Hand grip strength and fatigability: correlation with clinical parameters and diagnostic suitability in ME/CFS

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease accompanied by muscular fatigue and pain. A functional measure to assess muscle fatigability of ME/CFS patients is, however, not established in clinical routine. The aim of this study is to evaluate by assessing repeat maximum handgrip strength (HGS), muscle fatigability as a diagnostic tool and its correlation with clinical parameters. Methods: We assessed the HGS of 105 patients with ME/CFS, 18 patients with Cancer related fatigue (CRF) and 66 healthy controls (HC) using an electric dynamometer assessing maximal (Fmax) and mean force (Fmean) of ten repetitive measurements. Results were correlated with clinical parameters, creatinine kinase (CK) and lactate dehydrogenase (LDH). Further, maximum isometric quadriceps strength measurement was conducted in eight ME/CFS patients and eight HC. Results: ME/CFS patients have a significantly lower Fmax and Fmean HGS compared to HC (p < 0.0001). Further, Fatigue Ratio assessing decline in strength during repeat maximal HGS measurement (Fmax/Fmean) was higher (p <= 0.0012). The Recovery Ratio after an identical second testing 60 min later was significantly lower in ME/CFS compared to HC (Fmean2/Fmean1; p <= 0.0020). Lower HGS parameters correlated with severity of disease, post-exertional malaise and muscle pain and with higher CK and LDH levels after exertion. Conclusion: Repeat HGS assessment is a sensitive diagnostic test to assess muscular fatigue and fatigability and an objective measure to assess disease severity in ME/CFS

protocol and rationale of a randomized clinical trial (AMINO-Stroke Study)

Background Patients with stroke are at a high risk for long-term handicap and disability. In the first weeks after stroke muscle wasting is observed frequently. Early post-stroke rehabilitation programs are directed to improve functional independence and physical performance. Supplementation with essential amino acids (EAAs) might prevent muscle wasting and improve rehabilitation outcome by augmenting muscle mass and muscle strength. We aim to examine this in a double blinded, randomized placebo-controlled clinical trial. Methods Patients with ischemic or haemorrhagic stroke will be enrolled at begin of the early post-stroke rehabilitation in a parallel group interventional trial. Oral supplementation of EAAs or placebo will be given for 12 weeks in a double blinded manner. Physical and functional performance will be assessed by exercise testing before supplementation of EAAs as well as at discharge from the in-patient rehabilitation, at 12 weeks and 1 year afterwards. Discussion This is the first randomized double-blinded placebo- controlled clinical study aiming to assess the effect of the EAAs supplementation on muscle strength, muscle function and physical performance in stroke patients during early post-stroke rehabilitation. Supplementation of EAAs could prevent muscle mass wasting and improve functional independence after stroke

Intestinal blood flow in patients with chronic heart failure: A link with bacterial growth, gastrointestinal symptoms, and cachexia

Background: Blood flow in the intestinal arteries is reduced in patients with stable heart failure (HF) and relates to gastrointestinal (GI) symptoms and cardiac cachexia. Objectives: The aims of this study were to measure arterial intestinal blood flow and assess its role in juxtamucosal bacterial growth, GI symptoms, and cachexia in patients with HF. Methods: A total of 65 patients and 25 controls were investigated. Twelve patients were cachectic. Intestinal blood flow and bowel wall thickness were measured using ultrasound. GI symptoms were documented. Bacteria in stool and juxtamucosal bacteria on biopsies taken during sigmoidoscopy were studied in a subgroup by fluorescence in situ hybridization. Serum lipopolysaccharide antibodies were measured. Results: Patients showed 30% to 43% reduced mean systolic blood flow in the superior and inferior mesenteric arteries and celiac trunk (CT) compared with controls (p < 0.007 for all). Cachectic patients had the lowest blood flow (p < 0.002). Lower blood flow in the superior mesenteric artery and CT was correlated with HF severity (p < 0.04 for all). Patients had more feelings of repletion, flatulence, intestinal murmurs, and burping (p < 0.04). Burping and nausea or vomiting were most severe in patients with cachexia (p < 0.05). Patients with lower CT blood flow had more abdominal discomfort and immunoglobulin A–antilipopolysaccharide (r = 0.76, p < 0.02). Antilipopolysaccharide response was correlated with increased growth of juxtamucosal but not stool bacteria. Patients with intestinal murmurs had greater bowel wall thickness of the sigmoid and descending colon, suggestive of edema contributing to GI symptoms (p < 0.05). In multivariate regression analysis, lower blood flow in the superior mesenteric artery, CT (p < 0.04), and inferior mesenteric artery (p = 0.056) was correlated with the presence of cardiac cachexia. Conclusions: Intestinal blood flow is reduced in patients with HF. This may contribute to juxtamucosal bacterial growth and GI symptoms in patients with advanced HF complicated by cachexia

