Mitigating the Functional Deficit after Neurotoxic Motoneuronal Loss by an Inhibitor of Mitochondrial Fission.

Amyotrophic lateral sclerosis (ALS) is an extremely complex neurodegenerative disease involving different cell types, but motoneuronal loss represents its main pathological feature. Moreover, compensatory plastic changes taking place in parallel to neurodegeneration are likely to affect the timing of ALS onset and progression and, interestingly, they might represent a promising target for disease-modifying treatments. Therefore, a simplified animal model mimicking motoneuronal loss without the other pathological aspects of ALS has been established by means of intramuscular injection of cholera toxin-B saporin (CTB-Sap), which is a targeted neurotoxin able to kill motoneurons by retrograde suicide transport. Previous studies employing the mouse CTB-Sap model have proven that spontaneous motor recovery is possible after a subtotal removal of a spinal motoneuronal pool. Although these kinds of plastic changes are not enough to counteract the functional effects of the progressive motoneuron degeneration, it would nevertheless represent a promising target for treatments aiming to postpone ALS onset and/or delay disease progression. Herein, the mouse CTB-Sap model has been used to test the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) as a tool to counteract the CTB-Sap toxicity and/or to promote neuroplasticity. The homeostasis of mitochondrial fission/fusion dynamics is indeed important for cell integrity, and it could be affected during neurodegeneration. Lesioned mice were treated with Mdivi-1 and then examined by a series of behavioral test and histological analyses. The results have shown that the drug may be capable of reducing functional deficits after the lesion and promoting synaptic plasticity and neuroprotection, thus representing a putative translational approach for motoneuron disorders.

Discussion of hemodynamic optimization strategies and the canonical understanding of hemodynamics during biventricular mechanical support in cardiogenic shock: does the flow balance make the difference?

BACKGROUND: Mechanical circulatory support (MCS) devices may stabilize patients with severe cardiogenic shock (CS) following myocardial infarction (MI). However, the canonical understanding of hemodynamics related to the determination of the native cardiac output (CO) does not explain or support the understanding of combined left and right MCS. To ensure the most optimal therapy control, the current principles of hemodynamic measurements during biventricular support should be re-evaluated. METHODS: Here we report a protocol of hemodynamic optimization strategy during biventricular MCS (VA-ECMO and left ventricular Impella) in a case series of 10 consecutive patients with severe cardiogenic shock complicating myocardial infarction. During the protocol, the flow rates of both devices were switched in opposing directions (+ / - 0.7 l/min) for specified times. To address the limitations of existing hemodynamic measurement strategies during biventricular support, different measurement techniques (thermodilution, Fick principle, mixed venous oxygen saturation) were performed by pulmonary artery catheterization. Additionally, Doppler ultrasound was performed to determine the renal resistive index (RRI) as an indicator of renal perfusion. RESULTS: The comparison between condition 1 (ECMO flow > Impella flow) and condition 2 (Impella flow > VA-ECMO flow) revealed significant changes in hemodynamics. In detail, compared to condition 1, condition 2 results in a significant increase in cardiac output (3.86 ± 1.11 vs. 5.44 ± 1.13 l/min, p = 0.005) and cardiac index (2.04 ± 0.64 vs. 2.85 ± 0.69, p = 0.013), and mixed venous oxygen saturation (56.44 ± 6.97% vs. 62.02 ± 5.64% p = 0.049), whereas systemic vascular resistance decreased from 1618 ± 337 to 1086 ± 306 s*cm-5 (p = 0.002). Similarly, RRI decreased in condition 2 (0.662 ± 0.05 vs. 0.578 ± 0.06, p = 0.003). CONCLUSIONS: To monitor and optimize MCS in CS, PA catheterization for hemodynamic measurement is applicable. Higher Impella flow is superior to higher VA-ECMO flow resulting in a more profound increase in CO with subsequent improvement of organ perfusion.

Lack of correlation between different congestion markers in acute decompensated heart failure.

