Download - Research update for articles published in EJCI in 2009

Research update for articles published in EJCI in2010Christopher Adlbrecht1, Elmar Aigner2, Juan M. Bellon3,4, Izolde Bouloukaki5, Alberto Bouzas-Mosquera6,Alexandre J. F. Carrilho7, Kuo-Chu Chang8, Nipon Chattipakorn9, Siriporn C. Chattipakorn9, Yi-Jen Chen10,11,Yuan-Chiang Chung12, Roshan Colah13, Christian Datz14, Jens B. Frøkjær15, Shunji Fujimori16, PanagiotaGeorgiadou17, Cintia M. Grion7, Chih-Ping Hsu18, Martin Hulsmann1, Ming-Jui Hung19, Ming-Yow Hung20,21,Efstathios K. Iliodromitis22, Irene M. Lang1, Ting- I. Lee10,23, Winfried Marz24,25,26, Sona B. Nair13, GemmaPascual3,4, Jesus Peteiro6, Choitsu Sakamoto16, Atsushi Satomura27, Sophia E. Schiza5, Peter Starkel28,29,Tatjana Stojakovic24, David L. Vesely30,31, Darren L.Walters32 and Yusuf Yilmaz33,34

1Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria, 2First Departmentof Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria, 3Detartment of Medical Specialities and Surgery,University of Alcala, Alcala de, Spain, 4Networking Research Centre on Biomaterials, Bioengineering and Nanomedicine(CIBER-BBN), Madrid, Spain, 5Sleep Disorders Unit, Department of Thoracic Medicine, Medical School, University of Crete,Heraklion, Greece, 6Department of Cardiology, Hospital Universitario A Coruna, A Coruna, Spain, 7Department of InternalMedicine, Londrina State University, Londrina, PR, Brazil, 8Department of Physiology, College of Medicine, National TaiwanUniversity, Taipei, Taiwan, 9Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai,Thailand, 10Graduate Institute of Clinical Medicine, College of Medicine, Taipei, Taiwan, 11Division of CardiovascularMedicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, 12Department ofSurgery, Cheng-Ching General Hospital, Taichung, Taiwan, 13National Institute of Immunohematology (I.C.M.R.), K.E.M Hos-pital Campus, Parel, Mumbai, India, 14Department of Internal Medicine, General Hospital Oberndorf, Oberndorf, Austria,15Mech-Sense, Department of Radiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark, 16Department ofGastroenterology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan, 172nd Division of InterventionalCardiology, Onassis Cardiac Surgery Center, Athens, Greece, 18Department of Medical Laboratory Science and Biotech-nology, Yuanpei University, Hsinchu, Taiwan, 19Department of Cardiology, Chang Gung Memorial Hospital, Keelung, ChangGung University College of Medicine, Gueishan, Taoyuan, Taiwan, 20Department of Internal Medicine, School of Medicine,College of Medicine, Taipei, Taiwan, 21Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, TaipeiMedical University, New Taipei City, Taiwan, 222nd University Department of Cardiology, Medical School, Attikon UniversityGeneral Hospital, Athens, Greece, 23Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan FangHospital, Taipei Medical University, Taipei, Taiwan, 24Clinical Institute of Medical and Chemical Laboratory Diagnostics,Medical University of Graz, Graz, Austria, 25Institute of Public Health, Social and Preventive Medicine, MannheimMedicalFaculty, University of Heidelberg, Mannheim, Germany, 26Synlab Academy, Synlab Services GmbH, Mannheim, Germany,27Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo,Japan, 28Institut de recherche experimentale et clinique (IREC), Universite Catholique de Louvain, Brussels, Belgium,29Department of Gastroenterology, St. Luc University Hospital, Brussels, Belgium, 30Departments of Internal Medicine andMolecular Pharmacology and Physiology, James A. Haley Veterans Hospital, Tampa, FL, USA, 31University of South FloridaHealth Sciences Cardiac Hormone Center, Tampa, FL, USA, 32The Prince Charles Hospital, University of Queensland,Brisbane, Qld, Australia, 33Institute of Gastroenterology, Istanbul, Turkey, 34Department of Gastroenterology, School ofMedicine, Marmara University, Istanbul, Turkey

Differential effects of fluvastatin alone or incombinationwith ezetimibe on lipoproteinsubfractions in patients at high risk ofcoronary events (Tatjana Stojakovic andWinfried Marz)

Recently [1] Winkler et al. [2] reported that total cholesterol,

LDL-C and small, dense LDL (sdLDL) were significantly

reduced with ezetimibe 10 mg (E10), simvastatin 20 mg (S20)

and the combination of E10 ⁄ S20 in patients with type 2 dia-

betes and a preponderance of sdLDL. The further decrease

of sdLDL by adding ezetimibe to simvastatin was not signif-

icant. Florentin et al. [3] showed that S10 plus E10 is simi-

larly effective to S40 in improving sdLDL and LDL particle

size in patients with primary hypercholesterolaemia. In the

study of Berneis et al. [4], healthy men were treated with

European Journal of Clinical Investigation Vol 42 1149

DOI: 10.1111/eci.12001

RESEARCH UPDATE

E10, S40 or their combination. The authors stated that eze-

timibe alone increased sdLDL so that potentially athero-

protective effects of simvastatin are offset by ezetimibe.

However, using relative proportions of individual subfrac-

tions alone may be misleading when assessing the effects of

lipid-lowering therapy on LDL metabolism [5]. The most

balanced interpretation of the available evidence is that

ezetimibe is less effective than statins in reducing sdLDL

when administered at doses equally effective in reducing

LDL-C.

