C-reactive Protein Tertile Research Articles

Primary inflammatory disease in heart failure with preserved ejection fraction

Abstract Background Inflammation plays a fundamental role in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFpEF). In most patients, inflammation develops secondary to cardiometabolic comorbidities, but in some, HFpEF develops in the setting of underlying systemic inflammatory diseases represented by rheumatoid arthritis. Purpose This study aimed to investigate the prevalence, pathophysiology, and outcome of patients with HFpEF and primary inflammatory diseases. Methods Consecutive patients undergoing hemodynamic exercise testing with concurrent expiratory gas analysis to evaluate dyspnea of unknown cause were identified. HFpEF was defined as left ventricular ejection fraction ≥50% and pulmonary capillary wedge pressure ≥15 mmHg (rest) or ≥25 mmHg (exercise). Patients with HFpEF were divided into groups with and without primary inflammatory diseases. Patients without inflammatory disease were divided into tertiles according to the value of C-reactive protein (CRP). Results Of 982 consecutively evaluated patients with HFpEF diagnosed (577 female, mean age 68 years), 79 (8%) had primary inflammatory disease. In multivariable logistic regression, female sex (OR 1.88; 95% CI 1.01-3.52), higher resting heart rate (OR 1.18; 95% CI 1.08-1.30), lower hemoglobin level (OR 0.84; 95% CI 0.70-0.99), absence of history of atrial fibrillation (OR 0.45; 95% CI 0.24-0.86) and absence of epicardial coronary artery disease (OR 0.45; 95% CI 0.22-0.93) were independently associated with inflammatory disease. Hemodynamics at rest and exercise did not differ between the groups, but peripheral oxygen extraction was lower in those with inflammatory disease, reflected by lower arterial-venous oxygen content difference (Ca-vO2) at rest (4.2±0.7 mL/dL vs 4.6±1.0 mL/dL, P<.001) and during exercise (9.3±2.2 mL/dL vs 10.4±2.2 mL/dL, P<.001) (Figure 1A), suggesting a greater peripheral deficit, and ventilatory efficiency (VE/VCO2 slope) was also more impaired (38.0±7.9 vs 36.2±7.3, P=.035). The HFpEF patients without inflammatory disease falling in the highest tertile of CRP) displayed lower Ca-vO2 during exercise, more closely resembling peripheral deficits observed in those with inflammatory disease (Figure 1B). During a median follow-up of 3.0 years, the composite outcome of all-cause deaths and HF hospitalization occurred in 127 patients (14%). Patients with HFpEF and inflammatory disease showed a higher incidence of composite outcome than those without (log-rank P=.030; Figure 2). Patients with inflammatory disease had higher risk of composite outcome compared to those without in adjusted analyses (HR 1.93; 95% CI 1.15-3.23), which was primarily attributable to higher risk of HF hospitalization (HR 2.85; 95% CI 1.08-7.52). Conclusion Patients with HFpEF and primary inflammatory disease have similar hemodynamic derangements but greater peripheral deficits in oxygen transport and higher risk for adverse outcome compared to those without.

Systemic inflammation and subsequent risk of amyotrophic lateral sclerosis: Prospective cohort study

BackgroundWhile systemic inflammation has been implicated in the etiology of selected neurodegenerative disorders, its role in the development of amyotrophic lateral sclerosis (ALS), a condition with high case-fatality, is untested. Accordingly, we quantified the relationship of C-reactive protein (CRP), an acute-phase reactant and marker of systemic inflammation, with subsequent ALS occurrence. MethodsWe used data from UK Biobank, a prospective cohort study of 502,649 participants who were aged 37 to 73 years when examined at research centers between 2006 and 2010. Venous blood was collected at baseline in the full cohort and assayed for CRP, and repeat measurement was made 3–7 years later in a representative subgroup (N = 14,514) enabling correction for regression dilution. ALS was ascertained via national hospitalization and mortality registries until 2021. We computed multivariable hazard ratios with accompanying 95% confidence intervals for log-transformed CRP expressed as standard deviation and tertiles. ResultsIn an analytical sample of 400,884 initially ALS-free individuals (218,203 women), a mean follow-up of 12 years gave rise to 231 hospitalizations and 223 deaths ascribed to ALS. After adjustment for covariates which included health behaviors, comorbidity, and socio-economic status, a one standard deviation higher log-CRP was associated with elevated rates of both ALS mortality (hazard ratios; 95% confidence intervals: 1.32; 1.13, 1.53) and hospitalizations (1.20; 1.00, 1.39). There was evidence of dose–response effects across tertiles of CRP for both outcomes (p for trend ≤ 0.05). Correction for regression dilution led to a strengthening of the relationship with CRP for both mortality (1.62; 1.27, 2.08) and hospitalizations (1.37; 1.05, 1.76). ConclusionsHigher levels of CRP, a blood-based biomarker widely captured in clinical practice, is associated with moderately increased future risk of amyotrophic lateral sclerosis.

