Holger Nef

Bivalirudin started during emergency transport for primary PCI

BACKGROUND Bivalirudin, as compared with heparin and glycoprotein IIb/IIIa inhibitors, has been shown to reduce rates of bleeding and death in patients undergoing primary percutaneous coronary intervention (PCI). Whether these benefits persist in contemporary practice characterized by prehospital initiation of treatment, optional use of glycoprotein IIb/IIIa inhibitors and novel P2Y12 inhibitors, and radial-artery PCI access use is unknown. METHODS We randomly assigned 2218 patients with ST-segment elevation myocardial infarction (STEMI) who were being transported for primary PCI to receive either bivalirudin or unfractionated or low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors (control group). The primary outcome at 30 days was a composite of death or major bleeding not associated with coronary-artery bypass grafting (CABG), and the principal secondary outcome was a composite of death, reinfarction, or non-CABG major bleeding. RESULTS Bivalirudin, as compared with the control intervention, reduced the risk of the primary outcome (5.1% vs. 8.5%; relative risk, 0.60; 95% confidence interval [CI], 0.43 to 0.82; P=0.001) and the principal secondary outcome (6.6% vs. 9.2%; relative risk, 0.72; 95% CI, 0.54 to 0.96; P=0.02). Bivalirudin also reduced the risk of major bleeding (2.6% vs. 6.0%; relative risk, 0.43; 95% CI, 0.28 to 0.66; P<0.001). The risk of acute stent thrombosis was higher with bivalirudin (1.1% vs. 0.2%; relative risk, 6.11; 95% CI, 1.37 to 27.24; P=0.007). There was no significant difference in rates of death (2.9% vs. 3.1%) or reinfarction (1.7% vs. 0.9%). Results were consistent across subgroups of patients. CONCLUSIONS Bivalirudin, started during transport for primary PCI, improved 30-day clinical outcomes with a reduction in major bleeding but with an increase in acute stent thrombosis. (Funded by the Medicines Company; EUROMAX ClinicalTrials.gov number, NCT01087723.).

Mechanisms of stress (Takotsubo) cardiomyopathy

Stress cardiomyopathy, also referred to as Takotsubo cardiomyopathy, transient apical ballooning or broken heart syndrome, is a disorder associated with transient left ventricular dysfunction. Symptoms include acute chest pain and dyspnea accompanied by electrocardiographic changes, such as ST-segment elevation and T-wave inversions, minimal elevation of cardiac enzyme levels and transient wall-motion abnormalities in the absence of substantial coronary artery obstruction. Complete recovery of contractile function has been documented in nearly all cases, but the mechanisms of disease remain unclear and the cause has not been established. Coronary artery vasospasm, microcirculation dysfunction, and transient obstruction of the left ventricular outflow tract have been proposed as possible causes of this disorder. An excessive release of catecholamines also seems to have a pivotal role in the development of stress cardiomyopathy. This Review summarizes published data on stress cardiomyopathy, focusing primarily on the most likely causes of this cardiac entity.

Current status of bioresorbable scaffolds in the treatment of coronary artery disease.

State-of-the-art drug-eluting metal stents are the gold standard for interventional treatment of coronary artery disease. Although they overcome some disadvantages and limitations of plain balloon angioplasty and bare-metal stents, some limitations apply, most notably a chronic local inflammatory reaction due to permanent implantation of a foreign body, restriction of vascular vasomotion due to a metal cage, and the risk of late and very late stent thrombosis. The development of biodegradable scaffolds is a new approach that attempts to circumvent these drawbacks. These devices provide short-term scaffolding of the vessel and then dissolve, which should theoretically circumvent the side effects of metal drug-eluting stents. Various types of these bioresorbable scaffolds are currently under clinical evaluation. This review discusses different concepts of bioresorbable scaffolds with respect to material, design, and drug elution and presents the most recent evidence.

Classically and alternatively activated macrophages contribute to tissue remodelling after myocardial infarction