Five a-globin chain variants identified duringscreening for haemoglobinopathies (Sona B. Nairand Roshan Colah)

The evidence that has accumulated reinforces our statement

to undertake systematic investigations while screening for

b-haemoglobinopathies to identify rare a-chain variants in a

population [6]. The first case of Hb Fontainebleu

[a-21(B2)GCT fi CCT] with Hb S was identified in a new-

born and her mother along with one case each of Hb O

Indonesia [a-116(GH4) GAG fi AAG] and Hb Koya Dora

[a-142(B2) TAA fi TCA] during our newborn screening pro-

gramme for sickle cell anaemia [7]. We have identified four

new cases of Hb J Paris I [a-12(A10) GCC fi GAC] and

two of Hb O Indonesia during our routine screening for

b-haemoglobinopathies (unpublished data). There are reports

of one case each of Hb O Indonesia and Hb J Meerut [a-120(H3) GCG fi GAG], both identified in two pregnant ladies

who came for antenatal screening for b-thalassaemia ⁄A1c

estimation [8,9]. We also identified many cases of Hb Sal-

lanches [a-104(G11)TGC fi TAC] causing HbH disease

using HPLC, cellulose acetate electrophoresis (pH 8Æ9) andDNA sequencing while investigating cases with a b-thalas-saemia intermedia like presentation [10,11].

Epidermal Growth Factor’s Activation of Ras isInhibited by Four Cardiac Hormones (David L.Vesely)

The conclusions of this investigation were that (i) four cardiac

hormones specifically inhibit (up to 79%) epidermal growth fac-

tor’s activation of Ras and (ii) that these cardiac hormones’ anti-

cancer effects involve the inhibition of mitogens such as

epidermal growth factor’s ability to activate Ras (1) as well as

their inhibiting unstimulated basal activity of Ras [12–14].

There is evidence that other mitogen besides epidermal growth

factor that is insulin’s stimulation of Ras can also be blocked by

these four cardiac hormones [15]. There is very recent evidence

that there may be a negative feedback relationship of the

cardiac hormones’ inhibition of Ras as dexamethasone-induced

Ras protein 1 inhibits one of the cardiac hormones that is atrial

natriuretic peptide’s release [16]. Thus, the cardiac hormones

inhibit mitogen stimulated Ras and Ras, in turn, can inhibit

ANP’s release. There is no new evidence that weakens the

previously conclusions.

Cardiovascular Hormones Eliminate SomeSquamous Cell Carcinomas in Athymic Mice(David L. Vesely)

The conclusions of this investigation were that (i) three of the

four cardiac hormones synthesised by the atrial natriuretic pep-

tide gene (namely vessel dilator, kaliuretic peptide and atrial

natriuretic peptide) can eliminate human squamous cell lung

carcinomas in athymic mice when treated subcutaneously for

four weeks and (ii) the fourth cardiac hormones that is long-

acting natriuretic peptide, decreased the volume of one squa-

mous cell lung carcinoma to 2% of that of untreated animals,

suggesting that it, too, has beneficial effects on squamous cell

lung cancers [17]. Noteworthy, there is a much more robust

elimination of another lung cancer with these cardiac hormones

in that they eliminate up to 86% of human small-cell lung

cancers in athymic mice [18]. Both of these lung cancers, once

eliminated, never return in the lifespan of the mice [17,18].

There have been no further studies on the cardiac hormones

and lung cancers in vivo.

Distribution of small intestinal mucosal injuriesas a result of NSAID administration (ShunjiFujimori and Choitsu Sakamoto)

In our study [19], many small intestinal mucosal breaks were

detected after dicrofenac and omeprazole concomitant treat-

ment. Recently, Wallace et al. [20] reported that proton pump

inhibitors (PPIs) exacerbate nonsteroidal anti-inflammatory

drug (NSAID)-induced small intestinal injury in rat. The study

shows that omeprazole and lansoprazole impair the ability to

disinfect by PPI-induced low acid gastric environment and

resulted in transubstantiation of intestinal flora exacerbated

NSAID-induced small intestinal injury. If PPI exacerbating

small intestinal injury is true, our study might have over-evalu-

ated the frequency of NSAID-induced small intestinal injury.

However, our results partially supported the new idea because

the severe small intestinal lesions such as ulcers were predomi-

nantly located in the distal small intestine in our study. The dis-

tal small intestine maintains a more diverse microflora and a

higher bacterial population [21]. Microflora must have an

important role in NSAID-induced small intestinal injury in the

studies.

1150 ª 2012 The Authors. European Journal of Clinical Investigationª 2012 Stichting European Society for Clinical Investigation Journal Foundation

C. ADLBRECHT ET AL. www.ejci-online.com

Long-term outcome after thrombectomy in acutemyocardial infarction (Christopher Adlbrecht andIreneM. Lang)

Acute myocardial infarction (AMI) is caused by thrombotic

coronary occlusion. In our publication, we documented long-

term risk reduction for death or cardiac rehospitalisation for

patients with AMI randomised to thrombectomy prior to per-

cutaneous coronary intervention (PCI), compared to PCI

without thrombectomy [22]. Few studies have evaluated

long-term outcome in patients with AMI after thrombectomy

[23], however, one-year cardiac mortality was recently shown

to be reduced in large-scale randomised controlled trials [24],

and thrombectomy prior to PCI is now recommended in

practice guidelines [25]. A new challenge comes from more

recent trials where administration of glycoprotein IIb ⁄ IIIaantibodies via a perfusion balloon during PCI significantly

reduced infarct size [26]. Ongoing thrombectomy trials

(e.g. TOTAL) will contribute to a better understanding of the

role of this strategy in contemporary AMI treatment algo-

rithms and of its impact on long-term outcomes.