A Mechanistic Link to Peripheral Endothelial Dysfunction

Background: Sleep‐disordered breathing (SDB) after acute ischemic stroke is frequent and may be linked to stroke‐induced autonomic imbalance. In the present study, the interaction between SDB and peripheral endothelial dysfunction (ED) was investigated in patients with acute ischemic stroke and at 1‐year follow‐up. Methods and Results: SDB was assessed by transthoracic impedance records in 101 patients with acute ischemic stroke (mean age, 69 years; 61% men; median National Institutes of Health Stroke Scale, 4) while being on the stroke unit. SDB was defined by apnea‐hypopnea index ≥5 episodes per hour. Peripheral endothelial function was assessed using peripheral arterial tonometry (EndoPAT‐2000). ED was defined by reactive hyperemia index ≤1.8. Forty‐one stroke patients underwent 1‐year follow‐up (390±24 days) after stroke. SDB was observed in 57% patients with acute ischemic stroke. Compared with patients without SDB, ED was more prevalent in patients with SDB (32% versus 64%; P<0.01). After adjustment for multiple confounders, presence of SDB remained independently associated with ED (odds ratio, 3.1; [95% confidence interval, 1.2–7.9]; P<0.05). After 1 year, the prevalence of SDB decreased from 59% to 15% (P<0.001). Interestingly, peripheral endothelial function improved in stroke patients with normalized SDB, compared with patients with persisting SDB (P<0.05). Conclusions: SDB was present in more than half of all patients with acute ischemic stroke and was independently associated with peripheral ED. Normalized ED in patients with normalized breathing pattern 1 year after stroke suggests a mechanistic link between SDB and ED

Evaluation of C-terminal Agrin Fragment as a marker of muscle wasting in patients after acute stroke during early rehabilitation.

BACKGROUND C-terminal Agrin Fragment (CAF) has been proposed as a novel biomarker for sarcopenia originating from the degeneration of the neuromuscular junctions. In patients with stroke muscle wasting is a common observation that predicts functional outcome. We aimed to evaluate agrin sub-fragment CAF22 as a marker of decreased muscle mass and physical performance in the early phase after acute stroke. METHODS Patients with acute ischaemic or haemorrhagic stroke (n = 123, mean age 70 ± 11 y, body mass index BMI 27.0 ± 4.9 kg/m(2)) admitted to inpatient rehabilitation were studied in comparison to 26 healthy controls of similar age and BMI. Functional assessments were performed at begin (23 ± 17 days post stroke) and at the end of the structured rehabilitation programme (49 ± 18 days post stroke) that included physical assessment, maximum hand grip strength, Rivermead motor assessment, and Barthel index. Body composition was assessed by bioelectrical impedance analysis (BIA). Serum levels of CAF22 were measured by ELISA. RESULTS CAF22 levels were elevated in stroke patients at admission (134.3 ± 52.3 pM) and showed incomplete recovery until discharge (118.2 ± 42.7 pM) compared to healthy controls (95.7 ± 31.8 pM, p < 0.001). Simple regression analyses revealed an association between CAF22 levels and parameters of physical performance, hand grip strength, and phase angle, a BIA derived measure of the muscle cellular integrity. Improvement of the handgrip strength of the paretic arm during rehabilitation was independently related to the recovery of CAF22 serum levels only in those patients who showed increased lean mass during the rehabilitation. CONCLUSIONS CAF22 serum profiles showed a dynamic elevation and recovery in the subacute phase after acute stroke. Further studies are needed to explore the potential of CAF22 as a serum marker to monitor the muscle status in patients after stroke

Parallels in the metabolic characteristics and the endothelial function in patients with acute stroke and chronic heart failure patients

