The relationship between the key markers of myocardial fibrosis and gut microbiota composition in patients with heart failure and preserved ejection fraction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.N Kaburova ◽  
O.M Drapkina ◽  
S.M Uydin ◽  
M.S Pokrovskaya ◽  
S.N Koretsky ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Gut Microbiota ◽  
Myocardial Fibrosis ◽  
Interquartile Range ◽  
Enzyme Linked Immunosorbent Assay ◽  
Type I ◽  
Microbiota Composition ◽  
Preserved Ejection Fraction ◽  
Gut Microbiota Composition

Abstract Background Increased myocardial fibrosis may play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology. The current gold standard for the diagnosis and assessment of myocardial fibrosis is endomyocardial biopsy. A number of circulating biomarkers have been proposed for the assessment of myocardial fibrosis, however the most consistent results have been found for C-terminal propeptide of procollagen type I (PICP) and N-terminal propeptide of pro-collagen type III (PIIINP). Some evidence suggests the possible link between the gut microbiota composition and myocardioal fibrosis. Purpose The aim of the study was to investigate the association between the serum markers of myocardial fibrosis (PICP and PIIINP) with gut microbial genera in patients with HFpEF. Methods 42 patients with confirmed HF-pEF (mediana and interquartile range of age 67 [64; 72] years, 47% men, body mass index <35 kg/m2 with no history of myocardial infarction or diabetes mellitus) were enrolled in the study. The patients underwent transthoracic echocardiography with Doppler study, HF-pEF was confirmed according to the recent ESC guidelines (based on E/e' ratio, N-terminal pro-B type natriuretic peptide >125 pg/ml and symptoms of HF). The levels of PICP and PIIINP were evaluated in patients' serum using enzyme-linked immunosorbent assay. The intestinal microbiome was investigated using high-throughput sequencing of bacterial 16S rRNA gene. Results The mediana and interquartile range in PICP was 918 [700; 1044] pg/ml, in PIIINP it was 6.215 [3.99; 8.29] pg/ml. The analysis revealed significant correlations between PICP and the following bacterial genera of Firmicutes:Ruminococcus (r=−0,36); Gemmiger (r=−0,35), Allisonella (r=0,32) and Howardella (r=−0,30). PIIINP significantly correlated with 2 genera: Blautia which belongs to Firmicutes phylum (r=0,36) and Bilophila which belongs to Proteobacteria phylum (r=−0,33). All values with p<0,05. Conclusion Both PICP and PIIINP had negative significant correlations with beneficial bacterial genera and positive correlations with several potencially harmful gut bacterial genera. This type of relationship might become the novel field of research in the group of patients with HF-pEF due to myocardial fibrosis. Funding Acknowledgement Type of funding source: None

scholarly journals The link between left ventricular extracellular volume determined by T1 myocardial mapping and gut microbiota composition in individuals with heart failure and preserved ejection fraction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.N Kaburova ◽  
O.M Drapkina ◽  
S.M Uydin ◽  
M.V Vishnyakova ◽  
M.S Pokrovskaya ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Gut Microbiota ◽  
Myocardial Fibrosis ◽  
Volume Fraction ◽  
Extracellular Volume ◽  
Left Ventricular ◽  
Diffuse Myocardial Fibrosis ◽  
Rrna Gene ◽  
Preserved Ejection Fraction

Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) represents a major challenge in modern cardiology. As described previously, in HFpEF comorbidities promote a systemic inflammatory state, leading to diffuse myocardial fibrosis resulting in myocardial stiffening. Gut dysbiosis which is considered as the novel source of chronic systemic inflammation has been actively investigated as the risk factor for the development and aggravation of cardiovascular diseases including heart failure. Cardiac magnetic resonance T1-mapping is a novel tool, which allows noninvasive quantification of the extracellular space and diffuse myocardial fibrosis. Moreover, the extracellular volume (ECV) fraction can be calculated, providing information on the relative expansion of the extracellular matrix, thus being a noninvasive alternative to myocardial biopsy studies. Purpose The research was aimed at investigating the correlation between the left ventricular ECV and gut microbial genera in patients with HFpEF. Methods 42 patients with confirmed HF-pEF (mediana and interquartile range of age 67 [64; 72] years, 47% men, body mass index <35 kg/m2 with no history of myocardial infarction or diabetes mellitus) were enrolled in the study. The patients underwent transthoracic echocardiography with Doppler study, HF-pEF was confirmed according to the recent ESC guidelines (based on E/e' ratio, N-terminal pro-B type natriuretic peptide >125 pg/ml and symptoms of heart failure). The intestinal microbiome was investigated using high-throughput sequencing of bacterial 16S rRNA gene. As the last step of research T1-myocardial mapping with the modified look-locker inversion-recovery protocol (MOLLI) sequence at 1.5 Tesla was performed to assess left ventricular extracellular volume fraction. Results The mean±std in ECV was 31.02±4.4%. The relative abundance (%) of the most prevalent phyla in gut microbiota was 48±22.5 for Firmicutes, 47.4±22.8 for Bacteroidetes and 1.5 [1.5; 2.5] for Proteobacteria. The analysis showed significant negative correlations between ECV and the following bacterial genera: Faecalibacterium (r=−0.35), Blautia (r=−0.43), Lachnoclostridium (r=−0.32). Moreover ECV positively correlated with Holdemania (r=0.4), Victivallis (r=0.38), Dehalobacterium (r=0.38), Enterococcus (r=0.33) and Catabacter (r=0.32). All correlation values with p<0.05. Conclusion We discovered both negative and positive significant correlations between ECV – the non-invasive marker of myocardial fibrosis and several bacterial genera, which may have negative impact on myocardial remodeling in HF-pEF. Funding Acknowledgement Type of funding source: None

scholarly journals Relationship between gut microbiota and markers of myocardial fibrosis in with chronic heart failure with preserved ejection fraction

2021 ◽  
Vol 20 (4) ◽  
pp. 2834
Author(s):  
A. N. Kaburova ◽  
O. M. Drapkina ◽  
S. M. Yudin ◽  
S. N. Koretsky ◽  
V. V. Makarov ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Gut Microbiota ◽  
Myocardial Fibrosis ◽  
Relative Abundance ◽  
Multivariate Regression ◽  
Inverse Relationship ◽  
Preserved Ejection Fraction ◽  
Procollagen Type ◽  
The Relationship

Aim. To study the relationship of gut microbiota (GM) with serum myocardial fibrosis markers in patients with heart failure with preserved ejection fraction (HFpEF).Material and methods. The composition of the gut microbiota among 42 patients with HFpEF aged 67,0 [64,0; 71,5] years (men, 57,1%) was assessed by 16S ribosomal ribonucleic acid sequencing. The quantitative determination of myocardial fibrosis markers was carried out by enzyme-linked immunosorbent assay. Correlation and multivariate regression analysis of relationships between the relative abundance of intestinal bacteria and the concentration of the procollagen type I carboxy-terminal propeptide (PICP) and N-terminal propeptide of procollagen type III (PIIINP) was carried out.Results. The PICP and PIIINP concentrations were 918,0 [700,0; 1032,8] pg/ml and 6,2±2,7 pg/ml, respectively. Correlation analysis revealed a direct relationship between the relative abundance of Allisonella and PICP (r=0,32), as well as Blautia, Enterobаcteriaceae (unclassified) and PIIINP (r=0,37 and r=0,32), p<0,05. The inverse relationship was determined for the relative abundance of the genera Ruminococcus (r=-0,37), Ruminococcaceae (unclassified) (r=-0,31), Gemmiger (r=(-0,35) and PICP, as well as Bilophila and PIIICP (r=(-0,34). Multivariate regression found (normalized coefficient in parentheses) that the abundance of Butyricimonas (0,27) и Blautia (0,35) was directly related to the PICP levels, while the abundance of the genus Intestinimonas ((-0,23) showed an inverse association with the marker level. The abundance of most genera had an inverse relationship with PIIINP: Atopobium (-0,25), Cellulosilyticum (-0,31), Solobacterium (-0,32), Turicibacter (-0,47), Bilophila (-0,30). The directness of the association with  PIIINP concentration was demonstrated for the relative abundance of Paraprevotella (0,32) и Desulfovibrio (0,28). The p-value for all associations is <0,05.Conclusion. The relative abundance of GM genera in patients with HFpEF is associated with fibrosis markers (PICP and PIIINP). The results obtained make it possible to deepen the understanding of the relationship between GM and pathogenesis of HFpEF, which may become a step towards understanding the GM role in the progression of left ventricular diastolic dysfunction and rationale for future studies.

