bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic and lifestyle risks for coronary artery disease and risk of incident dementia
Authors: Sittichokkananon A , Garfield V , Chiesa S T
Published: October 2024

Background

Lifestyle risk factors for coronary artery disease (CAD) have been associated with neurodegeneration and dementia. Whether an underlying genetic risk for the development of CAD further increases this risk, however, remains unclear.

Purpose

To examine whether an increased genetic risk for CAD is associated with an increased risk of dementia, and to investigate whether lifestyle factors modify these associations.

Methods

A prospective cohort study of 457,353 participants of European ancestry without dementia at baseline (mean [SD], age 57 [8] years; 55% were female) was conducted within the UK Biobank study. Exposures were a genome-wide polygenic risk score (PRS) for CAD and a modified version of the American Heart Association’s Life’s Essential 8 (LE8) cardiovascular health score comprising four biological (BMI, BP, lipids, glucose) and four lifestyle (smoking status, diet, physical activity, and sleep duration) risk factors previously linked to both CAD and dementia. Dementia diagnoses were obtained from death register and inpatient records.

Results

9,337 cases of all-cause dementia were observed over a median 13.9-year follow-up. There were no significant interactions between genetic risk for CAD and lifestyle factors for all-cause dementia, or any other dementia subtype. After adjusting for potential demographic confounders, a higher genetic risk for CAD was associated with elevated risk of developing all-cause dementia (hazard ratio (HR) per 1-SD increase in PRS = 1.08 [95% CI, 1.05-1.10]), Alzheimer’s disease (HR 1.08 [1.03-1.12]), and vascular dementia (HR 1.13 [1.06-1.19]). An unfavourable LE8 cardiovascular health score was also associated with an increased risk of developing all-cause dementia (HR 1.05 [1.02-1.08]), predominantly through its association with vascular dementia (HR 1.14 [1.06-1.22]), as we found no evidence for any associations between LE8 and Alzheimer’s disease (HR 1.00 [0.97-1.02]).

Conclusion

These findings indicate that a high genetic risk for CAD is associated with an increased risk of developing major dementia subtypes. Regardless of this underlying genetic risk, however, our results suggest that lifestyle interventions designed to reduce the risk of CAD may also reduce one’s risk of developing dementia, particularly in those with underlying vascular pathology.
Coronary artery calcium scans powered by artificial intelligence (AI-CAC) predicts atrial fibrillation and stroke comparably to cardiac magnetic resonance imaging: MESA
Authors: Naghavi M , Reeves A P , Atlas K , Zhang C , Li D , Atlas T , Henschke C , Wong N D , Roy S K , Budoff M J , Yankelevitz D
Published: October 2024

Background

AI-CAC provides more actionable information than the Agatston coronary artery calcium (CAC) score. We have recently shown in the Multi-Ethnic Study of Atherosclerosis (MESA) that AI-CAC automated left atrial (LA) volumetry enabled prediction of atrial fibrillation (AF) as early as one year. In this study we evaluated the performance of AI-CAC LA volumetry versus LA measured by human experts using cardiac magnetic resonance imaging (CMRI) for predicting AF and stroke, and compared them with CHARGE-AF risk score, Agatston score, and NT-proBNP.

Methods

We used 15-year outcomes data from 3552 asymptomatic individuals (52.2% women, age 61.7±10.2 years) who underwent both CAC scans and CMRI in the MESA baseline examination. CMRI LA volume was previously measured by human experts. Data on BNP, CHARGE-AF risk score and the Agatston score were obtained from MESA. Discrimination was assessed using the time-dependent area under the curve (AUC).

Results

Over 15 years follow-up, 562 cases of AF and 140 cases of stroke accrued. The AUC for AI-CAC versus CMRI for AF and stroke were not significantly different (0.802 vs. 0.798 and 0.762 vs. 0.751 respectively, p=0.60). AI-CAC significantly improved the continuous Net Reclassification Index (NRI) for prediction of AF and stroke when added to CHARGE-AF risk score (0.28, 0.21), NT-proBNP (0.43, 0.37), and Agatston score (0.69, 0.41) respectively (p for all<0.0001).

Conclusion

AI-CAC automated LA volumetry and CMRI LA volume measured by human experts similarly predicted incident AF and stroke over 15 years. Further studies to investigate the clinical utility of AI-CAC for AF and stroke prediction are warranted.
Deciphering lipoprotein(a) atherogenicity with use of high-throughput proteomics
Authors: Morze J , Marston N A , Melloni G E M , Da Silva G R , Rynkiewicz A , Wittenbecher C
Published: October 2024

Background

Accumulating observational and genetic evidence suggests that lipoprotein(a) [Lp(a)], is significantly more atherogenic than other apolipoprotein-B containing particles. Systemic inflammation is thought to mediate the atherogenic effects of Lp(a). Previous studies have predominantly focused on single inflammatory biomarkers, an approach that fails to capture the broader molecular response to elevated Lp(a) levels.

Purpose

The aim of this study was to derive a proteome-wide signature of plasma Lp(a) concentrations and subsequently identify the pathways through which Lp(a) influences the risk of coronary artery disease (CAD).

Methods

This study included 41,123 UK Biobank participants with baseline Lp(a) measurements who also underwent a proteomic assessment. Relative concentration of 2,920 proteins was quantified in EDTA plasma samples using a high-throughput proximity extension assay. Lp(a)-associated proteins were identified in linear regression models, adjusting for age, sex, body mass index, race, smoking status, estimated glomerular filtration rate, medication use, and apolipoprotein B. Proteins linked with Lp(a) concentration were then evaluated for their association with incident CAD risk using Cox proportional hazards models. Significant traits were further included in pathway enrichment analysis.

