Gut Microbiota and Coronary Artery Disease: Current Therapeutic Perspectives.

The human gut microbiota is the community of microorganisms living in the human gut. This microbial ecosystem contains bacteria beneficial to their host and plays important roles in human physiology, participating in energy harvest from indigestible fiber, vitamin synthesis, and regulation of the immune system, among others. Accumulating evidence suggests a possible link between compositional and metabolic aberrations of the gut microbiota and coronary artery disease in humans. Manipulating the gut microbiota through targeted interventions is an emerging field of science, aiming at reducing the risk of disease. Among the interventions with the most promising results are probiotics, prebiotics, synbiotics, and trimethylamine N-oxide (TMAO) inhibitors. Contemporary studies of probiotics have shown an improvement of inflammation and endothelial cell function, paired with attenuated extracellular matrix remodeling and TMAO production. Lactobacilli, Bifidobacteria, and Bacteroides are some of the most well studied probiotics in experimental and clinical settings. Prebiotics may also decrease inflammation and lead to reductions in blood pressure, body weight, and hyperlipidemia. Synbiotics have been associated with an improvement in glucose homeostasis and lipid abnormalities. On the contrary, no evidence yet exists on the possible benefits of postbiotic use, while the use of antibiotics is not warranted, due to potentially deleterious effects. TMAO inhibitors such as 3,3-dimethyl-1-butanol, iodomethylcholine, and fluoromethylcholine, despite still being investigated experimentally, appear to possess anti-inflammatory, antioxidant, and anti-fibrotic properties. Finally, fecal transplantation carries conflicting evidence, mandating the need for further research. In the present review we summarize the links between the gut microbiota and coronary artery disease and elaborate on the varied therapeutic measures that are being explored in this context.

The impact of SGLT2 inhibition on imaging markers of cardiac function: A systematic review and meta-analysis.

OBJECTIVES: The use of sodium-glucose cotransporter-2 inhibitors (SGLT2-Is) has resulted in significant benefits in patients with heart failure irrespective of left ventricular ejection fraction (LVEF) and the presence of diabetes mellitus. The aim of this systematic review and meta-analysis was to assess the impact of SGLT2-Is on cardiac function indices. METHODS: We conducted a systematic literature search for studies assessing the changes in LVEF, global longitudinal strain (GLS), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular mass index (LVMi), left atrial volume index (LAVi), and E/e' following the initiation of an SGLT2-I. RESULTS: A total of 32 studies with 2351 patients were included. SGLT2 inhibition resulted in a significant improvement of LVEF [MD 1.97 (95%CI 0.92, 3.02), p < .01, I2:84%] in patients with heart failure, an increase in GLS [MD 1.17 (95% CI 0.25, 2.10), p < .01], a decrease in LVESV [MD: -3.60 (95% CI -7.02, -0.18), p = .04, I2:9%] while the effect was neutral concerning LVEDV [MD: -3.10 (95% CI -6.76, 0.56), p = .40, I2:4%]. LVMi [MD: -3.99 (95% CI -7.16 to -0.82), p = .01, I2:65%], LAVi [MD: -1.77 (95% CI -2.97, -0.57), p < .01, I2:0%], and E/e' [MD: -1.39 (95% CI -2.04, -0.73), p < .01, I2:55%] were significantly reduced. CONCLUSIONS: In this systematic review and meta-analysis, the use of SGLT2 inhibitors was associated with an improvement in markers of cardiac function, confirming the importance of SGLT2 inhibition towards the reversal of cardiac remodeling.

Mechanisms, therapeutic implications, and methodological challenges of gut microbiota and cardiovascular diseases: a position paper by the ESC Working Group on Coronary Pathophysiology and Microcirculation.

The human gut microbiota is the microbial ecosystem in the small and large intestines of humans. It has been naturally preserved and evolved to play an important role in the function of the gastrointestinal tract and the physiology of its host, protecting from pathogen colonization, and participating in vitamin synthesis, the functions of the immune system, as well as glucose homeostasis and lipid metabolism, among others. Mounting evidence from animal and human studies indicates that the composition and metabolic profiles of the gut microbiota are linked to the pathogenesis of cardiovascular disease, particularly arterial hypertension, atherosclerosis, and heart failure. In this review article, we provide an overview of the function of the human gut microbiota, summarize, and critically address the evidence linking compositional and functional alterations of the gut microbiota with atherosclerosis and coronary artery disease and discuss the potential of strategies for therapeutically targeting the gut microbiota through various interventions.

