Background and aims : Coronary heart disease (CHD) occurs even in individuals classified as “low-risk” by traditional cardiovascular risk factors (CVRFs). We aimed to investigate whether the combinations of high-sensitivity C-reactive protein (hsCRP), lipoprotein (a) (Lp(a)), or triglycerides (TGs) would modulate relative and absolute CHD risk within a low-risk population. Methods : A total of 63,740 individuals free of CHD at baseline were included. Participants were stratified according to CVRF burden at baseline: 0/1 vs. ≥2 CVRFs. Biomarkers were analyzed dichotomously: hsCRP (<vs.≥2 mg/L), Lp(a) (<vs.≥ 90th percentile), TGs (<vs.≥1.69 mmol/L/150 mg/dL). Fine and Gray regression models were applied to examine the associations between biomarker combinations and incident CHD. Results: During a median follow-up of 9.91 years, 3,417 participants developed a CHD event (0/1 CVRF n=984; ≥2 CVRFs: n=2,433). In the overall population, individuals with elevated levels of all three biomarkers demonstrated a multivariable-adjusted sub-distribution hazard ratio (sHR) of 2.58 (95% CI, 2.10-3.17) for incident CHD, compared with those with no elevated biomarkers. The highest risk was observed in the low-risk subgroup with elevated levels of all three biomarkers, showing a sHR of 3.19 (95 % CI, 1.96-5.20) compared to the reference group. In contrast, among individuals with ≥2 CVRFs, the association between combined biomarker elevation and CHD was attenuated (sHR 2.20 (95% CI, 1.76-2.76)) (pinteraction between groups 0.023). Conclusions : A single-time-point assessment of three elevated biomarkers along the lipid-inflammatory axis (hsCRP, Lp(a) and TG) might help to identify increased CHD risk, especially among individuals classified as low-risk by traditional risk factors.

INTRODUCTION:The majority of clinical studies investigating patients with heart failure and a reduced ejection fraction (HFrEF) exclusively included patients with symptomatic heart failure. There is a paucity of information concerning the clinical characteristics, progression to symptomatic heart failure, heart failure hospitalization rates and survival in patients with asymptomatic systolic left ventricular dysfunction (ASLVD). We address this knowledge gap by describing the baseline characteristics of participants in the prospective observational TransitionCHF study of patients with reduced left ventricular Function in New York Heart Association (NYHA) functional Class I and comparing them to those of other recent trials in HFrEF. METHODS:In total, 1005 individuals with ASLVD NYHA I with an ejection fraction ≤ 40% were recruited. Patient characteristics were compared with other studies involving patients with symptomatic heart failure. Multivariable linear regression and Pearson coefficients were used to determine the association between quality of life, mental health, markers of organ function, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) plasma levels, and exercise performance. RESULTS:The mean age of participants was 60 ± 14 years and 18% were women. The mean ejection fraction was 36% and the mean left ventricular end-diastolic diameter was 59 mm. When compared with studies involving patients with symptomatic heart failure, the age was ≈ 5 years younger and the frequency of comorbidities was lower. The Short Form Health Survey-36 physical functioning score was moderately correlated with the Maastricht Vital Exhaustion Questionnaire (MQ; r = -0.44 and weakly with 6-min walking distance (r = 0.32), peak VO2 at ergospirometry (r = 0.28), and Heart Focus Anxiety (HAF17; r = -0.34). NT-proBNP levels showed a weak association with peak VO2 (r = -0.29) and the 6-min walk distance (r = -0.21). CONCLUSIONS:Patients included in the TransitionCHF study are younger and suffer from fewer comorbidities as compared with symptomatic heart failure patients. Associations between NT-proBNP levels and markers of exercise performance were weak.

