Browsing by Subject "ISCHEMIA"

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  • Koskimäki, Janne; Tarkia, Miikka; Ahtola-Satila, Tuula; Saloranta, Lasse; Laakso, Aki; Frantzen, Janek (2016)
    Nimodipine is an L-type calcium channel blocker and is used to treat vasospasm in patients with subarachnoid hemorrhage. Its putative mechanism of action is relaxation of smooth muscle cells in cerebral arteries. In addition, nimodipine may have pleiotropic effects against vasospasm. Systemic hypotension is an adverse effect when patients are treated with oral or intravenous nimodipine. Intracranial administration of nimodipine formulations may produce higher concentration of nimodipine in the cerebrospinal fluid (CSF) than is possible to achieve orally or intravenously, while resulting in lower incidence of systemic hypotension. The aim of this study was to provide information on plasma and CSF levels of nimodipine in beagle dogs as a comparative data for development of experimental intracranial treatment modalities. Plasma levels of nimodipine were measured after current 30 and 60 mg single oral dose of nimodipine (Nimotop(A (R)) 30 mg tablets), a single intravenous bolus 0.72 mg/dog of nimodipine (Nimotop(A (R)) 0.2 mg/ml infusion solution) and CSF levels after 60 mg single oral dose of nimodipine. CSF/Plasma concentration ratio of nimodipine after oral administration of 60 mg at 1 h was 0.013 +/- A 0.0005. The mean terminal elimination half-life of nimodipine after i.v. bolus dose 0.72 mg was 1.8 h and mean plasma clearance was 40.3 and 3.4 l/h/kg. Absolute bioavailability was 22 %. Maximum plasma concentration and area under the plasma concentration-time curve from time of administration until the last measurable plasma concentration increased in a dose-proportional manner comparing the exposure parameters at oral doses of 30 and 60 mg. Individual variation in the kinetic profile of nimodipine was measured.
  • Kallioinen, Minna; Posti, Jussi P.; Rahi, Melissa; Sharma, Deepak; Katila, Ari; Grönlund, Juha; Vahlberg, Tero; Frantzén, Janek; Olkkola, Klaus T.; Saari, Teijo I.; Takala, Riikka (2020)
    Abstract Background Cerebral autoregulation is often impaired after aneurysmal subarachnoid haemorrhage (aSAH). Dexmedetomidine is being increasingly used, but its effects on cerebral autoregulation in patients with aSAH have not been studied before. Dexmedetomidine could be a useful sedative in patients with aSAH as it enables neurological assessment during the infusion. The aim of this preliminary study was to compare the effects of dexmedetomidine on dynamic and static cerebral autoregulation with propofol and/or midazolam in patients with aSAH. Methods Ten patients were recruited. Dynamic and static cerebral autoregulation were assessed using transcranial Doppler ultrasound during propofol and/or midazolam infusion and then during three increasing doses of dexmedetomidine infusion (0.7, 1.0 and 1.4 µg/kg/h). Transient hyperaemic response ratio (THRR) and strength of autoregulation (SA) were calculated to assess dynamic cerebral autoregulation. Static rate of autoregulation (sRoR)% was calculated by using noradrenaline infusion to increase the mean arterial pressure 20 mmHg above the baseline. Results Data from 9 patients were analysed. Compared to baseline, we found no statistically significant changes in THRR or sROR%. THRR was (mean±SD) 1.20 ±0.14, 1.17±0.13(p=0.93), 1.14±0.09 (p=0.72) and 1.19±0.18 (p=1.0) and sROR% was 150.89±84.37, 75.22±27.75 (p=0.08), 128.25±58.35 (p=0.84) and 104.82±36.92 (p=0.42) at baseline and during 0.7, 1.0 and 1.4 µg/kg/h dexmedetomidine infusion, respectively. Dynamic SA was significantly reduced after 1.0 µg/kg/h dexmedetomidine (p=0.02). Conclusions Compared to propofol and/or midazolam, dexmedetomidine did not alter static cerebral autoregulation in aSAH patients, whereas a significant change was observed in dynamic SA. Further and larger studies with dexmedetomidine in aSAH patients are warranted.