Diagnostic performance of coronary angiography utilizing intraprocedural 320-row computed tomography with minimal contrast medium.

Recently developed coronary angiography with intraprocedural 320-row computed tomography can be performed in a catheterization laboratory (XACT) by injecting contrast medium from a place close to the coronary arteries, thereby requiring a minimal amount of contrast medium. However, its clinical application has not yet been established. This study aimed to evaluate the diagnostic accuracy of XACT angiography with a minimal volume of contrast medium in patients with suspected coronary artery disease (CAD). A total of 167 coronary segments were analyzed in 14 patients (9 males, median age 70 years) with suspected CAD by XACT angiography with 7.5 ml of contrast medium and invasive coronary angiography (ICA) with standard techniques. The segmental-based diagnostic accuracy of XACT angiography in detecting stenosis of ≥ 50% and ≥ 75% and visualized by ICA was good (sensitivity: 74% and 62%, specificity: 99% and 99%, positive predictive value: 93% and 80%, and negative predictive value: 97% and 97%, respectively). These results suggest that XACT angiography with a very low amount of contrast medium may have strong clinical utility for screening coronary arteries in patients with renal dysfunction or undergoing clinical procedures such as pacemaker implantation.

The intestinal microbiota and cardiovascular disease.

The intestinal microbiota of human hosts is the community of microorganisms living in the small and, mainly, the large intestine of humans. This microbial ecosystem has co-evolved with humans across the millennia, has come to play an important interactive role in human physiology and has been aptly called our forgotten organ. Significant properties of the microbiota benefiting its host include energy harvest from food sources indigestible by humans, protection from pathogen colonization, and vitamin synthesis. Mounting evidence has linked changes in the composition or metabolic profiles of the microbiota with human disease, including disorders of the cardiovascular spectrum. Although cause and effect mechanisms are as yet essentially unproven in the relevant literature, the established associations point to the importance of the microbiota in the pathophysiology of cardiovascular disease (CVD). In this review, we first summarize key information on the gut microbial communities and the elaborate tools developed to analyse their structure and metabolic functions. Ecological terms are explained and analytical techniques are simplified, to enhance the understanding of published studies. Statistical methods used in microbial analysis are also described in simple terms. We then present published literature on the association of the compositional and functional changes of the microbiota with CVD, including heart failure, hypertension, and atherosclerosis. Each section of the review deals with the underlying pathophysiology of the relevant associations, connecting the observational and mechanistic aspects. Finally, we discuss the challenges that remain to be met before this field of research can generate knowledge which can impact everyday clinical practice.

Liver Stiffness Reflecting Right-Sided Filling Pressure Can Predict Adverse Outcomes in Patients With Heart Failure.

OBJECTIVES: This study sought to investigate whether elevated liver stiffness (LS) values at discharge reflect residual liver congestion and are associated with worse outcomes in patients with heart failure (HF). BACKGROUND: Transient elastography is a newly developed, noninvasive method for assessing LS, which can be highly reflective of right-sided filling pressure associated with passive liver congestion in patients with HF. METHODS: LS values were determined for 171 hospitalized patients with HF before discharge using a Fibroscan device. RESULTS: The median LS value was 5.6 kPa (interquartile range: 4.4 to 8.1 kPa; range 2.4 to 39.7 kPa) and that of right-sided filling pressure, which was estimated based on LS, was 5.7 mm Hg (interquartile range: 4.1 to 8.2 mm Hg; range 0.1 to 18.9 mm Hg). The patients in the highest LS tertile (>6.9 kPa, corresponding to an estimated right-sided filling pressure of >7.1 mm Hg) had advanced New York Heart Association functional class, high prevalence of jugular venous distention and moderate/severe tricuspid regurgitation, large inferior vena cava (IVC) diameter, low hemoglobin and hematocrit levels, high serum direct bilirubin level, and a similar left ventricular ejection fraction compared with the lower tertiles. During follow-up periods (median: 203 days), 8 (5%) deaths and 33 (19%) hospitalizations for HF were observed. The patients in the highest LS group had a significantly higher mortality rate and HF rehospitalization (hazard ratio: 3.57; 95% confidence interval: 1.93 to 6.83; p < 0.001) compared with the other tertiles. Although LS correlated with IVC diameter and serum direct bilirubin and brain natriuretic peptide levels, LS values were predictive of worse outcomes, even after adjustment for these indices. CONCLUSIONS: These data suggest that LS is a useful index for assessing systemic volume status and predicting the severity of HF, and that the presence of liver congestion at discharge is associated with worse outcomes in patients with HF.