Results

Out of 2,920 analyzed proteins (Figure 1), 140 showed a positive association with Lp(a) concentration, while 336 exhibited a negative association after adjustment for multiple testing (False discovery rate < 0.05). The strongest positive associations were observed for apolipoprotein F, group 10 secretory phospholipase A, and C4b-binding protein beta chain. The strongest negative associations were observed for asporin, aminoacylase-1, and retinol-binding protein 5. Among 140 proteins positively associated with Lp(a), 49 were associated with an increased risk of CAD. Conversely, among the 336 proteins negatively associated with Lp(a), 10 were associated with a decreased risk of CAD. Pathway enrichment analysis (Figure 2) indicated that proteins linked with both Lp(a) levels and CAD risk predominantly upregulated pathways related to peptide-ligand receptor signalling, platelet degranulation, neutrophil degranulation, and cytosolic calcium response. Conversely, pathways related to HDL remodeling, PI3K/AKT, KIT, and nuclear receptor signalling were downregulated.

Conclusions

The greater atherogenic potential of Lp(a) may be attributable to the modulation of several molecular pathways, particularly those involving platelet and neutrophil responses, cell signalling, and lipoprotein metabolism.
Sex differences in secondary prevention and outcomes post-myocardial infarction in Scotland
Authors: Pana T , Mamas M A , Myint P K , Dawson D
Published: October 2024

Background

Sex differences in outcomes after myocardial infarction (MI) are of increasing interest. Differential receipt of evidence-based treatments may contribute to such disparities.

Purpose

In this study, we investigate sex differences in the burden of risk factors, in-hospital and long-term treatment and outcomes in contemporary practice in Scotland, by analysing a nationwide sample of consecutive MI admissions.

Methods

All MI admissions centrally recorded between 2010-2016 by Public Health Scotland were included and followed up until the end of 2021. Poisson regressions analysed in-hospital outcomes (percutaneous coronary intervention (PCI), mortality and post-discharge secondary prevention medication). Models were adjusted for age, co-morbidities and ST-elevation on the electrocardiogram. Royston-Parmar models analysed long-term outcomes (all-cause and cardiovascular mortality, major adverse cardiovascular events (MACE)) and were sequentially adjusted for confounders (age, comorbidities, secondary prevention medications). A 2:1 age and sex-matched general population were included as controls.

Results

Of a total 47,063 MI patients, 15,776 (33.5%) were women. They were matched with 81,641 controls free of major cardiovascular disease. Median (interquartile range) age was 64 (56-72) years for men and 69 (60-75) years for women. Obesity, hypertension and renal disease were the risk factors more prevalent amongst women, while men had higher rates of previous MI, peripheral vascular disease and atrial fibrillation. Compared to men, women were less likely to undergo PCI (risk ratio (95% confidence interval) – 0.87 (0.86-0.89)) or receive secondary prevention (0.94 (0.93-0.95)), but had similar in-hospital mortality (1.06 (0.99-1.13)), after multi-variable adjustment. Over a median follow-up of 8.4 (6.8-10.2) years, women had higher raw rates of adverse outcomes. However, after full confounder adjustment, this translated into lower risk for women of all cause-mortality 0.92 (0.89-0.95), cardiovascular mortality 0.82 (0.78-0.87) and MACE 0.92 (0.88-0.95) (Figure 1). The female survival advantage was attenuated post-MI in comparison to controls free of significant cardiovascular disease (Figure 2).

Conclusions

Women and men have different MI risk factor profiles. Women had overall worse crude outcome rates after MI, driven by age and comorbidities. This may have been driven further by undertreatment after MI, including PCI and secondary prevention. Urgent identification of drivers for such disparities in care is warranted in order to improve outcomes and ensure health equity.
Beyond secondary prevention drugs: added benefit in survival and events of a healthy lifestyle in patients after an acute coronary syndrome
Authors: Canovas Rodriguez E C , Kallmeyer A K , Tarin N T , Cristobal C C , Huelmos A H , Pello A P , Acena A A , Gutierrez Landaluce C G , Gonzalez Lorenzo O G , Lumpuy Castillo J L , Alonso J A , Lopez Bescos L L , Lorenzo O L , Blanco Colio L B C , Tunon J T
Published: October 2024

Background

Despite advances in drug treatment and secondary prevention programs, cardiovascular disease remains the leading cause of death. The full extent and independent benefit of a healthy lifestyle, particularly after optimal medical therapy in secondary prevention, has not been widely reported.

Purpose

To quantify the added benefit on survival and events of a healthy lifestyle following an acute coronary syndrome (ACS). Our study seeks to answer the question: Is adherence to medical therapy sufficient or a healthy lifestyle provides additional improvement?.

Methods

This a prospective observational multi-center study of 685 patients included during admission for ACS. At 6 months patients were asked about their post-ACS lifestyle and were given a score (range: 0-7) with the following items: Intake of ≥3 fruits and vegetables/day, ≥2 fish servings/week, ≤7 alcohol beverages/week, feeling stress RESULTS: After adjusting for demographic variables, cardiovascular risk factors, characteristics of the index event, high-sensitivity C-reactive protein (hs-CRP), and drug therapy, multivariate Cox regression showed that the lifestyle SCORE was independently and inversely associated with both the incidence of the primary outcome (ischemic events [any ACS, stroke, or Transient Ischemic Attack] or death) (HR 0.65 (CI95% 0.44-0.96); p=0.029) and death (HR 0.41 [95%CI 0.18-0.91]; p=0.029). Statin therapy was also independently and inversely associated with both the incidence of the primary outcome. Kaplan-Meier curves showed a higher event-free survival for both outcomes in patients with SCORE≥4 than in those with SCORE<4 (p=0.03 and p<0.001, respectively). Additionally, patients with a SCORE≥4 had a significantly greater decrease of total cholesterol (-52 [-16.5, -79] vs -38 [-7.5, -68] mg/dl; p=0.040) and hs-CRP (-1.1 [-0.1, 2.5] vs -0.5 [0.7, -1.9] mg/L; p=0.001) at six months.

