Gut Microbiota Composition and Cardiovascular Disease: A Potential New Therapeutic Target?

A great deal of evidence has revealed an important link between gut microbiota and the heart. In particular, the gut microbiota plays a key role in the onset of cardiovascular (CV) disease, including heart failure (HF). In HF, splanchnic hypoperfusion causes intestinal ischemia resulting in the translocation of bacteria and their metabolites into the blood circulation. Among these metabolites, the most important is Trimethylamine N-Oxide (TMAO), which is responsible, through various mechanisms, for pathological processes in different organs and tissues. In this review, we summarise the complex interaction between gut microbiota and CV disease, particularly with respect to HF, and the possible strategies for influencing its composition and function. Finally, we highlight the potential role of TMAO as a novel prognostic marker and a new therapeutic target for HF.

Diabetes influences cancer risk in patients with increased carotid atherosclerosis burden.

BACKGROUND AND AIMS: Atherosclerosis and cancer share several risk factors suggesting that at least in part their pathogenesis is sustained by common mechanisms. To investigate this relation we followed a group of subjects with carotid atherosclerosis at baseline up for malignancy development. METHODS AND RESULTS: we carried out an observational study exploring cancer incidence (study endpoint) in subjects with known carotid atherosclerosis at baseline (n = 766) without previous cancer or carotid vascular procedures. During the follow-up (160 ± 111 weeks) 24 cancer occurred, corresponding to an overall annual incidence rate of 0.11%. 10 diagnosis of cancer occurred in individuals with a carotid stenosis >50% (n = 90) whereas 14 in patients with a carotid stenosis <50% patients (n = 676) (p < 0.001). Respect to patients without cancer, diabetes was markedly more common in subjects with cancer diagnosis during the FU (37.3%vs75.0%, p < 0.001). After controlling for classic risk factors, carotid stenosis >50% (HR = 2.831, 95%CI = 1.034-5.714; p = 0.036) and diabetes (HR = 4.831, 95%CI = 1.506-15.501; p = 0.008) remained significantly associated with cancer diagnosis. CONCLUSIONS: to our knowledge this is the first study reporting a significant risk of cancer development in subjects with diabetes and high risk of cerebrovascular events, highlighting the need of a carefully clinical screening for cancer in diabetic patients with overt carotid atherosclerosis.

Carotid intimal medial thickness in rotating night shift is related to IL1ß/IL6 axis.

BACKGROUND AND AIMS: Sleep disturbances may promote glucose abnormalities and inflammatory burden among shift workers. Therefore, precocious subclinical atherosclerotic process might develop in healthy shift workers even without known metabolic and cardiovascular risk factors. METHODS AND RESULTS: We measured anthropometric parameters, glucose, lipids, inflammation and common carotid Intimal Medial Thickness (cIMT) in rotating-night shift workers (r-NSW, n = 88, age = 40.3 ± 7.8 y) in comparison with former-night shift workers (f-NSW, n = 35, age = 44.2 ± 6.4 y) and with day-only workers (DW, n = 64, age = 44.1 ± 8.9 y). R-NSW and f-NSW showed significantly higher cIMT and high sensitivity C-Reactive Protein (hs-CRP) respect to DW (p = 0.043 and p = 0.025, respectively). IL-1ß levels were higher in r-NSW than in DW and f-NSW (p = 0.043) and significantly correlated with IL6 (r = 0.365, p < 0.001). In addition, r-NSW and f-NSW had higher HbA1c levels in comparison with DW (p = 0.047). Carotid-IMT was significantly related to night shift work (p = 0.023), with age (p < 0.001), with HOMA IR (p = 0.009), with insulin (p = 0.006) with HbA1c (p = 0.002), with LDL cholesterol (p < 0.001), with diastolic BP (p < 0.001), with WBC (p = 0.002) and with IL6 (p = 0.004). After performing a multivariate analysis night shift work remained statistically related to cIMT (B = 2.633, 95%CI = 0.489-4.776, p = 0.016). CONCLUSIONS: Our result described a possible link bridging night shift work, inflammation and carotid Intimal Medial Thickness. Future studies are warranted to understand if carotid atherosclerosis process should be mainly driven by the IL1ß/IL6 citokine axis connected to sleep disturbances.

