Publications by authors named "Juho Jalkanen"

20 Publications

  • Page 1 of 1

Intravenous Interferon-β1a for the Treatment of Ischemia-Reperfusion Injury in Acute Myocardial Infarct in Pigs.

Heart Surg Forum 2021 Apr 27;24(2):E409-E413. Epub 2021 Apr 27.

Heart Center, Turku University Hospital and University of Turku, Turku, Finland.

Background: To investigate the potential of intravenously administered porcine recombinant interferon-β1a (IFN-β1a) for myocardial protection during acute ischemia-reperfusion (IR) injury in an experimental animal model.

Methods: Twenty-two piglets (mean ± standard deviation, 26.7 ± 1.65 kg) were assigned to either the IFN group (n = 12) or the control group (n = 10). IR injury was induced by occluding the distal left descending coronary artery for 30 minutes, with a reperfusion period of 6 h. In the IFN group, the animals received 12.5 µg IFN-β1a intravenously repeatedly; the control group received saline solution. The levels of interleukin-6 (IL-6) and cardiac troponin I (TnI) were measured, and the amount of myocardial damage was quantified by analyzing myocardial apoptosis and the mean fluorescence intensity (MFI) of methylene blue-stained cardiac tissue.

Results: In the IFN group, significantly more premature deaths occurred compared with the control group (25% versus 17%, P = .013). Between the groups, the mean heart rate was higher in the IFN group (102 ± 22 versus 80 ± 20 beats per minute, P = .02). IL-6 and TnI levels were comparable between the groups, with no significant difference, and there was no difference between the study groups in myocardial apoptosis in the infarcted myocardium. The percentage of MFI differed significantly between the IFN and control groups (90.75% ± 4.90% versus 96.02% ± 2.73%, P = .01).

Conclusion: In this acute IR injury animal model, IFN-β1a did not protect the myocardium from IR injury, but rather increased some of the unfavorable outcomes studied.
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http://dx.doi.org/10.1532/hsf.3639DOI Listing
April 2021

Interferon beta-1a for COVID-19: critical importance of the administration route.

Crit Care 2020 06 12;24(1):335. Epub 2020 Jun 12.

MediCity Research Laboratory and Institute of Biomedicine, University of Turku, Turku, Finland.

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http://dx.doi.org/10.1186/s13054-020-03048-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290144PMC
June 2020

Glucocorticoids inhibit type I IFN beta signaling and the upregulation of CD73 in human lung.

Intensive Care Med 2020 10 19;46(10):1937-1940. Epub 2020 May 19.

Medicity Research Laboratory, University of Turku, Turku, Finland.

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http://dx.doi.org/10.1007/s00134-020-06086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235433PMC
October 2020

Effect of Intravenous Interferon β-1a on Death and Days Free From Mechanical Ventilation Among Patients With Moderate to Severe Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

JAMA 2020 02;323(8):725-733

Critical Care, University College London Hospitals, NHS Foundation Trust and National Institute for Health Research Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London, London, United Kingdom.

Importance: Acute respiratory distress syndrome (ARDS) is associated with high mortality. Interferon (IFN) β-1a may prevent the underlying event of vascular leakage.

Objective: To determine the efficacy and adverse events of IFN-β-1a in patients with moderate to severe ARDS.

Design, Setting, And Participants: Multicenter, randomized, double-blind, parallel-group trial conducted at 74 intensive care units in 8 European countries (December 2015-December 2017) that included 301 adults with moderate to severe ARDS according to the Berlin definition. The radiological and partial pressure of oxygen, arterial (Pao2)/fraction of inspired oxygen (Fio2) criteria for ARDS had to be met within a 24-hour period, and the administration of the first dose of the study drug had to occur within 48 hours of the diagnosis of ARDS. The last patient visit was on March 6, 2018.

Interventions: Patients were randomized to receive an intravenous injection of 10 μg of IFN-β-1a (144 patients) or placebo (152 patients) once daily for 6 days.

Main Outcomes And Measures: The primary outcome was a score combining death and number of ventilator-free days at day 28 (score ranged from -1 for death to 27 if the patient was off ventilator on the first day). There were 16 secondary outcomes, including 28-day mortality, which were tested hierarchically to control type I error.