Conclusions

Among patients with ACS and similar medical therapy, a healthy lifestyle is an independent and added marker of a lower incidence of ischemic events and death. It is also associated with a better lipid profile and lower inflammation.
National dispensing of evidence-based treatment for New Zealand patients before and after peripheral arterial or percutaneous coronary procedures; undertreatment in plain sight
Authors: Wells S , Zhao J , Choi Y , Poppe K , Jackson R , Kerr A
Published: October 2024

Background/Introduction

Cardiovascular management guidelines recommend that those undergoing arterial procedures for atherosclerotic disease should be on a long-term antithrombotic agent, statin and blood pressure (BP) lowering (triple therapy) to prevent or delay future ischaemic events or death. Internationally, treatment gaps have been reported for people having peripheral arterial disease (PAD) procedures.

Purpose

We aimed to investigate national rates of triple therapy dispensing before and after admission for a percutaneous coronary intervention (PCI) compared to a PAD procedure.

Methods

All people aged 18-84 years admitted for a publicly-funded PCI or PAD procedure in New Zealand between 1 January 2015 and 30 June 2020 were identified. Data were linked to national community dispensing records for antithrombotic agents, statins and BP lowering and the adjusted relative risk (adjRR) of dispensing individual medication classes and triple therapy investigated 6 months prior-procedure and 0-6 months and 7-12 months post-procedure. Analyses were controlled for age, sex, prioritised ethnicity, socioeconomic deprivation index, diabetes and prior cardiovascular disease.

Results

During the study period, 26,383 people were admitted for a PCI procedure and 10,938 people for PAD. Compared to PCI, those with PAD were more likely to be women, older (median age 69 vs 66 years), of Māori or Pacific ethnicity, living in more deprived communities, more likely to have diabetes (33% vs 24%) and a prior admission for cardiovascular disease (63% vs 52%). Triple therapy in the 6 months prior to procedure was 48% for PAD compared to 37% for PCI (adjRR 1.04; 1.03-1.05); however, in the 6 months post-discharge, improved for PCI more than PAD (PAD 58% vs PCI 91%, [adjRR 0.82; 0.81-0,83]) with decreased dispensing in both cohorts by 7-12 months post procedure (PAD 55% vs PCI 83%, [adjRR 0.84; 0.83-0,84]).

Conclusions

Patients undergoing atherosclerotic arterial procedures are at high risk of future fatal and nonfatal cardiovascular events. Less than half the patients who were admitted for a PCI or PAD procedure had been dispensed triple therapy in the 6 months prior to admission. Post procedure, 91% of PCI patients were on triple therapy but this substantial increase did not occur for PAD patients. The risk management gap for those who have peripheral arterial compared to coronary procedures indicates clear clinical and system-related deficiencies and a national quality improvement approach is required to address these issues.

Figure 1. Adjusted relative risk of being dispensed preventive medications for patients who had a PAD procedure, compared to patients who had a PCI procedure [after adjusting for age, sex, ethnicity, NZDep, history of CHD (including prior PCI and CABG), stroke/TIA, haemorrhagic stroke, heart failure, PVD, and diabetes]
Impact of the severe familial hypercholesterolemia status on atherosclerotic risks
Authors: Tada H , Kojima N , Takeji Y , Nohara A , Kawashiri M , Takamura M
Published: October 2024

Backgrounds

Risks of atherosclerotic events substantially vary even among patients with familial hypercholesterolemia (FH) with extremely high risk based on life-long exposure to high low-density lipoprotein cholesterol levels.

Purpose

This study aimed to examine the impact of the severe FH status defined by the International Atherosclerosis Society (IAS).

Methods

Data of patients with FH (N = 1,050, male = 490) who were admitted to our university hospital between 2000 and 2020 and who were followed up were retrospectively reviewed. The number of major adverse cardiac events (MACEs), including mortality associated with cardiovascular disease, acute coronary syndrome, and ischemic heart disease requiring coronary revascularization per 1,000 person-years, was calculated. Hazard ratio was also calculated using Cox proportional model.

Results

Overall, 545 (51.9%) patients had severe FH. The median follow-up duration was 12.6 years. In total, 171 MACEs were recorded during the follow-up period. Severe FH was significantly associated with MACE (hazard ratio = 6.48, 95% confidence interval = 2.56–10.40, P < 0.001). The event rates per 1,000 person-years in the primary prevention group of non-severe FH and severe FH, were 0.0 and 15.6, respectively. The event rates per 1,000 person-years in the secondary prevention group of non-severe FH and severe FH, were 2.0 and 32.3, respectively.

Conclusions

Patients with severe FH exhibited significantly higher risks in primary and secondary prevention settings. This simple criterion provides useful information for identifying patients with even higher risk who may need further management.
Usefulness of visual classification for cardiac pathophysiology using count-washout rate map in iodine-123-beta-methyl-P-iodophenyl-pentadecanoic acid scintigraphy
Authors: Ono R , Miyauchi H , Iimori T , Hoshi K , Kobayashi Y
Published: October 2024

Background

Myocardial washout rate (WR) analysis of radiopharmaceuticals is utilized in nuclear cardiology to evaluate the clinical pathophysiology of the heart. WR is defined as the ratio of the difference between the counts in the early image and time-decay-corrected delayed image divided by the former. The myocardial WR of iodine-123-β-methyl iodophenyl-pentadecanoic acid (BMIPP) is an indicator of myocardial lipolysis, and a decreased WR (<10%) of BMIPP is one of the diagnostic criteria for triglyceride deposit cardiomyovasculopathy (TGCV). However, decreased BMIPP uptake in the early images, as in old myocardial infarction (OMI), would also cause a markedly decreased WR. Since the distinction between these clinical conditions cannot be made based on WR alone, simultaneous evaluation of the counts in the early image and WR is needed to properly understand the cardiac pathophysiology.

