Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 582
Filtrar
2.
Am J Med ; 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33872583

RESUMO

BACKGROUND: Choline is a dietary precursor to the gut microbial generation of the pro-thrombotic and pro-atherogenic metabolite trimethylamine-N-oxide (TMAO). Eggs are rich in choline, yet the impact of habitual egg consumption on TMAO levels and platelet function in human subjects remains unclear. METHODS: Healthy volunteers (41% male, 81% Caucasian, median age 28) with normal renal function (eGFR>60) were recruited and assigned to one of five daily interventions for four weeks: (i) hardboiled eggs (N=18); (ii) choline bitartrate supplements (N=20); (iii) hardboiled eggs + choline bitartrate supplements (N=16); (iv) egg whites + choline bitartrate supplements (N=18); (v) phosphatidylcholine supplements (N=10). Fasting blood and urine samples were collected for quantification of TMAO, its precursors, and platelet aggregometry. RESULTS: Participant's plasma TMAO levels increased significantly in all three intervention arms containing choline bitartrate (all P<0.0001), but daily ingestion of four large eggs (P=0.28) or phosphatidylcholine supplements (P=0.27) failed to increase plasma TMAO levels. Platelet reactivity also significantly increased in the three intervention arms containing choline bitartrate (all P<0.01), but not with eggs (P=0.10) or phosphatidylcholine supplements (P=0.79). CONCLUSIONS: Despite high choline content in egg yolks, healthy participants consuming four eggs daily showed no significant increase in TMAO or platelet reactivity. However, choline bitartrate supplements providing comparable total choline raised both TMAO and platelet reactivity, demonstrating that the form and source of dietary choline differentially contributes to systemic TMAO levels and platelet responsiveness.

3.
Hum Genet ; 140(6): 957-967, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33745059

RESUMO

While newborns and children with hearing loss are routinely offered genetic testing, adults are rarely clinically tested for a genetic etiology. One clinically actionable result from genetic testing in children is the discovery of variants in syndromic hearing loss genes. EYA4 is a known hearing loss gene which is also involved in important pathways in cardiac tissue. The pleiotropic effects of rare EYA4 variants are poorly understood and their prevalence in a large cohort has not been previously reported. We investigated cardio-auditory phenotypes in 11,451 individuals in a large biobank using a rare variant, genome-first approach to EYA4. We filtered 256 EYA4 variants carried by 6737 participants to 26 rare and predicted deleterious variants carried by 42 heterozygotes. We aggregated predicted deleterious EYA4 gene variants into a combined variable (i.e. "gene burden") and performed association studies across phenotypes compared to wildtype controls. We validated findings with replication in three independent cohorts and human tissue expression data. EYA4 gene burden was significantly associated with audiometric-proven HL (p = [Formula: see text], Mobitz Type II AV block (p = [Formula: see text]) and the syndromic presentation of HL and primary cardiomyopathy (p = 0.0194). Analyses on audiogram, echocardiogram, and electrocardiogram data validated these associations. Prior reports have focused on identifying variants in families with severe or syndromic phenotypes. In contrast, we found, using a genotype-first approach, that gene burden in EYA4 is associated with more subtle cardio-auditory phenotypes in an adult medical biobank population, including cardiac conduction disorders which have not been previously reported. We show the value of using a focused approach to uncover human disease related to pleiotropic gene variants and suggest a role for genetic testing in adults presenting with hearing loss.

