Association of Segment-Specific Pulse Wave Velocity With Vascular Calcification: The ARIC (Atherosclerosis Risk in Communities) Study.

BACKGROUND: Pulse wave velocity (PWV) is a noninvasive measure of arterial stiffness and predictor of cardiovascular disease. However, the association between PWV and vascular calcification across different vascular beds has not been fully investigated. This study aimed to quantify the association between PWV and multiterritory calcification and to explore whether PWV can identify individuals with vascular calcification beyond traditional risk factors. METHODS AND RESULTS: Among 1351 older adults (mean age, 79.2 years [SD, 4.1]) from the ARIC (Atherosclerosis Risk in Communities) study, we measured segment-specific PWVs: heart-carotid, heart-femoral, carotid-femoral, heart-ankle, brachial-ankle, and femoral-ankle. Dependent variables were high calcium score (≥75th percentile of Agatston score) across different vascular beds: coronary arteries, aortic valve ring, aortic valve, mitral valve, ascending aorta, and descending aorta. Quartiles of carotid-femoral, heart-femoral, heart-ankle, and brachial-ankle PWV were significantly associated with coronary artery calcium (eg, adjusted odds ratio [OR] for the highest versus lowest quartile of carotid-femoral PWV, 1.84 [95% CI, 1.24-2.74]). Overall, PWVs were most strongly associated with descending aorta calcification, with significant results for carotid-femoral, heart-femoral, heart-ankle, and brachial-ankle PWV (eg, adjusted OR for the highest versus lowest quartile of carotid-femoral PWV, 3.99 [95% CI, 2.61-6.17]). In contrast, femoral-ankle PWV was inversely associated with descending aorta calcification. Some PWVs improved the discrimination of coronary artery calcium and descending aorta calcification beyond traditional risk factors. CONCLUSIONS: The associations of PWV with vascular calcification varied substantially across segments, with descending aorta calcification most closely linked to PWVs. Our study suggests that some PWVs, especially carotid-femoral PWV, are helpful to identify individuals with coronary artery calcium and descending aorta calcification.

Coronary Artery Calcium Scores in Older Adults With Diabetes and Their Association With Diabetes-Specific Risk Enhancers (from the Atherosclerosis Risk in Communities Study).

Coronary artery calcium (CAC) is a validated marker of atherosclerotic cardiovascular disease (ASCVD) risk; however, it is not routinely incorporated in ASCVD risk prediction in older adults with diabetes. We sought to assess the CAC distribution among this demographic and its association with "diabetes-specific risk enhancers," which are known to be associated with increased ASCVD risk. We used the ARIC (Atherosclerosis Risk in Communities) study data, including adults aged >75 years with diabetes, who had their CAC measured at ARIC visit 7 (2018 to 2019). The demographic characteristics of participants and their CAC distribution were analyzed using descriptive statistics. Multivariable-adjusted logistic regression models were used to estimate the association between diabetes-specific risk enhancers (duration of diabetes, albuminuria, chronic kidney disease, retinopathy, neuropathy, and ankle-brachial index) and elevated CAC, adjusting for age, gender, race, education level, dyslipidemia, hypertension, physical activity, smoking status, and family history of coronary heart disease. The mean age in our sample was 79.9 (SD 3.97) years, with 56.6% women and 62.1% White. The CAC scores were heterogenous, and the median CAC score was higher in participants with a greater number of diabetes risk enhancers, regardless of gender. In the multivariable-adjusted logistic regression models, participants with ≥2 diabetes-specific risk enhancers had greater odds of elevated CAC than those with <2 (odds ratio 2.31, 95% confidence interval 1.34 to 3.98). In conclusion, the distribution of CAC was heterogeneous among older adults with diabetes, with the CAC burden associated with the number of diabetes risk-enhancing factors present. These data may have implications for prognostication in older patients with diabetes and supports the possible incorporation of CAC in the assessment of cardiovascular disease risk in this population.

Cardiac Valve Disease and Prevalent and Incident CKD in Community-Dwelling Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study.