Purpose

To differentiate between TGCV and non-TGCV with OMI, both of which show decreased BMIPP WR, a new Count-WR Map (CWRM) method was evaluated. The purpose is to visually and easily distinguish between the two conditions using CWRM.

Methods

We introduced a CWRM consisting of two axes: counting in the early image, and WR. The count window was set to a maximum of the mean plus two standard deviations and a minimum of 50 counts, and the WR window was set to a maximum of 30 % and a minimum of -20%. CWRM was visually evaluated as normal, TGCV, non-TGCV with OMI, or TGCV with OMI.

Results

In normal cases, sufficient counts were observed in the early images, and WR did not decrease; CWRM showed light blue. In TGCV, sufficient counts were observed in the early image, but WRs markedly decreased; CWRM showed even orange. In non-TGCV with OMI, regions with decreased and preserved counts coexisted; CWRM showed light blue in the normal and black in the OMI region. In TGCV with OMI, CWRM showed orange in the TGCV myocardium and black in the OMI region (figure).

Conclusions

CWRM is useful for visually and easily differentiating TGCV from non-TGCV with OMI. CWRM can be applied to other cardiovascular diseases with count and WR variations for visual classification.
Lipoprotein(a) and cardiovascular prognosis of familial dyslipidemias: data from a 10-year follow-up study
Authors: Andrikou I , Skoumas I , Grigoriou K , Simantiris S , Dima I , Terentes D , Papanikolaou A , Kambaxis E , Tsioufis K , Vlachopoulos C
Published: October 2024

Background

Familial dyslipidemias, such as heterozygous familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) are associated with premature cardiovascular (CV) disease. On the other hand, increased lipoprotein(a) [Lp(a)] is considered as the most prevalent monogenic lipid disorder in the general population.

Purpose

This study aimed to longitudinally follow up two specific populations with familial dyslipidemias associated with increased CV risk, namely FH and FCH, and compare them with reference to their CV prognosis, investigating in parallel the effect of Lp(a) levels.

Methods

433 patients with FH (34% males, mean age 44.2±12.8 years) and 476 patients with FCH (57% males, mean age 49.0±11.1 years) from the outpatient lipid clinic of our hospital, without history of CV disease, who fulfilled the FH and FCH criteria, respectively, participated in the study. Participants were evaluated for a mean follow-up period of 9.6±7.6 years, with at least one annual visit. Venous blood samples were obtained at baseline in all patients for the determination of lipid profile and levels of Lp(a). All subjects were on lipid-lowering medication during the follow-up period. The endpoint of our study was the composite of major CV events (coronary artery disease events and stroke).

Results

The incidence of the composite endpoint of major CV events during the follow-up period in the total population was 6.5%, while it was greater in patients with FH compared to patients with FCH (8.1% vs 5.5%, p=0.03). Regarding CV risk factors, FCH compared to FH patients had greater prevalence of baseline hypertension (36% vs 9.7%, p<0.001) and diabetes (11% vs 2%, p<0.001), whereas FH patients had greater Lp(a) levels (37.4±40.3 vs 29.7±34.6 mg/dl, p<0.01). Multiple Cox regression analysis revealed that FH patients had greater CV risk compared to FCH patients (HR 2.17, 95% CI 1.10-4.26, p=0.02). Moreover, in FH patients, increased baseline Lp(a) levels (≥30mg/dl) were an independent predictor of major adverse CV events (HR 2.37 95% CI 1.41-4.90, p=0.02), whereas in FCH patients increased Lp(a) was not an independent predictor. In FCH patients the presence of diabetes at baseline was a strong independent prognosticator of adverse CV events (HR 3.56 95% CI 1.19-11.33, p=0.03), after adjustment for confounding factors.

Conclusions

FH patients have greater CV risk compared to FCH patients. In FH patients, the presence of increased Lp(a) doubles the CV risk, beyond low density lipoprotein cholesterol levels. On the other hand, in FCH patients the presence of diabetes triples the CV risk, whereas Lp(a) does not convey an independent prognostic value.
The association between remnant cholesterol and all-cause mortality and cardiovascular mortality was modified by aged in American adults: a retrospective cohort study
Authors: Du D J , Chen W H , Zhao Y , Li Z Y , Huang R C
Published: October 2024

Background

Limited evidence exists regarding the association between remnant cholesterol (RC) and both all-cause and cardiovascular mortality. Also, the effect of age on the association between RC and the risk of mortality in general population has not been studied comprehensively. Therefore, the aim of this study is to investigate how age modifies the relationship between RC and the risk of all-cause and cardiovascular mortality.

Methods

A total of 21722 participants aged over 18 years were obtained from the National Health and Nutrition Examination Survey (1999–2018) , with follow-up mortality outcomes records linked to the National Death Index (NDI) until December 31, 2019 and divided into two groups (<65 years old and ≥65 years old).Weighted multivariable cox proportional hazards models and weighted restricted cubic spline (RCS) were used to estimate the relationship of RC with the risk of all-cause mortality and cardiovascular mortality among American adults. The age interaction between RC and all-cause mortality and cardiovascular mortality was assessed. Restricted cubic spline (RCS) and sensitivity analysis were also used.

