Relation of Statin Use to Gut Microbial Trimethylamine N-Oxide and Cardiovascular Risk.
The American journal of cardiology
Accumulating evidence suggests that statins can influence the microbiota. We investigated the effects of statin therapy on circulating levels of atherogenic gut microbial metabolite, trimethylamine N-oxide (TMAO), and subsequent clinical outcomes. We examined the effects of statin use on plasma TMAO in patients who are statin-naive with dyslipidemia previously enrolled in 2 intervention studies, International Medical Innovations (n=79) and Advances in Atorvastatin Research Group (n=27) in a post hoc analysis. A propensity score matching model stratified by statin use was used to validate the associations between statin use, plasma TMAO, and major adverse cardiovascular events across 4,007 patients who underwent elective coronary angiography. In the International Medical Innovations cohort, at 4weeks, statin use was associated with decreased plasma TMAO (p=0.03) and a return to baseline after statin discontinuation. In both intervention cohorts, patients with higher baseline TMAO (predefined cutoff 6.18muM) showed significant reductions in TMAO (all p <0.05). Propensity score matching on statin use (1,196 patient-pairs) revealed lower plasma TMAO (p=0.002) with statin use. An adjusted cox regression model including statin use, TMAO, and cholesterol showed preserved association of statin use and TMAO but not cholesterol with major adverse cardiovascular events (p=0.005, p <0.001, p=0.24, respectively). A likelihood ratio test showed improved model fit (p <0.001) with the addition of TMAO. In conclusion, our findings demonstrate that statin therapy significantly decreases plasma TMAO levels, suggesting the potential contribution of a statin-mediated reduction of TMAO production in cardiovascular benefits in addition to improved lipid profile and attenuated inflammation.
View details for DOI 10.1016/j.amjcard.2022.05.010
View details for PubMedID 35787338
Loop Diuretics Inhibit Renal Excretion of Trimethylamine N-Oxide.
JACC. Basic to translational science
2021; 6 (2): 103–15
This study demonstrates, for the first time, that renal tubular excretion of trimethylamine N-oxide (TMAO) is inhibited by concomitant loop diuretic administration. The observed marked accumulation in the renal parenchyma, and to lesser extent, plasma, implies differential distributions of TMAO across various tissues and/or systems as a consequence of efflux channel control. A better understanding of TMAO renal clearance and its potential interactions with current and future therapies in patients with heart failure are warranted.
View details for DOI 10.1016/j.jacbts.2020.11.010
View details for PubMedID 33665512
Dietary metabolism, the gut microbiome, and heart failure
NATURE REVIEWS CARDIOLOGY
2019; 16 (3): 137–54
Advances in our understanding of how the gut microbiota contributes to human health and diseases have expanded our insight into how microbial composition and function affect the human host. Heart failure is associated with splanchnic circulation congestion, leading to bowel wall oedema and impaired intestinal barrier function. This situation is thought to heighten the overall inflammatory state via increased bacterial translocation and the presence of bacterial products in the systemic blood circulation. Several metabolites produced by gut microorganisms from dietary metabolism have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. These findings suggest that the gut microbiome functions like an endocrine organ by generating bioactive metabolites that can directly or indirectly affect host physiology. In this Review, we discuss several newly discovered gut microbial metabolic pathways, including the production of trimethylamine and trimethylamine N-oxide, short-chain fatty acids, and secondary bile acids, that seem to participate in the development and progression of cardiovascular diseases, including heart failure. We also discuss the gut microbiome as a novel therapeutic target for the treatment of cardiovascular disease, and potential strategies for targeting intestinal microbial processes.
View details for DOI 10.1038/s41569-018-0108-7
View details for Web of Science ID 000458642400007
View details for PubMedID 30410105
View details for PubMedCentralID PMC6377322
Genetic, dietary, and sex-specific regulation of hepatic ceramides and the relationship between hepatic ceramides and IR
JOURNAL OF LIPID RESEARCH
2018; 59 (7): 1164–74
Elevated hepatic ceramide levels have been implicated in both insulin resistance (IR) and hepatic steatosis. To understand the factors contributing to hepatic ceramide levels in mice of both sexes, we have quantitated ceramides in a reference population of mice, the Hybrid Mouse Diversity Panel that has been previously characterized for a variety of metabolic syndrome traits. We observed significant positive correlations between Cer(d18:1/16:0) and IR/hepatic steatosis, consistent with previous findings, although the relationship broke down between sexes, as females were less insulin resistant, but had higher Cer(d18:1/16:0) levels than males. The sex difference was due in part to testosterone-mediated repression of ceramide synthase 6. One ceramide species, Cer(d18:1/20:0), was present at higher levels in males and was associated with IR only in males. Clear evidence of gene-by-sex and gene-by-diet interactions was observed, including sex-specific genome-wide association study results. Thus, our studies show clear differences in how hepatic ceramides are regulated between the sexes, which again suggests that the physiological roles of certain hepatic ceramides differ between the sexes.