BACKGROUND: Hospitalizations for acute decompensated heart failure (ADHF) are commonly associated with congestion-related signs and symptoms. Objective and quantitative markers of congestion have been identified, but there is limited knowledge regarding the correlation between these markers. METHODS: Patients hospitalized for ADHF irrespective of left ventricular ejection fraction were included in a prospective registry. Assessment of congestion markers (e.g., NT-proBNP, maximum inferior vena cava diameter, dyspnea using visual analogue scale, and a clinical congestion score) was performed systematically on admission and at discharge. Telephone interviews were performed to assess clinical events, i.e., all-cause death or readmission for cardiovascular cause, after discharge. Missing values were handled by multiple imputation. RESULTS: In total, 130 patients were prospectively enrolled. Median length of hospitalization was 9 days (interquartile range 6 to 16). All congestion markers declined from admission to discharge (p < 0.001). No correlation between the congestion markers could be identified, neither on admission nor at discharge. The composite endpoint of all-cause death or readmission for cardiovascular cause occurred in 46.2% of patients. Only NT-proBNP at discharge was predictive for this outcome (hazard ratio 1.48, 95% confidence interval 1.15 to 1.90, p = 0.002). CONCLUSION: No correlation between quantitative congestion markers was observed. Only NT-proBNP at discharge was significantly associated with the composite endpoint of all-cause death or readmission for cardiovascular cause. Findings indicate that the studied congestion markers reflect different aspects of congestion.

[Mechanical Assist Devices in Cardiogenic Shock Complicating Myocardial Infarction]. / Mechanische Kreislaufunterstützung bei infarktbedingtem kardiogenem Schock.

In acute myocardial infarction cardiogenic shock is still one of the most feared complications. Although medical and interventional treatment of myocardial infarction improved significantly over the last decades mortality of cardiogenic shock patients remains on unacceptable high levels with 30-day mortality rates of 40-50 %. To date only an early revascularization of the culprit infarct lesion is the only intervention with proven survival benefit for patients. Active mechanical assist devices were introduced more than two decades ago to support left ventricular function as addition to medical treatment with inotropes and vasopressors. Yet, to date only insufficient date exists for these devices in cardiogenic shock patients and therefore no general recommendation can be given. This viewpoint gives an overview about the most used devices. The different mechanism of left ventricular support will be explained, and the current evidence discussed. Furthermore, ongoing randomized controlled trials are highlighted.

Inferior vena cava ultrasound in acute decompensated heart failure: design rationale of the CAVA-ADHF-DZHK10 trial.

AIMS: Treating patients with acute decompensated heart failure (ADHF) presenting with volume overload is a common task. However, optimal guidance of decongesting therapy and treatment targets are not well defined. The inferior vena cava (IVC) diameter and its collapsibility can be used to estimate right atrial pressure, which is a measure of right-sided haemodynamic congestion. The CAVA-ADHF-DZHK10 trial is designed to test the hypothesis that ultrasound assessment of the IVC in addition to clinical assessment improves decongestion as compared with clinical assessment alone. METHODS AND RESULTS: CAVA-ADHF-DZHK10 is a randomized, controlled, patient-blinded, multicentre, parallel-group trial randomly assigning 388 patients with ADHF to either decongesting therapy guided by ultrasound assessment of the IVC in addition to clinical assessment or clinical assessment alone. IVC ultrasound will be performed daily between baseline and hospital discharge in all patients. However, ultrasound results will only be reported to treating physicians in the intervention group. Treatment target is relief of congestion-related signs and symptoms in both groups with the additional goal to reduce the IVC diameter ≤21 mm and increase IVC collapsibility >50% in the intervention group. The primary endpoint is change in N-terminal pro-brain natriuretic peptide from baseline to hospital discharge. Secondary endpoints evaluate feasibility, efficacy of decongestion on other scales, and the impact of the intervention on clinical endpoints. CONCLUSIONS: CAVA-ADHF-DZHK10 will investigate whether IVC ultrasound supplementing clinical assessment improves decongestion in patients admitted for ADHF.