  • Wickstrom, Jan-Erik; Jalkanen, Juho M.; Venermo, Maarit; Hakovirta, Harri H. (2017)
    Background and aims: Limited data exist on the association of the anatomical distribution of atherosclerotic lesions and the extent of atherosclerosis at defined arterial segments with life expectancy. We recently presented a new classification of the extent of atherosclerosis in crural vessels and showed that Crural Index (CIx) was associated with mid-term survival of symptomatic peripheral artery disease (PAD) patients. This study evaluates the significance of the extent of crural atherosclerosis on long-term cardiovascular mortality. Methods: 887 consecutive patients with PAD, admitted for digital subtraction angiography (DSA) at Turku University Hospital Department of Vascular Surgery (Turku, Finland) between January 1st, 2009 and July 30th, 2011, were retrospectively analysed. Each crural angiographic image was graded according to CIx criteria. Aorto-iliac and femoro-popliteal arterial segments were similarly graded according to modified TASC II criteria. CIx was used as the categorical variable for the extent of atherosclerosis in crural vessels for survival analysis. Survival was also evaluated with respect to which arterial segment was most severely affected. Causes of death were provided by the Cause of Death Registry of Statistics Finland, updated on January 23rd, 2017. Results: Altogether, 408 (46%) patients died during follow-up. The majority of deaths were due to cardiovascular causes (n = 246, 60%). Cardiovascular mortality was strongly associated with a high CIx (CIx III (Hazard ratio (HR) 2.16, Confidence interval (CI) 95% 1.23-3.80, p = 0.007)) and CIx IV (HR 3.513, 95% CI 1.93-4.565, p <0.001), as compared to CIx 0. In patients having the crural segment as the most severely affected arterial segment, cardiovascular mortality was significantly increased (HR 2.321, 95% CI 1.45-3.73, p <0.001), as was overall mortality (HR 2.177, 95% CI 1.53-3.10, p <0.001). Conclusions: High Crural Index and extensive crural vessel atherosclerosis are associated with long-term cardiovascular mortality, and both may serve as useful indicators of survival among patients with symptomatic PAD. (c) 2017 Elsevier B.V. All rights reserved.
  • Babini, Giovanni; Ristagno, Giuseppe; Boccardo, Antonio; De Giorgio, Daria; De Maglie, Marcella; Affatato, Roberta; Ceriani, Sabina; Zani, Davide; Novelli, Deborah; Staszewsky, Lidia; Masson, Serge; Pravettoni, Davide; Latini, Roberto; Belloli, Angelo; Scanziani, Eugenio; Skrifvars, Markus (2019)
    Aim of the study: To evaluate in an established porcine post cardiac arrest model the effect of a mild hypercapnic ventilatory strategy on outcome. Methods: The left anterior descending coronary artery was occluded in 14 pigs and ventricular fibrillation induced and left untreated for 12 min. Cardiopulmonary resuscitation was performed for 5 min prior to defibrillation. After resuscitation, pigs were assigned to either normocapnic (end-tidal carbon dioxide (EtCO2) target: 35-40 mmHg) or hypercapnic ventilation (EtCO2 45-50 mmHg). Hemodynamics was invasively measured and EtCO2 was monitored with an infrared capnometer. Blood gas analysis, serum neuron-specific enolase (NSE) and high sensitive cardiac troponin T (hs-cTnT) were assessed. Survival and functional recovery were evaluated up to 96 h. Results: Twelve pigs were successfully resuscitated and eight survived up to 96 h, with animals in the hypercapnic group showing trend towards a longer survival. EtCO2 and arterial partial pressure of CO2 were higher in the hypercapnic group compared to the normocapnic one (p <0.01), during the 4-hour intervention. Hypercapnia was associated with higher mean arterial pressure compared to normocapnia (p <0.05). No significant differences were observed in hs-cTnT and in NSE between groups, although the values tended to be lower in the hypercapnic one. Neuronal degeneration was lesser in the frontal cortex of hypercapnic animals compared to the normocapnic ones (p <0.05). Neurological recovery was equivalent in the two groups. Conclusion: Mild hypercapnia after resuscitation was associated with better arterial pressure and lesser neuronal degeneration in this model. Nevertheless, no corresponding improvements in neurological recovery were observed.
