Clinical Covariates Research Articles

Healthcare costs in relation to kidney function among older people: the SCOPE study.

In this study, a comprehensive analysis of costs of chronic kidney disease (CKD) was performed, to understand factors associated with the economic burden of the disease in a multicentre international framework. The impact on costs of demographics, socio-economics, clinical, and functional variables was tested in 2204 subjects aged 75years or more attending outpatient clinics in Europe using a multicentre 2-year prospective cohort study. By means of collected resources consumption and unit cost data a comprehensive cost database was built and then investigated using multilevel regression modeling. Overall, hospitalization, medications and specialist visits were the main cost items, with a notable variability among countries. Estimated yearly costs were 4478€ ± 9804€, rising up to 6683€ ± 10,953€ for subjects with estimated Glomerular Filtration Rate (eGFR) < 30. Costs increased significantly according to the severity of the disease, gender and age. Clinical and functional covariates were also significantly associated with CKD-related total costs, even after correcting for the inter-country variability. Findings corroborate the importance of multidimensional assessment of participants with CKD, as multimorbidity and functional disability produce a detrimental impact on participant's prognosis and cost of care. Preservation of functional impairment and adequate management of comorbidities may thus help decreasing the overall consumption on health care resources in CKD patients, especially in older people.

Abstract 4135617: Large Scale Proteomics Identifies Circulating Biomarkers Relating Atrial Fibrillation to Heart Failure: the Atherosclerosis Risk in Communities Study

Introduction: There is a bidirectional relationship between atrial fibrillation (AF) and heart failure (HF) risk. Data regarding shared and unique pathways underlying each are limited. Aims: Identify plasma proteins associated with both incident AF and HF and determine the extent to which associations with one outcome are conditional on interval occurrence of the other outcome. Methods: Among participants in the community-based Atherosclerosis Risk in Communities study free of HF and AF at study visit 5 (2011-2013), we measured 4,955 plasma proteins (SomaScan aptamer-affinity assay). We performed parallel analyses of individual protein associations with incident HF and AF using multivariable Cox regression adjusted for demographic and clinical covariates at Bonferroni significance. We then repeated the analysis for each outcome in models censoring participants with interval occurrence of the other outcome (i.e. incident AF censoring for interval HF, and vice versa). We tested associations of AF-related proteins with echocardiographic and Zio patch measures at Visit 5. Results: Among 4,118 participants included, mean age was 75±5 years, 60% were female, and 18% reported Black race. We identified 83 proteins associated with incident HF (n=355 incident events at 7 [IQR 6-8] year follow-up) and 24 with incident AF (n=517 incident events at 8 [7-9] years), of which 10 were associated with both. In models of incident HF censoring for interval AF, 63 (76%) proteins remained significantly associated with HF. In contrast, in the analysis of incident AF censoring for interval HF, only 4 (17%) proteins remained associated with AF, of which 3 were also associated with HF risk (Figure). These 4 AF-related proteins were associated with measures of LV diastolic function (LA volume, E/e’. average), LV mass index, LA function (LA reservoir, LA contraction), and supraventricular ectopy density (all p&lt;0.05). Conclusion: Nearly half of proteins reflecting AF risk also associate with HF, greater than 80% of AF-associated proteins are HF-dependent, and even those that are not correlate with measures of LV remodeling and dysfunction. These findings suggest that AF-related mechanisms among older adults are part of a wider HF syndrome.

Abstract 4140126: Comparison of Clinical Risk Calculators for Atherosclerotic Cardiovascular Diseases: PREVENT, Pooled Cohort Equations, and QRISK3

Introduction: The cardio-kidney-metabolic pathway has a crucial role in ASCVD, motivating development of the PREVENT equation. There is a need for external validation of the PREVENT equation and assessment of its performance in independent cohorts to assess generalizability across diverse populations. Aim: To compare predictive performance of the PREVENT equation with previously developed risk calculators; pooled cohort equations (PCE), and QRISK3. Methods: We used data from 500k participants of the United Kingdom Biobank (UKB). ASCVD was defined as the composite outcome of fatal and non-fatal myocardial infarction, coronary revascularization, and stroke. We ascertained demographic and clinical covariates required to calculate ASCVD risk, using the base model of PREVENT, PCE, and QRISK3, at the time of recruitment. Those with a diagnosis of ASCVD at the time of recruitment or missing data on age, sex, or ethnicity were excluded. We used the area under the ROC curve (AUC) and calibration plots for analysis. Results: Of 459,681 participants (mean age 56.3±8.1 years, 44.4% male, and 94.7% White), 24,514 (5.4%) participants had a new diagnosis of ASCVD during a 10-year follow-up. The median [interquartile range] of estimated 10-y ASCVD risk was 3.7% [1.9% - 6.1%] for PREVENT, 5.6% [2.4% - 11.3%] for PCE, and 8.0% [3.9% - 13.8%] for QRISK3 (Figure 1A). The calibration slope (95% CI) was 1.71 (1.66 – 1.76) for PREVENT, 0.64 (0.63 – 0.66) for PCE, and 0.66 (0.64 – 0.67) for QRISK3 (Figure 1B). The AUC for ASCVD prediction was 0.741 (0.738 - 0.744) for PREVENT, 0.744 (0.741 – 0.747) for PCE, and 0.751 (0.749 – 0.755) for QRISK3 (Figure 1C). Conclusion: In the UKB cohort, the PREVENT equation underpredicted while the PCE and QRISK3 overpredicted ASCVD risk, with a similar discrimination. Consequently, fewer individuals would be eligible for primary prevention with statins, based on the actionable thresholds of 7.5% or 10% when considering ASCVD risk based on PREVENT. Therefore, the external application of the PREVENT equation requires recalibration and context-specific interpretation.

