Publications by authors named "Jukka Lehtonen"

57 Publications

Manifestations and Outcome of Cardiac Sarcoidosis and Idiopathic Giant Cell Myocarditis by 25-Year Nationwide Cohorts.

J Am Heart Assoc 2021 Mar 4;10(6):e019415. Epub 2021 Mar 4.

Heart and Lung Center University of Helsinki and Helsinki University Central Hospital Helsinki Finland.

Background Cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) share many histopathologic and clinical features. Whether they are parts of a one-disease continuum has been discussed. Methods and Results We compared medical record data of 351 CS and 28 GCM cases diagnosed in Finland since the late 1980s and followed until February 2018 for a composite end point of cardiac death, aborted sudden death, and heart transplantation. Heart failure was the presenting manifestation in 50% versus 15% (<0.001), and high-grade atrioventricular block in 21% versus 43% (=0.044), of GCM and CS, respectively. At presentation, left ventricular ejection fraction was ≤50% in 81% of cases of GCM versus in 48% of CS (=0.004). The median (interquartile range) of plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) was 5273 (2782-11309) ng/L on admission in GCM versus 859 (290-1950) ng/L in CS (<0.001), and cardiac troponin T exceeded 50 ng/L in 17 of 19 cases of GCM versus in 48 of 239 cases of CS (<0.001). The 5-year estimate of event-free survival was 77% (95% CI, 72%-82%) in CS versus 27% (95% CI, 10%-45%) in GCM (<0.001). By Cox regression analysis, GCM predicted cardiac events with a hazard ratio of 5.16 (95% CI, 2.82-9.45), which, however, decreased to 1.58 (95% CI, 0.71-3.52) after inclusion of markers of myocardial injury and dysfunction in the model. Conclusions GCM differs from CS in presenting with more extensive myocardial injury and having worse long-term outcome. Yet the key determinant of prognosis appears to be the extent of myocardial injury rather than the histopathologic diagnosis.
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http://dx.doi.org/10.1161/JAHA.120.019415DOI Listing
March 2021

Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document.

Circ Heart Fail 2020 11 12;13(11):e007405. Epub 2020 Nov 12.

Vita Salute University and San Raffaele Hospital, Milano, Italy (P.G.C.).

Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673642PMC
November 2020

Long-term outcome and its predictors in giant cell myocarditis. Letter regarding the article 'Long-term outcome and its predictors in giant cell myocarditis'.

Eur J Heart Fail 2020 07 28;22(7):1283-1284. Epub 2020 Jul 28.

Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.

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http://dx.doi.org/10.1002/ejhf.1953DOI Listing
July 2020

Idiopathic giant cell myocarditis or cardiac sarcoidosis? A retrospective audit of a nationwide case series.

ESC Heart Fail 2020 06 28;7(3):1362-1370. Epub 2020 Apr 28.

Heart and Lung Center, Helsinki University and Helsinki University Hospital, Helsinki, Finland.

Aims: Cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) are inflammatory cardiomyopathies sharing histopathological and clinical features. Their differentiation is difficult and susceptible of confusion and apparent mistakes. The possibility that they represent different phenotypes of a single disease has been debated.

Methods And Results: We made a retrospective audit of 73 cases of GCM diagnosed in Finland since the late 1980s. All available histological material was reanalyzed as were other examinations pertinent to the distinction between GCM and CS. Finding granulomas in or outside the heart was considered diagnostic of CS and exclusive of GCM. Altogether 45 of the 73 cases of GCM (62%) were reclassified as CS. In all except one case, this was based on finding sarcoid granulomas that either had been originally missed (n = 29) or misinterpreted (n = 11) or were found in additional posttransplant myocardial specimens (n = 3) or samples of extracardiac tissue (n = 1) accrued over the disease course. Supporting the reclassification, patients relocated to the CS group had less heart failure at presentation (prevalence 20% vs. 46%, P = 0.017) and better 1 year transplant-free survival (82% vs. 45%, P = 0.011) than patients considered to represent true GCM.

Conclusions: Recognizing granulomas in or outside the heart remains a challenge for the pathologist. Given that CS and GCM are considered distinct diseases and granulomas exclusive of GCM, many cases of GCM, if thoroughly scrutinized, may need reclassification as CS. However, whether CS and GCM are truly different entities or parts of a one-disease continuum has not yet been conclusively settled.
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http://dx.doi.org/10.1002/ehf2.12725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261562PMC
June 2020

Folate Receptor β-Targeted PET Imaging of Macrophages in Autoimmune Myocarditis.

J Nucl Med 2020 11 13;61(11):1643-1649. Epub 2020 Apr 13.

Turku PET Centre, University of Turku, Turku, Finland

Currently available imaging techniques have limited specificity for the detection of active myocardial inflammation. Aluminum F-labeled 1,4,7-triazacyclononane--triacetic acid conjugated folate (F-FOL) is a PET tracer targeting folate receptor β (FR-β), which is expressed on activated macrophages at sites of inflammation. We evaluated F-FOL PET for the detection of myocardial inflammation in rats with autoimmune myocarditis and studied the expression of FR-β in human cardiac sarcoidosis specimens. Myocarditis was induced by immunizing rats ( = 18) with porcine cardiac myosin in complete Freund adjuvant. Control rats ( = 6) were injected with Freund adjuvant alone. F-FOL was intravenously injected, followed by imaging with a small-animal PET/CT scanner and autoradiography. Contrast-enhanced high-resolution CT or F-FDG PET images were used for coregistration. Rat tissue sections and myocardial autopsy samples from 6 patients with cardiac sarcoidosis were studied for macrophages and FR-β. The myocardium of 10 of 18 immunized rats showed focal macrophage-rich inflammatory lesions, with FR-β expression occurring mainly in M1-polarized macrophages. PET images showed focal myocardial F-FOL uptake colocalizing with inflammatory lesions (SUV, 2.1 ± 1.1), whereas uptake in the remote myocardium of immunized rats and controls was low (SUV, 0.4 ± 0.2 and 0.4 ± 0.1, respectively; < 0.01). Ex vivo autoradiography of tissue sections confirmed uptake of F-FOL in myocardial inflammatory lesions. Uptake of F-FOL in inflamed myocardium was efficiently blocked by a nonlabeled FR-β ligand folate glucosamine in vivo. The myocardium of patients with cardiac sarcoidosis showed many FR-β-positive macrophages in inflammatory lesions. In a rat model of autoimmune myocarditis, F-FOL shows specific uptake in inflamed myocardium containing macrophages expressing FR-β, which were also present in human cardiac sarcoid lesions. Imaging of FR-β expression is a potential approach for the detection of active myocardial inflammation.
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http://dx.doi.org/10.2967/jnumed.119.241356DOI Listing
November 2020