4.
J Lipid Res ; 62: 100061, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33667465

RESUMO

Individuals with features of metabolic syndrome are particularly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus associated with the severe respiratory disease, coronavirus disease 2019 (COVID-19). Despite considerable attention dedicated to COVID-19, the link between metabolic syndrome and SARS-CoV-2 infection remains unclear. Using data from the UK Biobank, we investigated the relationship between severity of COVID-19 and metabolic syndrome-related serum biomarkers measured prior to SARS-CoV-2 infection. Logistic regression analyses were used to test biomarker levels and biomarker-associated genetic variants with SARS-CoV-2-related outcomes. Among SARS-CoV-2-positive cases and negative controls, a 10 mg/dl increase in serum HDL-cholesterol or apolipoprotein A1 levels was associated with ∼10% reduced risk of SARS-CoV-2 infection, after adjustment for age, sex, obesity, hypertension, type 2 diabetes, and coronary artery disease. Evaluation of known genetic variants for HDL-cholesterol revealed that individuals homozygous for apolipoprotein E4 alleles had ∼2- to 3-fold higher risk of SARS-CoV-2 infection or mortality from COVID-19 compared with apolipoprotein E3 homozygotes, even after adjustment for HDL-cholesterol levels. However, cumulative effects of all evaluated HDL-cholesterol-raising alleles and Mendelian randomization analyses did not reveal association of genetically higher HDL-cholesterol levels with decreased risk of SARS-CoV-2 infection. These results implicate serum HDL-cholesterol and apolipoprotein A1 levels measured prior to SAR-CoV-2 exposure as clinical risk factors for severe COVID-19 infection but do not provide evidence that genetically elevated HDL-cholesterol levels are associated with SAR-CoV-2 infection.

5.
Eur Heart J ; 42(18): 1742-1756, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33748830

RESUMO

AIMS: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1ß can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. METHODS AND RESULTS: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. CONCLUSION: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

6.
Mol Biol Cell ; 32(7): 622-633, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33534612

RESUMO

Dysregulation of immune responses has been linked to the generation of immunoglobulin G (IgG) autoantibodies that target human ß1ARs and contribute to deleterious cardiac outcomes. Given the benefits of ß-blockers observed in patients harboring the IgG3 subclass of autoantibodies, we investigated the role of these autoantibodies in human ß1AR function. Serum and purified IgG3(+) autoantibodies from patients with onset of cardiomyopathy were tested using human embryonic kidney (HEK) 293 cells expressing human ß1ARs. Unexpectedly, pretreatment of cells with IgG3(+) serum or purified IgG3(+) autoantibodies impaired dobutamine-mediated adenylate cyclase (AC) activity and cyclic adenosine monophosphate (cAMP) generation while enhancing biased ß-arrestin recruitment and Extracellular Regulated Kinase (ERK) activation. In contrast, the ß-blocker metoprolol increased AC activity and cAMP in the presence of IgG3(+) serum or IgG3(+) autoantibodies. Because IgG3(+) autoantibodies are specific to human ß1ARs, non-failing human hearts were used as an endogenous system to determine their ability to bias ß1AR signaling. Consistently, metoprolol increased AC activity, reflecting the ability of the IgG3(+) autoantibodies to bias ß-blocker toward G-protein coupling. Importantly, IgG3(+) autoantibodies are specific toward ß1AR as they did not alter ß2AR signaling. Thus, IgG3(+) autoantibody biases ß-blocker toward G-protein coupling while impairing agonist-mediated G-protein activation but promoting G-protein-independent ERK activation. This phenomenon may underlie the beneficial outcomes observed in patients harboring IgG3(+) ß1AR autoantibodies.

7.
Am Heart J ; 236: 80-86, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33626384

RESUMO

BACKGROUND: Recent studies show a mechanistic link between gut microbiota-dependent formation of the atherosclerosis- and thrombosis-promoting metabolite trimethylamine N-oxide (TMAO) and cardiovascular disease (CVD). The clinical utility of TMAO in apparently healthy subjects for predicting incident CVD risks is unclear. METHODS AND RESULTS: In the EPIC-Norfolk community-based study, we examined baseline fasting levels of TMAO and two of its nutrient precursors, choline and betaine, in a case:control design study comparing apparently European healthy middle-aged participants who subsequently develop CVD (Cases, n = 908) vs those who did not (Controls, n = 1,273) over an ensuing average follow-up period of 8 years. In participants who developed CVD vs controls, higher plasma TMAO (3.70 [IQR 2.50-6.41]µM vs 3.25 [IQR 2.19-52,1.15]µM; P < .001) and choline levels (9.09 [IQR 7.87-10.53]µM vs 8.89 [IQR 7.66-10.13]µM; P = .001) were observed. Following adjustments for traditional risk factors, elevated TMAO (adjusted odds ratio (OR) 1.58 [95% confidence interval (CI) 1.21-2.06], P < .001) and choline levels (adjusted OR 1.31 [95%CI 1.00-1.72], P < .05) remained predictive of incident CVD development. The clinical prognostic utility of TMAO remained significant and essentially unchanged regardless of the level of cutoff chosen between 1.5 uM (10%ile) to 10.5 uM (90%ile). CONCLUSION: In apparently healthy participants of the community-based middle-aged EPIC-Norfolk population, elevated plasma levels of the gut microbe-dependent metabolite TMAO, and its nutrient precursor choline, predict incident risk for CVD development independent of traditional risk factors.