Abstract 4143220: Racial Differences in Prescription of SGLT2 Inhibitors and GLP1 Receptor Agonists Among US Veterans with Type 2 Diabetes and Coronary Artery Disease

Background: Clinical trials have demonstrated that sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) reduce cardiovascular (CV) risk in patients (pts) with type 2 diabetes (T2D) with or at high risk for CV disease. Adoption of new therapies has often lagged for Black pts compared with non-Hispanic White pts, contributing to poorer health outcomes. Methods: We identified Veterans with T2D and angiographic CAD between 2015 and 2020 at 84 Veterans Affairs (VA) medical centers who met eligibility criteria for the EMPA-REG OUTCOME or LEADER trials that first established the clinical efficacy of SGLT2i and GLP1RA, respectively. Within each cohort (SGLT2i- and GLP1RA-eligible), we used multivariable logistic regression adjusted for demographic and clinical covariates to estimate associations of race with evidence-based drug prescription. We evaluated patterns of evidence-based prescription of SGLT2i and GLP1RA over time and by race in US Veterans with T2D and coronary artery disease (CAD). Results: Of 63,561 pts with T2D and CAD, 3,527 Black and 18,668 White pts met trial eligibility criteria for SGLT2i treatment and 2,020 Black and 10,103 White pts for GLP1RA treatment. Evidence-based prescription of both classes increased over time for both races ( Figure ) but reached only approximately 40% for SGLT2i and 15% for GLP1RA in 2023. For SGLT2i, race (Black/White) was not associated with evidence-based prescription (adjusted odds ratio [OR] 0.96, 95% CI 0.89-1.04, P=0.3). However, Black pts were less likely than White pts to receive evidence-based prescription of GLP1RA (adjusted OR 0.85, 95% CI 0.74-0.98, P=0.025). Conclusions: Among pts with T2D and CAD in the VA healthcare system, evidence-based prescription of SGLT2i and GLP1RA increased over time, but many eligible pts remained untreated. Prescription of SGLT2i did not differ by race, but Black pts were less likely than White pts to have evidence-based prescription of a GLP1RA. Disparities in evidence-based use of CV treatments may be specific to certain drug classes, even in a healthcare system with few economic barriers. Further investigation is needed to determine underlying causes and solutions for such disparities.

The serum uric acid/high-density lipoprotein cholesterol ratio: a novel predictor for the presence of abdominal aortic aneurysm

ObjectiveRobust evidence has demonstrated that inflammation plays an important role in the occurrence and development of abdominal aortic aneurysms (AAA). The serum uric acid (UA)/high-density lipoprotein cholesterol (HDL-C) ratio (UHR) has recently been recognized as a new biomarker for evaluating inflammatory and anti-inflammatory interactions. However, whether UHR is associated with AAA remains unclear. This study aimed to explore the association between UHR and presence of AAA.MethodsWe prospectively performed a hospital-based and community-based AAA screening program using ultrasonography in 9,064 individuals at Guangdong Provincial People’s Hospital and two communities in China. Logistic regression analysis was used to explore the association between UHR and presence of AAA. In addition, the restricted cubic spline (RCS) regression method was used to visually investigate the dose-response relationship between UHR and the presence of AAA. Propensity score matching (PSM) analysis was conducted to adjust for baseline variations and diminish selection bias, and subgroup analysis was performed to investigate the consistency of the conclusions.ResultsThe prevalence of AAA was 2.45% (222/9,064) in the present study. The optimal cut-off value of UHR was 17.0%, which was selected according to the receiver operator characteristic curve. The prevalence of AAA was 3.96% in the high-UHR group (UHR ≥ 17%) and 1.54% in the low-UHR group (UHR &amp;lt; 17%) (P &amp;lt; 0.001). After adjusting for other relevant clinical covariates, UHR was independently associated with the presence of AAA, either as a continuous variable (odds ratio [OR] 1.03, 95% confidence intervals [CI] 1.01–1.05, P &amp;lt; 0.001) or as a categorical variable (OR 1.63, 95% CI 1.18–2.26, P = 0.003). The RCS curve showed a nonlinear dose-response relationship between UHR and the presence of AAA. Moreover, the positive correlation between UHR and the presence of AAA remained significant after PSM and subgroup analyses.ConclusionsUHR was positively associated with the presence of AAA, and there was a non-linear dose-response relationship between them. Thus, UHR may serve as a novel and reliable predictor of AAA.

Associations of comorbid headache disorders and depression with leisure-time physical activity among 14,088 adults in The Brazilian Longitudinal Study of Adult Health.

