a coronary pressure wire is a specific index of the functional significance of a coronary lesion, with superior diagnostic accuracy for the detection of ischemia than any noninvasive stress test. FFR trials on patients with single and multivessel disease, such as the DEFER and FAME studies, have demonstrated that the clinical benefit of PCI with respect to patient outcome is greatest when revascularization is limited to lesions inducing ischemia, whereas lesions not inducing ischemia should be treated medically.

Influence of glycaemic control on platelet bound CD40-CD40L system, P-selectin and soluble CD40 ligand in Type 2 diabetes.

AIMS: Type 2 diabetes is a potent cardiovascular risk factor, associated with proinflammatory and prothrombotic processes. The purpose of this study was to investigate whether platelet-bound CD40-CD40L signalling, P-selectin expression and soluble CD40L were increased in patients with diabetes mellitus and can be normalized by improving glycaemic control. METHODS: Soluble (s) CD40L, platelet surface expression of CD40L, CD40 and P-selectin (CD62P) on platelets were measured by flow cytometry in 71 patients with Type 2 diabetes mellitus and 37 healthy volunteers. In addition, the relationship of HbA1c to CD40-CD40L and P-selectin expression was determined in a longitudinal follow-up. RESULTS: In patients with Type 2 diabetes, platelet membrane CD40 expression (Type 2 diabetes 3.1+/-0.61 vs. controls 2.5+/-0.85 mean fluorescence intensity; P=0.001), platelet-bound CD40L (1.2+/-0.32 vs. 1.1+/-0.14; P=0.034) as well as surface expression of CD62P (0.66+/-0.19 vs. 0.57+/-0.12; P=0.007) were higher than in control subjects. Plasma sCD40L values (3.2+/-1.70 vs. 1.8+/-0.50 ng/ml; P<0.001) were also significantly increased in Type 2 diabetes. After improving glycaemic control in patients with initial HbA1c>8.5% (n=15), platelet P-selectin and CD40-CD40L expression decreased significantly by 54.0%, 36.22% and 16.26%, respectively 1 year later. CONCLUSIONS: Type 2 diabetes is associated with up-regulation of the platelet-bound CD40-CD40L system, platelet hyperactivity (enhanced P-selectin expression) and increased sCD40L levels. Improved glycaemic control, however, does help to correct abnormal platelet activation via down-regulation of CD40-CD40L system and P-selectin expression.

CD31+/Annexin V+ microparticles in healthy offsprings of patients with coronary artery disease.

BACKGROUND: First-degree relatives of patients with premature coronary artery disease (CAD) develop endothelial dysfunction even in the case they are apparently healthy. In this study we wanted to clarify whether reduced blood levels of circulating endothelial progenitor cells (EPCs), an endogenous repair mechanism to replace dysfunctional endothelium, or elevated endothelial-derived microparticles (EMPs), an indicator and a mediator of increased endothelial cell damage/apoptosis, are an initial step in the pathogenesis of endothelial dysfunction in genetically predisposed subjects. MATERIALS AND METHODS: Fifty-six healthy young men (aged 23 to 31 years) from a fire brigade were enrolled, of which 20 subjects had a positive family history (FH) for premature CAD. Subjects with or without a positive FH did not differ with respect to age, body mass index, risk factors and C-reactive protein. Endothelial function was assessed by hyperaemia-mediated relaxation of the brachial artery, blood levels of EPCs (VEGFR2(+)CD34(+) cells) and number of EMPs (CD31(+(bright))/Annexin V(+) particles) were analysed by flow cytometry. RESULTS: Hyperaemia-mediated relaxation of the brachial artery was similar in both groups, and the blood levels of EPCs were comparable. However, the number of EMPs were significantly increased in subjects with a positive FH compared to those with a negative FH (neg. FH: 55.31 +/- 4.88 vs. pos. FH: 70.37 +/- 6.32 particles microL(-1 )platelet poor plasma; P < 0.05). Number of EMPs correlate inversely with the FMD response. CONCLUSIONS: These results suggest that increased plasma levels of EMPs may be an initial step in the development of endothelial dysfunction in genetically predisposed subjects.