BACKGROUND:Familial hypercholesterolemia (FH) is among the more common monogenic diseases, yet population-based data on genetically confirmed FH (genFH) and its association with LDL cholesterol (LDL-C) in Germany are lacking. METHODS:In the Hamburg City Health Study (registration: Clinical Trials.gov, NCT03934957), five FH-associated genes were exam - ined for pathogenic mutations with whole genome sequencing and compared with LDL-C levels that had been corrected for lipidlowering medication. Severe hypercholesterolemia was defined as an LDL-C level of 190 mg/dL or above. RESULTS:There were 7373 adult participants (49.1% women; median age 62 years), of whom 23 had FH, corresponding to a prevalence of 0.31% (95% confidence interval [CI]: [0.21; 0.47]), or a prevalence ratio of 1:321 [1:213; 1:476]. All genFH cases were due to mutations in the LDLR gene. The median treatment-adjusted LDL-C level was higher in genFH cases (191 mg/dL) than in persons without genFH (128 mg/dL; p <0.001). Eleven of the participants with genFH had severe hypercholesterolemia. Among the 7253 participants without genFH, 465 had severe hypercholesterolemia. Only 2.3% (n = 11) of the severely hypercholesterolemic participants had genFH. Forty-three people would need to be genetically tested to identify one genFH case if an LDL-C threshold of ≥190 mg/dL is selected, 98 people at ≥160 mg/dL, and 175 people at ≥130 mg/dL. CONCLUSION:The prevalence of genFH in this German study was 0.31%, which corresponds to the global average. As only half of the persons from our adult cohort identified as having genFH had severe hypercholesterolemia, population-based genetic screening would seem to be of questionable benefit.

Die aktuelle Leitlinie der ESC (European Society of Cardiology) zum chronischen Koronarsyndrom (CCS) bringt einige Neuerungen in der medikamentösen Therapie von CCS-Patienten. Diese betreffen die antithrombotischen, lipidsenkenden, metabolischen, antihypertensiven sowie antiinflammatorischen Grundpfeiler der Therapie. Neben neuen Empfehlungen für eine individuelle antithrombotische Therapie wird erstmalig die Bedeutung einer antiinflammatorischen Medikation bei bestimmten CCS-Patienten zur Reduktion des residuellen Risikos berücksichtigt. Es werden zudem neue Konzepte der antimetabolischen Therapie zur Verbesserung des kardiovaskulären Outcomes vorgestellt. Die Optimierung der medikamentösen Therapieoptionen zur Behandlung der Risikofaktoren in Kombination mit einer modernen Thrombozytenaggregationshemmung würde zu wirksamen und personalisierten Präventionsstrategien für CCS-Patienten führen.

BACKGROUND:Targeting inflammation offers a unique possibility to address residual cardiovascular risk in almost two thirds of all patients with prevalent atherosclerotic cardiovascular disease (ASCVD). However, despite FDA approval and the ESC 2024 Guidelines for the Management of Chronic Coronary Syndrome recommendations to implement low-dose colchicine (0.5 mg daily) in the secondary prevention of ASCVD patients with residual inflammatory risk, its clinical adoption is still limited. In this regard, a simple screening for elevated high-sensitive C-reactive protein (hsCRP) on a routine basis might help to recognize low-grade inflammation as an important therapeutic target. RESULTS:Within the present review, we first provide recently published epidemiologic evidence that hsCRP is at least as strong a predictor of future ASCVD events as traditional lipoproteins. Furthermore, we summarize our recent knowledge on currently available strategies to modulate an inflammatory process in ASCVD and critically discuss still open issues regarding the benefit of colchicine therapy in the acute coronary setting or for stroke prevention. In addition, we also briefly touch upon some specific issues of safety related to the long-term use of colchicine. Finally, we discuss the next diagnostic and therapeutic frontiers in targeting residual inflammatory risk, such as detection of vascular/coronary inflammation by pericoronary fat attenuation or the use of ziltivekimab, a human monoclonal antibody targeting interleukin-6. CONCLUSION:Thus, the integration of interventions aimed at lowering the inflammatory burden in combination with aggressive lipid-modifying therapy in secondary prevention may hold the potential to further reduce the still substantial burden of ASCVD.

