a prospective cohort study

Background The effects of target temperature management (TTM) on the heart aren’t thoroughly studied yet. Several studies showed the prolongation of various ECG parameters including Tpeak-Tend-time under TTM. Our study’s goal is to evaluate the acute and long-term outcome of these prolongations. Methods In this study we included patients with successful resuscitation after cardiac arrest who were admitted to the Charité Virchow Klinikum Berlin or the Heart and Vascular Centre of the Ruhr University Bochum between February 2006 and July 2013 (Berlin) or May 2014 to November 2015 (Bochum). For analysis, one ECG during TTM was recorded after reaching the target temperature (33–34 °C) or in the first 6 h of TTM. If possible, another ECG was taken after TTM. The patients were being followed until February 2016. Primary endpoint was ventricular arrhythmia during TTM, secondary endpoints were death and hospitalization due to cardiovascular diseases during follow-up. Results One hundred fifty-eight patients were successfully resuscitated in the study period of which 95 patients had usable data (e.g. ECGs without artifacts). During TTM significant changes for different parameters of ventricular de- and repolarization were noted: QRS (103.2 ± 23.7 vs. 95.3 ± 18.1; p = 0.003),QT (405.8 ± 76.4 vs. 373.8 ± 75.0; p = 0.01), QTc (474.9 ± 59.7 vs. 431.0 ± 56.8; p < 0.001), JT (302.8 ± 69.4 vs. 278.5 ± 75.2; p = 0.043), JTc (354.3 ± 60.2 vs. 318.7 ± 59.1; p = 0.001). 13.7% of the patients had ventricular arrhythmias during TTM, however these patients showed no difference regarding their ECG parameters in comparison to those were no ventricular arrhythmias occurred. We were able to follow 69 Patients over an average period of 35 ± 31 months. The 14 (21.5%) patients who died during the follow-up had significant prolongations of the TpTe-time in the ECGs without TTM (103.9 ± 47.2 vs. 75.8 ± 28.6; p = 0.023). Conclusion Our results show a significant prolongation of ventricular repolarization during TH. However, there was no significant difference between the ECG parameters of those who developed a ventricular arrhythmia and those who did not. The temporary prolongation of the repolarization during TTM seems to be less important for the prognosis of the patient. Whereas the prolongation of the repolarization in the basal ECG is associated with a higher mortality in our study

Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance - The BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan) to improve antiplatelet therapy

<p>Abstract</p> <p>Background</p> <p>Dual antiplatelet therapy using acetylsalicylic acid (ASA, aspirin) and clopidogrel is of great importance following coronary stenting. However, the variable platelet inhibitory effectiveness compromises the antithrombotic advantages provided by dual antiplatelet therapy. The aim of this single-center prospective study was to reduce the low response incidence of dual antiplatelet therapy with ASA and clopidogrel according to a prespecified therapy algorithm.</p> <p>Methods</p> <p>Platelet function testing using whole blood aggregometry (Chronolog 590) was performed 48 hours following coronary stenting (for either acute coronary syndromes or stable coronary artery disease) on 504 patients. The antiplatelet therapy included a loading dose of 600 mg clopidogrel and 500 mg ASA, followed by 75 mg clopidogrel and 100 mg ASA once daily. Clopidogrel low responders (CLR: >5 ohm; adenosine diphosphate (ADP) 5 μM) and/or ASA low responders (ALR: >0 ohm; arachidonic acid 10 μM) were treated according to a structured therapy plan: in the case of CLR, the maintenance + dose was doubled (repeated loading dose followed by 150 mg daily), and when still ineffective ticlopidine or prasugrel, if available and not contraindicated, were used. ALR was treated by increasing the dose to 300 mg in a first step or to 500 mg ASA when the first modification did not take effect sufficiently. In addition, ADP receptor antagonist 2-methylthioadenosine 5'-monophosphate triethylammonium salt (MeSAMP) testing and ASA incubation were performed to rule out either a platelet ADP-receptor defect or an ASA pharmacokinetic resistance.</p> <p>Results</p> <p>Of the total cohort of 504 patients, we detected 30.8% clopidogrel low-responders and 19.4% aspirin low-responders. For ALR, with a dose adjustment of 300 mg ASA daily, 94.6% of ALR were effectively treated and the residual 5.4% by administration of daily dosages of 500 mg ASA. This means that after modification of the ASA maintenance dose, all initial ALRs had an adequate antiplatelet response.</p> <p>The results for clopidogrel revealed that 69% of the CLR were treated effectively by increasing the clopidogrel dose to 150 mg daily. When prasugrel was not available or contraindicated, 12.7% of the remaining low responders showed an adequate result after being switched to ticlopidine. Consequently, by applying the therapy algorithm, we were able to reduce the CLR prevalence by 86.6%. On including prasugrel in the therapy plan, we were finally able to eliminate thienopyridine low response. In addition, no ADP receptor defect was found in this study as a potential reason for CLR.</p> <p>We identified the following factors associated with both CLR and ALR status: acute coronary syndromes, positive troponin values as well as diabetes mellitus and elevated HbA_1Cvalues and a higher platelet count. Furthermore, our data revealed for CLR elevated C-reactive protein values and a high PREDICT-score (including an age >65 years, acute coronary syndrome, diabetes mellitus, renal failure, and reduced left ventricular function) as risk factors. The following factors correlated with the risk of ASA low response: patients with elevated hemoglobin, serum creatinine and C-reactive protein values. In addition, medication with nitrates reduced the risk of being CLR. As also holds true for CLR, we found the PREDICT-score to be correlated to the risk of being ALR. However, by far the strongest risk factor for CLR or ALR was the fact of dual resistance.</p> <p>Conclusion</p> <p>Following a structured therapy plan based on a "test and treat" strategy, the prevalence of clopidogrel or aspirin low response can be significantly reduced and the risk of inadequate dual antiplatelet therapy minimized.</p> <p>Trial Registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01212302">NCT01212302</a> (Clinicaltrials.gov)</p

