Karim Ibrahim

High rates of prasugrel and ticagrelor non-responder in patients treated with therapeutic hypothermia after cardiac arrest.

INTRODUCTION After cardiac arrest due to acute coronary syndromes (ACS) therapeutic hypothermia (HT) is the standard care to reduce neurologic damage. Additionally, the concomitant medical treatment with aspirin and a P2Y12 receptor inhibitor like clopidogrel (Cl), prasugrel (Pr) or ticagrelor (Ti) is mandatory. The platelet inhibitory effect of these drugs under hypothermia remains unclear. METHODS 164 patients with ACS were prospectively enrolled in this study. 84 patients were treated with HT, 80 patients were under normothermia (NT). All patients were treated with aspirin and one of the P2Y12 receptor inhibitors Cl, Pr or Ti. 24h after the initial loading dose the platelet reactivity index (PRI/VASP-index) was determined to achieve the platelet inhibitory effect. RESULTS In the HT-group the PRI/VASP-index was significantly higher compared to the NT-group (54.86%±25.1 vs. 28.98%±22.8; p<0.001). In patients under HT receiving Cl, the platelet inhibition was most markedly reduced (HT vs. NT: 66.39%±19.1 vs. 33.36%±22.1; p<0.001) compared to Pr (HT vs. NT: 37.6%±25.0 vs. 27.04%±25.5; p=0.143) and Ti (HT vs. NT: 41.5%±21.0 vs. 17.83%±14.5; p=0.009). The rate of non-responder defined as PRI/VASP-index>50% was increased in HT compared to NT (60.7% vs. 22.5%; p<0.001) with the highest rates in the group receiving Cl (CL: 82% vs. 26%, p<0.001; Pr: 32% vs. 23%; n.s.; Ti: 30% vs. 8%, n.s.). CONCLUSION The platelet inhibitory effect in patients treated with HT after cardiac arrest is significantly reduced. This effect was most marked with the use of Cl. The new P2Y12-inhibitors Pr and Ti improved platelet inhibition in HT, but could not completely prevent non-responsiveness.

Pushing the limits—further evolutions of transcatheter valve procedures in the mitral position, including valve-in-valve, valve-in-ring, and valve-in-native-ring

OBJECTIVE Transcatheter heart valve (THV) procedures are constantly evolving. We report our experience with valve-in-valve, valve-in-ring, and direct-view valve-in-native-ring implantation in the mitral position. METHODS Fourteen patients undergoing THV implantation in the mitral position were included. Clinical and postoperative data, including echocardiography and further follow-up, were analyzed. RESULTS Ten valve-in-valve and 2 valve-in-ring procedures were successfully performed using the transapical access route. For the third valve-in-ring procedure we used an antegrade left-atrial access via right anterolateral minithoracotomy. In 1 patient surgical mitral valve replacement was planned. Intraoperatively, the annulus appeared severely calcified and regular implantation of a bioprosthesis was not possible. As a last resort, a 29-mm Sapien XT valve (Edwards Lifesciences Inc, Irvine, Calif) was implanted under direct view. The initial result was satisfactory, but on the first postoperative day relevant paravalvular regurgitation occurred. Subsequently, the valve was fixed to an atrial cuff by 1 running suture. In this series 27-, 29-, and 31-mm bioprostheses and 28- and 30-mm annuloplasty rings were treated with 26- or 29-mm Sapien XT valves. Postoperative echocardiography on day 10 and after 6 weeks revealed good prosthesis function in all cases. In 2 valve-in-valve patients who solely received anticoagulation therapy with acetylsalicylic acid, signs of beginning valve thrombosis occurred after 8 weeks and 3 months, respectively. During further course, valve function was normalized using warfarin therapy. CONCLUSIONS Our results demonstrate feasibility of valve-in-valve and valve-in-ring THV procedures in the mitral position. Permanent anticoagulation therapy with warfarin seems to be necessary to prevent valve dysfunction. THV implantation in a calcified native mitral ring for bailout seems not to be reproducible and thus cannot be recommended.