Optogenetic Control of Spine-Head JNK Reveals a Role in Dendritic Spine Regression.

eNeuro 2020 Jan/Feb;7(1). Epub 2020 Feb 20.

Turku Bioscience, University of Turku and Åbo Akademi University, Turku FI-20500, Finland

In this study, we use an optogenetic inhibitor of c-Jun NH-terminal kinase (JNK) in dendritic spine sub-compartments of rat hippocampal neurons. We show that JNK inhibition exerts rapid (within seconds) reorganization of actin in the spine-head. Using real-time Förster resonance energy transfer (FRET) to measure JNK activity, we find that either excitotoxic insult (NMDA) or endocrine stress (corticosterone), activate spine-head JNK causing internalization of AMPARs and spine retraction. Both events are prevented upon optogenetic inhibition of JNK, and rescued by JNK inhibition even 2 h after insult. Moreover, we identify that the fast-acting anti-depressant ketamine reduces JNK activity in hippocampal neurons suggesting that JNK inhibition may be a downstream mediator of its anti-depressant effect. In conclusion, we show that JNK activation plays a role in triggering spine elimination by NMDA or corticosterone stress, whereas inhibition of JNK facilitates regrowth of spines even in the continued presence of glucocorticoid. This identifies that JNK acts locally in the spine-head to promote AMPAR internalization and spine shrinkage following stress, and reveals a protective function for JNK inhibition in preventing spine regression.
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http://dx.doi.org/10.1523/ENEURO.0303-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053173PMC
February 2020

Inflammatory cardiomyopathies: short- and long-term outcomes after heart transplantation-a protocol for a systematic review and meta-analysis.

Heart Fail Rev 2020 05;25(3):481-485

Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.

Heart transplantation (HTx) for patients with "giant cell myocarditis" (GCM) or "cardiac sarcoidosis" (CS) is still controversial. However, no single center has accumulated enough experience to investigate post-HTx outcome. The primary aim of this systematic review is to identify, appraise, and synthesize existing literature investigating whether patients who have undergone HTx because of GCM or CS have worse outcomes as compared with patients transplanted because of other etiologies. A systematic and comprehensive search will be performed using PubMed, Scopus, Web of Science, EMBASE, and Google Scholar, for studies published up to December 2019. Observational and interventional population-based studies will be eligible for inclusion. The quality of observational studies will be assessed using the Newcastle-Ottawa scale, while the interventional studies will be assessed using the Cochrane Effective Practice Organization of Care tool. The collected evidence will be narratively synthesized; in addition, we will perform a meta-analysis to pool estimates from studies considered to be homogenous. Reporting of the systematic review and meta-analysis will be in accordance with the Meta-analysis of Observational Studies in Epidemiology Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines. To our knowledge, this will be the first synthesis of outcomes, including survival, acute cellular rejection, and disease recurrence, in patients with either GCM or CS treated with HTx. Reviewing the suitability of HTx in this population and highlighting areas for further research will benefit both patients and healthcare providers. Trial registration: CRD42019140574.
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http://dx.doi.org/10.1007/s10741-020-09919-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181433PMC
May 2020

Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries.

Eur Heart J 2019 10;40(37):3121-3128

Heart and Lung Center, Helsinki University and Helsinki University Hospital, Stenbäckinkatu 9, Helsinki, Finland.

Aims: The present study was done to assess the role of sudden cardiac death (SCD) among the presenting manifestations of and fatalities from cardiac sarcoidosis (CS).

Methods And Results: We analysed altogether 351 cases of CS presenting from year 1998 through 2015 in Finland. There were 262 patients with a clinical diagnosis and treatment of CS, 27 patients with an initial lifetime diagnosis of giant cell myocarditis that was later converted to CS, and 62 cases detected at autopsy and identified by screening >820 000 death certificates from the national cause-of-death registry. The total case series comprised 253 females and 98 males aged on average 52 years at presentation. High-grade atrioventricular block was the most common first sign of CS (n = 147, 42%) followed by heart failure (n = 58, 17%), unexpected fatal (n = 38) or aborted (n = 12) SCD (14%), and sustained ventricular tachycardia (n = 48, 14%). Severe coronary artery disease was found at autopsy concomitant with CS in four of the 38 cases presenting with fatal SCD. Of all deaths recorded till the end of 2015, 64% (n = 54/84) were unexpected SCDs from CS that had either been silent during life or defied all attempts at diagnosis. The Kaplan-Meier estimate (95% CI) of survival from symptom onset was 85% (80-90%) at 5 years and 76% (68-84%) at 10 years.

Conclusion: Together fatal and aborted SCD constitute 14% of the presenting manifestations of CS. Nearly two-thirds of all fatalities from CS are caused by undiagnosed granulomas in the heart.
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http://dx.doi.org/10.1093/eurheartj/ehz428DOI Listing
October 2019

Spontaneous coronary artery dissection in cardiac sarcoidosis.

Oxf Med Case Reports 2019 May 31;2019(5):omz033. Epub 2019 May 31.