While headache disorders are linked to low physical activity levels, the impact of depression on this relationship is unclear. To assess how single and comorbid diagnoses of migraine and tension-type headache (TTH) interact with depression and leisure-time physical activity (LTPA) levels in The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). In this cross-sectional analysis based on the ELSA-Brasil baseline data, the relationship of migraine, TTH (both assessed with the International Classification of Headache Disorders, Second Edition), and depression (assessed with the Clinical Interview Schedule-Revised) with LTPA levels (International Physical Activity Questionnaire) was investigated by employing linear regression models. Models were adjusted for sociodemographic, lifestyle, and clinical covariates, and interaction terms were created to examine additive effects of comorbid conditions. Among 14,088 participants, 54.4% (7668/14,088) were female, prevalence rates were: TTH = 39.6% (5573/14,088), migraine = 27.0% (3806/14,088), depression = 0.7% (94/14,088), depression + TTH = 1.1% (148/14,088), and depression + migraine = 2.5% (356/14,088). The mean (standard deviation) LTPA levels across the groups were: no headache + no depression = 148.7 (183.0) min/week, TTH = 133.5 (170.1) min/week, migraine = 110.3 (154.8) min/week, depression = 76.5 (146.3) min/week, depression + TTH = 84.5 (127.7) min/week, and depression + migraine = 64.3 (123.2) min/week. Negative associations were found for depression (β = -55.1, 95% confidence interval [CI] -93.6 to -17.0; p = 0.005), migraine (β = -24.7, 95% CI -33.2 to -15.4; p < 0.001), and TTH (β = -15.5, 95% CI -23.1 to -7.6; p < 0.001) with LTPA. No interaction effect was observed for depression + TTH (β = 36.0, 95% CI -12.6 to 84.6; p = 0.147) and depression + migraine (β = 31.7, 95% CI -11.3 to 74.7; p = 0.149), indicating no additive effect of comorbid conditions on LTPA levels. After adjusting for headache attack frequency, only depression + migraine remained negatively associated with LTPA (β = -38.7, 95% CI -71.6 to -5.8; p = 0.021). Headache disorders and depression were independently and inversely associated with LTPA, with the strongest effects seen in depression alone or comorbid with migraine.

Predictive Value of NT-proBNP, FGF21, Galectin-3 and Copeptin in Advanced Heart Failure in Patients with Preserved and Mildly Reduced Ejection Fraction and Type 2 Diabetes Mellitus

Background and Objectives: Heart failure (HF) is one of the most common initial presentations of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM). There are different cardiac biomarkers related to the pathophysiological mechanisms of HF in T2DM. The current research aims to identify additional biomarkers that could improve the diagnosis and prognosis of HFpEF, which is currently assessed using NT pro-BNP levels. NT pro-BNP is a valuable tool for diagnosing heart failure but may not always correlate with clinical symptom severity or can present normal levels in certain cases, such as obesity. Biomarkers like FGF-21 and galectin-3 could provide greater insight into heart failure severity, especially in diabetic patients. The main objective of the current study is to assess the performance of NT-proBNP, FGF21, Galectin-3 and Copeptin to discriminate between advanced and mild HF. Materials and Methods: A total of 117 patients were enrolled in this study and divided into two groups: 67 patients in NYHA functional class I-II (mild HF) and 50 patients in NYHA III-IV (advanced HF). NT-pro BNP, FGF21, Galectin 3 and Copeptin serum levels were determined with the ELISA method. Receiver operating characteristic (ROC) analysis and binomial logistic regression analysis were used to measure the ability of the studied biomarkers to distinguish between advanced and mild HF patients. Results: In patients with T2DM with advanced HF, serum FGF21 level was significantly positively correlated with eGFR (ρ = 0.35, p = 0.0125) and triglycerides (ρ = 0.28, p = 0.0465) and significantly negatively correlated with serum levels of HDL cholesterol (ρ = −0.29, p = 0.0386) and with RV-RA gradient (ρ = −0.30, p = 0.0358). In patients with mild HF, serum FGF21 level was significantly negatively correlated with NT-proBNP levels (ρ = −0.37, p = 0.0022), E/e’ ratio (ρ = −0.29, p = 0.0182), TR velocity (ρ = −0.24, p = 0.0470) and RV-RA gradient (ρ = −0.24, p = 0.0472). FGF21 (AUC = 0.70, 95% CI: 0.60−0.79) and NT-proBNP (AUC = 0.73, 95% CI: 0.63–0.82) demonstrated significant predictive value to discriminate T2DM patients with advanced HF from those with mild HF. Elevated values for FGF21 (≥377.50 ng/mL) or NTproBNP (≥2379 pg/mL) were significantly associated with increased odds of advanced HF after adjusting for demographic and clinical covariates. Conclusions: NTpro-BNP and FGF21 have a similar ability to discriminate T2DM patients with advanced HF from those with mild HF. Univariable and multivariable logistic models showed that, FGF21 and NTproBNP were independent predictors for advanced HF in patients with preserved and mildly reduced ejection fraction and T2DM.

Association of furosemide versus chlorothiazide exposures with serum sodium, potassium, and chloride among infants with bronchopulmonary dysplasia.

To examine the association of novel furosemide versus thiazide diuretic exposure with changes in serum sodium, potassium, and chloride levels among infants with grade 2/3 bronchopulmonary dysplasia (BPD). Retrospective cohort study of infants admitted to a level IV neonatal intensive care unit (NICU) with grade 2/3 BPD. We measured within-subject change in serum sodium, potassium, and chloride before and after diuretic initiation using multivariable regression to adjust for differences in dosing and clinical covariates. We identified 94 infants contributing 137 novel diuretic exposures. No significant difference was noted in the association between chlorothiazide versus furosemide and serum sodium, potassium, or chloride change in multivariable modeling. Changes in serum electrolytes were similar for chlorothiazide and furosemide, questioning the perception that chlorothiazide leads to less electrolyte derangement among preterm infants with grade 2/3 BPD.

Healthcare Access Domains and Treatment as Mediators of Ovarian Cancer Racial Disparities in Survival: A Structural Equation Modeling Analysis in SEER-Medicare.