Ratio of pulmonary artery diameter to ascending aortic diameter and severity of heart failure.

BACKGROUND: Treatment decisions in dilated cardiomyopathy (DCM) patients with severe heart failure (HF) and short clinical history are challenging because of the difficulty of determining HF stage or prognosis in the acute HF phase. We hypothesized that persistent decreased systemic or increased pulmonary arterial pressure, including in the sub-clinical phase, might affect the main pulmonary artery diameter (PAD), ascending aortic diameter (AoD), and their ratio (PAD/AoD). This study assessed AoD, PAD, and PAD/AoD by non-contrast computed tomography scans in DCM patients in the acute phase of HF and examined the association of these parameters with their clinical course. METHODS: Of 261 screened individuals, we studied 110 consecutive hospitalized patients with DCM suspected of being in advanced stage of HF and 45 age-matched controls, assessing clinical data and later events (cardiac death or left ventricular assist device implantation). RESULTS: Compared with controls, DCM patients had smaller AoD (26.6 ± 4.4 vs 30.6 ± 2.7 mm) and larger PAD (27.7 ± 3.5 vs 25.4 ± 2.8 mm) and PAD/AoD (1.05 ± 0.14 vs 0.83 ± 0.08; all p < 0.01). DCM patients with high PAD/AoD (median, > 1.05) had more frequent past HF hospitalizations, lower blood pressure, stroke volume, and ejection fraction, higher brain natriuretic peptide levels, smaller AoD, and similar PAD compared with patients with a low PAD/AoD. A higher PAD/AoD was associated with poorer outcomes even after adjusting for age, blood pressure, ejection fraction, or number of hospitalizations. CONCLUSION: Assessment of AoD and PAD may have important clinical implications in determining whether DCM patients are in an advanced stage of HF with a poorer prognosis.

Non-Ischemic Heart Failure With Reduced Ejection Fraction Is Associated With Altered Intestinal Microbiota.

BACKGROUND: Research suggests that heart failure with reduced ejection fraction (HFrEF) is a state of systemic inflammation that may be triggered by microbial products passing into the bloodstream through a compromised intestinal barrier. However, whether the intestinal microbiota exhibits dysbiosis in HFrEF patients is largely unknown.Methods and Results:Twenty eight non-ischemic HFrEF patients and 19 healthy controls were assessed by 16S rRNA analysis of bacterial DNA extracted from stool samples. After processing of sequencing data, bacteria were taxonomically classified, diversity indices were used to examine microbial ecology, and relative abundances of common core genera were compared between groups. Furthermore, we predicted gene carriage for bacterial metabolic pathways and inferred microbial interaction networks on multiple taxonomic levels.Bacterial communities of both groups were dominated by the Firmicutes and Bacteroidetes phyla. The most abundant genus in both groups wasBacteroides. Although α diversity did not differ between groups, ordination by ß diversity metrics revealed a separation of the groups across components of variation.StreptococcusandVeillonellawere enriched in the common core microbiota of patients, whileSMB53was depleted. Gene families in amino acid, carbohydrate, vitamin, and xenobiotic metabolism showed significant differences between groups. Interaction networks revealed a higher degree of correlations between bacteria in patients. CONCLUSIONS: Non-ischemic HFrEF patients exhibited multidimensional differences in intestinal microbial communities compared with healthy subjects.

Emotion Regulation of Neuroticism: Emotional Information Processing Related to Psychosomatic State Evaluated by Electroencephalography and Exact Low-Resolution Brain Electromagnetic Tomography.