Dual elevated remnant cholesterol and C-reactive protein in myocardial infarction, atherosclerotic cardiovascular disease, and mortality

Background and aimsElevated remnant cholesterol and low-grade inflammation each cause atherosclerotic cardiovascular disease (ASCVD); however, it is unknown whether joint elevation of both factors confers the highest risk. We tested the hypothesis that dual elevated remnant cholesterol and low-grade inflammation marked by elevated C-reactive protein is associated with the highest risk of myocardial infarction, ASCVD, and all-cause mortality. MethodsThe Copenhagen General Population Study randomly recruited white Danish individuals aged 20–100 years in 2003–2015 and followed them for a median 9.5 years. ASCVD was cardiovascular mortality, myocardial infarction, stroke, and coronary revascularization. ResultsIn 103,221 individuals, we observed 2,454 (2.4%) myocardial infarctions, 5,437 (5.3%) ASCVD events, and 10,521 (10.2%) deaths. The hazard ratios increased with each of stepwise higher remnant cholesterol and stepwise higher C-reactive protein. In individuals with the highest tertile of both remnant cholesterol and C-reactive protein compared to individuals with the lowest tertile of both, the multivariable adjusted hazard ratios were 2.2 (95%CI:1.9–2.7) for myocardial infarction, 1.9 (1.7–2.2) for ASCVD, and 1.4 (1.3–1.5) for all-cause mortality. Corresponding values for only the highest tertile of remnant cholesterol were 1.6 (1.5–1.8), 1.4 (1.3–1.5), and 1.1 (1.0–1.1), and those for only the highest tertile of C-reactive protein were 1.7 (1.5–1.8), 1.6 (1.5–1.7), and 1.3 (1.3–1.4), respectively. There was no statistical evidence for interaction between elevated remnant cholesterol and elevated C-reactive protein on risk of myocardial infarction (p = 0.10), ASCVD (p = 0.40), or all-cause mortality (p = 0.74). ConclusionsDual elevated remnant cholesterol and C-reactive protein confers the highest risk of myocardial infarction, ASCVD, and all-cause mortality, that is, compared to either of these two factors individually.

The relationship between diet, exercise, and inflammation in college students: A cross-sectional study.

Background: Important changes in lifestyle habits, especially diet, typically occur during the transitional period between high school and college and some of these changes may increase the risk of inflammation. Aim: The purpose of this study was to investigate the relationship between lifestyle factors and inflammation in college students. Methods: Students enrolled in a southeastern university participated in this cross-sectional study. Participants completed online questionnaires for assessment of demographics, supplement and dietary intake, sleep quality, and perceived stress. Body composition was measured during a clinic visit via air displacement plethysmography and blood and urine were collected for measurement of C-reactive protein (CRP) and cortisol, respectively. Analysis of variance was used to examine associations between tertiles of CRP levels and lifestyle variables and a linear regression model was fit to investigate whether there were any significant predictors of CRP levels. Results: Analysis included data for 83 participants for whom serum CRP levels and diet intake were available. Approximately 68% of the participants were female; mean age and body mass index (BMI) were 24 years and 23.4 kg/m2, respectively. Alcohol intake was significantly associated with increasing CRP levels (P = 0.017). No other dietary variables or lifestyle characteristics such as sleep quality, perceived stress, or BMI were associated with tertiles of CRP. The best model to predict CRP levels included urinary cortisol, aerobic exercise duration, alcohol, and vitamin E intake (adjusted R2=0.27). Conclusion: Alcohol and vitamin E intake were found to be associated with increased CRP levels.

C-reactive protein, but not neutrophil-lymphocyte ratio, is inversely associated with muscle strength only in older men: NHANES 1999–2002

To evaluate the association of inflammation (C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) levels) with muscle strength in older adults. We also aimed to evaluate whether these associations are sex-specific. A cross-sectional study was performed with data from the National Health and Nutrition Examination Survey (NHANES) 1999–2000 and 2001–2002. A total of 2387 individuals over 50 years of both sexes were evaluated, according to the eligibility criteria for the strength test. Muscle strength was measured by Kinetic Communicator isokinetic dynamometer; while the NLR was obtained by the ratio of the total neutrophil for lymphocyte count and CRP was quantified by latex nephelometry. Linear regression analyses, crude and adjusted for confounders, were used to estimate the coefficients and 95 % confidence intervals for peak strength (muscle strength) by tertiles of NLR and CRP. There was no association between NLR and peak strength for both sexes. CRP levels were inversely associated with peak force in men [2nd tertile β = −3.33 (−15.92; 9.25); 3rd tertile β = −24.69 (−41.18; −8.20), p for trend = 0.005], but not in women [2nd tertile β = −3.22 (−15.00; 8.56); 3rd tertile β = −9.23 (−28.40; −9.94), p for trend = 0.332]. In conclusion, NLR levels were not associated with muscle strength in both sexes. CRP levels were inversely associated with muscle strength in older men, but not in women, suggesting that the association between inflammation and muscle strength in older adults can be sex-specific.

