[Immune checkpoint inhibitors related cardiovascular toxicity: 3­mounth follow-up].

AIM: To analyze the condition of the cardiovascular system in oncological patients receiving immune antitumor therapy with immune checkpoint inhibitors (CPIs) based on results of laboratory and instrumental examinations during a 3-month follow-up. MATERIAL AND METHODS: This multicenter prospective observational study included 49 patients (25 men and 24 women aged 65.6±8.7 and 64.3±9.6 years, respectively). A laboratory screening (C-reactive proteins, troponin I, N-terminal pro-brain natriuretic peptide), EchoCG, and carotid ultrasound were performed for all patients. 27 patients were followed up at 3 months after the antitumor therapy initiation. Statistical analysis was performed with the StatPlus 8.0.3 software. RESULTS: Incidence of cardiovascular complications was 16.3 %. The following significant changes in EchoCG parameters were observed: LV EF; (p=0.017), increased LV end-systolic volume (ESV) (р=0.023), and increased LV index of myocardial performance (LIMP; р=0.016). The degree of changes in ESV (ΔESV) depended on a history of chronic heart failure (р=0.03), whereas the degree of changes in EF (ΔEF) depended on the patient's age at the initiation of antitumor therapy (р=0.006). Ultrasound showed an increase in maximum carotid stenosis (р=0.018). CONCLUSION: The study showed a high incidence of newly developed cardiovascular complications associated with the CPI treatment as well as the presence of changes in EchoCG parameters and data of carotid ultrasound.

Cardiopulmonary exercise testing for treatment effect assessment in chronic thromboembolic pulmonary hypertension patients.

Aim      To determine possibilities of the cardiopulmonary stress test (CPST) as an unbiassed, noninvasive method for evaluation of the effect of managing patients with chronic thromboembolic pulmonary hypertension (CTEPH).Material and methods  This study included 37 patients with CTEPH, 24 men (mean age, 53±15 years) and 13 women (mean age, 58±8.5 years). The diagnosis was verified and theCoperability was assessed according to 2015 European Society of Cardiology Clinical Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension (PH). The surgical treatment was used in 65 % (n=24) of CTEPH patients: the group with pulmonary thromboendarterectomy constituted 35 % (n=13); the group with balloon pulmonary angioplasty 30% (n=11); and the conservative tactics was used in 27 % (n=10) of patients.Results Baseline CPST parameters significantly correlated with parameters of right heart catheterization (RHC): mixed venous oxygen saturation (SvO2) significantly positively correlated with V´O2peak (r=0.640, p<0.05), V´O2 / heart rate (HR) (r=0.557; p<0.001), PETCO2 peak (r=0.598, p<0.05), and V´E / V´CO2 (r=0.587; p<0.001); cardiac output (CO) correlated with V´O2 / HR (r=0.555, p<0.001), PETCO2peak (r= -0.476; p<0.05 and r=0.555, p<0.001 for ´E / V´CO2). In repeated testing, the physical working capacity (V´O2peak) increased only in patients after the surgical treatment of CTEPH. Importantly in this process, significant correlations remained between a number of CPST and RHC parameters: SvO2 correlated with V´O2peak (r=0.743; p<0.05), V´O2 /HR (r=0.627; p<0.001), PETCO2peak (r=0.538; p<0.05), and V´E / V´CO2 (r=0.597; p<0.001); V´O2 / HR, PETCO2peak, and V´E / V´CO2 significantly correlated with CO (r=0.645, p<0.001; r= -0.516, p<0.001, and r=0.555, p<0.001, respectively.Conclusion      CPST can be used as a noninvasive instrument for evaluation of the effect of CTEPH treatment, particularly in the absence of echocardiographic data for residual PH.

[Experience with Selexipag to Treat Pulmonary Arterial Hypertension].

Aim To present an own experience in using a medication selexipag in patients with pulmonary arterial hypertension (PAH) included into the V. A. Almazov National Medical Research Center registry and participating in the GRIPHON and GRIPHON OL clinical studies.Material and methods 26 patients with PAH were included into this study since 2010: 20 patients with idiopathic PAH, 4 patients with PAH associated with systemic scleroderma, and 2 patients with corrected congenital heart defects. At the time of randomization, 19 patients had been receiving therapy with phosphodiesterase type 5 inhibitors for at least one month. Among the patients treated with selexipag (n=14), 4 patients reached a high individual maintenance dose (1200-1600 µg b.i.d.), 4 patients reached a medium dose (600-1000 µg b.i.d.), and 6 patients reached a low dose (200-400 µg b.i.d.).Results The selexipag therapy exerted a positive effect on secondary endpoints, specifically, on changes in the functional class of pulmonary hypertension, serum concentration of NT-proBNP, and physical working capacity of patients. Adverse events associated with the selexipag treatment, which resulted in termination of study participation, were observed in one patient.Conclusion To achieve the main goal of drug therapy, low risk of death with selexipag it is critical to observe the titration schedule and to aim at reaching the highest individual maintenance dose.