Results

During a median 110-month follow-up, a total of 3176 (10.77%) all-cause deaths and 1002 (3.22%) cardiovascular related deaths were recorded. A significant age interaction between RC and all-cause or cardiovascular mortality was found. After adjusting for multiple potential confounding factors, higher RC was associated with an increased risk of all-cause mortality[RC per unit increase Hazard Ratio (HR) 1.45, 95% Confidence Interval (CI) 1.16–1.81, p=0.001] and cardiovascular mortality (RC per unit increase HR 1.80, 95% CI 1.15–2.84, p=0.010) specifically in the younger age group but not in the older age group. Consistent findings were observed in restricted cubic spline analyses and sensitivity analyses.

Conclusion

In our study, we observed that the association between serum RC and all-cause mortality and cardiovascular mortality was modified by age. Specifically, higher RC levels were found to be significantly associated with an increased risk of all-cause mortality and cardiovascular mortality exclusively in patients below 65 years old. This novel finding warrants further confirmation through randomized controlled trials to provide robust evidence.
Clinical Deep Data Accumulation System (CLIDAS) reveals a "Lipid paradox" of hypertriglyceridemia in Japanese patients
Authors: Katsuki S , Kawahara T , Nakano Y , Kimura M , Rissei H , Matoba T
Published: October 2024

Background

The association between triglycerides (TG), HDL cholesterol (HDL-C) and the prognosis of cardiovascular disease has not been established.

Purpose

The aim of this study was to elucidate the relationships between the combination of TG and HDL-C levels and the risk of a major adverse cardiac and cerebral events (MACCE) and to verify the usefulness of TG and HDL-C as a risk stratification factor using the Clinical Deep Data Accumulation System (CLIDAS) database.

Methods

CLIDAS is a database that accumlates electronic medical records in seven tertiary hospitals in Japan including patient characteristics, medications, laboratory test, physiological test, cardiac catheterization, and PCI treatment. We analyzed 9,690 patients who underwent PCI between April 2014 and March 2020. These patients were stratified into the acute coronary syndrome (ACS) group (N=4,135; 43%) and the chronic coronary syndrome (CCS) group (N=5,555; 57%). Furthermore, patients were divided into four groups based on mean serum TG levels (175 mg/dL) and HDL-C levels (40 mg/dL) as cutoff values: high TG/low HDL-C, low TG/low HDL-C, high TG/high HDL-C, and low TG/high HDL-C, and compared for major adverse cardiac and cerebrovascular events (MACCE). The median follow-up duration was 2.5 years.

Results

The patients with high TG/low HDL-C showed the highest event rates in myocardial infarction among the ACS group. The hazard ratio for high TG/low HDL-C versus low TG/high HDL-C was 1.76 (95% CI, 1.08 to 2.87, P < 0.05) after adjustment for age, sex, eGFR, and mean LDL-C levels, while we observed no risk stratification by the combination of TG and HDL-C levels in the CCS group (Figure 1). In contrast, the patients with low TG levels showed the paradoxically higher event rates of MACCE in both the ACS and CCS groups, as well as cardiovascular death in the CCS group, compared to those with high TG levels (Figure 2). The hazard ratio for low TG/low HDL-C versus high TG/low HDL-C was 3.21 (95% CI, 1.44 to 7.13, P <0.005), and the hazard ratio for low TG/high HDL-C versus high TG/high HDL-C was 2.23 (95% CI, 1.03 to 4.84, P < 0.05) in the CCS group after adjustment for age, sex, eGFR, and mean LDL-C levels.

Conclusion

In the CLIDAS database, while high TG and low HDL-C levels stratified the risk of ACS, low TG levels showed worsening prognosis for CV death, suggesting a "Lipid paradox" in the real world.Figure 1Figure 2
Lipoprotein(a) levels in acute myocardial infarction patients and their associations with prior events and coronary artery disease severity: a real-world cohort study
Authors: Azevedo S , Da Silva Correia D , Barbosa Sousa R , Amador R , Sousa Paiva M , Gomes D , Certo Pereira J , Carvalho R , Bello R , Fonseca I , Tralhao A , Trabulo M , Figueira J , Sousa Almeida M , Ferreira J
Published: October 2024

Introduction

Circulating lipoprotein(a) [Lp(a)] has been associated with the risk of atherosclerotic coronary artery disease (CAD) and is an emergent therapeutic target.

The objective of this study is to explore the association between serum levels of Lp(a) and previous myocardial infarction (MI) and/or coronary revascularization and the extension of obstructive CAD in patients with acute MI undergoing coronary angiography.

Methods

All consecutive patients with MI who underwent coronary angiography and Lp(a) measurement between May and November 2023 were included. Patient data were either registered prospectively or completed retrospectively using electronic health records. Lp(a) was measured using the Immunoturbidimetric Assay method with reaction intensification by particles, employing the World Health Organization/International Federation of Clinical Chemistry and Laboratory Medicine (WHO/IFCC) International Reference Reagent (SRM2B), on the "Roche Cobas C702" chemistry analyzer.

The number of major coronary arteries (left main, left anterior descending, left circumflex and right coronary arteries) with stenosis >50% on the coronary angiography were registered. In the primary analysis we explored the association between Lp(a) levels using tertiles and previous occurrence of MI/revascularization, as well as the extension of obstructive CAD. In the secondary analysis we compared Lp(a) levels in patients with and without previous MI/revascularization and patients with 3-4 major vessels CAD vs. 0-2 vessels.