Racial differences in healthcare access (HCA) may contribute to disparities in ovarian cancer (OC) survival. We used structural equation models (SEM) to examine associations between race and HCA domains (affordability, availability, accessibility) in relation to overall and OC-specific mortality. Non-Hispanic (NH)-Black and non-Black (Hispanic, NH-White) women diagnosed with OC in 2008-2015 were identified from SEER-Medicare. Cox proportional hazards regression was used to conduct mediation analysis for associations between race and HCA domains with overall and OC-specific mortality. SEM models adjusting for demographic and clinical covariates were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). A total of 4,629 eligible OC patients were identified, including 255 (5.5%) patients who were NH-Black. In SEM adjusting for demographic, clinical, and HCA latent variables, there was a total effect of NH-Black race on overall (HR: 1.11, 95% CI: 1.03,1.19) and OC-specific mortality (HR: 1.16, 95% CI: 1.08, 1.24), which was primarily driven by a direct effect. There was a modest indirect association between NH-Black race and mortality through decreased treatment receipt, though not through HCA. There is a need for studies investigating additional social and biological mechanisms that contribute to worse cancer survival among NH-Black patients.

Long-term prognostic value of microvascular obstruction by cardiac magnetic resonance in ST-segment elevation myocardial infarction

Abstract Background Microvascular obstruction (MVO) has been associated with a higher risk of cardiac remodelling and adverse events following ST-segment elevation myocardial infarction (STEMI). However, long-term prognostic implications of MVO in STEMI beyond five years of follow-up have not been assessed to date. Purpose To investigate the relation of MVO with all-cause mortality and recurrent ischemic events at long-term follow-up after STEMI. Methods This is a pooled analysis of three observational studies including 876 prospectively enrolled reperfused first STEMI patients, who underwent cardiac magnetic resonance imaging with late gadolinium enhancement, between 2003-2019, from four university medical centers in the Netherlands and Spain. Median follow-up duration was 6.3 (IQR 3.6-9.3) years. The primary outcome was all-cause mortality. The secondary outcome was a combined endpoint of all-cause mortality and recurrent ischemic events (i.e. myocardial infarction or stroke). We performed Cox regression analyses with a time-dependent covariate. Model 1 included correction for clinical covariates only, i.e. age, sex, smoking, diabetes mellitus, hypertension, and LAD culprit artery. Model 2 included imaging characteristics, i.e. infarct size and left ventricular ejection fraction, in addition to the clinical covariates. Results The study population consisted of 876 patients, mean age 59 years ± 12, 720 men (82%). MVO was present in 499 patients (58%). The presence of MVO was significantly associated with all-cause mortality up to six years post-STEMI, independent from clinical characteristics (Hazard Ratio [HR] 2.23, 95% CI 1.09-4.57, p=0.029), but not after six years post-STEMI (HR 0.98, 95% CI 0.45-2.12, p=0.958). Presence of MVO was not significantly associated with a combined endpoint of all-cause mortality and recurrent ischemic events before or after six years of follow-up (HR 1.27, 95% CI 0.81-1.99, p=0.294 and HR 0.68, 95% CI 0.35-1.31, p=0.244, respectively). All other traditional prognosticators, except age, also lacked predictive value at long-term follow-up beyond six years. Conclusions In STEMI patients, the presence of MVO by cardiac magnetic resonance imaging is associated with a more than two-fold higher risk of all-cause mortality up to six years after the index event. This relation seems to dissipate beyond this time period. Furthermore, presence of MVO was not associated with recurrent ischemic events at long-term follow-up post-STEMI.

Differences in risk profiles and clinical outcomes according to age in patients with high-risk myocardial infarction: insights from the PARADISE-MI trial

Abstract Introduction Temporal declines in rates of rehospitalization and death after acute myocardial infarction (MI) have not been uniform across age groups. A better understanding of how risk profiles and clinical outcomes differ after MI by age may allow for targeted treatment and prevention strategies. Aims To investigate risk profiles and clinical outcomes following high-risk MI according to age in the Prospective ARNI vs ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI). Methods Adults without prior heart failure (HF) were randomized to sacubitril/valsartan versus ramipril within 0.5 to 7 days of a MI complicated by transient pulmonary congestion and/or left ventricular systolic dysfunction and additional risk-augmenting factors. Associations between age and clinical outcomes were analyzed using Cox proportional hazards regression models, which were additionally adjusted for baseline demographic and clinical covariates (Figure). Results The mean age of the 5,661 PARADISE-MI participants was 64 ± 11 years. Patients aged ≥75 years (n=1051) were more likely women, had more hypertension and atrial fibrillation and lower estimated glomerular filtration rate, were less likely to present with ST-segment elevation MI and regardless of type of MI were less likely to receive primary reperfusion and guideline-based medical therapy (Table). Age was significantly associated with all-cause death (HR 1.54 per 10-year increase; 95% CI, 1.41-1.68) and was more strongly associated with non-CV death (HR 2.09; 95% CI, 1.70-2.56) than with CV death (HR 1.43; 95% CI, 1.29-1.57). Age was also associated with incident HF (HR 1.37; 95% CI, 1.25-1.49) (Figure). Multivariable adjustment attenuated the risk relationship of age with recurrent fatal or non-fatal MI (HR 1.08; 95% CI, 0.96-1.21) and the coronary composite outcome (HR 1.01; 95% CI, 0.93-1.09). The relative treatment effect of sacubitril/valsartan versus ramipril on the primary composite outcome of CV death or incident HF was not significantly modified by age (p-interaction = 0.19). Conclusions Following high-risk MI, age was most strongly associated with subsequent non-CV death followed by CV death and incident HF, but was not independently associated with recurrent coronary events. The heightened risk of CV death and HF with advancing age was not explained by differences in clinical characteristics. Older patients may require closer surveillance and more aggressive treatment after MI to mitigate the elevated risk of CV death and HF.