Hypothermia induced alteration of repolarization - impact on acute and long-term outcome: a prospective cohort study

Abstract Background The effects of target temperature management (TTM) on the heart aren’t thoroughly studied yet. Several studies showed the prolongation of various ECG parameters including Tpeak-Tend-time under TTM. Our study’s goal is to evaluate the acute and long-term outcome of these prolongations. Methods In this study we included patients with successful resuscitation after cardiac arrest who were admitted to the Charité Virchow Klinikum Berlin or the Heart and Vascular Centre of the Ruhr University Bochum between February 2006 and July 2013 (Berlin) or May 2014 to November 2015 (Bochum). For analysis, one ECG during TTM was recorded after reaching the target temperature (33–34 °C) or in the first 6 h of TTM. If possible, another ECG was taken after TTM. The patients were being followed until February 2016. Primary endpoint was ventricular arrhythmia during TTM, secondary endpoints were death and hospitalization due to cardiovascular diseases during follow-up. Results One hundred fifty-eight patients were successfully resuscitated in the study period of which 95 patients had usable data (e.g. ECGs without artifacts). During TTM significant changes for different parameters of ventricular de- and repolarization were noted: QRS (103.2 ± 23.7 vs. 95.3 ± 18.1; p = 0.003),QT (405.8 ± 76.4 vs. 373.8 ± 75.0; p = 0.01), QTc (474.9 ± 59.7 vs. 431.0 ± 56.8; p < 0.001), JT (302.8 ± 69.4 vs. 278.5 ± 75.2; p = 0.043), JTc (354.3 ± 60.2 vs. 318.7 ± 59.1; p = 0.001). 13.7% of the patients had ventricular arrhythmias during TTM, however these patients showed no difference regarding their ECG parameters in comparison to those were no ventricular arrhythmias occurred. We were able to follow 69 Patients over an average period of 35 ± 31 months. The 14 (21.5%) patients who died during the follow-up had significant prolongations of the TpTe-time in the ECGs without TTM (103.9 ± 47.2 vs. 75.8 ± 28.6; p = 0.023). Conclusion Our results show a significant prolongation of ventricular repolarization during TH. However, there was no significant difference between the ECG parameters of those who developed a ventricular arrhythmia and those who did not. The temporary prolongation of the repolarization during TTM seems to be less important for the prognosis of the patient. Whereas the prolongation of the repolarization in the basal ECG is associated with a higher mortality in our study

