Coronary Artery Plaque Research Articles

Prevalence of clonal hematopoiesis driver mutations in patients undergoing coronary angiography and its association with coronary artery disease severity

Abstract Background Clonal hematopoiesis of indeterminate potential (CHIP) is an acquired, genetic cardiovascular (CV) risk factor affecting about 10% of the general population at the age of 70 years. Experimental studies suggest a causal link between CHIP and inflammation-driven atherosclerosis. We hypothesized that CHIP is more frequent in patients undergoing coronary angiography and associates with coronary artery disease (CAD) severity. Methods Patients at the age of 40 or older, presenting indications for a left heart coronary angiography examination at the Freiburg Heart Center, Germany, were eligible for screening. Study participants presenting abnormal hematological readouts, C-reactive protein >10 mg/L, glomerular filtration rate <30 mL/min/m2, undergoing antibiotics treatments, having history of malignancy or chronic inflammatory diseases were excluded. Genomic DNA (gDNA) extracted from citrated arterial blood, sampled during angiography, was subjected to CHIP-driver gene mutation screening (TruSight Myeloid Sequencing Panel, Illumina). Targeted genomic sequencing. CAD severity was determined in coronary angiograms using Gensini score by investigators blinded to DNA sequencing results. Results We enrolled 178 out of 815 patients that were screened for our observational study, which did not feature exclusion criteria such as hematologic abnormalities or relevant comorbidities (see methods). Median age was 69 years. With a cutoff of 2% variant allele frequency (VAF), nearly 30% of the included patients carried CHIP driver mutations – a prevalence at least three times higher compared to the general public. Most CHIP carriers harbored only one mutation, nearly 80% of mutations were located in the epigenetic regulator genes, DNMT3A and TET2. Among the included patients, the clinical characteristics were generally comparable between the CHIP-carriers and the non-carriers in terms of gender, body mass index, differential blood count, C-reactive protein, lipid profiles, and CV comorbidities. As expected, CHIP-carriers were significantly older. Approximately 80% of patients in our cohort were diagnosed with CAD, the severity of which was quantified by Gensini score, accounting for both the degree and location of coronary artery plaque stenosis. Overall, CHIP-carriers presented with higher scores. in the middle-aged population (40-69 years old) harboring DNMT3A or TET2 mutations, Gensini scores were twice as high compared to non-carriers. Conclusion Our findings support a role of CHIP as a novel acquired cardiovascular risk factor independent of other modifiable risk factors, in particular in the middle-aged population that is more affected by genetic traits. CHIP carrier status is disproportionally high among patients in the catherization laboratory and may represent a population to consider additional anti-inflammatory therapy.

Abstract 18628: Focal Pericoronary Adipose Tissue Evaluated by Electron Density Numbers on Contrast Spectral Computed Tomography Was Associated With Coronary Arterial Plaques: A Site-by-Site Analysis

Introduction: Inflammation in pericoronary adipose tissue (PCAT) around the coronary arterial wall causes coronary arterial sclerosis. Many studies evaluated the relationship between total PCAT volume and coronary arterial sclerosis on a patient-by-patient basis. Hypothesis: Inflammation in PCAT may occur focally in coronary arterial system to which coronary arterial plaques localize. Using novel spectral CT, based on electron density number (EDN) as a new parameter, the focal characteristics of PCAT were evaluated. Methods: 17 patients (10 males, mean age 70 years) underwent cardiac spectral CT (7500, Philips, Tokyo, Japan). From contrast data, EDNs of PCAT were determined at a 1) right side site and 2) left anterior side site of a proximal portion of the right coronary arteries (RCA), 3) anterior side site of the left main coronary arteries, 4) left side site of a proximal portion of the left circumflex artery, and left side site of a distal portion of the RCA (five sites each patient). We also evaluated coronary arterial plaques on enhanced CT images at five corresponding sites for which EDNs were determined. Results: For a total of 85 sites among 17 patients using enhanced CT, 31 sites had no plaques (group 1), 14 sites had only non-calcified plaques (group 2), 20 sites had only calcified plaques (group 3), 16 sites had mixed plaques (group 4), and four sites had stent implantations (group 5). The mean of EDNS (%EDW) for 81 sites, excluding four sites with a stent implantation, were 93.7, 93.9, 94.0, and 94.3 in groups 1-4, respectively (P=NS). For a total of 81 sites, excluding four implantation sites, we evaluated the relationship between age and EDNs in groups 1-4. No correlations were observed in group 1 (R= 0.05), 3 (R= 0.09), and 4 (R= 0,15), however negative correlation was observed in group 2 (R= -0.42) between age and EDNs. No significant differences in EDNs were noted between males and females (P=NS). Conclusions: This is the first study in which focal PCAT was evaluated by EDNs and the relationship to coronary arterial plaques determined by site-by-site analysis. This new CT parameter may evaluate the status of PCAT and be a predictor of the future occurrence of coronary arterial plaques, which are related to PCAT inflammation.