Results: Among 301 patients who were randomized (mean age, 58 years; 103 women [34.2%]), 296 (98.3%) completed the trial and were included in the primary analysis. At 28 days, the median composite score of death and number of ventilator-free days at day 28 was 10 days (interquartile range, -1 to 20) in the IFN-β-1a group and 8.5 days (interquartile range, 0 to 20) in the placebo group (P = .82). There was no significant difference in 28-day mortality between the IFN-β-1a vs placebo groups (26.4% vs 23.0%; difference, 3.4% [95% CI, -8.1% to 14.8%]; P = .53). Seventy-four patients (25.0%) experienced adverse events considered to be related to treatment during the study (41 patients [28.5%] in the IFN-β-1a group and 33 [21.7%] in the placebo group).

Conclusions And Relevance: Among adults with moderate or severe ARDS, intravenous IFN-β-1a administered for 6 days, compared with placebo, resulted in no significant difference in a composite score that included death and number of ventilator-free days over 28 days. These results do not support the use of IFN-β-1a in the management of ARDS.

Trial Registration: ClinicalTrials.gov Identifier: NCT02622724.
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http://dx.doi.org/10.1001/jama.2019.22525DOI Listing
February 2020

Association between anatomical distribution of symptomatic peripheral artery disease and cerebrovascular disease.

Vascular 2020 Jun 24;28(3):295-300. Epub 2020 Jan 24.

Department of Vascular Surgery, Turku University Hospital, Turku, Finland.

Aim: Peripheral arterial disease is frequently associated with significant atherosclerosis of other vascular beds. The aim of the present study was to investigate a possible association between peripheral arterial disease segment-specific disease burden and cerebrovascular disease.

Methods: Two-hundred and twenty-six patients with clinically symptomatic peripheral arterial disease from the prospective PureASO registry were followed up after revascularization. The breadth of peripheral arterial disease was quantified at the time patients entered the study. The segment-specific peripheral arterial disease burden was correlated to cerebrovascular disease and imaging findings during a five-year follow-up.

Results: At five years, cerebrovascular disease-free survival after lower limb revascularization was 31%. Patients with peripheral arterial disease involving the crural arteries had significantly more ischemic degenerative changes at brain imaging ( = 0.031), whereas patients with aorto-iliac and femoropopliteal segment peripheral arterial disease had more significant (>50% uni- or bilaterally) internal carotid artery stenosis compared to patients with crural peripheral arterial disease ( = 0.006). According to Cox regression analyses, crural arteries burden was associated with a significantly increased risk of mortality (adjusted HR 2.07, CI 95% 1.12-3.28,  = 0.021) and cerebrovascular events (adjusted HR 1.97, CI 95% 1.19-3.26,  = 0.008).

Conclusions: Present results suggest that atherosclerosis burden at different lower limb artery segments is associated with defined cerebrovascular disease. This further suggests that risk factors and pathophysiological mechanisms are congruent across particular vascular beds.
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http://dx.doi.org/10.1177/1708538119893825DOI Listing
June 2020

Metastable Atrial State Underlies the Primary Genetic Substrate for MYL4 Mutation-Associated Atrial Fibrillation.

Circulation 2020 01 16;141(4):301-312. Epub 2019 Nov 16.

Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Background: Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with heart failure, stroke, and increased mortality. The myocardial substrate for AF is poorly understood because of limited access to primary human tissue and mechanistic questions around existing in vitro or in vivo models.

Methods: Using an knock-in reporter line, we developed a protocol to generate and highly purify human pluripotent stem cell-derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells. We modeled human mutants, one of the few definitive genetic causes of AF. To explore non-cell-autonomous components of AF substrate, we also created a zebrafish knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations.

Results: There was evidence of increased retinoic acid signaling in both human embryonic stem cells and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins, and loss of intracellular nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide + hydrogen. To identify potentially druggable proximate mechanisms, we performed a chemical suppressor screen integrating multiple human cellular and zebrafish in vivo endpoints. This screen identified Cx43 (connexin 43) hemichannel blockade as a robust suppressor of the abnormal phenotypes in both models of MYL4 (myosin light chain 4)-related atrial cardiomyopathy. Immunofluorescence and coimmunoprecipitation studies revealed an interaction between MYL4 and Cx43 with altered localization of Cx43 hemichannels to the lateral membrane in mutants, as well as in atrial biopsies from unselected forms of human AF. The membrane fraction from MYL4-/- human embryonic stem cell derived atrial cells demonstrated increased phospho-Cx43, which was further accentuated by retinoic acid treatment and by the presence of risk alleles at the Pitx2 locus. PKC (protein kinase C) was induced by retinoic acid, and PKC inhibition also rescued the abnormal phenotypes in the atrial cardiomyopathy models.

