Triglyceride-glucose Index and Mortality in a Large Regional-based Italian Database (Urrah Project).

PURPOSE: Recently, a novel index (triglyceride-glucose index-TyG) was considered a surrogate marker of insulin resistance (IR); in addition, it was estimated to be a better expression of IR than widely used tools. Few and heterogeneous data are available on the relationship between this index and mortality risk in non-Asian populations. Therefore, we estimated the predictive role of baseline TyG on the incidence of all-cause and cardiovascular (CV) mortality in a large sample of the general population. Moreover, in consideration of the well-recognized role of serum uric acid (SUA) on CV risk and the close correlation between SUA and IR, we also evaluated the combined effect of TyG and SUA on mortality risk. METHODS: The analysis included 16,649 participants from the URRAH cohort. The risk of all-cause and CV mortality was evaluated by the Kaplan-Meier estimator and Cox multivariate analysis. RESULTS: During a median follow-up of 144 months, 2569 deaths occurred. We stratified the sample by the optimal cut-off point for all-cause (4.62) and CV mortality (4.53). In the multivariate Cox regression analyses, participants with TyG above cut-off had a significantly higher risk of all-cause and CV mortality, than those with TyG below the cut-off. Moreover, the simultaneous presence of high levels of TyG and SUA was associated with a higher mortality risk than none or only one of the two factors. CONCLUSIONS: The results of this study indicate that these TyG (a low-cost and simple non-invasive marker) thresholds are predictive of an increased risk of mortality in a large and homogeneous general population. In addition, these results show a synergic effect of TyG and SUA on the risk of mortality.

Serum Uric Acid/Serum Creatinine Ratio and Cardiovascular Mortality in Diabetic Individuals-The Uric Acid Right for Heart Health (URRAH) Project.

Several studies have detected a direct association between serum uric acid (SUA) and cardiovascular (CV) risk. In consideration that SUA largely depends on kidney function, some studies explored the role of the serum creatinine (sCr)-normalized SUA (SUA/sCr) ratio in different settings. Previously, the URRAH (URic acid Right for heArt Health) Study has identified a cut-off value of this index to predict CV mortality at 5.35 Units. Therefore, given that no SUA/sCr ratio threshold for CV risk has been identified for patients with diabetes, we aimed to assess the relationship between this index and CV mortality and to validate this threshold in the URRAH subpopulation with diabetes; the URRAH participants with diabetes were studied (n = 2230). The risk of CV mortality was evaluated by the Kaplan-Meier estimator and Cox multivariate analysis. During a median follow-up of 9.2 years, 380 CV deaths occurred. A non-linear inverse association between baseline SUA/sCr ratio and risk of CV mortality was detected. In the whole sample, SUA/sCr ratio > 5.35 Units was not a significant predictor of CV mortality in diabetic patients. However, after stratification by kidney function, values > 5.35 Units were associated with a significantly higher mortality rate only in normal kidney function, while, in participants with overt kidney dysfunction, values of SUA/sCr ratio > 7.50 Units were associated with higher CV mortality. The SUA/sCr ratio threshold, previously proposed by the URRAH Study Group, is predictive of an increased risk of CV mortality in people with diabetes and preserved kidney function. While, in consideration of the strong association among kidney function, SUA, and CV mortality, a different cut-point was detected for diabetics with impaired kidney function. These data highlight the different predictive roles of SUA (and its interaction with kidney function) in CV risk, pointing out the difference in metabolic- and kidney-dependent SUA levels also in diabetic individuals.

Neurological hypertensive emergencies: Correlation of blood pressure values with in-hospital outcomes in ischemic stroke.

BACKGROUND: Few certainties exist regarding optimal management of Blood Pressure (BP) in the very first hours after an ischemic stroke and many questions remain still unanswered. Our work aimed to evaluate the role of BP and its trend as possible determinants of in-hospital mortality (primary outcome), discharge disabilities and hospitalization length (secondary outcomes) in ischemic stroke patients presented with Hypertensive Emergencies (HE). METHODS: We retrospectively evaluated patients presented to Niguarda Hospital, Emergency Department (ED), from 2015 to 2017 with a neurological ischemic HE. BP at ED presentation (T0), its management in ED (T1) and its values at the stroke unit admission (T2) were evaluated. RESULTS: 267 patients were included (0.13 % of all ED accesses and 17.9 % of all ischemic strokes). In the whole population, BP values were not associated with in-hospital mortality while T0 and T2 SBP result were associated to discharge disability and hospitalization length. In pre-specified subgroup analysis these associations were confirmed only in untreated subjects (not anti-hypertensive nor thrombolysis). In fact, no significant relationship can be found between BP values and any secondary outcome in thrombolysis and anti-hypertensive treated patients. CONCLUSIONS: BP values and its management can not be related to in-hospital mortality in stroke patients, presented with HE, while they are associated to discharge disability and hospitalization length. In subgroup analysis, results were confirmed only in untreated (not anti-hypertensive therapies nor thrombolytic).

