Impact of a dedicated center for atrial fibrillation on resource utilization and costs.

BACKGROUND: Atrial fibrillation (AF) affects millions of Americans each year and can lead to high levels of resource utilization through emergency department (ED) visits and inpatient stays. HYPOTHESIS: We hypothesized that referral of patients to a dedicated Center for AF from the ED would reduce costs of care. METHODS: The University of Pittsburgh Center for AF serves as a rapid referral center for patients with AF to avoid unnecessary inpatient admissions and provide specialized care. Patients that presented to the ED with AF and met prespecified criteria were directed to rapid outpatient follow-up instead of inpatient admission. The primary outcome of interest was 30-day total costs. Secondary outcomes included outpatient costs, inpatient costs, 90-day costs, and inpatient stay characteristics. RESULTS: We identified 96 patients (median age 65, 38% women) referred to the center for AF for a new diagnosis of AF between October 2017 and December 2019 and matched 96 control patients. After 30 days of follow-up, patients referred to the center for AF had a lower average cost ($619 vs. $1252, p < 0.001) compared to controls, driven by lower costs of ED care tempered by slightly higher outpatient costs. Thirty-day admissions and lengths of stay were also lower. These differences were persistent at 90 days. CONCLUSION: Directing patients with AF that present to the ED to follow-up at a dedicated Center for AF significantly reduced overall costs, while reducing subsequent inpatient admissions and total lengths of stay in the hospital.

Targeting the latest site of left ventricular mechanical activation is associated with improved long-term outcomes for recipients of cardiac resynchronization therapy.

Background: Previous studies have suggested that targeting the site of latest mechanical activation of the left ventricle (LV) results in improved cardiac resynchronization therapy (CRT) outcomes. It is not known whether these benefits are sustained over medium-term follow-up. Objective: To assess the clinical outcome of imaging-guided LV lead position. Methods: We sought to assess the medium-term clinical outcome by performing a patient-level meta-analysis of 2 previously published randomized controlled trials (the "STARTER" trial and the "CRT Clinic" trial). These 2 trials compared imaging-guided LV lead placement in the latest activated scar-free segment (intervention group) to standard of care (control). Mortality and heart failure hospitalization outcomes over extended follow-up were gathered from the medical records and merged. Results were stratified for native electrocardiogram (ECG) morphology. Results: A total of 289 patients were followed for a median of 6.3 years. Seven years post implant, 47 (28%) in the intervention group had died, vs 47 (38%) in the control group (P = .13); 49 (30%) vs 53 (42%) had been hospitalized for heart failure (P = .035); and 47% vs 59% (P = .057) had reached the combined endpoint. In Kaplan-Meier analysis, patients in the intervention group had better survival free of heart failure hospitalization (P = .045) and lower risk of heart failure hospitalization (P = .019). Conclusion: Targeting the latest mechanically activated segment in CRT results in better medium-term clinical outcome, mainly driven by a reduced risk of hospitalization for heart failure. The effect was seen regardless of native ECG morphology.

Gut microbiota and host genetics modulate the effect of diverse diet patterns on metabolic health.

Metabolic diseases are major public health issues worldwide and are responsible for disproportionately higher healthcare costs and increased complications of many diseases including SARS-CoV-2 infection. The Western Diet (WD) specifically is believed to be a major contributor to the global metabolic disease epidemic. In contrast, the Mediterranean diet (MeD), Ketogenic diet (KD), and Japanese diet (JD) are often considered beneficial for metabolic health. Yet, there is a growing appreciation that the effect of diet on metabolic health varies depending on several factors including host genetics. Additionally, poor metabolic health has also been attributed to altered gut microbial composition and/or function. To understand the complex relationship between host genetics, gut microbiota, and dietary patterns, we treated four widely used metabolically diverse inbred mouse strains (A/J, C57BL/6J, FVB/NJ, and NOD/ShiLtJ) with four human-relevant diets (MeD, JD, KD, WD), and a control mouse chow from 6 weeks to 30 weeks of age. We found that diet-induced alteration of gut microbiota (α-diversity, ß-diversity, and abundance of several bacteria including Bifidobacterium, Ruminococcus, Turicibacter, Faecalibaculum, and Akkermansia) is significantly modified by host genetics. In addition, depending on the gut microbiota, the same diet could have different metabolic health effects. Our study also revealed that C57BL/6J mice are more susceptible to altered gut microbiota compared to other strains in this study indicating that host genetics is an important modulator of the diet-microbiota-metabolic health axis. Overall, our study demonstrated complex interactions between host genetics, gut microbiota, and diet on metabolic health; indicating the need to consider both host genetics and the gut microbiota in the development of new and more effective precision nutrition strategies to improve metabolic health.