Abstract 18549: Focal Pericoronary Adipose Tissue Evaluated by Atomic Numbers on Contrast Spectral Computed Tomography Was Associated With Coronary Arterial Plaques: A Site-by-Site Analysis

Introduction: Inflammation in pericoronary adipose tissue (PCAT) around the coronary arterial wall causes coronary arterial sclerosis. Many studies evaluated the relationship between total PCAT volume and coronary arterial sclerosis on a patient-by-patient basis. Hypothesis: Inflammation in PCAT may occur focally in coronary arterial system to which coronary arterial plaques localize. Using novel spectral CT, based on atomic number as a new parameter, the focal characteristics of PCAT were evaluated. Methods: 17 patients (10 males, mean age 70 years) underwent cardiac spectral CT (7500, Philips, Tokyo, Japan). From contrast data, atomic numbers of PCAT were determined at a 1) right side site and 2) left anterior side site of a proximal portion of the right coronary arteries (RCA), 3) anterior side site of the left main coronary arteries, 4) left side site of a proximal portion of the left circumflex artery, and left side site of a distal portion of the RCA (five sites each patient). We also evaluated coronary arterial plaques on enhanced CT images at five corresponding sites for which atomic numbers were determined. Results: For a total of 85 sites among 17 patients using enhanced CT, 31 sites had no plaques (group 1), 14 sites had only non-calcified plaques (group 2), 20 sites had only calcified plaques (group 3), 16 sites had mixed plaques (group 4), and four sites had stent implantations (group 5). The mean of atomic numbers for 81 sites, excluding four sites with a stent implantation, were 6.4, 6.8, 6.4, and 6.1 in groups 1-4, respectively (P=NS). For a total of 81 sites, excluding four implantation sites, we evaluated relationship between age and atomic numbers in groups 1-4. Positive correlations were observed in group 1 (R= 0.25) and 3 (R= 0.39), however negative correlation was observed in group 2 (R= -0.37) and 4 (R= -0.40) between age and atomic numbers. No significant differences in atomic numbers were noted between males and females. Conclusions: This is the first study in which focal PCAT was evaluated by atomic numbers and the relationship to coronary arterial plaques determined by site-by-site analysis. This new CT parameter may evaluate the status of PCAT and be a predictor of future occurrence of coronary arterial plaques, which are related to PCAT inflammation.

Abstract 18610: Focal Pericoronary Adipose Tissue Evaluated by Electron Density Numbers on Non-Contrast Spectral Computed Tomography Was Associated With Coronary Arterial Plaques: A Site-by-Site Analysis

Introduction: Inflammation in pericoronary adipose tissue (PCAT) around the coronary arterial wall causes coronary arterial sclerosis. Many studies evaluated the relationship between total PCAT volume and coronary arterial sclerosis on a patient-by-patient basis. Hypothesis: Inflammation in PCAT may occur focally in coronary arterial system to which coronary arterial plaques localize. Using novel spectral CT, based on electron density number (EDN) as a new parameter, the focal characteristics of PCAT were evaluated. Methods: 17 patients (10 males, mean age 70 years) underwent cardiac spectral CT (7500, Philips, Tokyo, Japan). From non-contrast data, EDNs of PCAT were determined at a 1) right side site and 2) left anterior side site of a proximal portion of right coronary arteries (RCA), 3) anterior side site of the left main coronary arteries, 4) left side site of a proximal portion of the left circumflex artery, and left side site of a distal portion of the RCA (five sites each patient). We also evaluated coronary arterial plaques on enhanced CT images at five corresponding sites for which EDNs were determined. Results: For a total of 85 sites among 17 patients using enhanced CT, 31 sites had no plaques (group 1), 14 sites had only non-calcified plaques (group 2), 20 sites had only calcified plaques (group 3), 16 sites had mixed plaques (group 4), and four sites had stent implantations (group 5). The mean of EDNS (%EDW) for 81 sites, excluding four sites with a stent implantation, were 93.5, 93.3, 93.2, and 93.8 in groups 1-4, respectively (P=NS). For a total of 81 sites, excluding four implantation sites, we evaluated the relationship between age and EDNs in groups 1-4. Positive correlations were observed in group 1 (R= 0.40), and 3 (R= 0.40), however negative correlation was observed in group 2 (R= -0.22) and 3 (R= -0.22) between age and EDNs. No significant differences in EDNs were noted between males and females (P=NS). Conclusions: This is the first study in which focal PCAT was evaluated by EDNs and the relationship to coronary arterial plaques determined by site-by-site analysis. This new CT parameter may evaluate the status of PCAT and be a predictor of the future occurrence of coronary arterial plaques, which are related to PCAT inflammation even on non-contrast CT alone.

