In Search of Optimal Criteria for Iron Deficiency in CHF Patients. Post-hoc Analysis of the Study "Prevalence of Iron Deficiency in Patients With Chronic Heart Failure in the Russian Federation (ID-CHF-RF)".

AIM: Comparative analysis of clinical, anamnestic, and laboratory and instrumental data of patients with chronic heart failure (CHF) and iron deficiency (ID) diagnosed according to the AHA/ESC/RSC criteria, and CHF patients diagnosed with ID based on decreased transferrin saturation (TSAT) ≤19.8% or serum iron (Fe) ≤13 µmol/l. MATERIAL AND METHODS: An additional analysis of the ID-CHF-RF study was performed. The analyzed population included 498 patients (198 women) with CHF. In addition to the ID criteria provided by the protocol (AHA/ESC/RSC criteria: ferritin <100 µg/l or ferritin from 100 to 299 µg/l and TSAT<20%), concentrations of ID biomarkers were assessed, which showed high sensitivity and specificity for the diagnosis of ID compared to the morphological picture of the bone marrow (TSAT<19.8% or Fe ≤13 µmol/l). Subgroups of patients with ID determined only by the AHA/ESC/RSC criteria, only by the TSAT≤19.8% and Fe ≤13 µmol/l criteria, and by both were analyzed. RESULTS: ID diagnosed by the AHA/ESC/RSC criteria was found in 83.1% of patients. The TSAT ≤19.8% and Fe ≤13 µmol/l criteria revealed ID in 74.5% of patients. In 341 patients (76.8%), ID was diagnosed using both criteria. Patients with ID diagnosed by the TSAT≤19.8% and Fe≤13 µmol/l criteria, compared with patients with ID diagnosed by the AHA/ESC/RKO criteria, had a 50% lower Fe (9.8 µmol/l vs. 19.4 µmol/l) and a higher incidence of anemia (43.3% vs. 23.3%) and diabetes mellitus (DM) (36.7% and 24.7%). Also, these patients had higher values of body mass index (BMI) and NT-proBNP concentration (2317 [1305;9092] vs. 1691 [709;3856] pg/ml), and lower LV EF values (41.5 [29.0;54.5]% vs. 45.0 [34.0;54.0]%), respectively. The most severe course of CHF and the greatest changes in laboratory tests associated with ID and anemia were observed in patients with ID determined by two criteria. Patients in this group were older, with a higher BMI, more frequent presence of atrial fibrillation, and higher NT-proBNP (4182 [1854;9341] pg/ml). CONCLUSION: Patients with isolated low ferritin are characterized by less severe clinical and functional impairment compared to patients with low TSAT or Fe. At the same time, patients with ferritin higher than 300 µg/l and low TSAT and/or Fe were characterized by very severe CHF and a low functional status, although this may not be related with ID. Thus, the use of the ferritin-based criteria of ID may lead to overdiagnosis of ID in some patients and, at the same time, miss some of the most "severe" patients who likely require the ID correction. Patients with ID who show a decrease in all three parameters are likely to benefit most from Fe supplementation. It is advisable to perform additional studies on the effect of Fe supplements on the course and prognosis of the disease in this cohort of patients.

[Clinical case of generalized amyloidosis (ATTR-amyloidosis) with a progressive course of chronic heart failure. Case report].

Despite the presence of various signs of cardiac amyloidosis ("red flags"), the introduction into routine practice of new non-invasive diagnostic methods (Speckle Tracking technology using echocardiography, myocardial scintigraphy with technetium pyrophosphate, genetic testing, screening for free light chains of immunoglobulins to exclude AL-amyloidosis), which have high specificity and sensitivity, transthyretinic (ATTR) cardiomyopathy is still a difficult to diagnose disease, especially in the early stages when treatment is most effective. The article presents a clinical case of ATTR-amyloidosis with predominant heart damage, manifested by severe diastolic heart failure resistant to treatment. The timing, from the moment of the first episode of decompensation of heart failure to death, is 4 months, which confirms the rapid progression of severe biventricular dysfunction of the heart. Despite the presence of cardiac and extracardial "red flags" of ATTR-amyloidosis in the patient, the diagnosis was established at autopsy. The paper analyzes possible errors of early diagnosis at the outpatient and inpatient stages of patient management.

Female and Male Phenotypes of Iron Deficiency in CHF. Additional analysis of the «The Prevalence of Iron Deficiency in Patients With Chronic Heart Failure in the Russian Federation (J-CHF-RF)¼ study.