Rationale & Objective: Recent literature suggests improvement in kidney function after percutaneous valvular replacement therapies, implying a pathophysiological contribution of valvular heart disease to chronic kidney disease (CKD). However, this association has not been investigated epidemiologically. We aimed to assess the association of valvular abnormality with prevalent and incident CKD. Study Design: Cross-sectional and prospective analyses. Setting & Participants: Community-dwelling participants (mean age 75.5 [standard deviation 5.1] years) from the Atherosclerosis Risk in Communities study (2011-2013). Exposure: Valvular abnormality defined as echocardiography-based aortic stenosis, aortic regurgitation, and mitral regurgitation. Outcomes: Prevalent CKD was defined as estimated glomerular filtration rate (eGFR]) <60 mL/min/1.73 m2. Incident CKD was defined as progression to eGFR <60 mL/min/1.73 m2 with ≥25% decline or hospitalization/deaths with CKD diagnosis. Analytical Approach: We cross-sectionally evaluated the association between valvular abnormality and prevalent CKD with logistic regression in 5,216 participants. Then, 3,752 participants without prevalent CKD were analyzed for incident CKD using Cox models. Results: There were 1.4% (n = 74) with any aortic stenosis, 10.6% (n = 555) with any aortic regurgitation, and 43.1% (n = 2,249) with any mitral regurgitation. After adjustment for potential confounders, any mitral regurgitation and moderate/severe aortic regurgitation showed significant associations with prevalent CKD (adjusted OR, 1.17 [95% CI, 1.03-1.34] and 2.82 [95% CI, 1.12-7.10]), as did any aortic stenosis in a sensitivity analysis with prevalent CKD defined including albuminuria ≥30 mg/g (1.83 [95% CI, 1.10-3.05]). Only any aortic stenosis showed an independent association with incident CKD (adjusted HR, 2.12 [95% CI, 1.13-4.00]). Limitations: Despite a relatively large study population, some subgroups had small numbers. Although we minimized reverse causation, we cannot completely rule it out. Conclusions: Different valvular abnormality types were associated with prevalent CKD. Only aortic stenosis was robustly associated with incident CKD. These findings suggest an etiological link between valvular abnormality and CKD, highlighting the importance of clinical attention to kidney function in individuals with aortic stenosis.

Lipoprotein(a) and Subclinical Vascular and Valvular Calcification on Cardiac Computed Tomography: The Atherosclerosis Risk in Communities Study.

Background Lipoprotein(a) (Lp(a)) is a potent causal risk factor for cardiovascular events and mortality. However, its relationship with subclinical atherosclerosis, as defined by arterial calcification, remains unclear. This study uses the ARIC (Atherosclerosis Risk in Communities Study) to evaluate the relationship between Lp(a) in middle age and measures of vascular and valvular calcification in older age. Methods and Results Lp(a) was measured at ARIC visit 4 (1996-1998), and coronary artery calcium (CAC), together with extracoronary calcification (including aortic valve calcium, aortic valve ring calcium, mitral valve calcification, and thoracic aortic calcification), was measured at visit 7 (2018-2019). Lp(a) was defined as elevated if >50 mg/dL and CAC/extracoronary calcification were defined as elevated if >100. Logistic and linear regression models were used to evaluate the association between Lp(a) and CAC/extracoronary calcification, with further stratification by race. The mean age of participants at visit 4 was 59.2 (SD 4.3) years, with 62.2% women. In multivariable adjusted analyses, elevated Lp(a) was associated with higher odds of elevated aortic valve calcium (adjusted odds ratio [aOR], 1.82; 95% CI, 1.34-2.47), CAC (aOR, 1.40; 95% CI, 1.08-1.81), aortic valve ring calcium (aOR, 1.36; 95% CI, 1.07-1.73), mitral valve calcification (aOR, 1.37; 95% CI, 1.06-1.78), and thoracic aortic calcification (aOR, 1.36; 95% CI, 1.05-1.77). Similar results were obtained when Lp(a) and CAC/extracoronary calcification were examined on continuous logarithmic scales. There was no significant difference in the association between Lp(a) and each measure of calcification by race or sex. Conclusions Elevated Lp(a) at middle age is significantly associated with vascular and valvular calcification in older age, represented by elevated CAC, aortic valve calcium, aortic valve ring calcium, mitral valve calcification, thoracic aortic calcification. Our findings encourage assessing Lp(a) levels in individuals with increased cardiovascular disease risk, with subsequent comprehensive vascular and valvular assessment where elevated.