Osteopontin as a novel prognostic marker instable ischaemic heart disease: a 3-year follow-upstudy (Panagiota Georgiadou and Efstathios KIliodromitis)

Baseline levels of osteopontin (OPN) were reported to be asso-

ciated with rapid coronary plaque progression and in-stent

restenosis at 6-month follow-up [27,28]. High levels of OPN in

carotid and femoral atherosclerotic plaques independently pre-

dicted the risk of new cardiovascular events and interventions

at 3-year follow-up; the predictive value of serum OPN levels

was less strong but still significant in these patients [29]. A posi-

tive association of OPN with arterial stiffness and the extent of

coronary artery disease (CAD) have been demonstrated in

patients with CAD [30]. Similarly, OPN levels correlated with

the severities of both coronary and aortic atherosclerosis but on

multivariate analysis, only aortic atherosclerosis remained sig-

nificant [31]. An independent association was also found

between OPN levels and the presence and severity of nephro-

pathy and CAD in diabetic patients [32]. Hence, OPN levels are

more likely to reflect not only coronary atherosclerosis but also

atherosclerosis in other vascular beds.

Lipoproteins and CETP levels as risk factors forsevere sepsis in hospitalised patients (AlexandreJ. F. Carrilho and Cintia M. Grion)

More recent studies have investigated [33] the anti-inflammatory

role of HDL particles in innate immunity. Hara et al. [34] dem-

onstrated that HDL obtained from knockout mice for endothe-

lial lipase, a member of the lipase gene family that promote

HDL catabolism, was more potent in neutralising microorgan-

ism endotoxin than control HDL in vivo and in vitro. This effect

was related to increase in phospholipid rather than protein con-

tent in HDL particles. In another study, Henning et al. [35] sug-

gest that the C-terminal half of apoA1 is the main domain

responsible for the endotoxin neutralisation of this protein.

These studies reinforce the known HDL role as immune modu-

lator; however, regarding to HDL cholesterol protection against

severe sepsis in hospitalised patients, there are not new data

confirming or refuting this hypothesis. We think that a multi-

centre study could shed light on this important question.

High-dose tirofiban with enoxaparin andinflammatory markers in high-risk percutaneousintervention (Darren L. Walters)

Since the publication of our article [36], we have continued to

work in the area of optimal anticoagulation in patients with

acute coronary syndromes and study the link between inflam-

matory markers and cardiac events. As a follow-up to our

study, we found that inflammatory markers continue to be

present long after the index event with increased expression of

monocyte tissue factor and soluble CD40 ligand at mid-term

follow-up following percutaneous coronary intervention [37].

In a related study, we also found that preoperative platelet acti-

vation as evidenced by platelet-bound CD40 ligand was associ-

ated with cardiac events [38]. In terms of optimal

anticoagulation in percutaneous intervention (PCI), there has

been an increasing recognition that heparin and routine use of

glycoprotein IIbIIIa inhibitors is associated with increased

bleeding events. These bleeding events are strongly associated

with an increased risk of subsequent mortality in patients

undergoing PCI [39]. Therapy is now more tailored and used in

a selective fashion. A number of studies have now demon-

strated the benefit of novel antiplatelet agents that exhibit both

a faster onset of action and a superior level of platelet inhibition

compared with clopidogrel [40,41]. Many new clinical chal-

lenges have been posed with the arrival of these more potent

agents. Therapies must balance bleeding risk against the throm-

botic complications of the disease and invasive treatments.

Increased serum FGF21 levels in patients withnonalcoholic fatty liver disease (Yusuf Yilmaz)

Recent clinical [42] studies have largely confirmed the associa-

tion between increased FGF21 levels and the presence of nonal-

coholic fatty liver disease (NAFLD). In addition, the evidence

that FGF21 chiefly mirrors the extent of hepatic steatosis has

reinforced. In this regard, Li et al. [43] reported that serum


RESEARCH UPDATE

FGF21 levels were significantly higher in patients with NAFLD

compared with the controls and had a high positive correlation

with intrahepatic triglyceride content. In addition, Yan et al.

[44] have shown that serum FGF21 increased progressively

with the increase of hepatic fat content as measured by proton

magnetic resonance spectroscopy, but when hepatic fat content

increased in the fourth quartile, FGF21 tended to decline. Taken

together, the data concordantly show that serum FGF21 may

serve as a potential biomarker to reflect the hepatic fat content

in patients with mild or moderate NAFLD.

Electrical optimisation of cardiacresynchronisation in chronic heart failure – still acontroversially discussed issue (ChristopherAdlbrecht andMartin Hulsmann)

Electrical optimisation of cardiac resynchronisation therapy

(CRT) in patients with chronic heart failure is recommended

by the manufacturers and by the study investigators of large

RCTs [45]. Similar to optimal medical background therapy

[46] in this setting evidence is still lacking. In 2010, we pub-

lished a retrospective analysis demonstrating a positive influ-

ence [45]. A randomised, patient and observer blinded study

compared a fixed AV-interval set at 120 ms, AV-delay pro-

grammed with the echocardiography-determined mitral

inflow method or by an algorithm. The authors found no dif-

ferences in outcome in 980 patients randomised and con-

cluded that routine use of echocardiographic optimisation as

well as algorithm-based AV-interval optimisation is not

clinically warranted [47].

While our data [45] are limited by the retrospective design,

other investigators stated that the study of Ellenbogen [47] was

underpowered and that one should not exclude patients from

electrical optimisation of the AV-interval [48].

Therefore, and in the light of small prospective studies [49]

and larger retrospective analyses [45], the exact role of optimi-

sation of the AV-interval and interventricular delay in CRT

remains to be determined, and the latest version of guidelines

still provide no recommendation on this issue [50].