View details for DOI 10.1194/jlr.M081398
View details for Web of Science ID 000437280100008
View details for PubMedID 29739864
View details for PubMedCentralID PMC6027922
- Oxidative Stress and Cardiovascular Risk in Type 1 Diabetes Mellitus: Insights From the DCCT/EDIC Study JOURNAL OF THE AMERICAN HEART ASSOCIATION 2018; 7 (10)
- RELATIONSHIP BETWEEN STATIN USE AND TRIMETHYLAMINE N-OXIDE IN CARDIOVASCULAR RISK ASSESSMENT ELSEVIER SCIENCE INC. 2018: 115
Contributory Role of Gut Microbiota and Their Metabolites Toward Cardiovascular Complications in Chronic Kidney Disease
SEMINARS IN NEPHROLOGY
2018; 38 (2): 193–205
The gut microbiome recently has emerged as a novel risk factor that impacts health and disease. Our gut microbiota can function as an endocrine organ through its unique ability to metabolize various dietary precursors, and can fuel the systemic inflammation observed in chronic disease. This is especially important in the setting of chronic kidney disease, in which microbial metabolism can contribute directly to accumulation of circulating toxins that then can alter and shift the balance of microbiota composition and downstream functions. To study this process, advances in -omics technologies are providing opportunities to understand not only the taxonomy, but also the functional diversity of our microbiome. We also reliably can quantify en masse a wide range of uremic byproducts of microbial metabolism. Herein, we examine the bidirectional relationship between the gut microbiome and the failing kidneys. We describe potential approaches targeting gut microbiota for cardiovascular risk reduction in chronic kidney disease using an illustrative example of a novel gut-generated metabolite, trimethylamine N-oxide.
View details for DOI 10.1016/j.semnephrol.2018.01.008
View details for Web of Science ID 000431356100010
View details for PubMedID 29602401
View details for PubMedCentralID PMC5881581
Gut Microbiota and Atherosclerosis
CURRENT ATHEROSCLEROSIS REPORTS
2017; 19 (10): 39
Studies in microbiota-mediated health risks have gained traction in recent years since the compilation of the Human Microbiome Project. No longer do we believe that our gut microbiota is an inert set of microorganisms that reside in the body without consequence. In this review, we discuss the recent findings which further our understanding of the connection between the gut microbiota and the atherosclerosis.We evaluate studies which illustrate the current understanding of the relationship between infection, immunity, altered metabolism, and bacterial products such as immune activators or dietary metabolites and their contributions to the development of atherosclerosis. In particular, we critically examine rec ent clinical and mechanistic findings for the novel microbiota-dependent dietary metabolite, trimethylamine N-oxide (TMAO), which has been implicated in atherosclerosis. These discoveries are now becoming integrated with advances in microbiota profiling which enhance our ability to interrogate the functional role of the gut microbiome and develop strategies for targeted therapeutics. The gut microbiota is a multi-faceted system that is unraveling novel contributors to the development and progression of atherosclerosis. In this review, we discuss historic and novel contributors while highlighting the TMAO story mainly as an example of the various paths taken beyond deciphering microbial composition to elucidate downstream mechanisms that promote (or protect from) atherogenesis in the hopes of translating these findings from bench to bedside.
View details for DOI 10.1007/s11883-017-0675-9
View details for Web of Science ID 000412843800001
View details for PubMedID 28842845
Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus
2017; 63 (1): 297–306
Recent studies show a mechanistic link between intestinal microbial metabolism of dietary phosphatidylcholine and coronary artery disease pathogenesis. Concentrations of a proatherogenic gut microbe-generated metabolite, trimethylamine N-oxide (TMAO), predict increased incident cardiovascular disease risks in multiple cohorts. TMAO concentrations are increased in patients with type 2 diabetes mellitus (T2DM), but their prognostic value and relation to glycemic control are unclear.We examined the relationship between fasting TMAO and 2 of its nutrient precursors, choline and betaine, vs 3-year major adverse cardiac events and 5-year mortality in 1216 stable patients with T2DM who underwent elective diagnostic coronary angiography.TMAO [4.4 μmol/L (interquartile range 2.8-7.7 μmol/L) vs 3.6 (2.3-5.7 μmol/L); P < 0.001] and choline concentrations were higher in individuals with T2DM vs healthy controls. Within T2DM patients, higher plasma TMAO was associated with a significant 3.0-fold increased 3-year major adverse cardiac event risk (P < 0.001) and a 3.6-fold increased 5-year mortality risk (P < 0.001). Following adjustments for traditional risk factors and high-sensitivity C-reactive protein, glycohemoglobin, and estimated glomerular filtration rate, increased TMAO concentrations remained predictive of both major adverse cardiac events and mortality risks in T2DM patients [e.g., quartiles 4 vs 1, hazard ratio 2.05 (95% CI, 1.31-3.20), P < 0.001; and 2.07 (95% CI, 1.37-3.14), P < 0.001, respectively].Fasting plasma concentrations of the proatherogenic gut microbe-generated metabolite TMAO are higher in diabetic patients and portend higher major adverse cardiac events and mortality risks independent of traditional risk factors, renal function, and relationship to glycemic control.