Die chronische Herzinsuffizienz (CHI) und der akute ischämische Schlaganfall (AIS) zählen zu den Erkrankungen mit den höchsten Sterberaten. Der Schlaganfall stellt außerdem die häufigste Ursache der körperlichen Behinderung im Erwachsenenalter dar. Beide Krankheitsbilder involvieren das Gefäßsystem der Patienten. Um die Entwicklung neuer Therapieoptionen zu ermöglichen, ist ein noch tiefergehendes Verständnis der zugrundeliegenden pathophysiologischen Mechanismen notwendig. Die endotheliale Dysfunktion (ED) wird zunehmend nicht nur als Charakteristikum bei chronischer Herzinsuffizienz sondern auch als wichtiger Baustein in der Pathophysiologie des akuten ischämischen Schlaganfalls erkannt. Bei der Regulation des Gefäßtonus spielen L-Arginin und sein Gegenspieler asymmetrisches Dimethylarginin (ADMA) eine wichtige Rolle. Erhöhte ADMA Werte im Zusammenhang mit ED wurden bereits bei CHI Patienten festgestellt. Das Ziel der vorliegenden Arbeit ist es, die periphere ED bei den Patienten mit AIS im Zusammenhang mit dem ADMA Plasmaspiegel zu untersuchen. Dabei sollte eine neue Untersuchungsmethode zur Bestimmung der peripheren ED, die Fingerplethysmographie, in unserer Arbeitsgruppe etabliert werden. Es wurden 60 Patienten (mittleres Alter 67±12J, BMI 28,0±4,4kg/m2) mit AIS im Bereich der A. cerebri media eingeschlossen. Der Infarkttyp wurde anhand der Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Klassifizierung bestimmt. Zum Vergleich wurden 46 ambulante Patienten mit stabiler CHI (65±9J, 28,7±4,7kg/m2, LVEF 34±11%, NYHA Klasse 2,4±0,7) als positive Kontrollgruppe und 23 gesunde Probanden (62±11 J, 25,0±2,9 kg/m2, LVEF 59±9%) als negative Kontrollgruppe verwendet. Die periphere ED wurde mittels eines EndoPAT2000 Gerätes als reaktiver Hyperämie Index (RHI) bestimmt. Beide Patientengruppen zeigten einen niedrigeren RHI als Hinweis auf eine ED im Vergleich zur Kontrollgruppe (AIS: 1,8±0,3 und CHI: 1,8±0,4 vs. 2,2±0,4, ANOVA p=0,01). Der RHI war bei kardioembolischem und mikroangiopathischem Infarkttyp und Schlaganfall unklarer Ursache vermindert (1,7±0,4, 1,8±0,5 und 1,7±0,3, p<0,001). Bei CHI war der RHI schrittweise entsprechend dem zunehmenden Schweregrad der Herzinsuffizienz vermindert (NYHA I oder II: 1,9±0,4; NYHA III oder IV: 1,6±0,3). Das L-Arginin/ADMA Verhältnis war bei den AIS und CHI Patienten reduziert im Vergleich zur Kontrollgruppe (148±32 und 126 ±38 vs.162±26). Patienten mit kardioembolischem Schlaganfall hatten das geringste L-Arginin/ADMA Verhältnis (133±29). Bei Patienten mit kardioembolischem Schlaganfall und CHI bestand eine Assoziation zwischen dem verminderten L-Arginin/ADMA Verhältnis und dem RHI (r=0,324, p<0,05 und r=0,429, p<0,001). Sowohl Patienten mit CHI als auch mit AIS zeigen demnach eine periphere ED. Während bei den Patienten mit AIS die ED in einem Zusammenhang mit dem Infarkttyp stand wurde bei den Patienten mit CHI eine Verbindung mit dem Schwergrad der Erkrankung beobachtet. Die Assoziation zwischen dem Schwergrad der ED und dem verringerten L-Arginin/ADMA Verhältnis wurde bei Patienten mit AIS und Patienten mit CHI festgestellt. Inwiefern die periphere ED, gemessen am Unterarm, bei CHI-Patienten auch mit einem verminderten Blutfluss im viszeralen Stromgebiet (Darmversorgende Gefäße) korreliert, haben wir im Weiteren untersucht. Die CHI-Patienten zeigten eine periphere ED am Unterarm sowie eine Reduktion des intestinalen Blutflusses. Die verminderten Darmflüsse korrelierten mit der Schwere der Herzinsuffizienz. Eine Assoziation des verminderten Blutflusses in der A. mesenterica superior und im Trunkus coeliacus mit dem Vorhandensein einer kardialen Kachexie wurde gezeigt. Diese Ergebnisse können für den bei CHI beobachteten pathologischen Gewichtsverlust prognostisch relevant sein. Ein Gewichtsverlust nach dem Schlaganfall wurde noch nicht systematisch untersucht. In einer weiteren Publikation wurden anhand des Mausmodels für den experimentellen Schlaganfall eine globale katabole Überaktivierung sowie ein vermehrter Muskelproteinabbau festgestellt. Bei diesen Mäusen wurde ein Gewichtsverlust beobachtet. Diese experimentelle Studie bringt neue Erkenntnisse zu metabolischen