Inhaled endotoxin induces a systemic neutrophil response without affecting cardiovascular measures in a randomized cross-over exposure study.

OBJECTIVE: The gram-negative bacterial cell wall component endotoxin (lipopolysaccharide, LPS) is a key component of particulate matter (PM). PM exposure is associated with cardiovascular morbidity and mortality. However, the contribution of individual components of PM to acute and chronic cardiovascular measures is not clear. This study examines whether systemic inflammation induced by LPS inhalation causes acute changes in cardiovascular physiology measures. MATERIALS AND METHODS: In this double blinded, placebo-controlled crossover study, fifteen adult volunteers underwent inhalation exposure to 20,000 EU Clinical Center Reference Endotoxin (CCRE). Peripheral blood and induced sputum neutrophils were obtained at baseline and six hours post-exposure. Blood pressure, measures of left ventricular function (ejection fraction (LVEF) and global longitudinal strain (LVGLS)), and indices of endothelial function (flow mediated dilation (FMD) and velocity time integral during hyperemia (VTIhyp)) were measured before and after treatment. Wilcoxon sign-rank tests and linear mixed models were used for statistical analysis. RESULTS: In comparison with normal saline, LPS inhalation resulted in significant increases in peripheral blood and sputum neutrophils but was not associated with significant alterations in blood pressure, LVGLS, LVEF, FMD, or VTIhyp. DISCUSSION AND CONCLUSIONS: In healthy adults, systemic inflammation after LPS inhalation was not associated with acute changes in cardiovascular physiology. Larger studies are needed to investigate the effects of other PM components on inflammation induced cardiovascular dysfunction.

Detection of Dolichoectasia and Atherosclerosis by Automated MRA Tortuosity Metrics in a Population-Based Study.

BACKGROUND: Intracranial vessel tortuosity is a key component of dolichoectasia and has been associated with atherosclerosis and adverse neurologic outcomes. However, the evaluation of tortuosity is mainly a descriptive assessment. PURPOSE: To compare the performance of three automated tortuosity metrics (angle metric [AM], distance metric [DM], and distance-to-axis metric [DTA]) for detection of dolichoectasia and presence of segment-specific plaques. STUDY TYPE: Observational, cross-sectional metric assessment. POPULATION: 1899 adults from the general population; mean age = 76 years, female = 59%, and black = 29%. FIELD STRENGTH/SEQUENCE: 3-T, three-dimensional (3D) time-of-flight MRA and 3D vessel wall MRI. ASSESSMENT: Tortuosity metrics and mean luminal area were quantified for designated segments of the internal carotid artery, middle cerebral artery, anterior cerebral artery, posterior cerebral artery, vertebral artery, and entire length of basilar artery (BA). Qualitative interpretations of BA dolichoectasia were assessed based on Smoker's visual criteria. STATISTICAL TESTS: Descriptive statistics (2-sample t-tests, Pearson chi-square tests) for group comparisons. Receiver operating characteristics area under the curve (AUC) for detection of BA dolichoectasia or segment-specific plaque. Model inputs included 1) tortuosity metrics, 2) mean luminal area, and 3) demographics (age, race, and sex). RESULTS: Qualitative dolichoectasia was identified in 336 (18%) participants, and atherosclerotic plaques were detected in 192 (10%) participants. AM-, DM-, and DTA-calculated tortuosity were good individual discriminators of basilar dolichoectasia (AUCs: 0.76, 0.74, and 0.75, respectively), with model performance improving with the mean lumen area: (AUCs: 0.88, 0.87, and 0.87, respectively). Combined characteristics (tortuosity and mean luminal area) identified plaques with better performance in the anterior (AUCs ranging from 0.66 to 0.78) than posterior (AUCs ranging from 0.54 to 0.65) circulation, with all models improving by the addition of demographics (AUCs ranging from 0.62 to 0.84). DATA CONCLUSION: Quantitative vessel tortuosity metrics yield good diagnostic accuracy for the detection of dolichoectasia. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Mortality in Patients Hospitalized With Acute Myocardial Infarction Without Standard Modifiable Risk Factors: The ARIC Study Community Surveillance.