Left main coronary artery compression by pulmonary artery aneurism in patients with long standing pulmonary arterial hypertension.

This review focuses on a rare complication of pulmonary arterial hypertension (PAH), extravasation compression of the left coronary artery (LCA) dilated by the pulmonary artery. The review described clinical manifestations and methods for diagnostics of LCA compression, and advantages of the endovascular correction of this complication in patients with pulmonary hypertension. Selection of a device to be implanted during the endovascular intervention in these patients was discussed with due account for concomitant treatment with oral anticoagulants. As an illustration of the issue under discussion, a clinical case of acute coronary syndrome in a female patient from the PAH Registry of the V. A. Almazov National Medical Research Center was provided.

Perspectives of using pulmonary arterial stiffness indicators to evaluate the prognosis of patients with pulmonary arterial hypertension.

AIM: The aim of the study was to characterize the mechanical properties of the pulmonary arterial wall (PA) in patients with pulmonary arterial hypertension (PAH) using magnetic resonance imaging (MRI) of the heart, and to determine their diagnostic and prognostic value. MATERIALS AND METHODS: 57 patients with PAH were examined. The diagnosis of PAH was verified according to the recommendations of the ERS/ESC from 2015. All patients underwent a detailed echocardiographic (ECHO) study, MRI of the heart and right heart catheterization (RHC). To calculate the stiffness of the pulmonary artery wall, the MRI and RHC data were used. RESULTS: We identified a correlation between the functional class of PAH and the parameters of hemodynamic, physical performance, ECHO parameters of the right chambers. There were no differences in the stiffness of the pulmonary artery wall, depending on the functional class of PAH. Among the six stiffness indicators, only pulsation index was associated with the structural and functional parameters of the right ventricle and pulmonary vascular resistance. CONCLUSION: The MRI pulsation index is the simpleststiffness index of the pulmonary artery wall and the most promising one for evaluating the prognosis of patients with PAH.

[Perspectives of using pulmonary arterial stiffness indicators to evaluate the prognosis of patients with pulmonary arterial hypertension].

OBJECTIVE: the aim of the study was to characterize the mechanical properties of the pulmonary arterial wall (PA) in patients with pulmonary arterial hypertension (PAH) using magnetic resonance imaging (MRI) of the heart, and to determine their diagnostic and prognostic value. MATERIALS AND METHODS: 57 patients with PAH were examined. The diagnosis of PAH was verified according to the recommendations of the ERS/ESC from 2015. All patients underwent a detailed echocardiographic (ECHO) study, MRI of the heart and right heart catheterization (RHC). To calculate the stiffness of the pulmonary artery wall, the MRI and RHC data were used. RESULTS: We identified a correlation between the functional class of PAH and the parameters of hemodynamic, physical performance, ECHO parameters of the right chambers. There were no differences in the stiffness of the pulmonary artery wall, depending on the functional class of PAH. Among the six stiffness indicators, only pulsation index was associated with the structural and functional parameters of the right ventricle and pulmonary vascular resistance. CONCLUSION: The MRI pulsation index is the simpleststiffness index of the pulmonary artery wall and the most promising one for evaluating the prognosis of patients with PAH.

[Value of Two Dimensional Echocardiography for Assessment of Disease Severity in Patients With Pulmonary Hypertension].