Sex-and race-specific burden of aortic valve calcification among older adults without overt coronary heart disease: The Atherosclerosis Risk in Communities Study.

BACKGROUND AND AIMS: The prevalence of aortic valve calcification (AVC) increases with age. However, the sex-and race-specific burden of AVC and associated cardiovascular risk factors among adults ≥75 years are not well studied. METHODS: We calculated the sex-and race-specific burden of AVC among 2283 older Black and White adults (mean age:80.5 [SD:4.3] years) without overt coronary heart disease from the Atherosclerosis Risk in Communities Study who underwent non-contrast cardiac-gated CT-imaging at visit 7 (2018-2019). Using Poisson regression with robust variance, we calculated the adjusted prevalence ratios (aPR) of the association of AVC with cardiovascular risk factors. RESULTS: The overall AVC prevalence was 44.8%, with White males having the highest prevalence at 58.2%. The prevalence was similar for Black males (40.5%), White females (38.9%), and Black females (36.8%). AVC prevalence increased significantly with age among all race-sex groups. The probability of any AVC at age 80 years was 55.4%, 40.0%, 37.3%, and 36.2% for White males, Black males, White females, and Black females, respectively. Among persons with prevalent AVC, White males had the highest median AVC score (100.9 Agatston Units [AU]), followed by Black males (68.5AU), White females (52.3AU), and Black females (46.5AU). After adjusting for cardiovascular risk factors, Black males (aPR:0.53; 95%CI:0.33-0.83), White females (aPR:0.68; 95%CI:0.61-0.77), and Black females (aPR:0.49; 95%CI:0.31-0.77) had lower AVC prevalence compared to White males. In addition, systolic blood pressure, non-HDL-cholesterol, and lipoprotein (a) were independently associated with AVC, with no significant race/sex interactions. CONCLUSIONS: AVC, although highly prevalent, was not universally present in this cohort of older adults. White males had ∼50-60% higher prevalence than other race-sex groups. Moreover, cardiovascular risk factors measured in older age showed significant association with AVC.

Changes in Serum Intact Fibroblast Growth Factor 23 Concentrations From Midlife to Late Life and Their Predictors in the Community: The ARIC Study.

Objective: To investigate longitudinal changes in the blood concentration of fibroblast growth factor 23 (FGF23) from midlife to late life and their major predictors in the general population. Patients and Methods: In 14,444 participants of the Atherosclerosis Risk in Communities Study, we analyzed the association of 31,095 measurements of serum intact FGF23 with age using data from 3 visits (visit 2 [N=13,460; mean age, 57 years]; visit 3 [N=12,323; mean age, 60 years]; and visit 5 [N=6122; mean age, 76 years]) and a linear mixed-effects model. Among 5804 participants who had FGF23 measurements at both visits 3 and 5, we explored predictors of FGF23 change from midlife to late life using linear regression models. Prespecified risk factors were estimated glomerular filtration rate, body mass index, ever smoking, ever drinker, diabetes, hypertension, history of cardiovascular disease, total cholesterol, and high-density lipoprotein cholesterol. Results: Median FGF23 concentrations were 41.9 pg/mL (interquartile interval [IQI], 33.9 to 51.8 pg/mL) at visit 2, 38.3 pg/mL (IQI, 30.6 to 48.3 pg/mL) at visit 3, and 55.0 pg/mL (IQI, 44.4 to 70.3 pg/mL) at visit 5. A linear mixed-effects model showed that the association of FGF23 with age was nonlinear, with a slight decline or no change in age 45-60 years and a monotonic increase in age greater than or equal to 65 years (FGF23, +10 to 15 pg/mL per 10 years of age). In a multivariable linear regression model, significantly greater increases in FGF23 were noted, with midlife estimated glomerular filtration rate less than 60 mL/min per 1.73 m2 vs more than or equal to 60 mL/min per 1.73 m2 (ΔFGF23, +4.4 pg/mL [95% CI, 0.9 to 8.0]), diabetes vs no diabetes (ΔFGF23, +6.2 pg/mL [95% CI, 4.1 to 8.3]), and hypertension vs no hypertension (ΔFGF23, +4.1 pg/mL [95% CI, 2.7 to 5.4]). Conclusion: FGF23 did not show any major changes in midlife but increased linearly in late life. Reduced kidney function, diabetes, and hypertension were robustly associated with a greater increase in FGF23. Further investigations are needed to understand the potential mechanisms linking these conditions to an increase in FGF23 concentrations.

