2014_rrc3

ISSN: 1583-2996

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TECHNICAL INFORMATIONResponsibility for the contents of the published articles falls entirely on the authors. Opinions, ideas, results of studies published in the Ro-manian Journal of Cardiology are those of the authors and do not refl ect the position and politics of the Romanian Society of Cardiology. No part of this publication can be reproduced, registered, transmitted under any form or means (electronic, mechanic, photocopied, recorded) without the previous written permission of the editor.All rights reserved to the Romanian Society of CardiologyContact: Societatea Romn de Cardiologie Str. Avrig nr. 63, Sector 2, Bucureti Tel./Fax: +40.21.250 01 00, +40.21.250 50 86, +40.21.250 50 87; E-mail: offi [email protected]

Hs-cTnT plasma levels and depression of ST segment at exercise stresstest in patients with anthracycline-induced cardiomyopathy 157A. Bisoc, M. Rdoi

Th e evolution of electrocardiographic changes in ST segment elevationmyocardial infarction during the optimal therapeutic decision interval 163M. R. Mirescu, C. Nicolae, G. Gheorghe, A. Ciobanu, A. Hodorogea, S. Almarichi, S. Onceanu, C. Ginghin, I. intoiu,I. T. Nanea

Statins - from bench to bedside 170G. S. Gheorghe, A. S. Hodorogea, I. T. Nanea

Diagnostic and therapeutic challenges in a case of cardio-oncology 178M. Simion, R. Radu, A. Popar, M. Mihil, L. Zarma, E. Apetrei

Which of the pacing leads has a vegetation? 183M. M. Gurzun, M. Serban, I. Bostan, C. Ginghin, B. A. Popescu

Stent implantation on nonculprit lesion for patient with STEMI 185M. Postu, I. Calin, A. Postu-Plugaru, A. Bucsa, L. Zarma, M. Croitoru, P. Platon, D. Deleanu

Updates in Cardiology 187

2013 ESC Guidelines on cardiac pacing and cardiac resynchronizationtherapy 191

National and international cardiology agenda 2014 248

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Nivelul plasmatic al hs-cTnT i subdenivelarea segmentului ST la testulde efort la pacienii cu cardiomiopatie indus de antracicline 157A. Bisoc, M. Rdoi

Evoluia modifi crilor electrocardiografi ce din infarctul miocardicacut cu supradenivelare de segment ST n intervalul optim de decizie terapeutic 163M. R. Mirescu, C. Nicolae, G. Gheorghe, A. Ciobanu, A. Hodorogea, S. Almarichi, S. Onceanu, C. Ginghin, I. intoiu,I. T. Nanea

Statinele - de la farmacologie la clinic 170G. S. Gheorghe, A. S. Hodorogea, I. T. Nanea

Provocri diagnostice i terapeutice ntr-un caz de cardio-oncologie 178M. Simion, R. Radu, A. Popar, M. Mihil, L. Zarma, E. Apetrei

Ce sond de stimulare are grefat o vegetaie? 183M. M. Gurzun, M. Serban, I. Bostan, C. Ginghin, B. A. Popescu

Implantare de stent pe arter non-responsabil de infarct la pacient cu STEMI 185M. Postu, I. Calin, A. Postu-Plugaru, A. Bucsa, L. Zarma, M. Croitoru, P. Platon, D. Deleanu

Actualiti n cardiologie 187

Ghidul Societii Europene de Cardiologie pentru cardiostimulare iterapie de resincronizare cardiac (2013) 191

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Romanian Journal of Cardiology | Vol. 24, No. 3, 2014

ORIGINAL ARTICLES

Hs-cTnT plasma level and depression of ST segment at exercise stress test in patients with anthracycline-induced cardiomyopathyAlina Bisoc1, Mariana Radoi2

INTRODUCTIONAnthracycline-induced cardiomyopathy (AIC) is a con sequence of myocyte damage caused by direct car-dio toxicity and myocyte apoptosis. Studies in animal models have shown the relationship between the my-cocyte injuries induced by doxorubicin and increased cardiac troponin levels (cTn) proportionally to the administered dose1, and clinical studies have shown that elevated levels of cTnT indicate cardiotoxicity2. In some studies in which dosing of troponin was done by

immunoassay, the cTn level did not correlate with car-diac dysfunction assessed by decreased LVEF3,4, which was explained by the diff erent cut-off values of im-mu noassay techniques and inaccuracy of echocardio-graphic estimation of the left ventricular ejection frac-tion (LVEF). Most clinical trials used the cTnI determi-nation to assess patients with neoplastic disease treated with anthracyclines and reported that cTnI determined by immunoassay is a biomarker of anthracycline cyto-toxicity, elevated cTnI levels were predictive for the

Abstract: Scop Evaluarea n cardiomiopatia indus de antracicline (CIA) a nivelelor troponinei T determinat prin tehnici de nalt sensibilitate (hs-cTnT) corelate cu modifi crile ECG de efort, nainte ca scderea FEVS s fi e diagnostic pentru CIA. Metod 68 de pacieni cu cancer tratai cu antracicline au fost supravegheai 6 luni pentru apariia CIA, diagnosticat prin scderea FEVS 0,009 ng/ml asociat cu o cretere>30% fa de momentul iniial este predic-tor pentru apariia CIA la 6 luni (p=0,001) cu sensibilitate de 53,3%, specifi citate de 100%, valoare predictiv pozitiv de 100% i valoare predictiv negativ de 88,3%. Concluzii La pacienii cu cancer tratai cu antracicline, nivelul hs-TnT la 3 luni este predictiv pentru apariia CIA la 6 luni i s-a asociat cu reducerea toleranei i apariia subdenivelrii segmentului ST la efort. Cuvinte cheie: cardiomiopatie precoce indus de antracicline, hs-cTnT, ECG de efort, capacitate maxim de efort, subdenive-lare de segment ST la efort.

Abstract: Purpose Th e evaluation of high-sensitive cardiac troponin T (hs-cTnT) levels and ECG exercise test changes in anthracyclines induced cardiomyopathy (AIC) occurring before the reduction at the diagnostic value of the left ventricle ejec-tion fraction (LVEF). Method 68 patients with cancer treated with anthracyclines were followed 6 months for the occurrence of AIC, diagnosed when LVEF decrease < 50% or by 10% units compared to baseline. Th e plasma levels of hs-cTnT and ECG exercise test were carried out at baseline, 3 and 6 months. Results At 6 months 15 patients (22.05%) were diagnosed with AIC (group1) and 53 (77.95%) evolved without AIC (group 2). Aft er 3 months, exercise test fi ndings in group 1 vs. group 2 showed the reduction of maximal work capacity (p=0.0489) and signifi cant increasing in the incidence of depression of ST segment 1mm (p=0.0014). At 3 months, hs-cTnT levels >0,009 ng/ml associated with percentage increased >30% is a predictor for AIC with 53.3% sensitivity, 100% specifi city, 100% positive predictive value and 83.3% negative predictive value. Conclusions In patients with cancer treated with antracyclines >hs-cTnT levels at 3 month were predictive for the occurrence of AIC at 6 months and associated with decreasing of exercise tolerance and increasing of incidence of ST segment depression.Keywords: early anthracycline-induced cardiomyopathy, hs-cTnT, ECG exercise test, maximal work capacity, depression of ST segment at exercise ECG test.

Contact address:Alina Bisoc. Faculty of Medicine, Transilvania University; Emergency Clinical Hospital, Cardiology Department, Brasov, RomaniaE-mail: [email protected].

1 Assistant Professor, cardiologist, Faculty of Medicine, Transilvania University; Emergency Clinical Hospital, Cardiology Department, Brasov, Romania2 Professor of cardiology, Faculty of Medicine, Transilvania University;Emergency Clinical Hospital, Cardiology Department, Brasov, Romania

Alina Bisoc et al.Hs-cTnT in anthracycline-induced cardiomyopathy

Romanian Journal of CardiologyVol. 24, No. 3, 2014

occurrence of early AIC5,6. In recent years, clinical tri-als wherein cTnI was determined by ultrasensitive te-chniques reconfi rms the increase of the cTnI level as bi-omarker of cardiotoxicity6,7 correlated with the degree of cardiac dysfunction6. Th e cTnI dynamics under the-rapy proved to be an indicator of cardiac dysfunction recovery8. Increase of cTnI in patients with cancer and treatment with anthracyclines has been shown to be predictive for the occurrence of early-onset AIC9, the development with clinical cardiovascular events9 and a useful indicator of initiating cardiac dysfunction thera-py with converting enzyme (ACE) inhibitors and beta blockers8. Concomitant use of biomarkers and imaging techniques has increased the predictive sensitivity of such investigations in the AIC diagnosis.

GOALEvaluation in patients with anthracycline-induced car-diomyopathy of the plasma troponin T levels determi-ned by high sensitivity techniques (hs-TnT) correlated with changes of exercise ECG testing before LVEF de-crease to be diagnostic for AIC.

METHODProspective study which enrolled a consecutive series of patients with various malignancies and indication for treatment with doxorubicin sent from oncology and hematology centers for cardiologic evaluation be-fore and during treatment with anthracyclines.

Th e patients were cardiologically monitored for the occurrence of early onset AIC. Th e AIC diagnostic was established by echocardiography in accordance with the recommendations of the ACC/AHA/ASE 2003 gui de when LVEF decreased below the value of 50% or by 10% under the initial value10,11 in the absence of another cause of cardiac dysfunction than treatment with anthracyclines.

We studied the correlation of hs-cTnT levels with the changes in exercise ECG testing in patients diagnosed with AIC versus those that have evolved without AIC during the 6 month follow-up period.

Eligible patients were aged over 18 years and had a left ventricular ejection fraction (LVEF) above 50%.

Th e study protocol was approved by the local Ethics Committee and each patient signed an informed con-sent on enrollment.