C-reactive protein and statins in heart failure with reduced and preserved ejection fraction.

High C-reactive protein (CRP) levels are associated with poor outcomes of heart failure (HF), and statins are known to reduce CRP levels. We investigated the prognostic value of CRP and statin in patients with HF with reduced and preserved ejection fraction (EF). Altogether, 3,831 patients from the Korean Acute Heart Failure registry were included and stratified according to the tertiles of CRP levels (T1: CRP < 0.30 mg/dL, T2: 0.30-1.14 mg/dL, and T3: CRP > 1.14 mg/dL). HF with reduced EF (HFrEF), HF with mildly reduced EF (HFmrEF), and HF with preserved EF (HFpEF) were defined as left ventricular ejection fraction (LVEF) ≤ 40%, 41-49%, ≥50%, respectively. The primary endpoints were all-cause, in-hospital, and post-discharge mortality. No significant correlation was observed between CRP levels and LVEF (r = 0.02, P = 0.131). The prevalence of risk factors increased gradually from T1 to T3 in both the types of HF. Overall, 139 (3.6%) and 1,269 (34.4%) patients died during the index admission and follow-up (median: 995 days), respectively. After adjustment, each increase in the CRP tertiles was independently associated with in-hospital mortality (HFrEF: OR 1.58 and 95% CI 1.09-2.30, HFmrEF: OR 1.51 and 95% CI 0.72-3.52, and HFpEF: OR 2.98, 95% CI 1.46-6.73) and post-discharge mortality (HFrEF: HR 1.20, 95% CI 1.08-1.33, HFmrEF: HR 1.38 and 95% CI 1.12-1.70, and HFpEF: HR 1.37, 95% CI 1.02-1.85). In only patients with LVEF > 40% with highest CRP tertile, statin-users showed better survival trend than those without statins. CRP is an excellent prognostic marker for HFrEF, HFmrEF, and HFpEF, implying that the neurohumoral and inflammatory pathways might be independent pathways. Statins may be beneficial in HF patients with increased CRP levels. [https://clinicaltrials.gov/], identifier [NCT013 89843].

Is there an association between inflammatory markers and lower physical performance in older adults?

BackgroundMaintenance of physical performance is essential for achievement of healthy aging. A few studies have explored the association between inflammatory markers and physical performance in older adults with inconclusive results. Our aim was to analyze the association of tumor necrosis factor-alpha (TNF-α), Interleukin-10 (IL-10), and C-reactive protein (CRP) with physical performance in a sample of older adults in rural settings of Mexico.MethodsOur study comprised 307 community-dwelling older men and women who participated in the third wave of the Rural Frailty Study. We assessed the physical performance with the Short Physical Performance Battery (SPPB) and classified older adults as low performance if SPPB scored ≤8. Inflammatory markers were ascertained using serum by immunodetection methods. Logistic regression models were used to estimate the associations between inflammatory markers and physical performance.ResultsIn comparison with the normal physical performance group, low physical performance individuals mainly were female (P < 0.01), older (P < 0.01), more illiterate (P = 0.02), more hypertensive (P < 0.01), fewer smokers (P = 0.02), and had higher CRP levels (P < 0.01). The logistic model results showed a significant association between the 3rd tertile of CRP and low physical performance (OR = 2.23; P = 0.03). IL-10 and TNF-α levels did not show a significant association.ConclusionsThe results of this study were mixed, with a significant association of physical performance with higher CRP levels but nonsignificant with IL-10 and TNF-α. Further studies with improved designs are needed by incorporating a broader set of inflammatory markers.

Relationship Between C-Reactive Protein and Respiratory Diseases in Patients with Type 2 Diabetic Retinopathy.

