Outcomes of ECLS-SHOCK Eligibility Criteria Applied to a Real-World Cohort.

BACKGROUND: Cardiogenic shock (CS) exhibits high (~50%) in-hospital mortality. The recently published Extracorporeal life Support in Cardiogenic Shock (ECLS-SHOCK) trial demonstrated the neutral effects of the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) on all-cause death, as well as on all secondary outcomes in subjects presenting with myocardial-infarction (MI)-related CS. Here, we compared ECLS-SHOCK eligibility criteria with a real-world cohort of CS patients. METHODS AND RESULTS: ECLS-SHOCK eligibility criteria were applied to a prospective single-center CS registry (the PREPARE CS registry) consisting of 557 patients who were consecutively admitted to the catheterization laboratory (cath lab) of the Medical University of Graz, Austria, due to CS (SCAI C-E). Overall use of mechanical circulatory support (MCS) in this cohort was 19%. Sixty-nine percent of the entire cohort had MI-related CS, 38% of whom would have met ECLS-SHOCK eligibility criteria, thus representing only 27% of the PREPARE CS registry. Exclusion from the ECLS-SHOCK trial was based on patients with initial lactate values below 3 mmol/L (n = 168; 43.6%), aged over 80 years (n = 65; 16.9%), and with a duration of cardiopulmonary resuscitation (CPR) exceeding 45 min (n = 22; 5.7%). The 30-day mortality of patients of the PREPARE CS registry who met the ECLS-SHOCK eligibility criteria was 57.0%, compared to 48.4% of patients in the ECLS-SHOCK trial. The patients' baseline characteristics, however, differed considerably with respect to type of infarction, age, and gender. CONCLUSIONS: In a real-world cohort of patients with MI-related CS, only 38% of patients met the eligibility criteria of the ECLS-SHOCK trial. Thus, the impact of the use of VA-ECMO on outcome parameters in MI-related CS, as observed in the ECLS-SHOCK trial, may differ in a more heterogeneous real-world CS population of the PREPARE CS registry.

Timing of SGLT2i initiation after acute myocardial infarction.

BACKGROUND: Pharmacological post-MI treatment is routinely initiated at intensive/cardiac care units. However, solid evidence for an early start of these therapies is only available for dual platelet therapy and statins, whereas data on beta blockers and RAAS inhibitors are heterogenous and mainly limited to STEMI and heart failure patients. Recently, the EMMY trial provided the first evidence on the beneficial effects of SGLT2 inhibitors (SGLT2i) when initiated early after PCI. In patients with type 2 diabetes mellitus, SGLT2i are considered "sick days drugs" and it, therefore, remains unclear if very early SGLT2i initiation following MI is as safe and effective as delayed initiation. METHODS AND RESULTS: The EMMY trial evaluated the effect of empagliflozin on NT-proBNP and functional and structural measurements. Within the Empagliflozin group, 22 (9.5%) received early treatment (< 24 h after PCI), 98 (42.2%) within a 24 to < 48 h window (intermediate), and 111 (48.1%) between 48 and 72 h (late). NT-proBNP levels declined by 63.5% (95%CI: - 69.1; - 48.1) in the early group compared to 61.0% (- 76.0; - 41.4) in the intermediate and 61.9% (- 70.8; - 45.7) in the late group (n.s.) within the Empagliflozin group with no significant treatment groups-initiation time interaction (pint = 0.96). Secondary endpoints of left ventricular function (LV-EF, e/e`) as well as structure (LVESD and LVEDD) were also comparable between the groups. No significant difference in severe adverse event rate between the initiation time groups was detected. CONCLUSION: Very early administration of SGLT2i after acute myocardial infarction does not show disadvantageous signals with respect to safety and appears to be as effective in reducing NT-proBNP as well as improving structural and functional LV markers as initiation after 2-3 days.

Thermic sealing in femoral catheterization: First experience with the Secure Device.