AIM: To carry out complex assessment of the right ventricular (RV) function with two-dimensional echocardiography (2D-EchoCG) for detection of most informative markers of the disease severity in patients with pulmonary hypertension (PH). MATERIAL AND METHODS: We examined 63 patients with PH (38 with idiopathic PH, 7 with corrected congenital heart defects, 6 with systemic scleroderma, 12 with chronic inoperable thromboembolic PY). Examination included right heart catheterization, 2D-EchoCG, and cardiac magnetic resonance tomography (MRT). RESULTS: 2D-EchoCG revealed dilation of right chambers of the heart, hypertrophy of RV anterior wall, increase of ratio of right to left ventricular end-diastolic dimensions (RV:LV), reduction of LV stroke volume, diminution of amplitude and velocity of tricuspid annular plane systolic excursion, and significant increase of myocardial performance index Tei. MRT data evidenced for lowering of RV ejection fraction. Canonical correlation was found between integral characteristic of 2D-EchoCG and integral hemodynamic characteristic (r=0.77; p=0.007). We also determined threshold values of RV: LV to be used for stratification of risk in patients with PH. CONCLUSION: In patienns with PH calculation of simple 2D-EchoCG parameters provides information important for determination of disease severity, selection of optimal method of treatment, and monitoring of patients condition.

Hemodynamic Mechanisms Initiating Salt-Sensitive Hypertension in Rat Model of Primary Aldosteronism.

Few studies have investigated the hemodynamic mechanism whereby primary hyperaldosteronism causes hypertension. The traditional view holds that hyperaldosteronism initiates hypertension by amplifying salt-dependent increases in cardiac output (CO) by promoting increases in sodium retention and blood volume. Systemic vascular resistance (SVR) is said to increase only as a secondary consequence of the increased CO and blood pressure. Recently, we investigated the primary hemodynamic mechanism whereby hyperaldosteronism promotes salt sensitivity and initiation of salt-dependent hypertension. In unilaterally nephrectomized male Sprague-Dawley rats given infusions of aldosterone or vehicle, we found that aldosterone promoted salt sensitivity and initiation of salt-dependent hypertension by amplifying salt-induced increases in SVR while decreasing CO. In addition, we validated mathematical models of human integrative physiology, derived from Guyton's classic 1972 model - Quantitative Cardiovascular Physiology-2005 and HumMod-3.0.4. Neither model accurately predicted the usual changes in sodium balance, CO, and SVR that normally occur in response to clinically realistic increases in salt intake. These results demonstrate significant limitations with the hypotheses inherent in the Guyton models. Together these findings challenge the traditional view of the hemodynamic mechanisms that cause salt-sensitive hypertension in primary aldosteronism. Key words: Aldosterone, Blood pressure, Salt, Sodium, Rat.

[Computational methods for prediction of structure of membrane proteins using their amino acids sequences].

The structure of membrane proteins is interesting because of their functional properties that are important to medicine and pharmacology. The feature and an organic property of polytopic membrane proteins is the repetition of transmembrane regions consisting of hydrophobic amino acids. The ordered repetition--periodicity--can be identified by the Fourier method, applied to a digital image of symbolic sequence of amino acids in a protein. In this work it was carried out for the 24 transmembrane proteins, for 14 of them successfully. If the repetition of transmembrane regions is ordered insufficiently--non-periodic, then a different method is supposed to use for its detection--the method of multiple (4-5 times) averaging of function of hydrophobicity of the protein within a "window" with width 9-11 aa moved along the sequence. This new method was applied to the same 24 transmembrane proteins (for 19 of them successfully) and it was shown to be more suitable (than the Fourier method) for predicting of the secondary structure of such proteins and functional properties corresponding to it.

Conplastic strains for identification of retrograde effects of mitochondrial dna variation on cardiometabolic traits in the spontaneously hypertensive rat.

Mitochondrial retrograde signaling is a pathway of communication from mitochondria to the nucleus. Recently, natural mitochondrial genome (mtDNA) polymorphisms (haplogroups) received increasing attention in the pathophysiology of human common diseases. However, retrograde effects of mtDNA variants on such traits are difficult to study in humans. The conplastic strains represent key animal models to elucidate regulatory roles of mtDNA haplogroups on defined nuclear genome background. To analyze the relationship between mtDNA variants and cardiometabolic traits, we derived a set of rat conplastic strains (SHR-mtBN, SHR-mtF344 and SHR-mtLEW), harboring all major mtDNA haplotypes present in common inbred strains on the nuclear background of the spontaneously hypertensive rat (SHR). The BN, F344 and LEW mtDNA differ from the SHR in multiple amino acid substitutions in protein coding genes and also in variants of tRNA and rRNA genes. Different mtDNA haplotypes were found to predispose to various sets of cardiometabolic phenotypes which provided evidence for significant retrograde effects of mtDNA in the SHR. In the future, these animals could be used to decipher individual biochemical components involved in the retrograde signaling.