BackgroundThe aim of this study was to explore the relationship between C-reactive protein (CRP) and respiratory diseases in patients with diabetic retinopathy.Material/MethodsWe identified 855 patients with diabetic retinopathy who met the inclusion criteria from the “Diabetes Complications Data Set” in the National Population Health Data Center. We divided patients into 3 groups according to CRP tertiles: Q1 (<0.3 mg/dL), Q2 (0.3–0.35 mg/dL), and Q3 (>0.35 mg/dL). A multivariate logistic regression model was used to evaluate the relationship between CRP and respiratory diseases. The area under the receiver operating characteristic (ROC) curve was used to investigate the independent predictive effect of CRP on respiratory diseases.ResultsOf the 855 patients with diabetic retinopathy, 137 (16%) had respiratory diseases. Prevalence of respiratory diseases gradually increased with an increase in CRP level (P for trend=0.001). With CRP as a continuous variable in the logistic regression model adjusted for confounding factors (model 3), the odds ratio (OR) per 1 standard deviation increment of CRP was 1.25 (95% CI 1.07–1.45, P=0.004). When the lowest CRP tertile group was used as the reference group, the OR of the highest CRP tertile group was 1.99 (95% CI 1.22–1.3.26, P=0.006). Adding CRP to the risk factor model increased the area under the ROC curve (0.68 vs 0.65, P=0.017). Subgroup analysis showed that the relationship between CRP and respiratory diseases had no potential heterogeneity among subgroups.ConclusionsCRP can be used as an effective biomarker in predicting risk of respiratory diseases in patients with diabetic retinopathy.

Inflammatory biomarkers and motoric cognitive risk syndrome: Multicohort survey.

Inflammation may play a role in Motoric Cognitive Risk (MCR) syndrome, a pre-dementia syndrome comprised of slow gait and cognitive complaints. Our objective was to examine associations of inflammatory biomarkers with MCR. We examined association of interleukin-6 (IL-6) and C-reactive protein (CRP) with prevalent MCR using logistic regression in 3,101 older adults (52% female) from five cohorts (National Center for Geriatrics & Gerontology Study of Geriatric Syndromes [NCGG-SGS], Central Control of Mobility in Aging [CCMA], Tasmanian Study of Cognition and Gait [TASCOG], LonGenity, and Einstein Aging Study [EAS]). Associations were reported as odds ratios adjusted for sex, age, education, depressive symptoms, body mass index, and vascular diseases (aOR) with 95% confidence intervals (CI). Meta-analysis and analyses stratified by vascular disease were also done. Although associations between higher (worse) CRP and IL-6 tertiles and MCR were only seen in three out of the five cohorts (EAS, TASCOG, and LonGenity), when a pooled meta-analysis was performed, a robust association was demonstrated. In meta-analysis, highest tertiles of IL-6 (aOR 1.57, 95%CI 1.01- 2.44) and CRP (aOR 1.65, 95%CI 1.09-2.48) was associated with MCR versus lowest tertiles in the pooled sample. Higher CRP was associated with MCR among those with vascular disease in TASCOG and LonGenity cohorts, and among those without vascular disease in EAS. IL-6 and CRP levels are associated with MCR in older adults, and this association varies by presence of vascular disease.

Relationship Between Inflammation and Metabolism in Patients With Newly Presenting Rheumatoid Arthritis.

BackgroundSystemic inflammation in rheumatoid arthritis (RA) is associated with metabolic changes. We used nuclear magnetic resonance (NMR) spectroscopy–based metabolomics to assess the relationship between an objective measure of systemic inflammation [C-reactive protein (CRP)] and both the serum and urinary metabolome in patients with newly presenting RA.MethodsSerum (n=126) and urine (n=83) samples were collected at initial presentation from disease modifying anti-rheumatic drug naïve RA patients for metabolomic profile assessment using 1-dimensional 1H-NMR spectroscopy. Metabolomics data were analysed using partial least square regression (PLS-R) and orthogonal projections to latent structure discriminant analysis (OPLS-DA) with cross validation.ResultsUsing PLS-R analysis, a relationship between the level of inflammation, as assessed by CRP, and the serum (p=0.001) and urinary (p<0.001) metabolome was detectable. Likewise, following categorisation of CRP into tertiles, patients in the lowest CRP tertile and the highest CRP tertile were statistically discriminated using OPLS-DA analysis of both serum (p=0.033) and urinary (p<0.001) metabolome. The most highly weighted metabolites for these models included glucose, amino acids, lactate, and citrate. These findings suggest increased glycolysis, perturbation in the citrate cycle, oxidative stress, protein catabolism and increased urea cycle activity are key characteristics of newly presenting RA patients with elevated CRP.ConclusionsThis study consolidates our understanding of a previously identified relationship between serum metabolite profile and inflammation and provides novel evidence that there is a relationship between urinary metabolite profile and inflammation as measured by CRP. Identification of these metabolic perturbations provides insights into the pathogenesis of RA and may help in the identification of therapeutic targets.