Emotion regulation is the process that adjusts the type or amount of emotion when we experience an emotional situation. The aim of this study was to reveal quantitative changes in brain activity during emotional information processing related to psychosomatic states and to determine electrophysiological features of neuroticism. Twenty-two healthy subjects (mean age 25 years, 14 males and 8 females) were registered. Electroencephalography (EEG) was measured during an emotional audiovisual memory task under three conditions (neutral, pleasant and unpleasant sessions). We divided the subjects into two groups using the Cornell Medical Index (CMI): (CMI-I: control group, n = 10: CMI-II, III or IV: neuroticism group, n = 12). We analyzed the digital EEG data using exact low-resolution brain electromagnetic tomography (eLORETA) current source density (CSD) and functional connectivity analysis in several frequency bands (δ, θ, α, ß, γ and whole band). In all subjects, bilateral frontal α CSD in the unpleasant session increased compared to the pleasant session, especially in the control group (p < 0.05). CSD of the neuroticism group was significantly higher than that of the control group in the full band at the amygdala and inferior temporal gyrus, and in the α band at the right temporal lobe (p < 0.05). Additionally, we found an increase in functional connectivity between the left insular cortex and right superior temporal gyrus in all subjects during the unpleasant session compared to the pleasant session (p < 0.05). In this study, using EEG analysis, we could find a novel cortical network related to brain mechanisms underlying emotion regulation. Overall findings indicate that it is possible to characterize neuroticism electrophysiologically, which may serve as a neurophysiological marker of this personality trait. © 2015 S. Karger AG, Basel.

Noninvasive prediction of shunt operation outcome in idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is a syndrome characterized by gait disturbance, cognitive deterioration and urinary incontinence in elderly individuals. These symptoms can be improved by shunt operation in some but not all patients. Therefore, discovering predictive factors for the surgical outcome is of great clinical importance. We used normalized power variance (NPV) of electroencephalography (EEG) waves, a sensitive measure of the instability of cortical electrical activity, and found significantly higher NPV in beta frequency band at the right fronto-temporo-occipital electrodes (Fp2, T4 and O2) in shunt responders compared to non-responders. By utilizing these differences, we were able to correctly identify responders and non-responders to shunt operation with a positive predictive value of 80% and a negative predictive value of 88%. Our findings indicate that NPV can be useful in noninvasively predicting the clinical outcome of shunt operation in patients with iNPH.

Frontal midline theta rhythm and gamma power changes during focused attention on mental calculation: an MEG beamformer analysis.

Frontal midline theta rhythm (Fmθ) appears widely distributed over medial prefrontal areas in EEG recordings, indicating focused attention. Although mental calculation is often used as an attention-demanding task, little has been reported on calculation-related activation in Fmθ experiments. In this study we used spatially filtered MEG and permutation analysis to precisely localize cortical generators of the magnetic counterpart of Fmθ, as well as other sources of oscillatory activity associated with mental calculation processing (i.e., arithmetic subtraction). Our results confirmed and extended earlier EEG/MEG studies indicating that Fmθ during mental calculation is generated in the dorsal anterior cingulate and adjacent medial prefrontal cortex. Mental subtraction was also associated with gamma event-related synchronization, as an index of activation, in right parietal regions subserving basic numerical processing and number-based spatial attention. Gamma event-related desynchronization appeared in the right lateral prefrontal cortex, likely representing a mechanism to interrupt neural activity that can interfere with the ongoing cognitive task.

The association of Restless Legs Syndrome with hypertension and cardiovascular disease.

Restless Legs Syndrome (RLS), is a sensory-motor neurological disorder that appears to be surprisingly common in the community. Periodic limb movements in sleep are typically encountered in more than 80% of RLS patients and comprise involuntary muscular jerks in the lower limbs, such as flexion of the knees or ankles.  Iron deficiency and dopaminergic neuronal dysfunction in the central nervous system are currently thought to be the likely pathophysiological culprits. There is evidence linking RLS to hypertension and cardiovascular disease. This short review will first present a synopsis of epidemiological, clinical and pathophysiological data concerning the syndrome, and then information on the possible links between RLS and cardiovascular disorders.