An important goal in cardiology is to minimize myocardial necrosis and to support a discrete but resilient scar formation after myocardial infarction (MI). Macrophages are a type of cells that influence cardiac remodelling during MI. Therefore, the goal of the present study was to investigate their transcriptional profile and to identify the type of activation during scar tissue formation. Ligature of the left anterior descending coronary artery was performed in mice. Macrophages were isolated from infarcted tissue using magnetic cell sorting after 5 days. The total RNA of macrophages was subjected to microarray analysis and compared with RNA from MI and LV‐control. mRNA abundance of relevant targets was validated by quantitative real‐time PCR 2, 5 and 10 days after MI (qRT‐PCR). Immunohistochemistry was performed to localize activation type‐specific proteins. The genome scan revealed 68 targets predominantly expressed by macrophages after MI. Among these targets, an increased mRNA abundance of genes, involved in both the classically (tumour necrosis factor α, interleukin 6, interleukin 1β) and the alternatively (arginase 1 and 2, mannose receptor C type 1, chitinase 3‐like 3) activated phenotype of macrophages, was found 5 days after MI. This observation was confirmed by qRT‐PCR. Using immunohistochemistry, we confirmed that tumour necrosis factor α, representing the classical activation, is strongly transcribed early after ligature (2 days). It was decreased after 5 and 10 days. Five days after MI, we found a fundamental change towards alternative activation of macrophages with up‐regulation of arginase 1. Our results demonstrate that macrophages are differentially activated during different phases of scar tissue formation after MI. During the early inflammatory phase, macrophages are predominantly classically activated, whereas their phenotype changes during the important transition from inflammation to scar tissue formation into an alternatively activated type.

Tako-tsubo cardiomyopathy (apical ballooning)

In recent years, a new cardiac syndrome with transient left ventricular dysfunction has been described in Japanese patients. This new entity has been referred to as “tako-tsubo cardiomyopathy” or “apical ballooning”, named for the particular shape of the end-systolic left ventricle in ventriculography.1 To date, tako-tsubo cardiomyopathy has also been reported to occur in the western population. The following clinical characteristics of this phenomenon must be met: (1) transient akinesis or dyskinesis of left ventricular wall motion abnormalities (ballooning) with chest pain; (2) new electrocardiographic changes (either ST elevation or T wave inversion); (3) no significant obstructive epicardial coronary artery disease; (4) absence of recent significant head trauma, intracardial bleeding, phaeochromocytoma, myocarditis, and hypertrophic cardiomyopathy.2 Emotional or physical stress usually precedes this cardiomyopathy. A unifying mechanistic explanation responsible for this acute but rapidly reversible contractile dysfunction is still lacking. Multivessel epicardial coronary artery vasospasm, coronary microvascular dysfunction or spasm, impaired fatty acid metabolism, transient obstruction of the left ventricular outflow, and catecholamine-mediated myocardial dysfunction have been proposed as potential mechanisms.3–6 The optimal treatment of patients presenting with this syndrome depends primarily on the haemodynamic conditions and remains rather symptomatic in nature. This article primarily addresses the clinical setting of tako-tsubo cardiomyopathy and describes a broad spectrum of diagnostic tools. Moreover, currently proposed pathophysiological mechanisms are discussed in detail, providing more insight into this new cardiac entity. Tako-tsubo cardiomyopathy is characterised by acute onset of chest pain and a completely reversible regional contractile dysfunction. In left ventriculography typical wall motion abnormalities, such as apical and mid-ventricular akinesia and a hypercontractile basis, can be documented. Coronary angiography reveals no relevant epicardial coronary artery disease (fig 1). Recently, several cases of transient ballooning involving the mid-ventricular part, sparing the apical and basal segments, have also been documented.7 …

Contemporary practice and technical aspects in coronary intervention with bioresorbable scaffolds: a European perspective

AIMS Next to patient characteristics, the lack of a standardised approach for bioresorbable vascular scaffold (BVS) implantation is perceived as a potential explanation for the heterogeneous results reported so far. To provide some guidance, we sought to find a consensus on the best practices for BVS implantation and management across a broad array of patient and lesion scenarios. METHODS AND RESULTS Fourteen European centres with a high volume of BVS procedures combined their efforts in an informal collaboration. To get the most objective snapshot of different practices among the participating centres, a survey with 45 multiple choice questions was prepared and conducted. The results of the survey represented a basis for the technical advice provided in the document, whereas areas of controversy are highlighted. CONCLUSIONS Consensus criteria for patient and lesion selection, BVS implantation and optimisation, use of intravascular imaging guidance, approach to multiple patient and lesion scenarios, and management of complications, were identified.

Epidemiology and pathophysiology of Takotsubo syndrome

Takotsubo syndrome is an acute cardiac syndrome first described in 1990 and characterized by transient left ventricular dysfunction affecting more than one coronary artery territory, often in a circumferential apical, mid-ventricular, or basal distribution. Several pathophysiological explanations have been proposed for this syndrome and its intriguing appearance, and awareness is growing that these explanations might not be mutually exclusive. The reversible apical myocardial dysfunction observed might result from more than one pathophysiological phenomenon. The pathophysiology of Takotsubo syndrome is complex and integrates neuroendocrine physiology, potentially involving the cognitive centres of the brain, and including the hypothalamic–pituitary–adrenal axis. Cardiovascular responses are caused by the sudden sympathetic activation and surge in concentrations of circulating catecholamines. The multiple morphological changes seen in the myocardium match those seen after catecholamine-induced cardiotoxicity. The acute prognosis and recurrence rate are now known to be worse than initially thought, and much still needs to be learned about the epidemiology and the underlying pathophysiology of this fascinating condition in order to improve diagnostic and treatment pathways.

