Immediate versus staged complete revascularisation in patients presenting with STEMI and multivessel disease.

BACKGROUND: Complete revascularisation is supported by recent trials in patients with ST-elevation myocardial infarction (STEMI) and multivessel disease (MVD) without cardiogenic shock. However, the optimal timing of non-culprit lesion revascularisation is currently debated. AIMS: This prespecified analysis of the BioVasc trial aims to determine the effect of immediate complete revascularisation (ICR) compared to staged complete revascularisation (SCR) on clinical outcomes in patients with STEMI. METHODS: Patients presenting with STEMI and MVD were randomly assigned to ICR or SCR. The primary endpoint was the composite of all-cause mortality, myocardial infarction, any unplanned ischaemia-driven revascularisation, or cerebrovascular events at 1-year post-index procedure. RESULTS: Between June 2018 and October 2021, 608 (ICR: 305, SCR: 303) STEMI patients were enrolled. No significant differences between ICR and SCR were observed at 1-year follow-up in terms of the primary endpoint (7.0% vs 8.3%, hazard ratio [HR] 0.84, 95% confidence interval [CI]: 0.47-1.50; p=0.55): all-cause mortality (2.3% vs 1.3%, HR 1.77, 95% CI: 0.52-6.04; p=0.36), myocardial infarction (1.7% vs 3.3%, HR 0.50, 95% CI: 0.17-1.47; p=0.21), unplanned ischaemia-driven revascularisation (4.1% vs 5.0%, HR 0.80, 95% CI: 0.38-1.71; p=0.57) and cerebrovascular events (1.4% vs 1.3%, HR 1.01, 95% CI: 0.25-4.03; p=0.99). At 30-day follow-up, a trend towards a reduction of the primary endpoint in the ICR group was observed (ICR: 3.0% vs SCR: 6.0%, HR 0.50, 95% CI: 0.22-1.11; p=0.09). ICR was associated with a reduction in overall hospital stay (ICR: median 3 [interquartile range {IQR} 2-5] days vs SCR: median 4 [IQR 3-6] days; p<0.001). CONCLUSIONS: Clinical outcomes at 1 year were similar for STEMI patients who had undergone ICR and those who had undergone SCR.

Serial cardiac biomarkers, pulmonary artery pressures and traditional parameters of fluid status in relation to prognosis in patients with chronic heart failure: Design and rationale of the BioMEMS study.

AIMS: Heart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms. METHODS: The BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death. CONCLUSION: Since the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively.

Trends in population attributable fraction of modifiable risk factors for cardiovascular diseases across three decades.

AIM: To evaluate temporal trends, across three decades, in the population attributable fractions (PAFs) of modifiable risk factors for 5-year risk of cardiovascular diseases (CVDs). METHODS: Within population-based Rotterdam Study, we defined three time-groups of individuals without established CVD at 'baseline' with a mean age of 70 years, and followed for five years: Epoch 1990s (1989-1993, N=6195), Epoch 2000s (1997-2001, N=5572) and Epoch 2010s (2009-2014, N=5135). The prevalence of risk factors and related relative risks were combined to quantify PAFs. RESULTS: The PAF of the six risk factors combined for global CVD was 0.57 (95% confidence interval [CI] 0.47 to 0.65), 0.52 (0.39 to 0.62) and 0.39 (0.18 to 0.54) in three respective epochs. Hypertension contributed the highest PAF to global CVD in Epoch 1990s (0.37, 95% CI: 0.28 to 0.44) and 2000s (0.34, 95% CI: 0.22 to 0.43), while smoking was the largest contributor in Epoch 2010s (0.20, 95% CI: 0.06 to 0.32). Dyslipidemia changed population-level coronary heart disease risk over time. For stroke, hypertension became a less significant contributor over time, but smoking became a larger contributor. For heart failure, all risk factors showed non-significant PAFs in Epoch 2010s. PAFs related to individual risk factor varied among women and men. CONCLUSION: Six modifiable risk factors to population-level global CVD risk decreased over time, but still explained 39% of total CVD in the latest decade. PAFs changed considerably for hypertension, dyslipidemia, and smoking. Risk factors had different PAFs for different CVDs with pronounced sex differences.

The contribution of the individual cardiovascular risk factors to population CVD risk considerably changed over the past 3 decades, especially for hypertension, dyslipidemia, and smoking. Traditional modifiable risk factors exerted declining contributions to population burden of total CVD over the past three decades, suggesting good progress in CVD prevention. Nonetheless, in the latest decade, unfavorable risk factors accounted for 39% of total CVD burden. Sex differences in the contributions of abdominal obesity, diabetes and smoking to cardiovascular outcomes were observed.