Background Prevention strategies targeting standard modifiable cardiovascular risk factors (SMuRFs; diabetes, hypertension, smoking, hypercholesterolemia) are critical to improving cardiovascular disease outcomes. However, acute myocardial infarction (AMI) among individuals who lack 1 or more SMuRFs is not uncommon. Moreover, the clinical characteristics and prognosis of SMuRFless individuals are not well characterized. Methods and Results We analyzed AMI hospitalizations from 2000 to 2014 captured by the ARIC (Atherosclerosis Risk in Community) study community surveillance. AMI was classified by physician review using a validated algorithm. Clinical data, medications, and procedures were abstracted from the medical record. Main study outcomes included short- and long-term mortality within 28 days and 1 year of AMI hospitalization. Between 2000 and 2014, a total of 742 (3.6%) of 20 569 patients with AMI were identified with no documented SMuRFs. Patients without SMuRFs were less likely to receive aspirin, nonaspirin antiplatelet therapy, or beta blockers and less often underwent angiography and revascularization. Compared with those with one or more SMuRFs, patients without SMuRFs had significantly higher 28-day (odds ratio, 3.23 [95% CI, 1.78-5.88]) and 1-year (hazard ratio, 2.09 [95% CI, 1.29-3.37]) adjusted mortality. When examined across 5-year intervals from 2000 to 2014, the incidence of 28-day mortality significantly increased for patients without SMuRFs (7% to 15% to 27%), whereas it declined for those with 1 or more SMuRFs (7% to 5% to 5%). Conclusions Individuals without SMuRFs presenting with AMI have an increased risk of all-cause mortality with an overall lower prescription rate for guideline-directed medical therapy. These findings highlight the need for evidence-based pharmacotherapy during hospitalization and the need to discover new markers and mechanisms for early risk identification in this population.

Impact of Diabetes on Outcomes in Patients Hospitalized With Acute Myocardial Infarction: Insights From the Atherosclerosis Risk in Communities Study Community Surveillance.

Background Diabetes is associated with increased risk of acute myocardial infarction (AMI). The demographic trends, clinical presentation, management, and outcomes of patients with diabetes who are hospitalized with AMI have not been recently reported. Methods and Results The ARIC (Atherosclerosis Risk in Communities) study conducted hospital surveillance of AMI in 4 US communities. AMI was classified by physician review using a validated algorithm. Medications and procedures were abstracted from the medical record. From 2000 to 2014, 21 094 weighted hospitalizations for AMI were sampled. The prevalence of diabetes steadily increased, from 35% to 41% to 43% (P-trend<0.0001) across 2000 to 2004, 2005 to 2009, and 2010 to 2014, respectively. Patients with diabetes were older (61 versus 59 years of age), more often Black (44% versus 31%), and more commonly women (42% versus 34%). The burden of cardiovascular comorbidities was higher with diabetes and increased temporally. Patients with diabetes less often presented with ST-segment elevation (9% versus 17%) or acute chest pain (72% versus 80%), and had higher mean GRACE (Global Registry of Acute Coronary Syndrome) score (123 versus 109), Thrombolysis in Myocardial Ischemia (TIMI) score (4.3 versus 4.0), and Killip class (1.9 versus 1.5). Patients with diabetes had a lower adjusted probability of receiving aspirin (relative probability, 0.95 [95% CI, 0.91-0.99]), nonaspirin antiplatelets (0.93 [95% CI, 0.86-0.99]), coronary angiography (0.85 [95% CI, 0.78-0.92]), and coronary revascularization (0.85 [95% CI, 0.76-0.92]). Diabetes was associated with a 52% higher hazard of all-cause 1-year mortality (hazard ratio, 1.52 [95% CI, 1.23-1.89]). Conclusions Diabetes is associated with higher risk of death in patients hospitalized with AMI, highlighting the need for adherence to evidence-based therapies in this high-risk population.

Comparing Focused-Tracked and Plane Wave-Tracked ARFI Log(VoA) In Silico and in Application to Human Carotid Atherosclerotic Plaque, Ex Vivo.