An Investigation of Metabolic Risk Factors and Gut Microbiota in Unexplained Syncope.

BACKGROUND: The pathogenesis of many syncopal episodes remains unexplained. Intestinal dysbiosis could be involved in the pathophysiological mechanisms of syncope due to its connection with the central nervous system via the microbiota-gut-brain axis. This pilot study aimed to explore the specific cardiometabolic risk factors and gut microbiota in unexplained syncope (US), compared to other types of syncope, to assess their similarity or verify their different origins. METHODS: We studied 86 participants with syncope, who were divided into four groups: an orthostatic syncope group (OH, n = 24), a neuromediated syncope group (NMS, n = 26), a cardiological syncope group (CS, n = 9), and an unexplained syncope group (US, n = 27). We evaluated the anthropometric, clinical, and metabolic characteristics of the four groups; the α- and ß-diversity; and the differences in the abundance of the microbial taxa. RESULTS: The US group had a lower incidence of systolic hypertension at the first visit and a lower frequency of patients with nocturnal hypertension than the CS group. Compared to the OH and NMS groups, the US group had a higher incidence of carotid plaques and greater carotid intima-media thickness, respectively. The microbiota differed significantly between the US and CS groups, but not between the US group and the OH or NMS group. CONCLUSIONS: We observed significant differences in the gut microbiota between CS and US. Future studies are necessary to evaluate the involvement of the gut microbiota in the complex pathogenesis of syncope and whether its analysis could support the interpretation of the pathophysiological mechasnisms underlying some episodes classifiable as US.

Microbiota-gut-brain axis: relationships among the vagus nerve, gut microbiota, obesity, and diabetes.

AIMS: The purpose of this review is to explore the interconnected pathways of the microbiota-gut-brain axis (MGBA), focusing on the roles of the vagus nerve and glucagon like peptide-1 in appetite control, and in the development of obesity and diabetes. METHODS: Type 2 diabetes mellitus (T2DM) and obesity are metabolic disorders whose prevalence has significantly increased in recent decades and is expected to increase every year, to pandemic proportions. These two pathologies often coexist and have substantial public health implications. The term "diabesity" defines the pathophysiological connection between overweight and T2DM. The gut microbiota affects many aspects of the host. Beyond the regulation of intestinal functions and the activation of immune responses, the gut microbiota plays a role in central nervous system functions (i.e., mood, and psychiatric conditions associated with stress and memory) and is a central regulator of metabolism and appetite. RESULTS: The MGBA involves pathways such as the autonomic and enteric nervous systems, the hypothalamic- pituitary-adrenal axis, the immune system, enteroendocrine cells, and microbial metabolites. Notably, the vagus nerve plays an essential role in eating behavior by modulating appetite and learning nutritional preferences. CONCLUSIONS: Because of its enteroendocrine cell-mediated interaction with the gut microbiota, the vagus nerve may provide a potential pathway through which gut microorganisms influence host feeding behavior and metabolic control of physiological and pathological conditions.

Vasovagal syncope: An overview of pathophysiological mechanisms.

Syncope is a short-term transient loss of consciousness, characterized by rapid onset and complete spontaneous recovery. According to the 2018 European Society of Cardiology guidelines, three different types of syncope have been identified. However, all forms of syncope share a common final pathophysiological event, global cerebral hypoperfusion, which results from the inability of the circulatory system to maintain blood pressure at the level required to efficiently supply blood to the brain. The vasovagal syncope (VVS) is the most common form of syncope. Although, VVS is generally harmless, its frequent occurrence can negatively affect quality of life and increase the risk of adverse events. The pathophysiological mechanisms underlying VVS remain obscure. The multifaceted nature of VVS presents a veritable challenge to understanding this condition and developing preventative strategies. Thus, the aim of this review was to discuss the factors contributing to the pathogenesis of VVS and provide guidance for future research.

Impact of Insulin Degludec/Liraglutide Fixed Combination on the Gut Microbiomes of Elderly Patients With Type 2 Diabetes: Results From A Subanalysis of A Small Non-Randomised Single Arm Study.