The crucial role of inflammation in the pathogenesis and clinical outcomes of cardiovascular disease (CVD) has recently gained increased attention. In particular, residual inflammation, measured with high-sensitivity C-reactive protein (hsCRP) remains strongly predictive of recurrent events, even in statin-treated patients. Similarly, elevated hsCRP in apparently healthy individuals identifies a higher-risk group in whom statin therapy significantly reduces the risk of first major CVD events even if LDL-cholesterol is normal. This report provides an updated understanding of the role of chronic, low-grade inflammation in CVD and highlights new seminal research findings, especially in atherosclerosis, myocardial infarction, heart failure, and pericarditis. Consensus recommendations are summarized for screening, evaluation, and CVD risk assessment; inflammatory biomarkers in cardiovascular imaging; inflammation inhibition in behavioral and lifestyle risks; and anti-inflammatory approaches in primary and secondary prevention as well as in heart failure and other CVDs. This report also addresses current challenges and future opportunities. For example, it cautions that not all trials of anti-inflammatory therapy in secondary prevention have been successful and such trial evidence is needed before broad recommendations for other agents can be made. Additionally, in successful trials, the interplay between inflammation and key physiological systems often remains incompletely examined. Another promising area of research is the role that novel special pro-resolving bioactive lipid molecules play in promoting the resolution of inflammation and CVD risk reduction. In aggregate, the evidence linking inflammation with atherosclerotic CVD is no longer exploratory but is compelling and clinically actionable. The time for taking action has now arrived.

AIMS:We aimed to investigate the association between the burden of modifiable lifestyle risk factors (modLRF) with high-sensitivity cardiac troponins T and I (hsTnT/I) and clinical outcomes in a contemporary cohort. METHODS AND RESULTS:Patients undergoing coronary angiography with available hsTnT/I concentrations and information about modLRF were included in the current single-centre study. The modLRF investigated were overweight, lack of physical activity, poor adherence to a Mediterranean diet, and current smoking. To evaluate the impact of modLRF on hsTnT/I levels, a linear regression model was used. A Cox regression analysis was computed to investigate the association of hsTnT/I levels with clinical outcomes, stratified by the burden of modLRF, and a C-index was calculated to investigate the additive predictive benefit of the integration of hsTn on top of a base model containing modLRF only. Outcomes of interest were all-cause mortality and major adverse cardiovascular events (MACE). In the overall study population of n = 1716 patients, the median troponin levels were 15.0 ng/L (Interquartile [IQR] 8.0, 29.0) and 7.6 ng/L (IQR 3.3, 18.6) for hsTnT and I, respectively. An increasing number of modLRF were independently associated with elevated hsTnT and I concentrations. Moreover, hsTnT and hsTnI were independently associated with all-cause mortality in patients with 1-2 and ≥3 modLRF, and an incremental value of the integration of hsTnT and hsTnI was noted, especially in the prediction of all-cause mortality. Lastly, an independent association of hsTnI with MACE was documented in patients with 1-2 modLRF, which was not the case for hsTnT. CONCLUSION:Increasing numbers of modLRF are associated with elevated concentrations of hsTnT and I, whilst the predictive capability of troponins varied according to the presence of modLRF. Further prospective studies are needed to investigate whether targeting modLRF might result in lower hsTn concentrations and improved outcomes. LAY SUMMARY:This study investigated whether certain lifestyle risk factors, such as being overweight, lack of exercise, current smoking, and a poor diet, affect the levels of specific heart damage markers in the blood (high-sensitivity troponins T and I) as well as clinical outcomes.Patients with a number burden of unhealthy lifestyle factors had higher levels of both heart damage markers in their blood.How well troponin blood levels could predict health outcomes varied significantly based on a number of lifestyle risk factors.