A significant risk factor for ischemic stroke is carotid atherosclerotic plaque that is susceptible to rupture, with rupture potential conveyed by plaque morphology. Human carotid plaque composition and structure have been delineated noninvasively and in vivo by evaluating log(VoA), a parameter derived as the decadic log of the second time derivative of displacement induced by an acoustic radiation force impulse (ARFI). In prior work, ARFI-induced displacement was measured using conventional focused tracking; however, this requires a long data acquisition period, thereby reducing framerate. We herein evaluate if ARFI log(VoA) framerate can be increased without a reduction in plaque imaging performance using plane wave tracking instead. In silico, both focused- and plane wave-tracked log(VoA) decreased with increasing echobrightness, quantified as signal-to-noise ratio (SNR), but did not vary with material elasticity for SNRs below 40 dB. For SNRs of 40-60 dB, both focused- and plane wave-tracked log(VoA) varied with SNR and material elasticity. Above 60 dB SNR, both focused- and plane wave-tracked log(VoA) varied with material elasticity alone. This suggests that log(VoA) discriminates features according to a combination of their echobrightness and mechanical property. Further, while both focused- and plane-wave tracked log(VoA) values were artifactually inflated by mechanical reflections at inclusion boundaries, plane wave-tracked log(VoA) was more strongly impacted by off-axis scattering. Applied to three excised human cadaveric carotid plaques with spatially aligned histological validation, both log(VoA) methods detected regions of lipid, collagen, and calcium (CAL) deposits. These findings support that plane wave tracking performs comparably to focused tracking for log(VoA) imaging and that plane wave-tracked log(VoA) is a viable approach to discriminating clinically relevant atherosclerotic plaque features at a 30-fold higher framerate than by focused tracking.

Epidemiology and Outcomes of Aortic Stenosis in Acute Decompensated Heart Failure: The ARIC Study.

BACKGROUND: Few studies characterize the epidemiology and outcomes of aortic stenosis (AS) in acute decompensated heart failure (ADHF). This study investigates the significance of AS in contemporary patients who have experienced an ADHF hospitalization. METHODS: The ARIC study (Atherosclerosis Risk in Communities) surveilled ADHF hospitalizations for residents ≥55 years of age in 4 US communities. ADHF cases were stratified by left ventricular ejection fraction (LVEF). Demographic differences in AS burden and the association of varying AS severities with mortality were estimated using multivariable logistic regression. RESULTS: From 2005 through 2014, there were 3597 (weighted n=16 692) ADHF hospitalizations of which 48.6% had an LVEF <50% and 51.4% an LVEF ≥50%. AS prevalence was 12.1% and 18.7% in those with an LVEF <50% and ≥50%, respectively. AS was less likely in Black than White patients regardless of LVEF: LVEF <50% (odds ratio [OR], 0.34 [95% CI, 0.28-0.42]); LVEF ≥50% (OR, 0.51 [95% CI, 0.44-0.59]). Higher AS severity was independently associated with 1-year mortality in both LVEF subgroups: LVEF <50% (OR, 1.16 [95% CI, 1.04-1.28]); LVEF ≥50% (OR, 1.40 [95% CI, 1.28-1.54]). Sensitivity analyses excluding severe AS patients detected that mild/moderate AS was independently associated with 1-year mortality in both LVEF subgroups: LVEF <50% (OR, 1.23 [95% CI, 1.02-1.47]); LVEF ≥50% (OR, 1.31 [95% CI, 1.14-1.51]). CONCLUSIONS: Among patients who have experienced an ADHF hospitalization, AS is prevalent and portends poor mortality outcomes. Notably, mild/moderate AS is independently associated with 1-year mortality in this high-risk population.

Neighborhood Socioeconomic Disadvantage and Hospitalized Heart Failure Outcomes in the American Heart Association Get With The Guidelines-Heart Failure Registry.