  • Humaloja, Jaana; Vento, Maximo; Kuligowski, Julia; Andersson, Sture; Pineiro-Ramos, Jose David; Sanchez-Illana, Angel; Litonius, Erik; Jakkula, Pekka; Hästbacka, Johanna; Bendel, Stepani; Tiainen, Marjaana; Reinikainen, Matti; Skrifvars, Markus B. (2021)
    The products of polyunsaturated fatty acid peroxidation are considered reliable biomarkers of oxidative injury in vivo. We investigated ischemia-reperfusion-related oxidative injury by determining the levels of lipid peroxidation biomarkers (isoprostane, isofuran, neuroprostane, and neurofuran) after cardiac arrest and tested the associations between the biomarkers and different arterial oxygen tensions (PaO2). We utilized blood samples collected during the COMACARE trial (NCT02698917). In the trial, 123 patients resuscitated from out-of-hospital cardiac arrest were treated with a 10-15 kPa or 20-25 kPa PaO2 target during the initial 36 h in the intensive care unit. We measured the biomarker levels at admission, and 24, 48, and 72 h thereafter. We compared biomarker levels in the intervention groups and in groups that differed in oxygen exposure prior to randomization. Blood samples for biomarker determination were available for 112 patients. All four biomarker levels peaked at 24 h; the increase appeared greater in younger patients and in patients without bystander-initiated life support. No association between the lipid peroxidation biomarkers and oxygen exposure either before or after randomization was found. Increases in the biomarker levels during the first 24 h in intensive care suggest continuing oxidative stress, but the clinical relevance of this remains unresolved.
  • Koskimaki, Janne; Tarkia, Miikka; Ahtola-Satila, Tuula; Saloranta, Lasse; Simola, Outi; Forsback, Ari-Pekka; Laakso, Aki; Frantzen, Janek (2015)
  • Dijkstra, M. H.; Pirinen, E.; Huusko, J.; Kivelä, R.; Schenkwein, D.; Alitalo, K.; Yla-Herttuala, S. (2014)
  • Galli, Emilia; Rossi, Jari; Neumann, Thomas; Andressoo, Jaan-Olle; Drinda, Stefan; Lindholm, Päivi (2019)
    Dietary restriction induces beneficial metabolic changes and prevents age-related deterioration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) shows protective effects on cells in various models of degenerative diseases. Here we studied whether circulating concentrations of MANF are associated with fasting-induced positive effects. We quantified the levels of circulating MANF from 40 human subjects before and after therapeutic fasting. As measured by an enzyme-linked immunosorbent assay (ELISA), the mean concentration of plasma MANF increased after an average fasting of 15 days. Plasma MANF levels correlated inversely with adiponectin, a hormone that regulates metabolism, thus suggesting that MANF levels are related to metabolic homeostasis. To study the effects of dietary intervention on MANF concentrations in mice, we developed an ELISA for mouse MANF and verified its specificity using MANF knock-out (KO) tissue. A switch from high-fat to normal diet increased MANF levels and downregulated the expression of unfolded protein response (UPR) genes in the liver, indicating decreased endoplasmic reticulum (ER) stress. Liver MANF and serum adiponectin concentrations correlated inversely in mice. Our findings demonstrate that MANF expression and secretion increases with dietary intervention. The MANF correlation to adiponectin and its possible involvement in metabolic regulation and overall health warrants further studies.
  • Hamm, Alexander; Veschini, Lorenzo; Takeda, Yukiji; Costa, Sandra; Delamarre, Estelle; Squadrito, Mario Leonardo; Henze, Anne-Theres; Wenes, Mathias; Serneels, Jens; Pucci, Ferdinando; Roncal, Carmen; Anisimov, Andrey; Alitalo, Kari; De Palma, Michele; Mazzone, Massimiliano (2013)
  • Kiuru, Annika; Ahola, Terhi; Klenberg, Liisa; Tommiska, Viena; Lano, Aulikki; Kleemola, Päivi; Haavisto, Anu; Fellman, Vineta (2019)
  • Settembre, Nicla; Kauhanen , Petteri; Albäck, Anders; Spillerova, Kristyna; Venermo, Maarit (2017)
    Objectives Critical limb ischemia (CLI) is a clinical diagnosis, confirmed by objective tests, usually ankle-brachial index (ABI), toe pressure (TP) and TcPO2. Furthermore, the anatomical lesions in patients affected by CLI were visualized by ultrasound, angiography, CTA, or MRA. Indocyanine green fluorescence imaging (ICG-FI) is a diagnostic modality for assessing foot perfusion. We aimed to study the usefulness of ICG-FI in the quality control of revascularization. Materials and methods One hundred and four CLI limbs in 101 patients were studied with ICG-FI using SPY Elite before and after open or endovascular revascularization. ABI and TP were also measured. After ICG-FI, assessment of circulation was done using time-intensity curve derived from the two regions of interest the one being in the plantar side of the foot and the other in the dorsal side of the foot. Three parameters were derived from the curves: maximum intensity (the absolute value of the maximum intensity); intensity rate (the value from the time-intensity curve describing the increase in maximum intensity/s) and SPY10 (the intensity achieved during the first 10 s after the foot starts to gain intensity). Results Sixty-two limbs presented category 3 of Rutherford classification, 12 limbs category 4, and 30 limbs category 5. Ninety-five technically successful procedures were achieved, 63 (66.3%) endovascular and 32 (33.7%) surgical revascularizations. In 9 (9.5%) patients, an in-line flow from the aorta to the foot was not achieved due to a failure to recanalize the occlusion (n = 7) or due to distal embolization (n = 2). ABI was not reliable in 58 patients (57.4%) mostly due to pseudohypertension and TPs in 49 (48.5%) patients mostly due to previous minor amputations. ICG-FI was successful in all patients. The mean intensity values before and after the procedure in patients who underwent successful revascularization were 81 +/- 47 units and 120 +/- 5 units of intensity (p <001) and intensity rates 4.2 +/- 4 and 8.0 +/- 6.2 units/s (p =.001), respectively. In the PTA patients in whom the revascularization was unsuccessful, no changes were seen in the hemodynamic parameters. In 6 (8.8%) patients who underwent technically successful revascularization, the SPY values were worse after the revascularization than at the baseline. Conclusions ICG-FI with SPY Elite provides reliable information on the increase in perfusion after revascularization, in addition to implicating possible failure if there is no improvement in the ICG-FI variables. Unlike ABI and TP, it can be performed in all patients. It gives valuable information to complement traditional assessment methods.