scholarly journals Does Chronic Kidney Disease Facilitate Malignant Myocardial Fibrosis in Heart Failure with Preserved Ejection Fraction of Hypertensive Origin?

2020 ◽  
Vol 9 (2) ◽  
pp. 404 ◽  
Author(s):  
Rocio Eiros ◽  
Gregorio Romero-González ◽  
Juan Jose Gavira ◽  
Oscar Beloqui ◽  
Inmaculada Colina ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Ejection Fraction ◽  
Myocardial Fibrosis ◽  
Collagen Type I ◽  
Type I ◽  
Preserved Ejection Fraction ◽  
Matrix Metalloproteinase 1 ◽  
Carboxy Terminal

In hypertensive patients with heart failure (HF) a serum biomarker combination of high carboxy-terminal propeptide of procollagen type-I (PICP) and low carboxy-terminal telopeptide of collagen type-I to matrix metalloproteinase-1 (CITP:MMP-1) ratio identifies a histomolecular phenotype of malignant myocardial fibrosis (mMF) associated with severe diastolic dysfunction (DD) and poor outcomes. As chronic kidney disease (CKD) facilitates MF and DD, we investigated the influence of CKD on the mMF biomarker combination in HF patients with preserved ejection fraction (HFpEF). Hypertensives (n = 365), 232 non-HF and 133 HFpEF, were studied, and 35% non-HF and 46% HFpEF patients had CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2 or urine albumin-to-creatinine ratio ≥ 30 mg/g). Specific immunoassays were performed to determine biomarkers. Medians were used to establish the high PICP and low CITP:MMP-1 combination. A comparison with non-HF showed that the biomarker combination presence was increased in HFpEF patients, being associated with CKD in all patients. CKD influenced the association of the biomarker combination and HFpEF (p for interaction ≤ 0.019). The E:e’ ratio was associated with the biomarker combination in CKD patients. Among CKD patients with HFpEF, those with the biomarker combination exhibited higher (p = 0.016) E:e’ ratio than those without the pattern. These findings suggest that CKD facilitates the development of biomarker-assessed mMF and DD in hypertensive HFpEF patients.

scholarly journals Changes of myocardial fibrosis markers with the use of beta-blockers and mineralocorticoid receptor antagonists in patients with heart failure with mid-range ejection fraction of ischemic origin

2021 ◽  
Vol 20 (7) ◽  
pp. 3068
Author(s):  
O. A. Osipova ◽  
E. V. Gosteva ◽  
T. P. Golivets ◽  
O. N. Belousova ◽  
O. A. Zemlyansky ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Myocardial Fibrosis ◽  
Mineralocorticoid Receptor ◽  
Nyha Class ◽  
Class Ii ◽  
Class I ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mineralocorticoid Receptor Antagonist ◽  
Patients With Heart Failure