Independent and Interactive Effects of Genetic Background and Sex on Tissue Metabolomes of Adipose, Skeletal Muscle, and Liver in Mice.

Genetics play an important role in the development of metabolic diseases. However, the relative influence of genetic variation on metabolism is not well defined, particularly in tissues, where metabolic dysfunction that leads to disease occurs. We used inbred strains of laboratory mice to evaluate the impact of genetic variation on the metabolomes of tissues that play central roles in metabolic diseases. We chose a set of four common inbred strains that have different levels of susceptibility to obesity, insulin resistance, and other common metabolic disorders. At the ages used, and under standard husbandry conditions, these lines are not overtly diseased. Using global metabolomics profiling, we evaluated water-soluble metabolites in liver, skeletal muscle, and adipose from A/J, C57BL/6J, FVB/NJ, and NOD/ShiLtJ mice fed a standard mouse chow diet. We included both males and females to assess the relative influence of strain, sex, and strain-by-sex interactions on metabolomes. The mice were also phenotyped for systems level traits related to metabolism and energy expenditure. Strain explained more variation in the metabolite profile than did sex or its interaction with strain across each of the tissues, especially in liver. Purine and pyrimidine metabolism and pathways related to amino acid metabolism were identified as pathways that discriminated strains across all three tissues. Based on the results from ANOVA, sex and sex-by-strain interaction had modest influence on metabolomes relative to strain, suggesting that the tissue metabolome remains largely stable across sexes consuming the same diet. Our data indicate that genetic variation exerts a fundamental influence on tissue metabolism.

Sex-specific genetic architecture in response to American and ketogenic diets.

BACKGROUND/OBJECTIVES: There is a growing appreciation for individual responses to diet. In a previous study, mouse strain-specific responses to American and ketogenic diets were observed. In this study, we searched for genetic variants underlying differences in the responses to American and ketogenic diets between C57BL/6J (B6) and FVB/NJ (FVB) mouse strains. RESULTS: Genetic mapping of fat and lean mass gain revealed QTLs on Chromosome (Chr) 1 at 191.6 Mb (Fmgq1) (P < 0.001, CI = 180.2-194.4 Mb), Chr5 at 73.7 Mb (Fmgq2, Lmgq1) (P < 0.001, CI = 66.1-76.6 Mb), and Chr7 at 40.5 Mb (Fmgq3) (P < 0.01, CI = 36.6-44.5 Mb). Analysis of serum HDL cholesterol concentration identified a significant (P < 0.001, CI = 160.6-176.1 Mb) QTL on Chr1 at 168.6 Mb (Hdlq1). Causal network inference suggests that HDL cholesterol and fat mass gain are both linked to Fmgq1. CONCLUSIONS: Strong sex effects were identified at both Fmgq2 and Lmgq1, which are also diet-dependent. Interestingly, Fmgq2 and Fmgq3 affect fat gain directly, while Fmgq1 influences fat gain directly and via an intermediate change in serum cholesterol. These results demonstrate how precision nutrition will be advanced through the integration of genetic variation and sex in physiological responses to diets varied in carbohydrate composition.

An integrative multiomic network model links lipid metabolism to glucose regulation in coronary artery disease.

Elevated plasma cholesterol and type 2 diabetes (T2D) are associated with coronary artery disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explore the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic, and clinical data, we identify a glucose and lipid determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impact lipid and glucose levels in inverse directions. Experimental inhibition of one of the GLD network master regulators, lanosterol synthase (LSS), in mice confirms the inverse relationships to glucose and lipid levels as predicted by our model and provides mechanistic insights.

Transcriptional landscape of mouse-aged ovaries reveals a unique set of non-coding RNAs associated with physiological and environmental ovarian dysfunctions.

The progressive and physiological decline in ovarian function depends on the rate of follicular loss by atresia, contributing to the reduction in ovarian reserve. Genetics and environmental factors play important roles in ovarian senescence and in the onset of ovarian dysfunctions such as diminished ovarian reserve. A better understanding of the mechanisms underlying ovarian aging and their regulation by genetic and environmental factors is needed to evaluate ovarian reserve and to predict fertility potential by identification of more accurate and less invasive markers. We report transcriptomic data (i) implicating novel (e.g. EIF2 signalling) and well-known pathways (e.g. TGFß signalling), and (ii) defining a unique set of non-coding RNA (ncRNA), both associated with ovarian function. The latter includes miRNAs (e.g. Mir143 and Mir145), snoRNAs (e.g. Snord16a and Snora34), and one lncRNA (Gas5), which are differentially expressed in middle-aged ovaries (12 months) vs young-aged (3 months) from CD1 mice. Experimental analysis confirms that ovary lifespan varies across genetic backgrounds in mice and, genetics influences the response to environmental perturbations such as diet. Moreover, the identified ncRNAs were verified in a model of reproductive dysfunction promoted by the environmental toxicant ethylenthiourea. We also report the increase of miRNA143 and miRNA145 in follicular fluid of women with diminished ovarian reserve. Their levels inversely correlate with the hormonal profile and with the number of the oocytes recruited upon hormonal stimulation. Overall, we report a transcriptomic signature for ovarian dysfunction in vivo that provides a valuable resource for translational research in human reproductive aging.

Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential.

Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite that enhances both platelet responsiveness and in vivo thrombosis potential in animal models, and TMAO plasma levels predict incident atherothrombotic event risks in human clinical studies. TMAO is formed by gut microbe-dependent metabolism of trimethylamine (TMA) moiety-containing nutrients, which are abundant in a Western diet. Here, using a mechanism-based inhibitor approach targeting a major microbial TMA-generating enzyme pair, CutC and CutD (CutC/D), we developed inhibitors that are potent, time-dependent, and irreversible and that do not affect commensal viability. In animal models, a single oral dose of a CutC/D inhibitor significantly reduced plasma TMAO levels for up to 3 d and rescued diet-induced enhanced platelet responsiveness and thrombus formation, without observable toxicity or increased bleeding risk. The inhibitor selectively accumulated within intestinal microbes to millimolar levels, a concentration over 1-million-fold higher than needed for a therapeutic effect. These studies reveal that mechanism-based inhibition of gut microbial TMA and TMAO production reduces thrombosis potential, a critical adverse complication in heart disease. They also offer a generalizable approach for the selective nonlethal targeting of gut microbial enzymes linked to host disease limiting systemic exposure of the inhibitor in the host.

Tissue Level Diet and Sex-by-Diet Interactions Reveal Unique Metabolite and Clustering Profiles Using Untargeted Liquid Chromatography-Mass Spectrometry on Adipose, Skeletal Muscle, and Liver Tissue in C57BL6/J Mice.

Dietary intervention is commonly used for weight loss or to improve health, as diet-induced obesity increases the risk of developing type 2 diabetes, hypertension, cardiovascular disease, stroke, osteoarthritis, and certain cancers. Various dietary patterns are associated with effects on health, yet little is known about the effects of diet at the tissue level. Using untargeted metabolomics, this study aimed to identify changes in water-soluble metabolites in C57BL/6J males and females fed one of five diets (Japanese, ketogenic, Mediterranean, American, and standard mouse chow) for 7 months. Metabolite abundance was examined in liver, skeletal muscle, and adipose tissue for sex, diet, and sex-by-diet interaction. Analysis of variance (ANOVA) suggests that liver tissue has the most metabolic plasticity under dietary changes compared with adipose and skeletal muscle. The ketogenic diet was distinguishable from other diets for both males and females according to partial least-squares discriminant analysis. Pathway analysis revealed that the majority of pathways affected play an important role in amino acid metabolism in liver tissue. Not surprisingly, amino acid profiles were affected by dietary patterns in skeletal muscle. Few metabolites were significantly altered in adipose tissue relative to skeletal muscle and liver tissue, indicating that it was largely stable, regardless of diet alterations. The results of this study revealed that the ketogenic diet had the largest effect on physiology, particularly for females. Furthermore, metabolomics analysis revealed that diet affects metabolites in a tissue-specific manner and that liver was most sensitive to dietary changes.

Improving Metabolic Health Through Precision Dietetics in Mice.

The incidence of diet-induced metabolic disease has soared over the last half-century, despite national efforts to improve health through universal dietary recommendations. Studies comparing dietary patterns of populations with health outcomes have historically provided the basis for healthy diet recommendations. However, evidence that population-level diet responses are reliable indicators of responses across individuals is lacking. This study investigated how genetic differences influence health responses to several popular diets in mice, which are similar to humans in genetic composition and the propensity to develop metabolic disease, but enable precise genetic and environmental control. We designed four human-comparable mouse diets that are representative of those eaten by historical human populations. Across four genetically distinct inbred mouse strains, we compared the American diet's impact on metabolic health to three alternative diets (Mediterranean, Japanese, and Maasai/ketogenic). Furthermore, we investigated metabolomic and epigenetic alterations associated with diet response. Health effects of the diets were highly dependent on genetic background, demonstrating that individualized diet strategies improve health outcomes in mice. If similar genetic-dependent diet responses exist in humans, then a personalized, or "precision dietetics," approach to dietary recommendations may yield better health outcomes than the traditional one-size-fits-all approach.