Conclusions: These data establish a mechanistic link between the transcriptional, metabolic and electrical pathways previously implicated in AF substrate and suggest novel avenues for the prevention or therapy of this common arrhythmia.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044268DOI Listing
January 2020

Bilateral low systolic toe pressure and toe-brachial index are associated with long-term mortality in patients with peripheral artery disease.

J Vasc Surg 2019 12 7;70(6):1994-2004. Epub 2019 Aug 7.

Department of Vascular Surgery, Turku University Hospital and University of Turku, Turku, Finland. Electronic address:

Objective: Based on our previous reports, ipsilateral systolic toe pressure (STP) and toe-brachial index (TBI) have a strong association with midterm cardiovascular and overall mortality as well as with amputation-free survival in patients with symptomatic lower extremity peripheral artery disease (PAD). The effect of the often overlooked contralateral lower limb on patient outcome remains unknown. This study aimed to resolve the significance of contralateral STP (CL_STP) and contralateral TBI for long-term overall and cardiovascular mortality.

Methods: This is a retrospective cohort study of 727 consecutive patients with symptomatic lower extremity PAD. All patients admitted to the Department of Vascular Surgery at Turku University Hospital for digital subtraction angiography between January 2009 and August 2011 and for whom STP measurements were available were recruited and observed for up to 7 years. Dates and causes of death were collected from the national cause of death registry of Statistics Finland.

Results: In the study cohort, STP was <30 mm Hg in 67 contralateral limbs and 227 ipsilateral limbs. CL_STP <30 mm Hg resulted in a 60-month estimated freedom from cardiovascular death and overall survival of 39% (standard deviation [SD], 0.57) and 25% (SD, 0.41), respectively, and contralateral TBI <0.25, of 45% (SD, 0.54) and 36% (SD, 0.54), respectively. Cumulative freedom from cardiovascular death and overall survival at 60 months for patients with ipsilateral STP <30 mm Hg varied by CL_STP as follows: CL_STP <30 mm Hg: 41% (SD, 0.58) and 25% (SD, 0.43); CL_STP of 30 to 49 mm Hg: 56% (SD, 0.49) and 44% (SD, 0.49); STP ≥50 mm Hg: 62% (SD, 0.52) and 47% (SD, 0.52), respectively. In Cox regression analysis, low STP or TBI of either extremity was associated with significant (P < .001) risk of death for cardiovascular or any reason.

Conclusions: Low STP and TBI of both contralateral and ipsilateral lower extremities are associated with high cardiovascular and overall mortality in symptomatic PAD patients. Bilaterally low STP and TBI are associated with a particularly poor prognosis.
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http://dx.doi.org/10.1016/j.jvs.2019.03.073DOI Listing
December 2019

Serum cytokine levels differ according to major cardiovascular risk factors in patients with lower limb atherosclerosis.

Cytokine 2019 02 13;114:74-80. Epub 2018 Nov 13.

Department of Vascular Surgery, Turku University Hospital and Turku University, Turku, Finland.

Different cardiovascular risk factors present a heterogenic manifestation of lower limb atherosclerosis. The molecular mechanisms behind this phenomenon remain unknown. We aimed to clarify this phenomenon by studying the association of major cardiovascular risk factors with the profile of serum cytokines in 226 consecutive patients with lower limb atherosclerosis treated at a department of Vascular Surgery during a one-year enrollment period. Increasing age independently associated with higher levels of IFN-γ inducible factors MIG, CTACK and IP-10 (P < 0.001 for all). Patients with chronic kidney disease had higher serum levels of MIF, IL-16 and SCF (P = 0.001 or less for all). Smoking and hypertension associated with IL-17 (P = 0.037 and 0.015, respectively). In addition, smoking associated with growth factors known to induce myeloid progenitor cell proliferation: GM-CSF (P = 0.035), PDGF (P = 0.024), bFGF (P = 0.026), and HGF (P = 0.030). Dyslipidemia also associated with myeloproliferative factors: MIB-1α (P = 0.005) and PDGF (P = 0.01). Type II diabetes associated with Th2 mediated inflammation: IL-5 (P < 0.001), IL-7 (P = 0.004) and IL-13 (P = 0.015). Major cardiovascular risk factors are associated with different circulating cytokines implicating different immunological pathology.
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http://dx.doi.org/10.1016/j.cyto.2018.11.001DOI Listing
February 2019

Data on association of ankle pressure and ankle brachial index of symptomatic and contralateral lower extremities with overall and cardiovascular mortality in patients with lower extremity peripheral artery disease.