Abstract 18964: Long-Term Prognostication of Atherosclerotic Cardiovascular Disease Risk Based on the Discordance Between Coronary Artery Calcium Area and Density

Introduction and Hypothesis: Coronary artery calcium scoring is used to quantify the burden of atherosclerotic plaque in coronary arteries in patients with coronary artery disease. It is measured as a product of two variables: plaque area and density. Our study sought to evaluate the long-term prognosis of atherosclerotic cardiovascular disease (CVD) based on the discordance between these two variables. Methods: 1750 patients with a CAC score greater than 0 were enrolled in this retrospective, multicenter study. Agatston CAC score was used to quantify a lesion as the product of plaque area and a 4-level categorical peak calcium density factor. COX proportional hazards were performed for atherosclerotic CVD mortality over a median period of 5.2 years while adjusting the Agatston CAC score and other classic risk factors. Results: The mean age was 61.2 years, and 19% were female. The prevalence of plaque discordance was 23% (12% high calcium area/low calcium density, 11% low calcium area/high calcium density). Compared to those with low calcium area/low calcium density, patients with low calcium area/high calcium density had a 65% lower risk of ASCVD death (HR: 0.27 [95% CI: 0.08-0.95]). Female sex ([95% CI: 1.25-1.76]) and body mass index ([95% CI: 1.16-1.32], per 5 kg/m2 higher) were significantly associated with high calcium density discordance. Conclusions: Our study concluded that high calcium density relative to plaque area confers lower long-term ASCVD risk, likely as an imaging marker for lesion severity. Additional studies are needed to define a robust definition of calcium area/density discordance for real-life clinical risk prediction.

Abstract 11400: Coronary Artery and Carotid Artery Plaques in Patients With Heterozygous Familial Hypercholesterolemia

Background: Little is known regarding the formation coronary and carotid plaques and their impact on cardiovascular disease in patients with familial hypercholesterolemia (FH). Objectives: We aimed to determine 1) when coronary and carotid plaques develop, 2) if the development of coronary and carotid plaques are correlated and 3) if these plaques are associated with major adverse cardiac events (MACEs). Methods: This was a retrospective review of 622 patients with heterozygous FH at Kanazawa University Hospital, assessed coronary and carotid plaque scores using coronary computed tomography and carotid ultrasound within 1 year. Spearman correlation coefficients were assessed among variables. Risk factors for MACEs were determined using the Cox proportional hazard model. Results: These scores were significantly correlated (Spearman’s r=0.82; p <0.001 in males and Spearman’s r=0.87; p <0.001 in females). We observed 132 MACEs during the median follow-up period of 13.2 years. Coronary and carotid plaque scores were significantly associated with the occurrence of MACE (hazard ratio: 3.33; 95% confidence interval: 1.88-4.78; p <0.001, hazard ratio: 2.24; 95% confidence interval: 1.28-3.20; p <0.001, respectively). The regression equations between age and the coronary and carotid artery plaque scores, respectively, were Y=0.358X-9.44 and Y=0.146X-3.68 in males, and Y=0.330X-11.76 and Y=0.121X-3.60 in females ( p <0.001 for all). Conclusion: Coronary and carotid plaque scores were significantly correlated, and both were independently associated with MACEs. Based on the regression equations, the average age of onset of coronary and carotid artery plaque developments, respectively, were 26 and 25 years old in males and 35 and 30 years in females.

Abstract 14972: Association Between CEC Measured by Immobilized Liposome-Bound Gel Beads Method and the Size of Lipid-Rich Coronary Artery Plaque

Introduction/Background: High-density lipoprotein (HDL) exerts cholesterol efflux capacity (CEC), and it ameliorates cardiovascular disease (CVD). CEC had been expected as a surrogate biomarker in addition to HDL cholesterol (HDL-C), which has been found not always to reflect the CVD risk. However, the procedures of the conventional CEC assays were too complex to be introduced into clinical practice because of cell-based assay. Given this situation, we invented novel cell-free CEC assay named immobilized liposome-bound gel beads (ILG) method. ILG method utilizes liposomes which contain fluorescence labeled cholesterol instead of lipid loaded foam cells, and has advantage of simplicity of procedure and accuracy. Reserch Question/Hypothesis: Does ILG method show some associations between CEC and HDL subclass, and also reflect the condition of coronary artery plaque? Goals/Aim: We aim to demonstrate CEC by ILG method has clinical significance for assessment of the CVD risk. Methods/Approach: Patients who underwent diagnostic catheterization or percutaneous coronary intervention were enrolled, and 61 patients were examined through CEC analysis by ILG method and assessment of coronary artery plaque by optical coherence tomography (OCT) imaging. Large lipid-rich plaque was defined as a lipid plaque with a lipid arc ≥180°and lipid length ≥5 mm. Serum HDL subclass was analyzed by enzymatic assay (Denka). We defined the ratio apolipoprotein E(apoE)-containing HDL-C to HDL-C as %apoE, and we also calculated the value of HDL 3 -C/HDL 2 -C, and classified HDL 3 - or HDL 2 -rich group. Results/Data: HDL-C was positively associated with %apoE, and CEC of apoE-rich patients was higher than that of apoE-poor patients. This correlation was maintained after classified based on size of HDL. CEC and %apoE in patients with large lipid-rich plaque were significantly lower than in those in without. In contrast, there was no significant difference in HDL-C and LDL-C. Conclusion: In present study, ILG method showed that apoE has some influence on CEC, and CEC was inversely correlated with size of lipid-rich plaque. These results implied that ILG method, suitable CEC assay for clinical site, might be useful to assess the CVD risk.

