Crosstalk between the gut microbiota and the host has attracted considerable attention owing to its involvement in diverse diseases. Chronic kidney disease (CKD) is commonly associated with ...hypertension and is characterized by immune dysregulation, metabolic disorder and sympathetic activation, which are all linked to gut dysbiosis and altered host-microbiota crosstalk. In this Review, we discuss the complex interplay between the brain, the gut, the microbiota and the kidney in CKD and hypertension and explain our brain-gut-kidney axis hypothesis for the pathogenesis of these diseases. Consideration of the role of the brain-gut-kidney axis in the maintenance of normal homeostasis and of dysregulation of this axis in CKD and hypertension could lead to the identification of novel therapeutic targets. In addition, the discovery of unique microbial communities and their associated metabolites and the elucidation of brain-gut-kidney signalling are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials and treatments for CKD and hypertension.
Abstract
Contemporary data indicate that patients with signs and symptoms of ischaemia and non-obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD) with ...elevated risk for adverse outcomes. Coronary endothelial (constriction with acetylcholine) and/or microvascular (limited coronary flow reserve with adenosine) dysfunction are well-documented, and extensive non-obstructive atherosclerosis is often present. Despite these data, patients with INOCA currently remain under-treated, in part, because existing management guidelines do not address this large, mostly female population due to the absence of evidence-based data. Relatively small sample-sized, short-term pilot studies of symptomatic mostly women, with INOCA, using intense medical therapies targeting endothelial, microvascular, and/or atherosclerosis mechanisms suggest symptom, ischaemia, and coronary vascular functional improvement, however, randomized, controlled outcome trials testing treatment strategies have not been completed. We review evidence regarding CMD pharmacotherapy. Potent statins in combination with angiotensin-converting enzyme inhibitor (ACE-I) or receptor blockers if intolerant, at maximally tolerated doses appear to improve angina, stress testing, myocardial perfusion, coronary endothelial function, and microvascular function. The Coronary Microvascular Angina trial supports invasive diagnostic testing with stratified therapy as an approach to improve symptoms and quality of life. The WARRIOR trial is testing intense medical therapy of high-intensity statin, maximally tolerated ACE-I plus aspirin on longer-term outcomes to provide evidence for guidelines. Novel treatments and those under development appear promising as the basis for future trial planning.
Graphical Abstract
Graphical Abstract
Recent evidence indicates a link between gut pathology and microbiome with hypertension (HTN) in animal models. However, whether this association exists in humans is unknown. Thus, our objectives in ...the present study were to test the hypotheses that high blood pressure (BP) patients have distinct gut microbiomes and that gut-epithelial barrier function markers and microbiome composition could predict systolic BP (SBP). Fecal samples, analyzed by shotgun metagenomics, displayed taxonomic and functional changes, including altered butyrate production between patients with high BP and reference subjects. Significant increases in plasma of intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), and augmented gut-targetting proinflammatory T helper 17 (Th17) cells in high BP patients demonstrated increased intestinal inflammation and permeability. Zonulin, a gut epithelial tight junction protein regulator, was markedly elevated, further supporting gut barrier dysfunction in high BP. Zonulin strongly correlated with SBP (R
= 0.5301,
<0.0001). Two models predicting SBP were built using stepwise linear regression analysis of microbiome data and circulating markers of gut health, and validated in a separate cohort by prediction of SBP from zonulin in plasma (R
= 0.4608,
<0.0001). The mouse model of HTN, chronic angiotensin II (Ang II) infusion, was used to confirm the effects of butyrate and gut barrier function on the cardiovascular system and BP. These results support our conclusion that intestinal barrier dysfunction and microbiome function are linked to HTN in humans. They suggest that manipulation of gut microbiome and its barrier functions could be the new therapeutic and diagnostic avenues for HTN.
Patients with heart failure (HF) syndromes have been categorized as those with reduced ejection fraction (EF) or preserved EF (HFpEF), and ischemia plays a key role in both types. HF remains a major ...cause of morbidity and mortality worldwide, and with the aging of our population this burden continues to rise, predominantly as a result of hospitalizations for HFpEF. Patients with obstructive coronary artery disease more likely have HF with reduced EF, rather than HFpEF, secondary to acute ischemic injury resulting in myocardial infarction, and large outcomes trials of treatments with neurohumoral inhibition have documented reduced adverse outcomes. In contrast, similar treatments in patients with HFpEF have not proven beneficial. This therapeutic dilemma may be attributed, in part, to heterogeneity in the underlying pathophysiology with different systemic and myocardial signaling pathways, despite similar clinical presentations and findings, in patients with HFpEF. Also, emerging evidence indicates that impaired myocardial perfusion and inflammation secondary to multiple comorbidities are key mechanisms in HFpEF. We will thoroughly review the role of ischemic heart disease in the pathogenesis of HF with reduced EF and HFpEF, and discuss the medical management strategies available for these conditions.
