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Background:Periodontitis (a bacterially-driven, inflammatory disease) is a plausible risk factor for prediabetes and diabetes. We studied the association between clinical attachment loss (CAL – a cumulative measure of tooth-supporting tissues lost due to periodontitis), prediabetes, and glucose levels among non-diabetic younger adults.Hypothesis:We hypothesize that greater CAL is associated with higher levels of biomarkers of cardiometabolic risk cross-sectionally.Methods:We included n=1071 non-diabetic participants from the Oral Infections, Glucose Intolerance and Insulin Resistance Study (ORIGINS) who underwent full-mouth periodontal examinations and provided fasting blood at baseline. Baseline enrollment occurred in two waves: Wave 1 (2011-2013; n=293) and Wave 2 (2016-2020; n=778). HbA1c and glucose were measured during clinical exams. Prediabetes was defined as fasting glucose between 100-125 mg/dL or HbA1c between 5.7-6.4% per American Diabetes Association guidelines. We computed prevalence ratios and 95% confidence intervals of prediabetes among 2ndand 3rdCAL tertiles (vs. 1sttertile) via multivariable Poisson regression with robust variance estimation. Multivariable linear regression was used to assess the association between CAL tertiles (independent variable) and estimates of glucose and HbA1c. We adjusted for demographics, health variables, and study wave.Results:The mean age(SD) of participants was 32.3(9.6) years and 28% were male. Prediabetes prevalence was 8.7%. Multivariable adjusted prevalence ratios (95%CIs) for prediabetes in tertiles 2 and 3 (vs. 1) were 1.45(0.79,2.67) and 1.91(0.99,3.67), respectively, consistent with p for trend = 0.05 and stronger associations with continuous glucose and HbA1c (see Table).Conclusion:CAL, a cumulative measure of periodontitis, was cross-sectionally associated with increased prediabetes prevalence, glucose and HbA1c.

Introduction:Infections are associated with worse clinical outcomes among patients with heart failure (HF). However, little is known about the influence of infection-related hospitalizations on development of incident HF and its subtype.Hypothesis:We hypothesize that those with an infection-related hospitalization (hereafter ‘infection’) compared to those without infection, will experience an increased rate of incident HF events (any HF, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF)).Methods:We examined 14,398 participants enrolled in the Atherosclerosis Risk in Communities Study who were HF free at visit 1 (1987-1989). Hospitalized infections and HF were identified via participant self-report and active surveillance of hospitalizations. Among the hospitalized, infection was further defined using ICD-9/10 codes in the first five positions of hospital records. A subset of HF events was further classified as HFpEF or HFrEF via chart abstraction and adjudication by centrally trained and certified physicians. Infection was treated as a time-varying exposure and the co-occurrence of infection and HF in the same hospital visit were excluded. Multivariable-adjusted Cox proportional hazards models assessed the association between infection and incident HF, HFrEF, and HFpEF.Results:The overall baseline sample was 54% (7,835 of 14,398) female, 26% (3,688 of 14,398) Black and had a mean(SD) age of 54(5.8). Mean(SD) time to infection was 16.1(8.7) years, and 2.3(7.5) years from infection to incident HF. Average follow-up among the full sample was 23.0(8.5). Overall, 46% (6,603 of 14,398) had an infection and 3,561 developed any HF. Among participants with subtype adjudication, 470 had HFpEF and 450 had HFrEF. Infection-related hospitalization was associated with an increased risk for both HFpEF and HFrEF (Table).Conclusion:Infection-related hospitalization was associated with both incident HFpEF and HFrEF. A stronger effect is seen among those with HFpEF.

Introduction:The present study sought to characterize taxonomic and functional characteristics of the saliva microbiome and their cross-sectional association with cardiometabolic biomarkers.Hypothesis:Features of the saliva microbiome will be associated with cardiometabolic risk.Methods:Saliva microbiome composition from 265 ORIGINS participants was defined with 16S rRNA sequencing (Illumina, DADA2). Functional composition (KEGG orthologs; KOs) was inferred with PICRUSt2. Alpha Diversity was computed with the Shannon Index. Blood pressure was defined as normal (SBP<120, DBP<80, and no antihypertensive medication) vs elevated/high (hypertension: SBP≥120, DBP≥80 and/or antihypertensive medication). Prediabetes was defined as 5.7≤HbA1≤6.4% or 100≤fasting plasma glucose≤125 mg/dL. HOMA-IR was calculated from insulin and glucose. HOMA-IR and CRP were dichotomized as high/low using thresholds of 3 mg/L and 1.9, respectively. Multivariable multinomial regression with cross-validation was conducted for each feature (species, KOs) and outcome, ranking regression coefficients from most positively to most inversely associated features. Microbiota and KO ratios (Micro-R, KO-R) were computed as the log-ratio of the sum of abundances of taxa/KOs in the top vs bottom tertiles of cross-validated ranks, such that higher ratios are potentially adverse. Adjusted multivariable logistic regressions produced ORs summarizing the association between Shannon, Micro-R, and KO-R and each cardiometabolic outcome.Results:Participants were 71% female, 22% Black, 40% Hispanic, and 18% white, with mean age of 33±10 years. Prevalence of hypertension was 36%, prediabetes was 17%, high CRP was 23%, and high HOMA-IR was 25%. Estimated ORs for the association between microbiome metrics and cardiometabolic outcomes are summarized in Figure 1.Conclusion:Microbiome scores based on specific taxa or KOs are associated with hypertension, prediabetes, and increased inflammation and insulin resistance.