Abstract 17076: The Relationship Between Impaired Microvascular Function, Cardiovascular Risk Profile and Subclinical Atherosclerotic Burden in a Swedish Middle-Aged Cohort

Introduction: Microvascular function is associated with cardiovascular risk factors and deteriorates in individuals with cardiovascular disease. Hypothesis: The aim of this study was to investigate the relationship between microvascular function, cardiovascular risk profile and subclinical atherosclerotic burden. Methods: The study enrolled 3809 randomly selected individuals, 50-65 years old, participating in the population-based observational cross-sectional Swedish CArdioPulmonary bioImage Study (SCAPIS). Microvascular function was measured in forearm skin using an arterial occlusion and release protocol determining the peak blood oxygen saturation, OxyP. Cardiovascular risk was calculated using the updated Systematic Coronary Risk Evaluation (SCORE2; 10-year risk of fatal and non-fatal CVD events). OxyP was compared with Coronary artery calcification score (CACS) and plaques in the carotid arteries. Results: Individuals with OxyP values in the lowest quartile (Q1; impaired microvascular function), had a mean SCORE2 of 5.8% compared to 3.8% in those with the highest values of OxyP (Q4), a relative risk increase of 53%. In the low-risk SCORE2 level (<5% risk), 19.0% of the individuals have impaired microvascular function as compared to 48.1% in the high-risk SCORE2 level (>10% risk). OxyP was lower in individuals with coronary artery calcification (CACS>0) and those with both carotid plaque and CACS>0, as compared to individuals without subclinical atherosclerotic burden (CACS=0 and no carotid plaque; 87.5 ±5.6 % and 86.9 ±6.0 % vs 88.6 ± 5.8 %, p < 0.01). Conclusion: In a population without cardiovascular disease or diabetes mellitus, impaired microvascular function is associated with higher SCORE2 risk and CACS>0. Hence, assessment of microvascular function may be a useful tool for accurate cardiovascular risk prediction, in addition to imaging assessment of atherosclerosis in the coronary and carotid arteries.

Abstract 18637: Lower α-Klotho is Associated With Vulnerable Coronary Artery Plaque Characteristics

Introduction: α-Klotho (klotho) is a geroprotective protein inversely associated with coronary artery disease CAD and vascular aging. This study used intravascular ultrasound (IVUS) to study coronary artery plaque characteristics of patients with low circulating klotho. Hypothesis: Lower klotho is associated with vulnerable coronary artery plaque characteristics. Methods: Patients undergoing coronary angiogram for chest pain who had no CAD (<40% stenosis) underwent IVUS assessment. Images were obtained from the mid-LAD to the coronary ostium. Stored arterial plasma was used for α-klotho analysis by enzyme-linked immunosorbent assay. Results: A total of 58 consecutive patients were retrospectively studied. The median circulating klotho level of the cohort was 0.27 ng/mL [0.15; 1.24]. Patients with klotho less than the median were compared to those with levels greater than or equal to the median and were similar in age (53 ±11 vs. 56 ±10, p = 0.235) and sex distribution (86% vs. 76% female, p = 0.324). Patients with less klotho had higher coronary plaque burden (21.42% [17.185, 31.955] vs. 18.32 [10.5, 24.515], p=0.041) and larger plaque area (2.71 [2.03, 4.605] vs . 2.27 [1.41, 3.31] mm 3 /mm, p=0.058) compared to those with higher klotho. Lower klotho was associated with vulnerable plaque characteristics, including greater percentages of dense calcium (1.33% [0.265, 5.38] vs. 0.43% [0.015, 1.73], p=0.037) and necrotic core (5.43% [2.245, 10.5] vs. 2.22% [0.86, 4.50], p=0.011). Conclusions: Lower circulating klotho was associated with higher coronary plaque burden and vulnerable plaque characteristics. Klotho may be an early biomarker for risk in coronary artery disease.