Value of exercise echocardiography for predictingmortality in elderly patients (Alberto Bouzas-Mosquera and Jesus Peteiro)

Peak treadmill exercise echocardiography – the technique

employed in our study [51] – has recently shown to be more

sensitive than bicycle stress echocardiography, at least for

detecting multivessel coronary artery disease [52]; this may be

particularly relevant in elderly patients, in whom bicycle stress

echocardiography is often inconclusive owing to premature

interruption of exercise and ⁄or problems of coordination.

In patients unable to perform an exercise stress test, dobuta-

mine stress echocardiography has shown to predict cardiac

events and death in patients ‡60 years, but only cardiac events

in those <60 years [53].

Finally, a recent meta-analysis [54] on noninvasive imaging

techniques in patients >65 years confirmed that stress echocardio-

graphy effectively stratified risk in these patients; the annua-

lised cardiac event rate for a normal stress echocardiographic

study was 1Æ9% vs. 8% after an abnormal test (P < 0Æ001), andthere were no significant differences in the event rates between

patients undergoing pharmacological and exercise stress tests.

C-reactive protein evolution in obstructive sleepapnoea patients under CPAP therapy (Sophia E.Schiza and Izolde Bouloukaki)

Previously, our team has shown that, in patients with OSA and

without preexisting cardiac disease, effective CPAP treatment

results in a significant CRP reduction after 3 months and a

steeper decline after 6 months [55]. This is consistent with the

findings of a recent meta-analysis [56] and with the results from

another published study from our team, which shows that

CPAP’s protective role in males is achieved at an earlier time

point [57]. Furthermore, in another study, effective 3 month

CPAP treatment significantly decreased CRP [58]. In contrast,

Colish et al. [59] failed to find significant changes in CRP levels

after 12 months of CPAP therapy; however, the number of

patients was small, which is prone to a false conclusion, and

the baseline levels of CRP were within normal limits. In conclu-

sion, using CRP as a marker of systemic inflammation, CPAP

reduction of CRP levels may benefit patients’ cardiovascular

health.

Effects of acetyl-L-carnitine and oxfenicine onaorta stiffness in diabetic rats (Kuo-Chu Chang)

Malondialdehyde (MDA) [60] is a highly toxic by-product

formed by lipid oxidation-derived free radicals, which can react

with collagen to form MDA-collagen cross-links. Slatter et al.

[61] proposed a pathway of MDA cross-linking of cardio-

vascular collagen in diabetes mellitus: the glucose-glycated

collagen stimulates oxidation of LDL producing MDA, which

then cross-links the collagen; the MDA-mediated cross-linking

of collagen may in turn contribute to the reduction in its already

low turnover, stiffening the aortas, thereby promoting further

glycation. In our study, treating streptozotocin-induced dia-

betic rats with acetyl-L-carnitine had diminished aortic MDA

content, which might cause a fall in cross-links of collagen and

improve aortic distensibility [60]. By contrast, without any sig-

nificant changes in MDA content, oxfenicine therapy showed

no benefits for the mechanical properties of the elastic



reservoirs. Thus, we suggest that MDA-mediated cross-linking

of aortic collagen may be one of the major contributing factors

for arterial stiffening in intact diabetic animals.

Relationship between oligomer and functionalserummannose-binding lectin in chronic renalfailure (Atsushi Satomura)

Our study published in EJCI in 2010 showed functional man-

nose-binding lectin (MBL) levels were significantly lower in

both pre-haemodialysis and haemodialysis patients than in

healthy subjects, and moreover, lower in pre-haemodialysis

patients than in haemodialysis patients [62]. Therefore, we

sought to determine whether functional MBL would be

improved by haemodialysis therapy. Further evidence had

been found that the lower levels of functional MBL just before

haemodialysis therapy were improved significantly by hae-

modialysis therapy, although the functional MBL level of

patients on haemodialysis for one year was still lower at about

45–65% of healthy subjects [63]. Generally, the patient with low

functional MBL level might be associated with unusual and

severe infections [64]. As infectious disease has always ranked

high as a cause of death in patients undergoing dialysis, the

decline of functional MBL, as a component of innate immunity,

may be one of the underlying causes.

Effect of acute hyperglycaemia on sensoryprocessing in diabetic autonomic neuropathy(Jens Brøndum Frøkjær)

Recent studies have revealed that neuropatic-like changes and

reorganisation in the central nervous system are important

drivers for development of disturbed sensation and gastrointes-

tinal symptoms in patients with longstanding diabetes and

autonomic neuropathy [65].

Using recordings of evoked brain potential to oesophageal

stimulations in this patient group, we found reduced sensitiv-

ity, increased latencies and reduced amplitudes [66]. Also

changes in anatomical locations of the dominating electrical

brain sources were observed [66]. Furthermore, using mag-

netic resonance diffusion tensor imaging, we characterised

brain microstructure in areas involved in visceral sensory

processing [67]. We discovered microstructural changes in

several of these brain areas which were associated with the

presence of gastroparesis and with clinical gastrointestinal

symptoms [67].

These new functional and structural findings support that

microstructural reorganisation and neuropathic-like dysfunc-

tion of the brain, in contrast to acute hyperglycaemia itself, are

likely involved in the pathogenesis and persistence of gastroin-

testinal symptoms in diabetes patients.

Oxidative stress and inflammation modulateperoxisome proliferator-activated receptors withregional discrepancy in diabetic heart (Ting- I Leeand Yi-Jen Chen)

Diabetes mellitus (DM) modulated peroxisome proliferator-

activated receptors (PPARs) through oxidative stress and

inflammatory cytokines which are attenuated by ascorbate

treatment [68]. We further found that DM aggravated but

PPAR-c agonist (rosiglitazone) decreased the hypertensive

effects on cardiac PPAR-c expression, oxidative stress andinflammation [69].