BACKGROUND: Neighborhood socioeconomic status (SES) is associated with worse health outcomes, yet its relationship with in-hospital heart failure (HF) outcomes and quality metrics are underexplored. We examined the association between socioeconomic neighborhood disadvantage and in-hospital HF outcomes for patients from diverse neighborhoods in the Get With The Guidelines-Heart Failure registry. METHODS: SES-disadvantage scores were derived from geocoded US census data using a validated algorithm, which incorporated household income, home value, rent, education, and employment. We examined the association between SES-disadvantage quintiles with all-cause in-hospital mortality, adjusting for demographics and comorbidities. RESULTS: Of 593 053 patients hospitalized for HF between 2017 and 2020, 321 314 (54%) had residential ZIP Codes recorded. Patients from the most compared with least disadvantaged neighborhoods were younger (mean age 67 versus 76 years), more often Black (42% versus 9%) or Hispanic (14% versus 5%), and had higher comorbidity burden. Demographic-adjusted length of stay increased by ≈1.5 hours with each increment in worsening SES-disadvantage quintiles. Adjusted-mortality odds ratios increased with worsening SES-disadvantage quintiles (Ptrend=0.003), and was 28% higher (adjusted OR=1.28 [1.12-1.48]) for the most compared with least disadvantaged neighborhood groups. CONCLUSIONS: Patients hospitalized for HF from disadvantaged neighborhoods were younger and more often Black or Hispanic. SES disadvantage was independently associated with higher in-hospital mortality. Further research is needed to characterize care delivery patterns in disadvantaged neighborhoods and to address social determinants of health among patients hospitalized for HF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02693509.

Post-recovery COVID-19 and incident heart failure in the National COVID Cohort Collaborative (N3C) study.

Cardiac involvement has been noted in COVID-19 infection. However, the relationship between post-recovery COVID-19 and development of de novo heart failure has not been investigated in a large, nationally representative population. We examined post-recovery outcomes of 587,330 patients hospitalized in the United States (257,075 with COVID-19 and 330,255 without), using data from the National COVID Cohort Collaborative study. Patients hospitalized with COVID-19 were older (51 vs. 46 years), more often male (49% vs. 42%), and less often White (61% vs. 69%). Over a median follow up of 367 days, 10,979 incident heart failure events occurred. After adjustments, COVID-19 hospitalization was associated with a 45% higher hazard of incident heart failure (hazard ratio = 1.45; 95% confidence interval: 1.39-1.51), with more pronounced associations among patients who were younger (P-interaction = 0.003), White (P-interaction = 0.005), or who had established cardiovascular disease (P-interaction = 0.005). In conclusion, COVID-19 hospitalization is associated with increased risk of incident heart failure.

Prognostic significance of obstructive coronary artery disease in patients admitted with acute decompensated heart failure: the ARIC study community surveillance.

AIMS: We aimed to investigate the impact of obstructive coronary artery disease (CAD) in patients with acute decompensated heart failure (ADHF), and examine potential differences in prognostic utility for heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF). METHODS AND RESULTS: The Atherosclerosis Risk in Communities study conducted hospital surveillance of ADHF from 2005 to 2014. Obstructive CAD was defined as ≥50% or ≥75% stenosis, respectively, for the left main and other major epicardial arteries. Adjusted associations between obstructive CAD and 30-, 60-, and 90-day mortality were analysed. A total of 934 (4146 weighted) patients admitted with ADHF (mean age 72 years, 46% women, 30% Black, 30% HFpEF) had available angiography (61% performed in hospital). Obstructive CAD was more prevalent with HFrEF than HFpEF, whether at the left main (15% vs. 11%), left anterior descending (LAD) (48% vs. 30%), left circumflex (37% vs. 32%), right coronary (42% vs. 32%), or multiple coronary arteries (45% vs. 33%). In-hospital revascularization was performed in 25% and 22% of patients with HFrEF and HFpEF, respectively. Obstructive CAD was associated with higher adjusted mortality, particularly with left main or LAD involvement, and had a more pronounced association with 90-day mortality in HFrEF (odds ratio [OR] 2.77; 95% confidence interval [CI] 1.53-5.02) than HFpEF (OR 0.94; 95% CI 0.36-2.41) (p-interaction = 0.05). CONCLUSION: Patients hospitalized with ADHF and coexisting obstructive CAD have higher short-term mortality, warranting the need for effective interventions and secondary prevention.

Prevalence and Prognostic Significance of Polyvascular Disease in Patients Hospitalized With Acute Decompensated Heart Failure: The ARIC Study.