Department of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada.

Cardiac sarcoidosis (CS) is increasingly recognized as a cause of diverse cardiac manifestations. Spontaneous coronary artery dissection (SCAD) has emerged as an important cause of acute coronary syndrome especially among young females. The prevalence of sarcoidosis in the causal spectrum of SCAD has not been described before but sarcoidosis is cited as a potential yet rare cause of SCAD. We aimed to examine the frequency and characteristics of SCAD in CS. Searching two prospective CS registries with 481 CS patients, we found only one case of manifest SCAD. She is a 61-year-old female previously diagnosed with endomyocardial biopsy confirmed CS. She presented with chest pain and elevated troponin. Coronary angiogram revealed two-vessel SCAD. Fluorodeoxyglucose positron emission tomography scan showed likely reactivation of CS. The patient was treated with dual antiplatelet therapy and immunosuppression. Repeat angiogram showed complete resolution of the coronary lesions.
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http://dx.doi.org/10.1093/omcr/omz033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544419PMC
May 2019

Long-Term Outcome in Probable Versus Absolute Cardiac Sarcoidosis.

Am J Cardiol 2019 02 24;123(4):674-678. Epub 2018 Nov 24.

Division of Cardiology, Heart and Lung Center, Helsinki University Central Hospital, and University of Helsinki, Helsinki, Finland.

Suspicion of cardiac sarcoidosis (CS) arises when a patient has clinical cardiac manifestations and findings on cardiac imaging suggestive of inflammatory cardiomyopathy with or without history of extracardiac sarcoidosis. The additional requirement for diagnosis is proof of sarcoidosis histology. Endomyocardial biopsy (EMB) showing granulomatous inflammation in absence of other explanations confirms an absolute diagnosis of CS while similar histology in an extracardiac biopsy gives a probable diagnosis of CS. Our aim was to study the equivalence of probable to absolute CS in terms of patients' characteristics and outcome. We reviewed the available clinical information, diagnostic procedures, details of treatment and event-free survival of 149 consecutive patients (103 women, mean age 50 y) diagnosed with CS at our institution. The diagnosis was absolute in 68 patients and probable in 81 patients. There was no difference in age or sex distribution between the diagnostic subgroups but left ventricular dysfunction on echocardiography (ejection fraction <50%) was more common in absolute CS (60% vs 36%, p = 0.003) as was abnormal myocardial late gadolinium enhancement on magnetic resonance imaging (96% vs 78%, p = 0.006). Over a median of 54 months of follow-up, 19 of 68 patients with absolute CS versus 15 of 81 with probable CS either died, suffered an aborted sudden cardiac death or underwent cardiac transplantation (log rank p = 0.334). In conclusion, in terms of prognosis, clinical diagnosis of CS supported by extracardiac histology is equivalent to diagnosis confirmed by myocardial histology. No distinction should be made between probable and absolute CS as regards treatment and follow-up.
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http://dx.doi.org/10.1016/j.amjcard.2018.11.007DOI Listing
February 2019

Outcome of Cardiac Sarcoidosis Presenting With High-Grade Atrioventricular Block.

Circ Arrhythm Electrophysiol 2018 08;11(8):e006145

Heart and Lung Center (H.-K.N., J.L., K.E., R.K., P.S., M.K.).

Background: Symptomatic high-grade atrioventricular block (AVB) is the most common and often the only presenting manifestation (lone AVB) of cardiac sarcoidosis. Implantation of an intracardiac cardioverter defibrillator instead of a pacemaker is recommended, but the true risk of fatal arrhythmia, one incident to lone AVB in particular, remains poorly known.

Methods: We used Myocardial Inflammatory Diseases in Finland Study Group Registry to analyze the presentations, left ventricular (LV) function, pacemaker therapy, and ventricular arrhythmias in cardiac sarcoidosis. From year 1988 to 2015, altogether 325 cases of cardiac sarcoidosis were diagnosed in Finland. Of them, 143 patients (112 women, mean age 52 years) presented with Mobitz II second degree or third degree AVB in the absence of other explanatory cardiac disease.

Results: Concomitant with AVB at presentation, 20 patients had either ventricular tachycardia or severe LV dysfunction with ejection fraction <35% and 29 patients had nonsevere LV dysfunction (ejection fraction, 35%-50%) while 90 patients presented with AVB alone. During a median of 2.8 years' follow-up, 23 sudden cardiac deaths (fatal or aborted) and 19 ventricular tachycardias were recorded as arrhythmic end point events. Their composite 5-year incidence (95% confidence interval) was 56% (36%-88%) in the AVB subgroup with ventricular tachycardia or severe LV dysfunction versus 24% (12%-49%) in the subgroup with nonsevere LV dysfunction and 24% (15%-38%) with lone AVB ( P=0.019). The 5-year incidence of sudden cardiac death was 34% (16%-71%), 14% (6%-35%), and 9% (4%-22%) in the respective subgroups ( P=0.060).

Conclusions: The risk of sudden cardiac death is significant in cardiac sarcoidosis presenting with high-grade AVB with or without ventricular tachycardia or LV dysfunction. The consensus recommendation to implant an intracardiac cardioverter defibrillator whenever permanent pacing is needed seems well-founded.
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http://dx.doi.org/10.1161/CIRCEP.117.006145DOI Listing
August 2018

Mechanical compression devices for cardiac arrest: report of three cases.

Duodecim 2017;133(10):945-50

Mechanical compression devices enable transportation of patients with cardiac arrest to the catheterization laboratory. Coronary angiography and coronary interventions can be performed while the patients are being resuscitated with these devices. In this report, we describe three cases in whom resuscitation with mechanical compression devices and rapid transportation to the catheterization laboratory resulted in favorable cardiac and neurological outcome.
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January 2018

Recurrent pericarditis.