Identifying plasma proteomic signatures from health to heart failure, across the ejection fraction spectrum.

Circulating proteins may provide insights into the varying biological mechanisms involved in heart failure (HF) with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). We aimed to identify specific proteomic patterns for HF, by comparing proteomic profiles across the ejection fraction spectrum. We investigated 4210 circulating proteins in 739 patients with normal (Stage A/Healthy) or elevated (Stage B) filling pressures, HFpEF, or ischemic HFrEF (iHFrEF). We found 2122 differentially expressed proteins between iHFrEF-Stage A/Healthy, 1462 between iHFrEF-HFpEF and 52 between HFpEF-Stage A/Healthy. Of these 52 proteins, 50 were also found in iHFrEF vs. Stage A/Healthy, leaving SLITRK6 and NELL2 expressed in lower levels only in HFpEF. Moreover, 108 proteins, linked to regulation of cell fate commitment, differed only between iHFrEF-HFpEF. Proteomics across the HF spectrum reveals overlap in differentially expressed proteins compared to stage A/Healthy. Multiple proteins are unique for distinguishing iHFrEF from HFpEF, supporting the capacity of proteomics to discern between these conditions.

Timing of Complete Revascularization Stratified by Index Presentation During On- and Off-Hours.

Recent trials suggested immediate complete revascularization (ICR) as a safe alternative to staged complete revascularization (SCR), but the impact of the respective percutaneous coronary intervention strategies between on- versus off-hours is unclear. On-hours was defined as an index revascularization performed between 8:00 a.m. and 6:00 p.m., Monday to Friday, or else the procedure was defined as performed during off-hours. The primary end point consisted of a composite of all-cause mortality, myocardial infarction, unplanned ischemia-driven revascularization, and cerebrovascular events at 1-year follow-up. We used Cox regression models to relate randomized treatment with study end points. We evaluated multiplicative and additive interactions between on- versus off-hours and randomized treatment. The BIOVASC (Percutaneous Complete Revascularization Strategies Using Sirolimus Eluting Biodegradable Polymer Coated Stents in Patients Presenting With Acute Coronary Syndromes and Multivessel Disease) trial enrolled 1,097 and 428 patients during on- and off-hours, respectively. Patients randomized during off-hours were more likely to present with ST-segment elevation myocardial infarction (66.4% vs 29.5%, p <0.001). The composite primary outcome occurred in 8.4% and 10.1% of patients randomized to ICR and SCR, respectively, during on-hours (hazard ratio 0.80, 95% confidence interval 0.54 to 1.19). During off-hours, the primary composite outcome occurred in 5.4% and 7.7% in ICR and SCR (0.69, 95% confidence interval 0.32 to 1.46) with no evidence of a differential effect (interaction pmultiplicative = 0.70, padditive = 0.56). No differential effect was found between treatment allocation and on- versus off-hours in any of the secondary outcomes. In conclusion, no differential treatment effect was found when comparing ICR versus SCR in patients presenting with acute coronary syndrome and multivessel disease during on- or off-hours.

The perpetual need of randomized clinical trials: challenges and uncertainties in emulating the REDUCE-AMI trial.

Trial emulations in observational data analyses can complement findings from randomized clinical trials, inform future trial designs, or generate evidence when randomized studies are not feasible due to resource constraints and ethical or practical limitations. Importantly, trial emulation designs facilitate causal inference in observational data analyses by enhancing counterfactual thinking and comparisons of real-world observations (e.g. Mendelian Randomization) to hypothetical interventions. In order to enhance credibility, trial emulations would benefit from prospective registration, publication of statistical analysis plans, and subsequent prospective benchmarking to randomized clinical trials prior to their publication. Confounding by indication, however, is the key challenge to interpreting observed intended effects of an intervention as causal in observational data analyses. We discuss the target trial emulation of the REDUCE-AMI randomized clinical trial (ClinicalTrials.gov ID NCT03278509; beta-blocker use in patients with preserved left ventricular ejection fraction after myocardial infarction) to illustrate the challenges and uncertainties of studying intended effects of interventions without randomization to account for confounding. We furthermore directly compare the findings, statistical power, and clinical interpretation of the results of the REDUCE-AMI target trial emulation to those from the simultaneously published randomized clinical trial. The complexity and subtlety of confounding by indication when studying intended effects of interventions can generally only be addressed by randomization.

Quality-of-life and beliefs about medication in relation to a therapy adherence intervention in resistant hypertension: the Resistant HYpertension: MEasure to ReaCh Targets trial.