Favorable clinical response and drug retention of anti-IL-6 receptor inhibitor in rheumatoid arthritis with high CRP levels: the ANSWER cohort study

Objective Currently, biological disease-modifying anti-rheumatic drugs (bDMARDs) with different modes of action [tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL-6Ri), or cytotoxic T-lymphocyte antigen 4–immunoglobulin (CTLA4-Ig)] are used in clinical practice to treat rheumatoid arthritis (RA). However, it is unclear which type of bDMARD is the most efficacious for a specific clinical situation. C-reactive protein (CRP) is an acute-phase reactant driven by IL-6 signalling. Here, we aimed to establish whether therapeutic efficacy differs between IL-6Ri and other bDMARDs with alternative modes of action in RA patients according to their CRP level. Method RA patients treated with bDMARDs were enrolled from an observational multicentre registry in Japan. Patients were classified into three groups according to baseline CRP tertiles. The overall 3 year retention rates of each bDMARD category were assessed. The Clinical Disease Activity Index (CDAI) was also assessed before and 3, 6, and 12 months after bDMARD initiation. Results A total of 1438 RA patients were included and classified into three groups according to tertiles of baseline CRP levels (CRP1, 0–0.3; CRP2, 0.3–1.8; CRP3, 1.8–18.4 mg/dL). In CRP3, the overall 3 year drug retention rates were significantly higher for IL-6Ri than for TNFi and CTLA4-Ig (77.5 vs 48.2 vs 67.3, respectively). No significant difference was evident in terms of CDAI 12 months after bDMARD initiation in CRP1–CRP3. Conclusion IL-6Ri may be a favourable therapeutic option over TNFi and CTLA4-Ig in RA patients with high CRP levels.

Associations between inflammation, cardiovascular biomarkers and incident frailty: the British Regional Heart Study.

Introductioncardiovascular disease (CVD) and chronic inflammation are implicated in the development of frailty. Longitudinal analyses of inflammatory markers, biomarkers of cardiac dysfunction and incidence of frailty are limited.Methodsin the British Regional Heart Study, 1,225 robust or pre-frail men aged 71–92 years underwent a baseline examination, with questionnaire-based frailty assessment after 3 years. Frailty definitions were based on the Fried phenotype. Associations between incident frailty and biomarkers of cardiac dysfunction (high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro B-type natriuretic peptide (NT-proBNP)) and inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)) were examined, by tertile, with the lowest as reference.Resultsfollow-up data were available for 981 men. Ninety one became frail. Adjusted for age, pre-frailty, prevalent and incident CVD, comorbidity, polypharmacy and socioeconomic status, IL-6 (third tertile OR 2.36, 95% CI 1.07–5.17) and hs-cTnT (third tertile OR 2.24, 95% CI 1.03–4.90) were associated with increased odds of frailty. CRP (third tertile OR 1.83, 95% CI 0.97–4.08) and NT-proBNP (second tertile OR 0.48, 95% CI 0.23–1.01) showed no significant association with incident frailty. The top tertiles of CRP, IL-6, hscTnT and NT-proBNP were strongly associated with mortality prior to follow-up.ConclusionIL-6 is associated with incident frailty, supporting the prevailing argument that inflammation is involved in the pathogenesis of frailty. Cardiomyocyte injury may be associated with frailty risk. Associations between elevated CRP and frailty cannot be fully discounted; NT-proBNP may have a non-linear relationship with incident frailty. CRP, IL-6, hs-cTnT and NT-proBNP are vulnerable to survivorship bias.

Residual systemic inflammatory burden is a major determinant of myocardial recovery and late cardiovascular outcome in Takotsubo patients

Recent insights have emphasized the importance of myocardial and systemic inflammation in Takotsubo syndrome (TTS). In a large registry of unselected patients, we sought to evaluate whether residual high inflammatory response (RHIR) could impact cardiovascular outcome after TTS. Patients with TTS were retrospectively included between 2008 and 2018 in three general hospitals. 385 patients with TTS were split into three subgroups, according to tertiles of C-reactive protein (CRP) levels at discharge (CRP < 5.2 mg/l, CRP range 5.2 to 19 mg/l, and CRP > 19 mg/l). The primary endpoint was the impact of RHIR, defined as CRP > 19 mg/l at discharge, on cardiac death or hospitalization for heart failure. Follow-up was obtained in 382 patients (99%) after a median of 747 days. RHIR patients were more likely to have a history of cancer or a physical trigger. Left ventricular ejection fraction (LVEF) at admission and at discharge was comparable between groups. By contrast, RHIR was associated with lower LVEF at follow-up (61.7 vs. 60.7 vs. 57.9%; P = 0.004) and increased cardiac late mortality (0% vs. 0% vs. 10%; P = 0.001). By multivariate Cox regression analysis, RHIR was an independent predictor of cardiac death or hospitalization for heart failure (hazard ratio: 1.97; 95% confidence interval: 1.11 to 3.49; P = 0.02). RHIR was associated with impaired LVEF recovery and was evidenced as an independent factor of cardiovascular events. All together these findings underline RHIR patients as a high-risk subgroup, to target in future clinical trials with specific therapies to attenuate RHIR.