Introduction:Discrepancies between cystatin C (CysC)- and serum creatinine (sCr)- estimated glomerular filtration rate (eGFR) may reflect sarcopenia and malnutrition. Among pts with heart failure and reduced ejection fraction (HFrEF) enrolled in PARADIGM-HF (Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting-Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF), we investigated the difference between eGFRCysC and eGFRsCr and its association with clinical outcomes, quality of life (QoL) and frailty.Methods:Intra-individual differences between eGFRCysC and eGFRsCr (eGFRdiff) were calculated at randomization (n=1,970) and 8-month follow-up (n=1,631). Study outcomes included a composite of cardiovascular (CV) mortality or HF admission, and, separately, CV and all-cause mortality, worsening kidney function, poor QoL and frailty. Worsening HF was defined as outpatient intensification of HF therapy, emergency department visit or HF admission between randomization and 8-month follow-up.Results:At randomization, eGFRdiff was >10 and <-10 ml/min/1.73 m2in 25 and 36% of the pts, respectively. More negative values of eGFRdiff were associated with worse outcomes (adjusted hazard ratio per 1-standard deviation [SD]: CV mortality or HF admission 1.20, p=.003; CV mortality 1.37, p<.001; all-cause mortality 1.42, p<.001; worsening kidney function 1.30, p=.066). For each 1-SD decrease in eGFRdiff, the prevalence of poor QoL and frailty increased by 28% and 19%, respectively (p ≤.003). Pts with worsening HF had more marked decline in eGFRCysC than eGFRsCr. As a result, worsening HF was associated with a change in 8-month eGFRdiff by -4.7 ml/min/1.73 m2(Figure).Conclusions:In HFrEF pts, discrepancies between eGFRCysC and eGFRsCr are common and are associated with clinical outcomes, QoL and frailty. In pts with worsening HF, sCr may underestimate decline in kidney function due to changes in muscle mass and diet.

Background:Sarcopenia is associated with disability and mortality. Coexistence of sarcopenia and obesity (sarcopenic obesity) relates to particularly poor outcomes. The prevalence of sarcopenia is increased in heart failure (HF) up to ~50%. Dual-energy x-ray absorptiometry (DXA) is the gold standard for body composition assessment but is limited by cost and radiation exposure. We studied whether the relationship between two renal biomarkers (ie, serum creatinine (sCr) - muscle mass dependent, and cystatin C (CysC) - muscle mass independent) could be used to reliably estimate body composition in the general population and in HF.Methods:We included National Health and Nutritional Examination Surveys participants who underwent DXA between 1999 and 2002. Multivariable linear models assessed the association between sCr/CysC and CysC- and sCr-based estimated glomerular filtration rate difference (eGFRdiff) with DXA-derived appendicular skeletal muscle index (ASMI m2) and total body fat percentage (TBF%). Sample weights were used to account for complex survey design to ensure that estimates were representative of the general US population.Results:Among 3280 participants (44±22.9yo,49%F,190 with HF), 440, 1241, and 359 met criteria for sarcopenia, obesity and sarcopenic obesity. Overall and in HF, mean ASMI and TBF% were 7.4m2and 32.5% and 7.0m2and 36.9%, respectively. Overall and in HF, higher sCr/CysC and eGFRdiff were associated with increased ASMI and decreased TBF% (Table). sCr/CysC was the lowest in patients with lowest ASMI tertile (<6.26 m2) and highest TBF% tertile (>40.3%) (Fig). A similar pattern was also seen in HF.Conclusions:Measures of discrepancy between sCr and CysC are strongly associated with gold-standard measures of body composition both in the general and HF populations. This biomarker approach is easy and inexpensive, allowing clinicians new opportunities for timely recognition and possibly early treatment of sarcopenic obesity.