Use of automated external defibrillators for in-hospital cardiac arrest : Any time, any place?

BACKGROUND: Acute treatment of in-hospital cardiac arrest (IHCA) is challenging and overall survival rates are low. However, data on the use of public-access automated external defibrillators (AEDs) for IHCA remain controversial. The aim of our study was to evaluate characteristics of patients experiencing IHCA and feasibility of public-access AED use for resuscitation in a university hospital. METHODS: IHCA events outside the intensive care unit were analysed over a period of 21 months. Patients' characteristics, AED performance, return of spontaneous circulation (ROSC) and 24 h survival were evaluated. Outcomes following adequate and inadequate AED use were compared. RESULTS: During the study period, 59 IHCAs occurred. AED was used in 28 (47.5%) of the cases. However, AED was adequately used in only 42.8% of total AED cases. AED use was not associated with an increased survival rate (12.9 vs. 10.7%, p = 0.8) compared to non-AED use. However, adequate AED use was associated with a higher survival rate (25 vs. 0%, p = 0.034) compared to inadequate AED use. Time from emergency call to application of AED >3 min was the most important factor of inadequate AED use. Adequate AED use was more often observed between 7:30 and 13:30 and in the internal medicine department. CONCLUSION: AEDs were applied in less than 50% of the IHCA events. Furthermore, AED use was inadequate in the majority of the cases. Since adequate AED use is associated with improved survival, AEDs should be available in hospital areas with patients at high risk of shockable rhythm.

Echocardiographic findings in patients with acute coronary syndrome and normal angiogram.

Coronary angiograms performed at the time of an acute coronary syndrome typically present vessel occlusions, ruptured plaques or thrombotic lesions that require reperfusion therapy. However, occasionally, no coronary artery stenoses are detected. Myocardial ischemia frequently causes left ventricular wall motion abnormalities that can be seen easily by echocardiography. In our study we aimed to analyze echocardiographic findings in patients with acute coronary syndrome and normal angiogram. After standardized risk stratification, a total of 897 patients were classified as an acute coronary syndrome and underwent a coronary angiography immediately. In 76/897 patients angiography excluded coronary macroangiopathy. Routine echocardiographic assessment in patients with normal angiogram showed in 21.1% a reduced left ventricular systolic function and 32.9% presented with segmental wall motion abnormalities. In summary, by detection of segmental wall motion abnormalities in 1/3 of patients with suspected acute coronary syndrome and normal angiogram, obviously, an echocardiographic evaluation in this patient population is of clinical relevance. Recommendations for performing echocardiography in patients with suspected acute coronary syndromes independent of angiographic findings are strongly supported. Further analyses should implement echocardiographic techniques as contrast and tissue doppler imaging.

Patient-prosthesis mismatch and left ventricular remodelling after implantation of Shelhigh SuperStentless aortic valve prostheses.