Abstract 18480: Type 2 Diabetic Patients Have Increased Coronary Plaque Burden and Plaque Progression During 10-Year Serial Coronary CT Angiography Follow-Up

Background Individuals diagnosed with type 2 diabetes are at high risk for coronary artery disease, however, data on long-term progression of coronary artery plaque burden is lacking. This study investigated atherosclerotic plaque characteristics and long-term plaque progression in patients with and without type 2 diabetes mellitus (T2DM). Methods: Per-protocol, patients from a coronary CT angiography (CCTA) cohort were invited for repeat CCTA imaging, regardless of symptoms. A total of 299 patients underwent follow-up CCTA imaging with a median scan interval of 10.2 [IQR 8.7-11.2] years. Patients who underwent coronary artery bypass grafting and vessels revascularized by percutaneous coronary intervention were excluded. Scans were analyzed using atherosclerosis imaging-quantitative CCTA (AI-QCT; Cleerly Inc.). The associations between diabetic status, baseline and follow-up plaque burden and characteristics were evaluated using multivariable regression adjusted for clinical risk factors, statin use and scanner settings. Results: In total, 274 patients were included, 43 (15.7%) had T2DM at baseline. The mean age was 57±7 years, 42% were women. At baseline, patients with T2DM had a median percent atheroma volume (PAV) of 6.80 (2.80, 17.70) at baseline; patients without T2DM had a median PAV of 3.20 (0.80, 9.55). Adjusted for clinical risk factors, patients with T2DM had a higher rate of plaque progression (Figure 1). The difference in PAV caused by T2DM was similar to the effect of a 13-year age difference. At baseline patients with T2DM had a higher prevalence of high-risk plaque (OR 2.11; p=0.025). After 10 years of follow-up, patients with T2DM had a higher prevalence of both high-risk plaque (OR 3.49; p<0.001) and low-density plaque (OR 3.74; p<0.001). Conclusion Patients with T2DM had a more than twofold higher coronary plaque burden, increased plaque progression during 10-year follow-up and had an increased prevalence of high-risk and low-density plaque.

Clonal Proliferation Within Smooth Muscle Cells in Unstable Human Atherosclerotic Lesions.

Studies in humans and mice using the expression of an X-linked gene or lineage tracing, respectively, have suggested that clones of smooth muscle cells (SMCs) exist in human atherosclerotic lesions but are limited by either spatial resolution or translatability of the model. Phenotypic clonality can be detected by X-chromosome inactivation patterns. We investigated whether clones of SMCs exist in unstable human atheroma using RNA in situ hybridization (BaseScope) to identify a naturally occurring 24-nucleotide deletion in the 3'UTR of the X-linked BGN (biglycan) gene, a proteoglycan highly expressed by SMCs. BGN-specific BaseScope probes were designed to target the wild-type or deletion mRNA. Three different coronary artery plaque types (erosion, rupture, and adaptive intimal thickening) were selected from heterozygous females for the deletion BGN. Hybridization of target RNA-specific probes was used to visualize the spatial distribution of mutants. A clonality index was calculated from the percentage of each probe in each region of interest. Spatial transcriptomics were used to identify differentially expressed transcripts within clonal and nonclonal regions. Less than one-half of regions of interest in the intimal plaque were considered clonal with the mean percent regions of interest with clonality higher in the intimal plaque than in the media. This was consistent for all plaque types. The relationship of the dominant clone in the intimal plaque and media showed significant concordance. In comparison with the nonclonal lesions, the regions with SMC clonality had lower expression of genes encoding cell growth suppressors such as CD74, SERF-2 (small EDRK-rich factor 2), CTSB (cathepsin B), and HLA-DPA1 (major histocompatibility complex, class II, DP alpha 1), among others. Our novel approach to examine clonality suggests atherosclerosis is primarily a disease of polyclonally and to a lesser extent clonally expanded SMCs and may have implications for the development of antiatherosclerotic therapies.

Insulin resistance is associated with high-risk coronary artery plaque composition in asymptomatic men between 65 and 75 years and no diabetes: A DANCAVAS cross-sectional sub-study

Background and aimsInsulin resistance (IR) and pre-diabetes are associated with an increased risk of cardiovascular disease (CVD). We aimed to investigate vulnerable plaque composition in relation to IR and pre-diabetes in asymptomatic non-diabetic men. MethodsAll participants underwent a contrast-enhanced coronary computed tomography angiography (CCTA) to evaluate coronary artery plaque burden and plaque composition (necrotic core, dense calcium, fibrotic and fibrous-fatty volume). Homeostasis model assessment of IR (HOMA-IR) was used, and participants were stratified into tertiles. Participants underwent a standard oral glucose tolerance test (OGTT) and were categorized into 2 groups (normal glucose tolerance (NGT) or pre-diabetes). A multivariable linear regression model was used to evaluate the association between vulnerable plaque composition and IR or glycemic group. ResultsFour-hundred-and-fifty non-diabetic men without known CAD were included. The mean age was 70 ± 3 years. Participants in the higher HOMA-IR tertile (H-IR) had higher median necrotic plaque volume compared to the lower HOMA-IR tertile (L-IR) (18.2 vs. 11.0 mm3, p = 0.02). H-IR tertile (β 0.37 [95% CI 0.10–0.65], p = 0.008), pack-years (β 0.07 [95% CI 0.007–0.14], p = 0.03) and total atheroma volume (TAV) (β 0.47 [95% CI 0.36–0.57], p < 0.001) remained associated with necrotic plaque volume in the multivariable linear regression model. ConclusionsIR was associated with necrotic plaque volume in asymptomatic men without diabetes. Thus, even in asymptomatic men without diabetes, IR seems to have an incremental effect on necrotic plaque volume and vulnerable plaque composition.