Impact of residual inflammation on myocardial recovery and cardiovascular outcome in Takotsubo patients.

AimsRecent insights have emphasized the importance of myocardial and systemic inflammation in Takotsubo syndrome (TTS). In a large registry of unselected patients, we sought to evaluate whether residual high inflammatory response (RHIR) could impact cardiovascular outcome after TTS.Methods and resultsPatients with TTS were retrospectively included between 2008 and 2018 in three general hospitals. Three hundred eighty‐five patients with TTS were split into three subgroups, according to tertiles of C‐reactive protein (CRP) levels at discharge (CRP <5.2 mg/L, CRP range 5.2 to 19 mg/L, and CRP >19 mg/L). The primary endpoint was the impact of RHIR, defined as CRP >19 mg/L at discharge, on cardiac death or hospitalization for heart failure.Follow up was obtained in 382 patients (99%) after a median of 747 days. RHIR patients were more likely to have a history of cancer or a physical trigger. Left ventricular ejection fraction (LVEF) at admission and at discharge were comparable between groups. By contrast, RHIR was associated with lower LVEF at follow up (61.7% vs. 60.7% vs. 57.9%; P = 0.004) and increased cardiac late mortality (0% vs. 0% vs. 10%; P = 0.001). By multivariate Cox regression analysis, RHIR was an independent predictor of cardiac death or hospitalization for heart failure (hazard ratio: 1.87; 95% confidence interval: 1.08 to 3.25; P = 0.025).ConclusionsResidual high inflammatory response was associated with impaired LVEF at follow up and was evidenced as an independent factor of cardiovascular events. All together, these findings underline RHIR patients as a high‐risk subgroup, to target in future clinical trials with specific therapies to attenuate RHIR.

Residual inflammation is a major determinant of myocardial recovery and cardiovascular outcome in takotsubo patients

Abstract Background Recent insights have emphasized the importance of myocardial and systemic inflammation in Takotsubo Syndrome (TTS). Objective In a large registry of unselected patients, we sought to evaluate whether residual high inflammatory response (RHIR) could impact cardiovascular outcome after TTS. Methods Patients with TTS were retrospectively included between 2008 and 2018 in three general hospitals. 385 patients with TTS were split into three subgroups, according to tertiles of C-reactive protein (CRP) levels at discharge (CRP&amp;lt;5.2 mg/l, CRP range 5.2 to 19 mg/l, and CRP&amp;gt;19 mg/L). The primary endpoint was the impact of RHIR, defined as CRP&amp;gt;19 mg/L at discharge, on cardiac death or hospitalization for heart failure. Results Follow-up was obtained in 382 patients (99%) after a median of 747 days. RHIR patients were more likely to have a history of cancer or a physical trigger. Left ventricular ejection fraction (LVEF) at admission and at discharge were comparable between groups. By contrast, RHIR was associated with lower LVEF at follow-up (61.7 vs. 60.7 vs. 57.9%; p=0.004) and increased cardiac late mortality (0% vs. 0% vs. 10%; p=0.001). By multivariate Cox regression analysis, RHIR was an independent predictor of cardiac death or hospitalization for heart failure (hazard ratio: 1.97; 95% confidence interval: 1.11 to 3.49; p=0.02). Conclusions RHIR was associated with impaired LVEF recovery and was evidenced as an independent factor of cardiovascular events. All together these findings underline RHIR patients as a high-risk subgroup, to target in future clinical trials with specific therapies to attenuate RHIR. Main results Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): GERCA (Groupe pour l'Enseignement, la prévention et la Recherche Cardiovasculaire en Alsace)

Von Willebrand factor, its cleaving protease (ADAMTS13), and inflammation in young adults: The African-PREDICT study