Patients were evaluated by clinical examination, transthoracic 2D echocardiography (2D-ETT), hs-cTnT plasma levels, resting ECG and exercise ECG test at the initial moment, 3 and 6 months aft er starting the

treatment with anthracyclines. Resting ECG was per-formed on a NIHON KOHDEN Cardiofax GEM car-diograph, transthoracic 2D echocardiography on an ALOKA Prosound SSD-4000SV echograph. LVEF was calculated by the modifi ed biplane Simpson method. Th e hs-TnT determinations were made on the Cobas e411 device by Roche electrochemiluminescence. Exer-cise ECG testing was done on the treadmill, Schiller device, using the Bruce protocol and was limited by symptoms. We noted the maximal exercise capacity (METs), heart rate at maximum tolerated stress and depression of ST segment 1 mm in two contingent derivatives defi ning for the positive exercise ECG test.

STUDY GROUPTh ere were included in the study 68 patients with can-cer and anthracycline treatment indication, 27 men (39.7%) and 41 women (60.3%) with mean age 56.6 years (range 23-73 years of age). 38 patients (55.9%) had breast cancer, 21 patients (30.9%) lung cancer and 9 patients (13.2%) malignant lymphomas. Th e patients received a cumulative doxorubicin dose ranging betwe-en 220-280 mg/m2 up to 3 months and 420-500 mg/m2 up to 6 months. Treatment also included the therapy of cardiovascular risk factors up to target levels re-commended for each patient aft er cardiovascular risk assessment using the SCORE charts for countries with high cardiovascular risk12.

Th e study was conducted during 2012-2014 in the Department of Cardiology of the County Emergency Hospital in Brasov.

STATISTICAL ANALYSISTh e database was prepared using the Microsoft Excel program. Statistical analysis was performed using the GraphPad InStat 3 and SPSS 20.0 programs. Data were summarized using the median value and percentiles 25 and 75 due to non-Gaussian distribution. Nominal variables were expressed as a percentage (%). In order to compare nominal variables we used Fishers exact test or X2. Th e nonparametric Mann-Whitney test was applied for quantitative variables. Dynamic assessment of changes derived from exercise testing parameters and hs-cTnT plasma levels at baseline, 3 and 6 months in patients with AIC was performed by using the nonpa-rametric Friedman test. Spearman correlation test was used for quantitative variables and Chi-squared test for nominal variables. p



fi cantly higher incidence of depression of ST segment 1mm [11 pts (73.3%) vs. 7 pts (13.2%), p=0.0001], asso-ciating a decreased maximal exercise capacity [7(6.4;8) METs vs. 9.2(6.7;12.4) METs, p=0.0489] and heart rate at maximum stress tolerated [120(110;131) beats/minute vs. 145(124;150.5) beats/minute (p=0.0051)] (Table 3). Compared to the initial assessment, at the exercise test aft er 3 months they showed ECG crite-ria for positive test in another 6 patients, 5 (33.3%) of group 1 and 1 patient (1.9%) of group 2, with signi-fi cant diff erence between the two groups (p=0.0014). Patients with depression of ST segment during exercise occurred aft er 3 months of treatment with anthracycli-nes were considered with cytotoxic myocardial injury caused by the treatment with anthracyclines.

Aft er 3 months of treatment, in patients in group 1 versus group 2 there was a signifi cant increase of the median value of hs-cTnT (0.00998 ng/ml vs. 0.00498 ng/ml, p=0.0003). Th e percentage of increase compa-red to the initial value of hs-cTnT was 38.5% in group 1 versus 0.6% in group 2 (p=0.0001) (Table 3).

Aft er 6 months of initiation of treatment with an-thracyclines, the resting electrocardiogram showed no notable changes in the ST segment and T wave compa-red with the changes at 3 months. In the exercise test, depression of ST segment 1mm was signifi cantly more frequent in patients in group 1 versus those in group 2 [12 pts (80%) vs. 7 pts (13.2%), p=0.0001)] and associ-ated with an important and statistically signifi cant de-crease in maximum exercise capacity [6(4.6;6.8) METs vs. 8.8(6.2;12.1) METs, (p=0.0009)] and the heart rate at maximum stress tolerated [110(90;123) beats/minu-te vs. 130(126;148.5) beats/minute, p=0.0001]. Compa-red with the assessment at 3 months, the exercise test at 6 months had ECG criteria for positive test in 1 more patient (8.5%) in group 1 and no patient in group 2.

Th ere was a signifi cant decrease of the median va-

RESULTSAft er 6 months of treatment with anthracyclines, 15 pa-tients of the 68 patients included in the study were dia-gnosed with asymptomatic AIC (22.05%) (group 1), 53 patients (77.95%) evolving without decrease of LVEF diagnostic for AIC (group 2). Th ere were no signifi cant diff erences in the cumulative dose of anthracyclines between the two groups. Incidence of cardiovascular risk factors (hypertension, diabetes, smoking, dyslipi-demia) and cardiac medication (inhibitors of angioten-sin converting enzyme/ARBs, beta-blockers, statins, aspirin) showed no statistically signifi cant diff erences between the two groups (Table 1).

Patients in group 1 were older than those in group 2.Th ere were no signifi cant changes in the ST segment

on the resting electrocardiogram at baseline and under evolution, arrhythmias or impaired driving.

At the moment of enrollment in the trial, plasma hs-cTnT levels were not signifi cantly diff erent between the two groups (Table 2).

Assessment on enrollment by exercise ECG test showed a signifi cantly higher incidence of positive exercise ECG tests in patients in group 1 versus those in group 2 (p=0.0186), with no diff erences in the ma-ximal exercise capacity and heart rate obtained at ma-ximum stress tolerated (Table 2). Patients with positive exercise ECG test on enrollment were considered with exercise-induced myocardial ischemia.

Aft er 3 months of treatment with anthracyclines, nonspecifi c ST-T changes occurred in the resting elec-trocardiogram in all patients. In the exercise ECG tes-ting, the patients in group 1 versus group 2 had a sig ni-

Table 1. Demographic data, cardiovascular risk factors and cardiac treatment

Parameter Group 1 (n=15)Group 2 (n=53) p

Number of patients 15 (22.05%) 53 (77.95%)Men 5 (33.3%) 22 (42%) 0.7762Women 10 (66.7%) 31 (58%)Age (years) (mean DS) 62.57.2 54.910.4 0.0090Smokers 5 (33.3%) 21 (39.6%) 0.7686Arterial hypertension under treatment

12 (80%) 30 (56.6%) 0.1362

Diabetes 6 (40%) 12 (22.6%) 0.1983Atherogenic dyslipidemia 9 (60%) 33 (62.3%) 1.0000Obesity 6 (40%) 14 (26.4%) 0.2388Cardiac treatmentACE inhibitors/Satrani 12 (80%) 34 (64.2%) 0.3528Beta-blockers 9 (60%) 21 (39.6%) 0.5544Statins 9 (60%) 33 (62.3%) 1.0000Aspirin 12 (80%) 39 (73.6%) 0.7754ACE inhibitors = angiotensin converting enzyme inhibitors

Table 2. Parameters obtained from exercise testing and the hs-cTnT value at the time of enrollment

Parameter Group 1 (n=15) Group 2 (n=53) pHeart rate at rest (beats/min)

74(70;75)

77(65;92)

0.2027

Heart rate at maxi-mum stress tolerated (beats/min)

135(125;143)

150(123,5;158)

0.1016

Maximal exercise capacity (METs)

7.8(7;9.2)

9.6(6.9;12.9)

0.2421

Positive exercise ECG test (no. of patients)

6 (40%) 6 (11%) 0.0186

Hs-cTnT (ng/ml) 0.00713(0.00430;0.00787)

0.00435(0.00381;0.00748)

0.0848

Data are expressed as median and percentiles 25 and 75



6 months (p=0.0495). Th e plasma hs-cTnT levels incre-ased progressively under treatment with anthracycli-nes, signifi cantly from the initial moment at 3 months (p=0.0001) and from 3 to 6 months (p=0.0041).

Analysis of ROC curves in monitored patients of hs-cTnT values at baseline and at 3 months, and the per-centage increase of hs-cTnT in the fi rst 3 months shows that the hs-cTnT level at 3 months (AUC=0.806, 95% CI 0.665-0.946, p=0.0001) and the percentage increase of hs-cTnT in the fi rst 3 months (AUC=0.849, 95% CI 0.714-0.984, p=0.0001) are predictors for the develop-ment of AIC at 6 months (Figure 1, Table 6).

lues of hs-cTnT found in the patients of group 1 versus group 2 (0.01006 ng/ml vs. 0.00643 ng/ml, p=0.0001) (Table 4).

In patients diagnosed with AIC at 6 months, the dynamic assessment of changes in exercise testing and plasma hs-cTnT levels during the three evaluations is shown in Table 5. Th e data revealed that patients who developed AIC at 6 months showed a signifi cant and progressive decrease in maximal exercise capacity from the initial moment to 3 months (p=0.0001) and from 3 to 6 months (p=0.0001) associated with progressive de-crease in heart rate at maximum stress tolerated from the initial moment to 3 months (p=0.0001) and from 3 to 6 months (p=0.0001). In these patients the incidence of depression of ST segment 1mm on exercise ECG increased progressively during the follow-up period from 40% at the initial moment to 73.3% at 3 months (p=0.1394) and to 80% at 6 months with statistical sig-nifi cance between the initial moment and assessment at

Table 3. Parameters obtained from exercise testing and hs-cTnT value at 3 months

Parameter Group 1 (n=15) Group 2 (n=53) pHeart rate at rest (beats/min) 73

(68;78)77

(68;80.5)0.4130

Heart rate at maximum stress tolerated (beats/min) 120(110;131)

145(124;150.5)

0.0051

Maximal exercise capacity (METs) 7(6.4;8)

9.2(6.7;12.4)

0.0489

Positive exercise ECG test (no. of patients) 11 (73.3%) 7 (13.2%) 0.0001Exercise ECG test turned to positive at 3 months compared with the initial assessment (no. of patients)

5 (33.3%) 1 (1.9%) 0.0014

Hs-cTnT (ng/ml) 0.00998(0.00737;0.01354)

0.00498(0.00387;0.00830)