Association of serum cystatin C level with coronary atherosclerotic plaque burden: a comprehensive analysis of observational studies and genetic study

Background and AimsEpidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. However, the relationship between serum cystatin C level and coronary atherosclerotic plaque burden is limited. We aimed to evaluate the relationship between circulating cystatin C and coronary atherosclerotic plaque burden.MethodsThis study was a cross-sectional study based on China community population. Measurements of plaque burden were based on the segment-involvement score (SIS) and segment stenosis score (SSS), which derived from the Coronary Artery Tree Model Depicting Coronary Artery Plaque Scores. Logistic regression model was used to demonstrate the association between cystatin C level and coronary artery plaque burden. Mendelian randomization (MR) analyses were conducted to assess the causal effect of cystatin C level on coronary atherosclerosis risk.ResultsA total of 3,043 objects were included in the present study. The odds risks (OR) of severe plaque burden in the highest serum cystatin C levels (OR: 2.50; Cl:1.59–3.91; P < 0.001) and medium-level cystatin C levels (OR: 1.86; 95% Cl: 1.21–2.88; P = 0.005) were significantly higher after fulled adjusted confounders compared with the lowest levels of serum cystatin C by SSS. The MR analysis showed that genetic predicted cystatin C levels was associated with an increased risk of coronary atherosclerosis (OR, 1.004; 95% CI, 1.002–1.006, P < 0.001) .ConclusionElevated serum cystatin C levels were associated with coronary atherosclerotic plaque burden. Cystatin C levels had a causal effect on an increased risk of coronary atherosclerosis at the genetic level.What is already known on this topic?Coronary artery disease is currently the most common cardiovascular disease and the leading global cause of mortality. Previous studies reported that higher serum cystatin C levels were associated with an increased risk for future cardiovascular events, independent of the normal creatinine levels or estimated glomerular filtration rate (eGFR) values. The presence of high-risk coronary atherosclerotic plaque burden is associated with increased risk of cardiovascular events. However, the association between serum cystatin C and coronary atherosclerotic plaque burden is not very clear.What this study adds?Our study demonstrated that the elevated serum cystatin C levels were associated with coronary atherosclerotic plaque burden. In addition, we found that serum cystatin C levels had a causal effect on an increased risk of coronary atherosclerosis at the genetic level.How this study might affect research, practice or policy?Current research finds that serum cystatin C levels were associated with coronary atherosclerosis. The metabolic pathway of cystatin C could be a target for new therapies against CAD.

Testing the Effects of App-Based Motivational Messages on Physical Activity and Resting Heart Rate Through Smartphone App Compliance in Patients With Vulnerable Coronary Artery Plaques: Protocol for a Microrandomized Trial.

Achieving the weekly physical activity recommendations of at least 150-300 minutes of moderate-intensity or 75-150 minutes of vigorous-intensity aerobic exercise is important for reducing cardiometabolic risk, but evidence shows that most people struggle to meet these goals, particularly in the mid to long term. The Messages Improving Resting Heart Health (MIRTH) study aims to determine if (1) sending daily motivational messages through a research app is effective in improving motivation and in promoting adherence to physical activity recommendations in men and women with coronary heart disease randomized to a 12-month intensive lifestyle intervention, and (2) the time of the day when the message is delivered impacts compliance with exercise training. We will conduct a single-center, microrandomized trial. Participants will be randomized daily to either receive or not receive motivational messages over two 90-day periods at the beginning (phase 1: months 4-6) and at the end (phase 2: months 10-12) of the Lifestyle Vulnerable Plaque Study. Wrist-worn devices (Fitbit Inspire 2) and Bluetooth pairing with smartphones will be used to passively collect data for proximal (ie, physical activity duration, steps walked, and heart rate within 180 minutes of receiving messages) and distal (ie, change values for resting heart rate and total steps walked within and across both phases 1 and 2 of the trial) outcomes. Participants will be recruited from a large academic cardiology office practice (Central Sydney Cardiology) and the Royal Prince Alfred Hospital Departments of Cardiology and Radiology. All clinical investigations will be undertaken at the Charles Perkins Centre Royal Prince Alfred clinic. Individuals aged 18-80 years (n=58) with stable coronary heart disease who have low attenuation plaques based on a coronary computed tomography angiography within the past 3 months and have been randomized to an intensive lifestyle intervention program will be included in MIRTH. The Lifestyle Vulnerable Plaque Study was funded in 2020 and started enrolling participants in February 2022. Recruitment for MIRTH commenced in November 2022. As of September 2023, 2 participants were enrolled in the MIRTH study and provided baseline data. This MIRTH microrandomized trial will represent the single most detailed and integrated analysis of the effects of a comprehensive lifestyle intervention delivered through a customized mobile health app on smart devices on time-based motivational messaging for patients with coronary heart disease. This study will also help inform future studies optimizing for just-in-time adaptive interventions. Australian New Zealand Clinical Trials Registry ACTRN12622000731796; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382861. DERR1-10.2196/46082.