Prognostic Value and Relative Cutoffs of Triglycerides Predicting Cardiovascular Outcome in a Large Regional-Based Italian Database.

BACKGROUND: Despite longstanding epidemiologic data on the association between increased serum triglycerides and cardiovascular events, the exact level at which risk begins to rise is unclear. The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension has conceived a protocol aimed at searching for the prognostic cutoff value of triglycerides in predicting cardiovascular events in a large regional-based Italian cohort. METHODS AND RESULTS: Among 14 189 subjects aged 18 to 95 years followed-up for 11.2 (5.3-13.2) years, the prognostic cutoff value of triglycerides, able to discriminate combined cardiovascular events, was identified by means of receiver operating characteristic curve. The conventional (150 mg/dL) and the prognostic cutoff values of triglycerides were used as independent predictors in separate multivariable Cox regression models adjusted for age, sex, body mass index, total and high-density lipoprotein cholesterol, serum uric acid, arterial hypertension, diabetes, chronic renal disease, smoking habit, and use of antihypertensive and lipid-lowering drugs. During 139 375 person-years of follow-up, 1601 participants experienced cardiovascular events. Receiver operating characteristic curve showed that 89 mg/dL (95% CI, 75.8-103.3, sensitivity 76.6, specificity 34.1, P<0.0001) was the prognostic cutoff value for cardiovascular events. Both cutoff values of triglycerides, the conventional and the newly identified, were accepted as multivariate predictors in separate Cox analyses, the hazard ratios being 1.211 (95% CI, 1.063-1.378, P=0.004) and 1.150 (95% CI, 1.021-1.295, P=0.02), respectively. CONCLUSIONS: Lower (89 mg/dL) than conventional (150 mg/dL) prognostic cutoff value of triglycerides for cardiovascular events does exist and is associated with increased cardiovascular risk in an Italian cohort.

Long-term increase in serum uric acid and its predictors over a 25 year follow-up: Results of the PAMELA study.

BACKGROUND AND AIMS: Hyperuricemia (HU) has been shown to be associated with an adverse impact on cardiovascular and metabolic risk. Scanty data are available in the general population on the longitudinal changes in serum uric acid (SUA), the occurrence of HU and their potential predictors. We examined during a 25-year follow-up the SUA changes and the factors associated with HU development in the Pressioni Arteriose Monitorate E loro Associazioni (PAMELA) study. METHODS AND RESULTS: We analyzed data collected in 561 subjects of the PAMELA study evaluated during an average follow-up time amounting to 25.4 ± 1.0 years (mean ± SD). HU was defined by the Uric Acid Right for Heart Health (URRAh) cutoff (5.1 for females and 5.6 mg/dl for males). Mean SUA values during follow-up increased from 4.7 ± 1.1 to 5.0 ± 1.2 mg/dl (P<0.001), the average SUA elevation amounting to of 0.3 ± 1.1 mg/dl 26.7 % of the subjects displayed HU at the follow-up. This was associated at the multivariable analysis with female gender, office, home and 24-h blood pressure, diuretic treatment, serum triglycerides and baseline SUA, as well as the increase in waist circumference and the reduction in renal function. CONCLUSION: The present study provides longitudinal evidence that in the general population during a 25 year follow-up there is a progressive increase in SUA and HU development. Baseline SUA represents the most important factor associated with these modifications. Gender, renal dysfunction, triglycerides, obesity, diuretic treatment and blood pressure represent other variables capable to predict future occurrence of HU.

The Results of the URRAH (Uric Acid Right for Heart Health) Project: A Focus on Hyperuricemia in Relation to Cardiovascular and Kidney Disease and its Role in Metabolic Dysregulation.