Aim. To compare the effect of 12-month pharmacotherapy with a betablocker (BB) (bisoprolol and nebivolol) and a combination of BB with a mineralocorticoid receptor antagonist (bisoprolol+eplerenone, nebivolol+eplerenone) on following fibrosis markers: matrix metalloproteinases 1 and 9 (MMP-1, MMP-9) and tissue inhibitor of MMP-1 (TIMP-1) in patients with heart failure with mid-range ejection fraction (HFmrEF) of ischemic origin.Material and methods. The study included 135 patients, including 40 (29,6%) women and 95 (70,4%) men aged 45-60 years (mean age, 53,1±5,7 years). Patients were randomized into subgroups based on pharmacotherapy with BB (bisoprolol or nebivolol) and their combination with eplerenone. The enzyme-linked immunosorbent assay was used to determine the level of MMP-1, MMP-9, TIMP-1 (ng/ml) using the commercial test system “MMP-1 ELISA”, “MMP-9 ELISA”, “Human TIMP-1 ELISA” (“Bender Medsystems “, Austria).Results. In patients with HFmrEF of ischemic origin, there were following downward changes in serum level of myocardial fibrosis markers, depending on the therapy: bisoprolol  — MMP-1 decreased by 35% (p<0,01), MMP-9  — by 56,3% (p<0,001), TIMP-1  — by 17,9% (p<0,01); nebivolol  — MMP-1 decreased by 45% (p<0,001), MMP-9  — by 57,1% (p<0,001), TIMP-1  — by 30,1% (p<0,01); combination of bisoprolol with eplerenone  — MMP-1 decreased by 43% (p<0,001), MMP-9  — by 51,2% (p<0,001), TIMP-1  — by 25,1% (p<0,01); combination of nebivolol with eplerenone  — MMP-1 decreased by 53% (p<0,001), MMP-9 — by 64,3% (p<0,001), TIMP-1 — by 39% (p<0,01). In patients with NYHA class I HFmrEF after 12-month therapy, the decrease in MMP-1 level was 39,9% (p<0,01), MMP-9  — 57,5% (p<0,001). In class II, the decrease in MMP-1 level was 47% (p<0,001), MMP-9 — 49,7% (p<0,001). A significant decrease in TIMP-1 level was revealed in patients with class I by 29% (p<0,01), in patients with class II by 27,1% (p<0,01) compared with the initial data.Conclusion. A significant decrease in the levels of myocardial fibrosis markers (MMP-1, MMP-9, TIMP-1) was demonstrated in patients with HFmrEF of ischemic origin receiving long-term pharmacotherapy. The most pronounced effect was determined in patients with NYHA class I HF.

3057Relation of atrial remodeling to circulating biomarkers of myocardial fibrosis and apoptotic microparticles in patients with atrial fibrillation and heart failure with preserved ejection fraction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M S Dzeshka ◽  
E Shantsila ◽  
V A Snezhitskiy ◽  
G Y H Lip
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Ejection Fraction ◽  
Matrix Metalloproteinase ◽  
Myocardial Fibrosis ◽  
Univariate Analysis ◽  
Volume Index ◽  
Atrial Remodeling ◽  
Preserved Ejection Fraction ◽  
Circulating Biomarkers