18-year change in serum intact fibroblast growth factor 23 from midlife to late life and risk of mortality: the ARIC Study.

Objective: Fibroblast growth factor 23 (FGF23) concentration increases in response to declining kidney function to preserve normal phosphate concentrations. However, the etiological association of change in FGF23 concentration with mortality has not been examined in the general population. Design and methods: We analyzed 5458 participants of the Atherosclerosis Risk in Communities Study who had intact FGF23 and estimated glomerular filtration rate (eGFR) assessed during midlife (visit 3, 1993-1995, mean age: 58 years) and late life (visit 5, 2011-2013, 76 years) to examine the association of FGF23 change over 18 years from mid-life to late life with the subsequent risk of mortality in late life using Cox regression models. Results: The median 18-year change in intact FGF23 was +17.3 pg/mL. During a median follow-up of 7.2 years following visit 5, 1176 participants died. In multivariable Cox models, elevated mortality was seen in the highest quartile of FGF23 change (ΔFGF23: ≥31.3 pg/mL) (adjusted hazard ratio (aHR): 1.61 (95%CI: 1.36-1.90), or 1.37 (1.15-1.64) after additionally adjusting for eGFR change, compared with the lowest quartile (≤6.4 pg/mL)). When both FGF23 change and FGF23 in late life were simultaneously entered into the Cox model, FGF23 in late life, but not FGF23 change, was an independent predictor of mortality; however, we observed a high correlation between FGF23 change from midlife to late life and FGF23 in late life (r = 0.77). Conclusions: Serum intact FGF23 change from midlife to late life was associated with subsequent risk of mortality independent of decline in kidney function. Our findings further support the implications of FGF23 beyond its association with kidney function.

The association of fibroblast growth factor 23 at mid-life and late-life with subsequent risk of cardiovascular disease: The Atherosclerosis Risk in Communities (ARIC) Study.

Background: Fibroblast growth factor 23 (FGF-23) regulates phosphorus and is associated with cardiovascular disease (CVD), particularly in patients with chronic kidney disease. However, data are limited regarding its contribution to different CVD subtypes across wide age ranges in the general population. Methods: Using data from ARIC, we evaluated the associations of FGF-23 with heart failure (HF), coronary heart disease (CHD), stroke, and composite CVD (any CVD event) in 12,039 participants at mid-life (visit 3 [1993-1995], mean age 60.0 [SD 5.7] years) and 5608 of the same participants at late-life (visit 5 [2011-2013], 75.5 [5.1] years). Results: During a median of 9.0 years from visit 3 and 6.9 years from visit 5, we observed 1636 and 1137 composite CVD events, respectively. Higher FGF-23 at visit 5, but not necessarily at visit 3, was significantly associated with the risk of CVD independently of potential confounders including kidney function (adjusted HRs for top vs. bottom quartile, 1.56 [95% CI, 1.30-1.87] at visit 5 and 1.10 [95% CI, 0.95-1.27] at visit 3, p-for-difference < 0.001). We observed similar patterns in key demographic and clinical subgroups without interactions. Among CVD subtypes, HF was the only subtype robustly associated with higher FGF-23 at both visits. Conclusion: Higher FGF-23 concentrations at late-life but not necessarily at mid-life were independently associated with the risk of CVD. Among CVD subtypes tested, only HF showed robust associations with FGF-23 at both mid-life and late-life.