0.0003

Plasma levels of hs-cTnT0.009 ng/ml (no. of patients) 10 (66.7%) 9 (17%) 0.0005Percentage of increase of hs-cTnT value at 3 months compared to the value at the time of enrollment

38.5%(27.9%;80.8%)

0.6%(-8.1%;14.5%)

0.0001

Percentage increase 30% of hs-cTnT at 3 months compared to the initial value (no. of patients)

11 (73.3%) 5 (9.4%) 0.0001


Table 4. Parameters obtained from exercise testing and the hs-cTnT value at 6 months

Parameter Group 1 (n=15) Group 2 (n=53) pHeart rate at rest (beats/min)

82(74;84)

71(69;86)

0.0670

Heart rate at maxi-mum stress tolerated (beats/min)

110(90;123)

130(126;148.5)

0.0001

Maximal exercise capacity (METs)

6(4.6;6.8)

8.8(6.2;12.1)

0.0009

Positive exercise ECG test (no. of patients)

12 (80%) 7 (13.2%) 0.0001

Hs-cTnT (ng/ml) 0.01006(0.01006;0.01620)

0.00643(0.00442;0.00920)

0.0001


Figure 1. ROC curves: the hs-cTnT value on enrollment, at 3 months, and the percentage increase of hs-cTnT in the fi rst 3 months to predict the evolution of AIC.



elevated plasma cTnT levels were predictive of left ven-tricular dilatation detected by echocardiography14 and decrease of LVEF15, which made the determination of cTnT to be used for assessing the eff ectiveness of car-dioprotection with dexrazoxane in patients at high risk for the occurrence of AIC16.

Using new ultrasensitive techniques for measuring extremely small quantities of cTnI (cTnI-u) brou-ght substantial information on the biomarker value of cTnI-u in assessing anthracycline cardiotoxicity6. Th e negative predictive value of cTnI low levels makes cTnI-u levels important in identifying patients with low risk of AIC occurrence9. Assessment of cTnI levels by highly sensitive techniques (hs-TnI), simultaneously with the imaging study of cardiac dysfunction by mo-dern echocardiography techniques such as spackle tracking and tissue Doppler showed that the increase of the hs-cTnI level and decrease of longitudinal forei-gn 19% at 3 months are predictors of LVEF reduction at 3 months17.

In our study, dynamic assessment of plasma hs-cTnT levels, tolerance and ST segment depression 1mm during exercise combines two accessible and cost-eff ective methods for the diagnosis of cardiotoxicity. Th e reduction at 3 months of the exercise tolerance and heart rate at maximum stress tolerated appear to be predictive for the decrease of LVEF diagnosed for AIC at 6 months. Increase of hs-cTnT levels at 3 months was predictive for AIC at 6 months, the cut-off value abo-

For a cut-off value of hs-cTnT at 3 months above 0.009 ng/ml associated with a percentage increase of over 30% in the fi rst 3 months, we obtained a sensiti-vity of 53.3% and a specifi city of 100% for the evolution to AIC at 6 months, with a positive predictive value of 100% and a negative predictive value of 88.3%.

Using the binomial logistic regression model we analyzed the positivation of exercise test and hs-cTnT level >0.009 ng/ml associated with a percentage incre-ase >30% at 3 months compared to baseline. Th e fi nal regression model showed that the positivation of exer-cise stress test at 3 months did not correlate with the occurrence of AIC at 6 months (p=0.086), whereas the hs-cTnT value >0.009 ng/ml at 3 months associated with an increase of >30% from baseline predicts the development of AIC at 6 months (p=0.001).

Th e binomial logistic regression analysis of the occurrence of ST segment depression ST 1mm on exercise testing at 3 months compared to baseline and exercise test at 6 months compared to baseline showed that ST segment changes during exercise correlate with the diagnosis of AIC (p=0.05).

DISCUSSIONSStudies conducted in animal models of disease showed that in anthracycline-induced cardiotoxicity the histo-pathological changes were correlated with plasma le-vels of cTnT13. Clinical studies that determined cTnT in assessing anthracycline cardiotoxicity revealed that

Table 5. Evolution of parameters obtained from exercise testing and Hs-cTnT value during the 6 follow-up months in patient who evolved with AIC

Parameter Initial assessment (n=15)Assessment at 3 months (n=15) p

Sperman (rho)

Assessment at 6 months (n=15) p Sperman (rho)

HR* rest 74(70;75)

73(68;78)

0.0001 0.8521 82(74;84)

0.0001 0.7964

HR eff ort 135(125;143)

120(110;131)

0.0001 0.7887 110(90;123)

0.0001 0.7776

METs 7.8(7;9.2)

7(6.4;8)

0.0001 0.8518 6(4.6;6.8)

0.0001 0.7402

Positive exercise ECG test

6 (40%) 11 (73.3%) 0.1394 12 (80%) 1.000 0.049

Hs-cTnT (ng/ml) 0.00713(0.00430;0.00787)

0.00998(0.00737;0.01354)

0.0001 0.7093 0.01006(0.01006;0.01620)

0.0041 0.5088

Data are expressed as median and percentiles 25 and 75; HR* = heart rate

Table 6. Area under the curve

Variables tested Area Standard errorSignifi cance

level (p)

95% Confi dence IntervalMinimum

limitMaximum

limitHs-cTnT on enrollment 0.647 0.072 0.084 0.506 0.788Hs-cTnT at 3 months 0.806 0.072



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4. Germanakis I, Anagnostatou N, Kalmanti M. Troponins and natriu-retic peptides in the follow-up of anthracycline cardiotoxicity. Pediatr Blood Cancer 2008; 51:327

5. Morris PG, Chen C, Steingart R, et al. Troponin I and C-reactive protein are commonly detected in patients with breast cancer treated with dose-dense chemotherapy incorporating trastuzumab and lapa-tinib. Clin Cancer Res. 2011;17:34903499.

6. Cardinale D, Sandri MT, Martinoni A, et al. Left ventricular dysfunc-tion predicted by early troponin I release aft er high-dose chemothe-rapy. J Am Coll Cardiol 2000;36:517.

7. Ky B, Putt M, Sawaya H, et al. Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer trea-ted with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol 2014;63:809.

8. Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of tropo-nin I in cardiac risk stratifi cation of cancer patients undergoing high-dose chemotherapy. Circulation 2004;109:2749.

9. Cardinale D, Colombo A, Torrisi R, et al. Trastuzumab-induced car-diotoxicity: clinical and prognostic implications of troponin I evalua-tion. J Clin Oncol 2010;28:3910-6.

10. Cheitlin MD, Armstrong WF, Aurigemma GP, et al. ACC/AHA/ASE 2003 guideline update for the clinical application of echocar-diography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guide-lines for the Clinical Application of Echocardiography). Circulation. 2003;108(9):1146-1162.

11. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: inci-dence, treatment and prevention. Drug Saf. 2000;22(4):263-302.

12. Conroy R, Pyorala K, Fitzgerald AP et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003;24:987-1003.

13. Herman E, Lipshultz S, Rifai N, et al. Use of cardiac troponin T levels as an indicator of doxorubicin-induced cardiotoxicity. Cancer Res. 1998;58:195-197.

14. Lipshultz SE, Lipsitz SR, Sallan SE, et al. Chronic progressive cardi-ac dysfunction years aft er doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 2005;23:2629.

15. Auner HW, Tinchon C, Linkesch W, et al. Prolonged follow-up of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies. Ann Hematol 2003; 82:218.

16. Lipshultz SE, Scully RE, Lipsitz SR, et al. Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 2010;11:950-61.

17. Sawaya H, Sebag IA, Plana JC, et al., Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol, 2011; 107(9):137580.

18. Eschenhagen T, Force T, Ewer MS, et al. Cardiovascular side eff ects of cancer therapies: a position statement from the Heart Failure Associ-ation of the European Society of Cardiology. Eur J Heart Fail. 2011; 13(1):1-10.

19. Giulia Bacchiani, Daniela Cardinale. Using biomarkers and early pro-phylactic treatment to prevent cardiotoxicity in cancer patients on chemotherapy. Biomarkers:detection and treatment of cardiotoxicity. Spring 2012;112(4):250-260.

ve 0.009 ng/ml associated with a percentage increase of over 30% in the fi rst 3 months had a sensitivity of 53.3%, a specifi city of 100%, a positive predictive value of 100% and a negative predictive value of 88.3% for the evolution of AIC at 6 months. In this context the occur-rence at 3 months of the ST segment depression 1mm at maximum stress tolerated associate with a signifi cant and progressive increase at 3 months of the hs-cTnT le-vel was interpreted as secondary for the myocyte cyto-toxic lesions induced by treatment with anthracyclines.

Th e importance of measuring biomarkers in the diagnosis of cardiomyopathy caused by chemothera-py is emphasized in Th e position statement from the Heart Failure Association of ESC published in 2011, where the use of biomarkers is strongly recommended by highlighting the fact that biomarkers cannot sub-stitute the information provided by echocardiography or other imaging techniques in the diagnosis of cardi-omyopathy18. Th e importance of determining cTn in assessing cardiotoxicity is revealed by the follow-up al-gorithm of patients receiving anthracyclines, proposed by Giulia Bacchiani and Daniela Cardinale in 2012 by recommending concomitant assessment of TnI levels and 2D-ETT changes19. Recommendation for using 2D-ETT in clinical practice is due to the fact that echo-cardiographic techniques such as spackle tracking and tissue Doppler are still not readily available, which proved to be more refi ned and sensitive in assessment of geometry and abnormalities of contraction/relaxati-on of the LF (left ventricle), including diagnosis of AIC.

CONCLUSIONSIn cancer patients treated with doxorubicin, hs-TnT le-vels at 3 months and the percentage increase in the fi rst 3 months are predictive for the occurrence at 6 months of anthracycline-induced asymptomatic cardiomyo-pathy.

In patients diagnosed at 6 months with anthracycli-ne-induced asymptomatic cardiomyopathy, the increa-se at 3 months of the hs-TnT levels was associate with reduction of tolerance and occurrence of ST segment depression during exercise, as a possible expression of doxorubicin cardiotoxicity.

Confl ict of interest: none declared.