Long-term pioglitazone treatment augments insulin sensitivity and PKC-epsilon and PKC-theta activation in skeletal muscles in sucrose fed rats.

It has been suggested that thiazolidinediones (TZDs) ameliorate insulin resistance in muscle tissue by suppressing muscle lipid storage and the activity of novel protein kinase C (nPKC) isoforms. To test this hypothesis, we analyzed long-term metabolic effects of pioglitazone and the activation of nPKC-epsilon and -theta isoforms in an animal model of the metabolic syndrome, the spontaneously hypertensive rat (a congenic SHR strain with wild type Cd36 gene) fed a diet with 60 % sucrose from the age of 4 to 8 months. Compared to untreated controls, pioglitazone treatment was associated with significantly increased basal (809+/-36 vs 527+/-47 nmol glucose/g/2h, P<0.005) and insulin-stimulated glycogenesis (1321+/-62 vs 749+/-60 nmol glucose/g/2h, P<0.0001) in isolated gastrocnemius muscles despite increased concentrations of muscle triglycerides (3.83+/-0.33 vs 2.25+/-0.12 micromol/g, P<0.005). Pioglitazone-treated rats exhibited significantly increased membrane/total (cytosolic plus membrane) ratio of both PKC-epsilon and PKC-theta isoforms compared to untreated controls. These results suggest that amelioration of insulin resistance after long-term pioglitazone treatment is associated with increased activation of PKC-epsilon and -theta isoforms in spite of increased lipid concentration in skeletal muscles.

[The beta-helical domain of bacteriophage T4 controls the folding of the fragment of long tail fibers in a chimeric protein].

The key stage of the infection of the Escherichia coli cell with bacteriophage T4, the binding to the surface of the host cell, is determined by the specificity of the long tail fiber proteins of the phage, in particular, gp37. The assembly and oligomerization of this protein under natural conditions requires the participation of at least two additional protein factors, gp57A and gp38, which strongly hinders the production of the recombinant form of gp37. To overcome this problem, a modern protein engineering strategy was used, which involves the construction of a chimeric protein containing a carrier protein that drives the correct folding of the target protein. For this purpose, the trimeric beta-helical domain of another protein of phage T4, gp5, was used. It was shown that this domain, represented as a rigid trimeric polypeptide prism, has properties favorable for use as a protein carrier. A fragment of protein gp37 containing five pentapeptides repeats, Gly-X-His-X-His, which determine the binding to the receptors on the bacterial cell surface, was fused in a continuous reading frame to the C-terminus of the domain of gp5. The resulting chimeric protein forms a trimer that has the native conformation of gp37 and exhibits biological activity.

Long-term pioglitazone treatment enhances lipolysis in rat adipose tissue.

OBJECTIVES: The insulin-sensitizing effects of thiazolidinediones are believed to depend at least in part on reductions in circulating levels of nonesterified fatty acids (NEFA). The mechanisms that mediate the reductions in NEFA are not fully understood and could involve reductions in adipose tissue lipolysis, increases in glyceroneogenesis and NEFA reesterification in triglycerides in adipose tissue and increases in NEFA metabolism by oxidative tissues. METHODS: In a congenic strain of spontaneously hypertensive rats that fed a high-sucrose diet to promote features of the metabolic syndrome, we studied the effects of chronic pioglitazone treatment over 4 months on adipose tissue lipolysis and NEFA metabolism. RESULTS: We observed significant increases in basal and adrenaline-stimulated NEFA and glycerol release, and near-total suppression of NEFA reesterification in epididymal adipose tissue isolated from rats chronically treated with pioglitazone. However, pioglitazone-treated rats also exhibited significant increases in mitochondrial DNA levels in adipose tissue (3.2-fold increase, P=0.001) and potentially greater sensitivity to the antilipolytic effects of insulin than untreated controls. In addition, chronic pioglitazone treatment was associated with increased palmitate oxidation in soleus muscle, reduced fasting levels of serum NEFA and triglycerides, as well as reduced serum levels of insulin and increased serum levels of adiponectin. CONCLUSIONS: Despite suppressing NEFA reesterification and increasing basal and adrenaline-stimulated lipolysis, chronic pioglitazone treatment may decrease circulating NEFA levels in part by increasing adipose tissue sensitivity to the antilipolytic effects of insulin and by enhancing NEFA oxidation in skeletal muscle.

Acute toxic effects of telmisartan in spontaneously hypertensive rats fed a high fructose diet.