Data Brief 2018 Oct 23;20:691-697. Epub 2018 Aug 23.

Department of Vascular Surgery, Turku University Hospital and University of Turku, Finland.

Data on survival curves for overall survival and freedom from cardiovascular death at different ankle brachial index (ABI) and ankle pressure (AP) are shown separately for symptomatic and contralateral lower limbs in 721 patients with lower extremity peripheral artery disease at up to 7 years follow-up. Cox regression analysis with confounding factors for ABI and AP are also shown. Dates and causes of death were collected from the Finnish national statistics registry
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http://dx.doi.org/10.1016/j.dib.2018.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129675PMC
October 2018

Correlation between increasing tissue ischemia and circulating levels of angiogenic growth factors in peripheral artery disease.

Cytokine 2018 10 23;110:24-28. Epub 2018 Apr 23.

Department of Vascular Surgery, Turku University and Turku University Hospital, Turku, Finland. Electronic address:

Introduction: The aim of the present study was to assess the circulating levels of vascular endothelial growth factor (VEGF) and other suggested therapeutic growth factors with the degree of ischemia in patients with different clinical manifestations of peripheral arterial disease (PAD) according to the Rutherford grades.

Methods: The study cohort consists of 226 consecutive patients admitted to a Department of Vascular Surgery for elective invasive procedures. PAD patients were grouped according to the Rutherford grades after a clinical assessment. Ankle-brachial pressure indices (ABI) and absolute toe pressure (TP) values were measured. Serum levels of circulating VEGF, hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF) were measured from serum and analysed against Rutherford grades and peripheral hemodynamic measurements.

Results: The levels of VEGF (P = 0.009) and HGF (P < 0.001) increased significantly as the ischaemic burden became more severe according to the Rutherford grades. PDGF behaved in opposite manner and declined along increasing Rutherford grades (P = 0.004). A significant, inverse correlations between Rutherford grades was detected as follows; VEGF (Pearson's correlation = 0.183, P = 0.004), HGF (Pearson's correlation = 0.253, P < 0.001), bFGF (Pearson's correlation = 0.169, P = 0.008) and PDGF (Pearson's correlation = 0.296, P < 0.001). In addition, VEGF had a clear direct negative correlation with ABI (Pearson's correlation -0.19, P = 0.009) and TP (Pearson's correlation -0.20, P = 0.005) measurements.

Conclusions: Our present observations show that the circulating levels of VEGF and other suggested therapeutic growth factors are significantly increased along with increasing ischemia. These findings present a new perspective to anticipated positive effects of gene therapies utilizing VEGF, HGF, and bFGF, because the levels of these growth factors are endogenously high in end-stage PAD.
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http://dx.doi.org/10.1016/j.cyto.2018.04.012DOI Listing
October 2018

Crural Index and extensive atherosclerosis of crural vessels are associated with long-term cardiovascular mortality in patients with symptomatic peripheral artery disease.

Atherosclerosis 2017 Sep 22;264:44-50. Epub 2017 Jul 22.

Department of Vascular Surgery, Turku University Hospital, University of Turku, Finland. Electronic address:

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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2017.07.023DOI Listing
September 2017

Regulation of CD73 in the development of lower limb atherosclerosis.

Purinergic Signal 2017 03 10;13(1):127-134. Epub 2016 Nov 10.

Department of Vascular Surgery, Turku University Hospital, Hämeenkatu 11, 20521, Turku, Finland.