Gut Dysbiosis Is Linked to Hypertension Yang, Tao; Santisteban, Monica M; Rodriguez, Vermali ...
Hypertension,
2015-June, Volume:
65, Issue:
6
Journal Article
Peer reviewed
Open access
Emerging evidence suggests that gut microbiota is critical in the maintenance of physiological homeostasis. This study was designed to test the hypothesis that dysbiosis in gut microbiota is ...associated with hypertension because genetic, environmental, and dietary factors profoundly influence both gut microbiota and blood pressure. Bacterial DNA from fecal samples of 2 rat models of hypertension and a small cohort of patients was used for bacterial genomic analysis. We observed a significant decrease in microbial richness, diversity, and evenness in the spontaneously hypertensive rat, in addition to an increased Firmicutes/Bacteroidetes ratio. These changes were accompanied by decreases in acetate- and butyrate-producing bacteria. In addition, the microbiota of a small cohort of human hypertensive patients was found to follow a similar dysbiotic pattern, as it was less rich and diverse than that of control subjects. Similar changes in gut microbiota were observed in the chronic angiotensin II infusion rat model, most notably decreased microbial richness and an increased Firmicutes/Bacteroidetes ratio. In this model, we evaluated the efficacy of oral minocycline in restoring gut microbiota. In addition to attenuating high blood pressure, minocycline was able to rebalance the dysbiotic hypertension gut microbiota by reducing the Firmicutes/Bacteroidetes ratio. These observations demonstrate that high blood pressure is associated with gut microbiota dysbiosis, both in animal and human hypertension. They suggest that dietary intervention to correct gut microbiota could be an innovative nutritional therapeutic strategy for hypertension.
RATIONALE:Sympathetic nervous system control of inflammation plays a central role in hypertension. The gut receives significant sympathetic innervation, is densely populated with a diverse microbial ...ecosystem, and contains immune cells that greatly impact overall inflammatory homeostasis. Despite this uniqueness, little is known about the involvement of the gut in hypertension.
OBJECTIVE:Test the hypothesis that increased sympathetic drive to the gut is associated with increased gut wall permeability, increased inflammatory status, and microbial dysbiosis and that these gut pathological changes are linked to hypertension.
METHODS AND RESULTS:Gut epithelial integrity and wall pathology were examined in spontaneously hypertensive rat and chronic angiotensin II infusion rat models. The increase in blood pressure in spontaneously hypertensive rat was associated with gut pathology that included increased intestinal permeability and decreased tight junction proteins. These changes in gut pathology in hypertension were associated with alterations in microbial communities relevant in blood pressure control. We also observed enhanced gut–neuronal communication in hypertension originating from paraventricular nucleus of the hypothalamus and presenting as increased sympathetic drive to the gut. Finally, angiotensin-converting enzyme inhibition (captopril) normalized blood pressure and was associated with reversal of gut pathology.
CONCLUSIONS:A dysfunctional sympathetic–gut communication is associated with gut pathology, dysbiosis, and inflammation and plays a key role in hypertension. Thus, targeting of gut microbiota by innovative probiotics, antibiotics, and fecal transplant, in combination with the current pharmacotherapy, may be a novel strategy for hypertension treatment.
Currently as many as one-half of women with suspected myocardial ischemia have no obstructive coronary artery disease (CAD), and abnormal coronary reactivity (CR) is commonly found.
The authors ...prospectively investigated CR and longer-term adverse cardiovascular outcomes in women with and with no obstructive CAD in the National Heart, Lung, and Blood Institute–sponsored WISE (Women’s Ischemia Syndrome Evaluation) study.
Women (n = 224) with signs and symptoms of ischemia underwent CR testing. Coronary flow reserve and coronary blood flow were obtained to test microvascular function, whereas epicardial CR was tested by coronary dilation response to intracoronary (IC) acetylcholine and IC nitroglycerin. All-cause mortality, major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, stroke, and heart failure), and angina hospitalizations served as clinical outcomes over a median follow-up of 9.7 years.