BACKGROUND: Devices currently used to achieve hemostasis of the femoral artery following percutaneous cardiac catheterization are associated with vascular complications and remnants of artificial materials are retained at the puncture site. The Secure arterial closure Device induces hemostasis by utilizing thermal energy, which causes collagen shrinking and swelling. In comparison to established devices, it has the advantage of leaving no foreign material in the body following closing. This study was designed to evaluate the efficacy and safety of the Secure Device to close the puncture site following percutaneous cardiac catheterization. METHODS: The Secure Device was evaluated in a prospective non-randomized single-center trial with patients undergoing 6 F invasive cardiac procedures. A total of 67 patients were enrolled and the device was utilized in 63 patients. Fifty diagnostic and 13 interventional cases were evaluated. Femoral artery puncture closure was performed immediately after completion of the procedure. Time to hemostasis (TTH), time to ambulation (TTA) and data regarding short-term and 30-day clinical follow-up were recorded. RESULTS: Mean TTH was 4:30 ± 2:15 min in the overall observational group. A subpopulation of patients receiving anticoagulants had a TTH of 4:53 ± 1:43 min. There were two access site complications (hematoma > 5 cm). No major adverse events were identified during hospitalization or at the 30 day follow-up. CONCLUSIONS: The new Secure Device demonstrates that it is feasible in diagnostic and interventional cardiac catheterization. With respect to safety, the Secure Device was non-inferior to other closure devices as tested in the ISAR closure trial.

Cangrelor Induces More Potent Platelet Inhibition without Increasing Bleeding in Resuscitated Patients.

Dual antiplatelet therapy is the standard of care for patients with myocardial infarction (MI), who have been resuscitated and treated with therapeutic hypothermia (TH). We compare the antiplatelet effect and bleeding risk of intravenous cangrelor to oral P2Y12-inhibitors in patients with MI receiving TH in a prospective comparison of two matched patient cohorts. Twenty-five patients within the CANGRELOR cohort were compared to 17 patients receiving oral P2Y12-inhibitors. CANGRELOR group (NCT03445546) and the ORAL P2Y12 Group (NCT02914795) were registered at clinicaltrials.gov. Platelet function testing was performed using light-transmittance aggregometry and monitored for 4 days. P2Y12-inhibition was stronger in CANGRELOR compared to ORAL P2Y12 (adenosine diphosphate (ADP) (area under the curve (AUC)) 26.0 (5.9⁻71.6) vs. 160.9 (47.1⁻193.7)) at day 1. This difference decreased over the following days as more patients were switched from CANGRELOR to oral P2Y12-inhibitor treatment. There was no difference in the effect of aspirin between the two groups. We did not observe significant differences with respect to thrombolysis in myocardial infarction (TIMI) or Bleeding Academic Research Consortium (BARC) classified bleedings, number of blood transfusions or drop in haemoglobin B (Hb) or hematocrit (Hct) over time. Cangrelor treatment is not only feasible and effective in resuscitated patients, but also inhibited platelet function more effectively than orally administered P2Y12-inhibitors without an increased event rate for bleeding.

Heart rate-reducing therapy with add-on ivabradine and bisoprolol before coronary computed tomographic angiography in a fast-track ambulatory setting.

Objective This study was performed to determine whether add-on oral ivabradine in patients treated with beta blockers 1 hour before coronary computed tomographic angiography (CCTA) is effective in lowering the heart rate and thus improving CCTA quality. Methods In this single-center cohort study, the data of 294 patients referred for ambulant CCTA were retrospectively screened. Patients with an initial heart rate of ≥75 bpm (n = 112) were pretreated with either a combination of bisoprolol and ivabradine or with bisoprolol alone. Results During the scan, there was no difference in heart rate between the two groups Likewise, there was no significant difference in additionally administered intravenous bradycardic agents, the number of motion artifacts, or the radiation dose. Both drug regimens were tolerated well. Conclusion Additive oral ivabradine 1 hour before CCTA does not result in a further reduction of the heart rate. Consequently, neither movement artifacts nor radiation dose can be reduced. Therefore, pretreatment with ivabradine does not seem reasonably appropriate in an outpatient clinical setting with short patient contact.

Impairment of brainstem implicit learning paradigms differentiates multiple system atrophy (MSA) from idiopathic Parkinson syndrome.