ORIGINAL ARTICLES

The evolution of electrocardiographic changes in ST segment elevation myocardial infarction during the optimal therapeutic decision intervalMagda Ruxandra Mirescu1, Camelia Nicolae2, Gabriela Gheorghe2, Ana Ciobanu2, Andreea Hodorogea2,Simona Almarichi3, Sorina Onceanu2, Carmen Ginghina4, Ion intoiu5, Ioan Tiberiu Nanea2

Contact address:Mirescu Magda Ruxandra, 13 Vitan-Brzeti Street, Bucharest, Romania. E-mail: [email protected]

1 Carol Davila University of Medicine and Pharmacy, Department of In-ternal Medicine Saint John Hospital Bucharest2 Carol Davila University of Medicine and Pharmacy, Department of Car-diology, Th eodor Burghele Hospital Bucharest3 Department of Cardiology Army Emergency Center of Cardiology Bu-charest4 Carol Davila University of Medicine and Pharmacy, Department of Cardiology, Institute of Emergency for Cardiovascular Diseases Prof.C.C Iliescu, Bucharest5 Carol Davila University of Medicine and Pharmacy, Department of Car-diology Department of Cardiology Army Emergency Center of Cardiology Bucharest

Abstract: Objectives Electrocardiogram (ECG) remains a landmark concerning ST segment elevation myocardial infarc-tion (STEMI) diagnostic and prognostic, off ering data for optimizing treatment strategy. Th e trial quantifi ed ischemic lesions (ST segment) and loss of myocardial mass (R wave) during the optimal therapeutic decision interval. Methods ST segment elevation magnitude and R wave amplitude correlated with pain onsetpresentation interval were measured for 100 STEMI patients with TIMI 0/1 fl ow. Results Th e ST magnitude during the 0-30 minutes interval displayed substantial variability (increasing 46.16%, stationary 30.87%, decreasing 22.96%). Th e R wave amplitude emphasized a mostly decreasing tendency (74.82% of cases) or remained stationary (25.18%). During the optimal therapeutic decision interval, a statistically signifi cant correlation was established between the ST segment elevation magnitude (increasing, stationary or decreasing) and the de-creasing R wave amplitude (r=0.45, p

Magda Ruxandra Mirescu et al.ST segment and R wave in STEMI


INTRODUCTION AND OBJECTIVESCardiovascular conditions represent a major health is-sue having coronary artery disease as the most frequent pathology. Acute myocardial infarction (AMI) con-stitutes the main cause of death with maximum risk during the fi rst hours1. Early diagnosis and identifying high-risk patients remain a real issue in clinical prac-tice. Th erefore, the development of diagnostic abilities led to permanent modifi cations concerning the AMI classifi cation criteria. Electrocardiogram (EKG) still remains a landmark with regard to AMI diagnostic and prognosis, off ering essential data while aiming to outli-ne the optimal treatment strategy2.

Th e purpose of the study was to determine the is-chemic lesions and loss of myocardial tissue in STEMI cases during the optimal therapeutic decision interval through the looking glass of EKG changes evolution.

MATERIALS AND METHODS Th e present trial is based on a retrospective analysis which included patients admitted in the Cardiology Clinical Departments of Caritas, C.C Iliescu Emer-gen cy Institute of Cardiovascular Disease and the Army Emergency Center of Cardiology between 2009 and 2010. Th e fi rst inclusion criterion consisted of chest pain (prolonged pain for over 20 minutes, common-ly having a retrosternal on epigastric location, which does not favorably respond to nitroglycerine adminis-tration) and EKG changes in accordance with the pre-sent guideline3 (ST segment elevation measured at the J point in 2 contiguous leads: 0.25 mV in men aged below 40 and 0.2 in those over 40; 0.15 mV in V2-V3 leads and/or 0.1 mV in other leads for women). Subsequent to angiography, patients with TIMI 0 and 1 fl ow were selected.

Th e exclusion criteria were represented by the pre-sence of Q wave on the initial EKG, a history of myo-cardial infarction, intraventricular conduction distur-bances, left ventricular hypertrophy (LVH), Killip gra-de III-IV heart failure, rescued ventricular tahiarytmia, echocardiographically visible ventricular aneurysm and angiographically established TIMI 2-3 fl ow.

During the course of the study, the selected series was analyzed with regard to demographics, medical history, associated co-morbidities and previous out-patient therapy. Th ere were evaluated the time passed from the onset of chest pain to fi rst medical exam, the EKG upon hospital admittance (moment M0) and 30 minutes later (moment M30). Th e 30 minutes interval is confi rmed by the European Guideline as optimal for considering the revasularization therapeutic alternati-

ve3. Th ere were determined the EKG related AMI lo-cation, the M0 and M30 magnitudes of the ST segment elevation as well as the R wave amplitude at the respec-tive moments. In accordance with the Guideline3, in each EKG lead, the ST segment elevation was assessed at J point and the R wave amplitude at the vertical dis-tance from baseline (defi ned as 2 PR consecutive inter-vals) to peak. Th e measurements were performed by 2 independent investigators.

Th e selected patients were divided into 3 subgroups in accordance with the time passed from the onset of chest pain to presentation as following: 0-3 ho-urs (subgroup I), 3-6 hours (subgroup II), 6-12 hours (subgroup III).

Ecocardiography upon admittance was performed in all cases and determined useful parameters for eva-luating the selection criteria (heart failure stage, the presence of ventricular aneurysm) such as the left ven tricular ejection fraction (LVEF Simpson bipla-ne method) and the segmentary kinetics anomalies. Coro narography was applied at 60-120 minutes from diag nostic in 90% of the patients and aft er 2-5 days in 10% of the cases.

All included patients underwent percutaneous co-ronary intervention with stent placement and sub-sequently successful reperfusion (fi nal TIMI-3 fl ow).

Th e statistical analysis performed using the STATIS-TICA 8.0 and EpiInfo 3.5.1. soft ware. Th e outcomes were displayed as frequencies for the category variables (2 and Fischer tests) and as mean values ( standard deviation) for the numeric variables (Student t-test). Th e level for statistical signifi cance was set at p value



RESULTS Th e study group included 100 patients with a mean age of 60.27 years. Th e most signifi cant cardiovascular risk factors were represented by smoking, hyperten-sion, dislipidemia and diabetes. Th e main associated co-morbidities were angina (present in the majority of cases 85%), cardiac stents and chronic renal failure (Table 1, Figure 1).

In the analyzed series, the location of the myocardial infarction process was anterior in 71% of the cases and inferior in 29%. Th e coronary arteries most commonly responsible for infarction were the left anterior descen-

ding coronary artery (65% of patients) and the right coronary artery (20%) (Figure 2).

In relation with the time period from chest pain on-set to presentation, subgroup III was found to include the largest number of cases (37%) followed by subgroup I (33%) and lastly by subgroup II (30%) (Figure 3).

Th e analysis of the ST segment elevation increase revealed the highest proportion of cases characterized by this process in subgroup I (59.38%), followed by subgroup II (46.67%) and aft erwards by subgroup III (32.43%). Consequently, it may be stated that the rise in ST segment elevation decreases progressively with the time length passed from chest pain onset to hospital admittance (Figures 4, 5).

From another point of view, it was observed that the R wave decreases mostly during the fi rst 6 hours from chest pain onset (80.65% in subgroup I and 86.67% in subgroup II) by comparison to the delayed presenta-tion study arm (6-12 hours 57.14%). Th e rest of the patients were characterized by a stationary R wave amplitude (19.35%, 13.33% and 42.86% respectively) (Figures 6, 7). On the other hand, it was underlined the signifi cant reduction of the R wave amplitude re-gardless of the evolution of the ST segment elevation in all of the 3 series.

Th e EKG data analysis was focused on the increase, stationary evolution or reduction of the magnitude of

Figure 2. Coronary arteries responsible for infarction.Figure 4. ST segment elevation magnitude in accordance with the chest pain onset.

Figure 5. Increasing ST segment elevation magnitude during the 0-30 min-utes interval.Figure 3. Series distribution according to presentation interval.

Figure 1. Previous outpatient medical treatment.



the ST segment elevation while drawing a parallel with the R wave amplitude. Th e assessment of the respective outcomes particularly referred to the V1-V5, DII, DIII and aVF leads measured during the fi rst 30 minutes from admission.

While summarizing the obtained results, it was showed that the R wave amplitude diminishes signifi -cantly and in an independent fashion when compared to variations specifi c for the ST segment elevation.

Taking into consideration the proportion of cases displaying an R wave amplitude reduction (74.82%) versus the stationary or decreasing ST segment eleva-tion category (26.9%), variations regarding the R wave may be considered as a more dynamic parameter when assessing the STEMI related electric evolution from the perspective of pain presentation intervals (Figure 8).

Furthermore, the magnitude of the myocardial infarc-tion process was suggested by the R wave voltage.

Th e most statistically signifi cant connection was able to be distinguished between the size of ST segment ele-vation (increase) and the R wave amplitude (decrease) (Figure 9). From the electro-physiologic point of view, this statistical correlation underlines the relationship between epicardial injury (ST segment) and myocar-dial viability (R wave) with regard to the myocardial necrosis evolution.

During the optimal therapeutic decision interval, the correlation between the ST segment stationary evo-lution and the R wave amplitude decreasing tendency was r=0.29 (p



mained a challenge. Further along this line, EKG modi-fi cations related to myocardial injury as well as viability might be able to provide supplementary useful infor-mation concerning the clinical outcome.

It is widely acknowledged that, in a STEMI case, the ST segment elevation constitutes the most sensitive EKG marker. Some of the published trials showed that the ST segment elevation magnitude on the initial EKG represents a quite important predictive factor for the infarction size, thus proving useful during the process of risk stratifi cation in STEMI patients immediately af-ter hospital admission. Th e positive predictive value of ST elevation size could be further improved through correlations with symptoms, risk factors and clinical features4.