Psychosocial factors and subsequent risk of hospitalizations with peripheral artery disease: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND AND AIMS: Psychosocial factors are associated with increased risk of cardiovascular disease (CVD). However, associations with peripheral artery disease (PAD) remain uncharacterized. We aimed to compare associations of psychosocial factors with the risk of PAD and two other major atherosclerotic CVD: coronary heart disease (CHD) and ischemic stroke, in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: In 11,104 participants (mean age 56.7 [SD 5.7] years) without a clinical history of PAD and CHD/stroke at baseline (1990-1992), we evaluated four psychosocial domains: depressive/fatigue symptoms by the Maastricht Questionnaire, social support by the Interpersonal Evaluation List, social networks by the Lubben Scale, and trait anger by the Spielberger Scale. PAD was defined as hospitalizations with diagnosis or related procedures. CHD included adjudicated coronary heart disease and stroke included ischemic stroke. RESULTS: We observed 397 PAD and 1940 CHD/stroke events during a median follow-up of 23.1 years. Higher depressive/fatigue symptoms and less social support were significantly associated with incident PAD (adjusted hazard ratios for top vs. bottom quartile 1.65 [95%CI, 1.25-2.19] and 1.40 [1.05-1.87], respectively). When these factors were simultaneously modeled, only depressive/fatigue symptoms remained significant. Incident CHD/stroke was not associated with either of depressive/fatigue symptoms or social support. Social networks and trait anger were not independently associated with PAD or CHD/stroke. CONCLUSIONS: Depressive/fatigue symptoms and social support (especially the former) were independently associated with the risk of hospitalizations with PAD but not CHD/stroke in the general population. Our results support the importance of depressive/fatigue symptoms in vascular health and suggest the need of including PAD when studying the impact of psychosocial factors on CVD.

The Relationship of COVID-19 Severity with Cardiovascular Disease and Its Traditional Risk Factors: A Systematic Review and Meta-Analysis.

BACKGROUND: Whether cardiovascular disease (CVD) and its traditional risk factors predict severe coronavirus disease 2019 (COVID-19) is uncertain, in part, because of potential confounding by age and sex. METHODS: We performed a systematic review of studies that explored pre-existing CVD and its traditional risk factors as risk factors of severe COVID-19 (defined as death, acute respiratory distress syndrome, mechanical ventilation, or intensive care unit admission). We searched PubMed and Embase for papers in English with original data (≥10 cases of severe COVID-19). Using random-effects models, we pooled relative risk (RR) estimates and conducted meta-regression analyses. RESULTS: Of the 661 publications identified in our search, 25 papers met our inclusion criteria, with 76,638 COVID-19 patients including 11,766 severe cases. Older age was consistently associated with severe COVID-19 in all eight eligible studies, with RR >~5 in >60-65 versus <50 years. Three studies showed no change in the RR of age after adjusting for covariate(s). In univariate analyses, factors robustly associated with severe COVID-19 were male sex (10 studies; pooled RR = 1.73, [95% CI 1.50-2.01]), hypertension (8 studies; 2.87 [2.09-3.93]), diabetes (9 studies; 3.20 [2.26-4.53]), and CVD (10 studies; 4.97 [3.76-6.58]). RR for male sex was likely to be independent of age. For the other three factors, meta-regression analyses suggested confounding by age. Only four studies reported multivariable analysis, but most of them showed adjusted RR ~2 for hypertension, diabetes, and CVD. No study explored renin-angiotensin system inhibitors as a risk factor for severe COVID-19. CONCLUSIONS: Despite the potential for confounding, these results suggest that hypertension, diabetes, and CVD are independently associated with severe COVID-19 and, together with age and male sex, can be informative for predicting the risk of severe COVID-19.

Prevalence, Determinants, and Prognostic Significance of Hospital Acquired Pneumonia in Patients with Acute Heart Failure.