BACKGROUND: Polyvascular disease is associated with increased mortality rates and decreased quality of life. Whether its prevalence or associated outcomes differ for patients hospitalized with heart failure with reduced vs preserved ejection fraction (HFrEF vs HFpEF, respectively) is uncertain. METHODS: The Atherosclerosis Risk in Communities (ARIC) study conducted hospital surveillance of acute decompensated heart failure (ADHF) from 2005-2014. Polyvascular disease (coexisting disease in ≥ 2 arterial beds) was identified based on the finding of prevalent coronary artery disease, peripheral artery disease or cerebrovascular disease. Mortality risks associated with polyvascular disease were analyzed separately for HFpEF and HFrEF, with adjustment for potential confounders. All analyses were weighted by the inverse of the sampling probability. RESULTS: Of 24,937 weighted (5460 unweighted) hospitalizations due to ADHF (52% female, 32% Black, mean age 75 years), polyvascular disease was prevalent in 22% with HFrEF and in 17% with HFpEF. One-year mortality risks increased sequentially with 0, 1 and ≥ 2 arterial bed involvement, both for patients with HFrEF (29%-32%-38%; P trend = 0.0006) and for those with HFpEF (26%-32%-37%; P trend < 0.0001). After adjustments, polyvascular disease was associated with a 26% higher mortality hazard for patients with HFrEF (HR = 1.26; 95% CI: 1.07-1.50) and a 29% higher hazard for patients with HFpEF (HR = 1.29; 95% CI: 1.03-1.62), with no interaction by HF type (P interaction = 0.9). CONCLUSION: Patients hospitalized with ADHF and coexisting polyvascular disease have an increased risk of death, irrespective of HF type. Clinical attention should be directed toward polyvascular disease, with implementation of secondary prevention strategies to improve the prognosis of this high-risk population. SUMMARY: Polyvascular disease is known to be associated with myocardial infarction, stroke or cardiovascular death and is a major risk factor for decreased quality of life. This study sought to evaluate the relationship between polyvascular disease and mortality in patients hospitalized with acute decompensated heart failure (ADHF), and to understand whether the associations differ based on ejection fraction. Patients hospitalized with ADHF and coexisting polyvascular disease had an increased risk of death, irrespective of heart failure type, implying the need for increased clinical attention directed toward polyvascular disease, along with implementation of secondary prevention strategies to improve prognosis. TWEET: Patients hospitalized with acute HF and coexisting polyvascular disease face an increased risk of death, irrespective of HF type.

Temporal Trends and Prognosis of Physical Examination Findings in Patients With Acute Decompensated Heart Failure: The ARIC Study Community Surveillance.

BACKGROUND: Bedside evaluation of congestion is a mainstay of heart failure (HF) management. Whether detected physical examination signs have changed over time as obesity prevalence has increased in HF populations, or if the associated prognosis differs for HF with reduced or preserved ejection fraction (HFrEF or HFpEF) is uncertain. METHODS: From 2005 to 2014, the ARIC study (Atherosclerosis Risk in Communities) conducted adjudicated hospital surveillance of acute decompensated HF. We analyzed trends in physical examination findings, imaging signs, and symptoms related to congestion, both over time and by obesity class, and associated 28-day mortality risks. RESULTS: Of 24 937 weighted hospitalizations for acute decompensated HF (mean age 75 years, 53% women, 32% Black), 47% had HFpEF. The prevalence of obesity increased from 2005 to 2014 for both HF types. With increasing obesity category, detected edema increased, while jugular venous distension decreased, and rales remained stable. Detected edema also increased over time, for both HF types. Associations between 28-day mortality and individual signs and symptoms of congestion were similar for HFpEF and HFrEF; however, the adjusted mortality risk with all 3 (edema, rales, and jugular venous distension) versus <3 physical examination findings was higher for patients with HFpEF (odds ratio, 2.41 [95% CI, 1.53-3.79]) than HFrEF (odds ratio, 1.30 [95% CI, 0.87-1.93]); P for interaction by HF type =0.02. CONCLUSIONS: In patients hospitalized with acute decompensated HF, detected physical examination findings differ both temporally and by obesity. Combined findings from the physical examination are more prognostic of 28-day mortality for patients with HFpEF than HFrEF.