Type 2 diabetes individuals have a shorter QRS duration, prolonged QTc interval, flatter T wave, and reduced left ventricular cycle volumes compared to matched controls in the UK Biobank

Abstract Background Type 2 diabetes is associated with an increased risk of heart failure even in the absence of overt coronary artery disease, though underlying mechanisms are unclear. ECG and cardiac magnetic resonance (CMR) imaging provide windows into subclinical changes in myocardial structure and function and could be exploited to understand this. Purpose We investigate differences in ECG and CMR biomarkers in a large cohort of participants with type 2 diabetes, compared to a matched control cohort. We hypothesise that individuals with diabetes may exhibit concurrent differences in biomarkers, reflecting underlying cardiac remodelling. Methods We carried out a pair-matched cross-sectional study to examine the association between type 2 diabetes and multi-modal cardiac biomarkers. The exposure cohort consists of 1,781 UK Biobank participants with an imaging and ECG visit, prevalent type 2 diabetes and no known cardiovascular events at the time of visit. The control cohort is matched on age, sex and body mass index (BMI), and consists of 1,781 participants without diabetes. ECG and CMR biomarkers derived from UK Biobank data were used as outcome variables. We built four multiple multivariate linear regression models, incrementally adjusted for socio-demographic, lifestyle, and clinical covariates. Results Both cohorts were mostly male (63.6%), had a median age of 67 years [IQR: 72-85] and a median BMI of 27.8 kg/m2 [24.6-31.0]. Individuals with type 2 diabetes were more likely to be non-white (7.9% vs 2.7%, p&amp;lt;0.001), current or previous smokers (43.6% vs 40.6%, p=0.04), have lower diastolic blood pressure (79 [72-85] vs 81 [74-88] mmHg, p&amp;lt;0.001), and take cholesterol medication (72.3% vs 27.2%, p&amp;lt;0.001); anti-hypertensives (56.3% vs 27.3%, p&amp;lt;0.001); insulin (13.7% vs 0.1%, p&amp;lt;0.001); and metformin (53.1% vs 0.1%, p&amp;lt;0.001). They had a higher ventricular rate, shorter QRS duration, longer QTc interval, and flatter T wave amplitude, as well as lower left ventricular end-diastolic and end-systolic volumes, among other differences (Table 1). Covariates including cholesterol medication, metformin, and HbA1c were excluded as they were strongly correlated with diabetes, age and/or sex (Pearson correlation coefficient &amp;gt;0.3 or &amp;lt;-0.3). After full adjustment, we found that the exposure variable, diabetes, had a statistically significant association with ventricular rate, QRS duration, T wave offset, T wave amplitude in lead V3, left ventricular stroke volume and global average thickness (p&amp;lt;0.05) (Table 2). Conclusion Our results reveal that individuals with type 2 diabetes exhibit a shorter QRS, longer QTc, and lower end-diastolic and end-systolic volumes, compared to matched controls. This may be indicative of subclinical cardiac abnormalities, both electrophysiological and mechanical. Our association analysis suggests that other factors correlated with diabetes may be also responsible for certain biomarker differences and their underlying causes.

Prognostic importance of persistent elevations in high-sensitivity troponin T in the early convalescent phase (two weeks) following high-risk myocardial infarction: insights from the PARADISE-MI trial

Abstract Introduction Myocardial infarction (MI) is defined by a rise and fall in cardiac troponin (cTn) with clinical evidence of acute myocardial ischemia. How often cTn remains elevated in high-risk patients stabilized following MI and the relation between convalescent cTn levels and subsequent clinical outcomes in these patients is unknown. Aims To evaluate the prognostic importance of high-sensitivity cTn T (hs-cTnT) in the early convalescent phase of a MI for a range of cardiovascular (CV) outcomes in patients enrolled in the Prospective ARNI vs ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI). Methods Patients ≥18 years without prior heart failure (HF) (n=5661) were randomized to sacubitril/valsartan or ramipril within 0.5 to 7 days of MI complicated by transient pulmonary congestion, LVEF ≤40%, or both. Hs-cTnT was measured using the Roche Elecsys Troponin T-high-sensitive assay in 1093 patients two weeks after randomization (median 2.6 weeks after the index MI). Associations between log (2)-transformed hs-cTnT and clinical outcomes were investigated in landmark analyses using Cox regression models adjusted for clinical covariates of known prognostic importance and NT-proBNP (Figure). Results Median week 2 hs-cTnT concentration was 34 ng/L [IQR 17-94 ng/L] and exceeded the 99th percentile upper reference limit in 69% of patients. Patients with persistently elevated hs-cTnT concentrations (n=753) were older, more likely men, more commonly had atrial fibrillation and lower estimated glomerular filtration rate and less likely had a prior MI. They more commonly had presented with ST-segment elevation MI and pulmonary congestion and had higher concentrations of NT-proBNP. Rates of primary reperfusion were similar. Log(2)-transformed hs-cTnT was only weakly correlated with LVEF (rho = -0.15, p&amp;lt;0.001), irrespective of the type of MI. hs-cTnT was independently and linearly associated with the primary composite outcome of CV death or incident HF (adj HR 1.17 per doubling; 95% CI, 1.03 – 1.34), all-cause death (adj HR 1.20; 95% CI, 1.01 – 1.44) and CV death (adj HR 1.25; 95% CI, 1.02 – 1.52) but not with non-CV death (adj HR 1.04; 95% CI, 0.70-1.54). hs-cTnT was not significantly associated with recurrent fatal or non-fatal MI (adj HR 1.00; 95% CI, 0.85-1.18) (Figure). Concentrations of week 2 hs-cTnT were not altered by sacubitril/valsartan relative to ramipril (+4%; 95% CI, -8% to 18%). Conclusions Persistent elevations in hs-cTnT during the early convalescent phase following high-risk MI are common and are associated with heightened risk of all-cause death, CV death and incident HF but not of recurrent MI or non-CV death. hs-cTnT measured ~2.5 weeks after high-risk MI provides incremental prognostic information beyond traditional risk factors and NT-proBNP.