BACKGROUND AND AIMS:The major predictors of future coronary heart disease (CHD) events in individuals without traditional modifiable cardiovascular risk factors (CVRFs) remain unknown. We investigated the association between circulating biomarkers, reflecting residual risk, with incident CHD in a general population, according to the presence of five CVRFs (hypertension, diabetes mellitus, hypercholesterolemia, smoking and obesity) at baseline. METHODS:Overall 212,598 CHD-free individuals from 21 European population-based cohorts were stratified by CVRF burden into three groups, having zero (n = 35,707), one (n = 68,548) or ≥2 (n = 108,343) risk factors at baseline. Five biomarkers (triglycerides (TGs), high-sensitivity C-reactive protein (hsCRP), cystatin C, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I) were assessed in a subset with available measurements. RESULTS:During a median follow-up of 13.97 years, 17,499 participants developed incident CHD with 453 events occurring among individuals without CVRFs. Although increased concentrations of all biomarkers were related to incident CHD, significant risk modulation by CVRFs was seen only for TGs and, to a lesser extent, for hsCRP. The fully-adjusted sub-distribution Hazard Ratios (95 % CI) were for TGs (≥vs < 1.70 mmol/L) 1.66 (1.29-2.15) in those without CVRFs versus 1.35 (1.21-1.49)/1.14 (1.07-1.20) in those with 1 or ≥2 risk factors (pinteraction<0.01) and for hsCRP (≥vs < 2 mg/L) 1.39 (1.02-1.90) versus 1.42 (1.26-1.61) or 1.22 (1.13-1.32), respectively (pinteraction = 0.092). CONCLUSION:Even in the absence of CVRFs, elevated triglycerides and hsCRP were significantly associated with an increased risk of CHD. These results highlight the importance of residual risk assessment using those biomarkers in individuals deemed metabolically healthy by conventional standards.

Familial hypercholesterolemia (FH) is a monogenic disease characterized by pathogenic mutations in genes involved in low-density lipoprotein cholesterol (LDL-C) metabolism. Optimal strategies for identifying FH in the general population are still unknown. To assess the prevalence of genetic FH (genFH) in a contemporary population-based sample of adult Hamburg residents and to evaluate its association with hypercholesterolemia phenotype. In 7,373 participants of the population-based a City Health Study (HCHS) the FH genes LDLR, APOB, PCSK9, LDLRAP1, and APOE were analyzed to identify genFH, based on short-read whole-genome sequencing. LDL-C concentrations were adjusted for intake and intensity of lipid-lowering medication and categorized using the following thresholds: ≥130/≥160/≥190 mg/dL. Severe hypercholesterolemia was defined by LDL-C ≥190 mg/dL. Among 7,373 adults, median age was 62.0 (quartiles 54.0-69.0) years, and 49.1% of these were women. Twenty-three individuals had heterozygous genFH (prevalence 0.31%; 95%CI: 0.21% to 0.47% [corresponding to 1:321]), all caused by mutations in the LDLR gene. Median treatment-corrected LDL-C was higher in subjects with genFH (191 mg/dL, quartiles 149-210 mg/dL) compared to 128 mg/dL (quartiles 105-153 mg/dL) in those without genFH. Severe hypercholesterolemia was observed in 476 of 7,275 (6.5%) subjects with available LDL-C values. Of those, only 2.3% (n=11) were positive for genFH. Moreover, 9.1% of carriers of FH-causing variants had LDL-C values below 130 mg/dL, 32.8% below 160 mg/dL and only 50% of subjects with genFH had severe hypercholesterolemia (Table). Applying a phenotypic LDL-C threshold of ≥190 mg/dL, ≥160 mg/dL and ≥130 mg/dL to screen for genFH would results in numbers needed to screen of 43, 99 or 174, respectively. The prevalence of genetically verified FH in this contemporary German population-based cohort was very similar to the worldwide prevalence of FH (0.31% versus 0.32%, respectively). Only half of the adult individuals with genFH had severe hypercholesterolemia, and only (2.3%) of individuals with LDL-C ≥190 mg/dL had genFH. More robust evidence of genotype-phenotype associations of FH mutations is needed to accurately infer at-risk individuals from genetic screening. Two first and two last auhors contributed equally to this work.