In elderly Type 2 Diabetes (T2D) patients the relationship between the destabilization of gut microbiome and reversal of dysbiosis via glucose lowering drugs has not been explored. We investigated the effect of 6 months therapy with a fixed combination of Liraglutide and Degludec on the composition of the gut microbiome and its relationship with Quality of Life, glucose metabolism, depression, cognitive function, and markers of inflammation in a group of very old T2D subjects (n=24, 5 women, 19 men, mean age=82 years). While we observed no significant differences in microbiome biodiversity or community among study participants (N = 24, 19 men, mean age 82 years) who responded with decreased HbA1c (n=13) versus those who did not (n=11), our results revealed a significant increase in Gram-negative Alistipes among the former group (p=0.013). Among the responders, changes in the Alistipes content were associated directly with cognitive improvement (r=0.545, p=0.062) and inversely with TNFα levels (r=-0.608, p=0.036). Our results suggest that this combination drug may have a significant impact on both gastrointestinal microbes and cognitive function in elderly T2D individuals.

Beyond the Cardiovascular Effects of Glucagon-like Peptide-1 Receptor Agonists: Body Slimming and Plaque Stabilization. Are New Statins Born?

Atherosclerosis is a chronic inflammatory disease characterized by lipid and inflammatory cell deposits in the inner layer of large- and medium-sized elastic and muscular arteries. Diabetes mellitus (DM) significantly increases the risk of cardiovascular diseases and the overall and cardiovascular mortality, and it is a pro-atherogenic factor that induces atherosclerosis development and/or accelerates its progression through a multifactorial process. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of drugs, belonging to the armamentarium to fight type 2 DM, that have shown robust reductions in atherosclerotic events and all-cause mortality in all studies. Preclinical studies have shown that GLP-1RAs play a role in the immunomodulation of atherosclerosis, affecting multiple pathways involved in plaque development and progression. In this review, we wanted to explore the translational power of such preclinical studies by analyzing the most recent clinical trials investigating the atheroprotective effect of GLP-1RAs.

Relationship between retinal microvascular impairment and subclinical atherosclerosis in SLE.

OBJECTIVES: Patients with SLE have higher cardiovascular (CV) risk compared with healthy controls (HC) and are characterised by accelerated atherosclerosis; intima media thickness (IMT), marker of subclinical atherosclerosis, is higher in patients with SLE than in HCs. Retinal microvascular impairment detected through optical coherence tomography angiography (OCTA) was investigated as a marker of systemic vascular involvement in SLE.The aim of the study was to evaluate the relationship between retinal vascular impairment and IMT in SLE. METHODS: Cross-sectional study recruiting patients with SLE and HCs. Data of the study population were collected. CV risk was evaluated through the American College of Cardiology/American Heart Association (ACC/AHA) guidelines, Framingham and QRESEARCH risk estimator V.3 (QRISK3) scores. Both groups underwent OCTA and carotid ultrasound with IMT assessment.Statistical analysis was accomplished using Pearson/Spearman, t-test/Mann-Whitney or χ2 test. Variables statistically significant at univariate regression analysis were tested in an age-corrected and sex-corrected multivariate regression model. RESULTS: 43 patients with SLE and 34 HCs were recruited. Patients with SLE showed higher triglycerides (p=0.019), Triglycerides-Glucose (TyG) Index (p=0.035), ACC/AHA guidelines (p=0.001), Framingham Risk Scores (p=0.008) and a reduced superficial (p<0.001) and deep (p=0.005) whole retinal vessel density (VD) compared with HCs.In SLE univariate analysis, deep whole VD showed a negative correlation with IMT (p=0.027), age (p=0.001), systolic blood pressure (p=0.011), QRISK3 Score (p<0.001), Systemic Lupus International Collaborating Clinics Damage Index (p=0.006) and apolipoprotein B (p=0.021), while a positive correlation was found with female sex (p=0.029). Age-adjusted and sex-adjusted multivariate analysis confirmed QRISK3 Score (p=0.049) and IMT (p=0.039) to be independent risk factors for reduced retinal VD. CONCLUSIONS: Patients with SLE showed lower retinal VD and higher CV risk indicators compared with HCs. Among patients with SLE, QRISK3 Score and IMT were found to be independent risk factors for retinal vascular impairment, suggesting a role of OCTA in evaluating preclinical CV involvement in SLE. Moreover, TyG Index could represent a biomarker of CV risk in patients with SLE compared with HCs.