It was underlined that the infarction process dimen-sions are infl uenced by the ischemic risk area, duration of ischemia and the effi ciency of the protective mecha-nisms (such as the antegrade residual blood fl ow and the collateral circulation). Th e impact of the initial ST magnitude over the accurate assessment of the infarc-tion size during the invasive therapy is not yet fully un-derstood and does require further research5.

Th e present trial followed the evolution of ischemic injuries and concomitant myocardial mass losses while focusing on their EKG profi le. It was proven that the ST segment amplitude during coronary occlusion (0 to 30 minutes interval) displays a substantial variability, thus refl ecting the duration of the chest pain episode. Th e largest increase of the ST segment elevation was deter-mined during the 0 to 3 hours interval. Th is feature diminished progressively with prolonging time length from debut to presentation.

More over from this perspective, the literature data emphasized the fact that the ST segment amplitude re-aches a maximum at approximately 1 hour from the chest pain onset. Aft erwards, the respective elevation began to decrease and eventually became constant af-ter an average period of 12 hours. Th is plateau is then followed by a gradual decline over the next few weeks4, 6. According to another published trial, the ST elevati-on returns to isoelectrical line within 2 weeks for 95% of patients with inferior STEMI location and for 40% subsequent to the anterior STEMI4,7.

Th e increase in ST segment elevation is known to re-present proof of myocardial lesion evolution, while the 0 to 3 hours interval is most likely the optimal period for applying revascularization therapy. From another point of view, a decrease in ST magnitude or its stati-onary profi le during the very same 0-3 hours moment

could be related to either the progress or limitation of the myocardial necrosis phenomenon. In light of the present clinical research, the answer to this dilemma may be provided by a concomitant analysis of the ST elevation together with the R wave amplitude.

As far as the R wave is concerned, the available data confi rmed its amplitude as a myocardial injury se-verity marker in direct correlation with the degree of myocardial viability8. Usually, this feature has been assessed by means of pharmacologic stress echocar-diography or myocardial scintigraphy. However, some studies outlined a signifi cant correlation between the imagistically confi rmed myocardial viability and the R wave voltage variation in AMI cases9. Myocardial acti-vation subsequent to the depolarization phenomenon is relatively maintained in lesions limited to the level of the endocardium or epicardium, while the R wave amplitude slightly decreases10. Time dependent ische-mia progression leading towards the development of transmural lesions is associated with myocardial acti-vity reduction and a signifi cant decrease in the R wave amplitude9,11.

Th ere were reported data regarding the diagnostic and prognostic value of EKG modifi cations in cases of developed infarction. A recent study on non-human primates analyzed the several EKG features including the ST elevation as well as the R wave in diff erent stages of ischemia12. Th e ligation of the left anterior descen-ding artery was performed at diff erent levels, thus re-sulting in various sizes of the ischemic/infracted tissue area. It was noticed that R wave amplitude changes cor-related with the dimension of the myocardial infarcti-on both during the early as well as the late stage of the coronary occlusion experiment12.

Consequently, it became possible to establish the magnitude of the viable tissue by comparison to the irreversibly compromised myocardium by measuring the R wave changes. Th e authors concluded that these precocious predictive factors may help in making pre-ventive or precautious decisions aimed towards mini-mizing the risk of developing a severe AMI12.

Although the reversibility of the R wave voltage according to the precordial leads in AMI patients du-ring the post-revascularization period gathered a sig-nifi cant amount of interest, the electro-physiological mechanisms behind the R wave voltage variation were not yet fully understood. On the other hand, there were discovered substantial correlations between rises in R voltage and the amelioration of left ventricular functi-on or improvements concerning the scintigraphic pa-



rameters. Aft er revascularization, in cases of anterior AMI, the reversibility of the R wave was able to refl ect the presence of myocardial viability9.

Th e available data evaluating the post-angioplasty R wave amplitude in STEMI patients confi rmed it as a reliable predictive marker with regard to the short term prognostic for major adverse clinical events, thus outlining a remarkable clinical impact. From this per-spective, an R wave amplitude decrease according to precordial leads was associated with low LVEF and hi-gher heart failure degree. Th is aspect may be seen as demonstrating the possible use of R wave amplitude during risk stratifi cation for this particular category of patients8.

In light of the present fi ndings, the R wave evolution within the optimal treatment choice period displayed a predominantly decreasing tendency regardless of the pain onset hospital presentation time length. On the other hand, the previously proven R wave amplitude reduction suggested progression in the myocardial ne-crosis process8. Th erefore, the issue of an eventual cor-relation between the R wave reduction and the ST ele-vation increase became obvious and possibly sugges-ting a necrosis evolution.

Based on these premises, a thorough analysis of R wave modifi cations might become suitable for being included in the electric description of AMI evolution while preserving a direct relation not only with the ST segment elevation rise but also with its decrease or constant levels. In this regard, it may be considered as relevant the fact that an R voltage reduction was deter-mined in the majority of included patients (74.82%), uninfl uenced by whether the ST segment size decrea-sed or remained the same.

As far as the study limits are concerned, there may be underlined several aspects eventually leading to vol-tage measurements alterations. Among these, there are to be considered the subjectivity of time intervals evaluation by the patient (possibly unsure period from pain onset to presentation), the presence of extra-car-diac factors and the association of non-occlusive coro-nary injuries.

While looking towards the future, it may become useful to quantify the salvaged myocardium subsequent to the revascularization therapy in cases of decreasing R wave amplitude versus patients lacking any R change during the optimal treatment time window.

CONCLUSIONSInitial EKG at hospital admission constitutes the main landmark while evaluating the myocardial necrosis

size and evolution as well as the time length of the co-ronary occlusion related pain episode. Changes in the ST segment magnitude during the 0-30 minutes in-terval is rather variable, thus refl ecting the chest pain episode duration. Th e positive predictive value of the ST segment elevation may be further improved by cor-relating it to the R wave amplitude reduction. In the present study, it was emphasized a signifi cant R wave voltage decrease, even under the circumstances of in-creasing or stationary evolution of the ST segment ele-vation. Th is fi nding demonstrates that the R wave may be regarded as a remarkably dynamic parameter while aiming to assess the AMI specifi c electric evolution.

Under these circumstances, the analysis of R wave modifi cations (confi rmed myocardial viability mar-ker) may be considered as a potentially relevant aspect when aiming to obtain an accurate electric description of STEMI evolution. Th is perspective might be related not only to increases of the ST segment elevation but also to its possible stationary or decreasing variation. Based on these premises, the ST segment changes asso-ciated with the R wave amplitude reduction during the optimal therapeutic decision interval might suggest the progress of myocardial necrosis.

Confl ict of interests: none to declare.References1. Savonitto S, Ardissino D, Granger CB, Morando G, Prando MD, Ma-

frici A, Cavallini C, Melandri G, Th ompson TD, Vahanian A, Oh-man EM, Califf RM, Van de Werf F, Topol EJ. Prognostic value of the admission electrocardiogram in acute coronary syndromes. JAMA. 1999 Feb 24;281(8):707-13.

2. Ripa MS. Th eECGasdecisionsupportin STEMI. Dan Med J.2012 Mar; 59 (3): B4413.

3. Task Force on the management of ST-segment elevation acute myo-cardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK, Atar D, Badano LP, Blmstrom-Lundqvist C, Bor-ger MA, Di Mario C, Dickstein K, Ducrocq G, Fernandez-Aviles F, Gershlick AH, Giannuzzi P, Halvorsen S, Huber K, Juni P, Kastrati A, Knuuti J, Lenzen MJ, Mahaff ey KW, Valgimigli M, van t Hof A, Widimsky P, Zahger D.ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevati-on. Eur Heart J. 2012 Oct; 33(20): 2569-619.

4. Nable JV,Brady W. Th e evolution of electrocardiographic changes in ST-segment elevation myocardial infarction. Am J Emerg Med.2009 Jul;27(6):734-46.

5. Kurisu S, Inoue I, Kawagoe T, Ishihara M, Shimatani Y, Mitsuba N, Hata T, Nakama Y, Kisaka T, Kijima Y. Impact of the magnitu-de of the initial ST-segment elevation on left ventricular function in patients with anterior acute myocardial infarction. Circ J.2004 Oct; 68(10):903-8

6. Essen R, Merx W, Eff ert S. Spontaneous course of ST segment eleva-tion in acute anterior myocardial infarction. Circulation. 1979 Jan; 59(1):105-12.

7. Mills RM Jr,Young E,Gorlin R,Lesch M. Natural history of ST seg-ment elevation aft er acute myocardial infarction. Am J Cardiol.1975 May;35(5):609-14.

8. Tsai TH, Sun CK, Chung WJ, Lin YC, Leu S, Hussein H, Chen YL, Chung SY, Chai HT, Chua S, Fu M, Yip HK. Prognostic value



of R wave voltage in patients with anterior wall STsegment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Int Heart J. 2010;51 (5) : 325-30.

9. Isobe S, Okada M, Ando A, Nanasato M, Nonokawa M, Izawa H,Kondo T,Hirai M,YokotaM,TanahashiY,SaitoH. Clinical signi-fi cance of changes in electrocardiographic R-wave voltage on chest leads in patients with acute anterior myocardial infarction. J Electro-cardiol. 2002 Jul;35 (3): 173-80.

10. Nanea I.T., Ginghin C., intoiu I., Gheorghe G., Cristea A., Alma-richi S., Onceanu S., Hodorogea A. Evoluia supradenivelrilor seg-mentului ST din infarctul miocardic acut n intervalul optim de deci-

zie terapeutic date preliminare. Foaie de Informare Medicala. 2011 Aprilie; 24: 19-26.

11. Isobe S,Takada Y,Ando A,Ohshima S,Yamada K,Nanasato M,Unno K,Ogawa T,KondoT,IzawaH,IndenY,HiraiM,MuroharaT. Increa-se in electrocardiographic R-waves aft er revascularization in patients with acute myocardial infarction. Circ J. 2006 Nov; 70(11):1385-91.

12. SunX,CaiJ,FanX,HanP,XieY,ChenJ,XiaoY,KangYJ. Decreases in electrocardiographic R wave amplitude and QT interval predict myo-cardial ischemic infarction in Rhesus monkeys with left anterior des-cending artery ligation. PLoSOne. 2013Aug 13;8(8):e71876.