Results

A total of 116 patients were enrolled, with a mean age of 62±13 years, 79% males, 29% with known coronary artery disease, 71% with dyslipidemia, 24% with diabetes, 65% with hypertension, and 58% were either active or former smokers. The median Lp(a) level was 72 (20-183) nmol/L.

In the primary analysis (table 1), the number of previous MI/revascularizations was significantly higher in the third tertile of Lp(a) (T3) versus T1 (p=0.044). No significant differences were found for the remaining analyses. In the secondary analysis (figure 1) the level of Lp(a) was significantly higher in patients with 3-4 vessel CAD vs. 0-2 vessel (158.4±145.2 nmol/L vs. 103.16±104.6 p=0.044).

Conclusion

In this small real-world cohort population with acute MI, the number of previous MI or coronary revascularization was higher in patients with increased levels of Lp(a) and this marker of atherosclerotic disease was greater in patients with more extensive CAD.
Sex-specific guideline target value attainment and prognostic value of low-density lipoprotein cholesterol in tertiary care
Authors: Rumora K , Lopez Ayala P , Schaefer I , Durandi V , Walter J E , Leibfarth J P , Hure G , Isayeva G , Zellweger M J , Strebel I , Von Eckardstein A , Pfister O , Mueller C
Published: October 2024

Background

Factors contributing to guideline-target-level-attainment of low-density lipoprotein cholesterol (LDL-C) in countries with high healthcare expenditure are incompletely understood.

Purpose

the primary aim of this study was to test two hypotheses: 1) LDL-C control may be inferior in women versus men; 2) within the secondary prevention group, presence of a previous acute atherothrombotic event (acute myocardial infarction and stroke) may result in superior LDL-C control.

Methods

LDL-C levels and guideline target level attainment were determined in 4090 consecutive patients referred for myocardial perfusion single photon emission tomography (MPI-SPECT) between 2010 and 2016. Findings were validated in an independent cohort (n=1228) of consecutively enrolled patients in an outpatient cardiac rehabilitation program, between 2016 and 2023.

Results

About one third of patients (33%) were women, median age was 68 years, 1439 patients had a history of atherothrombosis, 759 patients a history of atherosclerosis without atherothrombosis, and 1892 were in primary prevention. LDL-C levels were higher and guideline target level attainment worse in women than in men in all three strata: age-adjusted difference in atherothrombosis 0.19 mmol/L (95%CI 0.03,0.35 mmol), guideline-target-value-attainment 39.5 % versus 49.4%, p<0.01; in atherosclerosis 0.33 mmol/L (95%CI 0.10-0.57), guideline-target-value-attainment 27.3 % versus 42.2 %, p<0.01; and in primary prevention 0.24 mmol/L (95% CI 0.13-0.38). This was confirmed in the validation cohort. LDL-C levels were higher and guideline-target-value-attainment worse in women versus men: age-adjusted difference age-adjusted difference 0.17 mmol/L (95%CI 0.02-0.33) guideline-target-value-attainment 43.8% versus 49.5%, After multivariate adjustment, female sex remained an independent predictor for higher LDL-C levels. LDL-C concentrations with atherothrombosis was 1.93 mmol/L (IQR 1.48-2.47) versus 2.07 mmol/L (IQR 1.40-2.72, p=0.003) with atherosclerosis and guideline target value attainment 47.5% vs 38.6%, p<0.001, respectively.

Conclusion

Concerning age-adjusted sex-inequalities with higher LDL-C levels and lower guideline-target-value-attainment in women were found in both primary and secondary prevention. Within secondary prevention, a previous atherothrombotic event was associated with lower LDL-C levels and higher guideline-target-value-attainment.
Identification of ischemia with no obstructive coronary arteries using 13N-ammonia positron emission tomography-derived myocardial strain ratio
Authors: Sakai A , Nagao M , Imakado R , Yamamoto A , Nakao R , Arashi H , Momose M , Yamaguchi J
Published: October 2024

Background

Ischemia with no obstructive coronary arteries (INOCA) is a chronic health problem with poor prognosis and remains challenging to diagnose. 13N-ammonia positron emission tomography (NH3-PET) is the most reliable method for detecting INOCA. We recently developed a unique myocardial strain analysis for NH3-PET to detect ischemia-related motion abnormalities.

Purpose

We examined the usefulness of NH3-PET strain analysis to identify patients with INOCA.

Methods

Overall, 98 patients with non-obstructive coronary arteries who underwent adenosine-stress NH3-PET were enrolled. INOCA was defined based on the ESC guidelines. Using an original feature-tracking algorithm dedicated to NH3-PET, the circumferential strain was calculated. Myocardial strain ratio (MSR) was defined as the ratio of strains at stress and rest. In addition, global myocardial flow reserve (MFR) was obtained.

Results

Finally, forty-seven patients were diagnosed with INOCA, and 51 without INOCA. Global MFR were significantly lower in patients with INOCA than in those without INOCA (1.82 ± 0.52 vs. 2.65 ± 0.65, p<0.0001). MSR were significantly lower in patients with INOCA than in those without INOCA (0.94 ± 0.11 vs. 1.04 ± 0.12, p<0.001). Receiver-operating characteristic analysis showed that using the optimal cutoff of the MSR, INOCA could be diagnosed with area under the curve of 0.71. At a median follow-up of 957 days, Kaplan–Meier analysis revealed that the survival rate worsened in patients with INOCA and low MSR (log-rank test, p<0.001).