The prognostic impact of hospital-acquired pneumonia (HAP) in acute heart failure (AHF) patients have not been fully elucidated. We evaluated 776 consecutive hospitalized AHF patients. The primary in-hospital outcomes were all-cause death and worsening heart failure (WHF), while the outcome following discharge was all-cause death. The clinical diagnosis of HAP was based on clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Patients with HAP had a significantly higher incidence of in-hospital death (12% vs. 1%, p < 0.001), WHF during the hospitalization (28% vs. 7%, p < 0.001), and longer length of hospital stay (p = 0.003) than those without. Among patients who survived at discharge, during a median follow-up period of 741 (interquartile range 422-1000) days, the incidence of all-cause death was significantly higher in patients with HAP than in those without (p < 0.001). In the multivariable Cox regression, HAP development was independently associated with all-cause death after discharge (HR [hazard ratio] 1.86, 95%CI [confidence interval] 1.08-3.19). Furthermore, older age (OR [odds ratio] 1.04, 95%CI 1.01-1.08), male sex (OR 2.21, 95%CI 1.14-4.28), and higher serum white blood cell count (OR 1.18, 95%CI 1.09-1.29) and serum C-reactive protein (OR 1.08, 95%CI 1.01-1.06) were independently associated with HAP development. In hospitalized patients with AHF, HAP development was associated with worse clinical outcomes, suggesting the importance of prevention and early screening for HAP.

Elevated admission urinary N-acetyl-ß-D-glucosamidase level is associated with worse long-term clinical outcomes in patients with acute heart failure.

BACKGROUND: The prognostic significance of urinary N-acetyl-ß-D-glucosamidase in acute heart failure has not been fully elucidated. Accordingly, this study investigated whether urinary N-acetyl-ß-D-glucosamidase could be associated with subsequent adverse events in acute heart failure patients. METHODS: We studied 708 consecutive acute heart failure patients who had accessible N-acetyl-ß-D-glucosamidase data on admission from the National Cerebral and Cardiovascular Center Acute Decompensated Heart Failure registry. We assessed the relationship between the admission N-acetyl-ß-D-glucosamidase level and the combined endpoint of all-cause death and worsening heart failure. Worsening heart failure was defined as worsening symptoms and signs of heart failure requiring intensification of intravenous therapy such as diuretics, vasodilators and inotropes or initiation of mechanical support after stabilisation with initial treatment during hospitalisation, or readmission due to heart failure after discharge. RESULTS: During a median follow-up period of 763 (interquartile range 431-1028) days, higher urinary N-acetyl-ß-D-glucosamidase was significantly related to increased events of all-cause death and worsening heart failure. In addition, patients with higher urinary N-acetyl-ß-D-glucosamidase and lower estimated glomerular filtration rate on admission had the worst clinical outcomes. In multivariable Cox regression, urinary N-acetyl-ß-D-glucosamidase on admission was independently associated with adverse events (hazard ratio 1.19, 95% confidence interval 1.04-1.35) even after adjustment by covariates including the baseline estimated glomerular filtration rate. CONCLUSIONS: Higher urinary N-acetyl-ß-D-glucosamidase level on admission was independently associated with worse clinical outcomes. Our findings indicate the potential value of assessing urinary N-acetyl-ß-D-glucosamidase on admission for further risk stratification in patients with acute heart failure.

Prognostic value of base excess as indicator of acid-base balance in acute heart failure.

BACKGROUND: Acid-base balance can change as a result of pulmonary oedema and low tissue perfusion in acute heart failure patients. However, its long-term prognostic significance remains to be clarified. METHODS: We prospectively examined a cohort of 472 consecutive acute heart failure patients who underwent arterial blood gas analysis on admission between January 2013 and May 2016. Acidaemia, alkalaemia and normal range of base excess were defined as pH <7.38, >7.42 and -2 to 2 mEq/L, respectively. The primary outcome was all-cause death. RESULTS: During a median follow-up period of 714 days, 101 patients died. Although there was no difference in mortality among patients with acidaemia, normal pH and alkalaemia (p = 0.92), patients with high base excess had the highest mortality compared with others. Multivariable Cox proportional hazard models revealed that high base excess was an independent determinant of mortality (hazard ratio 1.83, 95% confidence interval 1.08-3.13 (high versus normal base excess), hazard ratio 0.81, 95% confidence interval 0.47-1.41 (low versus normal base excess)), even after adjustment for significant prognostic covariates. Furthermore, regarding mortality stratified by base excess and carbon dioxide partial pressure (pCO2), patients with high base excess (>2.1 mEq/L) and high pCO2 (>40 mmHg) had the highest mortality compared with others. CONCLUSIONS: High base excess, but not low base excess, on admission was associated with long-term mortality in acute heart failure patients, indicating the importance of evaluating acid-base balance on admission by base excess for stratifying the risk of mortality in patients with acute heart failure.