OBJECTIVES: Learning as measured by eyeblink classical conditioning is preserved in patients with idiopathic Parkinson's disease, but severely affected in patients with progressive supranuclear palsy. We here sought to clarify whether procedural learning is impaired in multiple system atrophy (MSA), and whether it may be helpful for the differentiation of parkinsonian syndromes. DESIGN: We investigated learning using (1) eyeblink classical conditioning with a delay (interstimulus interval 0 ms) and a trace (600 ms) paradigm and (2) a serial reaction time task. SETTING: Participants were recruited from academic research centres. PARTICIPANTS: 11 patients with MSA and 11 healthy controls. RESULTS: Implicit learning in eyeblink classical conditioning (acquisition of conditioned responses) as well as the serial reaction time task measures of implicit learning (reaction time change) are impaired in patients with MSA as compared with controls, whereas explicit learning as measured by the sequence recall of the serial reaction time task is relatively preserved. ANALYSIS: We hypothesise that the learning deficits of patients with MSA are due to lesions of cerebellar and connected brainstem areas. CONCLUSIONS: A retrospective synopsis of these novel data on patients with MSA and groups of patients with idiopathic Parkinson's disease and progressive supranuclear palsy studied earlier suggest that eyeblink classical conditioning may contribute to the early differentiation of atypical Parkinson syndromes from idiopathic Parkinson's disease. This hypothesis should be tested in a prospective trial.

Towards physiological ankle movements with the ActiGait implantable drop foot stimulator in chronic stroke.

PURPOSE: Functional electrical stimulation represents an alternative to conventional and passive ankle foot orthosis (AFO) for the treatment of stroke-related drop foot. We evaluated the implantable 4-channel stimulator ActiGait, which selectively and directly stimulates the peroneal nerve. In addition, it bypasses the need for surface electrodes and cables. METHODS: Walking speed (10-meter gait test, [m/s]) and walking endurance (6-minute gait test [m/6min]) of 5 patients were tested prior to, as well as 6 and 12 weeks after, the implantation of the ActiGait implantable drop foot stimulator system. In addition, ankle joint angles were assessed during specific phases of the gait cycle, i.e. initiation angle (IA) at the first contact of the foot to the floor, initial plantar flexion (IPF), dorsiflexion (DF) and final plantar flexion (FPF) in [°] during stance phase. The ankle joint angles were measured at baseline and 12 weeks after ActiGait implantation. RESULTS: At the first follow-up, patients' gait speed was found to have increased (0.55; 0.77 m/s) as had walking endurance (211; 260 m). Improvement in gait speed (0.55; 0.77 m/s) and endurance (214; 248 m) was still present after 12 weeks. In addition, gait analysis after 12 weeks revealed a nearly normal physiological initiation angle (113° vs 122°) and an increase in the initial plantar flexion (7° vs. 0°). The initiation angle (IA) represents a well-suited parameter for adequate pre-positioning of the foot at the beginning of the stance phase and is necessary to prevent stumbling and falling. Furthermore, IA is identical to the maximum achieved dorsiflexion during the swing phase of gait. Thus, analysis of the IA of subjects walking with the implantable drop foot stimulator systems ActiGait is particularly useful in showing that the implantable system restores the IA towards physiological ankle movements. CONCLUSION: The ActiGait system increased gait speed, walking endurance and the physiology of important ankle joint kinematics. This is most likely a result of ankle dorsiflexion by active peroneal stimulation during the swing phase of gait and optimized prepositioning (IA) of the foot at the beginning of stance phase. The ActiGait system represents a therapeutic option for the treatment of patients suffering drop foot due to a cerebrovascular insult.

Efficacy of EMG-triggered electrical arm stimulation in chronic hemiparetic stroke patients.