Aim    To evaluate the incidence of iron deficiency (ID) in men and women with chronic heart failure (CHF) and to compare clinical and functional indexes in patient with and without ID depending on the gender.Material and methods    An additional analysis of the study "Prevalence of Iron Deficiency in Patients With Chronic Heart Failure in the Russian Federation (ID-CHF-RF)" was performed. The study included 498 (198 women, 300 men) patients with CHF, in whom, in addition to iron metabolism, the quality of life and exercise tolerance (ET) were studied. 97 % of patients were enrolled during their stay in a hospital. ID was defined in consistency with the European Society of Cardiology (ESC) Guidelines. Also, and additional analysis was performed according to ID criteria validated by the morphological picture of the bone marrow.Results    ID was detected in 174 (87.9 %) women and 239 (79.8 %) men (p=0.028) according to the ESC criteria, and in 154 (77.8 %) women and 217 (72.3 %) men (p=0.208) according to the criteria validated by the morphological picture of the bone marrow. Men with ID were older and had more severe CHF. They more frequently had HF functional class (FC) III and IV (63.4 % vs. 43.3 % in men without ID); higher concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and lower ET. HF FC III increased the probability of ID presence 3.4 times (p=0.02) and the probability of HF FC IV 13.7 times (p=0.003). This clinical picture was characteristic of men when either method of determining ID was used. In women, ID was not associated with more severe CHF.Conclusion    Based on the presented analysis, it is possible to characterize the male and female ID phenotypes. The male ID phenotype is associated with more severe CHF, low ET, and poor quality of life. In females of the study cohort, ID was not associated with either the severity of CHF or with ET.

[Iron deficiency in Russia heart failure patients. Observational cross-sectional multicenter study].

Aim    To evaluate the prevalence of iron deficiency (ID) in Russian patients with heart failure (HF).Material and methods    Iron metabolism variables were studied in 498 (198 women, 300 men) patients with HF. Data were evaluated at admission for HF (97 %) or during an outpatient visit (3 %). ID was determined according to the European Society of Cardiology Guidelines.Results    83.1 % of patients had ID; only 43.5 % of patients with ID had anemia. Patients with ID were older: 70.0 [63.0;79.0] vs. 66.0 years [57.0;75.2] (p=0.009). The number of patients with ID increased in parallel with the increase in HF functional class (FC). Among patients with ID, fewer people were past or current alcohol users (p=0.002), and a greater number of patients had atrial fibrillation (60.1 vs. 45.2 %, p=0.016). A multiple logistic regression showed that more severe HF (HF FC) was associated with a higher incidence of ID detection, whereas past alcohol use was associated with less pronounced ID. An increase in N-terminal pro-brain natriuretic peptide (NT-proBNP) by 100 pg/ml was associated with an increased likelihood of ID (odds ratio, 1.006, 95 % confidence interval: 1.002-1.011, p=0.0152).Conclusion    The incidence rate of HF patients is high in the Russian Federation (83.1 %). Only 43.5 % of these patients had anemia. The prevalence of ID in the study population increased with increases in HF FC and NT-proBNP.

[Practical guidelines for the diagnosis and treatment of transthyretin amyloid cardiomyopathy (ATTR-CM or transthyretin cardiac amyloidosis)].

This paper summarizes the data from updated international protocols and guidelines for diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). The invasive and non-invasive diagnosis techniques and their combinations are briefly reviewed; the evidentiary foundations for each diagnostic option and tool are analyzed. The paper describes a customized algorithm for sequential diagnosis and differential diagnosis of patients with suspected ATTR-CM with allowance for the combination of clinical signs and diagnostic findings. Along with the awareness of primary care providers about the red flags of the disease and visualization criteria, as well as providing information to the patients about the possibility of performing therapy of ATTR amyloidosis and the risks of delayed diagnosis, the proposed algorithm enables timely patient routing and prescribing specific treatment.

[Genetic Predisposition to Early Myocardial Infarction].