The relationship between Serum Uric Acid (UA) and Cardiovascular (CV) diseases has already been extensively evaluated, and it was found to be an independent predictor of all-cause and cardiovascular mortality but also acute coronary syndrome, stroke and heart failure. Similarly, also many papers have been published on the association between UA and kidney function, while less is known on the role of UA in metabolic derangement and, particularly, in metabolic syndrome. Despite the substantial number of publications on the topic, there are still some elements of doubt: (1) the better cut-off to be used to refine CV risk (also called CV cut-off); (2) the needing for a correction of UA values for kidney function; and (3) the better definition of its role in metabolic syndrome: is UA simply a marker, a bystander or a key pathological element of metabolic dysregulation?. The Uric acid Right for heArt Health (URRAH) project was designed by the Working Group on uric acid and CV risk of the Italian Society of Hypertension to answer the first question. After the first papers that individuates specific cut-off for different CV disease, subsequent articles have been published responding to the other relevant questions. This review will summarise most of the results obtained so far from the URRAH research project.

High blood pressure with elevated resting heart rate: a high risk "Sympathetic" clinical phenotype.

Epidemiological studies have unequivocally shown that elevated heart rate values measured at rest have an adverse prognostic impact in the hypertensive patient, being associated with an increased risk of cardiovascular events and complications. In recent years new data have been collected on this issue, strengthening the clinical relevance of elevated heart rate as a specific hypertensive phenotype. The present paper will review old and new data on the prognostic importance of resting tachycardia in the hypertensive patient. It will also examine the role of the sympathetic nervous system in the development of this alteration as well as its therapeutic implications. The different approaches to dynamically assess heart rate values in the clinical setting will be finally discussed.

Coffee consumption, clinic, 24-hour and home blood pressure. Findings from the PAMELA study.

BACKGROUND AND AIMS: Chronic coffee consuption has been reported to be associated with a modest but significant increase in blood pressure (BP), although some recent studies have shown the opposite. These data, however, largely refer to clinic BP and virtually no study evaluated cross-sectionally the association between chronic coffee consuption, out-of-office BP and BP variability. METHODS AND RESULTS: In 2045 subjects belonging to the population of the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, we analyzed cross-sectionally the association between clinic, 24-hour, home BP and BP variability and level of chronic coffee consumption. Results show that when adjusted for confounders (age, gender, body mass index, cigarette smoking, physical activity and alcohol drinking) chronic coffee consumption does not appear to have any major lowering effect on BP values, particulary when they are assessed via 24-hour ambulatory (0 Cup/day: 118.5 ± 0.7/72.8 ± 0.4 mmHg vs 3 cups/day: 120.2 ± 0.4/74.8 ± 0.3 mmHg, PNS) or home BP monitoring (0 cup/day: 124.1 ± 1.2/75.4 ± 0.7 mmHg vs 3 cups/day: 123.3 ± 0.6/76.4 ± 0.36 mmHg, PNS). However, daytime BP was significantly higher in coffee consumers (about 2 mmHg), suggesting some pressor effects of coffee which vanish during nighttime. Both BP and HR 24-hour HR variability were unaffected. CONCLUSION: Thus chronic coffee consumption does not appear to have any major lowering effect either on absolute BP values, particulary when they are assessed via 24-hour ambulatory or home BP monitoring, or on 24-hour BP variability.

Impact of the Increase in Left Ventricular Mass on the Risk of Long-Term Cardiovascular Mortality: A Prospective Cohort Study.

BACKGROUND: Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular events, and evidence has been obtained that an increase of a normal left ventricular mass (LVM) or new-onset LVH over time augments cardiovascular outcomes. METHODS: We addressed this issue in a sample of a general population at relatively low cardiovascular risk. We analyzed subjects with normal echocardiographic LVM enrolled in the PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) study to follow the increase of LVM over time and assess the prognostic impact of this change on the incidence of cardiovascular events (mean follow-up 18.5 years). RESULTS: In 990 subjects with no LVH at baseline, there was a significant average increase of LVM (21.2%), LVMIBSA (18.9%), and LVMIHT (22.3%) more than 10 years later. About a quarter developed LVH. The LVMIBSA change exhibited an association with the cardiovascular risk mortality during the following 18.5 years, and the association remained significant after adjustment for confounders (hazard ratio, 1.2 [1.0-1.5]). Similar findings were obtained for LVM in absolute values or indexed for height. The association was seen in both genders, but the link with the cardiovascular risk was statistically significant in males only. CONCLUSIONS: Thus, although over 10 years, the LVM increase does not reach a LVH status, it is associated with an augmented cardiovascular mortality risk. This suggests that it might be important to consider periodical LVM assessment, even when LVM is within the normal range, to timely detect its increase and cope with the need of cardiovascular risk restratification.