Telmisartan is an angiotensin receptor blocker (ARB) and a selective peroxisome proliferator activated receptor gamma (PPARG) modulator. Recently, we tested metabolic effects of telmisartan (5 mg/kg body weight) in spontaneously hypertensive rats (SHR) fed a diet containing 60 % fructose, a widely used model of the metabolic syndrome. Surprisingly, we observed acute toxic effects of telmisartan. Rats lost body weight rapidly and died within 2 to 3 weeks due to bleeding into the upper gastrointestinal tract. SHR fed a high fructose diet and treated with telmisartan exhibited rapid decrease in blood pressure when compared to the SHR fed a high fructose diet and treated with valsartan. Concentrations of both unconjugated telmisartan and telmisartan glucuronide in the liver of SHR rats fed a high fructose diet were approximately 4 fold higher when compared to Brown Norway (BN) rats fed the same diet. Plasma concentrations of unconjugated telmisartan in the SHR were about 5 fold higher when compared to BN rats while plasma levels of telmisartan glucuronide were similar between the strains. Testing of other rat strains, diets, and the ARB valsartan showed that toxic effects of telmisartan in combination with high fructose diet are specific for the SHR. These results are consistent with the possibility that in some circumstances, SHR are predisposed to telmisartan toxicity possibly because of a genetically determined disturbance in telmisartan metabolism.

Genetically determined folate deficiency is associated with abnormal hepatic folate profiles in the spontaneously hypertensive rat.

Increased levels of plasma cysteine are associated with obesity and metabolic disturbances. Our recent genetic analyses in spontaneously hypertensive rats (SHR) revealed a mutated Folr1 (folate receptor 1) as the quantitative trait gene associated with diminished renal Folr1 expression, lower plasma folate levels, hypercysteinemia, hyperhomocysteinemia and metabolic disturbances. To further analyse the effects of the Folr1 gene expression on folate metabolism, we used mass spectrometry to quantify folate profiles in the plasma and liver of an SHR-1 congenic strain, with wild type Folr1 allele on the SHR genetic background, and compared them with the SHR strain. In the plasma, concentration of 5-methyltetrahydrofolate (5mTHF) was significantly higher in SHR-1 congenic rats compared to SHR (60+/-6 vs. 42+/-2 nmol/l, P<0.01) and 5mTHF monoglutamate was the predominant form in both strains (>99 % of total folate). In the liver, SHR-1 congenic rats showed a significantly increased level of 5mTHF and decreased concentrations of dihydrofolate (DHF), tetrahydrofolate (THF) and formyl-THF when compared to the SHR strain. We also analysed the extent of folate glutamylation in the liver. Compared with the SHR strain, congenic wild-type Folr1 rats had significantly higher levels of 5mTHF monoglutamate. On the other hand, 5mTHF penta- and hexaglutamates were significantly higher in SHR when compared to SHR-1 rats. This inverse relationship of rat hepatic folate polyglutamate chain length and folate sufficiency was also true for other folate species. These results strongly indicate that the whole body homeostasis of folates is substantially impaired in SHR rats compared to the SHR-1 congenic strain and might be contributing to the associated metabolic disturbances observed in our previous studies.

Dissecting the role of Folr1 and Folh1 genes in the pathogenesis of metabolic syndrome in spontaneously hypertensive rats.

Increased levels of plasma cysteine predispose to obesity and metabolic disturbances. Our recent genetic analyses in spontaneously hypertensive rats (SHR) revealed mutated Folr1 (folate receptor 1) on chromosome 1 as a quantitative trait gene associated with reduced folate levels, hypercysteinemia and metabolic disturbances. The Folr1 gene is closely linked to the Folh1 (folate hydrolase 1) gene which codes for an enzyme involved in the hydrolysis of dietary polyglutamyl folates in the intestine. In the current study, we obtained evidence that Folh1 mRNA of the BN (Brown Norway) origin is weakly but significantly expressed in the small intestine. Next we analyzed the effects of the Folh1 alleles on folate and sulfur amino acid levels and consecutively on glucose and lipid metabolism using SHR-1 congenic sublines harboring either Folr1 BN and Folh1 SHR alleles or Folr1 SHR and Folh1 BN alleles. Both congenic sublines when compared to SHR controls, exhibited significantly reduced folate clearance and lower plasma cysteine and homocysteine levels which was associated with significantly decreased serum glucose and insulin concentrations and reduced adiposity. These results strongly suggest that, in addition to Folr1, the Folh1 gene also plays an important role in folate and sulfur amino acid levels and affects glucose and lipid metabolism in the rat.