PURPOSE: EMG-triggered electrostimulation (EMG-ES) may improve the motor performance of affected limbs of hemiparetic stroke patients even in the chronic stage. This study was designed to characterize cortical activation changes following intensified EMG-ES in chronic stroke patients and to identify predictors for successful rehabilitation depending on disease severity. METHODS: We studied 9 patients with severe residual hemiparesis, who underwent 8 weeks of daily task-orientated multi-channel EMG-ES of the paretic arm. Before and after treatment, arm function was evaluated clinically and cortical activation patterns were assessed with functional MRI (fMRI) and/or transcranial magnetic stimulation (TMS). RESULTS: As response to therapy, arm function improved in a subset of patients with more capacity in less affected subjects, but there was no significant gain for those with Box & Block test values below 4 at inception. The clinical improvement, if any, was accompanied by an ipsilesional increase in the sensorimotor cortex (SMC) activation area in fMRI and enhanced intracortical facilitation (ICF) as revealed by paired TMS. The SMC activation change in fMRI was predicted by the presence or absence of motor-evoked potentials (MEPs) on the affected side. CONCLUSIONS: The present findings support the notion that intensified EMG-ES may improve the arm function in individual chronic hemiparetic stroke patients but not in more severely impaired individuals. Functional improvements are paralleled by increased ipsilesional SMC activation and enhanced ICF supporting neuroplasticity as contributor to rehabilitation. The clinical score at inception and the presence of MEPs have the best predictive potential.

Towards a rationale of platelet aggregation monitoring in stroke prophylaxis?

The recurrence of ischemic cerebrovascular events despite treatment with aspirin (ASA) and/or clopidogrel remains a serious problem. Although there is increasing evidence that clinical failure may at least partially result from the nonresponsiveness of platelets to medication, the adjustment of the therapy according to ex vivo platelet responses is not yet common in clinical practice. Here, we compare two commonly used ex vivo platelet function tests under different treatment conditions. Blood samples from 142 patients with cerebrovascular disease receiving either ASA, clopidogrel, or a combined treatment, and 51 controls were evaluated by the platelet function analyzer (PFA)-100 (collagen/epinephrine cartridge), as well as collagen and ADP-induced aggregometry. The tests all demonstrated the interindividual heterogeneity of platelet aggregation inhibition, but the fractions of nonresponsiveness differed considerably with 58-62% of patients being nonresponsive to ASA by PFA-100 compared with 27-33% by collagen-induced aggregation. The clopidogrel nonresponsiveness was 44% by ADP-induced aggregation. The agreement of the test values between PFA-100 and collagen-induced aggregometry was weak (correlation coefficient r= -0.1 to -0.3). Only about half of the patients were consistently identified as either ASA responsive or nonresponsive by both tests. Under dual therapy conditions, the unspecificity of aggregometric tests prevented reliable measurements of platelet responses. In conclusion, there are currently considerable limitations in platelet aggregation monitoring. Nevertheless, we encourage prospective trials to improve the predictive value of platelet aggregation testing and to prove whether a systematic strategy of "platelet aggregation-adapted treatment" will improve the clinical outcome of patients with cerebrovascular events.

Low Ca2+ buffering in hypoglossal motoneurons of mutant SOD1 (G93A) mice.

Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are associated with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by a selective degeneration of brainstem and spinal motoneurons. The pathomechanism of degeneration is still incompletely understood, but includes a disruption in cellular Ca2+ homeostasis. Here we report a quantitative microfluorometric analysis of the Ca2+ homeostasis in vulnerable hypoglossal motoneurons of neonatal mutant (G93A) SOD1 transgenic mice, a mouse model of human ALS. Ca2+ transient decay times (tau = 0.3 s), extrusion rates (gamma = 92 s(-1)) and exceptionally low intrinsic Ca2+ binding ratios (kappaS = 30) were found to be in the same range as compared to non-transgenic animals. Together with the previous observation of high Ca2+ binding ratios in ALS-resistant neurons (e.g. oculomotor), this supports the assumption that low Ca2+ buffering in vulnerable motoneurons represents a significant risk factor for degeneration. On the other hand, alterations in buffering properties by expression of mutant SOD1 are unlikely to be involved in disease initiation.

T2*-weighted MRI in diagnosis of multiple system atrophy. A practical approach for clinicians.