Serum Uric Acid Predicts All-Cause and Cardiovascular Mortality Independently of Hypertriglyceridemia in Cardiometabolic Patients without Established CV Disease: A Sub-Analysis of the URic acid Right for heArt Health (URRAH) Study.

High serum uric acid (SUA) and triglyceride (TG) levels might promote high-cardiovascular risk phenotypes across the cardiometabolic spectrum. However, SUA predictive power in the presence of normal and high TG levels has never been investigated. We included 8124 patients from the URic acid Right for heArt Health (URRAH) study cohort who were followed for over 20 years and had no established cardiovascular disease or uncontrolled metabolic disease. All-cause mortality (ACM) and cardiovascular mortality (CVM) were explored by the Kaplan-Meier estimator and Cox multivariable regression, adopting recently defined SUA cut-offs for ACM (≥4.7 mg/dL) and CVM (≥5.6 mg/dL). Exploratory analysis across cardiometabolic subgroups and a sensitivity analysis using SUA/serum creatinine were performed as validation. SUA predicted ACM (HR 1.25 [1.12-1.40], p < 0.001) and CVM (1.31 [1.11-1.74], p < 0.001) in the whole study population, and according to TG strata: ACM in normotriglyceridemia (HR 1.26 [1.12-1.43], p < 0.001) and hypertriglyceridemia (1.31 [1.02-1.68], p = 0.033), and CVM in normotriglyceridemia (HR 1.46 [1.23-1.73], p < 0.001) and hypertriglyceridemia (HR 1.31 [0.99-1.64], p = 0.060). Exploratory and sensitivity analyses confirmed our findings, suggesting a substantial role of SUA in normotriglyceridemia and hypertriglyceridemia. In conclusion, we report that SUA can predict ACM and CVM in cardiometabolic patients without established cardiovascular disease, independent of TG levels.

Comparison of electrocardiographic versus echocardiographic detection of left ventricular mass changes over time and evaluation of new onset left ventricular hypertrophy.

We assessed the value of 3 electrocardiographic (EKG) voltage criteria in detecting variations of left ventricular mass (LVM) over time, taking echocardiographic (ECHO) LVM as reference, in the Pressioni Arteriose Monitorate E Loro Associazioni study. In 927 subjects (age 47 ± 13 years on entry, 49.9% men) an ECHO evaluation of LVM and EKG suitable for measurement of EKG-LVH criteria (Sokolow-Lyon voltage, Cornell voltage and R-wave voltage in aVL) were available at baseline and at a 2nd evaluation performed 10 years later. Δ (delta) LVM, Δ LVMI, and Δ EKG parameters values were calculated from 2nd evaluation to baseline. The sensitivity of the EKG criteria in the diagnosis of LVH, poor at baseline, becomes even worse after 10 years, reaching very low values. Only the sensitivity of R-wave amplitude exhibited slight increase over time but with unsatisfactory absolute values. Despite the prevalence of ECHO-LVH at the 2nd evaluation was threefold increased compared to baseline (29.3% and 33.7% for LVM indexed to BSA and height2.7 , respectively), the prevalence of EKG-LVH was unchanged when evaluated by Sokolow-Lyon criteria, significantly reduced when assessed by Cornell voltage index, while significantly increased using R-wave voltage in aVL criteria. Despite an ECHO-LVM increase over the time, mean EKG changes were of opposite sign, except for R-wave amplitude in aVL. Our study highlights the discrepancy between ECHO and EKG in monitoring LVM changes over the time, especially for Sokolow-Lyon and Cornell voltage. Thus, EKG is an unsuitable method for the longitudinal evaluation of LVM variations.

Hyperuricemia increases the risk of cardiovascular mortality associated with very high HdL-cholesterol level.