Genetics of Cd36 and the clustering of multiple cardiovascular risk factors in spontaneous hypertension.

Disorders of carbohydrate and lipid metabolism have been reported to cluster in patients with essential hypertension and in spontaneously hypertensive rats (SHRs). A deletion in the Cd36 gene on chromosome 4 has recently been implicated in defective carbohydrate and lipid metabolism in isolated adipocytes from SHRs. However, the role of Cd36 and chromosome 4 in the control of blood pressure and systemic cardiovascular risk factors in SHRs is unknown. In the SHR. BN-Il6/Npy congenic strain, we have found that transfer of a segment of chromosome 4 (including Cd36) from the Brown Norway (BN) rat onto the SHR background induces reductions in blood pressure and ameliorates dietary-induced glucose intolerance, hyperinsulinemia, and hypertriglyceridemia. These results demonstrate that a single chromosome region can influence a broad spectrum of cardiovascular risk factors involved in the hypertension metabolic syndrome. However, analysis of Cd36 genotypes in the SHR and stroke-prone SHR strains indicates that the deletion variant of Cd36 was not critical to the initial selection for hypertension in the SHR model. Thus, the ability of chromosome 4 to influence multiple cardiovascular risk factors, including hypertension, may depend on linkage of Cd36 to other genes trapped within the differential segment of the SHR. BN-Il6/Npy strain.

Mutant Wars2 gene in spontaneously hypertensive rats impairs brown adipose tissue function and predisposes to visceral obesity.

Brown adipose tissue (BAT) plays an important role in lipid and glucose metabolism in rodents and possibly also in humans. Identification of genes responsible for BAT function would shed light on underlying pathophysiological mechanisms of metabolic disturbances. Recent linkage analysis in the BXH/HXB recombinant inbred (RI) strains, derived from Brown Norway (BN) and spontaneously hypertensive rats (SHR), identified two closely linked quantitative trait loci (QTL) associated with glucose oxidation and glucose incorporation into BAT lipids in the vicinity of Wars2 (tryptophanyl tRNA synthetase 2 (mitochondrial)) gene on chromosome 2. The SHR harbors L53F WARS2 protein variant that was associated with reduced angiogenesis and Wars2 thus represents a prominent positional candidate gene. In the current study, we validated this candidate as a quantitative trait gene (QTG) using transgenic rescue experiment. SHR-Wars2 transgenic rats with wild type Wars2 gene when compared to SHR, showed more efficient mitochondrial proteosynthesis and increased mitochondrial respiration, which was associated with increased glucose oxidation and incorporation into BAT lipids, and with reduced weight of visceral fat. Correlation analyses in RI strains showed that increased activity of BAT was associated with amelioration of insulin resistance in muscle and white adipose tissue. In summary, these results demonstrate important role of Wars2 gene in regulating BAT function and consequently lipid and glucose metabolism.

Hepatotoxic effects of fenofibrate in spontaneously hypertensive rats expressing human C-reactive protein.

Dyslipidemia and inflammation play an important role in the pathogenesis of cardiovascular and liver disease. Fenofibrate has a well-known efficacy to reduce cholesterol and triglycerides. Combination with statins can ameliorate hypolipidemic and anti-inflammatory effects of fibrates. In the current study, we tested the anti-inflammatory and metabolic effects of fenofibrate alone and in combination with rosuvastatin in a model of inflammation and metabolic syndrome, using spontaneously hypertensive rats expressing the human C-reactive protein transgene (SHR-CRP transgenic rats). SHR-CRP rats treated with fenofibrate alone (100 mg/kg body weight) or in combination with rosuvastatin (20 mg/kg body weight) vs. SHR-CRP untreated controls showed increased levels of proinflammatory marker IL6, increased concentrations of ALT, AST and ALP, increased oxidative stress in the liver and necrotic changes of the liver. In addition, SHR-CRP rats treated with fenofibrate, or with fenofibrate combined with rosuvastatin vs. untreated controls, exhibited increased serum triglycerides and reduced HDL cholesterol, as well as reduced hepatic triglyceride, cholesterol and glycogen concentrations. These findings suggest that in the presence of high levels of human CRP, fenofibrate can induce liver damage even in combination with rosuvastatin. Accordingly, these results caution against the possible hepatotoxic effects of fenofibrate in patients with high levels of CRP.