Risk of atrial fibrillation recurrence after new-onset transient episode during ST-elevation myocardial infarction

Abstract Background Atrial fibrillation (AF) often complicates ST-elevation myocardial infarction (STEMI) and is associated with major in-hospital complications and increased mortality. The data on AF recurrence after new-onset transient STEMI-associated AF is scarce, and electrocardiographic (ECG) predictors of AF recurrence are unknown. Purpose Our aim was to assess the risk of AF recurrence and to find out the predictors of AF recurrence after transient STEMI-associated AF. Methods STEMI patients admitted during 2007-2010 for primary percutaneous coronary interventions (PCI) were followed up until 2018. All ECGs ever recorded before, during or after STEMI (n=58907) were exported from regional database in digital format and processed using Glasgow algorithm. Clinical characteristics and mortality status were retrieved from the Swedish national registries. Information regarding AF was obtained from the national registries and the regional ECG database. STEMI-associated AF was defined as first-ever AF episode occurring between symptom onset and hospital discharge. Patients with pre-existing AF, AF after acute coronary artery bypass surgery and patients discharged with ongoing AF were excluded from analysis. P-wave indexes were assessed from the latest sinus rhythm ECG before discharge. The primary endpoint was the first documented AF episode after discharge. The secondary endpoints were total mortality and ischemic stroke. Cox regression analysis was adjusted for relevant clinical covariates. Results 1) 1956 patients who were discharged alive on sinus rhythm were included in the analysis (age 65±12, 70% males), 127(6.5%) of them had transient STEMI-associated AF. 2) Patients with STEMI-associated AF were more likely to develop AF during follow-up (n=74 [58.3%]) than patients without AF before or during STEMI (No AF) (n=56 [3.1%], HR=4.80 95%CI 3.93-5.97) (Figure 1). 3) None of the clinical and demographic characteristics was associated with AF recurrence. P-wave duration, P-terminal force in V1 and P-voltage in lead I were associated with AF recurrence, however only reduced P-wave voltage in lead I &amp;lt;93 µV (75th percentile) (HR=2.29 95% CI 1.21-4.35, p=0.011) remained independently associated with AF recurrence in adjusted analysis (Figure 2). 4) During follow-up, 134 patients had an ischemic stroke and 522 died. STEMI-associated AF was associated with higher long-term mortality risk comparing to No AF (HR=1.18 95%CI 1.02-1.36). The risk of stroke was not associated with STEMI-associated AF (HR=1.08 95%CI 0.79-1.49). In patients with STEMI-associated AF, occurrence of stroke did not differ between patients with and without AF recurrence (5[7%] vs 8 [15%] respectively, p=0.147). Conclusion STEMI-associated transient AF is associated with a 4.8-fold increased risk of AF after discharge, reaching 28% by 1 year after discharge. ECG-based P-wave indexes reflecting atrial remodeling can be used for the prediction of AF recurrence after discharge.

Multivariate time-series clustering of cardiopulmonary exercise test data for cardiovascular risk stratification

Abstract Aims Current clinical practice assesses cardiorespiratory fitness (CRF) by evaluating summary indexes of cardiopulmonary exercise tests (CPET). Yet, the raw time series recordings may hold additional information with clinical relevance. In this study, we investigated if the interpretation of raw CPET data could identify distinct CRF phenogroups and improve risk stratification. Methods In 1399 participants (mean age, 56.4 years; 37.7% women), who underwent maximal CPET by cycle ergometer, we collected baseline clinical characteristics and information on incident cardiovascular (CV) events (n=297) on average 4.3 years later. We employed dynamic time warping combined with k-medoids to identify phenogroups from raw CPET time-series. To evaluate the clinical significance of the derived phenogroups we compared clinical characteristics and incidence of CV events, while an external population cohort (n=171) was used to further validate the trained model. Results The optimal number of clusters was 5. We observed significant differences in age, use of medication, spirometry indexes and disease prevalence across all clusters. Cluster 5 was associated with the worst CV profile with higher use of antihypertensive medication and history of CV disease while cluster 1 represented the most favourable risk profile. After adjusting for traditional clinical covariables, clusters 4 (HR: 1.30; 95%CI: 1.02-1.65; p=0.033) and 5 (HR: 1.36; 95%CI: 1.08-1.72; p=0.0088) had significantly higher risk for incident CV events compared to clusters 1 and 2. Comparing clinical characteristics across clusters in the external validation cohort revealed similar patterns. Conclusion – Employing unsupervised machine learning on time series CPET recordings, we identified clinically meaningful CRF phenogroups. An integrative CRF profiling might facilitate CV risk stratification and consequently risk management.