Atherosclerosis is an inflammatory process of the arterial wall. CD73 (also known as ecto-5'-nucleotidase) is a key regulator of cell signaling in response to inflammation and hypoxia, and may be important in the development of atherosclerosis. Recently, we have shown that high CD73 activity can be detected in the serum of patients with peripheral arterial disease (PAD). Using this same PAD patient cohort of 226 subjects with 38 femoral artery samples obtained during surgical endarcterectomy and control artery samples taken during autopsy, we explored the association of serum CD73 activity with overall atherosclerotic burden and the expression of CD73 in mature and developing plaques. Interestingly, we found that CD73 activity had a tendency to increase along with more severe presentation of PAD (from 249 nmol/mL/h in moderate disease to 332 nmol/mL/h in severe disease; P = 0.013) and that CD73 expression is elevated in the vasa vasorum of developing plaques, but completely lost in mature occlusive plaques removed during endarcterectomy (P < 0.001). The current findings implicate that as a result of shedding and loss of CD73 from the arterial wall, CD73 activity is elevated in the serum of patients with widespread atherosclerosis. These findings highlight the importance of a better understanding of the local role of CD73 in the development and maturation of arterial atherosclerotic plaques in man.
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http://dx.doi.org/10.1007/s11302-016-9545-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334204PMC
March 2017

Compared to Intermittant Claudication Critical Limb Ischemia Is Associated with Elevated Levels of Cytokines.

PLoS One 2016 9;11(9):e0162353. Epub 2016 Sep 9.

Department of Vascular Surgery, Turku University Hospital and Turku University, Turku, Finland.

Critical limb ischemia (CLI) is the advanced stage of peripheral artery disease (PAD) and associated with an extremely poor clinical outcome. In order to understand the possible role of circulating cytokines and poor outcome associated with CLI we compared the circulating cytokine profile of patients with CLI against patients with intermittent claudication (IC). The levels of 48 circulating cytokines were examined in 226 consecutive patients with peripheral artery disease (PAD) admitted for elective, non-urgent, invasive treatment of IC or CLI. The PAD patient cohort was evenly distributed between subjects with IC (46.5%) and CLI (53.5%). As accustomed in PAD, CLI was associated with higher age, chronic kidney disease and diabetes when compared to IC (P < 0.01 for all). In multivariable linear regression modeling taking into account the baseline differences between IC and CLI groups CLI was independently associated with elevated levels of a large number of cytokines: IL-1β, IL-1ra, IL-2Rα, IL-4, IL-6, IL-10, IFN-γ, GM-CSF, G-CSF (P < 0.01 for all), and IL-2, IL-7, IL-12, IL-13, IL-17, bFGF, VEGF, SCGF-β (P < 0.05 for all). The current findings indicate that CLI is associated with a circulating cytokine profile, which resembles serious medical conditions such as severe pancreatitis, sepsis, or even cancer. Compared to IC, CLI is a systemic inflammatory condition, which may explain the extremely poor outcome associated with it.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162353PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017674PMC
August 2017

Data on amputation free survival of patients with lower limb peripheral artery disease classified according TASC II classification and a new crural index.

Data Brief 2016 Sep 24;8:242-6. Epub 2016 May 24.

Department of Vascular Surgery, Turku University Hospital and University of Turku, Finland.

The results of amputation free survival (AFS) of a cohort of 887 caucasian patients is shown. The data is based on further analyses of data presented in Jalkanen et al. (2016) [1]. The 36-month amputation free survival of patients divided in new crural vessel disease classification (Crural Index), aortoiliac TASC II classification, femoropopliteal TASC II classification and most severe segment is presented. Also, in depth demographic data is presented for each Crural Index group Jalkanen et al., 2016 [1].
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http://dx.doi.org/10.1016/j.dib.2016.05.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900680PMC
September 2016

Systemic Dosing of Thymosin Beta 4 before and after Ischemia Does Not Attenuate Global Myocardial Ischemia-Reperfusion Injury in Pigs.

Front Pharmacol 2016 3;7:115. Epub 2016 May 3.

Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku Turku, Finland.