Prevalence of atherosclerosis in individuals with prediabetes and diabetes compared to normoglycaemic individuals—a Swedish population-based study

BackgroundPatients with type 2 diabetes have an increased risk of death and cardiovascular events and people with diabetes or prediabetes have been found to have increased atherosclerotic burden in the coronary and carotid arteries. This study will estimate the cross-sectional prevalence of atherosclerosis in the coronary and carotid arteries in individuals with prediabetes and diabetes, compared with normoglycaemic individuals in a large population-based cohort.MethodsThe 30,154 study participants, 50–64 years, were categorized according to their fasting glycaemic status or self-reported data as normoglycaemic, prediabetes, and previously undetected or known diabetes. Prevalence of affected coronary artery segments, severity of stenosis and coronary artery calcium score (CACS) were determined by coronary computed tomography angiography. Total atherosclerotic burden was assessed in the 11 clinically most relevant segments using the Segment Involvement Score and as the presence of any coronary atherosclerosis. The presence of atherosclerotic plaque in the carotid arteries was determined by ultrasound examination.ResultsStudy participants with prediabetes (n = 4804, 16.0%) or diabetes (n = 2282, 7.6%) had greater coronary artery plaque burden, more coronary stenosis and higher CACS than normoglycaemic participants (all, p < 0.01). Among male participants with diabetes 35.3% had CACS ≥ 100 compared to 16.1% among normoglycaemic participants. For women, the corresponding figures were 8.9% vs 6.1%. The prevalence of atherosclerosis in the coronary arteries was higher in participants with previously undetected diabetes than prediabetes, but lower than in patients with known diabetes. The prevalence of any plaque in the carotid arteries was higher in participants with prediabetes or diabetes than in normoglycaemic participants.ConclusionsIn this large population-based cohort of currently asymptomatic people, the atherosclerotic burden in the coronary and carotid arteries increased with increasing degree of dysglycaemia. The finding that the atherosclerotic burden in the coronary arteries in the undetected diabetes category was midway between the prediabetes category and patients with known diabetes may have implications for screening strategies and tailored prevention interventions for people with dysglycaemia in the future.

Long-axial field-of-view PET/CT for the assessment of inflammation in calcified coronary artery plaques with [68 Ga]Ga-DOTA-TOC

PurposeInflamed, prone-to-rupture coronary plaques are an important cause of myocardial infarction and their early identification is crucial. Atherosclerotic plaques are characterized by overexpression of the type-2 somatostatin receptor (SST2) in activated macrophages. SST2 ligand imaging (e.g. with [68 Ga]Ga-DOTA-TOC) has shown promise in detecting and quantifying the inflammatory activity within atherosclerotic plaques. However, the sensitivity of standard axial field of view (SAFOV) PET scanners may be suboptimal for imaging coronary arteries. Long-axial field of view (LAFOV) PET/CT scanners may help overcome this limitation. We aim to assess the ability of [68 Ga]Ga-DOTA-TOC LAFOV-PET/CT in detecting calcified, SST2 overexpressing coronary artery plaques.MethodsIn this retrospective study, 108 oncological patients underwent [68 Ga]Ga-DOTA-TOC PET/CT on a LAFOV system. [68 Ga]Ga-DOTA-TOC uptake and calcifications in the coronary arteries were evaluated visually and semi-quantitatively. Data on patients’ cardiac risk factors and coronary artery calcium score were also collected. Patients were followed up for 21.5 ± 3.4 months.ResultsA total of 66 patients (61.1%) presented with calcified coronary artery plaques. Of these, 32 patients had increased [68 Ga]Ga-DOTA-TOC uptake in at least one coronary vessel (TBR: 1.65 ± 0.53). Patients with single-vessel calcifications showed statistically significantly lower uptake (SUVmax 1.10 ± 0.28) compared to patients with two- (SUVmax 1.31 ± 0.29, p < 0.01) or three-vessel calcifications (SUVmax 1.24 ± 0.33, p < 0.01). There was a correlation between coronary artery calcium score (CACS) and [68 Ga]Ga-DOTA-TOC uptake, especially in the LAD (p = 0.02). Stroke and all-cause death occurred more frequently in patients with increased [68 Ga]Ga-DOTA-TOC uptake (15.63% vs. 0%; p:0.001 and 21.88% vs. 6.58%; p: 0.04, respectively) during the follow-up period.Conclusion[68 Ga]Ga-DOTA-TOC as a marker for the macrophage activity can reveal unknown cases of inflamed calcified coronary artery plaques using a LAFOV PET system. [68 Ga]Ga-DOTA-TOC uptake increased with the degree of calcification and correlated with higher risk of stroke and all-cause death. [68 Ga]Ga-DOTA-TOC LAFOV PET/CT may be useful to assess patients’ cardiovascular risk.