8.
Prog Nucl Magn Reson Spectrosc ; 122: 11-22, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33632415

RESUMO

Quantitative cardiac magnetic resonance has emerged in recent years as an approach for evaluating a range of cardiovascular conditions, with T1 and T2 mapping at the forefront of these developments. Cardiac Magnetic Resonance Fingerprinting (cMRF) provides a rapid and robust framework for simultaneous quantification of myocardial T1 and T2 in addition to other tissue properties. Since the advent of cMRF, a number of technical developments and clinical validation studies have been reported. This review provides an overview of cMRF, recent technical developments, healthy subject and patient studies, anticipated technical improvements, and potential clinical applications. Recent technical developments include slice profile and pulse efficiency corrections, improvements in image reconstruction, simultaneous multislice imaging, 3D whole-ventricle imaging, motion-resolved imaging, fat-water separation, and machine learning for rapid dictionary generation. Future technical developments in cMRF, such as B0 and B1 field mapping, acceleration of acquisition and reconstruction, imaging of patients with implanted devices, and quantification of additional tissue properties are also described. Potential clinical applications include characterization of infiltrative, inflammatory, and ischemic cardiomyopathies, tissue characterization in the left atrium and right ventricle, post-cardiac transplantation assessment, reduction of contrast material, pre-procedural planning for electrophysiology interventions, and imaging of patients with implanted devices.

9.
Curr Heart Fail Rep ; 18(2): 23-32, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33559845

RESUMO

PURPOSE OF REVIEW: Over the past decade, the gut microbiome has been shown to play an important role in the pathogenesis of heart failure (HF) and serves as a mediator that links host genomes and environmental exposure (especially dietary intake) to the development and progression of HF. Given that alterations in gut microbial composition and metabolism are commonly seen in patients with HF, the use of gut microbial metabolites as diagnostic and prognostic biomarkers, as well as novel therapeutic targets for HF, is promising. RECENT FINDINGS: Alterations in gut microbial composition and function have bidirectional relationships with HF. Gut microbial metabolites, including short-chain fatty acids, bile acids, trimethylamine N-oxide (TMAO), and amino acid metabolites, have been shown to play a significant role in HF. For example, TMAO has been consistently demonstrated as an independent predictor of worse prognosis in patients with HF, and a potential therapeutic target for cardiac remodeling and HF. However, clinical studies on dietary interventions targeting gut microbial metabolites have demonstrated inconsistent findings, which could be from variations in the study population, gut microbial communities, and study designs. Measurement of gut microbial metabolites can improve risk stratification and potentially identify HF patients who are more likely to respond to personalized pharmacologic or dietary interventions targeting specific pathways associated with the gut microbiome.

10.
Am J Transplant ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33527725

RESUMO

Simultaneous heart-kidney transplant (sHK) has enabled the successful transplantation of patients with end-stage heart disease and concomitant kidney disease, with non-inferior outcomes to heart transplant (HT) alone. The decision for sHK is challenged by difficulties in differentiating those patients with a significant component of reversible kidney injury due to cardiorenal syndrome who may recover kidney function after HT, from those with intrinsic advanced kidney disease who would benefit most from sHK. A consensus conference on sHK took place on June 1, 2019 in Boston, Massachusetts. The conference represented a collaborative effort by experts in cardiothoracic and kidney transplantation from centers across the United States to explore the development of guidelines for the interdisciplinary criteria for kidney transplantation in the sHK candidate, to evaluate the current allocation of kidneys to follow the heart for sHK, and to recommend standardized care for the management of sHK recipients. The conference served as a forum to unify criteria between the different specialties and to forge a pathway for patients who may need dual organ transplantation. Due to the continuing shortage of available donor organs, ethical problems related to multi-organ transplantation were also debated. The findings and consensus statements are presented.