View details for DOI 10.1373/clinchem.2016.263640
View details for Web of Science ID 000395048800042
View details for PubMedID 27864387
View details for PubMedCentralID PMC5659115
Autoantibodies Specifically Against beta(1) Adrenergic Receptors and Adverse Clinical Outcome in Patients With Chronic Systolic Heart Failure in the beta-Blocker Era: The Importance of Immunoglobulin G3 Subclass
JOURNAL OF CARDIAC FAILURE
2016; 22 (6): 417-422
To elucidate the prevalence and role of β1 adrenergic receptor autoantibodies (β1AR-AAb) belonging to the immunoglobulin (Ig)G3 subclass in patients with heart failure (HF) treated with β-adrenergic blockers.Several cardiac AAbs have been reported to be present in sera from patients with dilated cardiomyopathy and other etiologies. Among AAbs, those recognizing β1AR-AAbs show agonist-like effects, have detrimental effects on cardiomyocytes, and may induce persistent myocardial damage.We quantify total IgG and IgG3 subclass β1AR-AAb in subjects with chronic stable HF with long-term follow-up.In our study cohort of 121 subjects, non-IgG3-β1AR-AAb and IgG3-β1AR-AAb were found to be positive in 20 (17%) and 26 patients (21%), respectively. The positive rate of IgG3-β1AR-AAb was significantly higher for those with nonischemic compared with ischemic HF etiology (27% vs 8%, P = .01), but the positive rate for non-IgG3-β1AR-AAb was similar between the 2 groups (18% vs 16%, respectively, P = NS). There were no significant differences in clinical and echocardiographic measures among total β1AR-AAb negative, non-IgG3-β1AR-AAb positive, and IgG3-β1AR-AAb positive groups at baseline. During 2.2 ± 1.2 years of follow-up, we observed similar rates of the composite endpoint of all-cause mortality, cardiac transplantation, or hospitalization resulting from HF between total IgG-β1AR-AAb negative and positive patients. However, the composite endpoint events were significantly more common in the patients without than in those with IgG3-β1AR-AAb (P = .048, log-rank test).Presence of IgG3-β1AR-AAb, not total IgG, was associated with paradoxically more favorable outcomes in our cohort of patients with chronic systolic HF largely treated by β-blockers.
View details for DOI 10.1016/j.cardfail.2016.03.005
View details for Web of Science ID 000377844300003
View details for PubMedID 26997620
View details for PubMedCentralID PMC4893993
A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2
JOURNAL OF VIROLOGY
2016; 90 (1): 562–74
A recent phase 3 trial with soluble herpes simplex virus 2 (HSV-2) glycoprotein D (gD2t) in adjuvant failed to show protection against genital herpes. We postulated that live attenuated HSV-2 would provide more HSV antigens for induction of virus-specific antibodies and cellular immunity than would gD2t. We previously reported an HSV-2 mutant, HSV2-gD27, in which the nectin-1 binding domain of gD2 is altered so that the virus is impaired for infecting neural cells, but not epithelial cells, in vitro and is impaired for infecting dorsal root ganglia in mice (K. Wang, J. D. Kappel, C. Canders, W. F. Davila, D. Sayre, M. Chavez, L. Pesnicak, and J. I. Cohen, J Virol 86:12891-12902, 2012, doi:10.1128/JVI.01055-12). Here we report that the mutations in HSV2-gD27 were stable when the virus was passaged in cell culture and during acute infection of mice. HSV2-gD27 was attenuated in mice when it was inoculated onto the cornea, intramuscularly (i.m.), intravaginally, and intracranially. Vaccination of mice i.m. with HSV2-gD27 provided better inhibition of challenge virus replication in the vagina than when the virus was used to vaccinate mice intranasally or subcutaneously. Comparison of i.m. vaccinations with HSV2-gD27 versus gD2t in adjuvant showed that HSV2-gD27 induced larger reductions of challenge virus replication in the vagina and reduced latent viral loads in dorsal root ganglia but induced lower serum neutralizing antibody titers than those obtained with gD2t in adjuvant. Taken together, our data indicate that a live attenuated HSV-2 vaccine impaired for infection of neurons provides better protection from vaginal challenge with HSV-2 than that obtained with a subunit vaccine, despite inducing lower titers of HSV-2 neutralizing antibodies in the serum.Genital herpes simplex is one of the most prevalent sexually transmitted diseases. Though HSV-2 disease is usually mild, it can be life threatening in neonates and immunocompromised persons. In addition, genital herpes increases the frequency of HIV infection and transmission. HSV-2 maintains a latent infection in sensory neurons and cannot be cleared with antiviral drugs. The virus frequently reactivates, resulting in virus shedding in the genital area, which serves as a source for transmission. A prophylactic vaccine is needed to prevent disease and to control the spread of the virus. Previous human trials of subunit vaccines have been unsuccessful. Here we report the results of vaccinating mice with a new type of live attenuated HSV-2 vaccine that is impaired for infection of neurons and provides better protection of mice than that obtained with a subunit vaccine. The strategy of altering the cell tropism of a virus is a new approach for a live attenuated vaccine.