Abstract Introduction Left atrial (LA) remodeling is a mainstay for atrial fibrillation (AF) occurrence. AF further promotes structural changes in LA, as fibrosis and stretching, followed by AF progression to its permanent form. Many profibrotic pathways have been studied, and circulating microparticles (MPs) may have a role. MPs are extracellular submicron anucleoid phospholipid vesicles released from different cells. Annexin V-binding (AnV+) MPs were suggested as a marker of apoptosis. Purpose To evaluate association of circulating biomarkers of myocardial fibrosis and MPs subsets with LA remodeling in patients with AF and heart failure with preserved ejection fraction. Methods We studied 274 patients (median age 62 years, 37% females). Paroxysmal AF was diagnosed in 150 patients (55%) and non-paroxysmal AF (persistent or permanent) in 124 (45%). Median CHA2DS2-VASc score was 3 in males and 4 in females. Patients with valvular AF, recent (<6 months) thromboembolic or hemorrhagic event, advanced chronic kidney or hepatic dysfunction, malignancy or active inflammatory disorders were excluded. Transthoracic echocardiography was performed. LA maximum volume index (LAVi) was measured as an index of LA structural remodeling in AF. Average values from ten consecutive cardiac cycles were calculated. Blood levels of galectin 3, interleukin-1 receptor-like 1 (ST2), transforming growth factor beta 1 (TGF-β1), procollagen type III aminoterminal propeptide (PIIINP), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), angiotensin II and aldosterone were assayed as surrogate biomarkers of myocardial fibrosis with ELISA. Using microflow cytometry (Figure), numbers of platelet-derived (CD42b+), monocyte-derived (CD14+), endothelial (CD144+), and apoptotic MPs (AnV+) were quantified in plasma samples. Linear regression was used to reveal parameters associated with LAVi. Raw data were normalized with Box-Cox transformation. Results Median LAVi in studied patients was 48 (39–59) ml/m2 and increased from patients with paroxysmal AF (42 [35–51] ml/m2) to persistent AF (53 [43–62] ml/m2) and permanent AF (57 [46–69] ml/m2), p<0.001. On univariate analysis male gender (β=0.11, p=0.04); history of hypertension (β=0.18, p=0.03); AF type, i.e. progression from paroxysmal to permanent (β=0.38, p<0.001); AnV+ MPs (β=0.19, p=0.005); ST2 (β=0.15, p=0.02); and early mitral inflow velocity (E)/early mitral annular diastolic velocity (E/E') averaged for LV septal and lateral basal regions (β=0.18, p=0.005) were associated with LAVi. Using stepwise multivariate regression AnV+ MPs (β=0.14, p=0.03); AF type (β=0.35, p<0.001); and E/E' ratio (β=0.11, p=0.04) remained significant predictors of LAVi (adjusted for age and gender). Apoptotic MPs detection with microFCM Conclusion Level of circulating apoptotic MPs is associated with LAVi in AF patients with HFpEF, and may be involved in remodeling process or could represent surrogate markers of myocardial damage in AF. Acknowledgement/Funding ESC Research Grant, EHRA Academic Research Fellowship Programme

scholarly journals A Porcine Model of Heart Failure With Preserved Ejection Fraction Induced by Chronic Pressure Overload Characterized by Cardiac Fibrosis and Remodeling

2021 ◽  
Vol 8 ◽  
Author(s):  
Weijiang Tan ◽  
Xiang Li ◽  
Shuang Zheng ◽  
Xiaohui Li ◽  
Xiaoshen Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Pathological Examination ◽  
Type I ◽  
Preserved Ejection Fraction

Heart failure is induced by multiple pathological mechanisms, and current therapies are ineffective against heart failure with preserved ejection fraction (HFpEF). As there are limited animal models of HFpEF, its underlying mechanisms have not yet been elucidated. Here, we employed the descending aortic constriction (DAC) technique to induce chronic pressure overload in the left ventricles of Tibetan minipigs for 12 weeks. Cardiac function, pathological and cellular changes, fibrotic signaling activation, and gene expression profiles were explored. The left ventricles developed concentric hypertrophy from weeks 4 to 6 and transition to dilation starting in week 10. Notably, the left ventricular ejection fraction was maintained at &gt;50% in the DAC group during the 12-week period. Pathological examination, biochemical analyses, and gene profile analysis revealed evidence of inflammation, fibrosis, cell death, and myofilament dephosphorylation in the myocardium of HFpEF model animals, together with gene expression shifts promoting cardiac remodeling and downregulating metabolic pathways. Furthermore, we noted the activation of several signaling proteins that impact cardiac fibrosis and remodeling, including transforming growth factor-β/SMAD family members 2/3, type I/III/V collagens, phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, matrix metalloproteinases 2 and 9, tissue inhibitor of metalloproteinases 1 and 2, interleukins 6 and 1β, and inhibitor of κBα/nuclear factor-κB. Our findings demonstrate that this chronic pressure overload-induced porcine HFpEF model is a powerful tool to elucidate the mechanisms of this disease and translate preclinical findings.