Predictive Value of MR-proADM in the Risk Stratification and in the Adequate Care Setting of COVID-19 Patients Assessed at the Triage of the Emergency Department.

In the past two pandemic years, Emergency Departments (ED) have been overrun with COVID-19-suspicious patients. Some data on the role played by laboratory biomarkers in the early risk stratification of COVID-19 patients have been recently published. The aim of this study is to assess the potential role of the new biomarker mid-regional proadrenomedullin (MR-proADM) in stratifying the in-hospital mortality risk of COVID-19 patients at the triage. A further goal of the present study is to evaluate whether MR-proADM together with other biochemical markers could play a key role in assessing the correct care level of these patients. Data from 321 consecutive patients admitted to the triage of the ED with a COVID-19 infection were analyzed. Epidemiological; demographic; clinical; laboratory; and outcome data were assessed. All the biomarkers analyzed showed an important role in predicting mortality. In particular, an increase of MR-proADM level at ED admission was independently associated with a threefold higher risk of IMV. MR-proADM showed greater ROC curves and AUC when compared to other laboratory biomarkers for the primary endpoint such as in-hospital mortality, except for CRP. This study shows that MR-proADM seems to be particularly effective for early predicting mortality and the need of ventilation in COVID-19 patients admitted to the ED.

Effect of deprescribing in elderly patients with type 2 diabetes: iDegLira might improve quality of life.

Older people with type 2 diabetes (T2D) often have several comorbidities and take multiple drugs. This study tested a deprescribing strategy in older T2D patients, replacing a hypoglycemic therapeutic scheme with a single drug combination (iDegLira). In this 6-month, real-world, single-arm, open interventional study, we enrolled patients ≥ 75 years with T2D taking ≥ 2 medications for diabetes. Patients on a basal-bolus insulin regimen (n = 13), on a basal-insulin regimen plus oral glucose-lowering drugs (n = 9), and those on oral glucose-lowering drugs (n = 18) were switched to daily iDegLira. The primary clinical endpoint of the study was an improvement in CASP-19 and/or DTSQ score after 6 months. We also evaluated changes in glucose metabolism, depression, cognitive function, level of independence, and markers of inflammation. Thirty-five patients (12 women, mean age=81.4 y) completed the protocol. Results shown here are given as estimated mean difference (95%CI). DTSQ score improved [11.08 (7.13/15.02); p = 0.0001], whereas CASP-19 did not after 6 months of iDegLira treatment. We observed reductions in BMI [- 0.81 (- 1.27/0.35); p < 0.001], fasting glucose [- 52.07 (- 77.26/26.88); p < 0.001], HbA1c [- 0.58 (- 1.08/0.08); p < 0.05], and TNF-α [- 1.83 (- 3.12/- 0.54); p = 0.007]. Activities of daily living and cognitive function score increased [p = 0.006 and p = 0.02], whereas depression score significantly decreased [p = 0.02]. Notably, no patient reported episodes of severe hypoglycemia after initiation of iDegLira treatment. Among older patients with T2D, deprescribing using a single dose of iDegLira resulted in a greater likelihood of improving health and quality of life. Although our data indicate the effectiveness and safety of this approach, it must be confirmed in larger studies.

Morning blood pressure surge is associated with autonomic neuropathy and peripheral vascular disease in patients with diabetes.

Although vascular and autonomic nervous system have been involved in the regulation of morning surge in blood pressure (MBPS), data on clinical correlates of MBPS in diabetic population are scarce, in particular with regard to diabetic complications. This study was aimed at investigating predictors and correlates of MBPS in diabetes. In a cross-sectional study including 167 patients with diabetes (age 58.5 ± 11.1 years, duration 15.9 ± 12.1 years), clinical variables, diabetic and neuropathic complications, and MBPS (using 24-h ambulatory blood pressure monitoring) were measured. The upper quartile of MBPS (>30.5 mmHg) was associated with higher values of waist circumference (P = 0.027), triglycerides (P = 0.021), and Michigan Diabetic Neuropathy Score (P = 0.042), with lower HDL cholesterol (P = 0.030), and with the presence of cardiovascular autonomic neuropathy (CAN) (P = 0.016) and peripheral vascular disease (PVD) (P < 0.0001). In a logistic regression analysis, PVD (odds ratio: 10.2, P = 0.001), CAN (odds ratio: 6.09, P = 0.016), and diastolic blood pressure (BP) (odds ratio: 1.06, P = 0.022) predicted MBPS upper quartile (r2 = 0.20, P = 0.0005). In a multiple regression analysis, PVD (P = 0.002) and diastolic BP (P = 0.003) were the only determinants of MBPS (r2 = 0.20). MBPS upper quartile was associated with BP dipping (systolic BP day-night reduction > 10%) (P = 0.012), and MBPS was positively related to systolic (rho = 0.41, P < 0.0001) and diastolic BP day-night reduction. In conclusion, metabolic syndrome stigmata, diastolic BP, CAN and PVD are the main predictors of MBPS in the diabetic population. Excessive MBPS and nondipping are not concurrent 24-h BP alterations. Autonomic dysfunction might exert an exacerbating effect on MBPS phenomenon.