Clinical and Echocardiographic Characteristics of Patients Hospitalized With Acute Versus Chronic Heart Failure With Preserved Ejection Fraction (From the ARIC Study).

An expanding number of therapies are now indicated for comorbidity management in heart failure with preserved ejection fraction (HFpEF). Whether comorbidity burdens differ for patients with HFpEF who are hospitalized for acute decompensated heart failure (ADHF) versus those with chronic stable heart failure (CSHF) who are hospitalized for other causes is uncertain. Since 2005, the Atherosclerosis Risk in Communities (ARIC) study has conducted adjudicated community surveillance of hospitalized heart failure. Hospitalized ADHF and CSHF were sampled identically, using prespecified discharge codes and demographic strata, but were differentiated by signs or symptoms of acute or worsening heart failure upon physician review of the medical record. HFpEF was defined by an ejection fraction ≥50%. All events were weighted by the inverse of the sampling probability for statistical analyses. From 2005 to 2014, 13,706 weighted (2,936 unweighted) hospitalizations (mean age 77 years, 64% women, 29% Black) were sampled among patients with HFpEF and adjudicated ADHF (86%) or CSHF (14%). Comorbidity prevalence was high both for ADHF and CSHF hospitalizations, irrespective of gender. Women hospitalized with ADHF versus CSHF had greater prevalence of hypertension (89% vs 84%) diabetes mellitus (48% vs 39%) and renal disease (85% vs 74%). Echocardiographic features such as left ventricular hypertrophy and valvular abnormalities were more common with ADHF than CSHF, for both genders. However, the 28-day and 1-year mortality risk were comparable for ADHF and CSHF. In conclusion, hospitalized patients with HFpEF have a high comorbidity burden and risk of death, irrespective of the cause of hospitalization.

Prognostic value of shock index in patients admitted with non-ST-segment elevation myocardial infarction: the ARIC study community surveillance.

AIMS: Shock index (SI), defined as the ratio of heart rate (HR) to systolic blood pressure (SBP), is easily obtained and predictive of mortality in patients with ST-segment elevation myocardial infarction. However, large-scale evaluations of SI in patients with non-ST-segment elevation myocardial infarction (NSTEMI) are lacking. METHODS AND RESULTS: Hospitalizations for acute myocardial infarction were sampled from four US areas by the Atherosclerosis Risk in Communities (ARIC) study and classified by physician review. Shock index was derived from the HR and SBP at first presentation and considered high when ≥0.7. From 2000 to 2014, 18 301 weighted hospitalizations for NSTEMI were sampled and had vitals successfully obtained. Of these, 5753 (31%) had high SI (≥0.7). Patients with high SI were more often female (46% vs. 39%) and had more prevalent chronic kidney disease (40% vs. 32%). TIMI (Thrombolysis in Myocardial Infarction) risk scores were similar between the groups (4.3 vs. 4.2), but GRACE (Global Registry of Acute Coronary Syndrome) score was higher with high SI (140 vs. 118). Angiography, revascularization, and guideline-directed medications were less often administered to patients with high SI, and the 28-day mortality was higher (13% vs. 5%). Prediction of 28-day mortality by SI as a continuous measurement [area under the curve (AUC): 0.68] was intermediate to that of the GRACE score (AUC: 0.87) and the TIMI score (AUC: 0.54). After adjustments, patients with high SI had twice the odds of 28-day mortality (odds ratio = 2.02; 95% confidence interval: 1.46-2.80). CONCLUSION: The SI is easily obtainable, performs moderately well as a predictor of short-term mortality in patients hospitalized with NSTEMI, and may be useful for risk stratification in emergency settings.

Relationship Between Central Artery Stiffness, Brain Arterial Dilation, and White Matter Hyperintensities in Older Adults: The ARIC Study-Brief Report.

[Figure: see text].