The aim of the study was to identify the features of the genetic structure of myocardial infarction (MI) susceptibility depending on age ("early MI" denoting individuals who had the first MI before the age of 60 years, and "late MI" the group of patients with the first "MI after 60 years"). A total of 355 patients were examined (n = 121 early MI and n = 234 late MI) and 285 residents of the Siberian region (as a control group). Genotyping of 58 single nucleotide variants (SNPs) was performed using mass spectrometry using the Agena (ex Sequenom) MassARRAY® System. Statistical analysis was performed using Statistica 8.0 ("StatSoft Inc.", USA), as well as the "stats" and "genetics" packages in the R environment. The regulatory potential of SNPs was evaluated using the rSNPBase online service (http://rsnp.psych.ac.cn/). eQTL loci were identified using data from the Genotype-Tissue Expression (GTEx) project (http://www.gtexportal.org/) and the Blood eQTL online service (https://genenetwork.nl/bloodeqtlbrowser/). The GG genotype of ITGA4 rs1143674, the CC genotype of CDKN2B-AS1 rs1333049, and the CC genotype of KIAA1462 rs3739998, are generally associated with MI. The AA genotype of ADAMDEC1 rs3765124 (OR = 2.03; 95% CI 1.23-3.33; p = 0.004) and the GG genotype of AQP2 rs2878771 (OR = 2.24; 95% CI 1.23-4.09; p = 0.006) are associated with the development of MI at an early age, and the TT genotype of TAS2R38 rs1726866 (OR = 1.82; 95% CI 1.11-2.89; p = 0.009) was the high-risk genotype for the late MI. Genetic variants associated with MI are regulatory SNP (rSNP) and affect the affinity of DNA binding to transcription factors, carry out post-transcriptional control of gene activity and change the level of gene expression in various tissues. Thus, early and late MI are based on both common genetic variants of ITGA4, CDKN2B-AS1, KIAA1462 genes and specific ones (ADAMDEC1 and AQP2 for early MI and TAS2R38 for late MI).

[Fibrogenesis Genes and Susceptibility to Coronary Atherosclerosis].

OBJECTIVES: To study associations between genes of different functional classes, including fibrogenesis genes, with coronary atherosclerosis and specific features of its course. METHODS: We included in this study 404 patients with confirmed chronic ischemic heart disease (IHD) who had undergone coronary artery bypass grafting. Two groups of participants were distinguished - those with (n=188) and without (n=216) history of myocardial infarction (MI). Control group consisted of inhabitants of the Siberia region (n=285). Associations were analyzed using 48 single nucleotide polymorphisms (SNP) located in genes earlier determined as associated with diseases of the cardiovascular continuum (diabetes mellitus, MI, atherosclerosis). Multiplex genotyping was performed using mass spectrometry. For statistical analyses we used Statistica v8.0 and R-language with "stats" and "genetics" packages. RESULTS: We identified several genetic markers contributing to susceptibility to development of atherosclerosis. Same markers were identified as determinants of the character of the course of atherosclerotic disease. Risk of development of atherosclerosis was higher in carriers of the following genotypes: TT of ITGB5 gene (rs1007856) - by 1.6 times (OR=1.59; р=0.0153); GG of ITGA4 gene - by 1.85 times (OR=1.85; р=0.0016); GG of IGFBP7 gene (rs11133482) - by 2.4 times (OR=2.36; р=0.0031). The following genotypes were identified as protective against MI and determining stable course of the disease: AA of TLR4 gene (rs4986790) (OR=0.47; р=0.0104).; CC of LDLR gene (rs2738446) (OR=0,53; р=0.0041); GG of OAS1 gene (rs1131454) (OR=0.50; р=0.0274). CONCLUSION: Susceptibility to coronary atherosclerosis and prognosis of disease progression were found to be associated with polymorphism of certain genes, involved in metabolism of the extracellular matrix and processes of fibrogenesis (ADAMDEC1, ITGA4, ITGB5, CDKN2B-AS1, IGFBP7), lipid metabolism (LDLR), immune system functioning (TLR4, OAS1) and DNA repair (LIG1).

[The association of biological markers with echocardiographic indices in patients with myocardial infarction with ST segment elevation and preserved left ventricular ejection fraction].

AIM: To compare dynamics of biological marker concentrations with echocardiographic data in patients with ST elevation myocardial infarction (STEMI) and preserved LV function during the hospitalization period. MATERIALS AND METHODS: The study successively included 100 patients with diagnosis of STEMI and LV ejection fraction.

[Postregistration study of comparative assessment efficacy of the use of fixed combination of nebivolol and amlodipine for the treatment of patients with moderate and high degree of arterial hypertension].

AIM: of the study was to assess efficacy of the use of fixed combination of nebivolol and amlodipine in patients with moderate and high degree of arterial hypertension (AH). MATERIAL AND METHODS: Patients with diagnosis of primary AH (n=124) were divided into 2 groups by random sample method. Patients of group 1 (n=62) received of fixed combination of nebivolol and amlodipine, while those of group 2 (n=62) received free combination of nebivolol and amlodipine. Study drugs were administered both as initial therapy and replacement of preceding treatment. Duration of observation was 3 months with visits after first 2 weeks and in 1, 2, and 3 months after enrollment. RESULTS: Starting from 2nd week visit of fixed combination of nebivolol and amlodipine treated patients had significantly lower levels of systolic and diastolic AP. Already after 2 weeks of combined two-component therapy 60% of group 1 and 52% of group 2 patients achieved target AP. Target AP was achieved by the end of month 1 by 86 and 71%, of month 2 - by 93 and 78% of patients in groups 1 and 2, respectively. In 3 months almost all patients had target AP, but in 1.6% of group 1 and 2.3% of group 2 patients this level was achieved after addition of a thiazide diuretic. Patients receiving of fixed combination of nebivolol and amlodipine achieved noromosyslolia more quickly compared with patients who received free combination of nebivolol and amlodipine. CONCLUSION: Combined therapy with fixed combination of nebivolol and amlodipine appears to be one of effective approaches to treatment of patients with moderate and high degree AH.