Conclusions

MSR derived from feature-tracking of NH3-PET is reduced in patients with INOCA. It might suggest a predictive value to identify microvascular dysfunction or related motion abnormalities in patients with INOCA.
High intensity statin-ezetimibe combination therapy reduces mortality in patients with ischaemic heart disease and elevated Lipoprotein(a)
Authors: Loh W J , Koh X H , Mak Y H , Yeo C , Foo R , Heng C K , Watts G F
Published: October 2024

Background

Early and prompt reduction of low-density lipoprotein cholesterol concentrations (LDL-C) using combination lipid-lowering therapy (LLT) is recommended to lower cardiovascular risk in patients with ischaemic heart disease (IHD) and elevated LDL-C. Lowering LDL-C is also an important cardiovascular risk mitigation strategy in patients with elevated lipoprotein(a) [Lp(a)]. However, it is unknown if combination LLT reduces mortality in patients with elevated Lp(a).

Aim

To undertake an observational study to investigate the effect of combination LLT using high intensity statin with ezetimibe on cardiovascular outcomes in patients with and without elevated Lp(a).

Methods

Serum Lp(a) concentrations were measured in 520 consecutively recruited patients with IHD admitted to hospital, half of whom were admitted for acute myocardial infarction. Patients treated with high intensity statin and ezetimibe within the 1st year from admission to hospital (‘HI statin-ezetimibe group’, n=157) were compared with the rest of patients who had less intensive lipid lowering regimen (‘Others group’, n=363) for cardiovascular outcomes.

Results

During the 2-year follow-up period, 14.6%, 6.5%, and 53.1% of patients had all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE) respectively. Median age was 63.5 years and 82.3% were male. Multivariable Cox regression showed that baseline Lp(a) ≥70 nmol/L was associated with increased risk of all-cause mortality (HR 1.97, 95% CI 1.20-3.22, P=0.007). Compared with a less intensive regimen, HI statin-ezetimibe was associated with reduced risk of all-cause mortality (HR 0.44 [0.21-0.89], P=0.023) and MACE (HR 0.71 [0.52-0.95], P=0.027), with no statistically significant effect on cardiovascular mortality (HR 0.43, P=0.142). Notably, the cardiovascular benefits of HI statin-ezetimibe were more pronounced in patients with elevated Lp(a); a greater reduction in risk of MACE was seen for patients with Lp(a) ≥70 nmol/L (HR 0.51, P=0.007) or Lp(a) ≥100 nmol/L (HR 0.36, P=0.009), and in all-cause mortality risk for those with Lp(a) ≥70 nmol/L (HR 0.24, P=0.025). Although LDL-C reduction >50% was associated with reduced risk of all-cause mortality (p=0.027), this could not fully explain the overall cardiovascular benefit of HI statin-ezetimibe use in patients with or without elevated Lp(a).

Conclusion

Intensification of lipid-lowering therapy with high-intensity statin and ezetimibe improves cardiovascular outcomes in patients at very high cardiovascular risk, particularly those with elevated Lp(a). Larger studies are required to confirm our findings that this cardiovascular benefit is partially independent of LDL-C lowering.
Reduction of triglyceride-rich lipoproteins with retatrutide in type 2 diabetes may be explained by concurrent reduction in ANGPTL3/8 levels
Authors: Wen Y , Lemen D , Chen Y , Lin Y , Thomas M , Hartman M , Coskun T , Milicevic Z , Haupt A , Ruotolo G , Konrad R
Published: October 2024

Background/Introduction

In the recent phase 2 study (NCT04867785) in patients with type 2 diabetes (T2D), retatrutide, an agonist of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and glucagon receptors, reduced triglycerides (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) up to 35.0% and 20.7%, respectively. The angiopoietin-like 3/8 complex (ANGPTL3/8) is the most potent circulating inhibitor of lipoprotein lipase (LPL), and its serum levels have been shown to be directly correlated with TG and low-density lipoprotein cholesterol (LDL-C).

Purpose

In the aforementioned phase 2 study, we examined the effects of retatrutide on circulating ANGPTL3/8 complex concentrations to help understand the mechanism by which retatrutide reduced TG and non-HDL-C.

Methods

Patients with T2D were randomly assigned to receive once-weekly injections of placebo, 1.5 mg dulaglutide, or retatrutide doses of 0.5 mg, 4 mg, 8 mg, or 12 mg. Fasting serum samples were collected at baseline, week 2, week 4, week 8, week 12, week 16, and week 24, and ANGPTL3/8 levels were measured at all time points using a sensitive and selective immunoassay. Plasma PCSK9 levels were also measured at baseline and 24 weeks. Data were analyzed using a mixed model for repeated measures with log-transformation.

Results

Baseline ANGPTL3/8 levels (mean 26.3 ng/mL, IQR 17.4-33.0 ng/mL) were not different among all study groups. Mean percent changes of ANGPTL3/8 from baseline at week 24 were -1.3%, -12.0%, -48.7% and -51.0% in 0.5 mg, 4 mg, 8 mg and 12 mg retatrutide groups, respectively (Figure). Percent changes of ANGPTL3/8 in 8 mg and 12 mg retatrutide groups were significantly different from placebo group (p < 0.0001). Mean percent changes of PCSK9 levels from baseline to 24 weeks were not different from placebo for any treatment arm (+6.2%, -3.9%, -3.8% and -9.6% for retatrutide 0.5 mg, 4 mg, 8 mg and 12 mg groups, respectively, and -1.5% for dulaglutide and -6.5% for placebo).

