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JAMA Aug 2023Prior trials of extracranial-intracranial (EC-IC) bypass surgery showed no benefit for stroke prevention in patients with atherosclerotic occlusion of the internal... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Prior trials of extracranial-intracranial (EC-IC) bypass surgery showed no benefit for stroke prevention in patients with atherosclerotic occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA), but there have been subsequent improvements in surgical techniques and patient selection.
OBJECTIVE
To evaluate EC-IC bypass surgery in symptomatic patients with atherosclerotic occlusion of the ICA or MCA, using refined patient and operator selection.
DESIGN, SETTING, AND PARTICIPANTS
This was a randomized, open-label, outcome assessor-blinded trial conducted at 13 centers in China. A total of 324 patients with ICA or MCA occlusion with transient ischemic attack or nondisabling ischemic stroke attributed to hemodynamic insufficiency based on computed tomography perfusion imaging were recruited between June 2013 and March 2018 (final follow-up: March 18, 2020).
INTERVENTIONS
EC-IC bypass surgery plus medical therapy (surgical group; n = 161) or medical therapy alone (medical group; n = 163). Medical therapy included antiplatelet therapy and stroke risk factor control.
MAIN OUTCOMES AND MEASURES
The primary outcome was a composite of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years after randomization. There were 9 secondary outcomes, including any stroke or death within 2 years and fatal stroke within 2 years.
RESULTS
Among 330 patients who were enrolled, 324 patients were confirmed eligible (median age, 52.7 years; 257 men [79.3%]) and 309 (95.4%) completed the trial. For the surgical group vs medical group, no significant difference was found for the composite primary outcome (8.6% [13/151] vs 12.3% [19/155]; incidence difference, -3.6% [95% CI, -10.1% to 2.9%]; hazard ratio [HR], 0.71 [95% CI, 0.33-1.54]; P = .39). The 30-day risk of stroke or death was 6.2% (10/161) in the surgical group and 1.8% (3/163) in the medical group, and the risk of ipsilateral ischemic stroke beyond 30 days through 2 years was 2.0% (3/151) and 10.3% (16/155), respectively. Of the 9 prespecified secondary end points, none showed a significant difference including any stroke or death within 2 years (9.9% [15/152] vs 15.3% [24/157]; incidence difference, -5.4% [95% CI, -12.5% to 1.7%]; HR, 0.69 [95% CI, 0.34-1.39]; P = .30) and fatal stroke within 2 years (2.0% [3/150] vs 0% [0/153]; incidence difference, 1.9% [95% CI, -0.2% to 4.0%]; P = .08).
CONCLUSIONS AND RELEVANCE
Among patients with symptomatic ICA or MCA occlusion and hemodynamic insufficiency, the addition of bypass surgery to medical therapy did not significantly change the risk of the composite outcome of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01758614.
Topics: Female; Humans; Male; Middle Aged; Arteriosclerosis; Carotid Artery Diseases; Carotid Artery, Internal; Cerebral Revascularization; Infarction, Middle Cerebral Artery; Intracranial Arteriosclerosis; Ischemic Attack, Transient; Ischemic Stroke; Middle Cerebral Artery; Perfusion Imaging; Single-Blind Method; Stroke; Tomography, Emission-Computed; Platelet Aggregation Inhibitors; Combined Modality Therapy
PubMed: 37606672
DOI: 10.1001/jama.2023.13390 -
Cells Oct 2023Lipoprotein(a) (Lp(a)) molecule includes two protein components: apolipoprotein(a) and apoB100. The molecule is the main transporter of oxidized phospholipids (OxPL) in... (Review)
Review
Lipoprotein(a) (Lp(a)) molecule includes two protein components: apolipoprotein(a) and apoB100. The molecule is the main transporter of oxidized phospholipids (OxPL) in plasma. The concentration of this strongly atherogenic lipoprotein is predominantly regulated by the LPA gene expression. Lp(a) is regarded as a risk factor for several cardiovascular diseases. Numerous epidemiological, clinical and in vitro studies showed a strong association between increased Lp(a) and atherosclerotic cardiovascular disease (ASCVD), calcific aortic valve disease/aortic stenosis (CAVD/AS), stroke, heart failure or peripheral arterial disease (PAD). Although there are acknowledged contributions of Lp(a) to the mentioned diseases, clinicians struggle with many inconveniences such as a lack of well-established treatment lowering Lp(a), and common guidelines for diagnosing or assessing cardiovascular risk among both adult and pediatric patients. Lp(a) levels are different with regard to a particular race or ethnicity and might fluctuate during childhood. Furthermore, the lack of standardization of assays is an additional impediment. The review presents the recent knowledge on Lp(a) based on clinical and scientific research, but also highlights relevant aspects of future study directions that would approach more suitable and effective managing risk associated with increased Lp(a), as well as control the Lp(a) levels.