Obesity-dependent selection of driver mutations in cancer

Obesity is a risk factor for cancer, but whether obesity is linked to specific genomic subtypes of cancer is unknown. We examined the relationship between obesity and tumor genotype in two clinicogenomic corpora. Obesity was associated with specific driver mutations in lung adenocarcinoma, endometrial carcinoma and cancers of unknown primaries, independent of clinical covariates, demographic factors and genetic ancestry. Obesity is therefore a driver of etiological heterogeneity in some cancers.

Outcomes of intra-aortic balloon pump in patients with advanced heart failure and cardiogenic shock undergoing heart transplantation

Abstract Background Intra-aortic balloon pump (IABP) is generally used as a short-term device to maintain adequate organ perfusion in patients with cardiogenic shock (CS). However, whether IABP improves clinical outcomes as a bridge therapy for heart transplant (HTx) remains controversial. Purpose Evaluate the survival rate 30 days after heart transplant (HTx) in patients with advanced heart failure (HF) and CS using IABP pre transplant compared to non-IABP group. Methods We retrospectively analyzed consecutive patients with advanced HF and CS, admitted in the cardiac intensive care unit (ICU) of a tertiary university center, between 2009 and 2020, who underwent HTx. Study group included patients submitted to IABP implantation before HTx, and a non-IABP group submitted to HTx without left ventricular mechanical support. Propensity Score Matching was used to pair the groups according to relevant clinical covariates. The primary outcome of survival rate 30 days after HTx was estimated by the Kaplan-Meier method. Results 326 were enrolled, 199 in IABP group and 127 in non-IABP group. For non-IABP and IABP group, respectively, the most frequent etiology was Chagas disease (29,9% and 47,2%, p=0,006) followed by idiopathic cardiomyopathy and ischemic cardiomyopathy, the majority of patients were male (63% and 61,3%, p=0,760), the mean age was 46,9 ± 14,4 and 46,5 ± 12 years (p=0,791) and mean left ventricular ejection fraction was 25,9 ± 9,5% and 23,5 ± 5,9% (p=0,010). The Simplified Acute Physiology Score 3 (SAPS 3) at ICU admission was compared in both groups, which was 36,8% ± 17,8% in non-IABP group and 32,6% ± 18,6% in IABP group (p=0,042). At 30 days after HTx, there was no statistical difference in overall survival (p=0,459) between the groups (IABP: 18,1% mortality; non-IABP: 14,2% mortality). Survival rate after HTx was also similar in patients with Chagas disease compared to the other etiologies in both study groups (IABP group: p=0,221; non-IABP group: p=0,421). Conclusion In patients with advanced HF and CS submitted to HTx, the survival rate 30 days after HTx was equivalent in the IABP and non-IABP groups. In patients with Chagas disease the survival was also similar compared to other etiologies in both groups.Characteristics according to groupsKaplan-Meier survival estimates

Menopausal status and clinical outcomes in women with heart failure with reduced ejection fraction: the GALACTIC-HF trial

Abstract Introduction Mechanisms driving disease progression and potential responsiveness to investigational therapies may theoretically differ among women with heart failure (HF) based on menopausal status. However, few data are available describing the clinical course of premenopausal and postmenopausal women with HF. We investigated differences in baseline characteristics, clinical outcomes, and response to omecamtiv mecarbil in premenopausal and postmenopausal women participants of the GALACTIC-HF trial. Methods The GALACTIC-HF trial randomized patients with symptomatic HFrEF with LVEF of 35% or less to omecamtiv mecarbil or placebo. Menopausal status at randomization was collected. When menopausal status was unknown/unreported, menopausal status was inferred based on the expected distribution of age at menopause in the general population. The risk of the primary endpoint, worsening HF event or cardiovascular death, was compared among women by menopausal status using Cox regression models adjusted for clinical covariates, including age and baseline EF. Treatment effect heterogeneity was evaluated by menopausal status. Results Of the 8,232 patients enrolled, 1,749 (21.2%) were women. Menopausal status was available at baseline in 1,483 (84.8%). One hundred women reported being potentially childbearing (pre-menopausal) and 1,383 women reported being post-menopausal. Among the 266 patients that had unknown menopausal status, those younger than 47 years were additionally classified as pre-menopausal and those older than 56 years as post-menopausal based on estimated 10th /90th percentiles extrapolated from the general population. Compared to post-menopausal women, pre-menopausal women were younger, had higher eGFR, and had fewer comorbidities. Premenopausal women also had slightly higher BMI and lower LVEF, but lower NTproBNP and troponin at baseline compared to postmenopausal women. Premenopausal and postmenopausal women had similarly high burden of symptoms as assessed by the KCCQ-total symptoms score (median 63.5 vs. 64.6; P=0.79). During a median follow-up of 22 months, premenopausal and postmenopausal women experienced similar rates of primary and secondary outcomes (Table 1). Omecamtiv mecarbil was beneficial across the entire female cohort with no effect modification by menopausal status (Pinteraction=0.39). Sensitivity analysis excluding all women with unknown menopausal status yielded similar results. Conclusions In this high-risk HFrEF cohort, premenopausal women experienced similar rates of adverse cardiovascular outcomes as post-menopausal women despite younger age, fewer comorbidities, and lower cardiac biomarkers. Additional research is necessary to understand how risk factors unique to females might influence outcomes in those with heart failure. The benefit of omecamtiv mecarbil on reducing cardiovascular risk was consistent regardless of menopausal status.Primary/secondary outcomes by menopausal