Non-Calcified Coronary Artery Plaque on Coronary Computed Tomography Angiogram: Prevalence and Significance.

We aimed to assess the prevalence of non-calcified plaque (NCP) on computed tomography angiography (CCTA) in symptomatic and asymptomatic individuals. In addition, we seek to compare plaque assessment on CCTA with intravascular ultrasound-virtual histology (IVUS-VH) and to assess the prognostic value of non-calcified plaques (NCPs). The CCTA can characterize coronary plaques and help quantify burden. Furthermore, it can provide additional prognostic information which can enable further risk stratification of patients. We performed a broad comprehensive review of the current literature pertaining to CCTA and primarily isolated NCP in symptomatic and asymptomatic patients. In addition, our review included studies correlating plaque on CT with IVUS-VH. NCP is the initial precursor of calcified plaque and serves as a prominent marker of early coronary atherosclerosis. By detecting NCP during early stages, several measures can be implemented which can alter the evolutionary course of the underlying disease. This can potentially lead to a lower incidence of cardiovascular events.

Coronary Artery and Carotid Artery Plaques in Patients With Heterozygous Familial Hypercholesterolemia

BackgroundLittle is known regarding the formation of coronary and carotid plaques and their impact on cardiovascular disease in patients with familial hypercholesterolemia (FH). ObjectivesThis study aimed to determine: 1) if the development of coronary and carotid plaques is correlated; and 2) if these plaques are associated with major adverse cardiac events (MACEs) defined as cardiovascular-related death, unstable angina, myocardial infarction, or staged revascularization. MethodsThis was a retrospective review of 622 patients with heterozygous FH (HeFH) at Kanazawa University Hospital, assessed coronary and carotid plaque scores using coronary computed tomography and carotid ultrasound within 1 year. Spearman correlation coefficients were assessed among variables. Risk factors for MACEs were determined using the Cox proportional hazard model. ResultsCoronary and carotid plaque scores were significantly correlated in patients with HeFH in both sexes (Spearman’s r = 0.82; P < 0.001 in males and Spearman’s r = 0.87; P < 0.001 in females). We observed 132 MACEs during the median follow-up of 13.2 years. These scores were significantly associated with the occurrence of MACE (HR: 3.33; 95% CI: 1.88-4.78; P < 0.001, HR: 2.24; 95% CI: 1.28-3.20; P < 0.001, respectively). ConclusionsCoronary and carotid plaque scores were significantly correlated, and both were independently associated with MACEs. The assessments for coronary and/or carotid plaque are useful for further risk stratifications in patients with HeFH.

The Role of Shear Stress in Coronary Artery Disease.

Coronary artery disease is the leading cause of morbidity and mortality worldwide, especially in developed countries, with an increasing incidence in developing countries. Despite the advances in cardiology, there are yet many unanswered questions about the natural history of coronary atherosclerosis. However, it has not been fully explained why some coronary artery plaques remain quiescent over time, whereas others evolve to a high-risk, "vulnerable" plaque with a predisposition to destabilize and induce a cardiac event. Furthermore, approximately half of the patients with acute coronary syndromes demonstrate no prior symptoms of ischemia or angiographically evident disease. Recent findings have indicated that apart from cardiovascular risk factors, genetics, and other unknown factors, local hemodynamic forces, such as endothelial shear stress, blood flow patterns, and endothelial dysfunction of the epicardial and microvascular coronary arteries, are associated with the progression of coronary plaque and the development of cardiovascular complications with complex interactions. In this review article, we summarize the mechanisms that affect coronary artery plaque progression, indicating the importance of endothelial shear stress, endothelial dysfunction of epicardial and microvascular vessels, inflammation, and their complex associations, underlying in parallel the clinical perspectives of these findings.

Focused Ultrasound, an Emerging Tool for Atherosclerosis Treatment: A Comprehensive Review.

Focused ultrasound (FUS) has emerged as a promising noninvasive therapeutic modality for treating atherosclerotic arterial disease. High-intensity focused ultrasound (HIFU), a noninvasive and precise modality that generates high temperatures at specific target sites within tissues, has shown promising results in reducing plaque burden and improving vascular function. While low-intensity focused ultrasound (LIFU) operates at lower energy levels, promoting mild hyperthermia and stimulating tissue repair processes. This review article provides an overview of the current state of HIFU and LIFU in treating atherosclerosis. It focuses primarily on the therapeutic potential of HIFU due to its higher penetration and ability to achieve atheroma disruption. The review summarizes findings from animal models and human trials, covering the effects of FUS on arterial plaque and arterial wall thrombolysis in carotid, coronary and peripheral arteries. This review also highlights the potential benefits of focused ultrasound, including its noninvasiveness, precise targeting, and real-time monitoring capabilities, making it an attractive approach for the treatment of atherosclerosis and emphasizes the need for further investigations to optimize FUS parameters and advance its clinical application in managing atherosclerotic arterial disease.