Comparison of Mortality Prediction Models on Long-Term Mortality in Hospitalized Patients With Acute Heart Failure　- The Importance of Accounting for Nutritional Status.

BACKGROUND: The ideal mortality prediction model (MPM) for acute heart failure (AHF) patients would have sufficient and stable predictive ability for long-term as well as short-term mortality. However, published MPMs for AHF predominantly predict short-term mortality up to 90 days, and their prognostic performance for long-term mortality remains unclear. Methods and Results: We analyzed 609 AHF patients in a prospective registry from January 2013 to May 2016. We compared the prognostic performance for long-term mortality among 8 systematically identified MPMs for AHF that predict short-term mortality up to 90 days from admission. The PROTECT 7-day model showed the highest c-index for long-term as well as short-term mortality among the studied MPMs. Sensitivity analyses revealed serum albumin and total cholesterol to be the most important variables, as dropping these variables resulted in a significant decline in c-index, when compared with other variables specific to the PROTECT 7-day model. Furthermore, significant improvements in c-index and net reclassification were observed when serum albumin or serum albumin plus total cholesterol was added to the studied MPMs, other than the PROTECT 7-day model. CONCLUSIONS: The PROTECT 7-day model demonstrated the highest predictive performance for long-term as well as short-term mortality in AHF patients among the published MPMs. Our findings indicate the importance of accounting for nutritional status such as serum albumin and total cholesterol in AHF patients when developing a MPM.

Elevated Plasma D-Dimer Level Is Associated With Short-Term Risk of Ischemic Stroke in Patients With Acute Heart Failure.

BACKGROUND AND PURPOSE: The incidence of heart failure increases the subsequent risk of ischemic stroke, and its risk could be higher in the short-term period after an acute heart failure (AHF) event. However, its determinants remain to be clarified. Plasma D-dimer level reflects fibrin turnover and exhibits unique properties as a biomarker of thrombosis. The aim of this study is to investigate whether D-dimer level is a determinant of short-term incidence of ischemic stroke in patients with AHF. METHODS: We examined 721 consecutive hospitalized AHF patients with plasma D-dimer level on admission from our prospective registry between January 2013 and May 2016. The study end points were incidence of ischemic stroke during hospitalization and at 30 days after admission. RESULTS: Of the total participants (mean age, 76 years; male, 60%; atrial fibrillation, 54%; mean left ventricular ejection fraction, 38%), in-hospital ischemic stroke occurred in 18 patients (2.5%) during a median hospitalization period of 21 days, and 30-day ischemic stroke occurred in 16 patients (2.2%). Higher D-dimer level on admission was an independent determinant of subsequent risk of in-hospital ischemic stroke even after adjustment by CHA2DS2-VASc score (odds ratio, 2.29; 95% confidence interval, 1.46-3.60; P<0.001) or major confounders, including age, atrial fibrillation, and antithrombotic therapy (odds ratio, 2.31; 95% confidence interval, 1.43-3.74; P<0.001). Subgroup analyses showed consistent findings in patients without atrial fibrillation (odds ratio, 2.46; 95% confidence interval, 1.39-4.54; P=0.002) and those without antithrombotic therapy (odds ratio, 2.79; 95% confidence interval, 1.53-5.57; P<0.001). Similar results were obtained for 30-day ischemic stroke as an alternative outcome. CONCLUSIONS: Elevated plasma D-dimer level on admission was significantly associated with increased incidence of ischemic stroke shortly after admission for AHF, suggesting a predictive role of D-dimer for short-term ischemic stroke events in patients with AHF. CLINICAL TRIAL REGISTRATION: URL: https://www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000017024.