BACKGROUND AND AIMS: Whether the association between very high HDL-cholesterol levels and cardiovascular mortality (CVM) is modulated by some facilitating factors is unclear. Aim of the study was to investigate whether the risk of CVM associated with very high HDL-cholesterol is increased in subjects with hyperuricemia. METHODS AND RESULTS: Multivariable Cox analyses were made in 18,072 participants from the multicentre URRAH study stratified by sex and HDL-cholesterol category. During a median follow-up of 11.4 years there were 1307 cases of CVM. In multivariable Cox models a J-shaped association was found in the whole population, with the highest risk being present in the high HDL-cholesterol group [>80 mg/dL, adjusted hazard ratio (HR), 1.28; 95%CI, 1.02-1.61; p = 0.031)]. However, a sex-specific analysis revealed that this association was present only in women (HR, 1.34; 95%CI, 1.02-1.77; p = 0.034) but not in men. The risk of CVM related to high HDL-cholesterol was much greater in the women with high uric acid (>0.30 mmol/L, HR 1.61; 95%CI, 1.08-2.39) than in those with low uric acid (HR, 1.17; 95%CI, 0.80-1.72, p for interaction = 0.016). In women older than 70 years with hyperuricemia the risk related to high HDL-cholesterol was 1.83 (95%CI, 1.19-2.80, p < 0.005). Inclusion of BMI in the models weakened the strength of the associations. CONCLUSION: Our data indicate that very high HDL-cholesterol levels in women are associated with CVM in a J-shaped fashion. The risk of CVM is increased by concomitant hyperuricemia suggesting that a proinflammatory/oxidative state can enhance the detrimental cardiovascular effects associated with high HDL-cholesterol.

Uric acid relationships with lipid profile and adiposity indices: Impact of different hyperuricemic thresholds.

Previous studies focused on the relationships between Serum Uric Acid (SUA) and lipids have found an association mainly with triglycerides. Furthermore, previous studies on adiposity indices have been focused on the evaluation of the Visceral Adiposity Index (VAI). The present study was aimed at providing within the same population a systematic evaluation of lipids and adiposity indices with SUA, employing both the classic cutoff for hyperuricemia and the newly one identified by the Uric Acid Right for Heart Health (URRAH) study. We analyzed data collected in 1892 subjects of the Pressioni Arteriose Monitorate E loro Associazioni (PAMELA) study with available SUA, lipid profile and variables necessary to calculate VAI, Cardio-Metabolic Index (CMI) and Lipid Accumulation Product (LAP). At linear regression model (corrected for confounders) SUA correlated with all the lipids values (with the strongest ß for triglycerides) and adiposity indices. When the two different cutoffs were compared, the URRAH one was significantly related to atherogenic lipids profile (OR 1.207 for LDL and 1.33 for non-HDL, P < 0.001) while this was not the case for the classic one. Regarding adiposity indices the classic cutoff displays highest OR as compared to the URRAH one. In conclusions, newly reported URRAH cutoff for hyperuricemia better relate to atherogenic lipoprotein (LDL and non-HDL) when compared to the classic one. The opposite has been found for adiposity indexes where the classic cut-off seems to present highest performance. Among adiposity indexes, LAP present the highest OR for the relationship with hyperuricemia.

Serum uric acid / serum creatinine ratio as a predictor of cardiovascular events. Detection of prognostic cardiovascular cut-off values.

OBJECTIVE: In the frame of the Uric Acid Right for Heart Health (URRAH) study, a nationwide multicenter study involving adult participants recruited on a regional community basis from all the territory of Italy under the patronage of the Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension, we searched for the cut-off values of the ratio between serum uric acid (SUA) and serum creatinine (sCr) able to predict cardiovascular (CV) events. METHODS: Among 20 724 participants followed-up for 126 ± 64 months, after detecting cut-off by the receiver operating characteristic curves, we calculated by Cox models adjusted for confounders having CV events as dependent variable the hazard ratio (HR) of SUA/sCr > cut-off. We also verified if the role of cut-off varied with increasing SUA/sCr. RESULTS: A plausible prognostic cut-off of SUA/sCr was found and was the same in the whole database, in men and in women (>5.35). The HR of SUA/sCr > cut-off was 1.159 (95% confidence interval [CI] 1.092-1.131, P < 0.03) in all, 1.161 (95% CI 1.021-1.335, P < 0.02) in men, and 1.444 (95% CI 1.012-1.113, P < 0.03) in women. In increasing quintiles of SUA/sCr the cut-offs were >3.08, >4.87, >5.35, >6.22 and >7.58, respectively. The HRs significantly increased from the 3rd to the 5th quintile (1.21, 95% CI 1.032-1.467, P = 0.018; 1.294, 95% CI 1.101-1.521, P = 0.002; and 1.642, 95% CI 1.405-1.919, P < 0.0001; respectively), that is, over 5.35, whereas the 2nd quintile was not significantly different from the 1st (reference). CONCLUSION: Having SUA/sCr >5.35 is an independent CV risk indicator both in men and women. The cut-off is dynamic and significantly increases with increasing SUA/sCr.