Abnormalities in intracellular Ca2+ regulation contribute to the pathomechanism of Tako-Tsubo cardiomyopathy

AIMS The Tako-Tsubo cardiomyopathy (TTC) is characterized by a transient contractile dysfunction that has been assigned to excessive catecholamine levels after episodes of severe emotional or physical stress. Several studies have indicated that beta-adrenoceptor stimulation is associated with alteration in gene expression of Ca(2+)-regulatory proteins. Thus, the present study investigated the gene expression of crucial proteins [sarcoplasmic Ca(2+) ATPase (SERCA2a), sarcolipin (SLN), phospholamban (PLN), ryanodine receptor (RyR2), and sodium-calcium exchanger (NCX)] involved in the Ca(2+)-regulating system in TTC. METHODS AND RESULTS In 10 consecutive patients, TTC was diagnosed by coronary angiography, ventriculography, and echocardiography. Endomyocardial biopsies were taken during the phase of severely impaired left ventricular (LV) function and after functional recovery. Non-diseased LV tissue from three donor hearts not used for transplantation served as healthy controls. Expression levels of Ca(2+)-regulatory proteins were analysed by means of real-time PCR, western blot, and immunohistochemistry. SLN, predominantly expressed in the atrial component, showed a remarkable ventricular expression in TTC patients. Gene expression of SERCA2a was significantly down-regulated. Conversely, PLN/SERCA2a ratio was increased. For PLN, dephosphorylation was documented using western blot and immunostaining of PLN-Ser(16) and PLN-Thr(17). No changes could be documented for NCX and RyR2. CONCLUSION In TTC, ventricular expression of SLN and dephosphorylation of PLN potentially result in a reduced SERCA2a activity and its Ca(2+) affinity. Thus, the TTC is associated with specific alteration of Ca(2+)-handling proteins, which might be crucial for contractile dysfunction.

Immunohistological basis of the late gadolinium enhancement phenomenon in tako-tsubo cardiomyopathy

AIMS Tako-tsubo cardiomyopathy is characterized by transient contractile dysfunction after emotional or physical stress. Only few patients show late gadolinium enhancement (LGE) in cardiovascular magnetic resonance imaging (MRI). It was the purpose of this study to elucidate the histological basis of this phenomenon. METHODS AND RESULTS The study included 15 patients. Tako-tsubo cardiomyopathy was diagnosed by coronary angiography and ventriculography. Cardiac MRI was performed within 24 h of admission. Endomyocardial biopsies were taken during the acute phase and after recovery. The content of fibrosis was determined by immunohistochemical staining of collagen-1. In the acute phase, cardiac MRI revealed LGE in five patients. This was completely reversed at follow-up [14, inter-quartile range (IQR) 11-14.5 days]. All patients showed a significant increase of collagen-1 compared with control tissue. Moreover, the amount of collagen-1 was significantly higher in LGE positive patients (LGE positive: 18.84, IQR 13.82-19.75 AU/microm(2); LGE negative: 7.57, IQR 5.41-9.19 AU/microm(2), P = 0.001). The presence of LGE was not associated with poorer left ventricular function. CONCLUSION The presence of LGE cannot rule out tako-tsubo cardiomyopathy. Instead it defines a special subgroup of patients with a disproportionate increase of extracellular matrix.

Novel rat model reveals important roles of β-adrenoreceptors in stress-induced cardiomyopathy.

BACKGROUND Stress-induced cardiomyopathy (SIC), also known as Takotsubo cardiomyopathy, is an acute cardiac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular akinesia involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC but the pathophysiological pathways and receptors involved are unknown. METHODS Sprague Dawley rats (~300 g) were injected with a single dose of the β-adrenergic agonist isoprenaline (ISO, i.p.) and echocardiography was used to study cardiac function. The akinetic part of the left ventricle was biopsied in six SIC patients. Amount of intracellular lipid and glycogen as well as degree of permanent cardiac damage were assessed by histology. RESULTS In rats, ISO at doses ≥ 50 mg/kg induced severe SIC-like regional akinesia that completely resolved within seven days. Intracellular lipid content was higher in akinetic, but not in normokinetic myocardium in both SIC patients and rats. β2-receptor blockade or Gi-pathway inhibition was associated with less widespread akinesia and low lipid accumulation but significantly increased acute mortality. CONCLUSIONS We provide a novel rat model of SIC that supports the hypothesis of circulating catecholamines as initiators of SIC. We propose that the β-adrenoreceptor pathway is important in the setting of severe catecholamine overstimulation and that perturbations of cardiac metabolism occur in SIC.