Authors:
Jukka Lehtonen

Duodecim 2017;133(4):397-401

Recurrent pericarditis is the most common and problematic complication of acute pericarditis. After acute pericarditis, the pericarditis recurs in 20 to 50% of the patients. In most cases the etiology of pericarditis remains unclear, although it is generally thought to arise by an immunological mechanism. NSAID medication in combination with colchicine is the cornerstone of the treatment. Corticosteroids should be used mainly for those in whom the first-line drug treatment is not sufficient or first-line treatments are contraindicated.
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January 2018

Even mild reversible myocardial perfusion defects predict mortality in patients evaluated for kidney transplantation.

Eur Heart J Cardiovasc Imaging 2018 09;19(9):1019-1025

University of Helsinki, Haartmaninkatu 4, Helsinki, Finland.

Aims: The value of single-photon emission tomography (SPECT) in patients with severe chronic kidney disease is controversial, and the implications of SPECT finding with lower level of ischaemia are unknown. We assessed the prognostic value of SPECT in patients evaluated for kidney transplantation.

Methods And Results: Five hundred and forty-eight patients underwent SPECT as a part of routine evaluation for kidney transplantation. During the median follow-up of 43.7 months (IQR 22.4-68.4 months), 112 patients (20.4%) died, 49 of cardiovascular (CV) causes (8.9%). In comparison to those with no perfusion defects, mild perfusion abnormalities (1%-9.9%) had an adjusted Cox hazard ratio (HR) of 1.80 [95% confidence interval (95% CI) 1.02-3.17, P = 0.041] for all-cause mortality, while large perfusion defects (≥10%) demonstrated an HR of 2.20 (95% CI 1.38-3.50, P = 0.001). A competing risk analysis produced a similar prognostic capacity for CV mortality. SPECT also offered incremental prognostic impact with two reclassification methods. Revascularization was performed clearly more often on patients with severely than mildly abnormal or normal SPECT (28.0%, 4.3%, and 1.3%, respectively, P < 0.001). However, revascularization was not linked with better survival. Patients with a normal SPECT received a kidney transplant more often than patients with a mildly or severely abnormal SPECT (50.5%, 36.2%, and 36.6%, respectively, P = 0.010).

Conclusion: Myocardial ischaemia in SPECT is clearly linked with mortality in patients screened for kidney transplantation. Contrary to populations with coronary artery disease, even a mild perfusion defect in SPECT predicts poor prognosis in this patient population. The finding deserves further attention in forthcoming trials.
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http://dx.doi.org/10.1093/ehjci/jex200DOI Listing
September 2018

Congestive heart failure: more common as well as an important cardiovascular outcome: reply.

Eur Heart J Cardiovasc Pharmacother 2017 04;3(2):99

Heart and Lung Center, University of Helsinki and Helsinki University Hospital, HUS, 00029, Finland, PL 340.

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http://dx.doi.org/10.1093/ehjcvp/pvw050DOI Listing
April 2017

Hydroxychloroquine for the prevention of recurrent cardiovascular events in myocardial infarction patients: rationale and design of the OXI trial.

Eur Heart J Cardiovasc Pharmacother 2017 04;3(2):92-97

Heart and Lung Center, University of Helsinki and Helsinki University Hospital, PL 340, 00029 HUS, Finland.

Background: Inflammation of the arterial wall plays a central role in the pathogenesis of atherosclerosis. Among patients with rheumatic diseases, anti-rheumatic medication reduces the incidence of cardiovascular (CV) diseases, but only few studies have addressed their cardioprotective effects on patients with no rheumatic diseases. Hydroxychloroquine (HCQ) is an anti-rheumatic drug commonly used in the treatment of rheumatoid arthritis and systemic lupus erythematosus. In addition to its anti-inflammatory properties, HCQ reduces cholesterol levels and the risk of type II diabetes, and has also anti-platelet effects.

Design: The OXI trial is an event-driven trial that will randomize 2500 patients hospitalized for myocardial infarction (MI). Participants will receive active HCQ or placebo for at least 12 months, and until 350 CV events are confirmed. The primary trial endpoint is the composite of death, MI, hospitalization for unstable angina, urgent percutaneous coronary intervention, and urgent coronary artery bypass grafting. Secondary trial endpoints are the primary end point plus stroke, the effect of HCQ treatment on lipids, on the incidence of Type 2 diabetes, on the level of haemoglobin A1c, and on inflammatory parameters. A 6 months placebo-controlled safety pilot trial with 200 patients is currently ongoing to assess the safety of HCQ in the setting of MI.

Summary: The OXI trial will determine whether treatment with HCQ, as compared with placebo, will reduce recurrent CV events among MI patients. If positive, then the OXI trial would provide an entirely novel multitarget approach for the secondary prevention of atherosclerotic cardiovascular diseases (ACVD).
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http://dx.doi.org/10.1093/ehjcvp/pvw035DOI Listing
April 2017

Incidence, Risk Factors, and Outcome of Life-Threatening Ventricular Arrhythmias in Giant Cell Myocarditis.

Circ Arrhythm Electrophysiol 2016 Dec;9(12)

From the Heart and Lung Center (K.E., J.L., R.K., M.K.) and Department of Pathology, HUSLAB (A.R.-S., K.S.), Helsinki University Central Hospital, Helsinki, Finland.

Background: Ventricular tachyarrhythmias are characteristic of giant cell myocarditis, but their true incidence, predictors, and outcome are unknown.