AIM: Aortic valve replacement is a standard procedure for the treatment of severe aortic valve stenosis. Due to lower flow velocities stentless valves are associated with a more effective regression of left ventricular hypertrophy in comparison to stented valves. However, mismatch between body surface area and valve size supports unfavourable hemodynamic results. The aim of the study was to analyze hemodynamic parameters by echocardiography after implantation of the Shelhigh SuperStentless bioprosthesis and to analyze the occurrence of patient-prosthesis mismatch and left ventricular remodelling in this specific valve type. METHODS: A total of 20 patients with severe aortic stenosis underwent implantation of a Shelhigh Super Stentless prosthesis. Clinical and echocardiographic assessment was done prior to, immediate after and six months after surgery. RESULTS: All surgical procedures were successful, no surgery-related complication was documented perioperatively. One patient died after development of multiorgan failure. Echocardiography during the first eight days after surgery showed mean gradients of 16 mmHg, mean valve orifice areas of 1.8 cm(2) and indexed effective orifice areas at 0.95 cm(2)/m(2). Six-months follow-up data were obtained in 19/20 patients. There were no relevant changes in echocardiographic hemodynamic findings at the time of follow-up measurements. Significant regression of left ventricular hypertrophy was shown (P=0.0088). A patient-prosthesis mismatch occurred in one patient (0.54 cm(2)/m(2)). No recurrent symptoms were documented. CONCLUSION: Patient-prosthesis mismatch after implantation of SuperStentless Shelhigh prosthesis is rare. A significant regression of left ventricular hypertrophy could be shown after six months. Hemodynamic valve function assessed by echocardiography may be predicted early after surgery.

[Optimized programming during cardiac resynchronization therapy]. / Optimierte Programmierung der atrio-ventrikulären und ventrikulo-ventrikulären Verzögerungszeiten bei Patienten unter biventrikulärer Stimulation - ein pragmatischer Ansatz.

Cardiac resynchronization (CRT) has evolved as a therapeutic add-on tool in patients with refractory heart failure. Additional pacing of the left ventricle leads to relevant clinical and hemodynamic improvement. Optimized programming of these pacing systems may modulate therapeutic efficacy. Optimal atrio-ventricular (AV) and ventriculo-ventricular (VV) delay programming is documented to increase invasively and non-invasively determined parameters of cardiac hemodynamics. In this manuscript different options for determining optimal AV and VV delay are discussed and a pragmatic approach to optimize CRT programming is detailed. VV delay needs to be optimized as a first step of programming. Different techniques may estimate the individual need for sequential ventricular pacing. Especially electrocardiographic criteria during right and left ventricular pacing may approximate the time-delay for pre-excitation. Delay between aortic and pulmonic valve ejection can be determined using Doppler echocardiography may identify patients who benefit from sequential pacing. Optimizing AV delay is a domain of Doppler echocardiography where using a simple formula the AV delay that produces the best diastolic resynchronization of left atrial contraction and left ventricular ejection can be calculated.Using the above mentioned techniques a pragmatic, easy and fast method for increasing CRT performance can be established. In cases of worsening heart failure or relevant changes of left ventricular dimensions adaptions (re-optimization) of VV and AV delay may be needed.

Thienopyridines and statins: assessing a potential drug-drug interaction.

Clopidogrel and statins are frequently administered in patients with ischemic heart disease or other atherothrombotic manifestations and are effective in the prevention of cardiovascular disease. The thienopyridine clopidogrel is a pro-drug metabolised in the liver via the cytochrome P450 (CYP) 3A4 system to the active compound which inhibits the P2Y(12) ADP platelet receptor. The assumption exists that the effect of clopidogrel in inhibiting platelet aggregation is attenuated by co-administration of lipophilic statins such as atorvastatin or simvastatin which are metabolised by the CYP3A4 system to inactive substrates. Assessing a possible drug-drug interaction ex-vivo, inconclusive studies have been published: In an aggregometer study, a strong and dose-dependent interference between atorvastatin and the inhibitory effect of clopidogrel on platelet function was observed. Another study, measuring the effect of clopidogrel by flow cytometry, found a significant attenuation of the clopidogrel effect by lipophilic statins, predominantly in the loading phase. In contrast a recent study, which used 600 mg clopidogrel for loading, found no significant interference between various statins and clopidogrel on ADP-induced platelet aggregation and in addition another study revealed no attenuation of the clopidogrel effect despite statin co-medication after 5 weeks. Additionally, retrospective analysis of clinical studies (CREDO-study) or registries (MITRA-PLUS) revealed no significant influence of different statins on the clinical outcome in patients treated with clopidogrel. However, these clinical studies showed a trend towards a diminishing effect of clopidogrel on those treated with cytochrome CYP3A4 metabolised statins. Even more important seems to be the considerable variability in the response of the antiplatelet effect of clopidogrel. A certain percentage of patients apparently do not respond adequately to clopidogrel treatment. This effect of clopidogrel resistance seems to be more important as the potential interference between CYP3A4 metabolized statins and clopidogrel. Finally, up until now sufficient evidence has not been gained to prefer hydrophil statins on patients receiving clopidogrel co-medication or when to discontinue the use of statins in clopidogrel treatment. Prospective studies are necessary in order to evaluate the magnitude of clopidogrel resistance and the impact of clopidogrel co-medication as well as to redefine antithrombotic therapy for this subgroup.