BackgroundThe role of inflammation in the early development of vascular dysfunction remains complex. Interleukin-6 (IL-6) and C-reactive protein (CRP) can cause an acute imbalance in the von Willebrand factor (vWF)-ADAMTS13 interaction, indicating a possible link between markers of haemostasis and low-grade inflammation. To better understand these inter-relationships in the early phases of disease development, we investigated whether vWF and ADAMTS13 associate with the pro-inflammatory markers, IL-6 and CRP in healthy young adults. We considered the role of blood types, sex and race on these relationships. MethodsIn healthy black and white men and women (n = 1113; 24 ± 5 years; no previous diagnosis or medication use for chronic diseases) we analysed von Willebrand factor antigen (vWFag), ADAMTS13, IL-6 and CRP, and grouped blood types as non-O (A, B and AB) and O. Covariates included socioeconomic status, age, estimated glomerular filtration rate, 24-hour systolic blood pressure, waist circumference, glucose, total cholesterol, platelet count, γ-glutamyl transferase and total energy expenditure. ResultsIn the total group, vWFag was highest in the third tertile of both IL-6 and CRP (p ≤ 0.014), while ADAMTS13 was lowest in the third compared to the first IL-6 tertile (p = 0.006). In multivariate regression, vWFag associated positively with IL-6 (Adj R2 = 0.169; β = 0.123; p = 0.001) and CRP (Adj R2 = 0.163; β=0.094; p = 0.019) in the total group, in the O blood group (all p ≤ 0.051) and white men (all p ≤ 0.035). ADAMTS13 associated negatively with IL-6 (Adj R2 = 0.053; β = −0.154; p = 0.015) and CRP (Adj R2 = 0.055; β = −0.177; p = 0.009), only in the O blood group. ConclusionsMarkers of haemostasis associated independently with low-grade inflammation in the O type blood group and white men. An interplay between the haemostatic and inflammatory systems may already exist in young healthy adults and is dependent on blood groups, sex and race. This extends our understanding on the role of inflammation in the early development of vascular dysfunction prior to cardiovascular compromise.

Higher Levels of High-Sensitivity C-Reactive Protein Is Positively Associated with the Incidence of Hyperuricemia in Chinese Population: A Report from the China Health and Retirement Longitudinal Study.

Purpose The aim of the present cohort study was to explore the longitudinal association between high-sensitivity C-reactive protein (CRP) and hyperuricemia in Chinese population. Furthermore, we conducted subgroup analyses to explore this association according to age, sex, and body mass index. Methods A total of 5,419 healthy participants were enrolled in the final cohort analysis. The high-sensitivity CRP level was measured by immunoturbidimetric assay. Hyperuricemia was defined as serum uric acid ≥7.0 mg/dL (416 μmol/L) in men and ≥6.0 mg/dL (357 μmol/L) in women. Multivariate logistic regression was used to analyze the association. Results During the 4 years follow-up, 474 participants developed hyperuricemia. Compared with participants in the lowest tertile of high-sensitivity CRP, the multivariate-adjusted odds ratio (OR) (95% confidence interval [CI]) for incident hyperuricemia in the highest tertile was 1.36 (1.02, 1.82). In the subgroup analyses, high-sensitivity CRP was positively associated with the incidence of hyperuricemia after multivariate adjustments (P for trend = 0.04) in women. Compared with the women in the lowest tertile of high-sensitivity CRP, the multivariate-adjusted OR (95% CI) in the highest tertile was 1.69 (1.10, 2.66). No statistically significant association was found in other subgroups. Conclusions The findings of this prospective cohort study suggest that higher level of high-sensitivity CRP is an independent risk factor for hyperuricemia in Chinese, especially in women.

Poor Oral Health and Inflammatory, Hemostatic, and Cardiac Biomarkers in Older Age: Results From Two Studies in the UK and USA.

We examined the association of objective and subjective oral health markers with inflammatory, hemostatic, and cardiac biomarkers in older age. Cross-sectional analyses were based on the British Regional Heart Study (BRHS) comprising British men aged 71-92 years (n = 2,147), and the Health, Aging and Body Composition (HABC) Study comprising American men and women aged 71-80 years (n = 3,075). Oral health markers included periodontal disease, tooth count, dry mouth. Inflammatory biomarkers included C-reactive protein (CRP), interleukin-6 (IL-6) in both studies, and tissue plasminogen activator (t-PA), von Willebrand Factor (vWF), fibrin D-dimer, high-sensitivity Troponin T (hsTnT), and N-terminal pro-brain natriuretic peptide (NTproBNP) only in the BRHS. In both studies, tooth loss, was associated with the top tertile of CRP-odds ratios (ORs) (95% confidence interval [CI]) are 1.31 (1.02-1.68) in BRHS; and 1.40 (1.13-1.75) in the HABC Study, after adjusting for confounders. In the HABC Study, cumulative (≥3) oral health problems were associated with higher levels of CRP (OR [95% CI] =1.42 [1.01-1.99]). In the BRHS, complete and partial tooth loss was associated with hemostatic factors, in particular with the top tertile of fibrin D-dimer (OR [95% CI] = 1.64 [1.16-2.30] and 1.37 [1.05-1.77], respectively). Tooth loss and periodontal disease were associated with increased levels of hsTnT. Poor oral health in older age, particularly tooth loss, was consistently associated with some inflammatory, hemostatic, and cardiac biomarkers. Prospective studies and intervention trials could help understand better if poor oral health is causally linked to inflammatory, hemostatic, and cardiac biomarkers.