OBJECTIVE: To assess the impact of personalized feedback on therapy adherence testing results on quality of life and beliefs about medication in patients with resistant hypertension, as well as to identify patient-oriented predictors of therapy adherence. METHODS: This study was a prespecified post hoc analysis of the multicenter randomized controlled trial Resistant HYpertension: MEasure to ReaCh Targets (RHYME-RCT). Patients were randomized to a personalized feedback conversation on measured antihypertensive drug levels additional to standard-of-care, or standard-of-care only. The primary outcomes consisted of EuroQol EQ-5D-5L and Beliefs about Medicine Questionnaire (BMQ) scores at 12 months. RESULTS: A total of 56 patients with median age 61.5 [25th-75th percentile: 55.8-69.3] years (21.4% women) were included. Mean blood pressure ±SD was 149.8/84.1 ±â€Š14.9/13.8 mmHg while being on a median of 5.6 [4.8-7.3] defined daily dosages (DDD) of antihypertensive drugs. At 12 months, no differences were observed in EQ-5D-5L index (0.81 [0.69-0.89] vs. 0.89 [0.73-1.00]; P = 0.18) and visual analogue scale score on general patient-perceived health (70 [60-80] vs. 70 [60-82]; P = 0.53) between the intervention-arm and the standard-of-care only-arm. Likewise, individual EQ-5D-5L domain scores and BMQ scores did not differ between both arms. Irrespective of the intervention, independent positive predictors of the percentage adherence were patient age, EQ-5D-5L index score, BMQ-specific necessity score and concern score, whereas the total number of drugs prescribed was a negative predictor. CONCLUSION: Within this prespecified subanalysis of the randomized RHYME-RCT trial, implementation of a personalized feedback conversation targeting therapy adherence did not improve health-related quality-of-life and beliefs about medication in patients with resistant hypertension.

Immediate or staged complete revascularisation in patients presenting with acute coronary syndrome by number of diseased vessels: a substudy of the BIOVASC randomised trial.

BACKGROUND: In patients presenting with acute coronary syndrome (ACS), the number of diseased vessels may affect the efficacy of a complete revascularisation strategy. AIMS: The authors sought to evaluate the safety and efficacy of immediate complete revascularisation (ICR) and staged complete revascularisation (SCR) in patients presenting with ACS stratified by the number of diseased vessels. METHODS: In this prespecified analysis of the BIOVASC trial, ICR was compared with SCR in patients with two-vessel disease (2VD) or three-vessel disease (3VD). The primary endpoint was a composite of all-cause mortality, myocardial infarction (MI), any unplanned ischaemia-driven revascularisation or cerebrovascular events at 1 year after the index procedure. Comparisons were performed using Cox regression. RESULTS: A total of 1,525 patients were enrolled in the BIOVASC trial, of whom 1,177 presented with 2VD and 265 with 3VD. In the 2VD group, 613 patients were assigned to ICR and 564 to SCR. In the 3VD group, 117 patients were assigned to ICR and 148 to SCR. ICR and SCR led to similar results in both the 2VD (hazard ratio [HR] 0.76, 95% confidence interval [CI]: 0.50-1.13; p=0.18) and 3VD groups (HR 0.79, 95% CI: 0.39-1.59; p=0.51) (pinteraction=0.91) in terms of the primary endpoint. ICR was associated with a lower rate of MI in patients with 3VD (HR 0.21, 95% CI: 0.046-0.93; p=0.04) (pinteraction=0.30). CONCLUSIONS: ICR might be an option in patients presenting with extensive 3VD and might be associated with a lower rate of myocardial infarction compared with SCR.