Topics: Humans; Aortic Valve; Aortic Valve Stenosis; Atherosclerosis; Lipoprotein(a); Risk Factors
PubMed: 37887316
DOI: 10.3390/cells12202472 -
European Heart Journal Dec 2023Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily accessible inflammation biomarker, are associated... (Observational Study)
Observational Study
BACKGROUND AND AIMS
Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily accessible inflammation biomarker, are associated with atherosclerosis in experimental studies. This study aimed to investigate the associations between neutrophil counts and risk of nine cardiovascular endpoints using observational and genetic approaches.
METHODS
Observational studies were conducted in the Copenhagen General Population Study (n = 101 730). Genetic studies were firstly performed using one-sample Mendelian randomization (MR) with individual-level data from the UK Biobank (n = 365 913); secondly, two-sample MR analyses were performed using summary-level data from the Blood Cell Consortium (n = 563 085). Outcomes included ischaemic heart disease, myocardial infarction, peripheral arterial disease, ischaemic cerebrovascular disease, ischaemic stroke, vascular-related dementia, vascular dementia, heart failure, and atrial fibrillation.
RESULTS
Observational analyses showed associations between high neutrophil counts with high risks of all outcomes. In the UK Biobank, odds ratios (95% confidence intervals) per 1-SD higher genetically predicted neutrophil counts were 1.15 (1.08, 1.21) for ischaemic heart disease, 1.22 (1.12, 1.34) for myocardial infarction, and 1.19 (1.04, 1.36) for peripheral arterial disease; similar results were observed in men and women separately. In two-sample MR, corresponding estimates were 1.14 (1.05, 1.23) for ischaemic heart disease and 1.11 (1.02, 1.20) for myocardial infarction; multiple sensitivity analyses showed consistent results. No robust associations in two-sample MR analyses were found for other types of leucocytes.
CONCLUSIONS
Observational and genetically determined high neutrophil counts were associated with atherosclerotic cardiovascular disease, supporting that high blood neutrophil counts is a causal risk factor for atherosclerotic cardiovascular disease.
Topics: Male; Humans; Female; Cardiovascular Diseases; Neutrophils; Brain Ischemia; Stroke; Myocardial Infarction; Myocardial Ischemia; Atherosclerosis; Peripheral Arterial Disease; Coronary Artery Disease; Mendelian Randomization Analysis; Genome-Wide Association Study; Polymorphism, Single Nucleotide
PubMed: 37950632
DOI: 10.1093/eurheartj/ehad649 -
Nature Reviews. Cardiology Jul 2023Lipophagy is a type of selective autophagy that targets lipid droplets for degradation. Since the discovery of lipophagy in 2009, research has uncovered a central role...
Lipophagy is a type of selective autophagy that targets lipid droplets for degradation. Since the discovery of lipophagy in 2009, research has uncovered a central role for this process in cellular lipid metabolism, including in atherogenic foam cells. Therefore, increasing lipophagy might be a therapeutic target to reverse lipid build-up in atherosclerosis.
Topics: Humans; Atherosclerosis; Autophagy; Lipid Metabolism
PubMed: 37161064
DOI: 10.1038/s41569-023-00885-z -
European Heart Journal Aug 2023Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical...
AIMS
Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical atherosclerosis with accelerated epigenetic age and to investigate the underlying mechanisms mediating this association.
METHODS AND RESULTS
Whole blood methylomics, transcriptomics, and plasma proteomics were obtained for 391 participants of the Progression of Early Subclinical Atherosclerosis study. Epigenetic age was calculated from methylomics data for each participant. Its divergence from chronological age is termed epigenetic age acceleration. Subclinical atherosclerosis burden was estimated by multi-territory 2D/3D vascular ultrasound and by coronary artery calcification. In healthy individuals, the presence, extension, and progression of subclinical atherosclerosis were associated with a significant acceleration of the Grim epigenetic age, a predictor of health and lifespan, regardless of traditional cardiovascular risk factors. Individuals with an accelerated Grim epigenetic age were characterized by an increased systemic inflammation and associated with a score of low-grade, chronic inflammation. Mediation analysis using transcriptomics and proteomics data revealed key pro-inflammatory pathways (IL6, Inflammasome, and IL10) and genes (IL1B, OSM, TLR5, and CD14) mediating the association between subclinical atherosclerosis and epigenetic age acceleration.