Development and validation of optimal phenomapping methods to estimate long-term atherosclerotic cardiovascular disease risk in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes is a heterogeneous disease process with variable trajectories of CVD risk. We aimed to evaluate four phenomapping strategies and their ability to stratify CVD risk in individuals with type 2 diabetes and to identify subgroups who may benefit from specific therapies. METHODS: Participants with type 2 diabetes and free of baseline CVD in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial were included in this study (N = 6466). Clustering using Gaussian mixture models, latent class analysis, finite mixture models (FMMs) and principal component analysis was compared. Clustering variables included demographics, medical and social history, laboratory values and diabetes complications. The interaction between the phenogroup and intensive glycaemic, combination lipid and intensive BP therapy for the risk of the primary outcome (composite of fatal myocardial infarction, non-fatal myocardial infarction or unstable angina) was evaluated using adjusted Cox models. The phenomapping strategies were independently assessed in an external validation cohort (Look Action for Health in Diabetes [Look AHEAD] trial: n = 4211; and Bypass Angioplasty Revascularisation Investigation 2 Diabetes [BARI 2D] trial: n = 1495). RESULTS: Over 9.1 years of follow-up, 789 (12.2%) participants had a primary outcome event. FMM phenomapping with three phenogroups was the best-performing clustering strategy in both the derivation and validation cohorts as determined by Bayesian information criterion, Dunn index and improvement in model discrimination. Phenogroup 1 (n = 663, 10.3%) had the highest burden of comorbidities and diabetes complications, phenogroup 2 (n = 2388, 36.9%) had an intermediate comorbidity burden and lowest diabetes complications, and phenogroup 3 (n = 3415, 52.8%) had the fewest comorbidities and intermediate burden of diabetes complications. Significant interactions were observed between phenogroups and treatment interventions including intensive glycaemic control (p-interaction = 0.042) and combination lipid therapy (p-interaction < 0.001) in the ACCORD, intensive lifestyle intervention (p-interaction = 0.002) in the Look AHEAD and early coronary revascularisation (p-interaction = 0.003) in the BARI 2D trial cohorts for the risk of the primary composite outcome. Favourable reduction in the risk of the primary composite outcome with these interventions was noted in low-risk participants of phenogroup 3 but not in other phenogroups. Compared with phenogroup 3, phenogroup 1 participants were more likely to have severe/symptomatic hypoglycaemic events and medication non-adherence on follow-up in the ACCORD and Look AHEAD trial cohorts. CONCLUSIONS/INTERPRETATION: Clustering using FMMs was the optimal phenomapping strategy to identify replicable subgroups of patients with type 2 diabetes with distinct clinical characteristics, CVD risk and response to therapies.

Biomarker-Based Risk Prediction of Incident Heart Failure in Pre-Diabetes and Diabetes.

OBJECTIVES: This study evaluated the application of a biomarker-based risk score to identify individuals with dysglycemia who are at high risk for incident heart failure (HF) and to inform allocation of effective preventive interventions. BACKGROUND: Risk stratification tools to identify patients with diabetes and pre-diabetes at highest risk for HF are needed to inform cost-effective allocation of preventive therapies. Whether a biomarker score can meaningfully stratify HF risk is unknown. METHODS: Participants free of cardiovascular disease from 3 cohort studies (ARIC [Atherosclerosis Risk In Communities], DHS [Dallas Heart Study], and MESA [Multi-Ethnic Study of Atherosclerosis]) were included. An integer-based biomarker score included high-sensitivity cardiac troponin T ≥6 ng/l, N-terminal pro-B-type natriuretic peptide ≥125 pg/ml, high-sensitivity C-reactive protein ≥3 mg/l, and left ventricular hypertrophy by electrocardiography, with 1 point for each abnormal parameter. The 5-year risk of HF was estimated among participants with diabetes and pre-diabetes across biomarker score groups (0 to 4). RESULTS: The primary analysis included 6,799 participants with dysglycemia (diabetes: 33.2%; pre-diabetes: 66.8%). The biomarker score demonstrated good discrimination and calibration for predicting 5- and 10-year HF risk among pre-diabetes and diabetes cohorts. The 5-year risk of HF among subjects with a biomarker score of ≤1 was low and comparable to participants with euglycemia (0.78%). The 5-year risk for HF increased in a graded fashion with an increasing biomarker score, with the highest risk noted among those with scores of ≥3 (diabetes: 12.0%; pre-diabetes: 7.8%). The estimated number of HF events that could be prevented using a sodium-glucose cotransporter-2 inhibitor per 1,000 treated subjects over 5 years was 11 for all subjects with diabetes and ranged from 4 in the biomarker score zero group to 44 in the biomarker score ≥3 group. CONCLUSIONS: Among adults with diabetes and pre-diabetes, a biomarker score can stratify HF risk and inform allocation of HF prevention therapies.