C-reactive protein in midlife is associated with depressive symptoms two decades later among men with coronary heart disease

Aim: We investigated the relationship between midlife C-reactive protein (CRP) levels in men with coronary heart disease (CHD) and depressive symptoms at old age. CRP levels were measured in a subset of patients with CHD, who previously participated in a secondary prevention trial.Methods: Depressive symptoms were evaluated in survivors of the original cohort 15.0 ± 3 and 19.9 ± 1 years later (T1, n = 463 and T2, n = 314 respectively) using the Geriatric Depression Scale (GDS), 15-item version. Logistic regression was used to estimate ORs and 95%CIs for presence of potentially clinically significant depressive symptoms (GDS ≥5) at T1 and T2.Results: Adjusting for demographic and health-related variables, the OR (95%CI) for GDS ≥5 was 1.23 (0.65–2.33); p = .53 at T1 and 2.36 (1.16–4.83); p = .018 at T2 in the top CRP tertile compared to the others. Similarly, consistently high CRP levels in the top tertile at baseline and 2 years later, were associated with OR of 2.85 (95%CI 1.29–6.30); p = .01 for GDS ≥5 at T2.Conclusions: Presence and persistence of low-grade inflammation in men with CHD during midlife are associated with increased risk of depressive symptoms twenty years later. Among middle aged men with CHD, low-grade inflammation may provide an important added value for prediction of depression in old age.

2153The relation between systemic inflammation and incident cancer in patients with stable cardiovascular disease; a cohort study

Abstract Background Chronic systemic low-grade inflammation, measured by elevated plasma concentrations of high sensitive C-reactive Protein (CRP), is a risk factor for cardiovascular disease (CVD). There is evidence that systemic low-grade inflammation is also related to a higher risk of cancer. Purpose In the present prospective cohort study the relation between systemic low-grade inflammation and risk of cancer was evaluated in patients with clinically manifest vascular disease. Methods In total 7178 patients from the SMART cohort with manifest cardiovascular disease and plasma CRP levels ≤10 mg/L were included. Data of the cohort were linked to the Dutch national cancer registry. Cox regression models were fitted to study the relation between CRP and incident cardiovascular disease as well as incident cancer. Cancer types were classified according to anatomical location of origin, as well as histopathological subtype, irrespective of their anatomical location of origin. To adjust for potential confounding, age, sex, smoking status, packyears of smoking, and body mass index were added to the models, and additional cardiovascular risk factors, including diabetes mellitus, and systolic blood pressure. Results After a median follow-up time of 8.3 years (interquartile range 4.6–12.3) 1289 recurrent cardiovascular events (myocardial infarction, stroke, or vascular mortality) and 1072 incident cancer diagnoses were observed. CRP level was related to recurrent cardiovascular disease risk (HR 1.57; 95% CI 1.35–1.82) (Figure 1A), as well as risk of CVD and/or cancer (HR 1.45; 95% CI 1.29–1.62) (Figure 1B) comparing the third tertile of CRP to the first tertile. CRP concentration was related to total cancer risk (HR 1.33; 95% CI 1.13–1.55 for the third tertile of CRP compared to the first tertile) (Figure 1C). Especially incident lung cancer, independent of histopathological subtype, was related to CRP level (HR 2.64; 95% CI 1.77–3.93 for the third tertile of CRP compared to the first) (Figure 1D). No effect modification by smoking status or years of smoking cessation was observed of the relation between CRP and lung cancer (p-values for interaction &gt;0.05). Incidence of epithelial neoplasms and especially squamous cell neoplasms were related to CRP concentration, irrespective of their anatomical location of origin (HR 1.17; 95% CI 1.08–1.27, and HR 1.11; 95% CI 1.02–1.20 for 1 mg/L higher CRP level respectively). Sensitivity analyses accounting for reverse causality by excluding patients with a cancer diagnosis within 1 and within 2 years of follow up showed similar results. Kaplan Meier curves per CRP tertile Conclusion Chronic systemic low-grade inflammation, measured by plasma CRP levels ≤10mg/L, is a risk factor for incident cancer, markedly lung cancer, independent of smoking status, in patients with stable cardiovascular disease.