CONCLUSION
The presence, extension, and progression of subclinical atherosclerosis in middle-aged asymptomatic individuals are associated with an acceleration in the Grim epigenetic age. Mediation analysis using transcriptomics and proteomics data suggests a key role of systemic inflammation in this association, reinforcing the relevance of interventions on inflammation to prevent cardiovascular disease.
Topics: Middle Aged; Humans; Multiomics; Atherosclerosis; Coronary Artery Disease; Inflammation; Epigenesis, Genetic; Risk Factors
PubMed: 37339167
DOI: 10.1093/eurheartj/ehad361 -
Cardiovascular Diabetology Sep 2023The presence of type 1 diabetes mellitus (T1DM) has been demonstrated to pose an increased risk for developing cardiovascular diseases (CVDs). However, the causal...
BACKGROUND
The presence of type 1 diabetes mellitus (T1DM) has been demonstrated to pose an increased risk for developing cardiovascular diseases (CVDs). However, the causal relationships between T1DM and CVDs remain unclear due to the uncontrolled confounding factors and reverse causation bias of the observational studies.
METHODS
Summary statistics of T1DM and seven CVDs from the largest available genome-wide association studies (GWAS) of European ancestry and FinnGen biobank were extracted for the primary MR analysis, and the analysis was replicated using UK biobank (UKBB) for validation. Three complementary methods: inverse variance weighted (IVW), weighted median, and MR-Egger were used for the MR estimates. The potential pleiotropic effects were assessed by MR-Egger intercept and MR-PRESSO global test. Additionally, multivariable MR (MVMR) analysis was performed to examine whether T1DM has independent effects on CVDs with adjustment of potential confounding factors. Moreover, a two-step MR approach was used to assess the potential mediating effects of these factors on the causal effects between T1DM and CVDs.
RESULTS
Causal effects of T1DM on peripheral atherosclerosis (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.02-1.10; p = 0.002)] and coronary atherosclerosis (OR = 1.03, 95% CI: 1.01-1.05; p = 0.001) were found. The results were less likely to be biased by the horizontal pleiotropic effects (both p values of MR-Egger intercept and MR-PRESSO Global test > 0.05). In the following MVMR analysis, we found the causal effects of T1DM on peripheral atherosclerosis and coronary atherosclerosis remain significant after adjusting for a series of potential confounding factors. Moreover, we found that hypertension partly mediated the causal effects of T1DM on peripheral atherosclerosis (proportion of mediation effect in total effect: 11.47%, 95% CI: 3.23-19.71%) and coronary atherosclerosis (16.84%, 95% CI: 5.35-28.33%). We didn't find significant causal relationships between T1DM and other CVDs, including heart failure (HF), coronary artery disease (CAD), atrial fibrillation (AF), myocardial infarction (MI) and stroke. For the reverse MR from CVD to T1DM, no significant causal relationships were identified.
CONCLUSION
This MR study provided evidence supporting the causal effect of T1DM on peripheral atherosclerosis and coronary atherosclerosis, with hypertension partly mediating this effect.
Topics: Humans; Cardiovascular Diseases; Coronary Artery Disease; Diabetes Mellitus, Type 1; Genome-Wide Association Study; Mendelian Randomization Analysis; Hypertension; Atherosclerosis; Nonoxynol
PubMed: 37659996
DOI: 10.1186/s12933-023-01974-6 -
Journal of the American Heart... Jun 2023Management of elevated low-density lipoprotein cholesterol (LDL-C) is central to preventing atherosclerotic cardiovascular disease (ASCVD) and key to reducing the risk... (Review)
Review
Management of elevated low-density lipoprotein cholesterol (LDL-C) is central to preventing atherosclerotic cardiovascular disease (ASCVD) and key to reducing the risk of ASCVD events. Current guidelines on the management of blood cholesterol recommend statins as first-line therapy for LDL-C reduction according to an individual's ASCVD risk and baseline LDL-C levels. The addition of nonstatin lipid-lowering therapy to statins to achieve intensive LDL-C lowering is recommended for patients at very high risk of ASCVD events, including patients with familial hypercholesterolemia who have not achieved adequate LDL-C lowering with statins alone. Despite guideline recommendations and clinical trial evidence to support the use of lipid-lowering therapies for ASCVD risk reduction, most patients at high or very high risk do not meet LDL-C thresholds. This review explores the challenges associated with LDL-C lowering in contemporary clinical practice and proposes a framework for rethinking the binary definition of ASCVD, shifting from "primary" versus "secondary" prevention to a "continuum of risk." The approach considers the role of plaque burden and progression in subclinical disease and emphasizes the importance of early risk assessment and treatment for preventing first cardiovascular events. Patients at high risk of ASCVD events who require significant LDL-C lowering should be considered for combination therapies comprising statin and nonstatin agents. Practical guidance for the pharmacological management of elevated LDL-C, both now and in the future, is provided.