Trends, Management, and Outcomes of Acute Myocardial Infarction Hospitalizations With In-Hospital-Onset Versus Out-of-Hospital Onset: The ARIC Study.

Background Acute myocardial infarction (AMI) with in-hospital onset (AMI-IHO) has poor prognosis but is clinically underappreciated. Whether its occurrence has changed over time is uncertain. Methods and Results Since 1987, the ARIC (Atherosclerosis Risk in Communities) study has conducted adjudicated surveillance of AMI hospitalizations in 4 US communities. Our analysis was limited to patients aged 35 to 74 years with symptomatic AMI. Patients with symptoms initiating after hospital arrival were considered AMI-IHO. A total of 26 678 weighted hospitalizations (14 276 unweighted hospitalizations) for symptomatic AMI were identified from 1995 to 2014, with 1137 (4%) classified as in-hospital onset. The population incidence rate of AMI-IHO increased in the 4 ARIC communities from 1995 through 2004 to 2005 through 2014 (12.7-16.9 events per 100 000 people; P for 20-year trend <0.0001), as did the proportion of AMI hospitalizations with in-hospital onset (3.7%-6.1%; P for 20-year trend =0.03). The 10-year proportions were stable for patients aged 35 to 64 years (3.0%-3.4%; P for 20-year trend =0.3) but increased for patients aged ≥65 years (4.6%-7.8%; P for 20-year trend =0.008; P for interaction by age group =0.04). AMI-IHO had a more severe clinical course with lower use of AMI therapies or invasive strategies and higher in-hospital (7% versus 3%), 28-day (19% versus 5%), and 1-year (29% versus 12%) mortality (P<0.0001 for all). Conclusions In this population-based community surveillance, AMI-IHO increased from 2005 to 2014, particularly among older patients. Quality initiatives to improve recognition and management of AMI-IHO should be especially focused on hospitalized patients aged >65.

Racial Differences and Temporal Obesity Trends in Heart Failure with Preserved Ejection Fraction.

BACKGROUND/OBJECTIVES: Obesity increases with age, is disproportionately prevalent in black populations, and is associated with heart failure with preserved ejection fraction (HFpEF). An "obesity paradox," or improved survival with obesity, has been reported in patients with HFpEF. The aim of this study was to examine whether racial differences exist in the temporal trends and outcomes associated with obesity among older patients with HFpEF. DESIGN: Community surveillance of acute decompensated heart failure (ADHF) hospitalizations, sampled by stratified design from 2005 to 2014. SETTING: Atherosclerosis Risk in Communities Study (NC, MS, MD, MN). PARTICIPANTS: A total of 10,147 weighted hospitalizations for ADHF (64% female, 74% white, mean age 77 years), with ejection fraction ≥50%. MEASUREMENTS: ADHF classified by physician review, HFpEF defined by ejection fraction ≥50%. Body mass index (BMI) calculated from weight at hospital discharge. Obesity defined by BMI ≥30 kg/m2 , class III obesity by BMI ≥40 kg/m2 . RESULTS: When aggregated across 2005-2014, the mean BMI was higher for black compared to white patients (34 vs 30 kg/m2 ; P < .0001), as was prevalence of obesity (56% vs 43%; P < .0001) and class III obesity (24% vs 13%; P < .0001). Over time, the annual mean BMI and prevalence of class III obesity remained stable for black patients, but steadily increased for white patients, with annual rates statistically differing by race (P-interaction = .04 and P = .03, respectively). For both races, a U-shaped adjusted mortality risk was observed across BMI categories, with the highest risk among patients with a BMI ≥40 kg/m2 . CONCLUSION: Black patients were disproportionately burdened by obesity in this decade-long community surveillance of older hospitalized patients with HFpEF. However, temporal increases in mean BMI and class III obesity prevalence among white patients narrowed the racial difference in recent years. For both races, the worst survival was observed with class III obesity. Effective strategies are needed to manage obesity in patients with HFpEF.