PPAR isoforms are differentially expressed in the atria and

ventricles [68]. We found that ApoE knockout DMmice have a

higher arrhythmogenesis in the cardiomyocytes treated with

PPAR-c activator (piogliotazone, 1 lm) [70]. Therefore, we fur-

ther investigated on the electrophysiological effects of rosiglit-

azone in the ventricular cardiomyocytes of DM with or without

hypertension and evaluated its effects on the calcium regula-

tions. We found that DM and hypertension modulated calcium

handling. Rosiglitazone significantly changed the calcium regu-

lation and electrophysiological characteristics, and may contain

an arrhythmogenic potential in DM with hypertension [71].

Cardiac hormones inhibit proliferation ofpancreatic cancer but not normal cells (David L.Vesely)

The statement that ‘four cardiac hormones have strong anti-

proliferative effects on human pancreatic cancer while sparing

human kidney, lung, prostate and endothelial cells from a simi-

lar strong antiproliferative effect’ [72] has been confirmed for

atrial natriuretic peptide by other investigators [73].

In support of the statement, ‘This antiproliferative effect on

pancreatic cancer cells helps to explain why human pancreatic

cells in vivo treated with cardiac hormones decrease to >10% of

the volume of untreated pancreatic cells [74] as they proliferate

less’, the cardiac hormones cause cell death in up to 36% of

human pancreatic cancer cells as measured quantitatively by

nuclear matrix protein 41 ⁄ 7 released from dead or dying cells

while causing no cell death of normal cells [75]. Further support

for this statement is that the four cardiac hormones cause toxic-

ity in up to 58% of human pancreatic cancer cells while sparing

normal cells [76].

The effect of Longan seed polyphenols oncolorectal carcinoma cells (Yuan-Chiang Chungand Chih-Ping Hsu)

Longan seed polyphenols (LSP) induced S phase arrest of the

cell cycle and apoptosis on colorectal carcinoma cells [77].


RESEARCH UPDATE

Similar effects of LSP on lung (A549), liver (HepG2), cervix

(C33A) and breast carcinoma cells (MDA-MB-231) is under

revision [78]. LSP systemically suppressed cyclin D1 and

cyclin A and enhanced CIP ⁄p21 and KIP ⁄p27 in all four cell

lines and arrested C33A and MDA-MB-231 cells in S phase of

cell cycle. LSP also suppressed Bcl-2 and acivated caspase 3

in all cell lines and induced significant apoptosis in HepG2

and C33A cells. The induction of LSP on S phase arrest of

the cell cycle and apoptotic death in cancer cell lines seems

to be cancer type specific. However, the suppression of onco-

genic cyclin D1, A and Bcl-2 and the enhancement of tumour

suppressor CIP 1 ⁄p21 and KIP 1 ⁄p27 by LSP are systemic,

indicating LSP as a novel cancer chemoprevention and treat-

ment agent.

NFjB, cytokines, TLR 3 and 7 expression inhuman end-stage HCV and alcoholic liver disease(Peter Starkel)

Current research is focusing on the interaction between the gut

and the liver (gut-liver axis) as a driving force behind alcohol-

induced liver damage [79]. Evidence is accumulating that alco-

hol increases the gut permeability favouring the translocation

of gut-derived bacterial products into the portal circulation

[80]. How this affects the expression and activation of cytokines

and TLR signalling pathways in human liver remains to be elu-

cidated. Our own research tends to confirm activation of sev-

eral pro-inflammatory cytokines such as TNF-a and IL-1b in the

liver of alcoholic patients, whereas IL-6 seems to be inhibited

by alcohol in the absence of liver cirrhosis. Conflicting evidence

exists concerning the hepatitis C virus (HCV). In vitro studies

show that the HCV nonstructural protein 5A down-regulates

TLR4 signalling in HepG2 cells, whereas a study using liver tis-

sue from HCV-infected patients reports a good correlation

between hepatic inflammation, TNF-a, TLR2 and TLR4 expres-

sion [81,82]. Ongoing research by us and others will help to

clarify how different organ systems influence each other and

what pathways are implicated in the pathogenesis of the dam-

age of target organs such as the liver.

Interactions among gender, age, hypertensionand C-reactive protein in coronary vasospasm(Ming-Jui Hung andMing-Yow Hung)

Increased inflammatory status exists in patients with coronary

vasospastic angina and the anti-spastic treatment decreases

inflammation as reflected by the level of high-sensitivity C-

reactive protein (hsCRP) [83,84]. The hsCRP is a sex-dependent

inflammatory biomarker with a higher blood concentration in

female [85] and a gender interaction between fasting plasma

glucose and hsCRP [86]. Although hsCRP is elevated in patients

with coronary vasospastic angina, increased peripheral leuco-

cyte rho-kinase activity not only significantly predicts the pres-

ence of coronary vasospasm but also correlates with

vasospastic angina severity [84]. Although the precise mecha-

nism of coronary vasospasm is still not clear, both endothelial

and smooth muscle dysfunction have been suggested to play a

role [87]. Among the clinical associated factors, hypertension is

negatively associated with coronary vasospasm [87], suggesting

that pathogenesis of coronary vasospasm differs from that of

coronary atherosclerosis.