Timing of Complete Multivessel Revascularization in Patients Presenting With Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: Complete revascularization of the culprit and all significant nonculprit lesions in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and multivessel disease (MVD) reduces major adverse cardiac events, but optimal timing of revascularization remains unclear. OBJECTIVES: This study aims to compare immediate complete revascularization (ICR) and staged complete revascularization (SCR) in patients presenting with NSTE-ACS and MVD. METHODS: This prespecified substudy of the BIOVASC (Percutaneous Complete Revascularization Strategies Using Sirolimus Eluting Biodegradable Polymer Coated Stents in Patients Presenting With Acute Coronary Syndrome and Multivessel Disease) trial included patients with NSTE-ACS and MVD. Risk differences of the primary composite outcome of all-cause mortality, myocardial infarction (MI), unplanned ischemia-driven revascularization (UIDR), or cerebrovascular events and its individual components were compared between ICR and SCR at 1 year. RESULTS: The BIOVASC trial enrolled 1,525 patients; 917 patients presented with NSTE-ACS, of whom 459 were allocated to ICR and 458 to SCR. Incidences of the primary composite outcome were similar in the 2 groups (7.9% vs 10.1%; risk difference 2.2%; 95% CI: -1.5 to 6.0; P = 0.15). ICR was associated with a significant reduction of MIs (2.0% vs 5.3%; risk difference 3.3%; 95% CI: 0.9 to 5.7; P = 0.006), which was maintained after exclusion of procedure-related MIs occurring during the index or staged procedure (2.0% vs 4.4%; risk difference 2.4%; 95% CI: 0.1 to 4.7; P = 0.032). UIDRs were also reduced in the ICR group (4.2% vs 7.8%; risk difference 3.5%; 95% CI: 0.4 to 6.6; P = 0.018). CONCLUSIONS: ICR is safe in patients with NSTE-ACS and MVD and was associated with a reduction in MIs and UIDRs at 1 year.

Temporal evolution of liver function parameters predicts clinical outcome in chronic heart failure patients (Bio-SHiFT study).

BACKGROUND: Liver dysfunction contributes to worse clinical outcomes in heart failure (HF) patients. However, studies exploring temporal evolutions of liver function parameters in chronic HF (CHF) pa- tients, and their associations with clinical outcome, are scarce. Detailed temporal patterns of alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGTP), total bilirubin (TBIL) and albumin (ALB) were investigated, and their relation with clinical outcome, in patients with stable CHF with reduced ejection fraction. METHODS: Tri-monthly plasma samples were collected from 250 patients during 2.2 (1.4-2.5) years of follow-up. ALP, GGTP, ALB, and TBIL were measured in 749 selected samples and the relationship between repeatedly measured biomarker levels and the primary endpoint (PEP; composite of cardiovas- cular death, heart transplantation, left ventricular assist device implantation, and hospitalization for worsened HF) was evaluated by joint models. RESULTS: Mean age was 66 ± 13 years; 74% were men, 25% in New York Heart Association class III-IV. 66 (26%) patients reached the PEP. Repeatedly measured levels of TBIL, ALP, GGTP, and ALB were associated with the PEP after adjustment for N-terminal prohormone B-type natriuretic peptide and high sensitivity troponin T (hazard ratio [95% confidence interval] per doubling of biomarker level: 1.98 [1.32; 2.95], p = 0.002; 1.84 [1.09; 3.05], p = 0.018, 1.33 [1.08; 1.63], p = 0.006 and 1.14 [1.09; 1.20], p < 0.001, respectively). Serial levels of ALP and GGTP, and slopes of the temporal evolutions of ALB and TBIL, adjusted for clinical variables, were also significantly associated with the PEP. CONCLUSIONS: Changes in serum levels of TBIL, ALP, GGTP, and ALB precede adverse cardiovascular events in patients with CHF. These routine liver function parameters may provide additional prognostic information in heart failure with reduced ejection fraction patients in clinical practice.

Sex Differences in Diagnosis, Treatment, and Cardiovascular Outcomes in Homozygous Familial Hypercholesterolemia.

Importance: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by extremely increased low-density lipoprotein (LDL) cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Heterozygous familial hypercholesterolemia (HeFH) is more common than HoFH, and women with HeFH are diagnosed later and undertreated compared to men; it is unknown whether these sex differences also apply to HoFH. Objective: To investigate sex differences in age at diagnosis, risk factors, lipid-lowering treatment, and ASCVD morbidity and mortality in patients with HoFH. Design, Setting, and Participants: Sex-specific analyses for this retrospective cohort study were performed using data from the HoFH International Clinical Collaborators (HICC) registry, the largest global dataset of patients with HoFH, spanning 88 institutions across 38 countries. Patients with HoFH who were alive during or after 2010 were eligible for inclusion. Data entry occurred between February 2016 and December 2020. Data were analyzed from June 2022 to June 2023. Main Outcomes and Measures: Comparison between women and men with HoFH regarding age at diagnosis, presence of risk factors, lipid-lowering treatment, prevalence, and onset and incidence of ASCVD morbidity (myocardial infarction [MI], aortic stenosis, and combined ASCVD outcomes) and mortality. Results: Data from 389 women and 362 men with HoFH from 38 countries were included. Women and men had similar age at diagnosis (median [IQR], 13 [6-26] years vs 11 [5-27] years, respectively), untreated LDL cholesterol levels (mean [SD], 579 [203] vs 596 [186] mg/dL, respectively), and cardiovascular risk factor prevalence, except smoking (38 of 266 women [14.3%] vs 59 of 217 men [27.2%], respectively). Prevalence of MI was lower in women (31 of 389 [8.0%]) than men (59 of 362 [16.3%]), but age at first MI was similar (mean [SD], 39 [13] years in women vs 38 [13] years in men). Treated LDL cholesterol levels and lipid-lowering therapy were similar in both sexes, in particular statins (248 of 276 women [89.9%] vs 235 of 258 men [91.1%]) and lipoprotein apheresis (115 of 317 women [36.3%] vs 118 of 304 men [38.8%]). Sixteen years after HoFH diagnosis, women had statistically significant lower cumulative incidence of MI (5.0% in women vs 13.7% in men; subdistribution hazard ratio [SHR], 0.37; 95% CI, 0.21-0.66) and nonsignificantly lower all-cause mortality (3.0% in women vs 4.1% in men; HR, 0.76; 95% CI, 0.40-1.45) and cardiovascular mortality (2.6% in women vs 4.1% in men; SHR, 0.87; 95% CI, 0.44-1.75). Conclusions and Relevance: In this cohort study of individuals with known HoFH, MI was higher in men compared with women yet age at diagnosis and at first ASCVD event were similar. These findings suggest that early diagnosis and treatment are important in attenuating the excessive cardiovascular risk in both sexes.