Uptake of plant-derived specific alkaloids allows males of a butterfly to copulate.

Certain butterflies utilize plant-acquired alkaloids for their own chemical defense and/or for producing male sex pheromone; a trait known as pharmacophagy. Males of the danaine butterfly, Parantica sita, have been reported to ingest pyrrolizidine alkaloids (PAs) as adults to produce two PA-derived sex pheromone components, viz. danaidone (major) and 7R-hydroxydanaidal. We found, however, that not all PAs that can be precursors for the pheromone serve for mating success of males. Here we show that although the sex pheromone is regarded as a requisite for successful mating, uptake of specific PA(s) (lycopsamine-type PAs) is also imperative for the males to achieve copulation. The increase in the levels of two biogenic amines, octopamine and/or serotonin, in the brain and thoracic ganglia of males fed with specific PA(s) suggested that these alkaloids most likely enhance male mating activity. The results can present new evidence for the evolutionary provenance of pharmacophagous acquisition of PAs in PA-adapted insects.

Impact of iron deficiency on long-term clinical outcomes of hospitalized patients with heart failure.

BACKGROUND: Iron deficiency (ID) is commonly observed in chronic heart failure (HF) patients and is associated with worse clinical outcomes. While ID is frequent finding in hospitalized heart failure (HHF), its impact on long-term outcome in HHF patients remains unclear. METHODS: We evaluated iron status at discharge in 578 HHF patients. Absolute ID was defined as serum ferritin <100 µg/L, and functional ID (FID) was defined as serum ferritin of 100-299 µg/L with transferrin saturation <20%. The primary outcome of interest was the composite of all-cause mortality and HF admission at one year. RESULTS: Among the study population, 185 had absolute ID, 88 had FID and 305 had no evidence of ID. At one-year post-discharge, 64 patients had died and 112 had been readmitted with HF. Patients with absolute ID had more adverse events than those with FID or no ID (p = 0.021). In multivariate Cox regression analyses, absolute ID was significantly associated with increased risk of adverse events at one year (HR 1.50, 95% CI 1.02-2.21, p = 0.040) compared with the remaining patients. Sensitivity analysis revealed that its prognostic effect did not differ across anemic status, or between HF with reduced and preserved ejection fraction (p for interaction = 0.17, 0.68, respectively). CONCLUSION: Absolute ID, but not FID, at discharge was associated with increased risk of one-year mortality or HF admission in patients with HHF. Further studies are required to evaluate the role of repleting iron stores and its impact on clinical outcomes in patients with HHF.

Long-term prognostic significance of urinary sodium concentration in patients with acute heart failure.

BACKGROUND: Lower urinary sodium concentration (UNa) may reflect impaired renal perfusion, higher neurohormonal activity and diuretic resistance. However, the prognostic impact of UNa in patients with acute heart failure (AHF) has not been fully elucidated. METHODS: We investigate the association between UNa and clinical outcomes in 669 patients admitted with AHF in our prospective registry. Patients were stratified into tertiles based on UNa in a spot urine sample on admission. RESULTS: Patients with lower UNa were more likely to have a history of prior heart failure admission, ß-blockers and diuretics use, and had lower blood pressure and serum sodium level, and higher blood urea nitrogen, estimated glomerular filtration rate, blood glucose and troponin T levels on admission than those with higher UNa. Plasma renin activity, aldosterone, cortisol and dopamine levels were also significantly higher in patients with lower UNa (all p<0.001). Furthermore, patients with lower UNa had significantly less weight loss, lower net fluid loss/furosemide equivalent dose and higher incidence of worsening renal function during hospitalization than those with higher UNa (all p<0.01). During a median follow-up period of 560days, lower UNa was significantly associated with the composite of all-cause death and worsening heart failure (p<0.001). In multivariable Cox-proportional hazards model, UNa remained an independent determinant of long-term adverse events (HR, 1.24, 95% CI, 1.06-1.45, p=0.006). CONCLUSIONS: Lower UNa was associated with worse long-term clinical outcomes along with increased neurohormonal activities, impaired response to diuretics and higher incidence of worsening renal function in patients with AHF.