Active metalloproteinase-2 upregulation in theabdominal skin of patients with direct inguinalhernia (Gemma Pascual and JuanManvelBellon)

Previous findings have supported the hypothesis of impaired

regulation of collagen metabolism involving different constitu-

ents of the whole abdominal wall in patients with different

types of hernias [88–90]. Our group had already showed MMP-

2 overexpression in the transversalis fascia in patients with

direct hernia [91], and in cultured fibroblasts obtained from

patients this type of hernia [92]. The persistence of MMP-2

overexpression in the cell cultures appears to suggest a genetic

defect or irreversible change as the origin of this pathology

rather than environmental factors, which may later participate

in the development of the hernia process. Similar alterations

were also observed in the abdominal skin of patients with this

pathology in the present article.

Recent publications [93] also confirm, in accordance with our

article, an imbalance in MMP ⁄TIMP activity that indicates a

dysregulation of the extracellular matrix degradation process in

patients with inguinal hernia, suggesting that impaired colla-

gen metabolism may be an underlying pathophysiological

mechanism of inguinal hernia formation.

Plasma urocortin in acute myocardial infarctionpatients (Nipon Chattipakorn and Siriporn C.Chattipakorn)

Despite growing evidence that urocortins may provide cardio-

protective effects during cardiac ischaemia ⁄ reperfusion injury,

most studies were from pre-clinical reports using exogenous

urocortin administration [94–97]. In 2010, we demonstrated in

patients with acute myocardial infarction (AMI) that their

plasma urocortin levels were elevated for 5 days from onset,

and its high level within 24 h after the onset is associated with

high mortality [94]. At this time, no new evidence exists to con-

firm these findings regarding the plasma level of urocortins

and its time course after the onset in AMI patients. Further-

more, no new evidence exists regarding the association



between the plasma urocortin level (alone or in combination

with NT-proBNP) and the mortality in AMI patients. Future

clinical studies with larger sample size are required to warrant

the clinical usefulness of plasma urocortins as a prognostic

indicator in AMI patients.

Iron stores, liver transaminase levels andmetabolic risk in healthy teenagers (ChristianDatz and Elmar Aigner)

Iron excess is directly associated with insulin resistance. In

2010, we demonstrated that body iron stores were related to

metabolic risk markers in healthy, lean teenagers even within

the limits of normal [98]. Since then, progress has been made in

defining the relevance of hyperferritinemia in nonalcoholic

fatty liver disease (NAFLD) by demonstrating that iron deposi-

tion is related to advanced disease [99]. Elevated serum ferritin

has also been linked to liver transplantation associated mortal-

ity [100]. Furthermore, the first controlled clinical trial has been

published showing the benefit of iron reduction therapy on sev-

eral components of the metabolic syndrome, thus strengthening

the evidence to offer phlebotomy to these patients [101].

Recently, we were able to show that iron overload in NAFLD is

linked to low copper availability and that low copper status is a

frequently unrecognised trace metal abnormality in NAFLD

[102]. Moreover, we found that glucose ingestion modulates

serum iron concentrations [103].

Address

Division of Cardiology, Department of Internal Medicine II,

Medical University of Vienna, Vienna, Austria (C. Adlbrecht,

M. Hulsmann, I. M. Lang); First Department of Medicine, Para-

celsus Medical University Salzburg, Salzburg, Austria (E. Aig-

ner); Detartment of Medical Specialities and Surgery,

University of Alcala, Alcala de, Spain (J. M. Bellon, G. Pascual);

Networking Research Centre on Biomaterials, Bioengineering

and Nanomedicine (CIBER-BBN), Madrid, Spain, (J. M. Bellon,

G. Pascual); Sleep Disorders Unit, Department of Thoracic

Medicine, Medical School, University of Crete, Heraklion,

Voutes, Greece (I. Bouloukaki, S. E. Schiza); Department of

Cardiology, Hospital Universitario A Coruna, A Coruna, Spain

(A. Bouzas-Mosquera, J. Peteiro); Department of Internal Medi-

cine, Londrina State University, Londrina, PR, Brazil (A. J. F.

Carrilho, C. M. Grion); Department of Physiology, College of

Medicine, National Taiwan University, Taipei, Taiwan (K.-C.

Chang); Cardiac Electrophysiology Research and Training Cen-

ter, Chiang Mai University, Chiang Mai, Thailand (N. Chattip-

akorn, S. C. Chattipakorn); Graduate Institute of Clinical

Medicine, College of Medicine, Taipei Medical University, Tai-

pei, Taiwan (Y.-J. Chen, T.-I. Lee); Division of Cardiovascular

Medicine, Department of Internal Medicine, Wan Fang Hospi-

tal, Taipei Medical University, Taipei, Taiwan (Y.-J. Chen);

Department of Surgery, Cheng-Ching General Hospital, Tai-

wan (Y.-C. Chung); National Institute of Immunohematology

(I.C.M.R.), K.E.M Hospital Campus, Parel, Mumbai, India

(R. Colah, S. B. Nair); Department of Internal Medicine, General

Hospital Oberndorf, Oberndorf, Austria (C. Datz); Mech-Sense,

Department of Radiology, Aalborg Hospital, Aarhus University

Hospital, Aalborg, Denmark (J. B. Frøkjær); Department of Gas-

troenterology, Graduate School of Medicine, Nippon Medical

School, Tokyo, Japan (S. Fujimori, C. Sakamoto); 2nd Division

of Interventional Cardiology, Onassis Cardiac Surgery Center,

Athens, Greece (P. Georgiadou); Department of Medical Labo-

ratory Science and Biotechnology, Yuanpei University, Taiwan,

(C.-P. Hsu); Department of Cardiology, Chang Gung Memorial

Hospital, Keelung, Chang Gung University College of Medi-

cine, Taiwan (M.-J. Hung); Department of Internal Medicine,

School of Medicine, College of Medicine, Taipei Medical Uni-

versity, Taipei, Taiwan (M.-Y. Hung); Division of Cardiology,

Department of Internal Medicine, Shuang Ho Hospital, Taipei

Medical University, New Taipei City, Taiwan (M.-Y. Hung);