[Prevalence of acetylsalicylic acid (ASA) - low response in vascular surgery]. / Prävalenz der ASS-Low-Response in der Gefäßchirurgie.

BACKGROUND: Research has revealed that a decreased antiplatelet effect (low response [LR]/high on-treatment platelet reactivity [HPR]) of acetylsalicylic acid (ASA) and clopidogrel is associated with an increased risk of thromboembolic events. There are extensive ASA low response (ALR) and clopidogrel low response (CLR) prevalence data in the literature, but there are only a few studies concerning vascular surgical patients. The aim of this study was to examine the prevalence and risk factors of ALR and CLR in vascular surgical patients. MATERIALS AND METHODS: We examined n = 154 patients with an antiplatelet long-term therapy, who were treated due to peripheral artery occlusive disease (PAD) and/or arteria carotis interna stenosis (CVD). To detect an ALR or CLR, we examined full blood probes with impedance aggregometry (ChronoLog® Aggregometer model 590). Risk factors were examined by acquisition of concomitant disease, severity of vascular disease, laboratory test results and medication. RESULTS: We found a prevalence of 19.3 % in the ALR group and of 21.1 % in the CLR group. Risk factors for ALR were an increased platelet and leucocyte count and co-medication with pantoprazole. We found no significant risk factors for a decreased antiplatelet effect of clopidogrel treatment. CONCLUSION: The investigated prevalence for ALR and CLR are in the range of other studies, particularly based on cardiological patients. More investigations are needed to gain a better evaluation of the risk factors for HPR and to develop an effective antiplatelet therapy regime to prevent cardiovascular complications.

Identification of patent foramen ovale permitting paradoxic embolism.

OBJECTIVES: We sought to analyze the morphologic and functional characteristics of the patent foramen ovale in patients with different clinical likelihoods for paradoxic embolism. BACKGROUND: The incidence of patent foramen ovale is increased in patients with otherwise unexplained arterial ischemic events. Because signs of venous thrombosis are absent in most patients, the diagnosis of paradoxic embolism is often questioned, even when patent foramen ovale is the only potential explanation for the ischemic event. METHODS: Seventy-eight patients with a patent foramen ovale detected by contrast transesophageal echocardiography were studied: 21 patients with an otherwise unexplained arterial ischemic event and clinical evidence implying paradoxic embolism (group I), 30 patients with an unexplained ischemic event but no clinical evidence for paradoxic embolism (group II) and 27 patients without an ischemic event (group III). RESULTS: During transesophageal contrast echocardiography, patients in group I had more severe right to left shunting (mean +/- SD 52 +/- 16% of the left atrial area filled with contrast medium) and a wider opening of the patent foramen ovale (7.1 +/- 3.6-mm separation between the septum primum and the septum secundum) than did patients in group II (35 +/- 15% and 4.4 +/- 3.2 mm, respectively, p < 0.001) or group III (23 +/- 12% and 3.0 +/- 2.0 mm, respectively, p < 0.001). The incidence of atrial septal aneurysm was similar in the three groups. Severe contrast shunting (> or = 50% of the left atrial area filled with contrast medium) and wide opening of the patent foramen ovale (> or = 5-mm separation) revealed a high sensitivity (71% and 86%, respectively) and high specificity (86% and 96%, respectively) for identification of group I patients. CONCLUSIONS: Right to left contrast shunting is more severe and opening of the patent foramen ovale is larger in patients with ischemic arterial events considered to be due to paradoxic embolism. In patients with a patent foramen ovale as the only potential cause for ischemic events and no signs of venous thrombosis, morphologic and functional variables assessed by transesophageal echocardiography may be helpful in estimating the likelihood of paradoxic embolism.

