Gut Microbiota in Heart Failure Patients With Preserved Ejection Fraction (GUMPTION Study)

Introduction: Heart failure with preserved ejection fraction (HFpEF) is associated with disrupted intestinal epithelial function, resulting from intestinal congestion. Intestinal congestion changes the morphology and permeability of the intestinal wall, and it becomes easy for the gut microbiota to change and transfer. Intervention on gut microbiota may become a new target for HFpEF treatment. However, the characteristics of gut microbiota in patients with HFpEF remain unknown. This preliminary report aims to detect the structure of gut microbiota in HFpEF patients so as to explore their characteristic changes, thereby providing a theoretical basis for future research.Methods: This research recruited 30 patients diagnosed with HFpEF and 30 healthy individuals. Stool specimens of research subjects were collected separately, and the microarray analyses of gut microbiota were conducted by Illumina high-throughput DNA sequencing. The differences in gut microbiota composition, alpha diversity, and beta diversity between the two groups were finally obtained.Results: The composition of gut microbiota was significantly different between the two groups. At the phylum classification level, the abundance of Synergistetes tended to be higher in the HFpEF group (P = 0.012). At genus classification level, the abundance of Butyricicoccus (P < 0.001), Sutterella (P = 0.004), Lachnospira (P = 0.003), and Ruminiclostridium (P = 0.009) in the HFpEF group were lower, while the abundance of Enterococcus (P < 0.001) and Lactobacillus (P = 0.005) were higher. According to the Chao index of alpha diversity analysis, HFpEF patients showed a nominally significant lower species richness when compared with controls (P = 0.046). However, there was no statistical difference in the Shannon index (P = 0.159) and Simpson index (P = 0.495), indicating that there was no difference in species diversity between the two groups. Beta diversity analysis revealed a highly significant separation of HFpEF patients and controls.Conclusions: An imbalance in the gut microbiota of HFpEF patients was observed. Patients with HFpEF have an increased abundance of microbiota associated with inflammation and a decreased abundance of microbiota associated with anti-inflammatory effects in the gut environment. In line with that, the species richness of gut microbiota in HFpEF patients tended to be lower.

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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

European Heart Journal ◽

10.1093/ehjci/ehaa946.0864 ◽

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

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

European Heart Journal ◽

10.1093/ehjci/ehaa946.0861 ◽

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

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219Serum Trimethylamine N-Oxide levels and 16S rRNA gut microbiota profiling in patients with heart failure and preserved ejection fraction and healthy individuals

European Heart Journal ◽

10.1093/eurheartj/ehz747.0060 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

A N Kaburova ◽

S V Poyarkov ◽

V V Makarov ◽

O M Drapkina ◽

S M Uydin ◽

...

Keyword(s):