Automated cardiac arrest detection using a photoplethysmography wristband: algorithm development and validation in patients with induced circulatory arrest in the DETECT-1 study.

BACKGROUND: Unwitnessed out-of-hospital cardiac arrest is associated with low survival chances because of the delayed activation of the emergency medical system in most cases. Automated cardiac arrest detection and alarming using biosensor technology would offer a potential solution to provide early help. We developed and validated an algorithm for automated circulatory arrest detection using wrist-derived photoplethysmography from patients with induced circulatory arrests. METHODS: In this prospective multicentre study in three university medical centres in the Netherlands, adult patients (aged 18 years or older) in whom short-lasting circulatory arrest was induced as part of routine practice (transcatheter aortic valve implantation, defibrillation testing, or ventricular tachycardia induction) were eligible for inclusion. Exclusion criteria were a known bilateral significant subclavian artery stenosis or medical issues interfering with the wearing of the wristband. After providing informed consent, patients were equipped with a photoplethysmography wristband during the procedure. Invasive arterial blood pressure and electrocardiography were continuously monitored as the reference standard. Development of the photoplethysmography algorithm was based on three consecutive training cohorts. For each cohort, patients were consecutively enrolled. When a total of 50 patients with at least one event of circulatory arrest were enrolled, that cohort was closed. Validation was performed on the fourth set of included patients. The primary outcome was sensitivity for the detection of circulatory arrest. FINDINGS: Of 306 patients enrolled between March 14, 2022, and April 21, 2023, 291 patients were included in the data analysis. In the development phase (n=205), the first training set yielded a sensitivity for circulatory arrest detection of 100% (95% CI 94-100) and four false positive alarms; the second training set yielded a sensitivity of 100% (94-100), with six false positive alarms; and the third training set yielded a sensitivity of 100% (94-100), with two false positive alarms. In the validation phase (n=86), the sensitivity for circulatory arrest detection was 98% (92-100) and 11 false positive circulatory arrest alarms. The positive predictive value was 90% (95% CI 82-94). INTERPRETATION: The automated detection of induced circulatory arrests using wrist-derived photoplethysmography is feasible with good sensitivity and low false positives. These promising findings warrant further development of this wearable technology to enable automated cardiac arrest detection and alarming in a home setting. FUNDING: Dutch Heart Foundation (Hartstichting).

Acute Coronary Syndrome Subphenotypes Based on Repeated Biomarker Measurements in Relation to Long-Term Mortality Risk.