Echocardiography in infective endocarditis: reassessment of prognostic implications of vegetation size determined by the transthoracic and the transesophageal approach.

In 105 patients with active infective endocarditis, disease-associated complications defined as severe heart failure (New York Heart Association class IV), embolic events and in-hospital death were correlated to the vegetation size determined by both transthoracic and transesophageal echocardiography. A detailed comparison between anatomic and echocardiographic findings, performed in a subgroup of 80 patients undergoing surgery or necropsy, revealed that true valvular vegetations can be reliably identified by echocardiography in the vast majority of patients; the detection rate was significantly higher for the transesophageal (90%) than for the transthoracic (58%) approach, particularly when infected prosthetic valves were evaluated. However, an accurate echocardiographic differentiation between true vegetations and other endocarditis-induced valve destruction (ruptured leaflets or chordae) is impossible. The correlation of vegetation size with endocarditis-associated complications showed that patients with a vegetation diameter greater than 10 mm had a significantly higher incidence of embolic events than did those with a vegetation diameter less than or equal to 10 mm (22 of 47 versus 11 of 58; p less than 0.01). Particularly for patients with mitral valve endocarditis, a vegetation diameter greater than 10 mm was highly sensitive in identifying patients at risk for embolic events. Vegetation size, however, was not significantly different in patients with and without severe heart failure or in patients surviving or dying during acute endocarditis. In addition, no significant correlation was found between vegetation size and location of endocarditis or type of infective organism.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of left atrial appendage function by biplane transesophageal echocardiography in patients with nonrheumatic atrial fibrillation: identification of a subgroup of patients at increased embolic risk.

OBJECTIVES: This study was conducted to identify a subgroup of patients with nonrheumatic atrial fibrillation with an increased risk for cardiogenic embolism by assessing left atrial appendage function. BACKGROUND: Patients with nonrheumatic atrial fibrillation have an increased risk for thromboembolic complications. The left atrial appendage is the most likely source for thrombus formation. It is likely that the appendage function (contraction, filling dynamics) is related to the pathogenesis of thrombus formation. METHODS: Twenty-nine patients with nonrheumatic atrial fibrillation (group I) underwent biplane transesophageal echocardiography. The maximal and minimal areas during a cardiac cycle and the peak emptying and filling velocities of the appendage were measured in both scan planes. For comparison, two additional groups were also analyzed. Group II consisted of 12 patients with chronic atrial fibrillation due to significant mitral stenosis, and group III consisted of 30 patients who were in sinus rhythm. RESULTS: Patients with nonrheumatic atrial fibrillation showed two distinct appendage flow patterns: either well defined peak filling and emptying waves (> or = 25 cm/s) with visible fibrillatory contractions of the appendage wall ("high flow profile") or irregular, very low, peak filling and emptying waves (< 25 cm/s) associated with almost no visible appendage contractions ("low flow profile"). The left atrial appendage function in the first subgroup resembles that seen in patients with sinus rhythm, whereas the appendage function in the latter subgroup resembles more the "static pouch" seen in patients with rheumatic atrial fibrillation. Events suggestive of cardiogenic embolism occurred in six patients from group I, five of whom were in the low flow profile subgroup (p < 0.05). The spontaneous echo contrast phenomenon was observed in 80% of the low flow profile subgroup but in only 5% in the high flow profile subgroup (p < 0.05). Three thrombi confined to the left atrial appendage were detected by transesophageal echocardiography in group I; all three of the patients were in the low flow profile subgroup. CONCLUSIONS: The assessment of left atrial appendage function by transesophageal echocardiography may be helpful to identify subgroups of patients with nonrheumatic atrial fibrillation with an increased risk of thrombus formation.