2nd University Department of Cardiology, Medical School,

Attikon University General Hospital, Athens, Greece (E. K. Ilio-

dromitis); Division of Endocrinology and Metabolism, Depart-

ment of Internal Medicine, Wan Fang Hospital, Taipei Medical

University, Taipei, Taiwan (T.-I. Lee); Clinical Institute of Medi-

cal and Chemical Laboratory Diagnostics, Medical University

of Graz, Graz, Austria (W. Marz, T. Stojakovic); Institute of

Public Health, Social and Preventive Medicine, Mannheim

Medical Faculty, University of Heidelberg, Mannheim,

Germany (W. Marz); Synlab Academy, Synlab Services GmbH,

Mannheim, Germany (W. Marz); Division of Laboratory Medi-

cine, Department of Pathology and Microbiology, Nihon Uni-

versity School of Medicine, Tokyo, Japan, (A. Satomura);

Institut de recherche experimentale et clinique (IREC), Univer-

site Catholique de Louvain, Brussels, Belgium (P. Starkel);

St. Luc University Hospital, Brussels, Belgium (P. Starkel);

Departments of Internal Medicine and Molecular Pharmacol-

ogy and Physiology, James A. Haley Veterans Hospital, Tampa,

FL, USA (D. L. Vesely); University of South Florida Health Sci-

ences Cardiac Hormone Center, Tampa, Florida, USA (D. L.

Vesely); The Prince Charles Hospital, University of Queens-

land, Brisbane, Qld, Australia (D. L. Walters); Institute of Gas-

troenterology, Marmara University, Istanbul, Turkey (Y.

Yilmaz); Department of Gastroenterology, School of Medicine,

Marmara University, Istanbul, Turkey (Y. Yilmaz).

Correspondence to: Department of Hygiene and Epidemiol-

ogy, University of Ioannina Medical School, Ioannina 45110,

Greece. e-mail: [email protected]

Received: 20 August 2012; Accepted: 20 August 2012


RESEARCH UPDATE

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102 Aigner E, Strasser M, Haufe H, Sonnweber T, Hohla F, StadlmayrA et al. A role for low hepatic copper concentrations in nonalco-holic Fatty liver disease. Am J Gastroenterol 2010;105:1978–85.

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Appendix 1

Statements made in the Conclusions of the Abstract of original articles published by the European Journal of Clinical Investigation

in 2010 and current status for each statement as judged by the authors of each original study

References

Statements

made in 2010

Current status for the statement

Reinforced

n = 24

Modified

n = 3

Weakened

n = 0

No new evidence

n = 12 Other n = 2

[1] Addition of ezetimibe to fluvastatin resul-

ted in a further reduction of buoyant and

intermediate, but not of dense LDL com-

pared with fluvastatin alone

X

[6] This study emphasises the need to

undertake systematic investigations

while screening for the b-haemoglobin-

opathies to identify rare a-chain variants

in a population

X

[12] Four cardiac hormones specifically

inhibit epidermal growth factor’s activa-

tion of Ras. This investigation would sug-

gest that these cardiac hormones’