14.
JACC Clin Electrophysiol ; 7(1): 36-46, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33478710

RESUMO

OBJECTIVES: This study aimed to determine the long-term outcomes and predictors of left ventricular (LV) ejection fraction (LVEF) improvement in patients with severe cardiomyopathies undergoing cardiac resynchronization therapy (CRT). BACKGROUND: Whether patients with severe LV dysfunction benefit from CRT or have reached a point in disease severity past the point at which CRT is beneficial is unknown. METHODS: We collected clinical and echocardiographic data on 420 patients with an LVEF of ≤15% and a QRS duration of ≥120 ms undergoing CRT at the Cleveland Clinic and 2 hospitals in the Johns Hopkins Health System between April 2003 and May 2014. Multivariate models were created to determine factors associated with response to CRT, defined as an absolute improvement in LVEF of >5% and survival free of LVAD and heart transplant. Procedure-related deaths were also collected. RESULTS: A total of 298 patients had pre- and appropriately timed post-CRT echocardiograms, of whom 145 (48.7%) met the criteria for response. In multivariate analysis, LV size and left bundle branch block (LBBB) were associated with response. Among the most dilated quintile (LV end-diastolic diameter [LVEDD] of >7.8 cm), 30.4% met the criteria for response. In multivariate analysis, smaller LV end-diastolic dysfunction and presence of LBBB were associated with improved survival free of heart failure and LVAD over a mean follow-up period of 5.2 years. There were no procedure-related deaths. CONCLUSIONS: Patients with severe LV dysfunction respond to CRT, although at a lower rate compared to traditional CRT candidates. Smaller LV size and LBBB are important predictors of positive outcomes in this population. Even among the most dilated patients, 30.4% realized a meaningful improvement in LVEF with CRT. The CRT implant procedure itself appears well tolerated.

15.
J Card Fail ; 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33497809

RESUMO

BACKGROUND: The inflammatory cytokine IL-6 has been previously implicated in the pathophysiology of acute decompensated heart failure (HF). Prior observations in acute HF patients have suggested that IL-6 may be associated with outcomes and modulated by nesiritide. We aimed to evaluate the associations between serial IL-6 measurements, mortality and rehospitalization in acute HF. METHODS AND RESULTS: We analyzed the associations between IL-6 in acute HF, readmission, and mortality (30 and 180 days) using a cohort of 883 hospitalized patients from the ASCEND-HF trial (nesiritide vs placebo). Plasma IL-6 was measured at randomization (baseline), 48-72 hours, and 30 days. The median IL-6 was highest at baseline (14.1 pg/mL) and decreased at subsequent time points (7.6 pg/mL at 30 days). In a univariable Cox regression analysis, the baseline IL-6 was associated with 30- and 180-day mortality (hazard ratio per log 1.74, 95% confidence interval 1.09-2.78, P = .021; hazard ratio 3.23, confidence interval 1.18-8.86, P = .022, respectively). However, there was no association after multivariable adjustment. IL-6 at 48-72 hours was found to be independently associated with 30-day mortality (hazard ratio 8.2, confidence interval 1.2-57.5, P= .03), but not 180-day mortality in multivariable analysis that included the ASCEND-HF risk model and amino terminal pro-B-type natriuretic peptide as covariates. In comparison with placebo, nesiritide therapy was not associated with differences in serial IL-6 levels. CONCLUSIONS: Although elevated IL-6 levels were associated with higher all-cause mortality in acute HF, no independent association with this outcome was identified at baseline or 30-day measurements. In contrast with prior reports, we did not observe any impact of nesiritide over placebo on serial IL-6 levels.