BACKGROUND: We aimed to identify patients with subphenotypes of postacute coronary syndrome (ACS) using repeated measurements of high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and growth differentiation factor 15 in the year after the index admission, and to investigate their association with long-term mortality risk. METHODS AND RESULTS: BIOMArCS (BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome) was an observational study of patients with ACS, who underwent high-frequency blood sampling for 1 year. Biomarkers were measured in a median of 16 repeated samples per individual. Cluster analysis was performed to identify biomarker-based subphenotypes in 723 patients without a repeat ACS in the first year. Patients with a repeat ACS (N=36) were considered a separate cluster. Differences in all-cause death were evaluated using accelerated failure time models (median follow-up, 9.1 years; 141 deaths). Three biomarker-based clusters were identified: cluster 1 showed low and stable biomarker concentrations, cluster 2 had elevated concentrations that subsequently decreased, and cluster 3 showed persistently elevated concentrations. The temporal biomarker patterns of patients in cluster 3 were similar to those with a repeat ACS during the first year. Clusters 1 and 2 had a similar and favorable long-term mortality risk. Cluster 3 had the highest mortality risk. The adjusted survival time ratio was 0.64 (95% CI, 0.44-0.93; P=0.018) compared with cluster 1, and 0.71 (95% CI, 0.39-1.32; P=0.281) compared with patients with a repeat ACS. CONCLUSIONS: Patients with subphenotypes of post-ACS with different all-cause mortality risks during long-term follow-up can be identified on the basis of repeatedly measured cardiovascular biomarkers. Patients with persistently elevated biomarkers have the worst outcomes, regardless of whether they experienced a repeat ACS in the first year.

Complete Revascularization Strategies in Women and Men With Acute Coronary Syndrome and Multivessel Disease.

This prespecified substudy of the randomized Percutaneous Complete Revascularization Strategies Using Sirolimus Eluting Biodegradable Polymer Coated Stents in Patients Presenting With Acute Coronary Syndromes and Multivessel Disease (BIOVASC) trial aimed to compare immediate complete revascularization (ICR) and staged complete revascularization (SCR) in patients with acute coronary syndrome and multivessel disease, stratified by gender. The primary end point consisted of a composite of all-cause mortality, myocardial infarction, unplanned ischemia-driven revascularization, and cerebrovascular events at 1-year follow-up. The secondary end points included the individual components of the primary composite and major bleedings. We used Cox regression models to relate randomized treatment with study end points. We evaluated the multiplicative and additive interactions between gender and randomized treatment. The BIOVASC trial enrolled 338 women and 1,187 men. Women were older than men (median age 71.6 vs 63.7 years, p <0.001) and had a higher prevalence of chronic obstructive pulmonary disease (10.1% vs 5.6%, p = 0.003), renal insufficiency (7.7% vs 4.4%, p = 0.015), and hypertension (60.4% vs 51.7%, p = 0.005). In women, the composite primary outcome occurred in 7.3% versus 12.9% (hazard ratio 0.53, 95% confidence interval 0.26 to 1.08) in patients randomly allocated to ICR and SCR, respectively, and in men in 7.7% versus 8.4% (hazard ratio 0.89, 95% confidence interval 0.60 to 1.34), with no evidence of a differential effect (interaction pmultiplicative = 0.20, padditive = 0.87). No evidence of heterogeneity between women and men was found when comparing ICR with SCR in terms of the secondary outcomes. In conclusion, no differential treatment effect was found when comparing ICR versus SCR in women or men presenting with acute coronary syndrome and multivessel disease.

Targeted proteomics and metabolomics for biomarker discovery in abdominal aortic aneurysm and post-EVAR sac volume.

BACKGROUND AND AIMS: Abdominal aortic aneurysm (AAA) patients undergo uniform surveillance programs both leading up to, and following surgery. Circulating biomarkers could play a pivotal role in individualizing surveillance. We applied a multi-omics approach to identify relevant biomarkers and gain pathophysiological insights. MATERIALS AND METHODS: In this cross-sectional study, 108 AAA patients and 200 post-endovascular aneurysm repair (post-EVAR) patients were separately investigated. We performed partial least squares regression and ingenuity pathway analysis on circulating concentrations of 96 proteins (92 Olink Cardiovascular-III panel, 4 ELISA-assays) and 199 metabolites (measured by LC-TQMS), and their associations with CT-based AAA/sac volume. RESULTS: The median (25th-75th percentile) maximal diameter was 50.0 mm (46.0, 53.0) in the AAA group, and 55.4 mm (45.0, 64.2) in the post-EVAR group. Correcting for clinical characteristics in AAA patients, the aneurysm volume Z-score differed 0.068 (95 %CI: (0.042, 0.093)), 0.066 (0.047, 0.085) and -0.051 (-0.064, -0.038) per Z-score valine, leucine and uPA, respectively. After correcting for clinical characteristics and orthogonalization in the post-EVAR group, the sac volume Z-score differed 0.049 (0.034, 0.063) per Z-score TIMP-4, -0.050 (-0.064, -0.037) per Z-score LDL-receptor, -0.051 (-0.062, -0.040) per Z-score 1-OG/2-OG and -0.056 (-0.066, -0.045) per Z-score 1-LG/2-LG. CONCLUSIONS: The branched-chain amino acids and uPA were related to AAA volume. For post-EVAR patients, LDL-receptor, monoacylglycerols and TIMP-4 are potential biomarkers for sac volume. Additionally, distinct markers for sac change were identified.