Veränderungen und Muskelschwund sowie zu den Mechanismen der Gewebebeteiligung bei der katabolen Aktivierung nach dem Schlaganfall.Endothelial dysfunction (ED) has been implicated for the development of cerebrovascular and cardiovascular diseases. Asymmetric dimethylarginine (ADMA) competes with L-arginine and is relevant in the development of ED. Increased levels of ADMA have been observed in chronic heart failure (CHF). We hypothesized that peripheral ED in acute ischemic stroke (AIS) is associated with increased ADMA levels. We evaluated 60 patients (mean age 67±12y, BMI 28.0±4.4kg/m2) with AIS in the territory of the middle cerebral artery. Stroke patients were classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. We compared these patients to 23 healthy controls of similar age (62±11y, BMI 25.0±2.9kg/m2, left ventricular ejection fraction (LVEF) 59±9%) and 46 patients with stable CHF (65±9y, BMI 28.7±4.7kg/m2, LVEF 34±11%) with known ED. Peripheral ED was assessed by EndoPAT2000 technology using the reactive hyperemia index (RHI). RHI was significantly decreased in AIS and in CHF patients compared to controls (1.8±0.3 vs. 1.8±0.4 vs. 2.2±0.4, respectively, ANOVA p=0.01). A decreased RHI was observed in cardioembolic and lacunar infarcts and stroke of undetermined etiology (1.7±0.4, 1.8±0.5 and 1.7±0.3, p<0.001). L-arginine/ADMA ratio was significantly decreased in AIS and CHF patients (148±32 and 126±38 vs. controls: 162±26, p<0.001) and was lowest in AIS patients with the cardioembolic stroke (133±29, p<0.001). Lower L-arginine/ADMA ratio was associated with ED in cardioembolic stroke and CHF (r=0.324, p<0.05 and r=0.429, p<0.001). Peripheral ED occurs in patients with AIS and CHF. The impaired vasodilator capacity of peripheral arteries reflects the TOAST classification. ADMA may play a role in ED in both acute ischemic stroke and CHF. Further we examined a role of peripheral ED in connection with arterial intestinal blood flow, weight loss (cachexia) and gastrointestinal symptoms in CHF. We reported about an association between the reduction of intestinal blood flow and the presence of cachexia compared to the decreasing peripheral blood flow. Further, the patients with CHI presented more gastrointestinal symptoms in contrast to the control group. These results provide novel insights into the pathophysiology of cachexia. In addition, we systematically investigated pathophysiological pathways of muscle wasting after experimental acute ischemic stroke in mice. An activation of proteolytic and apoptotic pathways in skeletal musculature and myocardium and correlation of enzyme activities with the infarct size has been observed. These results indicate the presence of stroke-specific sarcopenia and a role of catabolic/anabolic imbalance in the pathological muscle loss

Ischemic Stroke and Heart Failure: Facts and Numbers. An Update

Heart failure (HF) is a severe clinical syndrome accompanied by a number of comorbidities. Ischemic stroke occurs frequently in patients with HF as a complication of the disease. In the present review, we aimed to summarize the current state of research on the role of cardio-cerebral interactions in the prevalence, etiology, and prognosis of both diseases. The main pathophysiological mechanisms underlying the development of stroke in HF and vice versa are discussed. In addition, we reviewed the results of recent clinical trials investigating the prevalence and prevention of stroke in patients with HF

Ischemic Stroke and Heart Failure: Facts and Numbers. An Update

Heart failure (HF) is a severe clinical syndrome accompanied by a number of comorbidities. Ischemic stroke occurs frequently in patients with HF as a complication of the disease. In the present review, we aimed to summarize the current state of research on the role of cardio–cerebral interactions in the prevalence, etiology, and prognosis of both diseases. The main pathophysiological mechanisms underlying the development of stroke in HF and vice versa are discussed. In addition, we reviewed the results of recent clinical trials investigating the prevalence and prevention of stroke in patients with HF