Heart Failure ◽

16S Rrna ◽

Ejection Fraction ◽

Gut Microbiota ◽

Intestinal Microbiome ◽

Rrna Gene ◽

Preserved Ejection Fraction ◽

Coronary Syndrome ◽

Doppler Study ◽

Α Diversity

Abstract Introduction Recent evidence suggests the role of gut microbiota dysregulation in the pathophysiology of chronic heart failure (HF). Elevated levels of Trimethylamine N-Oxide (TMAO) have shown to increase the risk of cardiovascular events and HF. Among patients with HF and preserved ejection fraction (HF-pEF) the link between TMAO levels and ventricular fibrosis was observed in studies, however, the data regarding 16S rRNA microbiome profiling in this particular group of HF are lacking. Purpose The research was aimed at investigating the gut microbiome diversity and composition as well as the serum TMAO levels among two groups of patients: healthy controls (HC) and HF-pEF. Methods 44 patients with HF-pEF and 45 HC with body mass index <35 kg/m2, no history of acute coronary syndrome, myocardial infarction or diabetes were enrolled in the study. All patients underwent transthoracic echocardiography with Doppler study to exclude diastolic dysfunction (E/e' <8 cm/s) or to prove HF-pEF (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 intestinal microbiome was investigated using high-throughput sequencing of bacterial 16S rRNA gene. TMAO levels were determined by liquid chromatography tandem mass spectrometry. Results The age in HC was 57,5 [48; 63] (28% men), age in HF-pEF group was 67 [64; 74] years (52% men). The serum concentration of TMAO in HC was 3.72 uM, in HF-pEF was 5.24 uM. The group of HF-pEF had significantly higher levels of the marker, p=0,003. Bacterial communities of both groups were dominated by the Firmicutes and Bacteroidetes phyla. The most abundant genus in both groups were Bacteroides. The Shannon index, the Chao 1 estimator, and the Simpson index assessing α diversity were not significantly different between groups. However, Bacteroides, Alistipes, Pseudomonas, and Fusobacterium were enriched in the common core microbiota of HF-pEF patients, while Lachnospira, Roseburia, Eubacterium, Methanobrevibacter and Faecalibacterium were depleted. To note, Lactobacillus and Bifidobacterium were depleted in HF-pEF patients too. TMAO levels in HC and HF-pEF groups Conclusions We have shown significant structural alterations of the intestinal microbiome and increased TMAO levels in HF-pEF patients' serum compared to HC. These findings may enable deeper understanding of the complex multifactorial pathogenesis of HF-pEF for the future development of personalized microbiome-based diagnostics and therapies for individuals at risk.

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The utility of cardiovascular imaging in heart failure with preserved ejection fraction: diagnosis, biological classification and risk stratification

Heart Failure Reviews ◽

10.1007/s10741-020-10047-9 ◽

2020 ◽

Author(s):

Gavin A. Lewis ◽

Keith Pearce ◽

Simon G. Williams ◽

Erik B. Schelbert ◽

Anita Macnab ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Risk Stratification ◽

Cardiovascular Imaging ◽

Disease Classification ◽

Future Research ◽

Preserved Ejection Fraction ◽

Wide Range ◽

Distinct Disease ◽

Disease Entities

Abstract Heart failure with preserved ejection fraction (HFpEF) does not exist as a singular clinical or pathological entity but as a syndrome encompassing a wide range of clinical and biological phenotypes. There is an urgent need to progress from the unsuccessful ‘one-size-fits-all’ approach to more precise disease classification, in order to develop targeted therapies, personalise risk stratification and guide future research. In this regard, this review discusses the current and emerging roles of cardiovascular imaging for the diagnosis of HFpEF, for distilling HFpEF into distinct disease entities according to underlying pathobiology and for risk stratification.

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

CARDIOVASCULAR THERAPY AND PREVENTION ◽

10.15829/1728-8800-2021-2834 ◽

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.

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Viewing the future research directions of heart failure from ge's phenotyping of heart failure with preserved ejection fraction

Cardiology Plus ◽

10.4103/2470-7511.320321 ◽

2021 ◽

Vol 6 (2) ◽

pp. 88

Author(s):

Wei-Min Li ◽

Yan-Xiang Zang ◽

Qi Lou ◽

Hong Wang ◽

Yu-Chen Duan

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Future Research ◽

Preserved Ejection Fraction ◽

Research Directions ◽

The Future ◽

Future Research Directions

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The Gut Microbiome of Heart Failure With Preserved Ejection Fraction

Journal of the American Heart Association ◽

10.1161/jaha.120.020654 ◽

2021 ◽

Author(s):

Anna L. Beale ◽

Joanne A. O’Donnell ◽

Michael E. Nakai ◽

Shane Nanayakkara ◽

Donna Vizi ◽

...

Keyword(s):