View details for DOI 10.1128/JVI.01845-15
View details for Web of Science ID 000366899000050
View details for PubMedID 26559846
View details for PubMedCentralID PMC4702532
Listening to Our Gut: Contribution of Gut Microbiota and Cardiovascular Risk in Diabetes Pathogenesis
CURRENT DIABETES REPORTS
2015; 15 (9): 63
What we understand about diabetes from decades of genetics research is now being supplemented with exciting new evidence based on a better understanding of how one of the biggest "environmental" factors the body is exposed to is influencing the pathogenesis of disease. The recent discovery that certain dietary nutrients possessing a trimethylamine (TMA) moiety (namely choline/phosphatidylcholine and L-carnitine) participate in the development of atherosclerotic heart disease has renewed attention towards the contributions of gut microbiota in the development of cardiovascular diseases. Collectively, animal and human studies reveal that conversion of these nutrient precursors to trimethylamine N-oxide (TMAO) depends on both microbial composition and host factors, and can be induced by dietary exposures. In addition, circulating TMAO levels are strongly linked to cardiovascular disease risks and various adverse cardio-renal consequences. Our group and others have further demonstrated that circulating TMAO levels are elevated in patients with type 2 diabetes mellitus compared to healthy controls and gut microbiota-dependent phosphatidylcholine metabolism has been implicated in metabolic dysregulation and insulin resistance in animal models. Therefore, preventive strategies to minimize adverse consequences associated with TMAO generation in the diabetic population are warranted.
View details for DOI 10.1007/s11892-015-0634-1
View details for Web of Science ID 000377953300007
View details for PubMedID 26208694
View details for PubMedCentralID PMC4832136
Loss of FHL1 induces an age-dependent skeletal muscle myopathy associated with myofibrillar and intermyofibrillar disorganization in mice
HUMAN MOLECULAR GENETICS
2014; 23 (1): 209–25
Recent human genetic studies have provided evidences that sporadic or inherited missense mutations in four-and-a-half LIM domain protein 1 (FHL1), resulting in alterations in FHL1 protein expression, are associated with rare congenital myopathies, including reducing body myopathy and Emery-Dreifuss muscular dystrophy. However, it remains to be clarified whether mutations in FHL1 cause skeletal muscle remodeling owing to gain- or loss of FHL1 function. In this study, we used FHL1-null mice lacking global FHL1 expression to evaluate loss-of-function effects on skeletal muscle homeostasis. Histological and functional analyses of soleus, tibialis anterior and sternohyoideus muscles demonstrated that FHL1-null mice develop an age-dependent myopathy associated with myofibrillar and intermyofibrillar (mitochondrial and sarcoplasmic reticulum) disorganization, impaired muscle oxidative capacity and increased autophagic activity. A longitudinal study established decreased survival rates in FHL1-null mice, associated with age-dependent impairment of muscle contractile function and a significantly lower exercise capacity. Analysis of primary myoblasts isolated from FHL1-null muscles demonstrated early muscle fiber differentiation and maturation defects, which could be rescued by re-expression of the FHL1A isoform, highlighting that FHL1A is necessary for proper muscle fiber differentiation and maturation in vitro. Overall, our data show that loss of FHL1 function leads to myopathy in vivo and suggest that loss of function of FHL1 may be one of the mechanisms underlying muscle dystrophy in patients with FHL1 mutations.
View details for DOI 10.1093/hmg/ddt412
View details for Web of Science ID 000328482300017
View details for PubMedID 23975679
View details for PubMedCentralID PMC3916749
- Holistic metabonomic profiling of urine affords potential early diagnosis for bladder and kidney cancers METABOLOMICS 2013; 9 (1): 119–29
- Protein Structure Modeling in a Grid Computing Environment IEEE. 2013: 301–6