Impaired coronary dilator responses to substance P and impaired flow-dependent dilator responses in heart transplant patients with graft vasculopathy.

OBJECTIVES: Because pathologic mechanisms for transplant vasculopathy are still uncertain, we tested the hypothesis that endothelial function, in terms of the release of endothelium-derived relaxing factor (EDRF), is impaired in patients with evidence of angiographic transplant vasculopathy. BACKGROUND: The long-term prognosis after heart transplantation is mainly determined by the development of transplant vasculopathy. METHODS: The study included 23 patients undergoing diagnostic cardiac catheterization approximately 40 months after heart transplantation. Patients were classified into those with (n = 8) and those without (n = 15) angiographic evidence of transplant vasculopathy. Coronary flow velocity (by intravascular Doppler echocardiography) and epicardial coronary diameter (by quantitative angiography) were determined after intracoronary bolus injections (1 ml) of the endothelium-dependent dilator substance P (20 pmol) and the endothelium-independent dilators nitroglycerin (0.1 mg) and papaverine (8 mg). Substances were injected through the lumen of the Doppler catheter, which was placed into the midportion of the left anterior descending artery. RESULTS: Increases in blood flow velocity in response to substance P were significantly less in patients with than in patients without evidence of transplant vasculopathy. In addition, flow-mediated dilation of epicardial coronary arteries in response to papaverine was abolished in patients with such evidence. Vasodilation of epicardial coronary arteries in response to nitroglycerin and increases in flow velocity in response to papaverine were similar in both groups. CONCLUSIONS: These results suggest that transplant vasculopathy in heart transplant patients is associated with endothelial dysfunction (that is, impaired EDRF-mediated vasodilation). Furthermore, responsiveness of epicardial arteries to increased flow appears to be abolished in patients with evidence of transplant vasculopathy. These abnormal vascular functions may contribute to the pathogenesis of transplant vasculopathy and its vascular complications.

Normal angiogram in acute coronary syndrome-preangiographic risk stratification, angiographic findings and follow-up.

BACKGROUND: Coronary angiographies performed during acute coronary syndrome show different coronary morphologies-vessel occlusions, thrombi and various types of stenoses. In a few cases of acute coronary syndrome, angiography reveals normal coronary arteries. It is the purpose of this study to analyze this specific subset of patients who presented with an acute coronary syndrome but had a normal coronary angiogram with respect to the preangiographic diagnostics, risk stratification and clinical follow-up. METHODS AND RESULTS: A total of 897 coronary angiographies were performed as an emergency procedure in our institution. The majority of patients (n = 821) presented with coronary artery disease and the majority was treated by mechanical revascularization (86.3%). In 76 patients (8.5%), no coronary artery stenosis was documented. However, according to the preangiographic risk stratification, coronary artery disease was expected in these patients. Observations documented angiographically included coronary spasms (6.6%) and muscle bridges (5.3%). During a mean follow-up of 11.2 +/- 6.4 months, one patient developed an acute myocardial infarction requiring coronary intervention. All other patients were free of any cardiac event. CONCLUSIONS: In summary, we have to consider that coronary angiography may not always detect the cause of myocardial ischemia in every patient. There is a small group of patients with normal coronary angiograms during acute coronary syndrome. Additional diagnostic procedures like intravascular ultrasound (IVUS) or the assessment of intracoronary physiological parameters may increase the diagnostic value of angiography.

Endothelium independent relaxation of human coronary arteries by 17 beta-oestradiol in vitro.