New-onset aortic dilatation in the population: a quarter-century follow-up.

BACKGROUND: Aortic size tends to increase with aging but the extent of this dynamic process has not been evaluated in long-term longitudinal population-based studies. We investigated the incidence of new-onset aortic root (AR) dilatation and its principal correlates among middle-aged adults over a 25-year time period. METHODS: A total of 471 participants with measurable echocardiographic parameters at baseline and after a 25-year follow-up were included in the analysis. Sex-specific upper limits of normality for absolute AR diameter, AR diameter indexed to body surface area (BSA) and to height were derived from healthy normotensive PAMELA participants. RESULTS: New AR dilatation occurred in 7.4% (AR/BSA), 9.1% (AR/height) and 14.6% (absolute AR), respectively. According to the AR/height index, the risk of new dilation was similar in men and women. As for echocardiographic parameters, baseline AR diameter emerged as a key predictor of AR dilation, regardless of the diagnostic criteria and the 10-year change in LVMI was positively associated to new AR/height dilatation. No significant relationship was observed between baseline office and ambulatory systolic/diastolic blood pressure or their changes over time with incident AR dilatation. Baseline and the 25-year change in 24-h pulse pressure were negatively related to new AR dilatation. CONCLUSIONS: The incidence of AR dilatation from mid to late adulthood occurs in a small but clinically relevant fraction of participants and is unaffected by both office and out-office BP. It is significant related to baseline AR diameter and to the 25-year change in LVMI. Our data suggest that echocardiography performed in middle-aged individuals of both sexes may identify those at increased risk of future AR dilatation; moreover, preventing LVH may reduce the risk of progressive AR enlargement.

Association between Berlin questionnaire index and blood pressure, organ damage and metabolic profilein a general population.

We evaluated the relationships between Berlin questionnaire (BQ) scores, hypertension and other metabolic variables in 598 subjects (age: 65.8 ± 10 years, mean ± SD) enrolled in the PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) study representative of the general population, treated or untreated with antihypertensive drugs. Two hundred and eleven subjects (35%) had a positive BQ with two or more positive categories of the inquiry. Compared to those without sleep disorders these subjects showed a greater male prevalence (55.9%), worse serum cholesterol, triglycerides and glucose profile, greater body mass index (BMI) (28.9 ± 4.9 vs. 24.9 ± 3.4 kg/m2 ), higher office (and to a lesser extent 24-h) BP and HR values, higher serum creatinine values and greater rate of echocardiographic left ventricular (LV) hypertrophy (25% vs. 13%). These differences were not detected when the data analysis was restricted to treated hypertensive patients. Thus, BQ scores allow to identify among subjects belonging to a general population those with elevated BP, organ damage and altered metabolic. When antihypertensive drug treatment is present, however, the approach fails to detect differences between groups with low or high BQ index.

Development and validation of a decision support tool for the diagnosis of acute heart failure: systematic review, meta-analysis, and modelling study.

OBJECTIVES: To evaluate the diagnostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) thresholds for acute heart failure and to develop and validate a decision support tool that combines NT-proBNP concentrations with clinical characteristics. DESIGN: Individual patient level data meta-analysis and modelling study. SETTING: Fourteen studies from 13 countries, including randomised controlled trials and prospective observational studies. PARTICIPANTS: Individual patient level data for 10 369 patients with suspected acute heart failure were pooled for the meta-analysis to evaluate NT-proBNP thresholds. A decision support tool (Collaboration for the Diagnosis and Evaluation of Heart Failure (CoDE-HF)) that combines NT-proBNP with clinical variables to report the probability of acute heart failure for an individual patient was developed and validated. MAIN OUTCOME MEASURE: Adjudicated diagnosis of acute heart failure. RESULTS: Overall, 43.9% (4549/10 369) of patients had an adjudicated diagnosis of acute heart failure (73.3% (2286/3119) and 29.0% (1802/6208) in those with and without previous heart failure, respectively). The negative predictive value of the guideline recommended rule-out threshold of 300 pg/mL was 94.6% (95% confidence interval 91.9% to 96.4%); despite use of age specific rule-in thresholds, the positive predictive value varied at 61.0% (55.3% to 66.4%), 73.5% (62.3% to 82.3%), and 80.2% (70.9% to 87.1%), in patients aged <50 years, 50-75 years, and >75 years, respectively. Performance varied in most subgroups, particularly patients with obesity, renal impairment, or previous heart failure. CoDE-HF was well calibrated, with excellent discrimination in patients with and without previous heart failure (area under the receiver operator curve 0.846 (0.830 to 0.862) and 0.925 (0.919 to 0.932) and Brier scores of 0.130 and 0.099, respectively). In patients without previous heart failure, the diagnostic performance was consistent across all subgroups, with 40.3% (2502/6208) identified at low probability (negative predictive value of 98.6%, 97.8% to 99.1%) and 28.0% (1737/6208) at high probability (positive predictive value of 75.0%, 65.7% to 82.5%) of having acute heart failure. CONCLUSIONS: In an international, collaborative evaluation of the diagnostic performance of NT-proBNP, guideline recommended thresholds to diagnose acute heart failure varied substantially in important patient subgroups. The CoDE-HF decision support tool incorporating NT-proBNP as a continuous measure and other clinical variables provides a more consistent, accurate, and individualised approach. STUDY REGISTRATION: PROSPERO CRD42019159407.