The current ESC guideline on chronic coronary syndrome (CCS) introduces several novel therapeutic concepts in the secondary prevention of CCS patients. These include new recommendations for individualised antithrombotic therapy to be considered in specific clinical scenarios. In addition, interventions aimed at reducing the inflammatory burden in all CCS patients are introduced for the first time. Finally, new treatment options for overweight and obese CCS patients are also presented. Optimisation of drug therapy to treat risk factors in combination with modern antiplatelet management would lead to effective and personalised prevention strategies for patients with CCS.

BACKGROUND:Residual congestion at hospital discharge after an episode of acute decompensated heart failure (ADHF) is associated with poor prognosis. There is no consensus on how optimal decongestion should be assessed. OBJECTIVES:This study aims to determine whether decongestive therapy guided by ultrasound measurements of inferior vena cava (IVC) diameters leads to greater reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels from baseline to hospital discharge as compared with decongestion treatment guided by clinical assessment alone. METHODS:In a randomized controlled multicenter trial, patients admitted for ADHF (NYHA functional class ≥III) exhibiting signs of pulmonary congestion, peripheral edema, and NT-proBNP levels >300 ng/L were randomized to either decongestion therapy guided by daily IVC ultrasound plus clinical assessment or clinical assessment alone. The primary endpoint was the change in NT-proBNP levels from baseline to discharge. RESULTS:A total of 388 patients were randomized, of which 327 were included in the primary intention-to-treat analysis. The between-group difference in primary endpoint of change in NT-proBNP levels was 5.4% (95% CI: -9.4% to 22.6%; P = 0.58). Safety events were numerically less frequent in the IVC ultrasound-guided group. No difference between groups was consistently observed in secondary endpoints with similar rates of hemoconcentration and intensity of diuretic treatment. CONCLUSIONS:Additional ultrasound evaluation of IVC diameters did not improve decongestion treatment compared with clinical assessment alone among patients admitted for ADHF. (Ultrasound Evaluation of the IVC in Addition to Clinical Assessment to Guide Decongestion in ADHF [CAVA-ADHF-DZHK10]; NCT03140566).

Background and aims Patients with atherosclerotic vascular disease (ASVD) affecting two or more different vascular beds, so called Polyvascular disease (PolyVD), are at an increased risk for adverse outcomes. In those patients, the prognostic utility of high-sensitivity troponin T and I (hsTnT/I) is under-investigated. We therefore aimed to explore the association between hsTnT/I with the extent of ASVD and outcomes in a contemporary cohort. Methods Patients undergoing coronary angiography with available hsTnT/I concentrations from the cohort study INTERCATH were included. Subgroups of patients without ASVD, monovascular disease (MVD), and PolyVD were created. Cox regression analyses were computed to investigate the associations of hsTnT/I with the extent of ASVD and clinical outcomes (all-cause mortality and major adverse cardiovascular events; MACE). Results In 2273 included patients, a stepwise increase of both hsTnT and hsTnI was observed according to the extent of ASVD. However, this association was statistically not significant after adjustment. hsTnT and hsTnI were independently associated with all-cause mortality for PolyVD (adjusted hazard ratio per standard deviation for hsTnT: 1.42 [95 %-CI: 1.16, 1.73]; p < 0.001 and hsTnI: 1.38 [1.14, 1.68]; p = 0.0013) and MVD (hsTnT: 1.32 [1.15, 1.51]; p < 0.001 and hsTnI: 1.35 [1.17, 1.56]; p < 0.001), whereas no association of hsTn with MACE was seen across the burden of ASVD. Conclusions Patients with a greater extent of ASVD had higher concentrations of hsTnT/I and an increased incidence of all-cause mortality as well as MACE. hsTnT/I concentrations were reliably linked to all-cause mortality in patients with ASVD, underscoring the role of biomarkers in risk prediction.