Introduction:Nitric oxide (NO) is important for cardiometabolic health. The enterosalivary nitrate-nitrite-NO pathway generates NO following oral microbiota-mediated production of salivary nitrite. We investigated the association between the abundance of genes in this pathway and cardiometabolic biomarkers.Hypothesis:Microbial genes favoring increased oral nitrite generation are associated with better cardiometabolic profile.Methods:We enrolled 784 diabetes-free adults in the Oral Infections, Glucose Intolerance and Insulin Resistance Study (ORIGINS). Subgingival plaques were collected from 6-8 teeth/participant. 16S rRNA microbial genes (Illumina, MiSeq) were sequenced; PICRUSt2 estimated abundance of microbial genes in the nitrate-nitrite pathway associated with either nitrite generation or depletion. Gene abundance was summed within each group, and a ratio between nitrite generation to depletion (GDR) was calculated; higher levels suggest increased nitrite generating capacity. Systolic and diastolic blood pressure were measured and HbA1C, insulin, and glucose levels were determined in fasting blood. Z-scores were calculated for cardiometabolic biomarkers and averaged to form a cardiometabolic z-score (CMZ-score). Adjusted multivariable linear models were used to regress the CMZ-score and individual Z-scores on GDR.Results:Participants were 69% female and aged 19-58 years (mean=32±9). Mean CMZ-score was 0.00±0.7. Mean (range) GDR was 1.88 (0.22-7.84). Mean CMZ-scores (SE) across GDR quartiles were 0.17 (0.06), 0.01 (0.05), -0.04 (0.05), and -0.14 (0.05), p-value for trend=0.02. Linear regression coefficients summarizing associations between GDR and individual Z-scores (Table) show lower Z-score for systolic and diastolic blood pressure, HbA1C, and insulin levels in those with higher GDR.Conclusions:Increased capacity for nitrite production by oral bacteria, assessed through a metagenome estimation approach, is associated with lower levels of cardiometabolic risk.

Introduction:Left ventricular assist devices (LVADs) are pivotal treatments for end-stage congestive heart failure (CHF) patients as destination or bridge to heart transplantation therapy. Atrial fibrillation (AF) is highly prevalent and associated with worse clinical outcomes in LVAD patients. Less is known regarding the association between AF and recurrentVAs in post-LVAD patients. This study examined a cohort of LVAD patients who had manifested pre-LVAD ventricular arrhythmias (VAs) in order to determine: (1) the rate of recurrent post-LVAD VAs, as well as (2) the incidence and impact of atrial fibrillation (AF) on recurrent post-LVAD VAs.Methods:Medical records of 195 patients who received a LVAD were reviewed. Descriptive statistics were generated and logistic regression was used to assess the association of clinical variables with the presence of VAs.Results:47% of 195 CHF patients who received an LVAD manifested significant VAs prior to LVAD implant (82%-Heartmate II, 14%-HVAD, 4%-other) and were followed for an average of 17 months post-LVAD. Of patients with pre-LVAD VAs, 41% continued to manifest recurrent VAs (92%-VT, 3%-VF, and 5%-VT&VF) after LVAD implantation. By multivariable logistic regression, a history of AF (present in 57% of recurrent VA patients) was associated with recurrent VAs after LVAD (OR=4.99; 95% CI 1.67, 14.96; p=0.004).Conclusions:AF is not only prevalent in over half of LVAD patients with recurrent VAs, but is also in independent predictor of recurrent VAs. Further studies regarding the effect of AF treatment on recurrent VAs are warranted.

Introduction:Pulse pressure (PP) amplification, defined as the peripheral-to-aortic PP ratio, is an independent risk factor for cardiovascular and all-cause mortality. In healthy populations, PP amplification is known to decrease at night due to the nocturnal reduction of heart rate (HR) associated with decreased sympathetic tone. Heart failure (HF) and left ventricle assist device (LVAD) support have been previously associated with increased sympathetic tone, but their effect on circadian variation of PP amplification has never been investigated. In the present study, we aimed at investigating whether: 1) HF and LVAD therapy reduce circadian variability of PP amplification; and 2) orthotopic heart transplantation (OHT) restores normal nocturnal reduction.Methods:27 healthy controls, 25 outpts with HF, 29 outpts on LVAD, and 25 OHT recipients were prospectively studied using the Mobil-O-Graph, a validated ambulatory blood pressure monitor that records HR, peripheral blood pressure and estimates central aortic blood pressure. Data were collected every 30 minutes for 24 consecutive hours following an outpatient visit. Day and night intervals were defined for each patient based on his/her habits. PP amplification was calculated as peripheral PP/aortic PP.Results:Demographics are summarized in table 1. Healthy controls and OHT recipients, but not HF and LVAD pts, maintain a significant physiological circadian reduction of PP amplification (table 2). Interestingly, LVAD pts showed an inverse though non significant trend towards an increase PP amplification at night. In accordance, HR decreased at night in healthy, HF and OHT pts, but not in LVAD recipients (table 2)Conclusions:HF pts have reduced circadian variability of PP amplification. OHT and not LVAD therapy restores normal physiological patterns. HR does not decline in LVAD pts at night. This result suggests persistent upregulation of the sympathetic tone in HF and LVAD pts that resolves after OHT.