Machine learning and LACE index for predicting 30-day readmissions after heart failure hospitalization in elderly patients.

Machine learning (ML) techniques may improve readmission prediction performance in heart failure (HF) patients. This study aimed to assess the ability of ML algorithms to predict unplanned all-cause 30-day readmissions in HF elderly patients, and to compare them with conventional LACE (Length of hospitalization, Acuity, Comorbidities, Emergency department visits) index. All patients aged ≥ 65 years discharged alive between 2010 and 2019 after a hospitalization for acute HF were included in this retrospective cohort study. We applied MICE (Multivariate Imputation via Chained Equations) method to obtain a balanced, fully valued dataset and LASSO (Least Absolute Shrinkage and Selection Operator) algorithm to get the most significant features. Training (80% of records) and test (20%) cohorts were randomly selected. Study population: 3079 patients, 394 (12.8%) presented at least one readmission within 30 days, and 2685 (87.2%) did not. In the test cohort AUCs (IC95%) of XGBoost, Ada Boost Classifier, Random forest, and Gradient Boosting, and LACE Index were: 0.803 (0.734-0.872), 0.782 (0.711-0.854), 0.776 (0.703-0.848), 0.786 (0.715-0.857), and 0.504 (0.414-0.594), respectively, for predicting readmissions. A SHAP analysis was performed to offer a breakdown of the ML variables associated with readmission. Positive and negative predicting values estimates of the different ML models and LACE index were also provided, for several values of readmission rate prevalence. Among elderly patients, the rate of all-cause unplanned 30-day readmissions after hospitalization due to an acute HF was high. ML models performed better than the conventional LACE index for predicting readmissions. ML models can be proposed as promising tools for the identification of subjects at high risk of hospitalization in this clinical setting, enabling care teams to target interventions for improving overall clinical outcomes.

Serum uric acid levels threshold for mortality in diabetic individuals: The URic acid Right for heArt Health (URRAH) project.

BACKGROUND AND AIM: The URRAH (URic acid Right for heArt Health) Study has identified cut-off values of serum uric acid (SUA) predictive of total mortality at 4.7 mg/dl, and cardiovascular (CV) mortality at 5.6 mg/dl. Our aim was to validate these SUA thresholds in people with diabetes. METHODS AND RESULTS: The URRAH subpopulation of people with diabetes was studied. All-cause and CV deaths were evaluated at the end of follow-up. A total of 2570 diabetic subjects were studied. During a median follow-up of 107 months, 744 deaths occurred. In the multivariate Cox regression analyses adjusted for several confounders, subjects with SUA ≥5.6 mg/dl had higher risk of total (HR: 1.23, 95%CI: 1.04-1.47) and CV mortality (HR:1.31, 95%CI:1.03-1.66), than those with SUA <5.6 mg/dl. Increased all-cause mortality risk was shown in participants with SUA ≥4.7 mg/dl vs SUA below 4.7 mg/dl, but not statistically significant after adjustment for all confounders. CONCLUSIONS: SUA thresholds previously proposed by the URRAH study group are predictive of total and CV mortality also in people with diabetes. The threshold of 5.6 mg/dl can predict both total and CV mortality, and so is candidate to be a clinical cut-off for the definition of hyperuricemia in patients with diabetes.