Long-term glucocorticoids in relation to the metabolic syndrome and cardiovascular disease: A systematic review and meta-analysis.

The striking link of Cushing's syndrome with the metabolic syndrome (MetS) and cardiovascular disease (CVD) suggests that long-term exposure to extremely high cortisol levels catalyzes cardiometabolic deterioration. However, it remained unclear whether the findings from the extreme glucocorticoid overabundance observed in Cushing's syndrome could be translated into more subtle variations in long-term glucocorticoid levels among the general population, for example, due to chronic stress. Here, we performed a systematic review (PROSPERO: CRD42023425541) of evidence regarding the role of subtle variations in long-term biological stress, measured as levels of scalp hair cortisol (HairF) and cortisone (HairE), in the context of MetS and CVD in adults. We also performed a meta-analysis on the cross-sectional difference in HairF levels between individuals with versus without CVD. Seven studies were included regarding MetS, sixteen regarding CVD, and one regarding both. Most articles indicated a strong, consistent cross-sectional association of higher HairF and HairE levels with CVD, which was confirmed by our meta-analysis for HairF (eight studies, SMD = 0.48, 95% confidence intervals [CIs]: 0.16-0.79, p = 0.0095). Moreover, these relationships appear largely independent of standard risk factors. Age seems relevant as the effect seems stronger in younger individuals. Results regarding the associations of HairF and HairE with MetS were inconsistent. Altogether, long-term biological stress, measured as HairF and HairE, is associated with the presence of CVD, and less consistently with MetS. Prospective studies need to evaluate the directionality of this relationship and determine whether HairF and HairE can be used in addition to standard risk factors in predicting future cardiometabolic deterioration.

Metabolic disorders mediate the relation of miscarriage with cardiovascular diseases.

AIMS: The extent to which the contribution of pregnancy loss to cardiovascular diseases (CVDs) can be explained by metabolic disorders is poorly elucidated but holds insights for reducing long-term cardiovascular risk. The aim of this study is to investigate the mediating effects of hypertension, diabetes mellitus (DM), and lipoprotein metabolism disorders on the association of miscarriage and stillbirth with coronary heart disease (CHD), stroke, heart failure, atrial fibrillation, and composite outcomes. METHODS AND RESULTS: A total of 163 283 ever-gravid women (age 55.3 ± 7.9 years) from the UK Biobank cohort without established metabolic disorders and CVDs were included and followed from 2007 to 2010 baseline until December 2020. Causal mediation analyses were used to estimate the proportion mediated. Hypertension mediated 11.1% (95% confidence interval, 3.7-18.5%) of the association between a history of miscarriage and incident CHD. Approximately, 9.5% (4.1-14.8%) of the effect of recurrent miscarriages on incident CHD was via hypertension, 8.4% (2.5-14.3%) of the effect was via lipoprotein metabolism disorders, 1.7% (0.5-2.9%) of the effect was via DM, and 10.7% (0.2-21.1%) of the effect of recurrent miscarriages on incident stroke was via hypertension. Hypertension mediated the largest proportion of effect for the atherosclerotic cardiovascular event (15.5% for a history of miscarriage and 9.4% for recurrent miscarriages), followed by lipoprotein metabolism disorders and DM. CONCLUSION: Hypertension, DM, and lipoprotein metabolism disorders mediated the association between miscarriage and various cardiovascular outcomes in later life. In particular, hypertension mediated a large proportion of the relationship between miscarriage and atherosclerotic CVD.

Hypertension, diabetes, and lipoprotein metabolism disorders mediated the association between miscarriage and various cardiovascular outcomes in later life. Hypertension mediated the largest proportion of effect for the atherosclerotic cardiovascular event (15.5% for a history of miscarriage and 9.4% for recurrent miscarriages). Women who have experienced miscarriage should be regularly monitored for possible required interventions on blood pressure, blood lipids, and glucose to reduce their long-term cardiovascular risk. Our findings contribute to ongoing research efforts to better understand the pathogenesis of pregnancy loss leading to CVD. In particular, we identified metabolic disorders processes as potential mediators. Implications: Our findings warrant early monitoring and intensive (preventive) treatment of hypertension and lipoprotein metabolism disorders among women who experience miscarriage(s) to lower their burden of later-life clinical cardiovascular events.

Heart rate: an accessible risk indicator in adult congenital heart disease.