The authors identified 129 events during the follow-up period. Low coronary flow reserve was a predictor of increased MACE rate (hazard ratio HR: 1.06; 95% confidence interval CI: 1.01 to 1.12; p = 0.021), whereas low coronary blood flow was associated with increased risk of mortality (HR: 1.12; 95% CI: 1.01 to 1.24; p = 0.038) and MACE (HR: 1.11; 95% CI: 1.03 to 1.20; p = 0.006) after adjusting for cardiovascular risk factors. In addition, a decrease in cross-sectional area in response to IC acetylcholine was associated with higher hazard of angina hospitalization (HR: 1.05; 95% CI: 1.02 to 1.07; p < 0.0001). There was no association between epicardial IC-nitroglycerin dilation and outcomes.
On longer-term follow-up, impaired microvascular function predicts adverse cardiovascular outcomes in women with signs and symptoms of ischemia. Evaluation of CR abnormality can identify those at higher risk of adverse outcomes in the absence of significant CAD. (Women's Ischemia Syndrome Evaluation WISE; NCT00000554)
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Persistence or recurrence of angina after a percutaneous coronary intervention (PCI) may affect about 20-40% of patients during short-medium-term follow-up. This appears to be true even when PCI is ...'optimized' using physiology-guided approaches and drug-eluting stents. Importantly, persistent or recurrent angina post-PCI is associated with a significant economic burden. Healthcare costs may be almost two-fold higher among patients with persistent or recurrent angina post-PCI vs. those who become symptom-free. However, practice guideline recommendations regarding the management of patients with angina post-PCI are unclear. Gaps in evidence into the mechanisms of post-PCI angina are relevant, and more research seems warranted. The purpose of this document is to review potential mechanisms for the persistence or recurrence of angina post-PCI, propose a practical diagnostic algorithm, and summarize current knowledge gaps.
National co-operative randomized trial comparing surgical and medical therapy in unstable angina and an R01 evaluating the aortic blood flow velocity in myocardial ischemia. The trial confirmed that ...such patients could be stabilized by IMT, which included propranolol and long-acting nitrates in pharmacologic doses, with good control of angina in most cases and no increase in early mortality or myocardial infarction. 1–4 Later, if angina failed to respond to IMT, elective CABG could be performed with a lower risk and with good clinical results. Dick continued his contributions in acute and chronic CAD over the next several decades as a committee member for key national randomized trials of B-Blockers in Myocardial Infarction, the Multiple Risk Factor Intervention Trial, the Thrombolysis in Myocardial Infarction trial, Chair of the NHLBI-Asymptomatic Cardiac Ischemia Pilot multicenter, multinational study and the NHLBI Cardiology Advisory Committee. Nitroglycerin was studied intensively. 11 These results led us to argue against the “routine use of nitroglycerin prior to coronary angiography” since its use would remove the possibility of documenting spontaneous CAS. 8,11–17 We studied most of the medications used for coronary spasm, often before they were approved for that indication. 18–22 IMPORTANCE OF PHYSICAL CHARACTERISTICS OF CORONARY NARROWING In the experimental physiology laboratory, Dick encouraged us to perform a series of studies to evaluate the functional importance of various physical characteristics of coronary artery narrowings in an animal model.
Zonulin is the master regulator of endothelial and epithelium tight junctions, modulating both gut and blood-brain barriers. 3 We analysed stool faecal microbiota and plasma in 50 subjects who ...self-reported to be asymptomatic for gastrointestinal physical disorders; 22 volunteers met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for a depressive disorder or an anxiety disorder (DEP/ANX), and 28 more were control reference subjects (NODEPANX). Figure 2; Plasma LPS endotoxin, zonulin and fatty acid-binding protein-2 (FABP2) blood markers of gut dysbiosis and gut permeability pathophysiological epithelium integrity. 3 4 Analysis of variance yielded significant mean differences (p<0.05) (see online supplementary material ). Funding: University of Florida Clinical and Translational Science Institute grant (BRS, CJP) from the National Center For Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001427; National Institute of Health (NIH) grants HL33610, HL56921 (MKR, CJP); UM1 HL087366 (CJP); Gatorade Trust through funds distributed by the University of Florida, Department of Medicine (CJP); PCORI-OneFlorida Clinical Research Consortium CDRN-1501-26692 (CJP); and internal funds from the University of Florida Department of Physiology and Functional Genomics (BRS, MKR).
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