Circulating metabolites associate with the QT interval in individuals without prevalent cardiovascular disease

Abstract Background Patients with metabolic syndrome have a higher prevalence of heart-rate corrected QT (QTc) interval prolongation. Despite this the effect of circulating metabolites on the QTc is largely unknown and limited to small studies. Purpose To test for association of circulating metabolites with the QTc interval in the UK Biobank study. Methods Participants were identified from the UK Biobank with same day plasma metabolite profiling and electrocardiograms. All 249 metabolites measured underwent quality control and log transformation to account for rightward skew and zero values. 149 metabolites with inter-correlations &amp;gt;0.7 were excluded. Participants taking QTc-prolonging medication or with a history of ischaemic heart disease or heart failure up to 6 months after the visit, were excluded. Participants were allocated to a training group (N=21,610) or an independent test group (N=5,304), if samples were obtained at recruitment or at a second visit, respectively. In the training group, each metabolite was tested separately for association with the QTc in linear regression analyses, adjusted for clinical covariates (age, sex, fasting time, body mass index (BMI), systolic blood pressure (SBP), smoking status, diabetes, lipid-lowering drug use and dietary factors). Significant metabolites (P&amp;lt;5x10-4) underwent validation in the test group. Sex-stratified analyses were also performed. In the training group, variables in two models underwent regularisation by LASSO regression (10-fold cross-validation) to reduce multicollinearity and downweigh less important variables; 1) clinical variables, 2) clinical variables and validated metabolites. Coefficients were used for QTc prediction in the test group. Significance between the models was evaluated by fisher’s transformation of R-squared statistics. Results In the per metabolite multivariate analysis, 56 metabolites were associated with the QTc interval. 19 metabolites validated in the test group. For 14 of these, absolute effect sizes were &amp;gt;5ms when comparing individuals in the top decile of the metabolite distribution verses the bottom (Figure 1), including the ketone body 3-hydroxybutyrate (9ms), and omega-6 fatty acid to total fatty acid ratio (7.2ms). For associations in males and females separately, significant effect size differences (P&amp;lt;0.05) were observed for 9 metabolites (Figure 2). In the training group, the combined LASSO model selected 17 (of 19) metabolites along with age, sex, SBP and BMI. In the test group, this model R-squared was 0.115 compared with 0.081 for clinical covariates alone, representing a significant 41.9% increase in QTc variation explained (P=0.002). Conclusions This study demonstrates clinically relevant metabolite associations with the QTc in individuals without cardiovascular disease and explain a significant proportion of QTc variation. Further investigation is warranted to test for direct effects on cardiac electrophysiology and proarrhythmic potential.Validated metabolitesSignificant sex differences

A larger reduction of spatial mean QRS-T angle during cardiac resynchronisation therapy is associated with a lower risk of mortality and heart failure hospitalisation

Abstract Background Predicting clinical outcome in heart failure patients undergoing cardiac resynchronization therapy (CRT) remains challenging, necessitating improved risk stratification for CRT recipients. Previous studies have shown an association between large spatial peak and mean QRS-T angles and cardiovascular disease. Little is known, however, about their relation to clinical outcome following CRT. Purpose To investigate the association between spatial peak and mean QRS-T angles and long-term clinical outcome following CRT initiation. Methods All patients with native LBBB receiving CRT at a large-volume tertiary care center between 2015 and 2020 were retrospectively evaluated. Spatial peak and mean QRS-T angles were derived from digital pre- and post-CRT 12-lead ECGs that were processed using Glasgow algorithm and Kors’ regression transformation. The QRS-T angles and their change after CRT were analyzed in relation to the primary composite endpoint of heart failure hospitalisation or all-cause mortality using Cox regression analysis adjusted for clinical covariates (age, gender, CRT-P or CRT-D, secondary ICD indication, ischemic etiology, NYHA class, LVEF, diabetes, atrial fibrillation, baseline QRS duration, NT-proBNP, and eGFR). Results The study group comprised 250 patients (a median age [Q1–Q3] of 72.2 years [64.5–76.3]; 22% female; 58% New York Heart Association (NYHA) class III-IV; LVEF 27% [22–30]) who were followed over a median follow-up time of 4.5 years [3.2–5.8] after CRT implantation. The median post-CRT spatial peak and mean QRS-angles were 142° [116–160] and 152° [127–166], and the median angle was decreased by 16° [-0.6–41] and 14° [-0.4–38], respectively. Both a larger post-CRT mean QRS-T angle (HR 1.20, 95%CI 1.08-1.33, p=&amp;lt;.001) and peak QRS-T angle (HR 1.08, 95%CI 1.01-1.17, p=0.046) were associated with the primary endpoint. A larger reduction of mean QRS-T angle, but not peak QRS-T angle, was associated with a risk reduction (HR 0.87, 95%CI 0.79-0.95, p&amp;lt;0.003). In Kaplan-Meier analysis, patients with a post-CRT mean QRS-T angle above median had a higher risk of reaching the endpoint (log-rank p=0.002, Figure 1). Conclusion Our results show that a larger magnitude of the post-CRT spatial peak and mean QRS-T angles, and a larger reduction of the latter, are associated with long-term heart failure hospitalisation and death. These findings suggest that spatial QRS-T angle may have a potential role in refined risk stratification of CRT patients.Figure 1.K-M curve spatial mean QRS-T