Risk Factors ◽

Heart Failure ◽

Ejection Fraction ◽

Gut Microbiota ◽

Gut Microbiome ◽

Short Chain ◽

Preserved Ejection Fraction ◽

Β Diversity ◽

Α Diversity ◽

Significant Difference

Background Risk factors for heart failure with preserved ejection fraction (HFpEF) include hypertension, age, sex, and obesity. Emerging evidence suggests that the gut microbiota independently contributes to each one of these risk factors, potentially mediated via gut microbial‐derived metabolites such as short‐chain fatty acids. In this study, we determined whether the gut microbiota were associated with HFpEF and its risk factors. Methods and Results We recruited 26 patients with HFpEF and 67 control participants from 2 independent communities. Patients with HFpEF were diagnosed by exercise right heart catheterization. We assessed the gut microbiome by bacterial 16S rRNA sequencing and food intake by the food frequency questionnaire. There was a significant difference in α‐diversity (eg, number of microbes) and β‐diversity (eg, type and abundance of microbes) between both cohorts of controls and patients with HFpEF ( P =0.001). We did not find an association between β‐diversity and specific demographic or hemodynamic parameters or risk factors for HFpEF. The Firmicutes to Bacteroidetes ratio, a commonly used marker of gut dysbiosis, was lower, but not significantly so ( P =0.093), in the patients with HFpEF. Compared with controls, the gut microbiome of patients with HFpEF was depleted of bacteria that are short‐chain fatty acid producers. Consistent with this, participants with HFpEF consumed less dietary fiber (17.6±7.7 versus 23.2±8.8 g/day; P =0.016). Conclusions We demonstrate key changes in the gut microbiota in patients with HFpEF, including the depletion of bacteria that generate metabolites known to be important for cardiovascular homeostasis. Further studies are required to validate the role of these gut microbiota and metabolites in the pathophysiology of HFpEF.

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Microbiome changes in patients with chronic heart failure with preserved ejection fraction correlate with fibrosis markers: Description of a Russian cohort

10.21203/rs.3.rs-94727/v1 ◽

2020 ◽

Author(s):

Aalexey Novoselov ◽

Anastasia Kaburova ◽

Maria Pokrovskaya ◽

Boris Zaitchik ◽

Stanislav Poyarkov ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Ejection Fraction ◽

Gut Microbiota ◽

Gut Microbiome ◽

Bile Acid Metabolism ◽

Metagenomic Sequencing ◽

Preserved Ejection Fraction ◽

Healthy Individuals ◽

Secondary Bile Acid

Abstract Background Chronic heart failure (CHF) affects approximately 26 million people worldwide. Nearly half of CHF patients develop heart failure with preserved ejection fraction (HFpEF), which is associated with myocardial hypertrophy and fibrosis. Although chronic inflammation was suggested as a critical factor contributing to fibrosis development, a new hypothesis of CHF pathogenesis suggested that altered gut microbiota contributes to leaky gut phenotype development and promotes a systemic inflammatory state. CHF patients have an altered gut microbiome. However, the effect of gut microbiota on fibrosis development in HFpEF patients is not yet known. Thus, this clinical study involving HFpEF patients (n = 47) and healthy volunteers (n = 43) intended to identify the correlations between microbiota changes and fibrosis markers in HFpEF patients. Methods We used 16S rRNA metagenomic sequencing to identify the microbiota changes in HFpEF patients. Myocardial fibrosis was quantified using T1 myocardial mapping by using cardiac magnetic resonance. We also assessed the levels of microbial metabolites—trimethylamin N-oxide (TMAO) and short-chain fatty acids (SCFAs)—and measured bloodstream miRNAs and cytokines. The gut microbiome functions were simulated using PICRUSt algorithm. Results The gut microbial communities of HFpEF patients were markedly different from those of healthy individuals. The abundance of Faecalibacterium, Prevotella, and Pseudomonas was significantly decreased, whereas that of Lachnoclostridium, Blautia, Haemophilus, Dorea, Peptococcus, and Tyzzerella was increased in HFpEF patients. These changes could have affected TMAO metabolism and SCFA production: TMAO and hydroxypyruvate levels were significantly higher, whereas isovaleric, methylbutyric, and propionic acids were significantly lower in HFpEF patients than in healthy individuals. The simulation with PICRUSt revealed that genes responsible for starch fermentation, SCFA production, and secondary bile acid metabolism were downregulated. Correlation analysis identified the involvement of microbiota changes and miRNAs 183-3p and 193b-3p. Conclusions Gut microbiome composition shifts in HFpEF patients impair biochemical functions, increase TMAO production, and decrease SCFA biosynthesis. The significant decrease in Faecalibacterium could have the most prominent effect on the host physiology. However, this needs to be determined by conducting experiments on animal models, because the mechanism by which the microbiota is associated with cardiac fibrosis development is not yet known.

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