Methods And Results: Our work involved 51 patients with giant cell myocarditis (35 women) aged 52±12 years. Their medical records were reviewed for history, results of laboratory and imaging studies, and occurrence of serious cardiac events, including life-threatening ventricular tachyarrhythmias. Sudden cardiac death (fatal or aborted) was the primary end point of our analyses, whereas the composite of sudden cardiac death and ventricular tachycardia requiring treatment constituted the secondary end point. Giant cell myocarditis presented as nonfatal ventricular tachyarrhythmia in 10 patients and as a fatal cardiac arrest in 1 patient. Overall, 14 of 50 patients suffered a sudden cardiac death during follow-up, with a cumulative incidence of 22% at 1 year and 26% at 5 years from presentation. The composite incidence of sudden cardiac death or ventricular tachycardia was 41% at 1 year and 55% at 5 years. The incidence of arrhythmias was associated with high plasma concentrations of troponin-T and N-terminal brain natriuretic propeptide, as well as with moderate-to-severe fibrosis on myocardial biopsy and history of ventricular tachyarrhythmias at presentation (P<0.05 for all). An intracardiac cardioverter defibrillator was implanted in 31 patients, of whom 17 had altogether 114 appropriate antiarrhythmic therapies by the device and none suffered an arrhythmic death.

Conclusions: In giant cell myocarditis, the risk of life-threatening ventricular arrhythmias exceeds 50% at 5 years from admission, being related to the presenting clinical manifestation and markers of myocardial injury and scarring.
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http://dx.doi.org/10.1161/CIRCEP.116.004559DOI Listing
December 2016

The Quest for New Approaches in Myocarditis and Inflammatory Cardiomyopathy.

J Am Coll Cardiol 2016 11;68(21):2348-2364

Cardiovascular Department, Mayo Clinic, Jacksonville, Florida. Electronic address:

Myocarditis is a diverse group of heart-specific immune processes classified by clinical and histopathological manifestations. Up to 40% of dilated cardiomyopathy is associated with inflammation or viral infection. Recent experimental studies revealed complex regulatory roles for several microribonucleic acids and T-cell and macrophage subtypes. Although the prevalence of myocarditis remained stable between 1990 and 2013 at about 22 per 100,000 people, overall mortality from cardiomyopathy and myocarditis has decreased since 2005. The diagnostic and prognostic value of cardiac magnetic resonance has increased with new, higher-sensitivity sequences. Positron emission tomography has emerged as a useful tool for diagnosis of cardiac sarcoidosis. The sensitivity of endomyocardial biopsy may be increased, especially in suspected sarcoidosis, by the use of electrogram guidance to target regions of abnormal signal. Investigational treatments on the basis of mechanistic advances are entering clinical trials. Revised management recommendations regarding athletic participation after acute myocarditis have heightened the importance of early diagnosis.
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http://dx.doi.org/10.1016/j.jacc.2016.09.937DOI Listing
November 2016

Long-term outcome and its predictors in giant cell myocarditis.

Eur J Heart Fail 2016 12 13;18(12):1452-1458. Epub 2016 Jul 13.

Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.

Aims: There are no studies focusing on prognostic factors in giant cell myocarditis (GCM). We aimed to identify predictors of transplant-free survival in GCM.

Methods And Results: We analysed the details of 46 patients with GCM (31 women, mean age 51 ± 12 years) seen at our hospital since 1991 and followed for the occurrence of cardiac death or transplantation till May 2015. The association of transplant-free survival with patient characteristics, laboratory data on admission, and myocardial histology in the 38 patients diagnosed prior to death or transplantation was examined. Altogether 26 patients died (n = 8) or underwent transplantation (n = 18) a median of 11 months following symptom onset. The 5-year estimate of transplant-free survival was 42% [95% confidence interval (CI) 35-48%]. By Cox regression analysis, the hazard ratio for death or transplantation was 0.87 (95% CI 0.75-0.99) per +5% difference in LVEF, 1.06 (95% CI 1.03-1.10) per + 1000 ng/L difference in NT-proBNP, and 4.57 (95% CI 1.63-11.28) for cardiac troponin-T above the median of 85 ng/L at presentation. The severity of necrosis and fibrosis in myocardial biopsy, graded by the consensus of two cardiac pathologists as none, mild, moderate, or severe, predicted the outcome with a hazard ratio of 7.17 (95% CI 2.29-22.40) for the presence of either necrosis or fibrosis of at least moderate extent.

Conclusions: In GCM, the probability of transplant-free survival is 42% at 5 years from symptom onset. Markers of myocyte injury and cardiac dysfunction help predict the outcome.
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http://dx.doi.org/10.1002/ejhf.606DOI Listing
December 2016

Magnetic Resonance Imaging as a Predictor of Survival Free of Life-Threatening Arrhythmias and Transplantation in Cardiac Sarcoidosis.

J Am Heart Assoc 2016 05 2;5(5). Epub 2016 May 2.

The Heart and Lung Center, Radiology, Helsinki University Central Hospital, Helsinki, Finland.

Background: Cardiac magnetic resonance imaging has a key role in today's diagnosis of cardiac sarcoidosis. We set out to investigate whether cardiac magnetic resonance imaging also helps predict outcome in cardiac sarcoidosis.

Methods And Results: Our work involved 59 patients with cardiac sarcoidosis (38 female, mean age 46±10 years) seen at our hospital since February 2004 and followed up after contrast-enhanced cardiac magnetic resonance imaging. The extent of myocardial late gadolinium enhancement (measured as percentage of left ventricular mass), the volumes and ejection fractions of the left and right ventricles, and the thickness of the basal interventricular septum were determined and analyzed for prognostic significance. By April 2015, 23 patients had reached the study's end point, consisting of a composite of cardiac death (n=3), cardiac transplantation (n=1), and occurrence of life-threatening ventricular tachyarrhythmias (n=19; ventricular fibrillation in 5 and sustained ventricular tachycardia in 14 patients). In univariate analysis, myocardial extent of late gadolinium enhancement predicted event-free survival, as did scar-like thinning (<4 mm) of the basal interventricular septum and the ejection fraction of the right ventricle (P<0.05 for all). In multivariate Cox regression analysis, extent of late gadolinium enhancement was the only independent predictor of outcome events on cardiac magnetic resonance imaging, with a hazard ratio of 2.22 per tertile (95% CI 1.07-4.59). An extent of late gadolinium enhancement >22% (third tertile) had positive and negative predictive values for serious cardiac events of 75% and 76%, respectively.