Broken heart syndrome: Tako Tsubo cardiomyopathy associated with an overdose of the serotonin–norepinephrine reuptake inhibitor Venlafaxine

OBJECTIVE To describe a case of Tako Tsubo cardiomyopathy [TTC] in a patient after an overdose of the serotonin-norepinephrine reuptake inhibitor [SNRI] Venlafaxine. METHODS We present a case study including clinical and laboratory data. Current relevant literature is reviewed and summarized in regard to Tako Tsubo syndrome and SNRI. RESULTS A 43year-old woman was admitted with acute angina pectoris after accidentally taking an overdose on Venlafaxine in order to treat major depression. Because of the ECG-T-wave-inversions in the precordial leads, the slightly increased Troponin/Creatine kinase levels and the apical systolic dysfunction of the left ventricle in echocardiogram a cardiac catheterization was performed. Coronary artery disease could be excluded by coronary angiography. The followed laevocardiography and cardiac MRI scan showed apical akinesis and basal hypercontractibility typical for apical ballooning (Tako Tsubo cardiomyopathy). Urine analysis revealed elevated normetanephrine level potentially caused by Venlafaxine. Six weeks after the first admission the echocardiogram showed a complete recovery to normal left ventricular function. CONCLUSIONS To our knowledge this is the first reported case of an overdose of Venlafaxine (SNRI) associated Tako Tsubo cardiomyopathy.

Regulation of the HIF-system in human macrophages--differential regulation of HIF-α subunits under sustained hypoxia.

Macrophages are often associated to pathophysiological processes and were found at hypoxic areas. However, cell adaption greatly depends on hypoxia-inducible factors (HIF). Activation of these transcription factors is induced by heterodimerization of an α-(HIF-1α, -2α, -3α) and HIF-1β subunit. The main regulatory pathway is represented by α-subunit stability. Beside, little is known about the exact mechanisms of fine-tuning in Hif-regulation. The present study characterizes the hypoxia-induced regulation of HIF-1α and -2α in human macrophages. The hypoxic increase of both subunits is initially mediated by protein stabilization. Sustained hypoxia caused a distinct regulation of HIF-1α and -2α. The striking increase of HIF-2α protein expression was contrasted by a dramatic decrease of HIF-1α. The long-term downregulation of HIF-1α is due to downregulation of its mRNA. This decrease was accompanied by increased expression of ahif, a natural cis-antisense transcript of HIF-1α. The ahif-transcript was strongly inducible by hypoxia and rapidly degraded under reoxygenation. Using an adenoviral overexpression and siRNA silencing approach revealed that the targeted regulation of ahif is mediated by the HIF-system itself. Furthermore it could be shown that ahif indeed is able to modulate the hypoxic expression of HIF-1α and influences the expression of the HIF-target gene Enolase-2. Taken together, this study characterizes a new regulation process of the HIF-transcription factor-system in human macrophages under hypoxia. For the first time evidence is provided that ahif is regulated by the HIF-system and influences HIF-1α expression in primary human macrophages.

Local inhibition of hypoxia-inducible factor reduces neointima formation after arterial injury in ApoE-/- mice.

OBJECTIVE Hypoxia plays a pivotal role in development and progression of restenosis after vascular injury. Under hypoxic conditions the hypoxia-inducible factors (HIFs) are the most important transcription factors for the adaption to reduced oxygen supply. Therefore the aim of the study was to investigate the effect of a local HIF-inhibition and overexpression on atherosclerotic plaque development in a murine vascular injury model. METHODS AND RESULTS After wire-induced vascular injury in ApoE-/- mice a transient, local inhibition of HIF as well as an overexpression approach of the different HIF-subunits (HIF-1α, HIF-2α) by adenoviral infection was performed. The local inhibition of the HIF-pathway using a dominant-negative mutant dramatically reduced the extent of neointima formation. The diminished plaque size was associated with decreased expression of the well-known HIF-target genes vascular endothelial growth factor-A (VEGF-A) and its receptors Flt-1 and Flk-1. In contrast, the local overexpression of HIF-1α and HIF-2α further increased the plaque size after wire-induced vascular injury. CONCLUSIONS Local HIF-inhibition decreases and HIF-α overexpression increases the injury induced neointima formation. These findings provide new insight into the pathogenesis of atherosclerosis and may lead to new therapeutic options for the treatment of in stent restenosis.