  • Nauck, Michael A.; McGuire, Darren K.; Pieper, Karen S.; Lokhnygina, Yuliya; Strandberg, Timo E.; Riefflin, Axel; Delibasi, Tuncay; Peterson, Eric D.; White, Harvey D.; Scott, Russell; Holman, Rury R. (2019)
    Background To examine the effects of the DPP-4i sitagliptin on CV outcomes during and after incident MI in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Methods TECOS randomized 14,671 participants with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) to sitagliptin or placebo, in addition to usual care. For those who had a within-trial MI, we analyzed case fatality, and for those with a nonfatal MI, we examined a composite cardiovascular (CV) outcome (CV death or hospitalization for heart failure [hHF]) by treatment group, using Cox proportional hazards models left-censored at the time of the first within-trial MI, without and with adjustment for potential confounders, in intention-to-treat analyses. Results During TECOS, 616 participants had >= 1 MI (sitagliptin group 300, placebo group 316, HR 0.95, 95% CI 0.81-1.11, P = 0.49), of which 25 were fatal [11 and 14, respectively]). Of the 591 patients with a nonfatal MI, 87 (15%) died subsequently, with 66 (11%) being CV deaths, and 57 (10%) experiencing hHF. The composite outcome occurred in 58 (20.1%; 13.9 per 100 person-years) sitagliptin group participants and 50 (16.6%; 11.7 per 100 person-years) placebo group participants (HR 1.21, 95% CI 0.83-1.77, P = 0.32, adjusted HR 1.23, 95% CI 0.83-1.82, P = 0.31). On-treatment sensitivity analyses also showed no significant between-group differences in post-MI outcomes. Conclusions In patients with type 2 diabetes and ASCVD experiencing an MI, sitagliptin did not reduce subsequent risk of CV death or hHF, contrary to expectations derived from preclinical animal models. Trial registration no. NCT00790205
  • Jalkanen, Juho M.; Wickstrom, Jan-Erik; Venermo, Maarit; Hakovirta, Harri H. (2016)
    Background and aims: Several studies report correlation of ankle brachial index (ABI) values and mortality. However, no studies exist on the predictive value of anatomical distribution of atherosclerotic lesions and the extent of atherosclerosis at defined arterial segments on life expectancy. The aim of the present study was to evaluate the significance of both extent and localisation of atherosclerotic lesions to mid-term patient survival. Methods: Digital subtraction angiography (DSA) images of 887 consecutive patients admitted to the Department of Vascular Surgery at Turku University Hospital (Turku, Finland) were retrospectively analysed. Each angiography was classified according to the TASC II classification for aorto-iliac and femoro-popliteal segments, and a similar four-grade index was created for crural arteries. Patients were followed until 36-months post DSA. Results: During 36-month follow-up 295 (33%) deaths occurred. Death during follow-up was strongly associated with extensive crural disease, but not with extensive proximal disease (Crural Index p = 0.044 and <0.001, respectively). In a Cox regression analysis incorporating baseline variables, Crural Index IV and most severe atherosclerosis on crural vessels were the strongest predictors of poor prognosis (HR 2.20 95% CI 1.3-3.7, p = 0.003 and HR 2.45 95% CI 1.5-4.0, p <0.001 respectively). Conclusions: The extent of crural atherosclerosis is independently associated with poor mid term life expectancy. Therefore, a classification of the extent of crural atherosclerosis could serve as an indicator of mortality among PAD patients and aid in clinical decision making. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Ritala, Joel F.; Lyne, Sean B.; Sajanti, Antti; Girard, Romuald; Koskimäki, Janne (2022)
    The role of neurotrophins in neuronal plasticity has recently become a strong focus in neuroregeneration research field to elucidate the biological mechanisms by which these molecules modulate synapses, modify the response to injury, and alter the adaptation response. Intriguingly, the prior studies highlight the role of p75 neurotrophin receptor (p75(NTR)) in various injuries and diseases such as central nervous system injuries, Alzheimer's disease and amyotrophic lateral sclerosis. More comprehensive elucidation of the mechanisms, and therapies targeting these molecular signaling networks may allow for neuronal tissue regeneration following an injury. Due to a diverse role of the p75(NTR) q in biology, the body of evidence comprising its biological role is diffusely spread out over numerous fields. This review condenses the main evidence of p75(NTR) for clinical applications and presents new findings from published literature how data mining approach combined with bioinformatic analyses can be utilized to gain new hypotheses in a molecular and network level.