[The role of matrix metalloproteinases in assessment of prognosis in patients with ST-elevation myocardial infarction during hospital stay].

Aim of the study was to investigate role of matrix metalloproteinases (MMP) in assessment of prognosis of repetitive cardiovascular events during hospital stay of patients with ST-elevation (STE) myocardial infarction (MI). We consecutively included into this study 175 patients with diagnosis of STEMI. Content of MMP-1, MMP-3 and MMP-9 in blood serum was measured at admission and on day 12 after onset of disease. Levels of all MMPs on day 12 were 1.1-1.6 times higher than on day 1 of MI (<0.05). Comparison of groups of patients with favorable and unfavorable outcome showed that patients with unfavorable outcome had higher median concentrations of MMP-3 and MMP-9 on day 1; this tendency was maintained on day 12. However these differences were significant only for MMP-9. Compared with patients with favorable outcome levels of this marker in patients with unfavorable outcome were higher by 19.4% (=0.04) on day 1 and by 48.8% (=0.03) on day 12. At logistic regression analysis for MMP-9 and unfavorable outcomes during hospital stay area under ROC-curve did not exceed 0.5. But when only inhospital deaths were considered 2 for MMP-9 (day 1) was 14.3 (<0.0001) while area under ROC-curve was 0.72 (0.64; 0.78; =0.02). Thus in patients with STEMI high concentrations of MMP-9 on day 1 of STEMI can come forward as independent marker of unfavorable outcome during hospital stay.

[Adherence to guidelines on management of acute coronary syndrome in Russian hospitals and outcomes of hospitalization (data from the RECORD-2 Registry)].

BACKGROUND: Complete following existing guidelines for management of acute coronary syndrome (ACS) is known to be associated with better outcomes. Partly this is explained by lesser adherence to recommendations in high risk patients. Aim of our study was to assess relationship between degree of following current guidelines and in hospital outcomes independently from initial assessment of risk. METHODS: Each key recommendation from guidelines issued between 2008 and 2011 (13 for STE ACS, 12 for NSTE ACS) was given weight of 1. Sum of these units constituted index of guideline adherence (IGA). IGA was retrospectively calculated for 1656 patients included in Russian independent ACS registry RECORD-2 (7 hospitals, duration 04.2009 to 04.2011). The patients were divided into 2 groups according to quartiles of IGA distribution: 1) low adherence group (quartiles I-II); 2) high adherence group (quartiles III-IV). RESULTS: In low adherence compared with high adherence group there were significantly more patients more or equal 65 years (=0.0007), with chronic heart failure [CHF] (<0.0001), previous stroke (<0.0001), atrial fibrillation [AF] (=0.0002), Killip class more or equal II (=0.0065), high risk of death by GRACE score (=0.035). Inhospital mortality was 9.3 and 2.4% in low and high adherence group, respectively (p<0.0001). The following independent predictors of inhospital death were identified: IGA quartiles I-II (odds ratio [OR] 4.0; 95% confidence interval [CI] 2.3-7.1; <0.0001), high GRACE score (OR 3.3; 95% CI 1.8-6.0; <0.0001), admission systolic BP less or equal 100 mm Hg (OR 3.1; 95% CI 1.8-5.4; <0.0001), admission serum glucose more or equal 8 mmol/l (OR 2.9; 95% CI 1.8-4.7; <0.0001), age more or equal 65 years (OR 2.3; 95% CI 1.3-4.0; =0.005), ST elevation more or equal 1 mm on first ECG (OR 1.7; 95% CI 1.1-2.5; =0.013). From groups with low and high adherence to guidelines we selected pairs of patients (n=588) with similar (or close) age, type of ACS, GRACE score, Killip class, presence of other important risk factors (CHF, AF, previous stroke), and formed 2 equal subgroups without significant differences in important demographic, anamnestic, clinical and laboratory data. Hospital mortality was 7.8 and 2.7% in low and high adherence subgroup, respectively (p<0.0001). CONCLUSIONS: In RECORD-2 ACS registry low adherence to guidelines was more frequent among high risk patients and was independent predictor of inhospital death. Association between degree of guidelines adherence and outcomes persisted after equalizing groups by some factors of risk of mortality.