The use of cardiopulmonary bypass (CPB) and aortic cross-clamping causes myocardial ischemia-reperfusion injury (I-RI) and can lead to reduced postoperative cardiac function. We investigated whether this injury could be attenuated by thymosin beta 4 (TB4), a peptide which has showed cardioprotective effects. Pigs received either TB4 or vehicle and underwent CPB and aortic cross-clamping for 60 min with cold intermittent blood-cardioplegia and were then followed for 30 h. Myocardial function and blood flow was studied by cardiac magnetic resonance and PET imaging. Tissue and plasma samples were analyzed to determine the amount of cardiomyocyte necrosis and apoptosis as well as pharmacokinetics of the peptide. In vitro studies were performed to assess its influence on blood coagulation and vasomotor tone. Serum levels of the peptide were increased after administration compared to control samples. TB4 did not decrease the amount of cell death. Cardiac function and global myocardial blood flow was similar between the study groups. At high doses a vasoconstrictor effect on mesentery arteries and a vasodilator effect on coronary arteries was observed and blood clot firmness was reduced when tested in the presence of an antiplatelet agent. Despite promising results in previous trials the cardioprotective effect of TB4 was not demonstrated in this model for global myocardial I-RI.
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http://dx.doi.org/10.3389/fphar.2016.00115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853610PMC
May 2016

The extent of atherosclerotic lesions in crural arteries predicts survival of patients with lower limb peripheral artery disease: A new classification of crural atherosclerosis.

Atherosclerosis 2016 08 22;251:328-333. Epub 2016 Apr 22.

Department of Vascular Surgery, Turku University Hospital and University of Turku, Finland. Electronic address:

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 III-IV, 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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2016.04.016DOI Listing
August 2016

Hypoxia-induced inflammation and purinergic signaling in cross clamping the human aorta.

Springerplus 2016 4;5. Epub 2016 Jan 4.

Department of Vascular Surgery, Turku University and Turku University Hospital, Hämeenkatu 11, 20521 Turku, Finland.

Open aortic surgery evokes a systemic inflammatory response and is associated with high morbidity and mortality. Purinergic signaling has been shown to be crucial for maintaining vascular integrity and attenuating inflammation related to hypoxia. The involvement of purinergic signaling in cross clamping of major human arteries is unknown. Our aim was to compare systemic inflammatory responses and hypoxia-induced purinergic signaling in patients undergoing either open infra-renal abdominal aortic repair or infra-inguinal revascularization. Pre- and 24 h post-operative blood samples were gathered from 6 patients undergoing aortic clamping and 6 similar patients undergoing common femoral artery cross-clamping. Using Biorad Multipex™ 21- and 27-panels 48 different cytokines, chemokines and growth factors were analyzed, in addition to circulating levels of ATP, ADP, CD39, CD73 and HIF-1α, and compared between the groups. Several inflammatory cytokines were elevated from baseline levels after aortic clamping, but not after femoral cross clamping. Most pronoun rises were seen in IL-6 (667 %, P = 0.016) and HGF (760 %, P = 0.016). HIF-1α values showed a steady increase after clamping of either artery unless the subject underwent blood transfusion. Despite an adequate increase in HIF-1α CD39 and CD73 activity decreased significantly after aortic clamping (P = 0.047 and P = 0.016, respectively). Aortic clamping is associated with a clear and strong systemic inflammatory response and impaired repair mechanisms in terms of purinergic signaling. Patients undergoing open aorta repair could benefit from pre-operative medical therapy, which enhances CD73 expression.
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http://dx.doi.org/10.1186/s40064-015-1651-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700025PMC
January 2016

Aberrant circulating levels of purinergic signaling markers are associated with several key aspects of peripheral atherosclerosis and thrombosis.

Circ Res 2015 Mar 2;116(7):1206-15. Epub 2015 Feb 2.

From the Department of Vascular Surgery (J.J., H.H.) and Heart Center (T.K.), Turku University Hospital, Turku, Finland; Medicity Research Laboratory, Department of Microbiology and Immunology, University of Turku, Turku, Finland (G.G.Y., M.H., K.A., S.J.); and National Institute for Health and Welfare, Helsinki, Finland (V.S.).

Rationale: Purinergic signaling plays an important role in inflammation and vascular integrity, but little is known about purinergic mechanisms during the pathogenesis of atherosclerosis in humans.

Objective: The objective of this study is to study markers of purinergic signaling in a cohort of patients with peripheral artery disease.

Methods And Results: Plasma ATP and ADP levels and serum nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39) and ecto-5'-nucleotidase/CD73 activities were measured in 226 patients with stable peripheral artery disease admitted for nonurgent invasive imaging and treatment. The major findings were that ATP, ADP, and CD73 values were higher in atherosclerotic patients than in controls without clinically evident peripheral artery disease (P<0.0001). Low CD39 activity was associated with disease progression (P=0.01). In multivariable linear regression models, high CD73 activity was associated with chronic hypoxia (P=0.001). Statin use was associated with lower ADP (P=0.041) and tended to associate with higher CD73 (P=0.054), while lower ATP was associated with the use of angiotensin receptor blockers (P=0.015).