Conclusions: Findings on cardiac magnetic resonance imaging and the extent of myocardial late gadolinium enhancement in particular help predict serious cardiac events in cardiac sarcoidosis.
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http://dx.doi.org/10.1161/JAHA.115.003040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889179PMC
May 2016

Cholesterol metabolism in cardiac sarcoidosis.

Atherosclerosis 2016 May 18;248:210-5. Epub 2016 Mar 18.

University of Helsinki and Helsinki University Central Hospital, Heart and Lung Center, Division of Cardiology, P.O. BOX 340, FI-00029 HUS, Helsinki, Finland. Electronic address:

Background And Aims: Patients with cardiac sarcoidosis (CS) suffer from myocardial inflammation, but atherosclerosis is not infrequent in these patients. However, the classical atherosclerotic risk factors, such as perturbed serum lipids and whole-body cholesterol metabolism, remain unravelled in CS.

Methods: We assessed serum non-cholesterol sterols, biomarkers of whole-body cholesterol synthesis and cholesterol absorption efficiency, with gas-liquid chromatography in 39 patients with histologically verified CS and in an age-adjusted random population sample (n = 124).

Results: CS was inactive or responding to treatment in all patients. Concentrations of serum, LDL, and HDL cholesterol and serum triglycerides were similar in CS patients and in control subjects. Cholesterol absorption markers were higher in CS patients than in controls (eg serum campesterol to cholesterol ratio in CS 246 ± 18 vs in controls 190 ± 8 10(2) x μmol/mmol of cholesterol, p = 0.001). Cholesterol synthesis markers were lower in CS patients than in controls (eg serum lathosterol to cholesterol ratio in CS 102 ± 8 vs in controls 195 ± 5 10(2) x μmol/mmol of cholesterol, p = 0.000). In CS patients, cholesterol absorption markers significantly correlated with plasma prohormone brain natriuretic peptide (proBNP), a marker of hemodynamic load.

Conclusion: High cholesterol absorption efficiency, which is suggested to be atherogenic, characterized the metabolic profile of cholesterol in CS patients. The association between cholesterol absorption efficiency and plasma proBNP concentration, which suggests a link between inflammation, cholesterol homeostasis, and hemodynamic load, warrants further studies in order to confirm this finding and to reveal the underlying mechanisms.
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http://dx.doi.org/10.1016/j.atherosclerosis.2016.03.018DOI Listing
May 2016

[Inflammatory heart diseases--cardiac sarcoidosis and giant cell myocarditis].

Duodecim 2015 ;131(22):2127-33

The most common symptoms of cardiac sarcoidosis and giant cell myocarditis are atrioventricular block, ventricular tachycardia and cardiac insufficiency. Magnetic resonance imaging of the heart or positron emission tomography are utilized to evaluate the possibility of inflammatory heart disease. The diagnosis is based on histologic examination of a cardiac muscle tissue specimen. For both diseases, the increase in the number of diagnoses is likely to be due to improved diagnostics. The cause of cardiac sarcoidosis is not known, but granulomatous inflammation can be suppressed with corticosteroids. In giant cell myocarditis, more powerful immunosuppression is utilized than in sarcoidosis, but one third of the patients still require heart transplantation within one year from the diagnosis.
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February 2016

Endoplasmic reticulum stress increases AT1R mRNA expression via TIA-1-dependent mechanism.

Nucleic Acids Res 2016 Apr 17;44(7):3095-104. Epub 2015 Dec 17.

Department of Medicine, University of Helsinki, Helsinki, FIN-00014, Finland Heart and Lung Center, Department of Cardiology, Helsinki University Central Hospital, Helsinki, FIN-00029, Finland

As the formation of ribonucleoprotein complexes is a major mechanism of angiotensin II type 1 receptor (AT1R) regulation, we sought to identify novel AT1R mRNA binding proteins. By affinity purification and mass spectroscopy, we identified TIA-1. This interaction was confirmed by colocalization of AT1R mRNA and TIA-1 by FISH and immunofluorescence microscopy. In immunoprecipitates of endogenous TIA- 1, reverse transcription-PCR amplified AT1R mRNA. TIA-1 has two binding sites within AT1R 3'-UTR. The binding site proximal to the coding region is glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-dependent whereas the distal binding site is not. TIA-1 functions as a part of endoplasmic reticulum (ER) stress response leading to stress granule (SG) formation and translational silencing. We and others have shown that AT1R expression is increased by ER stress-inducing factors. In unstressed cells, TIA-1 binds to AT1R mRNA and decreases AT1R protein expression. Fluorescence microscopy shows that ER stress induced by thapsigargin leads to the transfer of TIA-1 to SGs. In FISH analysis AT1R mRNA remains in the cytoplasm and no longer colocalizes with TIA-1. Thus, release of TIA-1-mediated suppression by ER stress increases AT1R protein expression. In conclusion, AT1R mRNA is regulated by TIA-1 in a ER stress-dependent manner.
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http://dx.doi.org/10.1093/nar/gkv1368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838341PMC
April 2016

F-18-fluorodeoxyglucose positron emission tomography-guided sampling of mediastinal lymph nodes in the diagnosis of cardiac sarcoidosis.

Am J Cardiol 2015 Nov 3;116(10):1581-5. Epub 2015 Sep 3.

Division of Cardiology, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.