Proceedings of the 11th Congress of the International Society of Nutrigenetics and Nutrigenomics (ISNN 2017).

The International Society of Nutrigenetics and Nutrigenomics (ISNN) held its 11th annual Congress in Los Angeles, California, between September 16 and 19, 2017. In addition to 2 keynote lectures, 4 plenary sessions included presentations by internationally renowned speakers on cutting-edge areas of research and new discoveries in genetics/genomics, the microbiome, and nutrition. Scientific topics included multi-omics approaches; diet and the microbiome; cancer, longevity, and metabolism; moving the field forward; and translational/educational aspects and the future of medicine. There was also an accepted oral abstracts session designed specifically to provide young investigators and trainees with the opportunity to present their work, as well as a session focused on industry-academic partnerships, which included a roundtable discussion afterwards. Overall, the 11th ISNN Congress was an exciting and intellectually stimulating meeting focused on understanding the impact of biological interactions between genes and nutrients on health and disease. These efforts continued the decade-long tradition of the annual ISNN Congress to provide an interdisciplinary platform for scientists from various disciplines to discuss research ideas and advance the fields of nutrigenetics and nutrigenomics.

Long-term outcome of defibrillator recipients included in the federal audit conducted by the Department of Justice.

Institutions across the United States have been subjected to a federal audit for defibrillator implantable cardioverter defibrillator [ICD] implantations that violated the Centers for Medicare and Medicaid payment policy. We examined the long-term outcome of ICD recipients whose implantation procedures were audited by the Department of Justice (DOJ). Patients (n = 225) included in the DOJ audit at the University of Pittsburgh Medical Center between the years 2003 and 2010 were followed to the end point of all-cause mortality. A cohort of 206 consecutive and contemporary ICD recipients not included in the federal audit served as controls. Compared with the controls, the audited cases were older (p <0.001), had more preserved ejection fraction (p <0.001), and were less likely to be implanted for a primary prevention indication (p = 0.001). They also had significantly shorter time from myocardial infarction (p <0.001) or revascularization (p <0.001) to ICD implantation. Over a median follow-up of 3.6 years, 187 patients died and 71 received ICD therapy for ventricular arrhythmias. Patients whose cases were audited had worse survival compared with controls (hazard ratio 1.41, 95% confidence interval 1.05 to 1.90, p = 0.023) even after correcting for differences in baseline characteristics (hazard ratio 1.46, 95% confidence interval 1.05 to 2.02, p = 0.023). Rates of appropriate and inappropriate ICD therapies were similar between the audited cases and controls. In conclusion, patients whose ICD implantations were audited by the DOJ have worse long-term survival compared with nonaudited control patients. These data support compliance with the Centers for Medicare and Medicaid guidelines when the individual patient's clinical condition allows it.

Frequency of toxicity with chemical conversion of atrial fibrillation with dofetilide.

Dofetilide is a class III antiarrhythmic agent approved for the maintenance of sinus rhythm in patients with persistent atrial fibrillation (AF). The goal of this study was to determine if chemical cardioversion (CCV) suggests a greater sensitivity to dofetilide and, therefore, portends a higher risk of proarrhythmia. We analyzed 99 consecutive patients with persistent AF who were loaded on dofetilide before cardioversion. CCV occurred after 2 ± 1.5 doses of dofetilide in 46 patients whereas electrical cardioversion (ECV) was required in the remaining 53 patients after 4.7 ± 1.3 doses. During index hospitalization, there were higher rates of dofetilide discontinuation because of QT prolongation or torsades de pointes (TdP) in the CCV group compared with the ECV group (24% vs 2%, p = 0.001). All patients with CCV requiring drug discontinuation converted after a single dose of dofetilide. Additionally, all 3 patients with TdP were in the CCV group. Furthermore, 15 of the 21 patients with CCV (71%) who converted after the first dose of dofetilide developed significant QT prolongation, requiring dose adjustment or discontinuation of drug. Among patients discharged on drug, AF recurrence and drug discontinuation rates were similar between groups at 2-year follow-up. In patients hospitalized for initiation of dofetilide, CCV occurs in almost 50% and is associated with higher rates of pathologic QT prolongation and TdP compared with those who require ECV. Once discharged on dofetilide, safety and efficacy is similar in both groups. In conclusion, patients with CCV may require closer monitoring for proarrhythmia.

Fluoroscopic screening of asymptomatic patients implanted with the recalled Riata lead family.