Conclusions: Purinergic signaling plays an important role in peripheral artery disease progression. Elevated levels of circulating ATP and ADP are especially associated with atherosclerotic diseases of younger age and smoking. The antithrombotic and anti-inflammatory effects of statins may partly be explained by their ability to lower ADP. We suggest that the prothrombotic nature of smoking could be a cause of elevated ADP, and this may explain why cardiovascular patients who smoke benefit from platelet P2Y12 receptor antagonists more than their nonsmoking peers.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.305715DOI Listing
March 2015

The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study.

Lancet Respir Med 2014 Feb 23;2(2):98-107. Epub 2013 Dec 23.

MediCity Research Laboratory, University of Turku, Finland; Department of Medical Microbiology, University of Turku, Finland. Electronic address:

Background: Pulmonary vascular leakage occurs early in acute respiratory distress syndrome (ARDS). Mortality is high (35-45%), but no effective pharmacotherapy exists. Production of anti-inflammatory adenosine by ecto-5'-nucleotidase (CD73) helps maintain endothelial barrier function. We tested whether interferon-beta-1a (IFN-beta-1a), which increases CD73 synthesis, can reduce vascular leakage and mortality in patients with ARDS.

Methods: In ex-vivo studies, we first established that IFN-beta-1a induced CD73 up-regulation in cultured human lung tissue samples. We then tested the safety, tolerability, and efficacy of intravenous human recombinant IFN-beta-1a (FP-1201) in patients with ARDS in an open-label study (comprising dose-escalation and expansion phases). We recruited patients from eight intensive care units in the UK. Eligible patients were aged 18 years or older, had ARDS, and were being treated with assisted ventilation. We established an optimal tolerated dose (OTD) in the first, dose-escalation phase. Once established, we gave all subsequently enrolled patients the OTD of intravenous FP-1201 for 6 days. We assessed 28-day mortality (our primary endpoint) in all patients receiving the OTD versus 28-day mortality in a group of patients who did not receive treatment (this control group comprised patients in the study but who did not receive treatment because they were screened during the safety windows after dose escalation). This trial is registered with ClinicalTrials.gov, number NCT00789685, and the EU Clinical Trials Register EudraCT, number 2008-000140-13.

Findings: IFN-beta-1a increased the number of CD73-positive vessels in lung culture by four times on day 1 (p=0·04) and by 14·3 times by day 4 (p=0·004). For the clinical trial, between Feb 23, 2009, and April 7, 2011, we identified 150 patients, of whom 37 were enrolled into the trial and given treatment. The control group consisted of 59 patients who were recruited to take part in the study, but who did not receive treatment. Demographic characteristics and severity of illness did not differ between treatment and control groups. The optimal tolerated FP-1201 dose was 10 μg per day for 6 days. By day 28, 3 (8%) of 37 patients in the treatment cohort and 19 (32%) of 59 patients in the control cohort had died-thus, treatment with FP-1201 was associated with an 81% reduction in odds of 28-day mortality (odds ratio 0·19 [95% CI 0·03-0·72]; p=0·01).

Interpretation: FP-1201 up-regulates human lung CD73 expression, and is associated with a reduction in 28-day mortality in patients with ARDS. Our findings need to be substantiated in large, prospective randomised trials, but suggest that FP-1201 could be the first effective, mechanistically targeted, disease-specific pharmacotherapy for patients with ARDS.
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http://dx.doi.org/10.1016/S2213-2600(13)70259-5DOI Listing
February 2014

[Mountain sickness].

Duodecim 2010 ;126(4):443-50

Tampereen yliopiston terveystieteen laitos Medisiinarinkatu 3, 33521 Tampere.

Mountain sickness is a common problem upon climbing rapidly to an elevation above 2500 metres. The symptoms are mostly mild, passing within a couple of days. If the symptoms and lack of adaptation to thin air are neglected, the symptoms may quickly become worse, leading to a life-threatening cerebral or pulmonary edema. Every physician providing travel counseling should be aware of this disease and the correct measures for its management.
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June 2010