Histologic proof of granulomatous inflammation is prerequisite for the diagnosis of cardiac sarcoidosis (CS). Because of the limited sensitivity of endomyocardial biopsy (EMB), confirmation of sarcoidosis often has to be acquired from extracardiac biopsies. We set out to review our experience of F-18-fluorodeoxyglucose positron emission tomography (F-18-FDG PET) in guiding extracardiac tissue biopsies in suspected CS. We included in this work 68 consecutive patients with proved CS who had undergone cardiac F-18-FDG PET with (n = 57) or without whole-body imaging as part of initial diagnostic evaluation. Their hospital charts, imaging studies, and diagnostic biopsies were reviewed in retrospect. Whole-body PET images showed extracardiac foci of abnormally high F-18-FDG uptake in 39 of 57 patients, of whom 38 had involvement of mediastinal lymph nodes (MLN). Parallel F-18-FDG uptake was found in other lymph nodes (n = 10), lungs (n = 9), liver (n = 3), spleen (n = 2), and thyroid gland (n = 1). Adding the mediastinal findings at cardiac PET without whole-body imaging, abnormal F-18-FDG uptake in MLN was found in totally 43 of the 68 patients with CS (63%). Histology of systemic sarcoidosis was known at presentation of cardiac symptoms in 8 patients. Of the 60 patients with missing histology, 24 patients underwent mediastinoscopy for sampling of PET-positive MLN, most often (n = 20) after nondiagnostic EMB; microscopy revealed diagnostic noncaseating granulomatous inflammation in 24 of the 24 cases (sensitivity 100%). In the remaining 36 patients, sarcoidosis histology was confirmed by EMB (n = 30), by biopsy of lungs (n = 2) or peripheral lymph nodes (n = 2), or at autopsy (n = 1) or post-transplantation (n = 1). In conclusion, MLN accumulate F-18-FDG at PET in most patients with CS and provide a highly productive source for diagnostic biopsies either primarily or subsequent to nondiagnostic EMB.
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http://dx.doi.org/10.1016/j.amjcard.2015.08.025DOI Listing
November 2015

Usefulness of Cardiac Troponins as Markers of Early Treatment Response in Cardiac Sarcoidosis.

Am J Cardiol 2015 Sep 26;116(6):960-4. Epub 2015 Jun 26.

Division of Cardiology, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.

Evaluation and treatment of cardiac sarcoidosis (CS) suffer from lack of sensitive and easily repeatable markers of disease activity. We studied measurements of high-sensitivity cardiac troponin T or troponin I (hs-cTnT/I) taken at presentation and during treatment in 62 patients with new-onset CS (48 women, mean age 49 years). Hs-cTnT was measured in 50 patients and was elevated (>13 ng/L) at presentation in 26 of them (52%). Hs-cTnI was measured in the remaining 12 patients and was elevated (>0.04 ng/mL) in 7 of them (58%). Left ventricular ejection fraction averaged 43 ± 14% in association with elevated hs-cTnT/I (n = 33) versus 53 ± 10% with normal hs-cTnT/I (n = 29; p = 0.001). Hs-cTnT/I was remeasured after 4 weeks of steroid therapy in 38 patients and was normalized in 16 of the 24 (67%) with an elevated pretreatment concentration and remained normal in the rest of the 14 patients (p <0.001). During follow-up (median, 17 months), cardiac death (n = 2), aborted sudden death (n = 5), sustained ventricular tachycardia (n = 8), or new complete atrioventricular block (n = 1) was recorded in 11 of 33 patients with elevated hs-cTnT/I versus in 5 of 29 with normal hs-cTnT/I (log-rank p = 0.068). Two-year event-free Kaplan-Meier cardiac survival estimate (95% confidence interval) was 67% (48% to 81%) with elevated hs-cTnT/I versus 93% (76% to 99%) with normal hs-cTnT/I. In CS, circulating hs-cTnT/I may help clinicians evaluate disease activity and treatment response. Their prognostic value remains tentative pending more follow-up data.
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http://dx.doi.org/10.1016/j.amjcard.2015.06.021DOI Listing
September 2015

Open chest core needle biopsy of left ventricle in the evaluation of suspected focal myocardial inflammation.

J Thorac Cardiovasc Surg 2015 Jun 19;149(6):e99-102. Epub 2015 Mar 19.

Division of Cardiology, Heart and Lung Center, Helsinki, Finland.

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http://dx.doi.org/10.1016/j.jtcvs.2015.03.016DOI Listing
June 2015

Cardiac sarcoidosis: epidemiology, characteristics, and outcome over 25 years in a nationwide study.

Circulation 2015 Feb 19;131(7):624-32. Epub 2014 Dec 19.

From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (R.K., J.L., M.K.); Heart Center, Turku University Hospital, Turku, Finland (J.A., T.V.); Heart Center, Kuopio University Hospital, Kuopio, Finland (H.M.); Medical Research Center Oulu, University and University Hospital of Oulu, Oulu, Finland (K.Y., K.K.); Heart Hospital, Tampere University Hospital, Tampere, Finland (S.T., P.H.); Päijät-Häme Central Hospital, Lahti, Finland (T.K.); Central Finland Central Hospital, Jyväskylä, Finland (J.K.); South Ostrobothnia Central Hospital, Seinäjoki, Finland (M.P.); Vaasa Central Hospital, Vaasa, Finland (P.P.-E.); and South Karelia Central Hospital, Lappeenranta, Finland (S.U.).

Background: This study was designed to assess the epidemiology, characteristics, and outcome of cardiac sarcoidosis (CS) in Finland.

Methods And Results: We identified in retrospect all adult (>18 years of age) patients diagnosed with histologically confirmed CS in Finland between 1988 and 2012. A total of 110 patients (71 women) 51±9 years of age (mean±SD) were found and followed up for outcome events to the end of 2013. The annual detection rate of CS increased >20-fold during the 25-year period, reaching 0.31 in 1×10(5) adults between 2008 and 2012. The 2012 prevalence of CS was 2.2 in 1×10(5). Nearly two thirds of patients had clinically isolated CS. Altogether, 102 of the 110 patients received immunosuppressive therapy, and 56 received an intracardiac defibrillator. Left ventricular function was impaired (ejection fraction <50%) in 65 patients (59%) at diagnosis and showed no overall change over 12 months of steroid therapy. During follow-up (median, 6.6 years), 10 patients died of a cardiac cause, 11 patients underwent transplantation, and another 11 patients suffered an aborted sudden cardiac death. The Kaplan-Meier estimates for 1-, 5-, and 10-year transplantation-free cardiac survival were 97%, 90%, and 83%, respectively. Heart failure at presentation predicted poor outcome (log-rank P=0.0001) with a 10-year transplantation-free cardiac survival of only 53%.