REVIEWS

Statins - from bench to bedsideGabriela Silvia Gheorghe1, Andreea Simona Hodorogea1, Ioan Tiberiu Nanea1

Contact address:Gabriela Silvia Gheorghe, Adress: Th eodor Burghele Clinical Hospital, No 20 Panduri Road, Bucharest, Romania, postal code 050653.E-mail: [email protected].

INTRODUCTIONStatins are among the most studied and prescribed drugs, indicated in primary and secondary prevention of cardiovascular diseases. Th ey are structural analogs of mevalonate and act on the rate limiting fi rst step of the cholesterol synthesis by blocking the hepatic hydoxi methyl glutaril coenzyme A (HMG CoA) reductase1. Given their importance in clinical practice, but also the existence of less well-known data, we conducted a review of the latest data from the medical literature using PubMed search through internet. Th e keywords used were statins, HMG Co A reductase, isopreno-ids, farnesyl pirophosphate, geranyl pirophosphate, ubiquinone. Th e research lasted fi ve months.

HISTORYStatin history began in 1971, when the Japanese bio-chemist Akira Endo (Sankyo) discovered microor-ganisms that synthesize inhibitors of HMG Co A re-ductase as a defense mechanism, since mevalonate is a precursor of cell wall components (ergosterol) and of the cytoskeleton (isoprenoids)2. He identifi ed Mevas-tatin produced by the fungus Penicillium citrum. In 1976 British researchers isolated Mevastatin (Compac-tin) of the fungus Penicillium brevicompactum, never marketed because of adverse eff ects. In 1978 P. Roy Vagelos (Merck&Co) isolated Lovastatin of the fungus Aspergillus cereus, the fi rst statin sold as lipid lowering agent, under the name Mevacor (1987). Soon appea-red Pravastatin, produced by fermentation of Nocardia

1 University of Medicine and Pharmacy Carol Davila, Faculty of Medi-cine, Bucharest, Romania, Th eodor Burghele Clinical Hospital

Abstract: Statins are probably the most prescribed drugs in cardiology worldwide, with evident effi ciency in primary and secondary prevention. Th ey act on the fi rst step of cholesterol synthesis by blocking the hepatic hydoxi methyl glutaril coenzy-me A (HMG CoA) reductase dose-dependent, reversible and competitive. Consequently, not only the cholesterol synthesis is blocked, but also the synthesis of many other intermediate products involved in other important biological processes: myth-ocondrial respiratory chain, infl ammation, oncogenesis. Th ese changes can explain the non lipidic (pleiotrophic) eff ects of statins, but also their adverse eff ects. Th e pharmacology of statins is complex. Th ey diff er in terms of lipophilicity, active or in-active form of administration, active metabolites, elimination. Th ere are genes correlated with the susceptibility of patients to adverse eff ects. Despite many studies, there is few data regarding the clinical implications of the pharmacological peculiarities of statins. Th is paper discusses some clinical issues about the biochemistry and pharmacology of statins.Keywords: statins; HMG Co A reductase; isoprenoids; farnesyl pirophosphate; geranyl pirophosphate; ubiquinone

Rezumat: Statinele sunt printre cele mai prescrise medicamente n cardiologie, cu efi cien dovedit n prevenia primar i secundar a bolilor cardiovasculare. Ele acioneaz n prima etap a sintezei hepatice de colesterol prin inhibarea competitiv, dependent de doz i reversibil a hidoxi metil glutaril coenzimei A (HMG CoA). Ca urmare, este blocat nu doar sinteza colesterolului, dar i cea a multor produi intermediari implicai n procese biologice importante: lanul respirator mitocon-drial, infl amaie, oncogenez. Aceste modifi cri ar putea explica efectele nonlipidice (pleiotrope) ale statinelor, dar i efectele adverse ale acestora. Statinele au o farmacologie complex, fi ind diferite ntre ele din punct de vedere al liposolubilitii, al formei de administrare - activ sau inactiv, al metaboliilor activi, al formei de eliminare. Susceptibilitatea la efectele adverse se coreleaz cu prezena anumitor gene. Dei studiile n care s-au folosit statine sunt foarte numeroase, efectele determinate de particularitile farmacologice ale acestora nu sunt bine cunoscute. Articolul se refer la o serie de aspecte clinice n relaie cu biochimia i farmacologia statinelor. Cuvinte cheie: statine, HMG Co A reductaza, izoprenoizi, farnezil pirofosfat, geranil pirofosfate, ubichinona


Gabriela Silvia Gheorghe et al.Statins-from bench to bedside

autotrophica (1988), Simvastatin, synthetically derived from the products of the fermentation of Aspergillus terreus, Fluvastatin, Atorvastatin, Rosuvastatin and Pitavastatin, the last 3 entirely produced by synthesis. Cerivastatin, very strong lipid-lowering statin also pro-duced by synthesis, was withdrawn from the market because of adverse eff ects.

Cholesterol synthesisCholesterol synthesis is a complex process (Figure 1) strictly regulated both short and long term (Figure 2). Th e molecules of geranyl and farnesyl occurring in intermediate stages of cholesterol synthesis bind va-rious prenylated proteins to cell membranes. Among these proteins there are some with cellular signals role, such as those related to Guanosine 5-Monophosphate (GMP) system and Ras gene, involved in oncogene-sis. Another isoprenoid is dolichol in cell membranes, involved in the synthesis of carbohydrate chains of glycoproteins. Coenzyme Q (ubiquinone), with a role in electron transfer in the mithocondrial respiratory chain, includes an isoprenoid side chain. Hem also has a farnesyl side chain.

Short-term control of cholesterol synthesis is achi-eved by the intervention of an adenosine monopho s-

phate (AMP)-dependent protein kinase, whose acti-vi ty depends on cellular energy levels. Increasing the amount of intracellular AMP (thus reducing the amo-unt of adenosine triphosphate (ATP)) activates the pro tein kinase that phosphorylates and inhibits HMG-CoA reductase1.

Long term control of cholesterol synthesis is made by adjustment of the HMG-CoA reductase synthesis and degradation. Th e synthesis of HMG-CoA reducta-se increases by its transcription activation by the action of SREBP-2 (Sterol Regulatory element binding proteins) in the endoplasmic reticulum membrane. Reducing the amount of cholesterol leads through complex mecha-nisms, to the cleavage between the SREBP-2 and the protein that keeps it anchored to the endoplasmic reti-culum membrane. Th us, SREBP-2 migrates to the nu-cleus and increases the transcription of the HMG-CoA reductase gene (Figure 2)1.

PHARMACOLOGY OF STATINS

The chemical structure of statinsStatins consist of two components: the pharmacopho-re, dihydroxyheptanoic acid derivative, that inhibits HMG-CoA reductase competitive, reversible, dose-dependent; a peripheral ring diff erently substituted, covalently bound to the pharmacophore1. It binds sta-tin to HMG-CoA reductase, preventing its removal by endogenous substrate, HMC-CoA. For each statin the substituents attached to the ring are diff erent and they determine its solubility3,4 (Figure 3). Lovastatin, fl uvas-tatin, simvastatin, atorvastatia, pitavastatin are lipophi-lic and pravastatin and rosuvastatin are hydrophilic. Statins lipophilicity infl uence their systemic bioavaila-bility.

Figure 1. Hepatic cholesterol synthesis.Hepatic cholesterol synthesis is an energy consuming process, involving cytochrome P450 (CYP450). It starts by condensing acetoacetyl coenzyme A (CoA) to acetyl CoA by the action of cytoplasmic hidroximetilglutaril CoA synthase (HMG-CoA). CoA - coenzyme A, NADP - nicotinamide ad-enine dinucleotide phosphate, NADPH - he reduced form of nicotinamide adenine dinucleotide phosphate, ATP - adenosine triphosphate, ADP - ad-enosine diphosphate

Figure 2. Long term adjustment of cholesterol synthesis.Reducing the amount of cholesterol, mevalonate, farnesole inhibits the deg-radation of the hydoxi methyl glutaril coenzyme A (HMG CoA) reductase. Reducing cholesterol activates SREBP-2 (sterol regulatory element binding protein) in the membrane of the endoplasmic reticulum, which migrates into the nucleus and induces transcription, and thus synthesis of HMG-CoA reductase. Increasing the amount of cholesterol has reverse eff ects.



hydroxy acids5. Th ey are absorbed in the intestinal cells by passive mechanism and by active transport, using transporters synthesized by ABC and SCL gene famili-es. Prodrug activation begins in the intestinal mucosa. Th eir absorption varies between 30% (lovastatin) and 98% (fl uvastin)6. Lovastatin is absorbed better when administered once with food; fl uvastatin, atorvastatin, pravastatin are better absorbed by fasting and simvas-tatin and rosuvastatin absorption is not infl uenced by food. Absorption is fast and the maximum level is rea-ched in about 4 hours. Th e blood concentration is not correlated with the intensity of eff ects3. Plasma protein binding is over 95% for fl uvastatin, lovastatin, simvas-tatin, atorvastatin and 35-50% for pravastatin and ro-suvastatin5,7. Lipophilic statins enter the hepatocyte by passive diff usion. Partly they remain in circulation and enter the peripheral tissues by passive mechanism due to their liposolubility. Hydrophilic statins are captured

PharmacokineticsStatins are given orally, most of them in the active form of the hydroxy acid. Lovastatin and simvastatin are gi-ven in inactive form, as lactone3, more lipophilic than