BACKGROUND: Putaminal iron deposition is a histopathological feature of multiple system atrophy (MSA), which is not observed in patients with idiopathic Parkinson's disease (PD). T2*-weighted magnetic resonance imaging (MRI) gradient echo (GE) sequences are sensitive for paramagnetic susceptibility changes and therefore may support the clinical differential diagnosis between MSA and PD. METHODS: We evaluated putaminal signal intensities on 1.0 Tesla scans of 52 MSA patients, 88 patients with PD and 29 healthy control subjects. RESULTS: The typical finding in T2* GE sequences of MSA patients was a signal loss of the dorsolateral putamen, which showed a high specificity (>0.91), but was present in only a subpopulation of patients (sensitivity 0.64-0.69). The combination of the latter with additional presence of a hyperintense lateral rim in fluid attenuated inversion recovery (FLAIR) sequences increased the specificity to 0.97. Using a quantitative evaluation of putaminal signal intensities in defined regions of interest MSA and PD could be discriminated with a diagnostic accuracy (r) of up to 0.82. CONCLUSION: Although the separation of groups remains incomplete, the use of T2*-weighted GE sequences combined with FLAIR may be helpful for the differential diagnosis of MSA versus PD considering its fast application, easy evaluation, broad availability, the specificity of findings and the presence of putaminal signal loss already at early disease stages.

Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS.

Motoneurons are selectively damaged in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Although the underlying mechanisms are not completely understood, increasing evidence indicates that motoneurons are particularly sensitive to disruption of mitochondria and Ca(2+)-dependent signalling cascades. Comparison of ALS-vulnerable and ALS-resistant neurons identified low Ca(2+)-buffering capacity and a strong impact of mitochondrial signal cascades as important risk factors. Under physiological conditions, weak Ca(2+) buffers are valuable because they facilitate rapid relaxation times of Ca(2+) transients in motoneurons during high-frequency rhythmic activity. However, under pathological conditions, weak Ca(2+) buffers are potentially dangerous because they accelerate a vicious circle of mitochondrial disruption, Ca(2+) disregulation and excitotoxic cell damage.

Mitochondrial Ca2+ buffering in hypoglossal motoneurons from mouse.

A variety of studies demonstrated a crucial role of mitochondria for clearance of Ca2+ loads in motoneurons. However, previous reports rarely addressed the potential influence of cell dialysis during patch-clamp recordings or temperature on mitochondrial processes. We therefore developed a protocol allowing investigation of Ca2+ dynamics in "undisturbed" AM-ester loaded hypoglossal motoneurons in a slice preparation. By comparing our findings to previous results, we argue against a significant disturbance of mitochondrial buffering by cell dialysis. By varying bath temperatures between 19 and 32 degrees C, we show that temperature alters the rate of mitochondrial uptake but not the relative contribution to maintenance of Ca2+ homeostasis. The results further indicate that mitochondria in hypoglossal motoneurons participate in intracellular Ca2+ regulation at concentrations much lower than has been generally observed for other neurons or neuroendocrine cells. Taken together, our findings further support the important role of mitochondria as regulators of Ca2+ homeostasis in motoneurons.

Extensive exercise is not harmful in amyotrophic lateral sclerosis.

Whether physical activity increases risk or promotes progression of motor neurone degeneration in amyotrophic lateral sclerosis (ALS) is still debated. Current pathophysiological hypotheses include excitotoxicity, oxidative stress and increased calcium loads as causes of selective degeneration of vulnerable motor neurones. Vigorous exercise might amplify these factors by increasing firing rates at motor neurones. To test this hypothesis, we constrained a transgenic mouse model of ALS overexpressing the mutant human form of the Cu/Zn superoxide dismutase-1 (SOD-1) to a lifetime exercise on motor-driven running wheels for 10 h daily (active group, n = 12). Onset and progression of disease were assessed by grip strength, stride length and tight rope test. Data were compared with SOD-1 mice placed in running wheels set to slow speed (sedentary group, n = 13). Untreated SOD-1 mice were an additional control group (n = 12). We found no differences in disease onset, which was determined by a change-point analysis using an iterative fitting of segmented linear regression models, or in disease progression. However, the running group showed a non-significant 6-day improvement in survival (133.7 +/- 3.2 days) compared with the sedentary group (127.2 +/- 3.2 days) and a 4-day improvement compared with the control group (129.1 +/- 2.5 days). We demonstrate that a lifetime of vigorous exercise does not promote onset or progression of motor degeneration in SOD-1-mediated ALS. Moreover, the results suggest that the level of excitatory input and calcium turnover at motor neurones, both of which should be increased by running activity, do not interfere with the pathophysiology of SOD-1-mediated ALS.