OBJECTIVE: There is accumulating evidence that oestrogen replacement therapy protects against the development of coronary atherosclerosis and myocardial infarction in postmenopausal women. The mechanism of this protective effect is uncertain. The aim of this study was to measure the effects of 17 beta-oestradiol on human epicardial coronary artery tone. METHODS: Coronary artery rings were obtained from explanted hearts during cardiac transplantation. The rings were suspended in organ baths for isometric tension measurements. The rings were precontracted with prostaglandin F2 alpha, and were then exposed to either 17 beta-oestradiol (0.3 nM-3 microM) or solvent control (0.2% ethanol v/v). In some rings, cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3',5'-monophosphate content were measured by radioimmunoassay. RESULTS: 17 beta-Oestradiol induced a significant relaxation [maximum effect: 84(SD 18)%]. The onset of the relaxant effect occurred within 5 min, and was maximal within 40 min. The relaxation in response to 3 microM 17 beta-oestradiol was of similar magnitude in rings with and without intact endothelium. The maximum relaxation induced by 3 microM 17 beta-oestradiol was greater in arteries from hearts obtained from women than in those obtained from men [-100.0(3.0)% v -77.5(17.6)%, respectively]. The exposure of rings to 3 microM 17 beta-oestradiol for 30 min resulted in a significant increase in both cyclic AMP and cyclic GMP content, by 88% and 182%, respectively. CONCLUSIONS: 17 beta-Oestradiol produced an endothelium independent relaxation of precontracted human coronary arteries in vitro, and this effect was associated with an increase in both cyclic AMP and the cyclic GMP content. This direct relaxant effect of oestrogens on coronary arteries may contribute to the beneficial effects of oestrogen replacement therapy in postmenopausal women.

Angiotensin II-induced superoxide anion generation in human vascular endothelial cells: role of membrane-bound NADH-/NADPH-oxidases.

BACKGROUND: Angiotensin II (ANG II) mediated hypertension accelerates atherosclerosis (AS) and thereby increases the incidence of myocardial infarction (MI). On the other hand, superoxide anion (O2-) is involved in the modification of low density lipoproteins, inhibition of prostacyclin (PGI2) formation and breakdown of nitric oxide. These events finally lead to rapid progression of AS and MI. In the present study, we investigate whether ANG II can induce O2- release from human vascular endothelial cells (HVECs) and the possible mechanisms involved. METHODS AND RESULTS: The expression of ANG receptors subtype-1 (AT-1) and subtype-2 (AT-2) were identified by using reverse transcription polymerase chain reaction and sequence analysis. The O2- production was dose-dependently increased in HVECs treated with ANG II (10(-7)-10(-9) M) and with a maximum rate after 1 h of incubation. This event was significantly inhibited by pretreatment of cells with the specific AT-1 blocker losartan (10(-7) M) and to a lesser extent by the specific AT-2 receptor blocker PD123319 (10(-7) M). The combined incubation of both receptor blockers was even more effective. In addition, our lucigenin-enhanced chemiluminescence assay showed that the activity of plasma membrane-bound NADH-/NADPH-oxidases derived from ANG II-treated cells was also significantly increased, this effect was reduced in cells pretreated with losartan or to lesser extent by PD123319. However, the activity of xanthine oxidase remained unchanged in response to ANG II. Furthermore, the basal O2- release from HVECs was inhibited in cells treated with angiotensin-converting enzyme (ACE) inhibitor, Lisinopril (10(-6) M), and this event could be reversed by ANG II. CONCLUSION: ANG II induces O2- release in HVECs via activation of membrane-bound NADH-/NADPH-oxidase, an effect, that is mediated by both AT-1 and AT-2 receptors. This suggests that acceleration of AS and MI in ANG II-mediated hypertension may at least be due to ANG II-induced O2- generation from vascular endothelial cells. In this case, the ACE inhibitors and the ANG receptor antagonists may act as causative "antioxidants".