anticancer effects involve the

inhibition of mitogens such as

epidermal growth factor’s ability to

activate Ras as well as inhibiting

unstimulated basal activity

of Ras

X


RESEARCH UPDATE

Appendix 1 Continued

References

Statements

made in 2010


Reinforced

n = 24

Modified

n = 3

Weakened

n = 0

No new evidence

n = 12 Other n = 2

[17] Three of four cardiac hormones

synthesised by the atrial natriuretic

peptide gene can eliminate human

squamous cell lung carcinomas in

athymic mice when treated

subcutaneously for 4 weeks. The 4th

cardiac hormone that is long-acting

natriuretic peptide, decreased the

volume of one squamous cell lung carci-

noma to 2% of that of untreated animals,

suggesting that it, too, has beneficial

effects on squamous cell lung cancers

X

[19] The impact of short-term NSAID

medication on the small intestine

differed according to intestinal site,

with most

denuded areas identified in the proximal

part and all ulcers in the distal part

X

[22] Thrombectomy in STEMI may decrease

the long-term risk for death or cardiac

rehospitalisation

X

[27] Osteopontin may provide significant

prognostic information independent of

other traditional prognostic markers in

patients with stable ischemic heart

disease

X*

[33] HDL cholesterol may have a protective

effect against sepsis. Each 1 mg dL-1

increase in HDL decreased the odds of

severe sepsis by 3% during

hospitalisation

X

HDL cholesterol may have a protective

effect against sepsis. Each 1 mg dL-1

increase in HDL decreased the odds of

severe sepsis by 3% during

hospitalisation

X

[36] The combination of high dose tirofiban

with enoxaparin resulted in an attenu

ated inflammatory response when com

pared with that of the combination of

high dose tirofiban with unfractionated

heparin

X**




References

Statements

made in 2010


Reinforced

n = 24

Modified

n = 3

Weakened

n = 0

No new evidence

n = 12 Other n = 2

[42] FGF21 levels are increased in patients

with nonalcoholic fatty liver disease and

chiefly mirror the extent of hepatic

steatosis

X

[46] Echocardiographic evaluation of the AV-

interval in patients with cardiac resyn

chronisation therapy was independently

associated with improved clinical

outcome, impacting on daily clinical

practice of heart failure patient care

X

[51] Exercise echocardiography is feasible in

elderly patients with suspected or

known coronary artery disease

X

Exercise echocardiography in elderly

patients with suspected or known

coronary artery disease provides useful

information for risk stratification in

these patients

X

[55] Good CPAP compliance results in a

significant C-reactive protein reduction

X

To achieve the best positive impact on

cardiovascular morbidity and mortality,

a time period of at least 6 months of

CPAP use is required

X

[60] Acetyl-L-carnitine attenuates aortic

stiffening and cardiac hypertrophy,

possibly through its decrease of lipid

oxidation-derived MDA ⁄TBARS in the

rats with insulin deficiency

X

Oxfenicine does not attenuate aortic

stiffening and cardiac hypertrophy

X

[62] We found significant reductions in the

ratios of serum functional MBL levels to

oligomer mannose-binding lectin levels

in hemodialysis patients compared with

healthy subjects

X

We found significant reductions in the

ratios of serum functional MBL levels to

oligomer mannose-binding lectin levels

in pre-hemodialysis patients compared

with healthy subjects

X


RESEARCH UPDATE


References

Statements

made in 2010


Reinforced

n = 24

Modified

n = 3

Weakened

n = 0

No new evidence

n = 12 Other n = 2

[65] Acute hyperglycaemia itself does not

contribute to the sensations in patients

with longstanding diabetes and

autonomic neuropathy

X

Any potential sensory effects of acute

hyperglycaemia can likely be blurred by

the neuropathic-like changes in the

sensory nervous system

X

[68] Peroxisome proliferator-activated

receptor isoforms are differentially

expressed in the atria and ventricles

X

Diabetes can modulate peroxisome

proliferator-activated receptors through

increased inflammatory cytokines and

oxidative stress, which are attenuated

by ascorbate treatment

X

[72] Four cardiac hormones have strong

anti-proliferative effects on human

pancreatic adenocarcinoma cells while

sparing human kidney, lung, prostate

and endothelial cells from a similar

strong anti-proliferative effect

X

This anti-proliferative effect on pancreatic

cancer cells helps to explain why human

pancreatic cancers in vivo treated with

the cardiac hormones decrease in less

than 10% of the volume of untreated

pancreatic cancers as they proliferate

less

X

[77] Longan seed polyphenols induces S

phase arrest of the cell cycle and

apoptotic death in three colorectal

carcinoma cell lines

X§ X¶

The results indicate that Longan seed

polyphenols is a potential novel

chemoprevention and treatment

agent for colorectal cancer

X§§

[79] Persistent NFjB activation together

with high pro-inflammatory cytokine

expression and upregulation of TLR3

and TLR7 is associated with end-stage

alcohol-induced liver damage in

humans

X




References

Statements

made in 2010


Reinforced

n = 24

Modified

n = 3

Weakened

n = 0

No new evidence

n = 12 Other n = 2

Persistent NFjB activation together with

high pro-inflammatory cytokine

expression and upregulation of TLR3

and TLR7 could contribute to disease

progression even in absence of

alcohol intake

X

[83] The relationship between high-sensitivity

C-reactive protein and coronary

vasospasm differed between men and

women

X

Our findings that there is a nonthreshold

model in men and a threshold model in

women provide evidence that more

smokers in men (life-style) and age

(induction time) contribute to the

natural history of coronary vasospasm

development

X

The negative effect of hypertension on

coronary vasospasm suggests that the

pathogenesis of coronary vasospasm

differs from that of coronary

atherosclerosis

X

[88] Our findings indicate active MMP-2

upregulation in the abdominal skin of

patients with direct inguinal hernia

X

This metalloproteinase plays a role in

matrix degradation, weakening the

abdominal wall

X

Skin disorders and previously described

transversalis fascia defects in these

patients could point to a systemic

collagen metabolism abnormality as

a risk factor for direct hernia

X

[94] Plasma urocortin level is elevated in

acute myocardial infarction patients for

5 days from onset

X

High plasma urocortin within 24 h after

the onset is associated with increased

mortality

X

Combined urocortin and NT-proBNP

enhance prognostic performance in

acute myocardial infarction patients

X


RESEARCH UPDATE


References

Statements

made in 2010


Reinforced

n = 24

Modified

n = 3

Weakened

n = 0

No new evidence

n = 12 Other n = 2

[98] These results provide evidence for link

age among body iron stores,

transaminase activity and the

prevalence of cardiometabolic risk

factors in apparently healthy, nonobese

adolescents even within the range of

normal laboratory and

anthropomorphic values and suggest

that iron stores should be investigated

as a potentially modifiable risk factor in

healthy teenagers

X

* The independent prognostic value of OPN for occurrence of atherothrombotic events may be extended to the entire vasculature.

** The evidence that has accumulated has supported the benefit of enoxaparin over unfractionated heparin with large clinical trials

showing a lower risk of cardiovascular outcomes compared with UFH in patients with STEMI undergoing primary PCI, without dif-

ferences in bleeding and procedural success. The link between improved anticoagulation and reduced measures of inflammatory

mediators has also been confirmed by other studies. Encouraging results have been reported with regard to the safety and efficacy

of high bolus dose tirofiban relative to proven agents such as abciximab. The current evidence based guidelines continue to recom-

mend a role for tirofiban with new generation antiplatelet agents for high-risk PCI (elevated troponin, visible thrombus) if the risk

of bleeding is low. Tirofiban and aspirin should be considered prior to angiography in high-risk patients not preloaded with P2Y12

inhibitors.

§The similar effects selectively occur in other types of cancer cells such as cervix, breast and liver cancer.

§§LSP is a potential novel chemoprevention and treatment agent for colorectal, cervix, breast, liver and lung cancer.

¶LSP systemically suppresses oncogenic cyclin D1, A, and Bcl-2 levels in colorectal, cervix, breast, liver and lung cancer cells.