BACKGROUND: The Food and Drug Administration recently issued a class I recall of the St. Jude Medical Riata implantable cardioverter-defibrillator lead presumably because of increased risk of electric failure and mechanical separation via inside-out abrasion. We sought to examine the incidence and time dependence of inside-out abrasion in asymptomatic patients implanted with the Riata lead. METHODS AND RESULTS: Asymptomatic patients implanted with the Riata lead at our institution were offered voluntary fluoroscopic screening in 3 views. Electric testing of the Riata lead with provocative isometric muscle contraction was performed at the time of fluoroscopic screening. Of the 245 patients undergoing fluoroscopic screening, 53 (21.6%) patients showed clear evidence of lead separation. Of these externalized leads, 0%, 13%, and 26% had a dwell time of <3 years, 3 to 5 years, and >5 years, respectively (P=0.037). Externalized leads had a significantly pronounced decrease in R-wave amplitude (-1.7±2.9 mV versus +0.35±2.5 mV; P<0.001), and more patients with externalized leads had ≥25% decrease in R-wave amplitude from baseline (28.0% versus 8.1%; P=0.018). One patient with externalization exhibited new noise on near-field electrogram. CONCLUSIONS: The Riata lead exhibits time-dependent high rates of cable externalization exceeding 20% at >5 years of dwell time. Externalized leads are associated with a more pronounced decrease in R-wave amplitude, which may be an early marker of future electric failure. The use of fluoroscopic and electric screening of asymptomatic patients with the Riata lead remains controversial in the management of patients affected by the recent Food and Drug Administration recall.

A novel manoeuvre for discerning supraventricular tachycardia mechanism.

AIMS: Discerning supraventricular tachycardia (SVT) mechanism during catheter ablation procedures can be difficult and time-consuming, which, when combined with diagnostic error, places patients at risk of unnecessary complications. Distinguishing atrial tachycardia (AT) from AV nodal re-entry tachycardia (AVNRT) may be particularly vexatious. Value-added techniques are thus always welcome, particularly if they are not time-consuming nor require complex intracardiac lead configurations. In this study, we assessed whether a new technique, simultaneous right atrial and right ventricular pacing (RA + RV) during ongoing SVT, met these criteria. METHODS AND RESULTS: Using a simple intracardiac lead configuration (right atrial appendage, His bundle, right ventricular apex), the response to RA + RV delivered at 80-90% of the SVT cycle length, was examined in 80 patients referred for catheter ablation. In each patient, the actual tachycardia mechanism was adjudicated by standard electrophysiologic criteria ± successful catheter ablation. Mechanisms of SVT included, non-exclusively, AVNRT (24 patients), accessory pathway-mediated (orthodromic) re-entry (AVRT; 23 patients), AT (10 patients), and sinus tachycardia (ST induced with isoproterenol; 49 patients). Immediately after cessation of RA + RV pacing during persistent SVT, the first intracardiac electrogram observed was right atrial in all AT whereas it was His bundle in all AVNRT. The response during AVRT was mixed. CONCLUSIONS: In this preliminary evaluation, RA + RV pacing appears to add value to the existing armamentarium of electrophysiologic indices to discern SVT mechanism, in particular with respect to discriminating between AVNRT and AT.

Food, stress, and reproduction: short-term fasting alters endocrine physiology and reproductive behavior in the zebra finch.

Stress is thought to be a potent suppressor of reproduction. However, the vast majority of studies focus on the relationship between chronic stress and reproductive suppression, despite the fact that chronic stress is rare in the wild. We investigated the role of fasting in altering acute stress physiology, reproductive physiology, and reproductive behavior of male zebra finches (Taeniopygia guttata) with several goals in mind. First, we wanted to determine if acute fasting could stimulate an increase in plasma corticosterone and a decrease in corticosteroid binding globulin (CBG) and testosterone. We then investigated whether fasting could alter expression of undirected song and courtship behavior. After subjecting males to fasting periods ranging from 1 to 10h, we collected plasma to measure corticosterone, CBG, and testosterone. We found that plasma corticosterone was elevated, and testosterone was decreased after 4, 6, and 10h of fasting periods compared with samples collected from the same males during nonfasted (control) periods. CBG was lower than control levels only after 10h of fasting. We also found that, coincident with these endocrine changes, males sang less and courted females less vigorously following short-term fasting relative to control conditions. Our data demonstrate that acute fasting resulted in rapid changes in endocrine physiology consistent with hypothalamo-pituitary-adrenal axis activation and hypothalamo-pituitary-gonadal axis deactivation. Fasting also inhibited reproductive behavior. We suggest that zebra finches exhibit physiological and behavioral flexibility that makes them an excellent model system for studying interactions of acute stress and reproduction.