Mental symptoms in patients with cardiac symptoms and normal coronary arteries

Objectives Patients with chest pain and normal coronary arteries often suffer from physical and psychological symptoms. Therefore, this study aimed to examine the incidence of mental symptoms in patients with angiographic exclusion of a coronary heart disease. Design In 253 patients with angiographic exclusion of a coronary heart disease the type and intensity of their symptoms were evaluated before and after coronary angiography. In addition, the incidence of psychopathological symptoms was quantified by standardised questionnaires such as general anxiety and depression (HADS), heart-focused anxiety (CAQ), hypochondria (Whiteley Index) and somatoform disorder (SOMS) and quality of life (SF-12). Finally, the incidence of psychological symptoms in these patients was compared to the incidence in the normal population. Results Despite the absence of a coronary artery disease, 70% of patients continue to suffer from cardiac symptoms. The incidence of general anxiety was increased by 37% in women and by 22% in men in comparison to the normal population. Heart-focused anxiety was raised by 27%. Somatoform disorder appeared 120% more often in patients after cardiac catheterisation in comparison to the normal population. In addition, the incidence of hypochondria was elevated by 68% in patients after coronary angiography compared to normal population. This increased appearance of psychological symptoms was reflected in a significantly lower quality of life (SF-12) in patients with inconspicuous coronary angiography. Conclusions Patients with cardiac symptoms and normal coronary arteries more often suffer from mental symptoms in comparison to the healthy population.

Intra-aortic balloon pump (IABP) counterpulsation improves cerebral perfusion in patients with decreased left ventricular function

Background: The current goal of treatment after acute ischemic stroke is the increase of cerebral blood flow (CBF) in ischemic brain tissue. Intra-aortic balloon pump (IABP) counterpulsation in the setting of cardiogenic shock is able to reduce left ventricular afterload and increase coronary blood flow. The effects of an IABP on CBF have not been sufficiently examined. We hypothesize that the use of an IABP especially enhances cerebral blood flow in patients with pre-existing heart failure. Methods: In this pilot study, 36 subjects were examined to investigate the effect of an IABP on middle cerebral artery (MCA) transcranial Doppler (TCD) flow velocity change and relative CBF augmentation by determining velocity time integral changes (ΔVTI) in a constant caliber of the MCA compared to a baseline measurement without an IABP. Subjects were divided into two groups according to their left ventricular ejection fraction (LVEF): Group 1 LVEF >30% and Group 2 LVEF ≤30%. Results: Both groups showed an increase in CBF using an IABP. Patients with a LVEF ≤30% showed a significantly higher increase of ΔVTI in the MCA under IABP augmentation compared to patients with a LVEF >30% (20.9% ± 3.9% Group 2 vs.10.5% ± 2.2% Group 1, p<0,05). The mean arterial pressure (MAP) increased only marginally in both groups under IABP augmentation. Conclusions: IABP improves cerebral blood flow, particularly in patients with pre-existing heart failure and highly impaired LVEF. Hence, an IABP might be a treatment option to improve cerebral perfusion in selected patients with cerebral misperfusion and simultaneously existing severe heart failure.

First bioprosthesis thrombosis after transcatheter mitral valve-in-valve implantation: diagnosis and treatment.

Universitaet Dresden, Heart Center, University Hospital, Department of Internal Medicine and Cardiology, Dresden, Germany. Manuscript received November 13, 2013; accepted November 26, 2013. Journal of the American College of Cardiology Vol. 63, No. 18, 2014 2014 by the American College of Cardiology Foundation ISSN 0735-1097/

Transient global amnesia and broken heart syndrome: two faces of one pathology

36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.11.067

Soluble ST2 and myocardial fibrosis in 3T cardiac magnetic resonance

We present a case of a 57-year-old female patient with transient global amnesia, who later developed broken heart syndrome also known as takotsubo cardiomyopathy. The present case underlines that co-occurrence of both pathologies might still be an under-recognized clinical problem.