Diabetic peripheral neuropathic pain is a stronger predictor of depression than other diabetic complications and comorbidities.

AIMS: To investigate the independent effect on depression of painless diabetic polyneuropathy, painful diabetic polyneuropathy, and general and diabetes-related comorbidities. METHODS: In 181 patients, the presence of painless diabetic polyneuropathy, painful diabetic polyneuropathy, comorbidities and depression was assessed using the Michigan Neuropathy Screening Instrument Questionnaire, the Michigan Diabetic Neuropathy Score, nerve conduction studies, the Douleur Neuropathique en 4 Questions, the Charlson Comorbidity Index and the Beck Depression Inventory-II. RESULTS: In all, 46 patients met the criteria of confirmed painless diabetic polyneuropathy and 25 of painful diabetic polyneuropathy. Beck Depression Inventory-II scores indicative of mild-moderate-severe depression were reached in 36 patients (19.7%). In a multiple logistic regression analysis (including age, sex, body mass index, being unemployed, duration, haemoglobin A1c, insulin treatment, systolic blood pressure, nephropathy, retinopathy, Charlson Comorbidity Index and painful diabetic polyneuropathy), female sex (odds ratio: 5.9, p = 0.005) and painful diabetic polyneuropathy (odds ratio: 4.6, p = 0.038) were the only independent predictors of depression. Multiple regression analysis, including Douleur Neuropathique en 4 Questions and Michigan Diabetic Neuropathy Score instead of painful diabetic polyneuropathy, showed that Douleur Neuropathique en 4 Questions, in addition to female sex, was a significant predictor of depressive symptoms severity (p =0.005). CONCLUSION: Painful diabetic polyneuropathy is a greater determinant of depression than other diabetes-related complications and comorbidities. Painful symptoms enhance depression severity more than objective insensitivity.

Preliminary evidence that obese patients with obstructive sleep apnea/hypopnea syndrome are refractory to the acute beneficial metabolic effects of a very low calorie diet.

Since obesity seems to play a causal role in both obstructive sleep apnea/hypopnea syndrome (OSAHS) and type 2 diabetes, the question arises whether diet-induced weight loss is equally efficacious in type 2 diabetic patients with and without OSAHS. The present study was aimed to investigate the effect of 1 week very low calorie diet (VLCD) on oxygen desaturation index (ODI) and on glucose regulation in OSAHS versus non-OSAHS patients. Fourteen patients with type 2 diabetes mellitus and morbid obesity were enrolled. According to ODI, patients were divided into 2 groups (with and without OSAHS) and evaluated by a hyperglycemic clamp study, before and after a 7 day-VLCD. After a VLCD, a significant reduction of anthropometric parameters, in the overall group and in subgroups, was observed. M-value and acute insulin response increased significantly only in patients without obstructive sleep apnea (990.10 ± 170.19 vs. 1,205.22 ± 145.73 µmol min(-1) m(-2), p = 0.046; -1.05 ± 8.40 vs. 48.26 ± 11. 90 pmol/L, p = 0.028, respectively). The average 24-h heart rate (24-h HR) fell significantly (p = 0.05), primarily because of a decrease during daytime (p = 0.041), in the whole group. In conclusion, we observed that morbidly obese patients with type 2 diabetes and OSAHS are specifically resistant to the acute beneficial effects of VLCD on metabolic parameters. Our preliminary observation deserves further investigation to clarify the pathogenetic mechanisms involved.