P3789Circulating biomarkers of myocardial fibrosis and cellular apoptosis in patients with atrial fibrillation and heart failure with preserved ejection fraction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M S Dzeshka ◽  
E Shantsila ◽  
V A Snezhitskiy ◽  
G Y H Lip
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Angiotensin Ii ◽  
Ejection Fraction ◽  
Matrix Metalloproteinase ◽  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Myocardial Fibrosis ◽  
Volume Index ◽  
Preserved Ejection Fraction

Abstract Introduction Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) commonly coexist. AF is associated with left atrial (LA) and ventricular (LV) myocardial fibrosis, contributing to diastolic dysfunction in HFpEF. Many profibrotic pathways have been studied in AF and HFpEF, but scarce data are available on the role of circulating microparticles (MPs). Purpose To evaluate association of circulating biomarkers of fibrosis and MPs subsets with Doppler-derived parameters of diastolic function in AF and HFpEF. Methods We studied 274 patients with non-valvular AF and HFpEF (median age 62 years, 37% females). Paroxysmal AF was diagnosed in 150 patients (55%) and non-paroxysmal AF (persistent or permanent) in 124 (45%). Median CHA2DS2-VASc score was 3 in males and 4 in females. Transthoracic echocardiography was performed to assess LV diastolic function, including early mitral inflow velocity (E), E/A velocities ratio (on sinus rhythm), early mitral annular diastolic velocity (E') for LV septal and lateral basal regions, E/E' ratio, LA maximum volume index (LAVi), E-wave velocity deceleration time (DT), flow propagation velocity (Vp). Average values from ten consecutive cardiac cycles were calculated. E/E' ratio was chosen as valid and reproducible index of diastolic function in AF patients for regression analysis. Blood levels of galectin 3, interleukin-1 receptor-like 1 (ST2), transforming growth factor beta 1 (TGF-β1), procollagen type III aminoterminal propeptide (PIIINP), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), angiotensin II and aldosterone level were assayed as surrogate biomarkers of myocardial fibrosis and profibrotic signaling. Using microflow cytometry, numbers of platelet-derived (CD42b+), monocyte-derived (CD14+), endothelial (CD144+), and apoptotic MPs (Annexin V+) were quantified in plasma samples. Linear regression was used to reveal parameters associated with diastolic function assessed as E/E' ratio. Data were normalized with Box-Cox transformation. Results Grade I diastolic dysfunction was found in 149 (54%); 94 (34%), and 31 (11%) patients had grade II and grade III diastolic dysfunction, respectively. On univariate analysis, age (β=0.23, p=0.0001); male gender (β=-0.19, p=0.02); history of hypertension (β=0.15, p=0.02); AF type, i.e. progression from paroxysmal to permanent (β=0.14, p=0.02); AnV+ MPs (β=0.19, p=0.01); angiotensin II (β=0.13, p=0.04); ST2 (β=0.1, p=0.04); and TIMP-1 (β=0.13, p=0.03) were associated with E/E' ratio. Using stepwise multivariate regression, AnV+ MPs (β=0.15, p=0.01) and TIMP-1 (β=0.3, p=0.04) remained significant predictors of E/E' ratio, adjusted for age, gender, hypertension and AF type. Relation of E/E' to TIMP-1 and AnV+ MPs Conclusion Apoptotic (AnV+) MPs and TIMP-1 were independently associated with diastolic dysfunction in AF and HFpEF. These may contribute to the pathophysiology of AF and HFpEF, and complications related to the presence of both. Acknowledgement/Funding ESC Research Grant, EHRA Academic Research Fellowship Programme

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