  • Naumenko, Nikolay; Huusko, Jenni; Tuomainen, Tomi; Koivumaki, Jussi T.; Merentie, Mari; Gurzeler, Erika; Alitalo, Kari; Kivela, Riikka; Yla-Herttuala, Seppo; Tavi, Pasi (2017)
    Vascular endothelial growth factor B (VEGF-B) is a potentmediator of vascular, metabolic, growth, and stress responses in the heart, but the effects on cardiac muscle and cardiomyocyte function are not known. The purpose of this study was to assess the effects of VEGF-B on the energy metabolism, contractile, and electrophysiological properties of mouse cardiac muscle and cardiac muscle cells. In vivo and ex vivo analysis of cardiac-specific VEGF-B TG mice indicated that the contractile function of the TG hearts was normal. Neither the oxidative metabolism of isolated TG cardiomyocytes nor their energy substrate preference showed any difference to WT cardiomyocytes. Similarly, myocyte Ca2+ signaling showed only minor changes compared to WT myocytes. However, VEGF-B overexpression induced a distinct electrophysiological phenotype characterized by ECG changes such as an increase in QRSp time and decreases in S and R amplitudes. At the level of isolated TG cardiomyocytes, these changes were accompanied with decreased action potential upstroke velocity and increased duration (APD60-70). These changes were partly caused by downregulation of sodium current (INa) due to reduced expression of Nav1.5. Furthermore, TG myocytes had alterations in voltage-gated K + currents, namely decreased density of transient outward current (Ito) and total K + current (Ipeak). At the level of transcription, these were accompanied by downregulation of Kv channel-interacting protein 2 (Kcnip2), a knownmodulatory subunit for Kv4.2/3 channel. Cardiac VEGF-B overexpression induces a distinct electrophysiological phenotype including remodeling of cardiomyocyte ion currents, which in turn induce changes in action potential waveform and ECG.
  • Husu, Henrik Leonard; Leppäniemi, Ari Kalevi; Mentula, Panu Juhani (2021)
    Background Selection of patients for open abdomen (OA) treatment in severe acute pancreatitis (SAP) is challenging. Treatment related morbidity and risk of adverse events are high; however, refractory abdominal compartment syndrome (ACS) is potentially lethal. Factors influencing the decision to initiate OA treatment are clinically important. We aimed to study these factors to help understand what influences the selection of patients for OA treatment in SAP. Methods A single center study of patients with SAP that underwent OA treatment compared with conservatively treated matched controls. Results Within study period, 47 patients treated with OA were matched in a 1:1 fashion with conservatively treated control patients. Urinary output under 20 ml/h (OR 5.0 95% CI 1.8-13.7) and ACS (OR 4.6 95% CI 1.4-15.2) independently associated with OA treatment. Patients with OA treatment had significantly more often visceral ischemia (34%) than controls (6%), P = 0.002. Mortality among patients with visceral ischemia was 63%. Clinically meaningful parameters predicting developing ischemia were not found. OA treatment associated with higher overall 90-day mortality rate (43% vs 17%, P = 0.012) and increased need for necrosectomy (55% vs 21%, P = 0.001). Delayed primary fascial closure was achieved in 33 (97%) patients that survived past OA treatment. Conclusion Decreased urine output and ACS were independently associated with the choice of OA treatment in patients with SAP. Underlying visceral ischemia was strikingly common in patients undergoing OA treatment, but predicting ischemia in these patients seems difficult.