Topics: Humans; Cholesterol, LDL; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cardiovascular Diseases; Cholesterol; Atherosclerosis
PubMed: 37260036
DOI: 10.1161/JAHA.122.028892 -
Circulation Aug 2023Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify...
BACKGROUND
Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography-based measures of coronary atherosclerosis and to explore relevant clinical correlates.
METHODS
We conducted a cross-sectional study of 8973 participants (50 to 65 years of age) without overt atherosclerotic disease from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study). Coronary atherosclerosis was measured using coronary artery calcium score and coronary computed tomography angiography. Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of fecal samples, and associations with coronary atherosclerosis were evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva.
RESULTS
The mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3%, and 5.4% had at least 1 stenosis with >50% occlusion. Sixty-four species were associated with coronary artery calcium score independent of cardiovascular risk factors, with the strongest associations observed for and subsp (<1×10). Associations were largely similar across coronary computed tomography angiography-based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations, and 16 with neutrophil counts. Gut microbial species that are commonly found in the oral cavity were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species, including 3 streptococci, correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid β-oxidation, and amino acid degradation were associated with coronary artery calcium score.
CONCLUSIONS
This study provides evidence of an association of a gut microbiota composition characterized by increased abundance of spp and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation markers. Further longitudinal and experimental studies are warranted to explore the potential implications of a bacterial component in atherogenesis.
Topics: Humans; Female; Middle Aged; Male; Coronary Artery Disease; Cross-Sectional Studies; Calcium; Atherosclerosis; Streptococcus
PubMed: 37435755
DOI: 10.1161/CIRCULATIONAHA.123.063914 -
Journal of the American Heart... Jun 2023Background Normal brain function depends on the ability of the vasculature to increase blood flow to regions with high metabolic demands. Impaired neurovascular...
Background Normal brain function depends on the ability of the vasculature to increase blood flow to regions with high metabolic demands. Impaired neurovascular coupling, such as the local hyperemic response to neuronal activity, may contribute to poor neurological outcome after stroke despite successful recanalization, that is, futile recanalization. Methods and Results Mice implanted with chronic cranial windows were trained for awake head-fixation before experiments. One-hour occlusion of the anterior middle cerebral artery branch was induced using single-vessel photothrombosis. Cerebral perfusion and neurovascular coupling were assessed by optical coherence tomography and laser speckle contrast imaging. Capillaries and pericytes were studied in perfusion-fixed tissue by labeling lectin and platelet-derived growth factor receptor β. Arterial occlusion induced multiple spreading depolarizations over 1 hour associated with substantially reduced blood flow in the peri-ischemic cortex. Approximately half of the capillaries in the peri-ischemic area were no longer perfused at the 3- and 24-hour follow-up (45% [95% CI, 33%-58%] and 53% [95% CI, 39%-66%] reduction, respectively; <0.0001), which was associated with contraction of an equivalent proportion of peri-ischemic capillary pericytes. The capillaries in the peri-ischemic cortex that remained perfused showed increased point prevalence of dynamic flow stalling (0.5% [95% CI, 0.2%-0.7%] at baseline, 5.1% [95% CI, 3.2%-6.5%] and 3.2% [95% CI, 1.1%-5.3%] at 3- and 24-hour follow-up, respectively; =0.001). Whisker stimulation at the 3- and 24-hour follow-up led to reduced neurovascular coupling responses in the sensory cortex corresponding to the peri-ischemic region compared with that observed at baseline. Conclusions Arterial occlusion led to contraction of capillary pericytes and capillary flow stalling in the peri-ischemic cortex. Capillary dysfunction was associated with neurovascular uncoupling. Neurovascular coupling impairment associated with capillary dysfunction may be a mechanism that contributes to futile recanalization. Hence, the results from this study suggest a novel treatment target to improve neurological outcome after stroke.
Topics: Mice; Animals; Ischemic Stroke; Microcirculation; Brain; Stroke; Brain Ischemia; Arterial Occlusive Diseases; Cerebrovascular Circulation
PubMed: 37232244
DOI: 10.1161/JAHA.123.029527