Trial/Primary prevention Statin/ mg Versus No subjects Duration (years) AFCAPS/TEXCAPS (1998) lovastatin/20-40 placebo 6605 5.2EXCEL (1991) lovastatin/20-80 placebo 8245 0.9WOSCOPS (1995) pravastatin/40 placebo 6595 4.9PROSPER (2002) pravastatin/40 placebo 5800 3.2ALLHAT LLT (2002) pravastatin /40 placebo 10355 4.8HPS (2002) simvastatin/40 placebo 20536 5ASAP (2001) atorvastatin/40-80 simvastatin/20-40 325 2ASCOT-LLA (2004) atorvastatin/10 placebo 10305 3.3CARDS (2004) atorvastatin/10 placebo 2838 4ASTEROID (2008) rosuvastatin 40 opened 292 2JUPITER (2008) rosuvastatin/20 placebo 17802 4METEOR (2007) rosuvastatin 40 placebo 984 2Trial/Secondary prevention statin versus No pts/years Duration (years)LIPS (2002) fl uvastatin/80 placebo 1677 3.9LIPID (1998) pravastatin/40 placebo 9014 6.1PROVE-IT-TIMI22 (2004) pravastatin 40 atorvastatin 80 4162 2CARE (1996) pravastatin/40 placebo 4159 5GISSI-P statin (2000) pravastatin/20 usual treatment 4271 24S (1994) simvastatin/20 placebo 4444 5.4SCAT (2000) simvastatin/10-40 placebo 460 4A to Z (2004) simvastatin/40-80 placebo 2265 1-4 luniSEARCH (2010) simvastatin 20 simvastatin 80 12064 6.7TNT (2005) atorvastatin 80 atorvastatin 10 15 464 4.9ALLIANCE (2004) atorvastatin/40-80 usual treatment 2442 4.3IDEAL (2006) atorvastatin 80 simvastatin 40 8888 4.8MIRACLE (2001) atorvastatin/80 placebo 3086 0.33GREACE (2002) atorvastatin/10-80 usual treatment 166 3CORONA (2007) rosuvastatin/10 placebo 5011 3GISSI-HF85 (2008) rosuvastatin/10 placebo 4574 3.9A to Z (Aggrastat to Zocor); LIPS (Lescol Interventional Prevention Study); LIPID (The Long-Term Intervention with Pravastatin in Ischaemic Disease ); TNT (Treating to New Target) PROVE IT TIMI 22 (A Comparison of Intensive Statin Therapy and Moderate Statin Therapy in Acute Coronary Syndrome Patients). MIRACLE (Myocardial Ischhemia Reductiion and Aggressive Cholesterol Lowering Trial); SEARCH (Intensive lowering of LDL cholesterol with 80 mg versus 20 mg Simvastatindaily in 12064 survivors of myocardial infarction: a doublee blind randomized study) 4S (Scandian Survival Simvastatin Study) IDEAL (Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study); GISSI-HF85 (Effects of Rosuvastatin in Chronic Heart Failure; a randomized, placebo control double blind trial) CORONA (Control Rosuvastatin in Multinational Trial in Heart Failure); GREACE (Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation ) ALLIANCE (Aggressive Lipid Lowering versus Usual Care in a Managed-Care Patient Population)

Figure 3. Chemical structure of statins4.

Table 1. Primary and secondary prevention trials with statins in atherosclerotic disease



vastatin (12 hours). It is recommended to take statins in the evening because cholesterol synthesis is more active at night. Atorvastatin and rosuvastatin may be given at any of the day5 (Table 2).

Mechanism of actionStatins reversible inhibit microsomal HMG-CoA re-ductase and decrease intracellular cholesterol biosyn-thesis. As a result, there is the phenomenon of tran-scriptional up regulation of the production of micro-somal HMG-CoA reductase and also of the number of membrane receptors for LDL cholesterol. Th e circula-ting LDL cholesterol particles are trapped intracellular and resets cholesterol homeostasis in extrahepatic tis-sues, but does not markedly infl uence global choleste-rol balance9. Th e LDL cholesterol level in blood decrea-ses in 4-6 weeks, usually by 20-35%, depending on the statin dose and not on the statin blood concentration. Th is is due to the complex metabolism of statins, during which active products may appear. Th e lipid-lowering eff ect of statins depends on the genetic polymorphism of HMG-CoA reductase and there are patients with low response3.

Clinical studiesTh e widespread use of statins coincided with the un-

derstanding of the role of cholesterol in atherosclerosis and with the development of primary and secondary prevention in ischemic heart disease. If in 1984 there were few prevention studies, the best known being Th e Coronary Primary Prevention Trial (cholestyramine)8, there are now more than 70 primary and secondary

by hepatocytes using specifi c carriers that do not exist in extrahepatic tissues. Th eir extrahepatic distribution is reduced. Statins administered as lactones are activa-ted in the liver to the acid form (beta hydroxy acids) by intracellular hydrolysis using esterases and paroxona-ses. Intrahepatic metabolism of statins is complex, in-volving reversible transformation between the lactone form (fat soluble) and acid form (less fat soluble), CoA, UDP glucuronosyl transferase glucuronidation and mi cro somal cytochrome P450 (CYP) participation8. Sim vastatin, atorvastatin, lovastatin are metabolised by CYP 3A4 pathway to active metabolites. Fluvasta-tin is metabolized predominantly by CYP2C9 pathway, but also by CYP3A4 and CYP2C8 to mostly inactive metabolites3. Rosuvastatin is minimum inactivated by CYP2C9 and CYP2C19 pathway. Pravastatin is parti-ally degraded in the stomach and limited metabolized in the cytosol of hepatocytes, by CYP 450-independent pathways5. Pitavastina is limited metabolized predo-minantly by glucuronidation3. Lipophilic statins are more likely to be metabolised by CYP 4505,6. Pravasta-tin, rosuvastatin, pitavastatin are excreted almost un-changed5. Statins are active eliminated predominantly by hepatic biliary excretion, with P-glycoprotein and MRAP-2 (Multidrug Resistance Protein Associated 2) transporters participation in the basal-lateral membra-ne of hepatocytes. Renal elimination is reduced, except for pravastatin, 60% eliminated by renal tubular secre-tion. Rosuvastatin is removed by the kidneys and the liver, mostly unchanged4. Th e half-life is 0.5-3 hours, with the exception of atorvastatin (10 hours) and rosu-

Table 2. Drug interactions according to the CYPa metabolism

Increase side eff ects

CYP3A4inhibitors

CYP3A4 CYP2C9 Other metabolic pathwayssimvastatinatorvastatin

lovastatin

Fluvastatin Pravastatin RosuvastatinCYP2C19

erythromycin + - - -clarithromycin + - - -telithromycin + - - -warfarin + (-atorvastatin) -/+ - -/+cyclosporine + + - -/+itraconazole + - -ketoconazole + -fl uconazole - + - -HIV antiretroviral therapy + + - +danazol + - -diltiazem + - - -verapamil + - - -amiodarone + - - -fi brates + + - -grapefruit juice + - - -aCYP - cytochrome



vel increases with atorvastatin, fl uvastatin, simvastatin, lovastatin and decreases with pravastatin. Lipoprotein a is increased by pravastatin and simvastatin and de-creased by lovastatin3. Monocyte adhesion to vascular endothelium is lowered by atorvastatin, fl uvastatin, lo-vastatin, simvastatin. High sensitivity CRP level is re-duced or unaltered by atorvastatin and simvastatin and decreases with pravastatin. All statins reduce LDL oxi-dation. Statins stabilize plaque by reducing its size, but especially by anti-infl ammatory action: reduce macro-phage accumulation and metalloproteinases activity, reduce IL-6, IL-8, IL-1, TGF-beta, NF-kB, matrix me-talloproteinases17, inhibit ICAM, CD18, CD4918, block expression major histocompatibility system II (HLA type 2) under the action of IFN-gamma on endothe-lial cells, macrophages, microglia. Th ey are immuno-suppressants, with potential clinical implications in transplant. Experimentally, statins are proangiogenic in low doses and antiangiogenic, including in tumors, at high doses3. Statins inhib plaque angiogennesis18. Th ey have dual eff ect on endothelial apoptosis and pre-vent senescence by altering isoprenylated proteins and by infl uencing the telomerase. Clinical translation of these experimental data is diffi cult. Th e variability of pleiotropic eff ects depends on many factors, including lipophilicity of molecules. Lipophylic statins have ex-trahepatic distribution and would have more important pleiotropic eff ects compared to the hydrophilic statins, with predominant hepatic distribution. However, the-re are proofs of pleiotropic eff ects for pravastatin and rosuvastatin whith limited extrahepatic distribution. In experimental and clinical studies14, rosuvastatin improves endothelial function, reduces adiposity and hepatic steatosis and pravastatin infl uences endothe-lial dysfunction and platelet aggregation6. Th e clinical relevance of the distinction between fat soluble and water soluble statins in terms of pleiotropic eff ects is not clear.Other actions have also been described: sim-vastatin ameliorates renal fi brosis19; statins are useful in preventing vasospasm aft er aneurysm rupture cerebral hemorrhage20; when administered preoperatively, they reduce the risk of postoperative acute renal failure21. Statins can prevent atrial fi brillation, have favorable eff ects in pneumonia, protect against nuclear cataract. Th ey prevent ischemic stroke, probably less by redu-cing serum cholesterol, as by increasing NO dependent cerebral vasodilatation22.

SIDE EFFECTSA meta-analysis that included 107 835 patients treated with statins (simvastatin and atrovastatin in 53% pa-

prevention studies, involving over 170,000 subjects7 (Table 1).

Reduction of LDL cholesterol by 20-35% is associ-ated with 30-40% reduction in major cardiovascular events9. Th is decrease is achieved with diff erent doses of diff erent statins: atorvastatin 10 mg, rosuvastatin 5 mg, simvastatin 20 mg, fl uvastatin 80 mg, lovastatin 40 mg, pravastatin 40 mg. Doubling statin dose leads to further reduction of LDL cholesterol level by 6%9,10. If there is a need to decrease LDL cholesterol by 50% from baseline, atorvastatin 40-80 mg / day, rosuvastatin 20-40 mg / day or simvastatin 40 mg / day are indica-ted. In absolute value, lowering LDL cholesterol by 1 mmol / l (38 mg% ml) reduces the risk of cardiovascu-lar death and non-fatal major cardiovascular events by 20-25%11-14.