16.
Am J Med ; 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33444594

RESUMO

Studies evaluating fish consumption and cardiovascular disease events have shown inconsistent results. We performed a systematic review of peer-reviewed publications from an extensive query of Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Scopus, and Web of Science from database inception to September 2020 for observational studies that reported the association between fish consumption and cardiovascular disease events. We identified and reviewed 24 studies related to fish consumption and the effect on cardiovascular outcomes. The study population included a total of 714,526 individuals and multiple cohorts from several countries. We found that nonfried fish consumption is probably associated with a reduced risk of overall cardiovascular disease events and myocardial infarction risk. In contrast, fried fish consumption is probably associated with an increased risk of overall cardiovascular disease events and myocardial infarction risk. No studies to date have shown any significant association between fish consumption and stroke. Our analysis suggests that fish consumption may reduce cardiovascular disease events, but fried fish consumption was associated with an increased risk of cardiovascular events.

17.
Am J Med ; 134(5): 637-642.e2, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33309597

RESUMO

INTRODUCTION: Edible mushrooms have a great nutritional value including high protein, essential amino acids, fiber, vitamins (B1, B2, B12, C, and D), minerals (calcium [Ca], potassium [K], magnesium [Mg], sodium [Na], phosphorus [P], copper [Cu], iron [Fe], manganese [Mn], and selenium [Se]), low fatty foods, and sodium. The objective of this systematic review was to determine the relationship between edible mushroom consumption and overall cardiovascular risk. METHODS: We systematically searched Ovid MEDLINE, Embase, Ovid Cochrane Database of Systematic Reviews, Scopus, and Web of Science from database inception from 1966 through August 2020 for observational studies that reported the association between edible mushroom consumption and cardiovascular risk. Two investigators independently reviewed data. Conflicts were resolved through consensus discussion. RESULTS: Of 1479 studies, we identified 7 prospective studies. Edible mushroom consumption may have favorable effects on lipid profiles by changing some metabolic markers such as low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, total cholesterol, and triglycerides. Moreover, edible mushroom consumption is probably associated with reduced mean blood pressure. The beneficial overall cardiovascular risk, stroke risk, and coronary artery disease of edible mushroom consumption are not consistent. CONCLUSIONS: Edible mushroom consumption has not been shown to conclusively affect cardiovascular risk factors to date. However, potential health benefits may exist, including a favorable alteration of lipid profiles and blood pressure reduction.

20.
Metabolism ; : 154457, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33275980

RESUMO

OBJECTIVE: Metabolomic studies suggest plasma levels of bile acids (BAs) are elevated amongst subjects with non-alcoholic fatty liver disease (NAFLD) compared to healthy controls. However, it remains unclear whether or not specific BAs are associated with the clinically relevant transition from nonalcoholic fatty liver (i.e. simple steatosis) to non-alcoholic steatohepatitis (NASH), or enhanced progression of hepatic fibrosis, or genetic determinants of NAFLD/NASH. METHODS: Among sequential subjects (n=102) undergoing diagnostic liver biopsy, we examined the associations of a broad panel of BAs with distinct histopathological features of NAFLD, the presence of NASH, and their associations with genetic variants linked to NAFLD and NASH. RESULTS: Plasma BA alterations were observed through the entire spectrum of NAFLD, with several glycine conjugated forms of the BAs demonstrating significant associations with higher grades of inflammation and fibrosis. Plasma 7-Keto-DCA levels showed the strongest associations with advanced stages of hepatic fibrosis [odds ratio(95% confidence interval)], 4.2(1.2-16.4), NASH 24.5(4.1-473), and ballooning 18.7(4.8-91.9). Plasma 7-Keto-LCA levels were associated with NASH 9.4(1.5-185) and ballooning 5.9(1.4-28.8). Genetic variants at several NAFLD/NASH loci were nominally associated with increased levels of 7-Keto- and glycine-conjugated forms of BAs, and the NAFLD risk allele at the TRIB1 locus showed strong tendency toward increased plasma levels of GCA (p=0.02) and GUDCA (p=0.009). CONCLUSIONS: Circulating bile acid levels are associated with histopathological and genetic determinants of the transition from simple hepatic steatosis into NASH. Further studies exploring the potential involvement of bile acid metabolism in the development and/or progression of distinct histopathological features of NASH are warranted.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...