BACKGROUND: Higher resting heart rate has been described as a risk factor for adverse outcome in healthy individuals and cardiovascular patients. The aim of this study was to evaluate resting heart rate as risk factor in adult congenital heart disease (ACHD). METHODS: In this prospective observational cohort study, patients with moderate or complex ACHD were included at routine outpatient visit. Standard 12-lead ECGs were obtained in rest. Heart rate was obtained from the ECG automatically by the Modular ECG Analysis System (MEANS). The primary endpoint was all-cause mortality and the secondary endpoint was a composite of all-cause mortality and heart failure. Survival was derived using the Kaplan-Meier estimator. Subgroups based on heart rate tertiles were compared by the log-rank test. Cox proportional hazards models were adjusted for clinical factors including age, sex and diagnosis (moderate vs complex ACHD). RESULTS: A total of 556 patients were included (median age 32 years (IQR 24-41), 57.6% male). Mean heart rate was 69±13 bpm. Negative chronotropic medication was used by 74 (13.3%) patients. During a median follow-up of 10.1 (IQR 9.6-10.5) years, 36 patients (6.5%) died and 83 (14.9%) reached the secondary endpoint. Patients with higher heart rates had significantly lower survival and heart failure-free survival. After adjusting for clinical factors, heart rate remained associated with mortality (HR 1.57 per 10 bpm, 95% CI 1.26 to 1.96) and mortality or heart failure (HR 1.33 per 10 bpm, 95% CI 1.13 to 1.57). CONCLUSION: Higher heart rate is associated with lower survival and heart failure-free survival in ACHD.

Sex-specific cardiovascular protein levels and their link with clinical outcome in heart failure.

AIMS: This study aims to provide insight into sex-specific cardiovascular protein profiles and their associations with adverse outcomes, which may contribute to a better understanding of heart failure (HF) pathophysiology and the optimal use of circulating proteins for prognostication in women and men. METHODS AND RESULTS: In 250 stable patients with HF with reduced ejection fraction (HFrEF), we performed trimonthly blood sampling (median follow-up: 26 [17-30] months). We selected all baseline samples and two samples closest to the primary endpoint (PEP; composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization) or one sample closest to censoring and applied the Olink Cardiovascular III panel. We used linear regression to study sex-based differences in baseline levels and joint models to study differences in the prognostic value of serially measured proteins. In 66 women and 184 men (mean age of 66 and 67 years, respectively), 21% and 28% reached the PEP, respectively. Mean baseline levels of fatty acid-binding protein 4, secretoglobin family 3A member 2, paraoxonase 3, and trefoil factor 3 were higher in women (Pinteraction : 0.001, 0.007, 0.018, and 0.049, respectively), while matrix metalloproteinase-3, interleukin 1 receptor-like 1, and myoglobin were higher in men (Pinteraction : <0.001, 0.001, and 0.049, respectively), independent of clinical characteristics. No significant differences between sexes were observed in the longitudinal associations of proteins with the PEP. Only peptidoglycan recognition protein 1 showed a suggestive interaction with sex for the primary outcome (Pinteraction  = 0.028), without multiple testing correction, and was more strongly associated with adverse outcome in women {hazard ratio [HR] 3.03 [95% confidence interval (CI), 1.42 to 6.68], P = 0.008} compared with men [HR 1.18 (95% CI, 0.84 to 1.66), P = 0.347]. CONCLUSIONS: Although multiple cardiovascular-related proteins show sex differences at baseline, temporal associations with the adverse outcome do not differ between women and men with HFrEF.

Cardiac rehabilitation for patients with obesity: lessons learned from the OPTICARE XL trial.

Obesity is a known and commonly encountered risk factor for the development of cardiac diseases. Patients with cardiac diseases who also have obesity do not benefit optimally from standard cardiac rehabilitation (CR) programs. Exercises performed during CR are not the best fit for patients with obesity and counselling sessions often do not address their specific needs. OPTICARE XL is the first large multicentre randomised controlled trial to investigate the added value of a dedicated one-year CR program specifically designed for patients with obesity and integrated in daily practice. The short-term effects on body weight and physical activity were promising and patients with obesity experienced the program as highly desirable. However, the OPTICARE XL CR program did not show long-term added value compared with standard CR on health-related quality of life, psychosocial well-being, body weight, physical activity and physical fitness, nor on costs. The current article offers an overview of the background of this trial and discusses the most important results of the OPTICARE XL trial and the reasons behind the unanticipated long-term outcomes. Furthermore, it offers recommendations for future research and how to redesign the OPTICARE XL CR program to expand the short-term results.