[Ten years of early defibrillation: "Bochum against sudden cardiac death". Acceptance and critical analysis of using automated external defibrillators]. / Zehn Jahre Frühdefibrillation: "Bochum gegen den plötzlichen Herztod". Akzeptanz und kritische Betrachtung des Einsatzes von automatisierten externen Defibrillatoren.

BACKGROUND: There is a comprehensive early defibrillation program in Bochum (Germany); since 2003 a total of 175 automated external defibrillators (AEDs) have been installed in urban areas by the city of Bochum and private companies. These were preferably installed in places with high foot traffic, e.g., public buildings, companies, and event/shopping centers. Approximately 15,000 laypeople who work in the vicinity of the AED locations were trained in the use of defibrillators and in basic resuscitation. In addition, rescue workers on fire trucks and medically trained personnel in physicians' medical practices were equipped as "first responders" with AEDs. RESULTS: After an initiation phase, all available information after each AED use since August 2004 has been collected by the project coordinator. During the period of data collection (August 2004 to August 2013), an AED was used in a total of 17 patients who had suffered sudden cardiac death (SCD) under the project in Bochum. Eleven patients had primary ventricular fibrillation (VF). Six of these survived without neurological deficit. In another 6 patients, a nondefibrillatable rhythm disorder was diagnosed. The AEDs are reliable and showed impeccable rhythm analysis before the instructions to provide any necessary shock. DISCUSSION: Compared to the number of existing units and an estimated number of 37-100 SCD/100,000, the use of the AEDs only 17 times appears relatively small. To improve the effectiveness of the AED program in Bochum, an analysis of the emergency service responses, which were necessary because of sudden circulatory collapse, is currently being performed. This will allow areas with an increased incidence of SCD to be identified and a plan for the strategic placement of AED and emergency services can be made.

Role of increased production of superoxide anions by NAD(P)H oxidase and xanthine oxidase in prolonged endotoxemia.

Superoxide anions (O2-) are supposedly involved in the pathogenesis of endothelial dysfunction. We investigated whether the enhanced formation of O2- is involved in the attenuation of endothelium-dependent relaxation induced by lipopolysaccharide (LPS). Rats were injected with LPS (10 mg/kg IP), the aorta was removed after 12 or 30 hours, and generation of O2-, H2O2, and ONOO- was measured using chemiluminescence assays. Protein tyrosine nitration and expression of xanthine oxidase (XO), NAD(P)H oxidase, and manganese superoxide dismutase were determined by Western or Northern blotting, and endothelium-dependent relaxation in aortic rings was studied. LPS treatment increased vascular O2- (from 35+/-2 cpm/ring at baseline to 166+/-21 cpm/ring at 12 hours and 225+/-16 cpm/ring at 30 hours) and H2O2 formation, which was partially sensitive to the NAD(P)H oxidase inhibitor diphenylene iodonium at both time points studied and to the XO inhibitor oxypurinol only 30 hours after LPS treatment. Expression of XO and NAD(P)H oxidase (p22phox, p67phox, and gp91phox) were increased by LPS in a time-dependent manner, as were protein tyrosine nitration and ONOO- formation. LPS also induced expression of the oxidative stress-sensitive protein manganese superoxide dismutase. Endothelium-dependent relaxation was impaired after LPS treatment and could not be restored by inhibition of inducible NO synthase. Inhibition of O2- with superoxide dismutase, oxypurinol, tiron, or the superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin chloride did not restore but further deteriorated the relaxation of LPS-treated rings. In summary, treatment of rats with LPS enhances vascular expression of XO and NAD(P)H oxidase and increases formation of O2- and ONOO-. Because removal of O2- compromised rather than restored endothelium-dependent relaxation, a direct role of O2- in the induction of endothelial dysfunction is unlikely. Other mechanisms, such as prolonged protein tyrosine nitration by peroxynitrite (which is formed from NO and O2-) or downregulation of the NO effector pathway, are more likely to be involved.