Conclusions: The detection rate of CS has increased markedly in Finland over the last 25 years. With current therapy, the prognosis of CS appears better than generally considered, but patients presenting with heart failure still have poor long-term outcome.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.114.011522DOI Listing
February 2015

Probabilistic prediction of contacts in protein-ligand complexes.

PLoS One 2012 14;7(11):e49216. Epub 2012 Nov 14.

Department of Natural Sciences, Mathematics and Statistics, Åbo Akademi University, Turku, Finland.

We introduce a statistical method for evaluating atomic level 3D interaction patterns of protein-ligand contacts. Such patterns can be used for fast separation of likely ligand and ligand binding site combinations out of all those that are geometrically possible. The practical purpose of this probabilistic method is for molecular docking and scoring, as an essential part of a scoring function. Probabilities of interaction patterns are calculated conditional on structural x-ray data and predefined chemical classification of molecular fragment types. Spatial coordinates of atoms are modeled using a Bayesian statistical framework with parametric 3D probability densities. The parameters are given distributions a priori, which provides the possibility to update the densities of model parameters with new structural data and use the parameter estimates to create a contact hierarchy. The contact preferences can be defined for any spatial area around a specified type of fragment. We compared calculated contact point hierarchies with the number of contact atoms found near the contact point in a reference set of x-ray data, and found that these were in general in a close agreement. Additionally, using substrate binding site in cathechol-O-methyltransferase and 27 small potential binder molecules, it was demonstrated that these probabilities together with auxiliary parameters separate well ligands from decoys (true positive rate 0.75, false positive rate 0). A particularly useful feature of the proposed Bayesian framework is that it also characterizes predictive uncertainty in terms of probabilities, which have an intuitive interpretation from the applied perspective.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049216PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498326PMC
May 2013

Diagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression.

Circ Heart Fail 2013 Jan 13;6(1):15-22. Epub 2012 Nov 13.

Division of Cardiology, Department of Medicine, HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.

Background: Giant-cell myocarditis often escapes diagnosis until autopsy or transplantation and has defied proper treatment trials for its rarity and deadly behavior. Current therapy rests on multiple-drug immunosuppression but its prognostic influence remains poorly known. We set out to analyze (1) our experience in diagnosing giant-cell myocarditis and (2) the outcome of patients on combined immunosuppression.

Methods And Results: We reviewed the histories, diagnostic procedures, details of treatment, and outcome of 32 consecutive patients with histologically verified giant-cell myocarditis treated in our hospital since 1991. Twenty-six patients (81%) were diagnosed by endomyocardial or surgical biopsies and 6 at autopsy or post-transplantation. Twenty-eight (88%) patients underwent endomyocardial biopsy. The sensitivity of transvenous endomyocardial biopsy increased from 68% (19/28 patients) to 93% (26/28) after up to 2 repeat procedures. The 26 biopsy-diagnosed patients were treated with combined immunosuppression (2-4 drugs) including cyclosporine in 20 patients. The Kaplan-Meier estimates of transplant-free survival from symptom onset were 69% at 1 year, 58% at 2 years, and 52% at 5 years. Of the transplant-free survivors, 10/17 (59%) experienced sustained ventricular tachyarrhythmias during follow-up and 3 received intracardiac defibrillator shocks for ventricular tachycardia or fibrillation.

Conclusions: Repeat endomyocardial biopsies are frequently needed to diagnose giant-cell myocarditis. On contemporary immunosuppession, two thirds of patients reach a partial clinical remission characterized by freedom from severe heart failure and need of transplantation but continuing proneness to ventricular tachyarrhythmias.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.112.969261DOI Listing
January 2013

Regulation of AT1R expression through HuR by insulin.

Nucleic Acids Res 2012 Jul 23;40(12):5250-61. Epub 2012 Feb 23.

Research Program for Molecular Medicine, Biomedicum Helsinki, FIN-00014 University of Helsinki, Finland.

Angiotensin II type 1 receptor (AT1R) has a pathophysiological role in hypertension, atherosclerosis and heart failure. Type 2 diabetes is hyperinsulinemic state and a major risk factor for atherosclerosis and hypertension. It is known that hyperinsulinemia upregulates AT1R expression post-transcriptionally by increasing the half-life of AT1R mRNA, but little is known about the mechanism of this effect. In the present study, we first identified AT1R 3'-UTR as a mediator of insulin effect. Using 3'-UTR as a bait, we identified through analysis of insulin-stimulated cell lysates by affinity purification and mass spectrometry HuR as an insulin-regulated AT1R mRNA binding protein. By ribonucleoprotein immunoprecipitation, we found HuR binding to AT1R to be increased by insulin. Overexpression of HuR leads to increased AT1R expression in a 3'-UTR-dependent manner. Both insulin and HuR overexpression stabilize AT1R 3'-UTR and their responsive element within 3'-UTR are located within the same region. Cell fractionation demonstrated that insulin induced HuR translocation from nucleus to cytoplasm increased HuR binding to cytoplasmic AT1R 3'-UTR. Consistent with HuR translocation playing a mechanistic role in HuR effect, a reduction in the cytoplasmic levels of HuR either by silencing of HuR expression or by inhibition of HuR translocation into cytoplasm attenuated insulin response. These results show that HuR translocation to cytoplasm is enhanced by insulin leading to AT1R upregulation through HuR-mediated stabilization of AT1R mRNA.
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http://dx.doi.org/10.1093/nar/gks170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384301PMC
July 2012