Conclusions

In patients with T2D, retatrutide dose-dependently decreased serum concentrations of ANGPTL3/8, the most potent circulating LPL inhibitor. These data suggest that retatrutide may reduce TG-rich lipoproteins by decreasing ANGPTL3/8 levels.
Interleukin-6 signalling, lipoprotein (a) lowering and cardiovascular disease: a mendelian randomisation study
Authors: Brennan S O , Kelly P J , Mccabe J J
Published: October 2024

Background

Elevated lipoprotein(a) (Lp[a]) levels and chronic low-grade inflammation play causal roles in cardiovascular disease (CVD) development, representing promising targets for managing residual risk. CVD prevention trials are currently assessing the efficacy of IL-6 pathway inhibition in ameliorating chronic pro-atherogenic inflammation. Lp(a) increases in response to interleukin 6 (IL-6) and acute inflammatory states, and Lp(a) itself induces an inflammatory response that accelerates atherosclerosis. Recent studies indicate that IL-6-receptor inhibitors may lower Lp(a) levels and reduce inflammation, potentially decreasing CVD risk in an additive manner.

Purpose

This drug-target Mendelian Randomisation (MR) study aims to elucidate the on-target effects of pharmacological IL-6R and LPA inhibition on CVD and explore the relationship between downregulated IL6R signalling and Lp(a) levels.

Methods

Independent genetic variants associated with C-reactive protein levels from around the IL6R gene locus, and Lp(a) lowering variants from around the LPA gene locus were utilised to assess the effect of genetically proxied IL6R and LPA inhibition on CVD risk in large genomic consortia. Two-step cis-MR was then employed to estimate the effect of lower genetically predicted IL6R signalling on CVD, after adjusting for its influence on Lp(a) levels.

Results

Genetically proxied LPA inhibition was associated with reduced odds of coronary artery disease (CAD) (OR 0.88, 95% CI 0.86-0.89), ischaemic stroke (IS) (OR 0.98, 95% CI 0.96-1.00), cardioembolic stroke (OR 0.95, 95% CI 0.92-0.97), heart failure (HF) (OR 0.96, 95% CI 0.92-1.00), and aortic stenosis (OR 0.88, 95% CI 0.85-0.91). IL6R inhibition was associated with reduced odds of CAD (OR 0.76, 95% CI 0.68-0.86), IS (OR 0.89, 95% CI 0.80-0.98), small vessel stroke (SVS) (OR 0.72, 95% CI 0.59-0.89), large artery stroke (LAS) (0.61, 95% CI 0.48-0.78) and atrial fibrillation (OR 0.73, 95% CI 0.65-0.83). Furthermore, downregulated IL6R signalling was associated with lower Lp(a) levels (SD change -0.04, 95% CI -0.08,-0.01). In two-step cis-MR, Lp(a) levels partially mediated the total effect of IL6R inhibition on CAD (proportion-mediated = -11.33%, 95% CI -11.35, -11.31%) and LAS (proportion mediated = -4.19%, 95% CI -4.21, -4.17%), but had little effect on IS (proportion-mediated = -1.78%, 95% CI -1.80, -1.76%), SVS (proportion-mediated = -2.50%, 95% CI -2.52, -2.48%), or atrial fibrillation (proportion-mediated = -0.20%, 95% CI -0.22, -0.18%).

Conclusion

IL6R and Lp(a) inhibition are independently associated with reduced risk of CVD. Furthermore, IL6R inhibition is associated with lower Lp(a) and its effect on CVD is independent of its Lp(a)-lowering effects. Targeting the IL6 signalling pathway offers a promising approach to mitigate residual CVD risk in individuals with elevated Lp(a) levels. Future trials should investigate the additive effects of combined IL-6 inhibition and Lp(a) lowering therapies.
Gender differences in the treatment with PCSK9 monoclonal antibodies real world experience from a dedicated prevention clinic
Authors: Hodeda L , Birati E Y , Rotholz A , Eisen A , Gurevitz C
Published: October 2024

Background

Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9 mAb) lower low-density lipoprotein cholesterol (LDL-C) levels and reduce atherosclerotic cardiovascular disease (ASCVD). There are gender differences in PCSK9 biological characteristics, which are not properly addressed in current data.

Purpose

Examining gender differences in treatment with PCSK9 mAb.

Methods

A retrospective study based on data from the Prevention Cardiology Clinic in Rabin Medical Center. Included were patients prescribed with PCSK9 mAb (evolocumab or alirocumab), for primary or secondary prevention. Data included medical background and treatment variables. Response to treatment was evaluated by changes in LDL-C at 3 and 12 months. Data was analyzed by gender.

Results

Study included 246 patients (mean age 67y, ASCVD 78.8%, mean baseline LDL-C 128.2 mg/dL). Women (42% of cohort) prescribed with PCSK9 mAb were older than men (69 vs. 65 years, respectively; p<0.001). The dominant indication for PCSK9 mAb for both genders was secondary prevention, while primary prevention indication was more prevalent in women vs. men (39.4% vs. 16.3%, respectively; p<0.001). Statin intolerance was observed in 82.4% and 58.6% were treated with combination therapy with PCSK9 mAb, without significant gender differences. Baseline mean LDL-C was higher among women vs. men (138.9 vs. 117.3 mg/dL; p<0.001). Overall, high adherence was observed (91.8% and 79.7% at 3 and 12 months, respectively). After 1-year, adherent men had lower LDL-C levels than women (46.8 mg/d and 61.9 mg/dL, respectively; P=0.001), and were more likely to reach their LDL-C therapy goals; below 70 mg/dL (76.1% vs. 62.2%, respectively; P=0.032) and below 55 mg/dL (60.1% vs. 39.8% respectively; P=0.003).

Conclusions

In patients treated with PCSK9 mAb, gender differences exist in prescription age, indications, baseline LDL-C and achieved LDL-C goals. In this study adherence to PCSK9 mAb was higher than reported before, possibly due to surveillance in a dedicated prevention clinic.LDL-C & Non-HDL-C levels under PCSK9 mABSex Differences in acheived LDL-C goals