In-hospital triggers of takotsubo syndrome

$\bf Background$ Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction, mimicking an acute myocardial infarction, in the absence of obstructed coronary arteries. It is often triggered by physical or emotional stress, with catecholamines playing a central role in its pathophysiology. Recent advances have been made in categorizing TTS patients based on trigger events and comorbidities, as well as proposed classifications differentiating primary and secondary TTS. In-hospital triggers for (secondary) TTS appear to be quite common, and our aim is to bring attention of this prevalent phenomenon. $\textbf {Case summary}$ We present the clinical course of an 80-year-old man who developed TTS after witnessing the sudden death of his roommate during his hospital stay. Initially hospitalized for bradycardia and complete atrioventricular block, the patient was discharged after a pacemaker implantation. However, he returned to the hospital 3 days later with chest pain and other symptoms indicative of TTS. Diagnostic tests confirmed apical ballooning consistent with TTS, and subsequent echocardiograms showed a substantial improvement in left ventricular function. $\bf Discussion$ The case is classified as in-hospital TTS, occurring unexpectedly during medical care, and suggests that secondary TTS could represent a certain ‘basic risk’ for hospitalized patients. We want to emphasize the importance of reducing pain and fear in the hospital setting and encourage further research to understand the association between TTS and medical procedures and therapies. Overall, this case underscores the need for strategies to reduce the frequency of TTS in hospitalized patients

Integration of Cardiac Actin Mutants Causing Hypertrophic (p.A295S) and Dilated Cardiomyopathy (p.R312H and p.E361G) into Cellular Structures

The human mutant cardiac α-actins p.A295S or p.R312H and p.E361G, correlated with hypertrophic or dilated cardiomyopathy, respectively, were expressed by the baculovirus/Sf21 insect cell system and purified to homogeneity. The purified cardiac actins maintained their native state but showed differences in Ca2+-sensitivity to stimulate the myosin-subfragment1 ATPase. Here we analyzed the interactions of these c-actins with actin-binding and -modifying proteins implicated in cardiomyocyte differentiation. We demonstrate that Arp2/3 complex and the formin mDia3 stimulated the polymerization rate and extent of the c-actins, albeit to different degrees. In addition, we tested the effect of the MICAL-1 monooxygenase, which modifies the supramolecular actin organization during development and adaptive processes. MICAL-1 oxidized these c-actin variants and induced their de-polymerization, albeit at different rates. Transfection experiments using MDCK cells demonstrated the preferable incorporation of wild type and p.A295S c-actins into their microfilament system but of p.R312H and p.E361G actins into the submembranous actin network. Transduction of neonatal rat cardiomyocytes with adenoviral constructs coding HA-tagged c-actin variants showed their incorporation into microfilaments after one day in culture and thereafter into thin filaments of nascent sarcomeric structures at their plus ends (Z-lines) except the p.E361G mutant, which preferentially incorporated at the minus ends

Functional Characterization of Cardiac Actin Mutants Causing Hypertrophic (p.A295S) and Dilated Cardiomyopathy (p.R312H and p.E361G)

Human wild type (wt) cardiac &alpha;-actin and its mutants p.A295S or p.R312H and p.E361G correlated with hypertrophic or dilated cardiomyopathy, respectively, were expressed by using the baculovirus/Sf21 insect cell system. The c-actin variants inhibited DNase I, indicating maintenance of their native state. Electron microscopy showed the formation of normal appearing actin filaments though they showed mutant specific differences in length and straightness correlating with their polymerization rates. TRITC-phalloidin staining showed that p.A295S and p.R312H exhibited reduced and the p.E361G mutant increased lengths of their formed filaments. Decoration of c-actins with cardiac tropomyosin (cTm) and troponin (cTn) conveyed Ca2+-sensitivity of the myosin-S1 ATPase stimulation, which was higher for the HCM p.A295S mutant and lower for the DCM p.R312H and p.E361G mutants than for wt c-actin. The lower Ca2+-sensitivity of myosin-S1 stimulation by both DCM actin mutants was corrected by the addition of levosimendan. Ca2+-dependency of the movement of pyrene-labeled cTm along polymerized c-actin variants decorated with cTn corresponded to the relations observed for the myosin-S1 ATPase stimulation though shifted to lower Ca2+-concentrations. The N-terminal C0C2 domain of cardiac myosin-binding protein-C increased the Ca2+-sensitivity of the pyrene-cTM movement of bovine, recombinant wt, p.A295S, and p.E361G c-actins, but not of the p.R312H mutant, suggesting decreased affinity to cTm