Pleiotropic effects Acute LDL cholesterol apheresis improves endothe-lium-dependent vasodilation15 but other experimen-tal studies show that the improvement of endothelial dysfunction occurs before reducing serum cholesterol level16. Pleiotropic eff ects of statins are not only rela-ted to the modifi cation of blood lipids, but also to the intervention on infl ammation, thrombosis, endothelial function, vascular smooth muscle cells proliferation. Th ese eff ects are partly due to isoprenylated prote-in reduction3. Th ese have multiple cellular functions: regulating onc genes Ras, Rac, Rho; involved in cell division, maintenance of cell shape, secretory functi-on of the cell, cell diff erentiation6. Inhibition of Rho and Rho kinase isoprenylation would reduce vascular smooth muscle cell sensitivity to calcium and therefo-re vasospasm, would alter the cytoskeleton actin, the transmembrane and intracellular transport, the mRNA stability and should be, at least in part, responsible for the pleiotropic vascular and extravascular eff ects of sta-tins15. Statins alter cell membrane raft s, the headquar-ters of molecules involved in immune signals. Atorvas-tatin, Fluvastatin, Lovastatin, Pravastatin, Simvastatin reduce the proliferation of vascular smooth muscle cells, improve endothelial vasodilation, reduce cyto-kine production. Platelet aggregation is reduced by atorvastatin, uninfl uenced or reduced by pravastatin and simvastatin, reduced or increased by lovastatin; no data for fl uvastatin3. Th e mechanism would consist in the reduction of the synthesis of thromboxane A2, and the amount of cholesterol in the platelet membrane16. Fibrinogen level decreases with fl uvastatin, decreases or is not infl uenced by pravastatin and simvastatin and may increase with atorvastatin and lovastatin. PAI-1 le-



increases the concentration of pravastatin, inhibiting its membrane transporters5. Cyclosporine increases blood levels of pravastatin, rosuvastatin and pitavasta-tin through the inhibition of membrane transporters5. Rifampin and carbamazepine are inducers of CYP 3A4 and reduce the concentration of simvastatin, lovasta-tin and atorvastatin. Th ey reduce the concentration of fl uvastatin and pravastatin by inducing transport proteins OATP1B1, MRP2. It is not known by which mechanism they reduce the concentration of rosuvas-tatin and pitavastatin5. In general this interaction has no clinical relevance5. Gemfi brozil inhibits CYP2C8 and liver transmembrane transporter OATP1B1 of acid statins. It increases blood levels of atorvastatin, rosu-vastatin, pravastatin, pitavastatin. It does not infl uence the blood level of simvastatin, lovastatin, fl uvastatin5,29. Th e association of gemfi brozil with fl uvastatin or pra-vastatin would lower the risk of adverse eff ects than other statins. Bezafi brate and fenofi brate do not aff ect serum levels of statin5 but the association cumulates adverse eff ects. Atorvastatin reduces clopidogrel eff ects inhibiting its activation by the CYP3A4 pathway. Th is interaction does not appear to have clinical relevance10. High doses of simvastatin and atorvastatin increase the blood level of digoxin by 20%, inhibiting MDR1 carrier membrane proteins5,29.

Genetics and adverse effects of statinsLovastatin induces atrogin-1 gene expression, whi-ch would initiate myopathy6. Th e variability of the le-vels of rosuvastatin in 165 pts is correlated to 2 gene-tic polymorphisms: SLCO1B1carrier gene (p



pid-lowering drugs: Mechanisms and clinical relevance. Clinical Pharmacology and Th erapeutics. 2006; 80: 565-575

6. Pang H Chong: Th erapeutic Controversies; Lack of Th erapeutic In-terchangeability of HMG-CoA Reductase Inhibitors. Ann Pharma-cother. 2002; 36:1907-1917

7. Lennerns H and Fager G: Clinical Pharmacokinetics and Pharmaco-dynamics of HMG-CoA reductase inhibitors: similarties and dissimi-larties. Clin Pharmacokin. 1997; 32: 403-425

8. Katharine Howe, Faizah Sanat, A E Th umser, Tanya Coleman, N Plant:. Th e statin class of HMGA CoA reductase inhibitors demons-trate diff erential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes: Xenobiotica; the Fate of Foreign Compounds in Biological Systems 2011, 41 (7): 519-29

9. Th e Lipid Research Clinics Coronary Primary Prevention Trial re-sults. I. Reduction in incidence of coronary heart disease. JAMA. 1984 Jan 20;251: 351-64

10. Opie LH, Gersh BJ. Class indication for Statins in Drugs for the Heart, eight edition, Elsevier-Saunders, 2013: 411-423

11. Stone NJ, Jennifer Robinson, Alice T Lichtenstein, et al.: 2013 ACC/AHA Guideline on the treatment of Blood Cholesterol to Reduce Cardiovascular Risk in Adults: A Report of the American College of Cardiiology /American Heart Association Task Force on Practice Guidelines Circulation, , http://circ:.ahajournals.org/content/early/2013/11/01.0000437738.63853.7acitation/;

12. Gielen S and Landmesser U. Th e Year in Cardiology:cardiovascular disease prevention. European Heart Journal. 2014; 35: 307-312

13. Ebrahim Shah, Taylor Fiona C, Brindle P. Statins for the primarry pre-vention of cardiovascular disease. BMJ. 2014; 348: .g280

14. Neto-Ferrera R, Rocha VN, Souza- Mello V, Mandarini de Lacerda, de Carvalho JJ: Pleiotropic eff ects of rosuvastatin on the glucose me-tabolism and the subcutaneous and visceral adipose tissue in C57B1/6 mice. Diabet Metab Syndrome. 2013; 5:32

15. Anderson TJ, Mereddith IT, Yeung AC, Frei B, Selwyn AP, Ganz: Th e eff ect of cholesterol lowering and antioxidant therapy on endothelium dependent coronary vasomotion. N. Engl J Med. 1995; 332:488-493

16. Takemoto M, Liao J K: Pleiotropic Eff ects of 3-Hydroxi-3 methylglu-taryl Coenzyme A Reductase Inhibitors. Atherosclerosis, Th rombo-sis, and Vascular Biology. 2001; 21:1712-1719

17. Weitz-Schmidt G. Lymphocyte function-associated antigen-1 blocka-de by statins: molecular basis and biological relevance. Endothelium. 2003; 10: 43-7.

18. Yoshifumi Hamasaki, Kent Doi, Koji Okamoto, Hideaki Ijichi, Geor-ge Seki, Rui Maeda-Mamiya, Toshiro Fujita, Eisei Noiri: 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin ameli-orates renal fi brosis through HOXA13USAG-1 pathway. Laboratory Investigation. 2012;92, 1161-1170

19. Jason L, Trimble and Denise R Kockler. Statin Treatment of Cerebral Vasospasm aft er Aneurysmal Subarachnoid Hemorrhage. Ann Phar-macother. 2007; 41: 2019-2023

20. Steven M. Brunelli, Sushrut S. Waikar, Brian T. Bateman, Tara I. Chang, Joyce Lii, Amit X. Garg, Wolfgang C. Winkelmayer, Niteesh K. Choudhry.: Preoperative Statin Use and postoperatory Acute Kidney Injury. Th e American Journal of Medicine. 2012; 125: 1195-1204

21. Huabing Zhang, Jorge Plutzky, Stephen Skentzos, Fritha Morrison, Perry Mar, Maria Shubina, Alexander Turchin: Discontinuation of Statins in Routine Care Settings: A Cohort Study. Ann Intern Med. 2013; 158: 526-534.

22. Nickole N Henyan, Daniel M Riche, Honey E East, Pamela N Gann: Impact of Statins on Risk of Stroke: A Meta-Analysis. Ann Pharma-cother. 2007 41: 1937-1945

23. EJ Mills, P. Wu, I. Chong G, Ghement I, Singh S, Akl EA, Eyawo O, Guyatt G, Berwanger O, Briel M: Effi cacy and safety of statin treat-ment for cardiovascular disease: a network meta-analysis of 170255 patients from 76 randomized trials. QJM. 2011; 104 : 109-24.

24. Wouter Jukema, Christopher P. Cannon,Anton J. M. de Craen, Rudi G. J. Westendorp, Stella Trompet: Th e Controversies of Statin Th era-py-Weighing the Evidence. JACC. 2012; 60: 875-881

25. Jaakko Allonen, Markku S. Nieminen, Maisa Lokki,Olavi Parkko-nen, Satu Vaara, Markus Perola, PhD; Tero Hiekkalinna, Timo E.

clinical problems remain. Could statins be exchanged between them? Apparently not, their ability to redu-ce LDL cholesterol level is diff erent and appropriate medications must be used in order to obtain the pro-posed target. Pharmacological diff erences between statins may infl uence their eff ects. Is it important the administration as prodrug (lactone) or active form (acid)? During their metabolism, statins pass from the lactone to the acid form and vice versa; it is hard to say whether form of administration infl uences the eff ects. Is it clinically relevant the diff erence between lipophilic and hydrophilic statins? Hydrophilic statins would have less adverse eff ects. On the other hand, side eff ects are correlated with the dose and the potency of drugs. Hydrophilic statins would have lower pleiotro-pic eff ects, their distribution in peripheral tissues being limited. Are pleiotrophic eff ects important in clinical practice? Statins largely diff er between them regarding these eff ects but all have proofs of clinical effi ciency.Statins may be discontinued? Apparently no. A study of patients with acute coronary syndromes treated with statins and followed 23 months showed that non-adhe-rence to statins increased the rate of cardiovascular mortality approximately 3-fold. However, for primary prevention, some studies show that statins can be ad-ministered intermittently in case of intolerance. Con-comitant administration of Q coenzyme can limit the adverse eff ects of statins? Studies are not clear in this regard. Is genetic testing useful in the treatment with statins? Probably yes, but we need more studies. Th e mechanisms long-term regulating cholesterol synthe-sis have a role in the eff ectiveness of statin therapy? It would be an interesting issue, but so far there are no studies in this regard.

Acknowledgement: Th is paper is supported by the Sec-toral Operational Programme Human Resources Deve-lopment (SOP HRD) 2007-2013, fi nanced from the Eu-ropean Social Fund and by the Romanian Government under the contract number POSDRU/107/1.5/S/82839

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